ORTHOGONAL FUNCTIONALIZATION OF BRIDGE-SUBSTITUTED BCPS
20250215019 ยท 2025-07-03
Assignee
Inventors
Cpc classification
B01J27/16
PERFORMING OPERATIONS; TRANSPORTING
International classification
B01J23/46
PERFORMING OPERATIONS; TRANSPORTING
Abstract
Disclosed herein are methods of synthesizing compounds of the formula wherein the variables are defined herein. Also provided are compounds produced using these methods. In some aspects, the methods provided herein may be used to create di- and tri-substituted BCPs.
##STR00001##
Claims
1. A method of preparing a compound comprising reacting a compound of the formula: ##STR00152## wherein: a and b are each independently selected from 0, 1, 2, or 3; x and y are each independently selected from 0, 1, 2, or 3; R.sub.1 is an organic moiety; R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are each hydroxy or R.sub.2 and R.sub.3 are taken together to form a B-containing heterocycloalkyl.sub.(C<12) or substituted B-containing heterocycloalkyl.sub.(C12); and R.sub.6, R.sub.6, R.sub.7, and R.sub.7 are each independently hydrogen, alkyl.sub.(C12), or substituted alkyl.sub.(C12); with a reactive compound to form a monoboronated compound of the formula: ##STR00153## wherein: a and b are each independently selected from 0, 1, 2, or 3; x and y are each independently selected from 0, 1, 2, or 3; R.sub.1 is an organic moiety; R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are each hydroxy or R.sub.2 and R.sub.3 are taken together to form a B-containing heterocycloalkyl.sub.(C12) or substituted B-containing heterocycloalkyl.sub.(C12); R.sub.6, R.sub.6, R.sub.7, and R.sub.7 are each independently hydrogen, alkyl.sub.(C12), or substituted alkyl.sub.(C12); and Y.sub.1 is hydrogen or an organic moiety.
2. The method of claim 1, further comprising reacting the monoboronated compound of formula II with a second reactive compound to form a compound of the formula: ##STR00154## wherein: a and b are each independently selected from 0, 1, 2, or 3; x and y are each independently selected from 0, 1, 2, or 3; R.sub.1 is an organic moiety; R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are each hydroxy or R.sub.2 and R.sub.3 are taken together to form a B-containing heterocycloalkyl.sub.(C12) or substituted B-containing heterocycloalkyl.sub.(C12); R.sub.6, R.sub.6, R.sub.7, and R.sub.7 are each independently hydrogen, alkyl.sub.(C12), or substituted alkyl.sub.(C12); and Y.sub.1 and Y.sub.2 are each independently hydrogen or an organic moiety.
3. The method of either claim 1 or claim 2, wherein the reactive compound is a catechol.
4. The method of claim 3, wherein the catechol is tert-butylcatechol.
5. The method of either claim 3 or claim 4, wherein Y.sub.1 is hydrogen.
6. The method according to any one of claims 1-4, wherein the method further comprises a coupling partner.
7. The method of claim 6, wherein the coupling partner is a cyanide source.
8. The method of claim 7, wherein the cyanide source is tosyl cyanide.
9. The method of claim 6, wherein the coupling partner is a sulfur source.
10. The method of claim 9, wherein the sulfur source comprises a SS bond.
11. The method of either claim 9 or claim 10, wherein the sulfur source is a sulfonothioic acid.
12. The method of claim 11, wherein the sulfur source is an S-phenyl ester of benzenesulfonothioic acid.
13. The method of claim 6, wherein the coupling partner is a nitrogen source.
14. The method of claim 13, wherein the nitrogen source comprises an azodicarboxylate group.
15. The method of claim 14, wherein the nitrogen source is di-tert-butyl azodicarboxylate or di-isopropyl azodicarboxylate.
16. The method of either claim 1 or claim 2, wherein the reactive compound is a hydrazone.
17. The method of claim 16, wherein the hydrazone further comprises an alkylsulfonyl.sub.(C12), arylsulfonyl.sub.(C12), or a substituted version of either group.
18. The method of either claim 16 or claim 17, wherein the hydrazone further comprises a group of the formula:
CR.sub.aR.sub.a wherein: R.sub.a and R.sub.a are each hydrogen, alkyl.sub.(C<12), cycloalkyl.sub.(C<12), alkenyl.sub.(C<12), cycloalkenyl.sub.(C12), alkynyl.sub.(C12), cycloalkynyl.sub.(C12), aryl.sub.(C12), heteroaryl.sub.(C12), heterocycloalkyl.sub.(C12), alkoxy.sub.(C12), aryloxy.sub.(C12), aralkoxy.sub.(C12), acyl.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), alkylsulfonyl.sub.(C12), arylsulfonyl.sub.(C12), or a substituted version of any of these groups.
19. The method according to any one of claims 16-18, wherein the hydrazone is further defined as: ##STR00155## wherein: R.sub.a and R.sub.a are each hydrogen, alkyl.sub.(C12), cycloalkyl.sub.(C12), alkenyl.sub.(C12), cycloalkenyl.sub.(C12), alkynyl.sub.(C12), cycloalkynyl.sub.(C12), aryl.sub.(C12), heteroaryl.sub.(C12), heterocycloalkyl.sub.(C12), alkoxy.sub.(C12), aryloxy.sub.(C12), aralkoxy.sub.(C12), acyl.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), alkylsulfonyl.sub.(C12), arylsulfonyl.sub.(C12), or a substituted version of any of these groups; and R.sub.b is alkyl.sub.(C12), aryl.sub.(C12), or a substituted version thereof.
20. The method of either claim 1 or claim 2, wherein the reactive compound is a Michael acceptor.
21. The method of claim 20, wherein the Michael acceptor comprises a double bond.
22. The method of claim 21, wherein the double bond is attached to an electron withdrawing group.
23. The method according to any one of claims 20-22, wherein the electron withdrawing group is an oxo group, an ester group, an amide group, or a cyano group.
24. The method according to any one of claims 20-23, wherein the method further comprises a metal catalyst.
25. The method of claim 24, wherein the metal catalyst is iridium catalyst.
26. The method according to any one of claims 20-25, wherein the method further comprises exposing the compound to an energy source.
27. The method of claim 26, wherein the energy source is a radiation source.
28. The method of claim 27, wherein the radiation source is UV light.
29. The method of either claim 1 or claim 2, wherein reactive compound is an organic halide.
30. The method of claim 29, wherein the organic halide is an organic bromide.
31. The method of claim 30, wherein the organic halide is an aromatic bromide.
32. The method of claim 31, wherein the aromatic bromide is further defined as: R.sub.dBr, wherein: aryl.sub.(C18), heteroaryl.sub.(C18), or a substituted version of either group.
33. The method of claim 30, wherein the organic bromide is an aliphatic bromide.
34. The method of claim 33, wherein the aliphatic bromide is further defined as: R.sub.dBr, wherein: alkyl.sub.(C18), alkenyl.sub.(C18), alkynyl.sub.(C18), or a substituted version of any of these group.
35. The method according to any one of claims 1, 2, or 29-34, wherein the method further comprises a metal catalyst.
36. The method of claim 35, wherein the metal catalyst is a nickel metal catalyst.
37. The method according to any one of claims 1, 2, or 29-36, wherein the method further comprises a Lewis acid.
38. The method of claim 37, wherein the Lewis acid is a metal salt.
39. The method of claim 38, wherein the metal salt is a zinc salt.
40. The method of claim 39, wherein the zinc salt is zinc triflate.
41. The method according to any one of claims 1, 2, or 29-40, wherein the method further comprises a photocatalyst.
42. The method of claim 41, wherein the photocatalyst is capable of generating a radical.
43. The method of either claim 41 or claim 42, wherein the photocatalyst is an organic compound.
44. The method according to any one of claims 41-43, wherein the photocatalyst is a photoredox catalyst.
45. The method of claim 44, wherein the photoredox catalyst is an isophthalonitrile.
46. The method of claim 45, wherein the isophthalonitrile is 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile.
47. The method according to any one of claims 1, 2, or 29-46, wherein the method further comprises exposing the compound to an energy source.
48. The method of claim 47, wherein the energy source is a radiation source.
49. The method of claim 48, wherein the radiation source is ultraviolet radiation.
50. The method of either claim 1 or claim 2, wherein reactive compound is a heteroarene.sub.(C18) or a substituted heteroarene.sub.(C18).
51. The method according to any one of claims 1, 2, or 50, wherein the method further comprises a metal salt.
52. The method of claim 51, wherein the metal salt is a manganese salt.
53. The method of either claim 51 or claim 52, wherein the metal salt is a manganese(III) salt.
54. The method of claim 53, wherein the manganese(III) salt is Mn(OAc).sub.3.
55. The method according to any one of claims 1, 2, and 50-54, wherein the method further comprises an acid.
56. The method of claim 55, wherein the acid has a pK.sub.a of less than 5.
57. The method of claim 56, wherein the acid has a pK.sub.a of less than 0.
58. The method according to any one of claims 55-57, wherein the acid is an alkylcarboxylate.sub.(C8) or a substituted alkylcarboxylate.sub.(C8).
59. The method of claim 58, wherein the acid is a substituted alkylcarboxylate.sub.(C8).
60. The method of claim 59, wherein the acid is trifluoroacetic acid.
61. The method according to any one of claims 2-60, wherein the second reactive compound is a peroxide.
62. The method according to any one of claims 2-60, wherein the second reactive compound is a base.
63. The method of claim 62, wherein the base is an organolithium compound.
64. The method of claim 63, wherein the organolithium compound is an alkyl lithium.
65. The method of claim 64, wherein the organolithium compound is nbutyllithium.
66. The method of claim 63, wherein the organolithium compound is an aromatic lithium.
67. The method of claim 66, wherein the aromatic lithium is an aryl lithium or a heteroaryl lithium.
68. The method of claim 67, wherein the aromatic lithium is phenyl lithium.
69. The method according to any one of claims 2-60 and 62, wherein the base is a metal carbonate.
70. The method of claim 69, wherein the base is an alkali metal carbonate.
71. The method of claim 70, wherein the base is CsCO.sub.3.
72. The method according to any one of claims 2-60 and 62-71, wherein the second reactive compound is a carbon atom source.
73. The method of claim 72, wherein the carbon source is a dihaloalkane.sub.(C12) or a substituted dihaloalkane.sub.(C12).
74. The method of claim 73, wherein the halogen atoms in the dihaloalkane.sub.(C12) or the substituted dihaloalkane.sub.(C12) are different.
75. The method of either claim 73 or claim 74, wherein the dihaloalkane.sub.(C12) is bromoiodomethane.
76. The method according to any one of claims 2-60 and 62-71, wherein the second reactive compound is a cyanide source.
77. The method of claim 76, wherein the cyanide source is tosyl cyanide.
78. The method according to any one of claims 2-60 and 62-71, wherein the second reactive compound is a Michael acceptor.
79. The method of claim 78, wherein the Michael acceptor comprises a double bond.
80. The method of claim 79, wherein the double bond is attached to an electron withdrawing group.
81. The method according to any one of claims 78-80, wherein the electron withdrawing group is an oxo group, an ester group, an amide group, or a cyano group.
82. The method according to any one of claims 2-60 and 62-71, wherein the second reactive compound is a hydrazone.
83. The method of claim 82, wherein the hydrazone further comprises an alkylsulfonyl.sub.(C12), arylsulfonyl.sub.(C12), or a substituted version of either group.
84. The method of either claim 82 or claim 83, wherein the hydrazone further comprises a group of the formula: CR.sub.aR.sub.a wherein: R.sub.a and R.sub.a are each hydrogen, alkyl.sub.(C12), cycloalkyl.sub.(C12), alkenyl.sub.(C12), cycloalkenyl.sub.(C12), alkynyl.sub.(C12), cycloalkynyl.sub.(C12), aryl.sub.(C12), heteroaryl.sub.(C12), heterocycloalkyl.sub.(C12), alkoxy.sub.(C12), aryloxy.sub.(C12), aralkoxy.sub.(C12), acyl.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), alkylsulfonyl.sub.(C12), arylsulfonyl.sub.(C12), or a substituted version of any of these groups.
85. The method according to any one of claims 82-84, wherein the hydrazone is further defined as: ##STR00156## wherein: R.sub.a and R.sub.a are each hydrogen, alkyl.sub.(C12), cycloalkyl.sub.(C12), alkenyl.sub.(C12), cycloalkenyl.sub.(C12), alkynyl.sub.(C12), cycloalkynyl.sub.(C12), aryl.sub.(C12), heteroaryl.sub.(C12), heterocycloalkyl.sub.(C12), alkoxy.sub.(C12), aryloxy.sub.(C12), aralkoxy.sub.(C12), acyl.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), alkylsulfonyl.sub.(C12), arylsulfonyl.sub.(C12), or a substituted version of any of these groups; and R.sub.b is alkyl.sub.(C12), aryl.sub.(C12), or a substituted version thereof.
86. The method according to any one of claims 2-60 and 62-71, wherein the second reactive compound is a nitroaromatic compound.
87. The method of claim 86, wherein the nitroaromatic compound is R.sub.eNO.sub.2, wherein R.sub.e is aryl.sub.(C18), heteroaryl.sub.(C18), or a substituted version thereof.
88. The method according to any one of claims 2-60 and 62-71, wherein the second reactive compound is a nitrogen source.
89. The method of claim 88, wherein the nitrogen source comprises an azodicarboxylate group.
90. The method of claim 89, wherein the nitrogen source is di-tert-butyl azodicarboxylate or di-isopropyl azodicarboxylate.
91. The method according to any one of claims 2-60 and 62-71, wherein the second reactive compound is a heteroarene.sub.(C18) or a substituted heteroarene.sub.(C18).
92. The method according to any one of claims 2-60 and 62-71, wherein the second reactive compound is an organic halide.
93. The method of claim 92, wherein the organic halide is an organic bromide.
94. The method of claim 93, wherein the organic halide is an aromatic bromide.
95. The method of claim 94, wherein the aromatic bromide is further defined as: R.sub.dBr, wherein: aryl.sub.(C18), heteroaryl.sub.(C8), or a substituted version of either group.
96. The method of claim 93, wherein the organic bromide is an aliphatic bromide.
97. The method of claim 96, wherein the aliphatic bromide is further defined as: R.sub.dBr, wherein: alkyl.sub.(C18), alkenyl.sub.(C18), alkynyl.sub.(C18), or a substituted version of any of these group.
98. The method according to any one of claims 2-60 and 62-71, wherein the second reactive compound is a sulfur source.
99. The method of claim 98, wherein the sulfur source comprises a SS bond.
100. The method of either claim 98 or claim 99, wherein the sulfur source is a sulfonothioic acid.
101. The method of claim 100, wherein the sulfur source is an S-phenyl ester of benzenesulfonothioic acid.
102. The method according to any one of claims 2-101, wherein the method further comprises exposing the monoboronated compound to an energy source.
103. The method of claim 102, wherein the energy source is a radiation source.
104. The method of claim 103, wherein the radiation source is ultraviolet radiation.
105. The method according to any one of claims 2-104, wherein the method further comprises a diol.
106. The method of claim 105, wherein the diol is pinacol.
107. The method of claim 105, wherein the diol is a catechol.
108. The method of claim 107, wherein the catechol is tert-butylcatechol.
109. The method according to any one of claims 2-108, wherein the method further comprises a phosphorus catalyst.
110. The method of claim 109, wherein the phosphorus catalyst is a phosphorus oxide compound.
111. The method according to any one of claims 2-110, wherein the method further comprises a metal catalyst.
112. The method of claim 111, wherein the metal catalyst is an iridium catalyst.
113. The method of claim 111, wherein the metal catalyst is a nickel catalyst.
114. The method of claim 111, wherein the metal salt is a manganese salt.
115. The method of either claim 111 or claim 114, wherein the metal salt is a manganese(III) salt.
116. The method of claim 115, wherein the manganese(III) salt is Mn(OAc).sub.3.
117. The method according to any one of claims 2-116, wherein the method further comprises an energy source.
118. The method of claim 117, wherein the energy source is a radiation source.
119. The method of claim 118, wherein the radiation source is ultraviolet radiation.
120. The method according to any one of claims 2-119, wherein the method further comprises a redox catalyst.
121. The method of claim 120, wherein the redox catalyst is a dimethylhydantoin.
122. The method of claim 121, wherein the redox catalyst is a dibromodimethylhydantoin.
123. The method of claim 120, wherein the redox catalyst is a boron compound.
124. The method of claim 123, wherein the redox catalyst is MeOB(catechol).
125. The method according to any one of claims 1-124, wherein R.sub.1 is hydrogen, alkyl.sub.(C24), cycloalkyl.sub.(C24), alkenyl.sub.(C24), cycloalkenyl.sub.(C24), alkynyl.sub.(C24), cycloalkynyl.sub.(C24), aryl.sub.(C24), heteroaryl.sub.(C24), heterocycloalkyl.sub.(C24), alkoxy.sub.(C24), aryloxy.sub.(C24), aralkoxy.sub.(C24), acyl.sub.(C24), alkylamino.sub.(C24), dialkylamino.sub.(C24), alkylthio.sub.(C24), arylthio.sub.(C24), alkylsulfonyl.sub.(C24), arylsulfonyl.sub.(C24), or a substituted version of any of these groups; or a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups; a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, or a protected thio group; or X.sub.1R.sub.9, wherein X.sub.1 is substituted alkanediyl.sub.(C12), cycloalkanediyl.sub.(C12), alkenediyl.sub.(C12), arenediyl.sub.(C12), heteroarenediyl.sub.(C12), heterocycloalkanediyl.sub.(C12), or a substituted version thereof; and R.sub.9 is alkyl.sub.(C24), cycloalkyl.sub.(C24), alkenyl.sub.(C24), cycloalkenyl.sub.(C24), alkynyl.sub.(C24), cycloalkynyl.sub.(C24), aryl.sub.(C24), heteroaryl.sub.(C24), heterocycloalkyl.sub.(C24), alkoxy.sub.(C24), aryloxy.sub.(C24), aralkoxy.sub.(C24), acyl.sub.(C24), alkylamino.sub.(C24), dialkylamino.sub.(C24), alkylthio.sub.(C24), arylthio.sub.(C24), alkylsulfonyl.sub.(C24), arylsulfonyl.sub.(C24), or a substituted version of any of these groups; or a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups; a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, or a protected thio group.
126. The method of claim 125, wherein R.sub.1 is hydrogen, alkyl.sub.(C24), cycloalkyl.sub.(C24), alkenyl.sub.(C24), cycloalkenyl.sub.(C24), alkynyl.sub.(C24), cycloalkynyl.sub.(C24), aryl.sub.(C24), heteroaryl.sub.(C24), heterocycloalkyl.sub.(C24), alkoxy.sub.(C24), aryloxy.sub.(C24), aralkoxy.sub.(C24), acyl.sub.(C24), alkylamino.sub.(C24), dialkylamino.sub.(C24), alkylthio.sub.(C24), arylthio.sub.(C24), alkylsulfonyl.sub.(C24), arylsulfonyl.sub.(C24), or a substituted version of any of these groups.
127. The method of claim 125, wherein R.sub.1 is or a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups.
128. The method of claim 125, wherein R.sub.1 is a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, or a protected thio group.
129. The method of claim 125, wherein R.sub.1 is X.sub.1R.sub.9, wherein X.sub.1 is substituted alkanediyl.sub.(C12), cycloalkanediyl.sub.(C12), alkenediyl.sub.(C12), arenediyl.sub.(C12), heteroarenediyl.sub.(C12), heterocycloalkanediyl.sub.(C12), or a substituted version thereof; and R.sub.9 is alkyl.sub.(C24), cycloalkyl.sub.(C24), alkenyl.sub.(C24), cycloalkenyl.sub.(C24), alkynyl.sub.(C24), cycloalkynyl.sub.(C24), aryl.sub.(C24), heteroaryl.sub.(C24), heterocycloalkyl.sub.(C24), alkoxy.sub.(C24), aryloxy.sub.(C24), aralkoxy.sub.(C24), acyl.sub.(C24), alkylamino.sub.(C24), dialkylamino.sub.(C24), alkylthio.sub.(C24), arylthio.sub.(C24), alkylsulfonyl.sub.(C24), arylsulfonyl.sub.(C24), or a substituted version of any of these groups; or a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups; a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, or a protected thio group.
130. The method according to any one of claims 125-129, wherein R.sub.1 is alkyl.sub.(C24), cycloalkyl.sub.(C24), aryl.sub.(C24), heteroaryl.sub.(C24), heterocycloalkyl.sub.(C24), a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, a protected thio group, R.sub.1 is X.sub.1R.sub.9, wherein X.sub.1 is substituted alkanediyl.sub.(C12) or a substituted version thereof; and R.sub.9 is cycloalkyl.sub.(C24), aryl.sub.(C24), heteroaryl.sub.(C24), heterocycloalkyl.sub.(C24), alkoxy.sub.(C24), aryloxy.sub.(C24), aralkoxy.sub.(C24), acyl.sub.(C24), alkylamino.sub.(C24), dialkylamino.sub.(C24), alkylthio.sub.(C24), arylthio.sub.(C24), alkylsulfonyl.sub.(C24), arylsulfonyl.sub.(C24), or a substituted version of any of these groups; or a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups; a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, or a protected thio group.
131. A compound of the formula: ##STR00157## wherein: a and b are each independently selected from 0, 1, 2, or 3; x and y are each independently selected from 0, 1, 2, or 3; R.sub.1 is an organic moiety; R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are each hydroxy or R.sub.2 and R.sub.3 are taken together to form a B-containing heterocycloalkyl.sub.(C12) or substituted B-containing heterocycloalkyl.sub.(C12); and R.sub.6, R.sub.6, R.sub.7, and R.sub.7 are each independently hydrogen, alkyl.sub.(C12), or substituted alkyl.sub.(C12).
132. The compound of claim 131, wherein the compound is not a compound of the formula: ##STR00158##
133. The compound of claim 131 or claim 132, wherein R.sub.1 is aralkoxy.sub.(C24), acyl.sub.(C24), alkylamino.sub.(C24), dialkylamino.sub.(C24), alkylthio.sub.(C24), arylthio.sub.(C24), alkylsulfonyl.sub.(C24), arylsulfonyl.sub.(C24), or a substituted version of any of these groups; or a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups; a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, or a protected thio group; or X.sub.1R.sub.9, wherein X.sub.1 is substituted alkanediyl.sub.(C12), cycloalkanediyl.sub.(C12), alkenediyl.sub.(C12), arenediyl.sub.(C12), heteroarenediyl.sub.(C12), heterocycloalkanediyl.sub.(C12), or a substituted version thereof; and R.sub.9 is alkyl.sub.(C24), cycloalkyl.sub.(C24), alkenyl.sub.(C24), cycloalkenyl.sub.(C24), alkynyl.sub.(C24), cycloalkynyl.sub.(C24), aryl.sub.(C24), heteroaryl.sub.(C24), heterocycloalkyl.sub.(C24), alkoxy.sub.(C24), aryloxy.sub.(C24), aralkoxy.sub.(C24), acyl.sub.(C24), alkylamino.sub.(C24), dialkylamino.sub.(C24), alkylthio.sub.(C24), arylthio.sub.(C24), alkylsulfonyl.sub.(C24), arylsulfonyl.sub.(C24), or a substituted version of any of these groups; or a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups; a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, or a protected thio group.
134. The method of claim 133, wherein R.sub.1 is hydrogen, alkyl.sub.(C24), cycloalkyl.sub.(C24), alkenyl.sub.(C24), cycloalkenyl.sub.(C24), alkynyl.sub.(C24), cycloalkynyl.sub.(C24), aryl.sub.(C24), heteroaryl.sub.(C24), heterocycloalkyl.sub.(C24), alkoxy.sub.(C24), aryloxy.sub.(C24), aralkoxy.sub.(C24), acyl.sub.(C24), alkylamino.sub.(C24), dialkylamino.sub.(C24), alkylthio.sub.(C24), arylthio.sub.(C24), alkylsulfonyl.sub.(C24), arylsulfonyl.sub.(C24), or a substituted version of any of these groups.
135. The method of claim 133, wherein R.sub.1 is or a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups.
136. The method of claim 133, wherein R.sub.1 is a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, or a protected thio group.
137. The method of claim 133, wherein R.sub.1 is X.sub.1R.sub.9, wherein X.sub.1 is substituted alkanediyl.sub.(C12), cycloalkanediyl.sub.(C12), alkenediyl.sub.(C12), arenediyl.sub.(C12), heteroarenediyl.sub.(C12), heterocycloalkanediyl.sub.(C12), or a substituted version thereof; and R.sub.9 is alkyl.sub.(C24), cycloalkyl.sub.(C24), alkenyl.sub.(C24), cycloalkenyl.sub.(C24), alkynyl.sub.(C24), cycloalkynyl.sub.(C24), aryl.sub.(C24), heteroaryl.sub.(C24), heterocycloalkyl.sub.(C24), alkoxy.sub.(C24), aryloxy.sub.(C24), aralkoxy.sub.(C24), acyl.sub.(C24), alkylamino.sub.(C24), dialkylamino.sub.(C24), alkylthio.sub.(C24), arylthio.sub.(C24), alkylsulfonyl.sub.(C24), arylsulfonyl.sub.(C24), or a substituted version of any of these groups; or a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups; a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, or a protected thio group.
138. The method according to any one of claims 133-137, wherein R.sub.1 is alkyl.sub.(C24), cycloalkyl.sub.(C24), aryl.sub.(C24), heteroaryl.sub.(C24), heterocycloalkyl.sub.(C24), a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, a protected thio group, R.sub.1 is X.sub.1R.sub.9, wherein X.sub.1 is substituted alkanediyl.sub.(C12) or a substituted version thereof; and R.sub.9 is cycloalkyl.sub.(C24), aryl.sub.(C24), heteroaryl.sub.(C24), heterocycloalkyl.sub.(C24), alkoxy.sub.(C24), aryloxy.sub.(C24), aralkoxy.sub.(C24), acyl.sub.(C24), alkylamino.sub.(C24), dialkylamino.sub.(C24), alkylthio.sub.(C24), arylthio.sub.(C24), alkylsulfonyl.sub.(C24), arylsulfonyl.sub.(C24), or a substituted version of any of these groups; or a group of the formula: C(O)R.sub.8, wherein R.sub.8 is alkoxy.sub.(C12), alkylamino.sub.(C12), dialkylamino.sub.(C12), or a substituted version of any of these groups; a monovalent protected amine group, a divalent protected amine group, a protected hydroxy group, or a protected thio group.
139. The compound according to any one of claims 131-138, wherein R.sub.2 and R.sub.3 are a B-containing heterocycloalkyl.sub.(C12).
140. The compound of claim 139, wherein R.sub.2 and R.sub.3 are a pinacol boronic ester.
141. The compound according to any one of claims 131-140, wherein R.sub.4 and R.sub.5 are a B-containing heterocycloalkyl.sub.(C12).
142. The compound of claim 141, wherein R.sub.4 and R.sub.5 are a pinacol boronic ester.
143. The compound according to any one of claims 131-142, wherein R.sub.6 is hydrogen.
144. The compound according to any one of claims 131-143, wherein R.sub.6 is hydrogen.
145. The compound according to any one of claims 131-144, wherein R.sub.7 is hydrogen.
146. The compound according to any one of claims 131-145, wherein R.sub.7 is hydrogen.
147. The compound according to any one of claims 131-146, wherein the compound is further defined as: ##STR00159##
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0064] For a more complete understanding of the features and advantages of the present disclosure, reference is now made to the detailed description of the disclosure along with the accompanying figures and in which:
[0065]
[0066]
[0067]
[0068]
[0069]
[0070]
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0071] In some aspects, the present disclosure provides methods of preparing sequential reaction of BCPs to obtain a BCPs substituted with 2 or 3 groups that have been orthogonally added to the BCP. These groups may be added starting from a bis-boronate that allows for the sequential reaction of the boronate at the tertiary position followed by a sequential reaction at a secondary position of the boronate there. These compounds allow higher yielding access to BCP derivatives than could be obtained through traditional methods. Furthermore, these methods provide simplified access to a wider array of compounds. Compounds for use in these method are also provided.
I. COMPOUNDS OF THE PRESENT DISCLOSURE
[0072] The compounds of the present disclosure are shown, for example, above, in the summary of the invention section, and in the claims below. They may be made using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated by reference herein. In addition, the synthetic methods may be further modified and optimized for preparative, pilot- or large-scale production, either batch or continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Anderson, Practical Process Research & DevelopmentA Guide for Organic Chemists (2012), which is incorporated by reference herein.
[0073] Compounds of the present disclosure may contain one or more asymmetrically-substituted carbon, sulfur, or phosphorus atom and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present disclosure can have the S or the R configuration. In some embodiments, the present compounds may contain two or more atoms which have a defined stereochemical orientation.
[0074] Chemical formulas used to represent compounds of the present disclosure will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended.
[0075] In addition, atoms making up the compounds of the present disclosure are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include .sup.13C and .sup.14C.
[0076] In some embodiments, compounds of the present disclosure exist in salt or non-salt form. With regard to the salt form(s), in some embodiments the particular anion or cation forming a part of any salt form of a compound provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.
[0077] It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as solvates. Where the solvent is water, the complex is known as a hydrate. It will also be appreciated that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof are within the scope of the present disclosure.
II. METHODS OF USE
[0078] The present disclosure relates to the use of the bis-BCPs to create di- and tri-substituted BCPs through traditional boronic acid based reaction techniques. These methods include a reduction to a hydrogen atom, oxidation to obtain a hydroxyl group or other oxygen containing groups, thiolation to install thio or mercapto containing groups, replacement of the boronic acid or ester with a halogen, an amination reaction to install an amine group, or a cross coupling reaction that forms one or more carbon-carbon bonds. A wide array of different carbon carbon bonding forming cross couplings are known including Suzuki, Chan-Lam, conjugate additions, a Giese alkylation, or a cross coupling with an heteroarene using the Minisci reaction. Many of these methods are catalyzed by one or more transition metal catalysts such as a Pd, Mn, Ni, Zn, or Ir catalyst. The compounds described herein may be transformed into a differentially modified BCP using these techniques in a sequential fashion with highly selectivity for each of the separate positions on the BCP.
III. DEFINITIONS
[0079] When used in the context of a chemical group: hydrogen means H; hydroxy means OH; oxo means O; carbonyl means C(O); carboxy means C(O)OH (also written as COOH or CO.sub.2H); halo means independently F, Cl, Br or I; amino means NH.sub.2; hydroxyamino means NHOH; nitro means NO.sub.2; imino means=NH; cyano means CN; isocyanyl means NCO; azido means N.sub.3; in a monovalent context phosphate means OP(O)(OH).sub.2 or a deprotonated form thereof; in a divalent context phosphate means OP(O)(OH)O or a deprotonated form thereof; mercapto means SH; and thio means=S; thiocarbonyl means C(S); sulfonyl means S(O).sub.2; and sulfinyl means S(O).
[0080] In the context of chemical formulas, the symbol means a single bond, means a double bond, and means triple bond. The symbol ---- represents an optional bond, which if present is either single or double. The symbol represents a single bond or a double bond. Thus, the formula
##STR00010##
covers, for example,
##STR00011##
And it is understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol , when connecting one or two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it covers all stereoisomers as well as mixtures thereof. The symbol , when drawn perpendicularly across a bond (e.g.,
##STR00012##
for methyl) indicates a point of attachment of the group. It is noted that the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment. The symbol means a single bond where the group attached to the thick end of the wedge is out of the page. The symbol
means a single bond where the group attached to the thick end of the wedge is into the page. The symbol
means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.
[0081] When a variable is depicted as a floating group on a ring system, for example, the group R in the formula:
##STR00013##
then the variable may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed. When a variable is depicted as a floating group on a fused ring system, as for example the group R in the formula:
##STR00014##
then the variable may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise. Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals CH), so long as a stable structure is formed. In the example depicted, R may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula above, the subscript letter y immediately following the R enclosed in parentheses, represents a numeric variable. Unless specified otherwise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydrogen atoms of the ring or ring system.
[0082] For the chemical groups and compound classes, the number of carbon atoms in the group or class is as indicated as follows: Cn or C=n defines the exact number (n) of carbon atoms in the group/class. Cn defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number as small as possible for the group/class in question. For example, it is understood that the minimum number of carbon atoms in the groups alkyl.sub.(C8), alkanediyl.sub.(C8), heteroaryl.sub.(C8), and acyl.sub.(C8) is one, the minimum number of carbon atoms in the groups alkenyl.sub.(C8), alkynyl.sub.(C8), and heterocycloalkyl.sub.(C8) is two, the minimum number of carbon atoms in the group cycloalkyl.sub.(C8) is three, and the minimum number of carbon atoms in the groups aryl.sub.(C8) and arenediyl.sub.(C8) is six. Cn-n defines both the minimum (n) and maximum number (n) of carbon atoms in the group. Thus, alkyl.sub.(C2-10) designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical groups or class it modifies and it may or may not be enclosed in parenthesis, without signifying any change in meaning. Thus, the terms C.sub.1-4-alkyl, C1-4-alkyl, alkyl.sub.(C1-4), and alkyl.sub.(C4) are all synonymous. Except as noted below, every carbon atom is counted to determine whether the group or compound falls with the specified number of carbon atoms. For example, the group dihexylamino is an example of a dialkylamino.sub.(C12) group; however, it is not an example of a dialkylamino.sub.(C6) group. Likewise, phenylethyl is an example of an aralkyl.sub.(C=8) group. When any of the chemical groups or compound classes defined herein is modified by the term substituted, any carbon atom in the moiety replacing the hydrogen atom is not counted. Thus methoxyhexyl, which has a total of seven carbon atoms, is an example of a substituted alkyl.sub.(C1-6). Unless specified otherwise, any chemical group or compound class listed in a claim set without a carbon atom limit has a carbon atom limit of less than or equal to twelve.
[0083] The term saturated when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted versions of saturated groups, one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded. When the term saturated is used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution.
[0084] The term aliphatic signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic compound or group. In aliphatic compounds/groups, the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds/groups can be saturated, that is joined by single carbon-carbon bonds (alkanes/alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes/alkenyl) or with one or more carbon-carbon triple bonds (alkynes/alkynyl).
[0085] The term aromatic signifies that the compound or chemical group so modified has a planar unsaturated ring of atoms with 4n+2 electrons in a fully conjugated cyclic system. An aromatic compound or chemical group may be depicted as a single resonance structure; however, depiction of one resonance structure is taken to also refer to any other resonance structure. For example:
##STR00015##
is also taken to refer to
##STR00016##
Aromatic compounds may also be depicted using a circle to represent the delocalized nature of the electrons in the fully conjugated cyclic system, two non-limiting examples of which are shown below:
##STR00017##
[0086] The term alkyl refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups CH.sub.3 (Me), CH.sub.2CH.sub.3 (Et), CH.sub.2CH.sub.2CH.sub.3 (n-Pr or propyl), CH(CH.sub.3).sub.2 (i-Pr, .sup.iPr or isopropyl), CH.sub.2CH.sub.2CH.sub.2CH.sub.3 (n-Bu), CH(CH.sub.3)CH.sub.2CH.sub.3 (sec-butyl), CH.sub.2CH(CH.sub.3).sub.2 (isobutyl), C(CH.sub.3).sub.3 (tert-butyl, t-butyl, t-Bu or .sup.tBu), and CH.sub.2C(CH.sub.3).sub.3 (neo-pentyl) are non-limiting examples of alkyl groups. The term alkanediyl refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups CH.sub.2 (methylene), CH.sub.2CH.sub.2, CH.sub.2C(CH.sub.3).sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2 are non-limiting examples of alkanediyl groups. The term alkylidene refers to the divalent group CRR in which R and R are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: CH.sub.2, CH(CH.sub.2CH.sub.3), and C(CH.sub.3).sub.2. An alkane refers to the class of compounds having the formula HR, wherein R is alkyl as this term is defined above.
[0087] The term cycloalkyl refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forming part of one or more non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: CH(CH.sub.2).sub.2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to a carbon atom of the non-aromatic ring structure. The term cycloalkanediyl refers to a divalent saturated aliphatic group with two carbon atoms as points of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The group
##STR00018##
is a non-limiting example of cycloalkanediyl group. A cycloalkane refers to the class of compounds having the formula HR, wherein R is cycloalkyl as this term is defined above.
[0088] The term alkenyl refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: CHCH.sub.2 (vinyl), CHCHCH.sub.3, CHCHCH.sub.2CH.sub.3, CH.sub.2CHCH.sub.2 (allyl), CH.sub.2CHCHCH.sub.3, and CHCHCHCH.sub.2. The term alkenediyl refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups CHCH, CHC(CH.sub.3)CH.sub.2, CHCHCH.sub.2, and CH.sub.2CHCHCH.sub.2 are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms alkene and olefin are synonymous and refer to the class of compounds having the formula HR, wherein R is alkenyl as this term is defined above. Similarly, the terms terminal alkene and -olefin are synonymous and refer to an alkene having just one carbon-carbon double bond, wherein that bond is part of a vinyl group at an end of the molecule.
[0089] The term alkynyl refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups CCH, CCCH.sub.3, and CH.sub.2CCCH.sub.3 are non-limiting examples of alkynyl groups. An alkyne refers to the class of compounds having the formula HR, wherein R is alkynyl.
[0090] The term aryl refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more aromatic ring structures, each with six ring atoms that are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. As used herein, the term aryl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, C.sub.6H.sub.4CH.sub.2CH.sub.3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl (e.g., 4-phenylphenyl). The term arenediyl refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structures, each with six ring atoms that are all carbon, and wherein the divalent group consists of no atoms other than carbon and hydrogen. As used herein, the term arenediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. Non-limiting examples of arenediyl groups include:
##STR00019##
An arene refers to the class of compounds having the formula HR, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes.
[0091] The term aralkyl refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.
[0092] The term heteroaryl refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroaryl does not preclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms. Non-limiting examples of heteroaryl groups include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (Im), indolyl, indazolyl, isoxazolyl, methylpyridinyl, oxazolyl, oxadiazolyl, phenylpyridinyl, pyridinyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term N-heteroaryl refers to a heteroaryl group with a nitrogen atom as the point of attachment. A heteroarene refers to the class of compounds having the formula HR, wherein R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes.
[0093] The term heteroaralkyl refers to the monovalent group -alkanediyl-heteroaryl, in which the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: pyridinylmethyl and 2-quinolinyl-ethyl.
[0094] The term heterocycloalkyl refers to a monovalent non-aromatic group with a carbon, nitrogen, or boron atom as the point of attachment, said carbon, nitrogen, or boron atom forming part of one or more non-aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the non-aromatic ring structure(s) is nitrogen, oxygen, sulfur, or boron and wherein the heterocycloalkyl group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen, sulfur, and boron. If more than one ring is present, the rings are fused. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to one or more ring atoms. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, oxiranyl, oxetanyl, 1,3,2-dioxaborolanyl, and 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl. The term N-heterocycloalkyl refers to a heterocycloalkyl group with a nitrogen atom as the point of attachment. N-pyrrolidinyl is an example of such a group. The term B-heterocycloalkyl refers to a heterocycloalkyl group with a boron atom as the point of attachment. 1,3,2-dioxaborolanyl and 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl are examples of such a group.
[0095] The term acyl refers to the group C(O)R, in which R is a hydrogen, alkyl, cycloalkyl, or aryl as those terms are defined above. The groups, CHO, C(O)CH.sub.3 (acetyl, Ac), C(O)CH.sub.2CH.sub.3, C(O)CH(CH.sub.3).sub.2, C(O)CH(CH.sub.2).sub.2, C(O)C.sub.6H.sub.5, and C(O)C.sub.6H.sub.4CH.sub.3 are non-limiting examples of acyl groups. A thioacyl is defined in an analogous manner, except that the oxygen atom of the group C(O)R has been replaced with a sulfur atom, C(S)R. The term aldehyde corresponds to an alkyl group, as defined above, attached to a CHO group.
[0096] The term alkoxy refers to the group OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: OCH.sub.3 (methoxy), OCH.sub.2CH.sub.3 (ethoxy), OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2 (isopropoxy), or OC(CH.sub.3).sub.3 (tert-butoxy). The terms cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, aralkoxy, heteroaryloxy, heterocycloalkoxy, and acyloxy, when used without the substituted modifier, refers to groups, defined as OR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The term alkylthio and acylthio refers to the group SR, in which R is an alkyl and acyl, respectively. The term alcohol corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term ether corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group.
[0097] The term alkylamino refers to the group NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: NHCH.sub.3 and NHCH.sub.2CH.sub.3. The term dialkylamino refers to the group NRR, in which R and R can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: N(CH.sub.3).sub.2 and N(CH.sub.3)(CH.sub.2CH.sub.3). The term amido (acylamino), when used without the substituted modifier, refers to the group NHR, in which R is acyl, as that term is defined above. A non-limiting example of an amido group is NHC(O)CH.sub.3.
[0098] The term alkylsilyl refers to the group Si(R).sub.3, in which R, R, and R are alkyl, as that term is defined above, and R, R, and R can be the same or different alkyl groups. Non-limiting examples include: Si(CH.sub.3).sub.3 and Si(CH.sub.3).sub.2C(CH.sub.3).sub.3.
[0099] An amine protecting group or amino protecting group is well understood in the art. An amine protecting group is a group which modulates the reactivity of the amine group during a reaction which modifies some other portion of the molecule. Amine protecting groups can be found at least in Greene and Wuts, 1999, which is incorporated herein by reference. Some non-limiting examples of amino protecting groups include formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxycarbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, ,-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkylaminocarbonyl groups (which form ureas with the protect amine) such as ethylaminocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Additionally, the amine protecting group can be a divalent protecting group such that both hydrogen atoms on a primary amine are replaced with a single protecting group. In such a situation the amine protecting group can be phthalimide (phth) or a substituted derivative thereof wherein the term substituted is as defined above. In some embodiments, the halogenated phthalimide derivative may be tetrachlorophthalimide (TCphth). When used herein, a protected amino group, is a group of the formula PG.sub.MANH or PG.sub.DAN wherein PG.sub.MA is a monovalent amine protecting group, which may also be described as a monovalently protected amino group and PG.sub.DA is a divalent amine protecting group as described above, which may also be described as a divalently protected amino group.
[0100] As used herein, a chiral auxiliary refers to a removable chiral group that is capable of influencing the stereoselectivity of a reaction. Persons of skill in the art are familiar with such compounds, and many are commercially available.
[0101] When a chemical group is used with the substituted modifier, one or more hydrogen atom has been replaced, independently at each instance, by OH, F, Cl, Br, I, NH.sub.2, NO.sub.2, CO.sub.2H, CO.sub.2CH.sub.3, CO.sub.2CH.sub.2CH.sub.3, CN, SH, OCH.sub.3, OCH.sub.2CH.sub.3, C(O)CH.sub.3, NHCH.sub.3, NHCH.sub.2CH.sub.3, N(CH.sub.3).sub.2, C(O)NH.sub.2, C(O)NHCH.sub.3, C(O)N(CH.sub.3).sub.2, OC(O)CH.sub.3, NHC(O)CH.sub.3, S(O).sub.2OH, or S(O).sub.2NH.sub.2. For example, the following groups are non-limiting examples of substituted alkyl groups: CH.sub.2OH, CH.sub.2Cl, CF.sub.3, CH.sub.2CN, CH.sub.2C(O)OH, CH.sub.2C(O)OCH.sub.3, CH.sub.2C(O)NH.sub.2, CH.sub.2C(O)CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2OC(O)CH.sub.3, CH.sub.2NH.sub.2, CH.sub.2N(CH.sub.3).sub.2, and CH.sub.2CH.sub.2C1. The term haloalkyl is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to halo (i.e. F, Cl, Br, or I) such that no other atoms aside from carbon, hydrogen and halogen are present. The group, CH.sub.2Cl is a non-limiting example of a haloalkyl. The term fluoroalkyl is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present. The groups CH.sub.2F, CF.sub.3, and CH.sub.2CF.sub.3 are non-limiting examples of fluoroalkyl groups. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-1-yl. The groups, C(O)CH.sub.2CF.sub.3, CO.sub.2H (carboxyl), CO.sub.2CH.sub.3 (methylcarboxyl), CO.sub.2CH.sub.2CH.sub.3, C(O)NH.sub.2 (carbamoyl), and CON(CH.sub.3).sub.2, are non-limiting examples of substituted acyl groups. The groups NHC(O)OCH.sub.3 and NHC(O)NHCH.sub.3 are non-limiting examples of substituted amido groups.
[0102] The use of the word a or an, when used in conjunction with the term comprising in the claims and/or the specification may mean one, but it is also consistent with the meaning of one or more, at least one, and one or more than one.
[0103] Throughout this application, the term about is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects or patients. When used in the context of X-ray powder diffraction, the term about is used to indicate a value of 0.22 from the reported value, preferably a value of 0.12 from the reported value. When used in the context of differential scanning calorimetry or glass transition temperatures, the term about is used to indicate a value of 10 C. relative to the maximum of the peak, preferably a value of 2 C. relative to the maximum of the peak. When used in other contexts, the term about is used to indicate a value of 10% of the reported value, preferably a value of 5% of the reported value. It is to be understood that, whenever the term about is used, a specific reference to the exact numerical value indicated is also included.
[0104] The terms comprise, have and include are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as comprises, comprising, has, having, includes and including, are also open-ended. For example, any method that comprises, has or includes one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.
[0105] The terms comprise, have and include are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as comprises, comprising, has, having, includes and including, are also open-ended. For example, any method that comprises, has or includes one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.
[0106] The term effective, as that term is used in the specification and/or claims, means adequate to accomplish a desired, expected, or intended result. The above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the invention in terms such that one of ordinary skill can appreciate the scope and practice the present invention.
[0107] The term hydrate when used as a modifier to a compound means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) water molecules associated with each compound molecule, such as in solid forms of the compound.
[0108] An isomer of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.
[0109] Pharmaceutically acceptable salts means salts of compounds disclosed herein which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).
[0110] A stereoisomer or optical isomer is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. Enantiomers are stereoisomers of a given compound that are mirror images of each other, like left and right hands. Diastereomers are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers will not exceed 2.sup.n, where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase substantially free from other stereoisomers means that the composition contains 15%, more preferably 10%, even more preferably 5%, or most preferably 1% of another stereoisomer(s).
[0111] The above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the invention in terms such that one of ordinary skill can appreciate the scope and practice the present invention.
IV. EXAMPLES
[0112] The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.
Example 1: Boronate Ligand Exchange Reaction
[0113] The striking reactivity difference between these two Bpin units of BCP 14 was initially observed in the boronate ligand exchange reaction (
Example 2: Synthesis and Reactions of BCP Bis-Boronates
[0114] The advantages of the strategy disclosed herein to access bridge-substituted BCPs not only draws from its modularity, but also is reinforced by the synthetic efficacy and practicality with which various BCP bis-boronates can be prepared. In a previous study (Yang et al., 2021b), the alkyl substituted BCP bis-boronate (14) was synthesized from readily accessible starting materials on gram scale and in moderate yield (
[0115] With a variety of BCP bis-boronates in hand, the selective deborylative alkylation, protonation and (hetero)arylation of the bridgehead C.sub.3 Bpin (
[0116] The derivatization of BCP C.sub.2-Bpins was explored to demonstrate broad applications of a sequential functionalization strategy for the late-stage synthesis of C.sub.1, C.sub.2-di-(
Example 3: Synthesis and Characterization
A. General Experimental
[0117] Tetrahydrofuran (THF), diethyl ether (Et.sub.2O), toluene and dichloromethane (CH.sub.2Cl.sub.2) were obtained by passing the previously degassed solvents through an activated alumina column. Dioxane and reagents were purchased at the highest commercial quality and used without further purification. All of the rest of the reagents were purchased from BLD Pharmatech Co., Sigma-Aldrich, TCI, Synthonix and/or Combi-Blocks and used without further purification. Yields refer to chromatographically and spectroscopically (.sup.1H NMR) homogeneous material. Reactions were monitored by GC-MS (Rtx-5MS, 30 m, 0.25 mm ID, 0.25 m), GC-FID (SH-Rxi-5Sil MS, 30 m, 0.25 mm ID, 0.25 m), LC/MS, and thin layer chromatography (TLC). TLC was performed using 0.25 mm E. Merck silica plates (60F-254), using short-wave UV light as the visualizing agent, and phosphomolybdic acid and CAM (H.sub.2SO.sub.4, ammonium molybdate and ceric ammonium sulfate), or KMnO.sub.4 and heat as developing agents. NMR spectra were recorded on Bruker Ascend-600 spectrometers, Varian Inova-400 spectrometers and Bruker Ascend-400 spectrometers instruments and are calibrated using residual undeuterated solvent (CHCl.sub.3 at 7.26 ppm .sup.1H NMR, 77.16 ppm .sup.13C NMR; acetone at 2.05 ppm .sup.1H NMR, 29.84, 206.26 ppm .sup.13C NMR; DMSO at 2.50 ppm .sup.1H NMR, 39.52 ppm .sup.13C NMR; methanol at 3.31 ppm .sup.1H NMR, 49.00 ppm .sup.13C NMR). The following abbreviations were used to explain multiplicities: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad. .sup.13C signals adjacent to boron are generally not observed due to quadrupolar relaxation. Column chromatography was performed using E. Merck silica (60, particle size 0.043-0.063 mm), and preparative TLC was performed on Merck silica plates (60F-254). Melting points were recorded on a Fisher Scientific melting point apparatus (12-144) and are uncorrected. Optical rotation data was recorded on a JAS DIP-360 digital polarimeter. Multi-gram Scale Preparation of BCP BisBoronates
Decagram-Scale Synthesis of BCP BisBoronates 23 (R.sup.1C.sub.2.sup.iPr)
##STR00020##
Step 1: Synthesis of Compound 29
[0118] A 2-L three-necked (24/40 joint) round-bottomed flask, equipped with a 6.4 cm Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate, compound 28, (103.8 g, 360 mmol, 1.0 equiv.). Methylene chloride (720 mL) was added into the flask and the mixture was cooled in a dried ice-acetone bath (78 C.) and stirred for 15 minutes. Next a solution of DIBAL-H (720 mL, 1 M in hexanes, 2.0 equiv., pre-cooled at 78 C.) was added dropwise into the flask through a dropping funnel at 78 C. in 2 hours and the mixture was allowed to stir at 78 C. for another 3 hours. After it was confirmed that the starting material, 28, was consumed through TLC analysis, the reaction was quenched at 78 C. with methanol (24 mL, 720 mmol, 2.0 equiv.). After the reaction was slowly warmed to room temperature, water (29 mL), 20% NaOH (29 mL) and water (72 mL) was slowly added into the reaction mixture in sequence and the mixture was allowed to stir for another 30 minutes. Next, excess Na.sub.2SO.sub.4 was added to dry the reaction mixture and the suspension was filtered through Celite. Solvents was removed under vacuum and the crude product was purified through flash chromatography (hexanes:ethyl acetate, 5:1) on silica gel to afford 63 g (76%) of the title compound 29 (Yang et al., 2021b). Spectroscopic data of the product 29 matches that reported in the literature. (Yang et al., 2021b).
Step 2: Synthesis of Compound 30
[0119] A 2-L three-necked (24/40 joint) round-bottomed flask, equipped with a 6.4 cm Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with triphenyl phosphite (78 mL, 300 mmol, 1.1 equiv.). Methylene chloride (340 mL) was added into the flask and the mixture was cooled to 78 C. Then bromine (15 mL, 300 mmol, 1.1 equiv.) was added slowly into the flask, followed by addition of triethyl amine (140 mL, 1.0 mol, 3.3 equiv.). (Note: a suspension of the mixture was formed.) Next, the solution of 29 (63 g, 270 mmol, 1.0 equiv.) in 160 mL methylene chloride was added into the mixture and the reaction was warmed up to room temperature. After it was confirmed that the starting material, 29, was consumed through TLC analysis, solvent was removed by rotary evaporator and the crude product was purified through flash chromatography (hexanes:ethyl acetate, 20:1) on silica gel to afford 87 g (97%) of the title compound 30 (Hazrati & Oestreich, 2018).
##STR00021##
isopropyl 1-(dibromomethyl)-3,3-dimethoxycyclobutane-1-carboxylate (30)
[0120] Physical State: colorless oil. .sup.1H NMR (600 MHz, CDCl.sub.3): 6.03 (s, 1H), 5.10 (hept, J=6.3 Hz, 1H), 3.16 (s, 3H), 3.15 (s, 3H), 2.72-2.66 (m, 2H), 2.48-2.42 (m, 2H), 1.28 (d, J=6.3 Hz, 6H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 170.41, 96.85, 69.77, 49.87, 48.79, 48.75, 48.57, 40.13, 21.74. ppm. MS (GCMS, EI): m/z=345 (1.5%), 343 (3%), 341 (1.5%), 255 (8%), 201 (29%), 88 (100%). TLC: R.sub.f=0.32 (10:1 hexanes:ethyl acetate).
Step 3: Synthesis of Compound 31
[0121] A 2-L one-necked (24/40 joint) round-bottomed flask, equipped with a 6.4 cm Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with copper(I) iodide (4.88 g, 25.6 mmol, 0.1 equiv.), B.sub.2pin.sub.2 (140 g, 550 mmol, 2.2 equiv.), and lithium tert-butoxide (44.0 g, 550 mmol, 2.2 equiv.). After being evacuated and backfilled with argon from a balloon 3 times, DMF (500 mL) was added into the flask at 0 C. Then a solution of compound 30 (256 mmol, 95.6 g, 1.0 equiv.) in DMF (250 mL) was added slowly into the mixture at 0 C. in 15 minutes and the reaction mixture was allowed to slowly warm to room temperature and stir for another 1 hour. After it was confirmed that the starting material, 30, was consumed through TLC analysis, the reaction was filtered through Celite, washed with diethyl ether (200 mL) and quenched at 0 C. with water (500 mL) (Caution: the quenching process is exothermic). The mixture was transferred into a 6-L flask and diluted with water (1.5 L) and diethyl ether (300 mL). After the mixture was stirred for 30 minutes at room temperature, the two-phase solution was transferred into a 3-L separation funnel. The aqueous phase was separated and extracted with two 200-mL portions of diethyl ether. The combined organic layers were washed with the mixture of 200 mL water and 200 mL saturated NaCl solution twice, dried over Na.sub.2SO.sub.4, and filtered through Celite. (Yang et al., 2011).
[0122] After solvent was removed by rotary evaporator, the crude product was redissolved in 250 mL acetonitrile in a 1-L flask. 2M H.sub.2SO.sub.4 (256 mL, 2.0 equiv.) was added into the mixture at room temperature and the reaction was allowed to stir for another 1.5 hours. After it was confirmed that the ketal intermediate was consumed through TLC analysis, the crude reaction was concentrated to remove excess acetonitrile. Then diethyl ether (400 mL) and saturated brine (150 mL) was added to the reaction mixture and the mixture was transferred to a 1-L separatory funnel. The aqueous layer was separated and further extracted with diethyl ether (3150 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered through Celite. Excess solvent was removed by rotary evaporator.
[0123] The crude product was redissolved in 250 mL methylene chloride in a 500 mL-flask and mesitylene sulfonyl hydrazide (54.9 g, 256 mmol, 1.0 equiv.) was added. The mixture was allowed to stir at room temperature for another 2 hours. After it was confirmed that the ketone intermediate was consumed through TLC analysis, the crude reaction was concentrated to remove excess solvent. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 4:1 to 2:1) on silica gel to afford 116 g (73%) of the title compound 31. (Yang et al., 2021b).
##STR00022##
Isopropyl 1-(bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-3-(2-(mesitylsulfonyl)-hydrazineylidene)cyclobutane-1-carboxylate (31)
[0124] Physical State: white solid. m.p.: 85-87 C. .sup.1H NMR (600 MHz, Acetone-d.sub.6) 9.17 (s, 1H), 7.02 (s, 2H), 4.90 (hept, J=6.2 Hz, 1H), 3.23 (ddd, J=17.6, 3.3, 1.7 Hz, 1H), 3.12 (dt, J=17.0, 2.5 Hz, 1H), 3.05-2.98 (m, 1H), 2.94 (ddd, J=17.1, 3.4, 1.5 Hz, 1H), 2.65 (s, 6H), 2.28 (s, 3H), 1.22 (s, 1H), 1.19 (d, J=6.3 Hz, 3H), 1.18 (d, J=6.6 Hz, 3H), 1.17 (s, 6H), 1.16 (s, 6H), 1.13 (s, 12H) ppm. .sup.13C NMR (151 MHz, Acetone-d.sub.6) 176.43, 154.40, 143.07, 140.75, 134.85, 132.46, 83.83, 83.78, 68.79, 45.17, 43.93, 40.62, 25.18, 25.06, 24.74, 23.44, 21.80, 21.76, 20.85 ppm.
[0125] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.98 ppm. HRMS (ESI-TOF): calc'd for C.sub.30H.sub.48B.sub.2N.sub.2O.sub.8S [M+H].sup.+: 619.3390, found: 619.3402. TLC: R.sub.f=0.30 (3:1 hexanes:ethyl acetate).
Step 4: Synthesis of 23
[0126] A 1-L one-necked (24/40 joint) round-bottomed flask, equipped with a 6.4 cm Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with 31 (61.8 g, 100 mmol, 1.0 equiv.) and dried cesium carbonate (100 g, 300 mmol, 3.0 equiv.). (Note: Cesium carbonate was dried at 120 C. under vacuum for 18 hours.) After being evacuated and backfilled with argon from a balloon 3 times, dioxane (500 mL) was added into the flask and the reaction mixture was allowed to stir at 100 C. for 40 minutes. After it was confirmed that the starting material, 31, was consumed through TLC analysis, the reaction was cooled to room temperature, filtered through Celite, washed with hexanes (500 mL), and concentrated to remove excess solvents. The crude reaction was purified through flash chromatography (hexanes:ethyl acetate, 10:1) on silica gel to afford the title compound 23, which was further purified through trituration in hexanes at 40 C. affording 19.0 g product (47% yield) with >99% purity as white solids. (Yang et al., 2021b).
Trituration procedure: The product (around 21 g) after chromatography was dissolved in hexanes (10 mL) at room temperature and then cooled to 40 C. After the solution of the product was slowly stirred at 40 C. for 1 h, the suspension was filtered and the white solid was washed with cooled hexanes (5 mL) quickly and dried under vacuum for 1 hour.
##STR00023##
isopropyl 2,3-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (23)
[0127] Physical State: white solid. m.p.: 41-43 C. .sup.1H NMR (600 MHz, CDCl.sub.3): 4.93 (hept, J=6.3 Hz, 1H), 2.71 (dd, J=9.4, 2.3 Hz, 1H), 2.14-2.08 (m, 2H), 2.03 (dd, J=8.1, 2.2 Hz, 1H), 1.88 (dd, J=8.2, 0.9 Hz, 1H), 1.22 (s, 12H), 1.21 (s, 6H), 1.20 (s, 6H), 1.19 (d, J=2.9 Hz, 3H), 1.18 (d, J=3.0 Hz, 3H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 169.49, 83.55, 83.10, 67.44, 55.81, 50.75, 44.87, 24.89, 24.87, 24.84, 24.79, 21.93 ppm. .sup.11B NMR (128 MHz, CDCl.sub.3): 31.18 ppm. MS (GCMS, EI): m/z=391 (0.2%), 363 (0.3%), 348 (1%), 305 (1%), 164 (30%), 83 (100%). TLC: R.sub.f=0.32 (5:1 hexanes:ethyl acetate).
Gram-Scale Synthesis of BCP BisBoronates 24 (R.SUP.1.=NBnBoc)
##STR00024##
Step 1: Synthesis of SI-2.
[0128] A flame-dried round-bottom flask charged with ethyl 1-([(tert-butoxy)carbonyl]amino)-3-oxocyclobutane-1-carboxylate, SI-1 (25 g, 100 mmol, 1.0 equiv.) dissolved in THF/methanol (500 mL, 4:1) was cooled to 0 C. Then NaBH.sub.4 (1.9 g, 50 mmol, 0.5 equiv.) was added slowly to the mixture at 0 C. and the reaction was allowed to stir at the same temperature for 1 h. After it was confirmed that the starting material, SI-1, was consumed totally, the reaction was quenched by water (1.0 mL). After excess solvent was removed, the mixture was diluted with ethyl acetate (200 mL) and water (200 mL) and transferred into a 1-L separatory funnel. The aqueous layer was separated and further extracted with ethyl acetate (3100 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered through Celite. Excess solvent was removed by rotary evaporator. The crude alcohol was used without further purification.
[0129] The crude alcohol was dissolved in THF/DMF (500 mL, 1:1) and the mixture was cooled to 0 C. NaH (10.0 g, 250 mmol, 2.5 equiv.) was added slowly to the reaction at 0 C. and the mixture was warmed to room temperature and stirred for 3 hours. After there were no bubbles being released, benzyl bromide (36 mL, 300 mmol, 3.0 equiv.) was added to the reaction at 0 C. and the mixture was allowed to stir at room temperature for around 12 hours. After it was confirmed that the alcohol intermediate was consumed totally, water (5.4 mL) was added to quench the reaction. Excess solvent was removed by rotary evaporator and the mixture was diluted with water (500 mL) and diethyl ether (200 mL) and then transferred into a 1-L separation funnel. The aqueous phase was separated and extracted with two 100-mL portions of diethyl ether. The combined organic layers were washed with the mixture of 100 mL water and 100 mL saturated NaCl solution twice, dried over Na.sub.2SO.sub.4, and filtered through Celite. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 4:1) on silica gel to afford 21.9 g (50%) of the title compound SI-2.
##STR00025##
ethyl 1-(benzyl(tert-butoxycarbonyl)amino)-3-(benzyloxy)cyclobutane-1-carboxylate (SI-2)
Note: 1H NMR showed the presence of diastereoisomers and rotamers.
[0130] Physical State: yellow oil. .sup.1H NMR (600 MHz, CDCl.sub.3): 7.31-7.14 (m, 10H), 4.49 (brs, 2H), 4.17 (brs, 2H), 4.12-4.06 (m, 2H), 3.65 (brs, 1H), 2.52 (brs, 4H), 1.35 (s, 9H). 1.24-1.13 (m, 3H) ppm. Note: The complexity of the 1H NMR is attributed to the diastereomerism and rotating isomerism. HRMS (ESI-TOF): calc'd for C.sub.26H.sub.33NO.sub.5 [M+H].sup.+: 440.2432, found: 440.2428.
[0131] TLC: R.sub.f=0.68 (3:1 hexanes:ethyl acetate).
Step 2: Synthesis of SI-3.
[0132] A flame-dried round-bottom flask charged with SI-2 (11.5 g, 25 mmol, 1.0 equiv.) dissolved in THF (100 mL) was cooled to 20 C. LiAlH.sub.4 (1.0 g, 26 mmol, 1.05 equiv.) was added slowly to the solution at 20 C. and the reaction was allowed to warm to room temperature and stir at 0 C. for 1 hour. After it was confirmed that SI-2 was consumed totally, the reaction was quenched at 0 C. with water (1.0 mL), followed by 20% NaOH (1.0 mL) and water (3.0 mL) and the mixture was stirred at 0 C. for 30 min. Then excess Na.sub.2SO.sub.4 was added, and the suspended solution was stirred at room temperature for another 1 hour. The mixture was filtered through Celite, and the solvent was removed under high vacuum. The crude alcohol was used without further purification.
[0133] The crude alcohol was redissolved in methylene chloride (75 mL) and Dess-Martin periodinane (13.8 g, 32.5 mmol, 1.3 equiv.) was added to mixture at 0 C. The reaction was allowed to warm to room temperature and stir for 2 hours. After it was confirmed that the alcohol intermediate was consumed totally, the reaction was quenched by excess saturated NaHCO.sub.3 solution and Na.sub.2S.sub.2O.sub.3 solution and extracted with methylene chloride (100 mL) three times. The organic phase was separated, washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The crude aldehyde was used without further purification.
[0134] The aldehyde was dissolved in 25 ml methylene chloride and then p-toluenesulfonyl hydrazide (5.2 g, 27.5 mmol, 1.1 equiv.) was added. The mixture was allowed to stir at room temperature for another 1 hours. After it was confirmed that the aldehyde was consumed through TLC analysis, the crude reaction was concentrated to remove excess solvent. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 3:1) on silica gel to afford 12.0 g (85%) of the title compound SI-3.
##STR00026##
tert-butylbenzyl(3-(benzyloxy)-1-((2-tosylhydrazineylidene)methyl)cyclobutyl)carbamate
(SI-3) Note: 1H NMR showed the presence of diastereoisomers (1/0.4) and trans/cis isomers. The 1H NMR of the main isomer is given.
[0135] Physical State: yellow oil. .sup.1H NMR (600 MHz, Acetone-d.sup.6): 9.81 (s, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.58 (s, 1H), 7.38-7.14 (m, 12H), 4.25 (s, 2H), 4.15 (s, 2H), 3.87 (tt, J=7.0, 4.2 Hz, 1H), 2.58 (dd, J=13.7, 6.9 Hz, 2H), 2.34 (s, 3H), 2.29 (dd, J=13.8, 4.1 Hz, 2H), 1.31 (s, 9H) ppm.
[0136] HRMS (ESI-TOF): calc'd for C.sub.31H.sub.37N.sub.3O.sub.5S [M+Na].sup.+: 586.2346, found: 586.2344. TLC: R.sub.f=0.32 (3:1 hexanes:ethyl acetate).
Step 3: Synthesis of SI-4
[0137] A dry round-bottom flask charged with SI-3 (12.0 g, 21 mmol, 1.0 equiv.), 60% NaH (1.68 g, 42 mmol, 2.0 equiv.) and B.sub.2pin.sub.2 (10.6 g, 42 mmol, 2.0 equiv.) was degassed and filled with argon three times. Toluene (210 mL) was added, and the mixture was heated at 75 C. for 5 h. After it was confirmed that the starting material SI-3 was consumed totally, the reaction was cooled to room temperature and the suspension was filtered by Celite and washed by diethyl ether (200 mL). After solvent was removed by rotary evaporator from the filtrate, the crude product was purified by flash chromatography (hexanes:ethyl acetate, 4:1) on silica gel to afford 5.3 g (42%) of the title compound SI-4. (Li et al., 2012)
##STR00027##
tert-butyl benzyl(3-(benzyloxy)-1-(bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)cyclo butyl)carbamate (SI-4)
[0138] Note: the main isomer was isolated and characterized.
[0139] Physical State: white solid. m.p.: 99-101 C. .sup.1H NMR (600 MHz, CDCl.sub.3): 7.25-7.04 (m, 10H), 4.59 (s, 2H), 4.07 (s, 2H), 3.48-3.33 (m, 1H), 2.69-2.63 (m, 2H), 2.36-2.28 (m, 2H), 2.09 (s, 1H), 1.38 (s, 9H), 1.17 (s, 12H), 1.17 (s, 12H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 140.90, 138.80, 128.37, 128.22, 127.92, 127.81, 127.29, 126.44, 126.40, 83.18, 69.66, 68.77, 49.84, 28.64, 25.05, 24.88 ppm. Note: BC, NC, NCH.sub.2 and Me.sub.3C were not observed. .sup.11B NMR (128 MHz, CDCl.sub.3): 30.66 ppm. HRMS (ESI-TOF): calc'd for C.sub.36H.sub.53B.sub.2NO.sub.7 [M+H].sup.+: 634.4081, found: 634.4096. TLC: R.sub.f=0.68 (3:1 hexanes:ethyl acetate).
Step 4: Synthesis of SI-5
[0140] A dry round-bottom flask was charged with SI-4 (7 g, 11 mmol, 1.0 equiv.) and Pd/C (10 w.t. %, 350 mg) and methanol (70 mL) was added then. The flask was then degassed and refilled with hydrogen three times. The reaction mixture was heated at 50 C. for 2 h. After it was confirmed that the starting material, SI-4, was consumed totally, the mixture was cooled to room temperature, filtered through Celite and concentrated. The crude alcohol was used without further purification.
[0141] The crude alcohol was redissolved in methylene chloride (40 mL) and Dess-Martin periodinane (6.4 g, 15 mmol, 1.3 equiv.) was added to mixture at 0 C. The reaction was allowed to warm to room temperature and stir for 2 hours. After it was confirmed that the alcohol intermediate was consumed totally, the reaction was quenched by excess saturated Na.sub.2CO.sub.3 solution and Na.sub.2S.sub.2O.sub.3 solution and extracted with methylene chloride (50 mL) three times. The organic phase was separated, washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The crude ketone was used without further purification.
[0142] The ketone was dissolved in 25 mL methylene chloride and then mesitylsulfonyl hydrazide (2.6 g, 12 mmol, 1.1 equiv.) was added. The mixture was allowed to stir at room temperature for another 3-5 hours. After it was confirmed that the aldehyde was consumed through TLC analysis, the crude reaction is concentrated to remove excess solvent. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 3:1) on silica gel to afford 4.48 g (55%) of the title compound SI-5.
##STR00028##
tert-butyl benzyl(1-(bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-3-(2-(mesityl sulfonyl)hydrazineylidene)cyclobutyl)carbamate (SI-5)
[0143] Physical State: white solid. m.p.: 161-163 C. .sup.1H NMR (600 MHz, Acetone-d.sub.6): 9.08 (s, 1H), 7.27 (t, J=7.6 Hz, 2H), 7.22-7.15 (m, 3H), 6.98 (s, 2H), 4.71-4.52 (m, 2H), 3.28-3.01 (m, 4H), 2.57 (s, 6H), 2.28 (s, 3H), 2.10 (s, 1H), 1.55-1.29 (m, 9H), 1.25-1.12 (m, 24H) ppm.
[0144] .sup.13C NMR (151 MHz, Acetone-d.sub.6): 142.98, 141.79, 140.73, 140.71, 135.00, 134.96, 132.44, 129.24, 127.21, 126.32, 84.09, 84.03, 50.70, 28.53, 25.21, 25.04, 25.01, 24.96, 23.43, 20.85 ppm. Note: BC, NC, NCH.sub.2 and Me.sub.3C were not observed. .sup.11B NMR (128 MHz, CDCl.sub.3): 37.71 ppm. HRMS (ESI-TOF): calc'd for C.sub.38H.sub.57B.sub.2N.sub.3O.sub.8S [M+H].sup.+: 738.4125, found: 738.4148.
[0145] TLC: R.sub.f=0.40 (3:1 hexanes:ethyl acetate).
Step 5: Synthesis of 24
[0146] A 250-mL one-necked (24/40 joint) round-bottomed flask, equipped with a Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with SI-5 (4.48 g, 6 mmol, 1.0 equiv.) and dried potassium carbonate (2.76 g, 20 mmol, 3.3 equiv.). (Note: Potassium carbonate was ground and dried at 120 C. under vacuum for 18 hours.) After being evacuated and backfilled with argon from a balloon 3 times, dioxane (60 mL) was added into the flask and the reaction mixture was allowed to stir at 105 C. for 8 hours. After it was confirmed that the starting material, SI-5, was consumed through TLC analysis, the reaction was cooled to room temperature, filtered through Celite, washed with diethyl ether (200 mL), and concentrated to remove excess solvents. The crude reaction was purified through flash chromatography (hexanes:ethyl acetate, 6:1) on silica gel to afford the title compound 24, which was further purified through trituration in hexanes at 40 C. affording 1.8 g product (57% yield) with >99% purity as white solids. (Yang et al., 2021b) Trituration procedure: The product (around 2.5 g) after chromatography was dissolved in hexanes (2.0 mL) at room temperature and then cooled to 40 C. After the solution of the product was slowly stirred at 40 C. for 40 minutes, the suspension was filtered and the white solid was washed with cooled hexanes (1.0 mL) quickly and dried under vacuum for 1 hour.
##STR00029##
tert-butyl benzyl(2,3-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (24)
[0147] Physical State: white solid. m.p.: 89-91 C. .sup.1H NMR (600 MHz, CDCl.sub.3): 7.29-7.12 (m, 5H), 4.47 (brs, 2H), 2.56 (s, 1H), 2.12 (dd, J=9.5, 1.4 Hz, 1H), 2.06-1.97 (m, 3H), 1.47 (s, 9H), 1.21 (s, 12H), 1.20 (s, 12H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 140.12, 128.26, 126.92, 126.51, 83.48, 83.07, 52.68, 48.28, 28.69, 25.00, 24.95, 24.84, 24.81 ppm. Note: NC(O), NC, NCH2, Me3C and BC were not observed. .sup.11B NMR (128 MHz, CDCl.sub.3): 30.94 ppm. HRMS (ESI-TOF): calc'd for C.sub.29H.sub.46B.sub.2NO.sub.6 [M+H].sup.+: 526.3506, found: 526.3518. TLC: R.sub.f=0.68 (3:1 hexanes:ethyl acetate).
Gram-Scale Synthesis of BCP BisBoronates 25 (R.sup.1=CH.sub.2OBn)
##STR00030##
Step 1: Synthesis of SI-6
[0148] To a solution of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate, 28, (115.2 g, 400 mmol, 1.0 equiv.) in dried THF (1.0 L) was added LiAlH.sub.4 (38 g, 1.0 mmol, 2.5 equiv.) at 0 C. The mixture was allowed to warm up to room temperature and stirred for 3 hours. After it was confirmed that the start material, SI-6, was totally consumed, water (38 mL) was slowly added at 0 C., followed by 20% w.t. NaOH (38 mL) and water (95 mL), and the mixture was stirred at 0 C. for 30 min. Then excess Na.sub.2SO.sub.4 was added, and the suspended solution was stirred at room temperature for another 1 hour. The mixture was filtered through Celite and the solvent was removed under high vacuum. The crude alcohol was used without further purification. The crude yield (90% from 28) was calculated by .sup.1H NMR with dibromomethane as inner standard.
[0149] To a solution of the crude alcohol in THE/DMF (800 mL, 1:1) was added NaH (16.0 g, 400 mmol, 1.0 equiv.) slowly at 0 C. (Caution: Hydrogen was released.) After the reaction was stirred for 1 hour at room temperature, benzyl bromide (52 mL, 440 mmol, 1.1 equiv.) was added and the mixture was allowed to stir for 12 hours at room temperature. After it was confirmed that the diol intermediate was totally consumed, the reaction was quenched with water (10 mL) at 0 C. Excess solvent was removed by rotary evaporator and the mixture was diluted with water (500 mL) and diethyl ether (200 mL) and then transferred into a 1-L separation funnel. The aqueous phase was separated and extracted with two 200-mL portions of diethyl ether. The combined organic layers were washed with the mixture of 200 mL water and 200 mL saturated NaCl solution twice, dried over Na.sub.2SO.sub.4, and filtered through Celite. The crude yield (75% from 28) was calculated by .sup.1H NMR with dibromomethane as inner standard.
[0150] After solvent was removed by rotary evaporator, the crude product was redissolved in methylene chloride (1.0 L) and Dess-Martin periodinane (153.5 g, 360 mmol, 0.9 equiv.) was added to mixture at 0 C. The reaction was allowed to warm to room temperature and stir for 2 hours. After it was confirmed that the alcohol intermediate was consumed totally, the reaction was quenched by excess saturated Na.sub.2CO.sub.3 solution and Na.sub.2S.sub.2O.sub.3 solution and extracted with methylene chloride (200 mL) three times. The organic phase was separated, washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The crude aldehyde was used without further purification. The crude yield (62.5% from 28 was calculated by 1H NMR with dibromomethane as inner standard.
[0151] The aldehyde was dissolved in 100 mL methylene chloride and then p-toluenesulfonyl hydrazide (56 g, 300 mmol, 0.75 equiv.) was added. The mixture was allowed to stir at room temperature for another 1 hours. After it was confirmed that the aldehyde was consumed through TLC analysis, the crude reaction was concentrated to remove excess solvent. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 3:1) on silica gel to afford 103.0 g (60% from 28) of the title compound SI-6. Cis/trans-isomerism (1/1.8) was observed. The 1H NMR characterization of main isomer was provided.
##STR00031##
N-((1-((benzyloxy)methyl)-3,3-dimethoxycyclobutyl)methylene)-4-methylbenzenesulfono-hydrazide (SI-6)
[0152] Physical State: yellow oil. H NMR (600 MHz, CDCl.sub.3): 7.93 (s, 1H), 7.78 (d, J=8.3 Hz, 2H), 7.36-7.09 (m, 8H), 4.43 (s, 2H), 3.52 (s, 2H), 3.06 (s, 3H), 3.02 (s, 3H), 2.37 (s, 3H), 2.24 (d, J=9.0 Hz, 2H), 2.11 (d, J=13.3 Hz, 2H) ppm. HRMS (ESI-TOF): calc'd for C.sub.22H.sub.28N.sub.2O.sub.5S [M+H].sup.+: 433.1792, found: 433.1786. TLC: R.sub.f=0.23 (2:1 hexanes:ethyl acetate).
Step 2: Synthesis of SI-7
[0153] A dry round-bottom flask charged with SI-6 (103.0 g, 238 mmol, 1.0 equiv.) was degassed and filled with argon for three times. Toluene (1.0 L) was added, then 60% NaH (10.5 g, 262 mmol, 1.1 equiv.) was added in small portions and the mixture was stirred at room temperature for 1 h. A solution of B.sub.2pin.sub.2 (90 g, 357 mmol, 1.5 equiv.) was added. Then the reaction mixture was heated at 100 C. for 1 h. (Li et al., 2012). After cooling to room temperature, the suspension was filtered by Celite, and washed by diethyl ether (500 mL). After solvent was removed by rotary evaporator from the filtrate, the crude product was redissolved in 250 mL acetonitrile in a 1-L flask. 2 M H.sub.2SO.sub.4 (250 mL, 2.0 equiv.) was added into the mixture at room temperature and the reaction was allowed to stir for another 2 hours. After it was confirmed that the ketal intermediate was totally consumed, the crude reaction was concentrated to remove excess acetonitrile. Then diethyl ether (600 mL) and saturated brine (500 mL) were added to the reaction mixture and the mixture was transferred to a separatory funnel. The aqueous layer was separated and further extracted with diethyl ether (3250 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered through Celite. Excess solvent was removed by rotary evaporator.
[0154] The crude ketone was redissolved in 250 mL methylene chloride in a 500 mL-flask and mesitylene sulfonyl hydrazide (55 g, 262 mmol, 1.1 equiv.) was added. The mixture was allowed to stir at room temperature for another 3-5 hours. After it was confirmed that the ketone intermediate was consumed through TLC analysis, the crude reaction was concentrated to remove excess solvent. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 4:1) on silica gel to afford 100 g (64%) of the title compound SI-7.
##STR00032##
N-(3-((benzyloxy)methyl)-3-(bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)cyclo-butylidene)-2,4,6-trimethylbenzenesulfonohydrazide (SI-7)
[0155] Physical State: white solid. m.p.: 198-200 C. .sup.1H NMR (600 MHz, Acetone-d.sub.6) 9.02 (s, 1H), 7.36-7.30 (m, 4H), 7.29-7.23 (m, 1H), 7.00 (s, 2H), 4.50 (s, 2H), 3.35 (d, J=8.9 Hz, 1H), 3.33 (d, J=8.9 Hz, 1H), 2.88-2.81 (m, 1H), 2.81-2.77 (m, 1H), 2.74 (ddd, J=17.3, 3.1, 2.1 Hz, 1H), 2.66 (ddd, J=17.3, 3.1, 2.1 Hz, 1H), 2.63 (s, 6H), 2.27 (s, 3H), 1.15 (s, 6H), 1.15 (s, 6H), 1.14 (s, 1H), 1.12 (s, 6H), 1.11 (s, 6H) ppm. .sup.13C NMR (151 MHz, Acetone-d.sub.6) 156.62, 142.96, 140.67, 139.71, 134.90, 132.41, 129.07, 128.36, 128.17, 83.67, 83.65, 78.27, 73.50, 43.34, 42.10, 36.28, 25.20, 25.08, 24.74, 23.39, 20.84 ppm. .sup.11B NMR (128 MHz, Acetone-d.sub.6): 33.11 ppm. HRMS (ESI-TOF): calc'd for C.sub.34H.sub.50B.sub.2N.sub.2O.sub.7S [M+H].sup.+: 653.3598, found: 653.3602.
[0156] TLC: R.sub.f=0.37 (3:1 hexanes:ethyl acetate).
Step 3: Synthesis of 25
[0157] A 500-mL one-necked (24/40 joint) round-bottomed flask, equipped with a Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with SI-7 (22 g, 33 mmol, 1.0 equiv.) and dried cesium carbonate (33 g, 100 mmol, 3.0 equiv.). (Note: Cesium carbonate was dried at 120 C. under vacuum for 18 hours.) After being evacuated and backfilled with argon from a balloon 3 times, dioxane (200 mL) was added into the flask and the reaction mixture was allowed to stir at 100 C. for 2 hours. After it was confirmed that the starting material, SI-7, was consumed through TLC analysis, the reaction was cooled to room temperature, filtered through Celite, washed with hexanes (500 mL), and concentrated to remove excess solvents. The crude reaction was purified through flash chromatography (hexanes:ethyl acetate, 10:1) on silica gel to afford the title compound 25, which was further purified through trituration in hexanes at 40 C. affording 8.3 g product (56% yield) with >99% purity as white solids. (Yang et al., 2021b). Trituration procedure: The product (around 10 g) after chromatography was dissolved in hexanes (6 mL) at room temperature and then cooled to 40 C. After the solution of the product was slowly stirred at 40 C. for 30 minutes, the suspension was filtered and the white solid was washed with cooled hexanes (4 mL) quickly and dried under vacuum for 1 hour.
##STR00033##
2,2-(3-((benzyloxy)methyl)bicyclo[1.1.1]pentane-1,2-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxa-borolane) (25)
[0158] Physical State: colorless crystal. m.p.: 65-67 C. H NMR (600 MHz, CDCl.sub.3): 7.36-7.28 (m, 4H), 7.24 (dd, J=8.2, 5.9 Hz, 1H), 4.52 (s, 2H), 3.38 (d, J=11.0, 1H), 3.36 (d, J=11.0, 1H), 2.38 (dd, J=9.7, 2.3 Hz, 1H), 1.93 (dd, J=9.7, 1.5 Hz, 1H), 1.88 (s, 1H), 1.82 (dd, J=8.3, 2.3 Hz, 1H), 1.67 (d, J=8.2 Hz, 1H), 1.23 (s, 12H), 1.20 (s, 6H), 1.19 (s, 6H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 139.14, 128.32, 127.55, 127.37, 83.35, 82.91, 72.88, 71.28, 54.69, 49.02, 46.50, 24.99, 24.90, 24.87, 24.84 ppm. .sup.11B NMR (128 MHz, CDCl.sub.3): 31.92 ppm. MS (GCMS, EI): m/z=425 (0.1%), 349 (0.2%), 325 (0.2%), 249 (5%), 91 (100%). TLC: R.sub.f=0.54 (5:1 hexanes:ethyl acetate).
Gram-Scale Synthesis of BCP BisBoronates 14 (R.SUP.1.=Me)
##STR00034##
Step 1: Synthesis of SI-9
[0159] To a solution of methyl 3,3-dimethoxy-1-methyl-cyclobutanecarboxylate, SI-8, (10.8 g, 57 mmol, 1.0 equiv.) in diethyl ether (160 mL) was added LiAlH.sub.4 (3.3 g, 85.5 mmol, 1.5 equiv.) at 0 C. The mixture was allowed to warm up to room temperature. After it was confirmed that the start material, SI-8, was totally consumed, water (3.3 mL) was slowly added at 0 C., followed by 20% w.t. NaOH (3.3 mL) and water (10 mL), and the mixture was stirred at 0 C. for 30 min. Then excess Na.sub.2SO.sub.4 was added, and the suspended solution was stirred at room temperature for another 1 hour. The mixture was filtered through Celite, and the solvent was removed under high vacuum. The crude alcohol was used without further purification.
[0160] To a solution of the crude alcohol in methylene chloride (250 mL) was added Dess-Martin periodinane (25 g, 60 mmol, 1.05 equiv.) at 0 C. and the reaction mixture was allowed to warm to room temperature and stir for 2 hours. Then the reaction was quenched by excess saturated Na.sub.2CO.sub.3 solution and Na.sub.2S.sub.2O.sub.3 solution and extracted with methylene chloride (100 mL) three times. The organic phase was separated, washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The crude aldehyde was used without further purification.
[0161] The aldehyde was dissolved in methylene chloride (60 mL) and then p-toluenesulfonyl hydrazide (11.2 g, 60 mmol, 1.05 equiv.) was added. The mixture was allowed to stir at room temperature for another 1 hour. After it was confirmed that the aldehyde was consumed through TLC analysis, the crude reaction was concentrated to remove excess solvent. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 3:1) on silica gel to afford 14.7 g (79%) of the title compound SI-9. Spectroscopic data of the product SI-9 matches that reported in the literature. (Yang et al., 2021b).
Step 2: Synthesis of SI-10
[0162] A dry round-bottom flask charged with SI-9 (14.7 g, 45 mmol, 1.0 equiv.), 60% NaH (2.2 g, 54 mmol, 1.2 equiv.) was degassed and filled with argon three times. Toluene (200 mL) was added, and the mixture was stirred at room temperature for 1 h. A solution of B.sub.2pin.sub.2 (17.0 g, 67 mmol, 1.5 equiv.) in toluene (50 mL) was added via syringe. Then the tube was sealed and heated at 100 C. for 1 h..sup.4 After cooling to room temperature, the suspension was filtered by Celite, and washed by diethyl ether (200 mL). After solvent was removed by rotary evaporator from the filtrate, the crude product was redissolved in 45 mL acetonitrile in a 100-mL flask. 2M H.sub.2SO.sub.4 (45 mL, 2.0 equiv.) was added into the mixture at room temperature and the reaction was allowed to stir for another 2 hours. After it was confirmed that the ketal intermediate was totally consumed, the crude reaction was concentrated to remove excess acetonitrile. Then diethyl ether (150 mL) and saturated brine (150 mL) were added to the reaction mixture and the mixture was transferred to a separatory funnel. The aqueous layer was separated and further extracted with diethyl ether (350 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered through Celite. Excess solvent was removed by rotary evaporator.
[0163] The crude ketone was redissolved in 50 mL methylene chloride in a 100 mL-flask and mesitylene sulfonyl hydrazide (10.7 g, 50 mmol, 1.1 equiv.) was added. The mixture was allowed to stir at room temperature for another 3-5 hours. After it was confirmed that the ketone intermediate was consumed through TLC analysis, the crude reaction was concentrated to remove excess solvent. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 4:1) on silica gel to afford 14.5 g (59%) of the title compound SI-10.
##STR00035##
N-(3-(bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-3-methylcyclobutylidene)-2,4,6-trimethylbenzenesulfonohydrazide (SI-10)
[0164] Physical State: white solid. m.p.: 111-113 C. .sup.1H NMR (600 MHz, Acetone-d.sup.6): 8.93 (s, 1H), 7.01 (s, 2H), 2.85 (dd, J=18.1, 3.3 Hz, 1H), 2.80 (dd, J=16.5, 2.2 Hz, 1H), 2.63 (s, 6H), 2.53 (dt, J=17.1, 2.9 Hz, 1H), 2.43 (dt, J=16.5, 3.0 Hz, 1H), 2.28 (s, 3H), 1.23 (s, 3H), 1.18 (s, 6H), 1.18 (s, 6H), 1.16 (s, 6H), 1.16 (s, 6H), 0.93 (s, 1H) ppm. .sup.13C NMR (151 MHz, Acetone-d.sup.6): 156.80, 143.01, 140.69, 134.87, 132.42, 83.62, 83.61, 48.06, 46.69, 32.54, 30.04, 25.20, 25.12, 24.80, 24.79, 23.38, 20.86 ppm. .sup.11B NMR (128 MHz, Acetone-d.sup.6): S 32.87 ppm. HRMS (ESI-TOF): calc'd for C.sub.27H.sub.44B.sub.2N.sub.2O.sub.6S [M+H].sup.+: 547.3179, found: 547.3177. TLC: R.sub.f=0.40 (3:1 hexanes:ethyl acetate).
Step 3: Synthesis of 14
[0165] A 500-mL one-necked (24/40 joint) round-bottomed flask, equipped with a Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with SI-10 (14.5 g, 26.5 mmol, 1.0 equiv.) and dried cesium carbonate (25.4 g, 78 mmol, 3.0 equiv.). (Note: Cesium carbonate was dried at 120 C. under vacuum for 18 hours.) After being evacuated and backfilled with argon from a balloon 3 times, dioxane (250 mL) was added into the flask and the reaction mixture was allowed to stir at 100 C. for 2 hours. After it was confirmed that the starting material, SI-10, was consumed through TLC analysis, the reaction was cooled to room temperature, filtered through Celite, washed with hexanes (500 mL), and concentrated to remove excess solvents. The crude reaction was purified through flash chromatography (hexanes:ethyl acetate, 30:1) on silica gel to afford the title compound 14, which was further purified through trituration in hexanes at 40 C. affording 4.5 g product (51% yield) with >99% purity as white solids. (Yang et al., 2021b) Trituration procedure: The product (around 6 g) after chromatography was dissolved in hexanes (5 mL) at room temperature and then cooled to 40 C. After the solution of the product was slowly stirred at 40 C. for 40 minutes, the suspension was filtered and the white solid was washed with cooled hexanes (3 mL) quickly and dried under vacuum for 1 hour. Spectroscopic data of the product 14 matches that reported in the literature. (Yang et al., 2021b)
Gram-Scale Synthesis of BCP BisBoronates 26 (R.sup.1CF.sub.3)
##STR00036##
Step 1: Synthesis of SI-12
[0166] A 500-mL round-bottomed flask, equipped with a Teflon-coated magnetic stir bar, was added SI-11 (22.8 g, 200 mmol, 1.0 equiv.) and TsOH.Math.H.sub.2O (760 mg, 4.0 mmol, 0.02 equiv.). Then EtOH (600 mL) and HC(OEt).sub.3 (67 mL, 400 mmol, 2.0 equiv.) were added, and the reaction mixture was refluxed at 90 C. for 12 h. The reaction was cooled to room temperature and concentrated under vacuum. The residue was purified through flash chromatography (hexanes:ethyl acetate, 10:1) on silica gel to afford 41.9 g (97%) of the title compound SI-12.
##STR00037##
ethyl 3,3-diethoxycyclobutane-1-carboxylate (SI-12)
[0167] Physical State: colorless oil. .sup.1H NMR (600 MHz, CDCl.sub.3): 4.14 (q, J=7.2 Hz, 2H), 3.46-3.37 (m, 4H), 2.88 (p, J=8.6 Hz, 1H), 2.48-2.35 (m, 4H), 1.24 (d, J=7.3 Hz, 3H), 1.20-1.16 (m, 6H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 175.06, 99.29, 60.75, 56.87, 56.59, 36.49, 29.40, 15.48, 15.30, 14.35 ppm. MS (GCMS, EI): m/z=205 (6%), 176 (8%), 131 (8%), 91 (100%), 65 (14%). TLC: R.sub.f=0.28 (10:1 hexanes:ethyl acetate).
Step 2: Synthesis of SI-13
[0168] A flame-dried 1-L flask equipped with rubber septum and magnetic stirring bar was charged under Ar atmosphere subsequently with diisopropylamine (27.7 mL, 198 mmol, 1.1 equiv.) and anhydrous THF (500 mL). To this well-stirred solution held at 78 C. was added within 20 minutes via a dropping funnel a solution of n-BuLi (86.4 mL, 2.5M in hexanes, 1.2 equiv.). The resulting solution was stirred at this temperature for 30 minutes. A solution of the SI-12 (38.9 g, 180 mmol, 1.0 equiv.) in anhydrous THF (100 mL) was slowly introduced dropwise via a dropping funnel within 20 minutes. After stirring at 78 C. for 2 h, neat trimethylchlorosilane (39 mL; 306 mmol; 1.7 equiv.) was introduced at once. The resultant reaction mixture was allowed to gradually warm up to room temperature and stir overnight. The turbid solution was concentrated in vacuo in the reaction flask. To the remaining white slurry hexane (200 mL) was introduced and the mixture was cooled to 0 C. The resulting suspension was poured into ice water and hexanes, and extracted with hexanes. The combined organic solution was dried with Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by distillation to afford the desired trimethylsilylketene acetal 43 g (83%) as colorless oil.
[0169] In a flame-dried 2-L flask equipped with rubber septum and magnetic stirring bar, trimethylsilyl ketene acetal (34.6 g, 120 mmol, 1.0 equiv.) was added under Ar. Then anhydrous methylene chloride (1.3 L) was added, and the reaction mixture was cooled to 78 C. (dry ice/acetone bath). TMSNTf.sub.2 (424 mg; 1.2 mmol; 0.01 equiv) was added via a syringe at once. To the resulting well-stirred solution was added solid 1-trifluoromethyl-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole (39.6 g, 120 mmol, 1.0 equiv). The mixture was allowed to reach room temperature with stirring for 4 h. NaHCO.sub.3 (50 mL) aqueous solution was added. The organic phase was separated and dried by Na.sub.2SO.sub.4. The solvent was concentrated, and the residue was purified through flash chromatography (hexanes:ethyl acetate, 10:1) on silica gel to afford 24.2 g (71%) of the title compound SI-13. (Katayev et al., 2015)
##STR00038##
ethyl 3,3-diethoxy-1-(trifluoromethyl)cyclobutane-1-carboxylate (SI-13)
[0170] Physical State: colorless oil. .sup.1H NMR (600 MHz, CDCl.sub.3): 4.26 (q, J=7.1 Hz, 2H), 3.40 (q, J=7.1 Hz, 2H), 3.40 (q, J=7.1 Hz, 2H), 2.83-2.72 (m, 2H), 2.61-2.52 (m, 2H), 1.30 (t, J=7.1 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 168.86, 125.22 (q, J=279.5 Hz), 97.02, 62.26, 56.91, 56.82, 44.13 (q, J=30.1 Hz), 38.07, 15.11, 15.06, 13.96 ppm. .sup.19F NMR (565 MHz, CDCl.sub.3): 73.10 ppm. MS (GCMS, EI): m/z=239 (30%), 211 (30%), 183 (48%), 116 (65%), 89 (100%). TLC: R.sub.f=0.59 (10:1 hexanes:ethyl acetate).
Step 3: Synthesis of SI-14
[0171] A 1-L one-necked (24/40 joint) round-bottomed flask, equipped with a 6.4 cm Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with SI-13 (20.2 g, 71 mmol, 1.0 equiv.). Dried THF (400 mL) was added into the flask and the mixture was cooled to 0 C. Then LiAlH.sub.4 (2.7 g, 71 mmol, 1.0 equiv.) was added into the flask slowly at 0 C. and the reaction mixture was allowed to stir at 0 C. for 1 hour. After it was confirmed that the start material, SI-13, was totally consumed, water (2.7 mL) was slowly added at 0 C., followed by 20% w.t. NaOH (2.7 ml) and water (8.0 mL), and the mixture was stirred at 0 C. for 30 min. Then excess Na.sub.2SO.sub.4 was added, and the suspended solution was stirred at room temperature for another 1 hour. The mixture was filtered through Celite, and the solvent was removed under high vacuum. The crude alcohol was used without further purification.
[0172] To a solution of the crude alcohol in methylene chloride (280 mL) was added Dess-Martin periodinane (42.4 g, 100 mmol, 1.4 equiv.) at 0 C. and the reaction mixture was allowed to warm to room temperature and stir for 2 hours. Then the reaction was quenched by excess saturated NaHCO.sub.3 solution and Na.sub.2S.sub.2O.sub.3 solution and extracted with methylene chloride (100 mL) three times. The organic phase was separated, washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 10:1) on silica gel to afford 13.0 g (80%) of the title compound SI-14.
##STR00039##
3,3-diethoxy-1-(trifluoromethyl)cyclobutane-1-carbaldehyde (SI-14)
[0173] Physical State: colorless oil. .sup.1H NMR (600 MHz, CDCl.sub.3): 9.73 (s, 1H), 3.44-3.39 (m, 2H), 3.40-3.36 (m, 2H), 2.67-2.62 (m, 2H), 2.50 (dt, J=11.5, 1.6 Hz, 2H), 1.19 (tt, J=7.1, 1.1 Hz, 3H), 1.15 (tt, J=7.1, 1.2 Hz, 3H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 193.87, 125.64 (q, J=279.3 Hz), 96.55, 56.95, 56.86, 47.30 (q, J=27.8 Hz), 34.98, 15.13 ppm. .sup.19F NMR (565 MHz, CDCl.sub.3): 72.10 ppm. MS (GCMS, EI): m/z=211 (48%), 195 (51%), 167 (40%), 135 (80%), 115 (100%). TLC: R.sub.f=0.53 (10:1 hexanes:ethyl acetate).
Step 4: Synthesis of SI-15
[0174] A 250-mL one-necked (24/40 joint) round-bottomed flask, equipped with a Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with triphenyl phosphite (21 mL, 80 mmol, 1.5 equiv.). Methylene chloride (50 mL) was added into the flask and the mixture was cooled to 78 C. Then bromine (4 mL, 78 mmol, 1.4 equiv.) was added slowly into the flask, followed by addition of triethyl amine (23 mL, 162 mmol, 3.0 equiv.). Next, the solution of SI-14 (13.0 g, 54 mmol, 1.0 equiv.) in 40 mL methylene chloride was added into the mixture and the reaction was warmed up to room temperature. After it was confirmed that the starting material, SI-14, was consumed through TLC analysis, solvent was removed by rotary evaporator and the crude product was purified through flash chromatography (hexanes:ethyl acetate, 20:1) on silica gel to afford 8.6 g (43%) of the title compound SI-15. (Hazrati & Oestreich, 2018)
##STR00040##
1-(dibromomethyl)-3,3-diethoxy-1-(trifluoromethyl)cyclobutane (SI-15)
[0175] Physical State: colorless oil. .sup.1H NMR (600 MHz, CDCl.sub.3): 5.96 (s, 1H), 3.43 (q, J=7.1 Hz, 2H), 3.40 (q, J=7.1 Hz, 2H), 2.66-2.59 (m, 2H), 2.42-2.36 (m, 2H), 1.22 (t, J=7.1 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 126.09 (q, J=281.8 Hz), 95.57, 57.10, 56.88, 45.76, 45.48 (q, J=27.8 Hz), 39.60 (q, J=2.3 Hz), 15.40, 15.17 ppm. .sup.19F NMR (565 MHz, CDCl.sub.3): 68.99 ppm. MS (GCMS, EI): m/z=341 (5%), 339 (10%), 337 (5%), 311 (9%), 211 (30%), 116 (100%). TLC: R.sub.f=0.69 (10:1 hexanes:ethyl acetate).
Step 5: Synthesis of SI-16
[0176] A 250-mL one-necked (24/40 joint) round-bottomed flask, equipped with a Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with copper(I) iodide (437 mg, 2.3 mmol, 0.1 equiv.), B.sub.2pin.sub.2 (12.9 g, 51 mmol, 2.2 equiv.), and lithium tert-butoxide (4.4 g, 55 mmol, 2.4 equiv.). After being evacuated and backfilled with argon from a balloon 3 times, DMF (23 mL) was added into the flask at 0 C. Then a solution of SI-15 (23 mmol, 8.6 g, 1.0 equiv.) in DMF (46 mL) was added slowly into the mixture at 0 C. and the reaction mixture was allowed to slowly warm to room temperature and stir for another 1 hour. After it was confirmed that the starting material, SI-15, was consumed through TLC analysis, the reaction was filtered through Celite, washed with diethyl ether (100 mL) and quenched at 0 C. with water (300 mL) (Caution: the quenching process is exothermic). The mixture was then transferred into a 1-L separation funnel. The aqueous phase was separated and extracted with two 100-mL portions of diethyl ether. The combined organic layers were washed with the mixture of 100 mL water and 100 mL saturated NaCl solution twice, dried over Na.sub.2SO.sub.4, and filtered through Celite. (Yang et al., 2011)
[0177] After solvent was removed by rotary evaporator, the crude product was redissolved in 23 mL acetonitrile in a 100-mL flask. 2M H.sub.2SO.sub.4 (23 mL, 2.0 equiv.) was added into the mixture at room temperature and the reaction was allowed to stir for another 1.5 hours. After it was confirmed that the ketal intermediate was consumed through TLC analysis, the crude reaction is concentrated to remove excess acetonitrile. Then diethyl ether (100 mL) and saturated brine (50 mL) were added to the reaction mixture and the mixture was transferred to a 125-mL separatory funnel. The aqueous layer was separated and further extracted with diethyl ether (350 mL). The combined organic layers are dried over Na.sub.2SO.sub.4, filtered through Celite. Excess solvent was removed by rotary evaporator.
[0178] The crude product was redissolved in 20 mL methylene chloride in a 100 mL-flask and mesitylene sulfonyl hydrazide (4.93 g, 23 mmol, 1.0 equiv.) was added. The mixture was allowed to stir at room temperature for another 2 hours. After it was confirmed that the ketone intermediate was consumed through TLC analysis, the crude reaction was concentrated to remove excess solvent. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 4:1) on silica gel to afford 9.8 g (71%) of the title compound SI-16.
##STR00041##
N-(3-(bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-3-(trifluoromethyl)cyclobutyl idene)-2,4,6-trimethylbenzenesulfonohydrazide (SI-16)
[0179] Physical State: white solid. m.p.: 186-188 C. .sup.1H NMR (600 MHz, Acetone-d.sub.6): 9.34 (s, 1H), 7.03 (s, 2H), 3.22 (dd, J=18.1, 3.3 Hz, 1H), 3.11 (dd, J=17.6, 3.2 Hz, 1H), 3.06 (ddd, J=18.2, 3.3, 1.9 Hz, 1H), 3.00 (ddd, J=17.7, 3.3, 1.9 Hz, 1H), 2.64 (s, 6H), 2.29 (s, 3H), 1.28 (s, 1H), 1.19 (s, 6H), 1.18 (s, 6H), 1.17 (s, 6H), 1.14 (s, 6H) ppm. .sup.13C NMR (151 MHz, Acetone-d.sub.6) 151.49, 143.20, 140.78, 134.71, 132.49, 130.17 (q, J=279.7 Hz), 84.32, 84.28, 41.54 (q, J=2.8 Hz), 40.49 (q, J=2.7 Hz), 39.96 (q, J=27.4 Hz), 25.17, 24.98, 24.66, 24.64, 23.40, 20.85 ppm. .sup.19F NMR (565 MHz, Acetone-d.sub.6): 78.92 ppm. .sup.11B NMR (128 MHz, Acetone-d.sub.6): 32.51 ppm. HRMS (ESI-TOF): calc'd for C.sub.27H.sub.41B.sub.2F.sub.3N.sub.2O.sub.6S [M+H].sup.+: 601.2896, found: 601.2903. TLC: R.sub.f=0.47 (10:1 hexanes:ethyl acetate).
Step 6: Synthesis of 26
[0180] A 250-mL one-necked (24/40 joint) round-bottomed flask, equipped with a Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with SI-16 (6.0 g, 10 mmol, 1.0 equiv.) and dried potassium carbonate (4.14 g, 30 mmol, 3.0 equiv.). (Note: Potassium carbonate was dried at 120 C. under vacuum for 18 hours.) After being evacuated and backfilled with argon from a balloon 3 times, dioxane (60 mL) was added into the flask and the reaction mixture was allowed to stir at 105 C. for 2 hours. After it was confirmed that the starting material, SI-16, was consumed through TLC analysis, the reaction was cooled to room temperature, filtered through Celite, washed with hexanes (200 mL), and concentrated to remove excess solvents. The crude reaction was purified through flash chromatography (hexanes:ethyl acetate, 20:1) on silica gel to afford the title compound 26, which was further purified through trituration in hexanes at 40 C. affording 2.2 g product (57% yield) with >99% purity as white solids. (Yang et al., 2021b) Trituration procedure: The product (around 3 g) after chromatography was dissolved in hexanes (2.0 mL) at room temperature and then cooled to 40 C. After the solution of the product was slowly stirred at 40 C. for 40 minutes, the suspension was filtered and the white solid was washed with cooled hexanes (1.0 mL) quickly and dried under vacuum for 1 hour.
##STR00042##
2,2-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1,2-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxa-borolane) (26)
[0181] Physical State: white solid. m.p.: 49-51 C. .sup.1H NMR (600 MHz, CDCl.sub.3): 2.68 (dd, J=9.6, 2.3 Hz, 1H), 2.07 (dd, J=9.6, 1.7 Hz, 1H), 2.02 (d, J=1.7 Hz, 1H), 1.96 (dd, J=8.2, 2.3 Hz, 1H), 1.84 (d, J=8.1 Hz, 1H), 1.25-1.18 (m, 24H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 121.70 (q, J=278.4 Hz), 83.82, 83.44, 53.05 (q, J=2.7 Hz), 47.47 (q, J=2.4 Hz), 43.37 (q, J=36.9 Hz), 24.88, 24.85, 24.81, 24.73 ppm. .sup.19F NMR (376 MHz, CDCl.sub.3): 74.97 ppm. .sup.11B NMR (128 MHz, CDCl.sub.3): 30.96 ppm. MS (GCMS, EI): m/z=387 (0.1%), 373 (0.4%), 288 (1%), 231 (5%), 131 (15%), 83 (100%). TLC: R.sub.f=0.28 (15:1 hexanes:ethyl acetate).
Gram-Scale Synthesis of BCP BisBoronates 27 (R.SUP.1.=4-MeOPh)
##STR00043##
[0182] Compound SI-17 was prepared according to previous literate. (JosienJohn et al., 2010)
Step 1: Synthesis of SI-18
[0183] A 500-mL round-bottomed flask, equipped with a Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with compound SI-17 (12.5 g, 50 mmol, 1.0 equiv.). Then methylene chloride (200 mL) was added and the reaction mixture was cooled to 0 C. Next, DIBAL-H (65 mL, 1.0 M, 1.3 equiv.) was added at 0 C. and the mixture was stirred at 0 C. for 3 hours. The cool mixture was added under vigorous stirring to saturated Rochelle salt solution at 0 C. and stirred overnight. The organic phase was separated, washed with brine, dried over Na.sub.2SO.sub.4 and evaporated. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 4:1) on silica gel to afford 7.1 g (57%) of the title compound SI-18.
##STR00044##
3,3-dimethoxy-1-(4-methoxyphenyl)cyclobutane-1-carbaldehyde (SI-18)
[0184] Physical State: white solid. m.p.: 56-58 C. .sup.1H NMR (600 MHz, CDCl.sub.3): 9.49 (s, 1H), 7.11-7.06 (m, 2H), 6.94-6.87 (m, 2H), 3.80 (s, 3H), 3.17 (s, 3H), 3.14 (s, 3H), 3.02-2.96 (m, 2H), 2.48-2.42 (m, 2H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 198.24, 158.95, 131.30, 128.25, 114.49, 98.60, 55.45, 48.77, 48.68, 48.21, 38.95 ppm. HRMS (ESI-TOF): calc'd for C.sub.14H.sub.18O.sub.4 [M+H].sup.+: 251.1278, found: 251.1278. TLC: R.sub.f=0.17 (10:1 hexanes:ethyl acetate).
Step 2: Synthesis of SI-19
[0185] A 250-mL one-necked (24/40 joint) round-bottomed flask, equipped with a Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with triphenyl phosphite (5.8 mL, 22 mmol, 1.1 equiv.). Methylene chloride (25 mL) was added into the flask and the mixture was cooled to 78 C. Then bromine (1.1 mL, 22 mmol, 1.1 equiv.) was added slowly into the flask, followed by addition of triethyl amine (8.4 mL, 60 mmol, 3.0 equiv.). Next, the solution of SI-18 (5.0 g, 20 mmol, 1.0 equiv.) in 25 mL methylene chloride was added into the mixture and the reaction was warmed up to room temperature. After it was confirmed that the starting material, SI-18, was consumed through TLC analysis, solvent was removed by rotary evaporator and the crude product was purified through flash chromatography (hexanes:ethyl acetate, 20:1) on silica gel to afford 2.31 g (29%) of the title compound SI-19. (Hazrati & Oestreich, 2018).
##STR00045##
1-(1-(dibromomethyl)-3,3-dimethoxycyclobutyl)-4-methoxybenzene (SI-19)
[0186] Physical State: white solid. m.p.: 59-61 C. .sup.1H NMR (600 MHz, CDCl.sub.3): 7.33-7.26 (m, 2H), 6.92-6.86 (m, 2H), 6.22 (s, 1H), 3.82 (s, 3H), 3.22 (s, 3H), 3.10 (s, 3H), 2.71-2.60 (m, 4H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 158.79, 133.80, 130.48, 112.67, 97.64, 58.64, 55.36, 48.81, 48.65, 45.40, 43.67 ppm. HRMS (ESI-TOF): calc'd for C.sub.14H.sub.18Br.sub.2O.sub.3[M+Na].sup.+: 414.9515, found: 414.9508. TLC: R.sub.f=0.45 (10:1 hexanes:ethyl acetate).
Step 3: Synthesis of SI-20
[0187] A 100-mL one-necked (24/40 joint) round-bottomed flask, equipped with a Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with copper(I) iodide (114 mg, 0.6 mmol, 0.1 equiv.), B.sub.2pin.sub.2 (3.7 g, 14.5 mmol, 2.5 equiv.), and lithium tert-butoxide (1.16 g, 14.5 mmol, 2.5 equiv.). After being evacuated and backfilled with argon from a balloon 3 times, DMF (5 mL) was added into the flask at 0 C. Then a solution of ST-19 (5.8 mmol, 2.3 g, 1.0 equiv.) in DMF (10 mL) was added slowly into the mixture at 0 C. and the reaction mixture was allowed to slowly warm to room temperature and stir for another 1 hour. After it was confirmed that the starting material, SI-19, was consumed through TLC analysis, the reaction was filtered through Celite, washed with diethyl ether (50 mL) and quenched at 0 C. with water (100 mL) (Caution: the quenching process is exothermic). The mixture was then transferred into a 3-L separation funnel. The aqueous phase was separated and extracted with two 50-mL portions of diethyl ether. The combined organic layers were washed with the mixture of 50 mL water and 50 mL saturated NaCl solution twice, dried over Na.sub.2SO.sub.4, and filtered through Celite. (Yang et al., 2011)
[0188] After solvent was removed by rotary evaporator, the crude product was redissolved in 10 mL acetonitrile in a 50-mL flask. 2M H.sub.2SO.sub.4 (6 mL, 2.0 equiv.) was added into the mixture at room temperature and the reaction was allowed to stir for another 1.5 hours. After it was confirmed that the ketal intermediate was consumed through TLC analysis, the crude reaction was concentrated to remove excess acetonitrile. Then diethyl ether (40 mL) and saturated brine (15 mL) were added to the reaction mixture and the mixture was transferred to a 125-mL separatory funnel. The aqueous layer was separated and further extracted with diethyl ether (330 mL). The combined organic layers are dried over Na.sub.2SO.sub.4, filtered through Celite. Excess solvent was removed by rotary evaporator.
[0189] The crude product was redissolved in 20 mL methylene chloride in a 50 mL-flask and mesitylene sulfonyl hydrazide (1.24 g, 5.8 mmol, 1.0 equiv.) was added. The mixture was allowed to stir at room temperature for another 2 hours. After it was confirmed that the ketone intermediate was consumed through TLC analysis, the crude reaction was concentrated to remove excess solvent. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 4:1 to 2:1) on silica gel to afford 2.72 g (73%) of the title compound SI-20.
##STR00046##
N-(3-(bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-3-(4-methoxyphenyl)cyclo-butylidene)-2,4,6-trimethylbenzenesulfonohydrazide (SI-20)
[0190] Physical State: white solid. m.p.: 155-157 C. .sup.1H NMR (600 MHz, Acetone-d.sub.6) 9.04 (s, 1H), 7.24 (d, J=8.8 Hz, 2H), 6.98 (s, 2H), 6.89-6.64 (m, 2H), 3.74 (s, 3H), 3.40 (ddd, J=17.8, 3.4, 1.9 Hz, 1H), 3.32 (ddd, J=17.1, 3.4, 1.9 Hz, 1H), 3.16 (ddd, J=17.7, 3.5, 1.6 Hz, 1H), 3.09 (ddd, J=17.0, 3.5, 1.6 Hz, 1H), 2.63 (s, 6H), 2.26 (s, 3H), 1.31 (s, 1H), 1.11 (s, 12H), 1.10 (s, 12H) ppm. .sup.13C NMR (151 MHz, Acetone-d.sub.6) 158.50, 156.01, 143.72, 142.96, 140.72, 134.91, 132.40, 128.11, 113.93, 83.78, 83.71, 55.41, 47.78, 46.24, 46.21, 39.47, 25.21, 25.03, 24.88, 24.84, 23.44, 20.84 ppm. .sup.11B NMR (128 MHz, Acetone-d.sub.6): 32.77 ppm. HRMS (ESI-TOF): calc'd for C.sub.33H.sub.48B.sub.2N.sub.2O.sub.7S [M+H].sup.+: 639.3441, found: 639.3447. TLC: R.sub.f=0.30 (3:1 hexanes:ethyl acetate).
Step 4: Synthesis of 27
[0191] A 100-mL one-necked (24/40 joint) round-bottomed flask, equipped with a Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with SI-20 (2.7 g, 4.2 mmol, 1.0 equiv.) and dried cesium carbonate (4.1 g, 12.6 mmol, 3.0 equiv.). (Note: Cesium carbonate was dried at 120 C. under vacuum for 18 hours.) After being evacuated and backfilled with argon from a balloon 3 times, dioxane (40 mL) was added into the flask and the reaction mixture was allowed to stir at 100 C. for 40 minutes. After it was confirmed that the starting material, SI-20, was consumed through TLC analysis, the reaction was cooled to room temperature, filtered through Celite, washed with hexanes (200 mL), and concentrated to remove excess solvents. The crude reaction was purified through flash chromatography (hexanes:ethyl acetate, 20:1) on silica gel to afford the title compound 27, which was further purified through trituration in hexanes at 20 C. affording 1.05 g product (59% yield) with >99% purity as white solids. (Yang et al., 2021b)
##STR00047##
2,2-(3-(4-methoxyphenyl)bicyclo[1.1.1]pentane-1,2-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (27)
[0192] Physical State: white solid. m.p.: 89-91 C. .sup.1H NMR (600 MHz, CDCl.sub.3): 7.22-7.17 (m, 2H), 6.85-6.78 (m, 2H), 3.77 (s, 3H), 2.73 (dd, J=9.7, 2.2 Hz, 1H), 2.17 (dd, J=9.7, 1.5 Hz, 1H), 2.15-2.12 (m, 1H), 2.04 (dd, J=8.2, 2.2 Hz, 1H), 1.93 (dd, J=8.2, 0.9 Hz, 1H), 1.25 (d, J=1.3 Hz, 12H), 1.24 (s, 6H), 1.23 (s, 6H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3) 158.23, 135.32, 127.21, 113.47, 83.41, 83.05, 56.34, 55.40, 51.87, 49.01, 25.02, 24.92, 24.91, 24.87 ppm. .sup.11B NMR (128 MHz, CDCl.sub.3): 32.00 ppm. HRMS (ESI-TOF): calc'd for C.sub.24H.sub.36B.sub.2O.sub.5 [M+H].sup.+: 427.2822, found: 427.2819. TLC: R.sub.f=0.43 (5:1 hexanes:ethyl acetate).
B. X-ray Crystallographic Data for BCP BisBpin Compounds 16, 23-25, 27
Compound 16 (See FIG. 6A)
TABLE-US-00001 TABLE 1 Crystal data and structure refinement for compound 16. CCDC reference number: 2158998. Empirical formula C22 H28 B2 N2 O2 Formula weight 374.08 Temperature 100.01(11) K Wavelength 1.54184 Crystal system monoclinic Space group P 1 21/c 1 Unit cell dimensions a = 9.47573(16) a = 90. b = 10.73100(19) b = 99.0998(15). c = 20.9064(3) g = 90. Volume 2099.09(6) 3 Z 4 Density (calculated) 1.184 Mg/m3 Absorption coefficient 0.578 mm 1 F(000) 800 Crystal size 0.41 0.25 0.14 mm3 Theta range for data collection 4.283 to 73.370. Index ranges 11 <= h <= 11, 13 <= k <= 13, 25 <= 1 <= 25 Reflections collected 11994 Independent reflections 4105 [R(int) = 0.0246] Completeness to theta = 67.684 99.6% Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.00000 and 0.88926 Refinement method Full-matrix least-squares on F2 Data/restraints/parameters 4105/39/353 Goodness-of-fit on F2 1.099 Final R indices [I > 2sigma(I)] R1 = 0.0488, wR2 = 0.1287 R indices (all data) R1 = 0.0522, wR2 = 0.1316 Extinction coefficient n/a Largest diff. peak and hole 0.277 and 0.248 e .Math. 3
TABLE-US-00002 TABLE 2 Atomic coordinates (10.sup.4) and equivalent isotropic displacement parameters (.sup.2 10.sup.3) for 1. U(eq) is defined as one third of the trace of the orthogonalized U.sup.ij tensor. x y z U(eq) N1 2334(1) 6798(1) 2618(1) 23(1) N2 560(1) 8336(1) 2763(1) 25(1) C1 1666(1) 6538(1) 1991(1) 22(1) C2 2192(2) 5657(1) 1607(1) 28(1) C3 1505(2) 5457(2) 968(1) 32(1) C4 311(2) 6112(2) 719(1) 29(1) C5 283(2) 7006(1) 1099(1) 25(1) C6 1535(2) 7689(1) 860(1) 30(1) C7 2060(2) 8547(2) 1246(1) 33(1) C8 1374(2) 8783(1) 1882(1) 30(1) C9 160(2) 8134(1) 2133(1) 23(1) C10 406(1) 7222(1) 1746(1) 22(1) C11 2660(1) 7938(1) 3721(1) 23(1) C15 3693(2) 8174(1) 4573(1) 27(1) C16 4506(2) 8338(2) 5246(1) 41(1) C17 6497(2) 5607(2) 3277(1) 37(1) C18 7402(2) 5924(1) 3944(1) 29(1) B2 1829(2) 7697(2) 3025(1) 23(1) O1 5191(9) 6303(6) 3308(4) 26(1) O2 6758(2) 7065(2) 4149(1) 30(1) C12 2818(3) 6979(2) 4288(1) 30(1) C13 2423(3) 8934(3) 4240(1) 32(1) C14 4316(2) 8186(2) 3929(1) 27(1) C19 7124(8) 6387(5) 2732(3) 65(2) C20 6278(6) 4340(6) 3089(2) 47(1) C21 8986(3) 6138(3) 3970(2) 50(1) C22 7186(3) 4929(3) 4438(1) 40(1) B1 5435(3) 7166(3) 3798(1) 27(1) O1A 5047(16) 6002(11) 3356(7) 44(3) O2A 6354(3) 6356(4) 4335(2) 40(1) C12A 3697(4) 7014(3) 4173(2) 18(1) C13A 3818(4) 8958(3) 3920(2) 22(1) C14A 2046(4) 8307(5) 4353(2) 26(1) C23 8259(7) 7089(6) 3832(3) 61(2) C24 8383(7) 4979(6) 4307(3) 62(2) B3 5069(4) 6491(4) 3947(2) 18(1) C20A 6059(13) 4088(11) 3318(6) 75(3) C19A 7037(9) 5785(9) 2692(5) 62(2)
TABLE-US-00003 TABLE 3 Crystal data and structure refinement for compound 23. CCDC reference number: 2158994. Empirical formula C21 H36 B2 O6 Formula weight 406.12 Temperature 100.04(15) K Wavelength 1.54184 Crystal system monoclinic Space group C 1 c 1 Unit cell dimensions a = 9.8439(9) a = 90. b = 16.3337(19) b = 90.304(8). c = 14.8019(9) g = 90. Volume 2379.9(4) 3 Z 4 Density (calculated) 1.133 Mg/m3 Absorption coefficient 0.642 mm 1 F(000) 880 Crystal size 0.2 0.14 0.055 mm3 Theta range for data collection 5.246 to 76.734. Index ranges 9 <= h <= 12, 20 <= k <= 20, 18 <= 1 <= 9 Reflections collected 6562 Independent reflections 2980 [R(int) = 0.0566] Completeness to theta = 67.684 96.7% Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.000 and 0.60810 Refinement method Full-matrix least-squares on F2 Data/restraints/parameters 2980/248/340 Goodness-of-fit on F2 1.064 Final R indices [I > 2sigma(I)] R1 = 0.0707, wR2 = 0.1960 R indices (all data) R1 = 0.0919, wR2 = 0.2156 Absolute structure parameter 0.3(3) Extinction coefficient n/a Largest diff. peak and hole 0.480 and 0.309 e .Math. 3
TABLE-US-00004 TABLE 4 Atomic coordinates (104) and equivalent isotropic displacement parameters (2 103) for 1. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. x y z U(eq) B1 6913(6) 6690(4) 3443(4) 50(1) C1 6524(6) 7115(4) 2018(4) 61(2) C2 7739(7) 6534(4) 2026(4) 62(2) C3 5213(9) 6730(6) 1681(6) 97(3) C4 6766(10) 7921(4) 1504(6) 86(2) C5 7704(12) 5842(6) 1336(6) 103(3) C6 9115(8) 6955(6) 2011(7) 99(3) C7 6719(6) 6572(4) 4477(4) 56(1) C11 6433(5) 6374(3) 5719(4) 50(1) C12 6171(5) 6190(3) 6685(4) 48(1) C13 7198(7) 6177(4) 8168(4) 67(2) C14 6572(9) 6857(6) 8659(6) 89(2) C15 8641(8) 5995(6) 8434(5) 87(2) O1 6344(5) 7309(3) 2970(3) 68(1) O2 7629(5) 6158(3) 2923(3) 71(1) O3 5129(4) 5897(3) 6976(3) 67(1) O4 7250(4) 6377(3) 7210(2) 58(1) B2 4240(20) 5903(14) 4737(11) 54(4) C8 5376(10) 6519(6) 4997(7) 49(2) C9 7355(15) 6990(9) 5301(10) 56(3) C10 7097(11) 5697(7) 5038(7) 55(2) C16 2250(30) 5565(12) 4070(20) 56(4) C17 2840(30) 4793(11) 4560(20) 58(4) C18 2420(40) 5536(18) 3090(30) 63(5) C19 1000(80) 5720(50) 4390(50) 78(7) C20 2890(50) 4010(20) 4060(30) 67(6) C21 2220(80) 4640(30) 5490(60) 71(6) O5 3045(11) 6221(7) 4431(8) 65(3) O6 4245(12) 5090(9) 4707(8) 66(3) B2A 4642(16) 5523(16) 4687(9) 38(3) C8A 6071(11) 5852(7) 4918(8) 45(2) C9A 7740(12) 6654(9) 5257(9) 39(3) C10A 5741(11) 7120(7) 5133(7) 42(2) C16A 2480(30) 5367(17) 4120(30) 56(4) C17A 2910(40) 4562(15) 4570(30) 58(4) C18A 2630(50) 5330(20) 3010(40) 63(5) C19A 850(100) 5800(60) 4290(60) 78(7) C20A 2700(60) 3850(30) 3950(40) 67(6) C21A 2300(100) 4460(40) 5510(70) 71(6) O5A 3596(16) 5969(7) 4450(11) 58(3) O6A 4362(12) 4694(7) 4703(8) 51(3)
Compound 24 (See FIG. 6C)
TABLE-US-00005 TABLE 5 Crystal data and structure refinement for compound 24. CCDC reference number: 2158995. Empirical formula C29 H45 B2 N O6 Formula weight 525.28 Temperature 100.02(12) K Wavelength 0.71073 Crystal system monoclinic Space group P 1 21 1 Unit cell dimensions a = 15.4484(4) a = 90. b = 12.6264(2) b = 102.262(2). c = 15.9625(4) g = 90 Volume 3042.57(11) 3 Z 4 Density (calculated) 1.147 Mg/m3 Absorption coefficient 0.077 mm 1 F(000) 1136 Crystal size 0.44 0.23 0.23 mm3 Theta range for data collection 2.319 to 33.170. Index ranges 22 <= h <= 22, 18 <= k <= 18, 22 <= 1 <= 23 Reflections collected 64772 Independent reflections 19333 [R(int) = 0.0441] Completeness to theta = 25.242 99.9% Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.000 and 0.65168 Refinement method Full-matrix least-squares on F2 Data/restraints/parameters 19333/750/1059 Goodness-of-fit on F2 1.046 Final R indices [I > 2sigma(I)] R1 = 0.0439, wR2 = 0.1030 R indices (all data) R1 = 0.0606, wR2 = 0.1103 Absolute structure parameter 0.1(3) Extinction coefficient n/a Largest diff. peak and hole 0.391 and 0.299 e .Math. 3
TABLE-US-00006 TABLE 6 Atomic coordinates (10.sup.4) and equivalent isotropic displacement parameters (.sup.2 10.sup.3) for 1. U(eq) is defined as one third of the trace of the orthogonalized U.sup.ij tensor. x y z U(eq) O1 10352(2) 2841(2) 2916(2) 31(1) O2 8946(2) 2778(1) 2104(2) 29(1) O3 8091(2) 4755(2) 3193(2) 26(1) O4 7492(2) 6210(3) 2422(3) 30(1) O5 9517(1) 8766(1) 1383(1) 32(1) O6 8949(1) 7198(1) 812(1) 25(1) N1 9828(1) 7222(1) 2116(1) 22(1) C1 10119(2) 1714(2) 2827(2) 28(1) C2 9094(2) 1758(2) 2548(2) 25(1) C3 10556(3) 1272(3) 2130(3) 41(1) C4 10458(3) 1172(5) 3668(5) 45(1) C5 8683(9) 892(12) 1949(11) 32(1) C6 8635(3) 1828(2) 3299(3) 42(1) C7 7386(4) 5124(3) 3598(3) 23(1) C8 6839(2) 5864(3) 2905(2) 32(1) C9 6901(4) 4167(5) 3853(4) 38(1) C10 7838(2) 5726(2) 4408(2) 33(1) C11 6124(2) 5278(4) 2271(2) 61(1) C12 6464(2) 6836(3) 3263(2) 52(1) C13 9700(1) 4612(1) 2292(1) 24(1) C14 8866(1) 5386(2) 1996(1) 21(1) C15 10078(2) 5427(2) 2985(1) 23(1) C16 10153(2) 5233(2) 1665(1) 23(1) C17 9750(1) 6085(1) 2170(1) 19(1) C18 10416(1) 7770(1) 2811(1) 25(1) C19 9432(1) 7811(1) 1425(1) 22(1) C20 8404(1) 7681(2) 44(1) 30(1) C21 8004(1) 6715(2) 465(1) 36(1) C22 8980(2) 8302(2) 449(1) 42(1) C23 7689(2) 8365(2) 291(2) 51(1) C24 9984(1) 8152(1) 3523(1) 24(1) C25 10527(1) 8404(1) 4319(1) 31(1) C26 10164(2) 8814(2) 4974(1) 37(1) C27 9267(2) 8975(2) 4847(1) 40(1) C28 8720(2) 8720(2) 4063(1) 35(1) C29 9080(1) 8305(1) 3403(1) 28(1) B1 9670(1) 3396(1) 2432(1) 24(1) B2 8150(3) 5467(2) 2552(3) 21(1) O7 6380(3) 7006(4) 5910(3) 25(1) O8 6978(3) 7253(4) 7334(3) 28(1) O9 5077(3) 5694(3) 7748(3) 34(1) O10 5784(2) 4825(2) 8977(1) 43(1) O11 6814(1) 1376(1) 8199(1) 40(1) O12 7517(1) 2951(1) 8526(1) 30(1) N2 6553(1) 2782(1) 7283(1) 28(1) C30 6583(3) 8128(5) 6010(3) 22(1) C31 6700(4) 8299(6) 6989(4) 26(1) C32 5854(3) 8774(3) 5469(3) 42(1) C33 7446(3) 8300(2) 5705(2) 33(1) C34 5849(4) 8542(3) 7278(4) 50(1) C35 7411(3) 9102(3) 7382(3) 36(1) C36 4460(3) 5639(3) 8330(2) 38(1) C37 5052(2) 5390(3) 9201(2) 43(1) C38 3824(3) 4719(4) 7995(3) 54(1) C39 3952(7) 6671(8) 8201(4) 45(1) C40 4636(4) 4716(4) 9794(3) 54(1) C41 5422(3) 6420(4) 9666(3) 60(1) C42 6707(1) 5338(1) 6861(1) 22(1) C43 6628(2) 4847(2) 7754(2) 22(1) C44 7401(2) 4468(2) 6807(2) 25(1) C45 5983(2) 4524(2) 6424(2) 26(1) C46 6651(1) 3895(1) 7112(1) 22(1) C47 6951(1) 2291(1) 8026(1) 29(1) C48 7930(1) 2659(2) 9417(1) 31(1) C49 8447(2) 3657(2) 9741(1) 42(1) C50 7226(2) 2445(2) 9922(1) 45(1) C51 8560(1) 1738(2) 9420(1) 36(1) C52 5951(1) 2167(1) 6638(1) 30(1) C53 6327(1) 1848(1) 5875(1) 26(1) C54 5756(1) 1669(1) 5088(1) 31(1) C55 6078(2) 1342(2) 4384(1) 38(1) C56 6980(2) 1185(2) 4461(1) 38(1) C57 7553(1) 1366(2) 5240(1) 35(1) C58 7230(1) 1698(1) 5945(1) 30(1) B3 6705(1) 6557(1) 6698(1) 22(1) B4 5819(2) 5107(2) 8156(2) 26(1) C64 10622(4) 5357(5) 2396(5) 23(2) C61 5883(4) 4641(5) 6910(5) 26(2) C60 7017(5) 4391(5) 6322(5) 29(2) C59 7219(4) 4730(4) 7676(4) 24(2) C62 9419(5) 5520(5) 2892(4) 18(1) C63 9339(5) 5285(5) 1522(4) 23(2) O2A 9275(5) 2681(4) 1842(4) 25(1) O1A 10109(6) 2962(5) 3184(5) 29(2) C1A 9845(7) 1843(6) 3166(5) 34(2) C3A 10690(11) 1252(17) 3637(17) 45(1) C4A 9122(9) 1778(8) 3678(7) 46(3) C5A 10258(8) 1244(9) 1773(8) 36(3) C6A 8730(30) 910(30) 1940(30) 32(1) C2A 9531(4) 1629(5) 2193(4) 22(2) O13 5123(5) 4232(5) 8189(6) 79(3) B5 5377(5) 4937(6) 7629(6) 31(2) C66 4503(5) 4784(7) 8608(6) 48(2) C65 4788(6) 6000(8) 8581(5) 37(2) C67 4565(13) 4263(15) 9463(10) 87(5) O17 5299(9) 5962(10) 7925(9) 66(3) C68 3508(7) 4529(11) 8043(9) 54(1) C70 4053(18) 6760(20) 8417(13) 45(1) C69 5501(7) 6219(9) 9289(7) 60(1) C34A 6336(14) 8615(8) 7642(10) 55(4) C31A 6931(12) 8373(18) 7043(10) 27(4) C35A 7718(11) 9116(10) 7146(11) 48(4) C30A 6439(11) 8265(15) 6116(10) 37(5) C32A 5578(8) 8855(8) 5832(12) 46(3) C33A 6992(13) 8346(8) 5452(8) 47(3) O4A 7731(6) 5977(7) 2387(8) 35(2) O3A 8127(7) 4883(8) 3512(6) 37(2) C7A 7175(10) 5105(12) 3466(9) 55(6) C9A 6720(15) 4097(16) 3619(13) 57(5) C10A 7184(9) 5937(9) 4169(8) 67(3) C8A 6902(6) 5538(7) 2539(7) 47(2) C12A 6216(7) 6372(9) 2418(11) 83(4) C11A 6671(7) 4632(9) 1881(7) 62(3) B6 8407(7) 5464(7) 2911(8) 28(2) O15 7272(8) 7271(11) 7266(10) 29(2) O14 6172(10) 7084(13) 6065(10) 29(2)
Compound 25 (See FIG. 6D)
TABLE-US-00007 TABLE 7 Crystal data and structure refinement for compound 25. CCDC reference number: 2159016. Empirical formula C25 H38 B2 O5 Formula weight 440.17 Temperature 100.01(11) K Wavelength 1.54184 Crystal system monoclinic Space group P 1 21/c 1 Unit cell dimensions a = 15.7568(3) a = 90. b = 10.60872(17) b = 93.4675(14). c = 14.8400(2) g = 90. Volume 2476.11(7) 3 Z 4 Density (calculated) 1.181 Mg/m3 Absorption coefficient 0.626 mm 1 F(000) 952 Crystal size 0.392 0.202 0.111 mm3 Theta range for data collection 5.029 to 77.049. Index ranges 16 <= h <= 19, 6 <= k <= 13, 17 <= 1 <= 18 Reflections collected 13236 Independent reflections 4940 [R(int) = 0.0257] Completeness to theta = 67.684 98.7% Absorption correction Gaussian and multi-scan Max. and min. transmission 1.000 and 0.625 Refinement method Full-matrix least-squares on F2 Data/restraints/parameters 4940/849/548 Goodness-of-fit on F2 1.024 Final R indices [I > 2sigma(I)] R1 = 0.0501, wR2 = 0.1365 R indices (all data) R1 = 0.0551, wR2 = 0.1409 Extinction coefficient n/a Largest diff. peak and hole 0.351 and 0.277 e .Math. 3
TABLE-US-00008 TABLE 8 Atomic coordinates (10.sup.4) and equivalent isotropic displacement parameters (.sup.2 10.sup.3) for 1. U(eq) is defined as one third of the trace of the orthogonalized U.sup.ij tensor. x y z U(eq) C8 2188(1) 5284(1) 3754(1) 27(1) C12 2420(1) 5272(2) 2512(1) 34(1) B1 1978(1) 5155(1) 4761(1) 27(1) O1 1239(4) 4665(8) 4995(2) 33(1) O2 2556(3) 5433(5) 5462(3) 28(1) O3 3576(1) 2798(2) 4147(1) 36(1) O4 4083(1) 3623(1) 2869(1) 35(1) O5 2406(1) 6305(1) 1080(1) 31(1) C2 2217(4) 4834(4) 6262(3) 27(1) C3 1246(4) 4766(7) 5980(3) 31(1) C4 2616(5) 3534(5) 6371(5) 36(1) C5 2441(6) 5673(8) 7067(5) 30(1) C6 768(6) 3638(9) 6321(6) 45(2) C7 773(7) 5981(9) 6188(8) 37(2) C9 2511(1) 4124(2) 3162(1) 25(1) C10 2859(1) 6099(2) 3250(1) 27(1) C11 1566(1) 5580(2) 2910(1) 28(1) C14 4424(3) 2248(5) 4081(5) 35(1) C15 4834(2) 3159(3) 3390(2) 31(1) C16 4256(4) 908(5) 3692(4) 43(1) C17 4858(2) 2215(3) 5018(2) 50(1) C18 5412(2) 2525(3) 2760(2) 41(1) C19 5263(2) 4286(2) 3842(2) 43(1) C20 2569(1) 5137(2) 1516(1) 31(1) C21 2493(2) 6233(2) 128(1) 33(1) C22 1768(2) 5548(2) 367(2) 30(1) C23 1806(2) 4249(2) 521(1) 30(1) C24 1114(2) 3611(2) 913(2) 34(1) C25 378(2) 4266(3) 1185(2) 38(1) C26 340(3) 5572(3) 1068(3) 41(1) C27 1033(2) 6191(3) 651(3) 36(1) B2 3405(2) 3520(3) 3400(2) 26(1) O1A 1139(6) 4926(8) 4991(6) 27(1) O2A 2502(7) 5237(11) 5522(6) 27(1) O3A 3455(5) 2870(9) 3759(5) 52(2) O4A 4470(5) 4308(6) 3589(5) 66(2) O5A 2064(5) 5552(8) 1093(4) 35(2) C2A 2031(8) 4822(11) 6287(7) 27(1) C3A 1099(8) 4953(11) 5978(7) 27(1) C4A 2341(15) 3465(14) 6445(13) 54(4) C5A 2284(12) 5600(20) 7131(11) 30(1) C6A 549(13) 3840(16) 6238(15) 46(4) C7A 708(17) 6195(19) 6228(19) 37(3) C9A 3060(5) 5323(8) 3446(5) 42(2) C10A 1899(6) 6344(9) 3126(5) 49(2) C11A 1899(6) 4319(8) 3037(5) 47(2) C14A 4243(13) 2267(18) 4090(20) 35(1) C15A 4885(9) 3077(13) 3672(6) 31(1) C16A 4439(16) 980(30) 3880(19) 77(7) C17A 4269(7) 2285(11) 5114(5) 59(2) C18A 5050(8) 2747(12) 2688(9) 56(3) C19A 5724(7) 3335(15) 4227(9) 92(4) C20A 2786(8) 5760(14) 1685(7) 38(2) C21A 2206(9) 5787(14) 135(9) 37(3) C22A 1538(11) 5224(15) 399(12) 32(2) C23A 1495(11) 3944(15) 580(11) 31(2) C24A 820(10) 3414(18) 1036(12) 36(2) C25A 134(12) 4105(19) 1321(13) 36(2) C26A 197(18) 5290(20) 1153(18) 38(3) C27A 822(15) 5952(19) 712(18) 33(2) B2A 3710(6) 4162(8) 3592(6) 40(2)
Compound 27 (See FIG. 6E)
TABLE-US-00009 TABLE 9 Crystal data and structure refinement for compound 27. CCDC reference number: 2159001. Empirical formula C24 H35.99 B2 O5 Formula weight 426.08 Temperature 100.01(11) K Wavelength 1.54184 Crystal system monoclinic Space group P 1 n 1 Unit cell dimensions a = 12.02588(16) a = 90. b = 6.61763(11) b = 93.5949(13). c = 14.9926(2) g = 90. Volume 1190.81(3) 3 Z 2 Density (calculated) 1.188 Mg/m3 Absorption coefficient 0.635 mm 1 F(000) 460 Crystal size 0.398 0.314 0.239 mm3 Theta range for data collection 4.576 to 76.923. Index ranges 11 <= h <= 15, 7 <= k <= 8, 18 <= 1 <= 18 Reflections collected 11284 Independent reflections 3931 [R(int) = 0.0230] Completeness to theta = 67.684 100.0% Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.00000 and 0.37195 Refinement method Full-matrix least-squares on F2 Data/restraints/parameters 3931/466/409 Goodness-of-fit on F2 1.031 Final R indices [I > 2sigma(I)] R1 = 0.0530, wR2 = 0.1448 R indices (all data) R1 = 0.0535, wR2 = 0.1454 Absolute structure parameter 0.13(7) Extinction coefficient n/a Largest diff. peak and hole 0.676 and 0.388 e .Math. 3
TABLE-US-00010 TABLE 10 Atomic coordinates (10.sup.4) and equivalent isotropic displacement parameters (.sup.2 10.sup.3) for 1. U(eq) is defined as one third of the trace of the orthogonalized U.sup.ij tensor. x y z U(eq) O1 2501(2) 5819(4) 6840(2) 36(1) O2 3006(2) 2933(4) 6139(2) 34(1) O3 9312(2) 11515(4) 4396(2) 36(1) C1 1577(3) 4393(5) 6916(2) 36(1) C2 2142(3) 2337(5) 6729(2) 33(1) C3 1150(4) 4579(7) 7848(3) 48(1) C4 683(3) 4972(6) 6201(3) 45(1) C5 2743(3) 1414(6) 7559(2) 42(1) C6 1387(4) 793(5) 6250(3) 41(1) C7 4260(3) 6047(5) 5964(2) 31(1) C11 5534(3) 7416(5) 5559(2) 29(1) C12 6524(3) 8504(5) 5252(2) 28(1) C13 7589(3) 7661(5) 5318(2) 32(1) C14 8497(3) 8700(5) 5037(2) 33(1) C15 8367(3) 10626(5) 4672(2) 28(1) C16 7315(3) 11506(5) 4607(2) 32(1) C17 6406(3) 10442(5) 4894(2) 32(1) C18 9184(3) 13382(6) 3924(3) 40(1) B1 3241(3) 4913(6) 6309(2) 30(1) O4 3406(6) 6690(9) 3540(4) 44(2) O5 3515(5) 9485(9) 4407(4) 42(2) C8 4588(4) 6318(6) 4971(3) 29(1) C9 5521(4) 5534(7) 6195(3) 34(1) C10 4610(4) 8307(7) 6124(3) 34(1) C19 2587(7) 8129(12) 3120(5) 30(1) C20 3028(6) 10189(10) 3514(4) 18(1) C21 2718(12) 7970(30) 2107(8) 52(3) C22 1440(8) 7489(18) 3365(8) 43(3) C23 3958(7) 11150(13) 3033(6) 38(2) C24 2112(10) 11691(15) 3745(7) 46(2) B2 3833(13) 7507(19) 4261(8) 25(1) C8A 4239(14) 8140(30) 5396(10) 32(3) C9A 5042(15) 5290(30) 5227(11) 29(3) C10A 5315(15) 6780(30) 6509(11) 29(3) O5A 4117(8) 9282(19) 3806(8) 52(3) O6A 2666(7) 7752(16) 4302(6) 42(2) B2A 3810(18) 7590(30) 4307(12) 25(1) C20A 3254(14) 9100(20) 2950(9) 68(5) C23A 3020(20) 7710(40) 2147(14) 52(3) C24A 3385(15) 11380(20) 2607(10) 35(3) C19A 2289(11) 9140(20) 3578(10) 64(4) C21A 1153(12) 8340(30) 3186(12) 39(2) C22A 2387(15) 11330(20) 4047(9) 46(2) O6B 2854(8) 6883(14) 3975(6) 32(2) O5B 3840(9) 10010(15) 3979(7) 47(3) C19B 2471(8) 8069(15) 3218(6) 30(1) C20B 2984(10) 10201(12) 3285(6) 18(1) C21B 1225(8) 8220(30) 3182(11) 39(2) C22B 2796(15) 7065(18) 2376(6) 52(3) C23B 3455(15) 10804(18) 2421(7) 35(3) C24B 2133(15) 11734(18) 3523(10) 46(2) B2B 3683(9) 8356(17) 4575(5) 25(1)
C. General Experimental Procedures and Characterization Data of Substrates in 1.SUP.st .Functionalization of BCP BisBoronates
##STR00048##
2-(3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)-2,3-dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinine (16)
[0193] A flame-dried culture tube was charged with BCP bis-boronate 14 (33.4 mg, 0.1 mmol, 1.0 equiv.) and 1,8-diaminonaphthalene (31.6 mg, 0.2 mmol, 2.0 equiv.). Then the tube was evacuated and backfilled with argon for three times, followed by addition of toluene (1.0 mL, 0.1 M) via a syringe. After stirring for at 100 C. for 12 hours, the reaction mixture was cooled to room temperature. Next, the solvent was removed under high vacuum, and the crude residue was purified by chromatography on silica gel (50:1, hexanes:ethyl acetate) to afford 22.4 mg (60%) of the title compound 16.
[0194] Physical State: white solid.
[0195] m.p.: 162-164 C.
[0196] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.08 (dd, J=8.2, 7.3 Hz, 2H), 6.97 (dd, J=8.3, 0.9 Hz, 2H), 6.28-6.23 (m, 4H), 2.07 (dd, J=9.8, 2.5 Hz, 1H), 1.79 (s, 1H), 1.77 (dd, J=9.8, 1.3 Hz, 1H), 1.73 (dd, J=8.8, 2.5 Hz, 1H), 1.55 (d, J=8.7 Hz, 1H), 1.35 (s, 12H), 1.19 (s, 3H) ppm.
[0197] .sup.13C NMR (151 MHz, CDCl.sub.3): 141.70, 136.56, 127.65, 119.93, 117.14, 105.36, 83.45, 55.08, 54.21, 44.23, 25.27, 25.05, 20.12 ppm.
[0198] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.50, 29.75 ppm.
[0199] TLC: R.sub.f=0.40 (10:1 hexanes:ethyl acetate).
General Procedure A for Hydrazone Coupling of BCP BisBoronates
##STR00049##
[0200] A screw-capped culture tube was charged with cesium carbonate (3.0 equiv.), 2-mesitylsulfonyl hydrazone (2.0 equiv.) and BCP bis-boronate (1.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of toluene (0.1 M) via a syringe. After stirring for at 70 C. for 18-48 hours, the reaction mixture was cooled to room temperature. Next, the suspended solution was filtered over Celite and washed with diethyl ether. The solvent was removed under high vacuum, and the crude residue was purified by chromatography on silica gel. (Yang et al., 2021a)
[0201] The following sulfonyl hydrazones were prepared through literature procedure (Yang et al., 2021a):
##STR00050##
4,4,5,5-tetramethyl-2-(2-(3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)propan-2-yl)-1,3,2-dioxaborolane (19)
[0202] Following General Procedure A on 0.1 mmol scale with BCP bisboronate 14 and 2-mesityl sulfonyl hydrazone SI-21 reacting for 48 h. Purification by flash chromatography (hexanes:diethyl ether, 20:1) afforded 16.0 mg (42%) of the title compound 19.
[0203] Physical State: colorless oil.
[0204] .sup.1H NMR (600 MHz, CDCl.sub.3): 2.27 (dd, J=9.7, 1.8 Hz, 1H), 1.52 (dd, J=9.7, 1.1 Hz, 1H), 1.43 (s, 1H), 1.37 (dd, J=8.1, 1.8 Hz, 1H), 1.28 (d, J=8.0 Hz, 1H), 1.22 (s, 12H), 1.21 (s, 12H), 0.86 (s, 3H), 0.85 (s, 3H) ppm.
[0205] .sup.13C NMR (151 MHz, CDCl.sub.3): 82.94, 82.54, 54.70, 48.90, 47.59, 37.02, 24.98, 24.94, 24.89, 22.04, 21.85, 18.79 ppm.
[0206] .sup.11B NMR (128 MHz, CDCl.sub.3): 33.30 ppm.
[0207] MS (GCMS, EI): m/z=361 (1%), 276 (15%), 261 (13%), 193 (18%), 107 (35%), 83 (100%).
[0208] TLC: R.sub.f=0.35 (15:1 hexanes:ethyl acetate).
Preparation of BCP 2-Acid
##STR00051## ##STR00052##
Step 1: Synthesis of Compound 29
[0209] A 2-L three-necked (24/40 joint) round-bottomed flask, equipped with a 6.4 cm Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate, compound 28, (103.8 g, 360 mmol, 1.0 equiv.). Methylene chloride (720 mL) was added into the flask and the mixture was cooled in a dried ice-acetone bath (78 C.) and stirred for 15 minutes. Next a solution of DIBAL-H (720 mL, 1 M in hexanes, 2.0 equiv., pre-cooled at 78 C.) was added dropwise into the flask through a dropping funnel at 78 C. in 2 hours and the mixture was allowed to stir at 78 C. for another 3 hours. After it was confirmed that the starting material, 28, was consumed through TLC analysis, the reaction was quenched at 78 C. with methanol (24 mL, 720 mmol, 2.0 equiv.). After the reaction was slowly warmed to room temperature, water (29 mL), 20% NaOH (29 mL) and water (72 mL) was slowly added into the reaction mixture in sequence and the mixture was allowed to stir for another 30 minutes. Next, excess Na.sub.2SO.sub.4 was added to dry the reaction mixture and the suspension was filtered through Celite. Solvents was removed under vacuum and the crude product was purified through flash chromatography (hexanes:ethyl acetate, 5:1) on silica gel to afford 63 g (76%) of the title compound 29..sup.1
##STR00053##
isopropyl 1-formyl-3,3-dimethoxycyclobutane-1-carboxylate (29)
[0210] Physical State: colorless oil.
[0211] .sup.1H NMR (600 MHz, CDCl.sub.3): 9.69 (s, 1H), 5.09 (hept, J=6.3 Hz, 1H), 3.16 (s, 3H), 3.13 (s, 3H), 2.65 (d, J=12.1 Hz, 2H), 2.61 (d, J=11.8 Hz, 2H), 1.25 (d, J=6.3 Hz, 6H) ppm.
[0212] .sup.13C NMR (151 MHz, CDCl.sub.3): 196.06, 170.25, 98.28, 69.74, 49.73, 48.79, 48.72, 37.30, 21.80 ppm.
[0213] HRMS (ESI-TOF): calc'd for C.sub.11H.sub.18O.sub.5 [M+Na].sup.+: 253.1047, found: 253.1035.
[0214] TLC: R.sub.f=0.31 (5:1 hexanes:ethyl acetate).
Step 2: Synthesis of Compound 30
[0215] A 2-L three-necked (24/40 joint) round-bottomed flask, equipped with a 6.4 cm Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with triphenyl phosphite (78 mL, 300 mmol, 1.1 equiv.). Methylene chloride (340 mL) was added into the flask and the mixture was cooled to 78 C. Then bromine (15 mL, 300 mmol, 1.1 equiv.) was added slowly into the flask, followed by addition of triethyl amine (140 mL, 1.0 mol, 3.3 equiv.). (Note: a suspension of the mixture was formed.) Next, the solution of 29 (63 g, 270 mmol, 1.0 equiv.) in 160 mL methylene chloride was added into the mixture and the reaction was warmed up to room temperature. After it was confirmed that the starting material, 29, was consumed through TLC analysis, solvent was removed by rotary evaporator and the crude product was purified through flash chromatography (hexanes:ethyl acetate, 20:1) on silica gel to afford 87 g (97%) of the title compound 30.
##STR00054##
Isopropyl 1-(dibromomethyl)-3,3-dimethoxycyclobutane-1-carboxylate (30)
[0216] Physical state: colorless oil.
[0217] .sup.1H NMR (600 MHz, CDCl.sub.3): 6.03 (s, 1H), 5.10 (hept, J=6.3 Hz, 1H), 3.16 (s, 3H), 3.15 (s, 3H), 2.72-2.66 (m, 2H), 2.48-2.42 (m, 2H), 1.28 (d, J=6.3 Hz, 6H) ppm.
[0218] .sup.13C NMR (151 MHz, CDCl.sub.3) 170.41, 96.85, 69.77, 49.87, 48.79, 48.75, 48.57, 40.13, 21.74. ppm.
[0219] HRMS (ESI-TOF): calc'd for C.sub.11H.sub.18Br.sub.2O.sub.4 [M+Na].sup.+: 394.9464, found: 394.9457.
[0220] TLC: R.sub.f=0.32 (10:1 hexanes:ethyl acetate).
Step 3: Synthesis of Compound 31
[0221] A 2-L one-necked (24/40 joint) round-bottomed flask, equipped with a 6.4 cm Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with copper(I) iodide (4.88 g, 25.6 mmol, 0.1 equiv.), B.sub.2pin.sub.2 (140 g, 550 mmol, 2.2 equiv.), and lithium tert-butoxide (44.0 g, 550 mmol, 2.2 equiv.). After being evacuated and backfilled with argon from a balloon 3 times, DMF (500 mL) was added into the flask at 0 C. Then a solution of compound 30 (256 mmol, 95.6 g, 1.0 equiv.) in DMF (250 mL) was added slowly into the mixture at 0 C. in 15 minutes and the reaction mixture was allowed to slowly warm to room temperature and stir for another 1 hour. After it was confirmed that the starting material, 30, was consumed through TLC analysis, the reaction was filtered through Celite, washed with diethyl ether (200 mL) and quenched at 0 C. with water (500 mL) (Caution: the quenching process is exothermic). The mixture was transferred into a 6-L flask and diluted with water (1.5 L) and diethyl ether (300 mL). After the mixture was stirred for 30 minutes at room temperature, the two-phase solution was transferred into a 3-L separation funnel. The aqueous phase is separated and extracted with two 200-mL portions of diethyl ether. The combined organic layers are washed with the mixture of 200 mL water and 200 mL saturated NaCl solution twice, dried over Na.sub.2SO.sub.4, and filtered through Celite.
[0222] After solvent was removed by rotary evaporator, the crude product was redissolved in 250 mL acetonitrile in a 1-L flask. 2M H.sub.2SO.sub.4 (256 mL, 2.0 equiv.) was added into the mixture at room temperature and the reaction was allowed to stir for another 1.5 hours. After it was confirmed that the ketal intermediate was consumed through TLC analysis, the crude reaction is concentrated to remove excess acetonitrile. Then diethyl ether (400 mL) and saturated brine (150 mL) is added to the reaction mixture and the mixture is transferred to a 1-L separatory funnel. The aqueous layer is separated and further extracted with diethyl ether (3150 mL). The combined organic layers are dried over Na.sub.2SO.sub.4, filtered through Celite. Excess solvent was removed by rotary evaporator. The crude product was redissolved in 250 mL methylene chloride in a 500 mL-flask and mesitylene sulfonyl hydrazide (54.9 g, 256 mmol, 1.0 equiv.) was added. The mixture was allowed to stir at room temperature for another 2 hours. After it was confirmed that the ketone intermediate was consumed through TLC analysis, the crude reaction is concentrated to remove excess solvent. The crude product was purified through flash chromatography (hexanes:ethyl acetate, 4:1 to 2:1) on silica gel to afford 116 g (73%) of the title compound 31.
##STR00055##
Isopropyl 1-(bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-3-(2-(mesitylsulfonyl)-hydrazineylidene)cyclobutane-1-carboxylate (31)
[0223] Physical State: white solid.
[0224] m.p.: 85-87 C.
[0225] .sup.1H NMR (600 MHz, Acetone-d.sub.6) 9.17 (s, 1H), 7.02 (s, 2H), 4.90 (hept, J=6.2 Hz, 1H), 3.23 (ddd, J=17.6, 3.3, 1.7 Hz, 1H), 3.12 (dt, J=17.0, 2.5 Hz, 1H), 3.05-2.98 (m, 1H), 2.94 (ddd, J=17.1, 3.4, 1.5 Hz, 1H), 2.65 (s, 6H), 2.28 (s, 3H), 1.22 (s, 1H), 1.19 (d, J=6.3 Hz, 3H), 1.18 (d, J=6.6 Hz, 3H), 1.17 (s, 6H), 1.16 (s, 6H), 1.13 (s, 12H) ppm.
[0226] .sup.13C NMR (151 MHz, Acetone-d.sub.6) 176.43, 154.40, 143.07, 140.75, 134.85, 132.46, 83.83, 83.78, 68.79, 45.17, 43.93, 40.62, 25.18, 25.06, 24.74, 23.44, 21.80, 21.76, 20.85 ppm.
[0227] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.98 ppm.
[0228] HRMS (ESI-TOF): calc'd for C.sub.30H.sub.48B.sub.2N.sub.2O.sub.8S [M+H].sup.+: 619.3390, found: 619.3402.
[0229] TLC: R.sub.f=0.30 (3:1 hexanes:ethyl acetate).
Step 4: Synthesis of 23
[0230] A 1-L one-necked (24/40 joint) round-bottomed flask, equipped with a 6.4 cm Teflon-coated magnetic stir bar, was flame-dried under vacuum, and then cooled to 23 C. under an atmosphere of argon. Then the flask was charged with 31 (61.8 g, 100 mmol, 1.0 equiv.) and dried cesium carbonate (100 g, 300 mmol, 3.0 equiv.). (Note: Cesium carbonate was dried at 120 C. under vacuum for 18 hours.) After being evacuated and backfilled with argon from a balloon 3 times, dioxane (500 mL) was added into the flask and the reaction mixture was allowed to stir at 100 C. for 40 minutes. After it was confirmed that the starting material, 31, was consumed through TLC analysis, the reaction was cooled to room temperature, filtered through Celite, washed with hexanes (500 mL), and concentrated to remove excess solvents. The crude reaction was purified through flash chromatography (hexanes:ethyl acetate, 10:1) on silica gel to afford the title compound 23, which was further purified through trituration in hexanes at 40 C., affording 19.0 g product (47% yield) with >99% purity as white solids. Trituration procedure: The product (around 21 g) after chromatography was dissolved in hexanes (10 mL) at room temperature and then cooled to 40 C. After the solution of the product was slowly stirred at 40 C. for 1 h, the suspension was filtered and the white solid was washed with cooled hexanes (5 mL) quickly and dried under vacuum for 1 hour.
[0231] In the second run, following procedures in step 4 on 87 mmol scale with the rest sulfonyl hydrazone 31. Purification by flash chromatography (hexanes:ethyl acetate, 10:1) and trituration afforded 18.0 g (47%) of the title compound 23.
##STR00056##
isopropyl 2,3-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (23)
[0232] Physical State: white solid.
[0233] m.p.: 41-43 C.
[0234] .sup.1H NMR (600 MHz, CDCl.sub.3): 4.93 (hept, J=6.3 Hz, 1H), 2.71 (dd, J=9.4, 2.3 Hz, 1H), 2.14-2.08 (m, 2H), 2.03 (dd, J=8.1, 2.2 Hz, 1H), 1.88 (dd, J=8.2, 0.9 Hz, 1H), 1.22 (s, 12H), 1.21 (s, 6H), 1.20 (s, 6H), 1.19 (d, J=2.9 Hz, 3H), 1.18 (d, J=3.0 Hz, 3H) ppm.
[0235] .sup.13C NMR (151 MHz, CDCl.sub.3) 169.49, 83.55, 83.10, 67.44, 55.81, 50.75, 44.87, 24.89, 24.87, 24.84, 24.79, 21.93 ppm.
[0236] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.18 ppm.
[0237] HRMS (ESI-TOF): calc'd for C.sub.21H.sub.36B.sub.2O.sub.6 [M+H].sup.+: 407.2771, found: 407.2778.
[0238] TLC: R.sub.f=0.32 (5:1 hexanes:ethyl acetate).
Step 5: Synthesis of 37
[0239] A screw-capped 13100 mm Pyrex culture tube or a flame-dried 250-mL Pyrex flask was charged with BCP bisboronate 23 (10 mmol, 4.06 g, 1.0 equiv.) and tert-butyl catechol (4.15 g, 25 mmol, 2.5 equiv.). Then the tube or the flask was evacuated and backfilled with air for three times, followed by addition of toluene (100 mL, 0.1 M) via a syringe. After stirring for at 100 C. for 2.5 hours when it is confirmed that the starting material was consumed totally, the reaction mixture was cooled to room temperature. Next, the solvent was removed under high vacuum, and the crude residue was purified by chromatography on silica gel.
##STR00057##
isopropyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (37)
[0240] Physical State: colorless oil.
[0241] .sup.1H NMR (600 MHz, CDCl.sub.3): 4.97 (hept, J=6.3 Hz, 1H), 2.58 (dd, J=9.5, 2.2 Hz, 1H), 2.55 (s, 1H), 2.10-2.04 (m, 2H), 2.02 (dd, J=8.2, 2.3 Hz, 1H), 1.89 (dd, J=8.2, 1.0 Hz, 1H), 1.25 (s, 12H), 1.22 (d, J=3.9 Hz, 3H), 1.20 (d, J=3.9 Hz, 3H) ppm.
[0242] .sup.13C NMR (151 MHz, CDCl.sub.3): 169.38, 83.32, 67.59, 55.03, 50.46, 44.96, 29.72, 25.01, 24.88, 21.96, 21.95 ppm.
[0243] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.65 ppm.
[0244] HRMS (ESI-TOF): calc'd for C.sub.15H.sub.25BO.sub.4 [M+H].sup.+: 289.1919, found: 289.1933.
[0245] TLC: R.sub.f=0.36 (10:1 hexanes:ethyl acetate).
Step 6: Synthesis of 39 (Bcp 2-Bpin)
[0246] To a stirred solution of the ester 37 (1.0 equiv.) in THF/MeOH/H.sub.2O (2:1:1, 0.2 M) was added LiOH.Math.H.sub.2O (1.5 equiv.) at room temperature and the reaction was stirred for 12 h by which time TLC analysis showed complete conversion. The excess solvent was removed, and reaction mixture was acidified by 3M HCl and the aqueous phase was extracted with CH.sub.2Cl.sub.2 (3 times). The combined organic phase was dried over Na.sub.2SO.sub.4 and evaporated to dryness. The acid residue was directly used without further purification.
[0247] The carboxylic acid (1.0 equiv.) was dissolved in methylene chloride (0.65 M) at 0 C., to which DMF (0.1 equiv.) was added followed by slow addition of oxalyl chloride (1.5 equiv.) under argon atmosphere. The reaction temperature was allowed to warm to ambient temperature and was stirred for additional 5 h (or until bubbling ceased).
[0248] The reaction was cooled to 0 C., wrapped in aluminum foil, and shielded from light. DMAP (0.1 equiv.) was added followed by portion-wise addition of 2-mercaptopyridine N-oxide (1.5 equiv.) (the reaction color was usually canary yellow or red). The reaction temperature was allowed to warm to ambient temperature and was stirred for 2 h. Upon completion of the reaction, the reaction flask was cooled to 0 C. and water was added. The layers were separated (in a separatory funnel that was wrapped in aluminum foil) and the organics were filtered through a pad of Celite while washing with methylene chloride (using a fritted funnel and round bottom flask that were covered with aluminum foil). The organics were concentrated under reduced pressure in a water bath no higher than 25 C. while shielded from light (the bath was covered aluminum foil). The flask was wrapped in aluminum foil and placed under high vacuum to remove any residual methylene chloride.
[0249] The yellow (or red) residue was dissolved in benzene (0.3 M) and tert-butyl thiol (2.5 equiv.) was added. The flask was fitted with a reflux condenser and the reaction was irradiated with a 600 W halogen lamp until consumption of the Barton ester. Upon completion of the reaction, the reaction mixtures were concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography to yield the pure compound. Note: The compound is volatile at high vacuum (0.1 mbar). Do not dry it under high vacuum of pump.
Step 7: Synthesis of Alcohol 40
[0250] BCP boronate 39 (1.0 equiv.) and bromoiodomethane (2.0 eq.) were dissolved in anhydrous THF (0.1 M) and cooled to 78 C. n-BuLi (2.0 equiv.) was added dropwise, and the solution was stirred 10 minutes at 78 C., and then warmed up to room temperature and stir overnight. The reaction mixture was quenched with saturated NH.sub.4Cl solution and dissolved in ethyl acetate. The aqueous phase was extracted with ethyl acetate twice. The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to afford the crude residue, which was used directed without further purification.
[0251] To a solution of BCP boronate crude and NaOAc (3.0 equiv.) in THE (0.1 M) at 0 C. was added H.sub.2O.sub.2 (35 wt. % in water, 10.0 equiv., 1.0 mL/mmol) dropwise. The resulting mixture was stirred at 0 C. for 1.5 hours. Na.sub.2S.sub.2O.sub.3 was added and the mixture was stirred at 0 C. for 10 min. Diethyl ether was added, the layers were separated, and the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with water and brine, dried over anhydrous MgSO.sub.4, concentrated, and purified by column chromatography on silica gel to obtain the alcohol 40.
Step 8: Synthesis of Bcp 2-Acid
[0252] To a solution of BCP alcohol 40 (1.0 equiv.) in water/MeCN (1:1, 0.1 M) was added ruthenium trichloride hydrate (0.02 equiv.) at 0 C., followed by portion-wise addition of sodium periodate (3.0 equiv.). The reaction was allowed to stir until the starting material is totally consumed. Upon completion of the reaction, excess solvent was removed, and the reaction was extracted with diethyl ether. The layers were separated, and the organics were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography to yield the pure compound.
[0253] Alternatively, the BCP 2-acid can also be prepared using the steps below and as described in Wiberg et al., 1993.
##STR00058##
tert-butyl benzyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)propan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (32)
[0254] Following General Procedure A on 0.05 mmol scale with BCP bisboronate 24 and 2-mesityl sulfonyl hydrazone SI-21 reacting for 24 h. Purification by flash chromatography (hexanes:ethyl acetate, 4:1) afforded 17.5 mg (62%) of the title compound 32.
[0255] Physical State: colorless oil.
[0256] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.22-7.14 (m, 4H), 7.11 (t, J=7.0 Hz, 1H), 4.46-4.24 (m, 2H), 2.58 (s, 1H), 1.85 (d, J=9.5 Hz, 1H), 1.78 (d, J=7.9 Hz, 1H), 1.67 (s, 1H), 1.66 (s, 1H), 1.38 (s, 9H), 1.139 (s, 6H), 1.136 (s, 6H) 1.11 (s, 12H), 0.80 (s, 3H), 0.79 (s, 3H) ppm.
[0257] .sup.13C NMR (151 MHz, CDCl.sub.3): 140.28, 128.22, 126.85, 126.47, 83.06, 82.80, 49.14, 48.76, 45.90, 28.61, 25.07, 24.92, 24.90, 22.40, 22.16 ppm. Note: NC(O), NC, NCH.sub.2, Me.sub.3C and BC were not observed.
[0258] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.08 ppm.
[0259] HRMS (ESI-TOF): calc'd for C.sub.32H.sub.51BNO.sub.6 [M+H].sup.+: 568.3975, found: 568.3975.
[0260] TLC: R.sub.f=0.56 (5:1 hexanes:ethyl acetate).
##STR00059##
isopropyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)propan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (33)
[0261] Following General Procedure A on 0.1 mmol scale with BCP bisboronate 23 and 2-mesityl sulfonyl hydrazone SI-21 reacting for 18 h. Purification by flash chromatography (hexanes:ethyl acetate, 4:1) afforded 27.7 mg (62%) of the title compound 33.
[0262] Physical State: white solid.
[0263] m.p.: 74-76 C.
[0264] .sup.1H NMR (600 MHz, CDCl.sub.3): 4.97 (hept, J=6.3 Hz, 1H), 2.69 (dd, J=9.5, 1.8 Hz, 1H), 1.89-1.85 (m, 2H), 1.81 (dd, J=7.9, 1.8 Hz, 1H), 1.66 (d, J=7.8 Hz, 1H), 1.23 (s, 6H), 1.22 (s, 6H), 1.20 (s, 12H), 1.195 (d, J=7.0 Hz, 6H), 0.88 (s, 3H), 0.87 (s, 3H) ppm.
[0265] .sup.13C NMR (151 MHz, CDCl.sub.3): 170.85, 83.14, 82.91, 67.44, 54.10, 49.29, 47.75, 38.82, 24.96, 24.94, 24.92, 24.86, 22.00, 21.80, 21.66 ppm.
[0266] .sup.11B NMR (128 MHz, CDCl.sub.3): 33.04 ppm.
[0267] MS (GCMS, EI): m/z=433 (0.8%), 348 (0.5%), 262 (15%), 205 (10%), 136 (38%), 83 (100%).
[0268] TLC: R.sub.f=0.54 (5:1 hexanes:ethyl acetate).
##STR00060##
isopropyl 3-(4-phenyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butan-2-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (34)
[0269] Following General Procedure A on 0.1 mmol scale with BCP bisboronate 23 and 2-mesityl sulfonyl hydrazone SI-22 reacting for 18 h. Purification by flash chromatography (hexanes:ethyl acetate, 4:1) and afforded 30.6 mg (57%) of the title compound 34. Note: two diastereoisomers (1/1) were observed. NMR characterization for the mixture was given.
[0270] Physical State: pale yellow solid.
[0271] m.p.: 53-55 C.
[0272] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.27-7.09 (m, 5H), 4.96 (hept, J=6.3 Hz, 1H), 2.75 (dd, J=9.6, 1.9 Hz, 1H), 2.56 (tdd, J=12.9, 5.1, 2.7 Hz, 1H), 2.49-2.38 (m, 1H), 1.92 (ddd, J=5.6, 4.3, 1.4 Hz, 1H), 1.89-1.78 (m, 3H), 1.67 (dd, J=7.8, 4.4 Hz, 1H), 1.26 (s, 6H), 1.26 (s, 6H), 1.21-1.19 (m, 7H), 1.18 (s, 3H), 1.17 (s, 3H), 1.12 (s, 3H), 1.11 (s, 3H), 0.97 (s, 1.5H), 0.96 (s, 1.5H) ppm.
[0273] .sup.13C NMR (151 MHz, CDCl.sub.3): 170.70, 170.69, 143.66, 143.62, 128.54, 128.52, 128.30, 128.28, 125.60, 83.44, 82.93, 67.51, 67.50, 54.19, 54.13, 49.17, 49.03, 48.18, 48.12, 39.23, 39.15, 39.07, 38.61, 33.54, 33.49, 25.37, 25.33, 25.07, 25.03, 24.90, 24.86, 24.78, 24.75, 21.99, 18.35, 18.31 ppm.
[0274] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.84 ppm.
[0275] HRMS (ESI-TOF): calc'd for C.sub.31H.sub.48B.sub.2O.sub.6 [M+H].sup.+: 539.3710, found: 539.3705.
[0276] TLC: R.sub.f=0.52 (5:1 hexanes:ethyl acetate).
##STR00061##
tert-butyl 4-((3-(isopropoxycarbonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)piperidine-1-carboxylate (35)
[0277] Following General Procedure A on 0.1 mmol scale with BCP bisboronate 23 and 2-mesityl sulfonyl hydrazone SI-23 reacting for 24 h. Purification by flash chromatography (hexanes:ethyl acetate, 4:1) afforded 45.1 mg (75%) of the title compound 35. Note: two diastereoisomers (1/1) were observed. NMR characterization for the mixture was given.
[0278] Physical State: colorless oil.
[0279] .sup.1H NMR (600 MHz, CDCl.sub.3): 4.96 (hept, J=6.3, 1.1 Hz, 1H), 4.03 (br., 2H), 2.69-2.56 (m, 3H), 2.06-1.93 (m, 3H), 1.90-1.83 (m, 1H), 1.72 (d, J=8.0 Hz, 1H), 1.69-1.58 (m, 3H), 1.46-1.42 (m, 11H), 1.24 (s, 3H), 1.23 (s, 3H), 1.23 (s, 6H), 1.22 (s, 12H), 1.21-1.18 (m, 6H) ppm.
[0280] .sup.13C NMR (151 MHz, CDCl.sub.3): 170.09, 155.06, 155.04, 83.31, 83.24, 83.10, 83.08, 79.20, 67.56, 56.10, 51.94, 42.97, 42.84, 40.75, 40.72, 36.60, 36.47, 28.60, 25.28, 25.24, 25.16, 25.10, 25.08, 24.84, 24.83, 21.99, 21.97 ppm.
[0281] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.78 ppm.
[0282] HRMS (ESI-TOF): calc'd for C.sub.32H.sub.55B.sub.2NO.sub.8 [M+H].sup.+: 604.4187, found: 604.4194.
[0283] TLC: R.sub.f=0.32 (5:1 hexanes:ethyl acetate).
General Procedure B for Protodeborylation of BCP Bisboronates
##STR00062##
[0284] A screw-capped culture tube or a flame-dried flask was charged with BCP bisboronate (1.0 equiv.) and tert-butyl catechol (2.5 equiv.). The tube or the flask was then evacuated and backfilled with argon or air (according to details shown below) three times, followed by addition of toluene (0.1 M) via a syringe. After stirring for at 100 C. for 2-12 hours, and after confirmation that the starting material was consumed totally, the reaction mixture was cooled to room temperature. Next, the solvent was removed under high vacuum, and the crude residue was purified by chromatography on silica gel. (Andr-Joyaux et al., 2020)
##STR00063##
2-(1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (36)
[0285] Following General Procedure B on 0.1 mmol scale with BCP bisboronate 25 under argon atmosphere heating for 12 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 22.0 mg (70%) of the title compound 36.
[0286] Following General Procedure B on 2.0 mmol scale with BCP bisboronate 25 under argon atmosphere heating for 5 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) and afforded 528 mg (84%) of the title compound 36.
[0287] Physical State: colorless oil.
[0288] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.37-7.30 (m, 4H), 7.28-7.24 (m, 1H), 4.54 (s, 2H), 3.45 (s, 2H), 2.69 (s, 1H), 2.22 (dd, J=9.8, 2.2 Hz, 1H), 1.82 (d, J=9.0 Hz, 2H), 1.78 (dd, J=8.3, 2.2 Hz, 1H), 1.61 (d, J=8.3 Hz, 1H), 1.225 (s, 6H), 1.222 (s, 6H) ppm.
[0289] .sup.13C NMR (151 MHz, CDCl.sub.3): 139.04, 128.37, 127.60, 127.45, 83.06, 72.96, 70.74, 53.55, 48.90, 46.48, 30.49, 24.94 ppm.
[0290] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.21 ppm.
[0291] MS (GCMS, EI): m/z=299 (0.2%), 244 (0.2%), 219 (0.5%), 151 (5%), 91 (100%).
[0292] TLC: R.sub.f=0.46 (10:1 hexanes:ethyl acetate).
##STR00064##
isopropyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (37)
[0293] Following General Procedure B on 0.1 mmol scale with BCP bisboronate 23 under air atmosphere heating for 3 h. Purification by flash chromatography (hexanes:ethyl acetate, 10:1) afforded 20.2 mg (72%) of the title compound 37.
[0294] Following General Procedure B on 3.0 mmol scale with BCP bisboronate 23 under air atmosphere heating for 2 h 20 minutes. Purification by flash chromatography (hexanes:ethyl acetate, 10:1) afforded 630.7 mg (75%) of the title compound 37.
[0295] Following General Procedure B on 10.0 mmol scale with BCP bisboronate 23 under air atmosphere heating for 2.5 h. Purification by flash chromatography (hexanes:ethyl acetate, 10:1) afforded 2.09 g (75%) of the title compound 37.
[0296] Physical State: colorless oil.
[0297] .sup.1H NMR (600 MHz, CDCl.sub.3): 4.97 (hept, J=6.3 Hz, 1H), 2.58 (dd, J=9.5, 2.2 Hz, 1H), 2.55 (s, 1H), 2.10-2.04 (m, 2H), 2.02 (dd, J=8.2, 2.3 Hz, 1H), 1.89 (dd, J=8.2, 1.0 Hz, 1H), 1.25 (s, 12H), 1.22 (d, J=3.9 Hz, 3H), 1.20 (d, J=3.9 Hz, 3H) ppm.
[0298] .sup.13C NMR (151 MHz, CDCl.sub.3): 169.38, 83.32, 67.59, 55.03, 50.46, 44.96, 29.72, 25.01, 24.88, 21.96, 21.95 ppm.
[0299] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.65 ppm.
[0300] MS (GCMS, EI): m/z=265 (1.5%), 222 (10%), 149 (12%), 138 (70%), 94 (100%).
[0301] TLC: R.sub.f=0.36 (10:1 hexanes:ethyl acetate).
##STR00065##
2-(1-(4-methoxyphenyl)bicyclo[1.1.1]pentan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (38)
[0302] General Procedure B was followed on a 0.1 mmol scale with BCP bisboronate 27 under argon atmosphere heating for 6 h. Purification by flash chromatography (hexanes:ethyl acetate, 4:1) afforded 19.6 mg (65%) of the title compound 38.
[0303] Physical State: colorless oil.
[0304] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.21 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 3.78 (s, 3H), 2.68 (s, 1H), 2.61 (dd, J=9.7, 2.1 Hz, 1H), 2.08 (d, J=9.6 Hz, 1H), 2.05 (s, 1H), 2.00 (dd, J=8.2, 2.1 Hz, 1H), 1.89 (d, J=8.2 Hz, 1H), 1.25 (s, 6H), 1.24 (s, 6H) ppm.
[0305] .sup.13C NMR (151 MHz, CDCl.sub.3): 158.23, 134.47, 127.43, 113.45, 83.15, 55.65, 55.39, 51.39, 49.27, 28.71, 24.99, 24.96 ppm.
[0306] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.18 ppm.
[0307] MS (GCMS, EI): m/z=300 (14%), 200 (18%), 172 (90%), 133 (100%), 84 (54%).
[0308] TLC: R.sub.f=0.50 (10:1 hexanes:ethyl acetate).
##STR00066##
4,4,5,5-tetramethyl-2-((1s,3s)-1-methylbicyclo[1.1.1]pentan-2-yl)-1,3,2-dioxaborolane (39)
[0309] General Procedure B was followed on a 0.1 mmol scale with BCP bisboronate 14 under argon atmosphere heating for 5 hours. Purification by flash chromatography (hexanes:ethyl acetate, 40:1) afforded 12.6 mg (61%) of the title compound 39. Note: The compound is volatile.
[0310] Physical State: colorless oil.
[0311] .sup.1H NMR (600 MHz, CDCl.sub.3): 2.59 (s, 1H), 2.07 (dd, J=9.7, 2.2 Hz, 1H), 1.71 (dd, J=9.7, 1.4 Hz, 1H), 1.69 (s, 1H), 1.64 (dd, J=8.4, 2.2 Hz, 1H), 1.49 (dd, J=8.4, 1.1 Hz, 1H), 1.258 (s, 6H), 1.256 (s, 6H), 1.17 (s, 3H) ppm.
[0312] .sup.13C NMR (151 MHz, CDCl.sub.3): 82.96, 55.95, 51.30, 44.81, 29.44, 25.04, 24.95, 19.39 ppm.
[0313] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.16 ppm.
[0314] MS (GCMS, EI): m/z=193 (7%), 151 (8%), 135 (7%), 108 (100%), 67 (62%).
[0315] TLC: R.sub.f=0.50 (20:1 hexanes:ethyl acetate).
##STR00067##
4,4,5,5-tetramethyl-2-(1-(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)-1,3,2-dioxaborolane (40)
[0316] General Procedure B was followed on a 0.1 mmol scale with BCP bisboronate 26 under argon atmosphere in benzene solution heating at 100 C. for 12 hours. Purification by flash chromatography (hexanes:ethyl acetate, 40:1) afforded 17.4 mg (66%) of the title compound 40.
[0317] Physical State: colorless oil.
[0318] .sup.1H NMR (600 MHz, CDCl.sub.3): 2.67 (s, 1H), 2.58 (dd, J=9.5, 2.3 Hz, 1H), 2.03-1.98 (m, 2H), 1.96 (dd, J=8.2, 2.3 Hz, 1H), 1.84 (d, J=8.2 Hz, 1H), 1.254 (s, 6H), 1.252 (s, 6H) ppm.
[0319] .sup.13C NMR (151 MHz, CDCl.sub.3): 122.03 (q, J=277.2 Hz), 83.46, 52.13, 47.33, 43.36 (q, J=37.5 Hz), 29.72, 24.70, 24.69 ppm.
[0320] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.45 ppm.
[0321] .sup.19F NMR (565 MHz, CDCl.sub.3): 73.45 ppm.
[0322] MS (GCMS, EI): m/z=247 (11%), 153 (9%), 131 (29%), 83 (52%), 59 (100%).
[0323] TLC: R.sub.f=0.50 (20:1 hexanes:ethyl acetate).
##STR00068##
tert-butyl benzyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (41)
[0324] In a 5 mL screw-capped culture tube was added 24 (0.1 mmol), DMAP (30 mol %), MeOBcat (30 mol %) and (Ir[dF(CF.sub.3)ppy].sub.2(dtbpy))PF.sub.6 (5 mol %). CH.sub.3OH (0.5 mL) and acetone (0.5 mL) was added and the tube was sealed. The reaction was stirred under irradiation by blue LED for 2 hours when TLC analysis showed the consume of the starting material. The solvent was concentrated and the residue was purified by flash chromatography (hexanes:ethyl acetate, 10:1), which afforded 20.5 mg (53%) of the title compound 41. Note: the protodeborylation product of bis-Bpins was observed as the reaction time is extended.
[0325] Physical State: colorless oil.
[0326] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.30-7.26 (m, 2H), 7.24-7.21 (m, 2H), 7.19 (td, J=7.1, 1.4 Hz, 1H), 4.57-4.33 (m, 2H), 2.80-2.28 (m, 2H), 2.04 (dd, J=9.6, 1.3 Hz, 1H), 2.00-1.91 (m, 3H), 1.45 (br., 9H), 1.23 (s, 12H) ppm.
[0327] .sup.13C NMR (151 MHz, CDCl.sub.3): 140.09, 128.29, 126.76, 126.57, 83.16, 52.11, 48.88, 28.58, 25.79, 25.00 ppm. Note: NC(O), NC, NCH2, Me3C and BpinC were not observed.
[0328] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.29 ppm.
[0329] HRMS (ESI-TOF): calc'd for C.sub.23H.sub.34BNO.sub.4 [M+H].sup.+: 400.2653, found: 400.2655.
[0330] TLC: R.sub.f=0.39 (10:1 hexanes:ethyl acetate).
General Procedures C for Cyanation of BCP Bisboronates
##STR00069##
[0331] A flame-dried screw-capped culture tube was charged with BCP bisboronate (1.0 equiv.), p-toluenesulfonyl cyanide (2.0 equiv.) and tert-butyl catechol (0.25 equiv.). Then the tube or the flask was evacuated and backfilled with argon three times, followed by addition of toluene (0.2 M) via a syringe. After stirring for at 70 C. for 18-24 hours, and upon confirmation that the starting material was consumed totally, the reaction mixture was cooled to room temperature. Next, the solvent was removed under high vacuum, and the crude residue was purified by chromatography on silica gel. (Andrd-Joyaux et al., 2020)
##STR00070##
3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile (42)
[0332] General Procedure C was followed on a 0.1 mmol scale with BCP bisboronate 25, p-toluenesulfonyl cyanide and guaiacol (1.0 equiv.) as additive. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 19.5 mg (57%) of the title compound 42.
[0333] Physical State: colorless oil.
[0334] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.30-7.24 (m, 4H), 7.24-7.21 (m, 1H), 4.45 (s, 2H), 3.39 (s, 2H), 2.69 (dd, J=9.9, 2.3 Hz, 1H), 2.19-2.14 (m, 2H), 2.10 (dd, J=8.2, 2.3 Hz, 1H), 1.98 (d, J=8.2 Hz, 1H), 1.19 (s, 6H), 1.18 (s, 6H) ppm.
[0335] .sup.13C NMR (151 MHz, CDCl.sub.3): 138.26, 128.44, 127.71, 127.61, 118.00, 83.85, 73.17, 68.93, 57.33, 52.55, 45.48, 26.01, 24.87, 24.84 ppm.
[0336] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.02 ppm.
[0337] MS (GCMS, EI): m/z=324 (0.2%), 238 (1%), 190 (4%), 176 (6%), 133 (5%), 91 (100%).
[0338] TLC: R.sub.f=0.28 (10:1 hexanes:ethyl acetate).
##STR00071##
3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile (43)
[0339] General Procedure C was followed on a 0.2 mmol scale with BCP bisboronate 14, and p-toluenesulfonyl cyanide. Purification by flash chromatography (hexanes:ethyl acetate, 50:1) afforded 23.0 mg (50%) of the title compound 43.
[0340] Physical State: white solid.
[0341] m.p.: 44-46 C.
[0342] .sup.1H NMR (600 MHz, CDCl.sub.3): 2.56 (dd, J=9.7, 2.3 Hz, 1H), 2.14-2.11 (m, 2H), 2.05 (dd, J=8.4, 2.4 Hz, 1H), 1.92 (d, J=8.3 Hz, 1H), 1.26 (s, 12H), 1.19 (s, 3H) ppm.
[0343] .sup.13C NMR (151 MHz, CDCl.sub.3): 118.13, 83.79, 59.60, 54.83, 43.87, 25.19, 24.96, 24.93, 17.82 ppm.
[0344] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.12 ppm.
[0345] MS (GCMS, EI): m/z=218 (23%), 176 (20%), 160 (23%), 133 (80%), 55 (100%).
[0346] TLC: R.sub.f=0.28 (10:1 hexanes:ethyl acetate).
General Procedures D for CS & CN Formation of BCP Bisboronates
##STR00072##
[0347] A flame-dried screw-capped culture tube was charged with BCP bisboronate (1.0 equiv.), radical trapping reagent (2.0 equiv., PhSO.sub.2SPh or DBAD) and tert-butyl catechol (0.25 equiv.). Then the tube or the flask was evacuated and backfilled with argon three times, followed by addition of toluene (0.2 M) via a syringe. The reaction mixture was stirred at 70 C. or 100 C. (according to details provided below) for 18-24 hours. After confirmation that the starting material was consumed totally, the reaction mixture was cooled to room temperature. Next, the solvent was removed under high vacuum, and the crude residue was purified by chromatography on silica gel.
##STR00073##
2-(1-((benzyloxy)methyl)-3-(phenylthio)bicyclo[1.1.1]pentan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (44)
[0348] General Procedure D was followed on a 0.1 mmol scale. BCP bisboronate 25, and PhSO.sub.2SPh were reacted at 100 C. for 24 h. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 29.6 mg (64%) of the title compound 44.
[0349] Physical State: colorless oil.
[0350] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.46-7.41 (m, 2H), 7.32-7.16 (m, 8H), 4.46 (s, 2H), 3.44 (s, 2H), 2.54 (dd, J=9.5, 1.9 Hz, 1H), 1.87 (dd, J=8.1, 1.9 Hz, 1H), 1.85-1.81 (m, 2H), 1.67 (d, J=8.0 Hz, 1H), 1.142 (s, 6H), 1.138 (s, 6H) ppm.
[0351] .sup.13C NMR (151 MHz, CDCl.sub.3): 138.67, 134.17, 134.12, 128.78, 128.40, 127.60, 127.57, 127.55, 83.22, 72.96, 69.71, 57.80, 52.05, 45.30, 42.19, 24.92, 24.87 ppm.
[0352] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.13 ppm.
[0353] MS (GCMS, EI): m/z=422 (0.1%), 331 (2%), 239 (10%), 187 (12%), 91 (100%).
[0354] TLC: R.sub.f=0.48 (10:1 hexanes:ethyl acetate).
##STR00074##
isopropyl 3-(phenylthio)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (45)
[0355] General Procedure D was followed on a 0.1 mmol scale. BCP bisboronate 23, and PhSO.sub.2SPh were reacted at 70 C. for 24 h. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 13.0 mg (35%) of the title compound 45.
[0356] Physical State: colorless oil.
[0357] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.48-7.43 (m, 2H), 7.31-7.27 (m, 3H), 4.95 (hept, J=6.3 Hz, 1H), 2.90 (dd, J=9.4, 1.9 Hz, 1H), 2.20-2.13 (m, 1H), 2.12 (s, 1H), 2.12-2.07 (m, 1H), 2.01-1.92 (m, 1H), 1.22 (s, 6H), 1.21 (s, 6H), 1.18 (d, J=6.3 Hz, 6H) ppm.
[0358] .sup.13C NMR (151 MHz, CDCl.sub.3): 168.60, 134.51, 133.16, 128.95, 128.04, 83.50, 68.10, 59.22, 53.67, 45.08, 41.21, 25.02, 25.01, 24.82, 21.90 ppm.
[0359] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.01 ppm.
[0360] MS (GCMS, EI): m/z=388 (1.2%), 345 (33%), 269 (10%), 237 (20%), 125 (44%), 83 (100%).
[0361] TLC: R.sub.f=0.45 (10:1 hexanes:ethyl acetate).
##STR00075##
di-tert-butyl 1-(3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)hydrazine-1,2-dicarboxylate (46)
[0362] General Procedure D was followed on a 0.1 mmol scale. BCP bisboronate 25, and di-tert-butyl azodicarboxylate (DBAD) were reacted at 100 C. for 24 h. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 27.2 mg (50%) of the title compound 46.
[0363] Physical State: red oil.
[0364] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.36-7.23 (m, 5H), 6.66 (s, 0.5H), 6.15 (s, 0.5H), 4.54 (s, 2H), 3.61 (s, 2H), 2.57-1.68 (m, 5H), 1.46 (s, 9H), 1.45 (s, 9H), 1.21 (s, 12H) ppm.
[0365] .sup.13C NMR (151 MHz, CDCl.sub.3): 138.82, 128.40, 127.61, 127.52, 83.37, 72.97, 69.05, 28.45, 28.34, 24.95, 24.90 ppm. Note: Me.sub.3C, C(O) and all the carbon of BCP skeleton were not observed.
[0366] .sup.11B NMR (128 MHz, CDCl.sub.3): 30.76 ppm.
[0367] HRMS (ESI-TOF): calc. for C.sub.29H.sub.45BN.sub.2O.sub.7[M+H].sup.+: 545.3393, found: 545.3374.
[0368] TLC: R.sub.f=0.59 (2:1 hexanes:ethyl acetate).
##STR00076##
di-tert-butyl 1-(3-(4-methoxyphenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo [1.1.1]pentan-1-yl)hydrazine-1,2-dicarboxylate (47)
[0369] General Procedure D was followed on a 0.1 mmol scale. BCP bisboronate 27, and di-tert-butyl azodicarboxylate (DBAD) were reacted at 100 C. for 24 h. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 23.9 mg (45%) of the title compound 47.
[0370] Physical State: light yellow foam.
[0371] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.21 (d, J=8.1 Hz, 2H), 6.82 (d, J=8.6 Hz, 2H), 6.65 (br., 0.5H), 6.16 (br., 0.5H), 3.78 (s, 3H), 2.98-2.60 (m, 1H), 2.52-2.25 (m, 2H), 2.20-1.97 (m, 2H), 1.54-1.44 (m, 18H), 1.24 (s, 12H) ppm.
[0372] .sup.13C NMR (151 MHz, CDCl.sub.3): 158.44, 131.80, 127.93, 113.59, 83.45, 55.41, 28.46, 28.34, 25.03, 24.92 ppm. Note: Me.sub.3C, C(O) and all the carbon of BCP skeleton were not observed.
[0373] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.11 ppm.
[0374] HRMS (ESI-TOF): calc. for C.sub.28H.sub.43BN.sub.2O.sub.7[M+H].sup.+: 531.3236, found: 531.3235.
[0375] TLC: R.sub.f=0.59 (2:1 hexanes:ethyl acetate).
General Procedure E for Giese-Type-Reaction of BCP BisBoronates
##STR00077##
[0376] A screw-capped culture tube was charged with (Ir[dF(CF.sub.3)ppy].sub.2(dtbpy))PF.sub.6 (5 mol %), DMAP (30 mol %), BCP bisboronate (1.0 equiv.) and Michael acceptor (2.0 equiv.). Then the tube or the flask was evacuated and backfilled with argon three times, followed by addition of methanol/acetone (0.1 M, 1:1) solvent via a syringe. The headspace of the tube was then purged with a gentle stream of argon for approximately 10 seconds. After stirring in a 450-nm photoreactor for 24 hours, it was confirmed that the starting material was totally consumed and the reaction mixture was concentrated under high vacuum. The crude residue was then purified by chromatography on silica gel (Lima et al., 2017).
##STR00078##
4-(3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)butan-2-one (48)
[0377] General Procedure E was followed on a 0.05 mmol scale with BCP bisboronate 25 and methyl vinyl ketone. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 13.5 mg (70%) of the title compound 48.
[0378] Physical State: colorless oil.
[0379] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.35-7.29 (m, 4H), 7.27-7.23 (m, 1H), 4.53 (s, 2H), 3.47 (s, 2H), 2.42 (dd, J=8.6, 6.9 Hz, 2H), 2.14 (s, 3H), 2.11 (dd, J=9.9, 2.0 Hz, 1H), 1.79 (t, J=7.7 Hz, 2H), 1.61-1.58 (m, 2H), 1.55 (dd, J=8.2, 2.0 Hz, 1H), 1.44-1.38 (m, 1H), 1.21 (s, 12H) ppm.
[0380] .sup.13C NMR (151 MHz, CDCl.sub.3): 209.17, 139.00, 128.36, 127.57, 127.44, 82.96, 72.93, 70.40, 53.49, 48.17, 42.45, 41.01, 40.72, 29.93, 26.48, 24.96, 24.95 ppm.
[0381] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.69 ppm.
[0382] MS (GCMS, EI): m/z=369 (0.1%), 326 (0.2%), 275 (0.2%), 149 (10%), 91 (100%).
[0383] TLC: R.sub.f=0.32 (4:1 hexanes:ethyl acetate).
##STR00079##
ethyl 3-(3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)propanoate (49)
[0384] General Procedure E was followed on a 0.1 mmol scale with BCP bisboronate 25 and ethyl acrylate. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 15.7 mg (38%) of the title compound 49.
[0385] Physical State: colorless oil.
[0386] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.36-7.30 (m, 4H), 7.29-7.23 (m, 1H), 4.53 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 3.48 (s, 2H), 2.29 (td, J=7.5, 1.8 Hz, 2H), 2.12 (dd, J=9.8, 2.0 Hz, 1H), 1.85 (t, J=7.8 Hz, 2H), 1.63-1.59 (m, 2H), 1.57 (dd, J=8.3, 2.0 Hz, 1H), 1.42 (d, J=8.2 Hz, 1H), 1.25 (t, J=7.2 Hz, 3H), 1.21 (s, 12H) ppm.
[0387] .sup.13C NMR (151 MHz, CDCl.sub.3): 173.95, 139.01, 128.36, 127.58, 127.44, 82.96, 72.94, 70.41, 60.34, 53.40, 48.12, 42.46, 40.69, 31.71, 27.58, 24.95, 24.93, 14.35 ppm.
[0388] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.62 ppm.
[0389] MS (GCMS, EI): m/z=399 (0.1%), 369 (0.1%), 323 (0.2%), 179 (10%), 91 (100%).
[0390] TLC: R.sub.f=0.54 (4:1 hexanes:eth acetate).
##STR00080##
3-(3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)propanenitrile (50)
[0391] General Procedure E was followed on a 0.1 mmol scale with BCP bisboronate 25 and acrylonitrile. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 20.0 mg (55%) of the title compound 50.
[0392] Physical State: colorless oil.
[0393] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.35-7.30 (m, 4H), 7.30-7.23 (m, 1H), 4.53 (s, 2H), 3.50 (s, 2H). 2.34 (t. J=7.5 Hz, 2H), 2.13 (dd, J=10.0, 2.2 Hz, 1H), 1.89 (t, J=7.5 Hz, 2H), 1.73-1.69 (m, 2H), 1.66 (dd, J=8.3, 2.1 Hz, 1H), 1.47 (d, J=8.2 Hz, 1H), 1.213 (s, 6H), 1.208 (s, 6H) ppm.
[0394] .sup.13C NMR (151 MHz, CDCl.sub.3): 138.88, 128.37, 127.57, 127.49, 120.28, 83.19, 72.99, 70.07, 53.51, 48.42, 41.61, 40.95, 28.16, 24.95, 14.52 ppm.
[0395] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.66 ppm.
[0396] MS (GCMS, EI): m/z=352 (0.1%), 338 (0.1%), 324 (0.1%), 161 (5%), 132 (10%), 91 (100%).
[0397] TLC: R.sub.f=0.39 (4:1 hexanes:ethyl acetate).
##STR00081##
3-(3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)cyclohexan-1-one (51)
[0398] General Procedure E was followed on a 0.1 mmol scale with BCP bisboronate 25 and cyclohexenone. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 22.8 mg (56%) of the title compound 51. Note: two diastereoisomers (1/1) were observed.
[0399] NMR spectroscopy of the mixture was given.
[0400] Physical State: colorless oil.
[0401] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.35-7.28 (m, 4H), 7.29-7.21 (m, 1H), 4.53 (s, 2H), 3.49 (s, 2H), 2.36-2.28 (m, 2H), 2.24-2.15 (m, 2H), 2.10-1.98 (m, 2H), 1.90 (tt, J=12.3, 3.7 Hz, 1H), 1.86-1.79 (m, 1H), 1.66-1.51 (m, 4H), 1.41 (dd, J=11.1, 8.1 Hz, 1H), 1.34-1.27 (m, 1H), 1.20 (s, 6H), 1.19 (s, 6H) ppm.
[0402] .sup.13C NMR (151 MHz, CDCl.sub.3): 212.61, 138.90, 128.37, 127.58, 127.47, 83.02, 83.00, 72.98, 70.37, 70.35, 51.37, 51.24, 46.22, 46.20, 46.09, 46.07, 44.87, 44.85, 41.38, 41.34, 40.57, 40.50, 39.97, 39.95, 28.08, 28.00, 25.59, 25.48, 24.91, 24.87 ppm.
[0403] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.00 ppm.
[0404] MS (GCMS, EI): m/z=395 (0.1%), 352 (0.2%), 301 (0.2%), 219 (3%), 175 (6%), 91 (100%).
[0405] TLC: R.sub.f=0.36 (4:1 hexanes:ethyl acetate).
##STR00082##
isopropyl 3-(3-oxobutyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (52)
[0406] General Procedure E was followed on a 0.1 mmol scale with BCP bisboronate 23 and methyl vinyl ketone. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 12.9 mg (38%) of the title compound 52.
[0407] Physical State: colorless oil.
[0408] .sup.1H NMR (600 MHz, CDCl.sub.3): 4.97 (hept, J=6.3 Hz, 1H), 2.47 (dd, J=9.9, 2.1 Hz, 1H), 2.44-2.38 (m, 2H), 2.13 (s, 3H), 1.87-1.83 (m, 2H), 1.82 (dd, J=8.1, 2.1 Hz, 1H), 1.78 (ddd, J=11.2, 6.7, 3.4 Hz, 2H), 1.67 (d, J=8.1 Hz, 1H), 1.241 (s, 6H), 1.238 (s, 6H), 1.21 (d, J=2.9 Hz, 3H), 1.20 (d, J=2.9 Hz, 3H) ppm. .sup.13C NMR (151 MHz, CDCl.sub.3): 208.53, 169.90, 83.26, 67.64, 55.18, 50.05, 41.72, 40.64, 39.95, 29.98, 25.85, 25.01, 24.89, 21.96, 21.95 ppm.
[0409] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.62 ppm.
[0410] MS (GCMS, EI): m/z=335 (0.8%), 292 (5%), 208 (10%), 190 (20%), 121 (80%), 55 (100%).
[0411] TLC: R.sub.f=0.29 (4:1 hexanes:ethyl acetate).
##STR00083##
tert-butyl benzyl(3-(3-oxobutyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (53)
[0412] General Procedure E was followed on a 0.1 mmol scale with BCP bisboronate 24 and methyl vinyl ketone. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 13.6 mg (29%) of the title compound 53.
[0413] Physical State: colorless oil.
[0414] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.42-7.22 (m, 2H), 7.23-7.16 (m, 3H), 4.52-4.41 (m, 2H), 2.37 (t, J=7.7 Hz, 2H), 2.10 (s, 3H), 1.84 (dd, J=9.6, 1.2 Hz, 1H), 1.82-1.71 (m, 5H), 1.57-1.32 (m, 10H), 1.22 (s, 12H) ppm.
[0415] .sup.13C NMR (151 MHz, CDCl.sub.3): 208.73, 140.05, 128.29, 126.73, 126.59, 83.11, 79.83 (br.), 51.62, 49.08 (br.), 41.25, 38.27, 29.93, 28.58, 25.05, 25.00, 24.44 ppm. Note: NC(O), NC, NCH.sub.2 and BpinC were not observed.
[0416] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.06 ppm.
[0417] HRMS (ESI-TOF): calc. for C.sub.27H.sub.40BNO.sub.5 [M+H].sup.+: 470.3072, found: 470.3069.
[0418] TLC: R.sub.f=0.32 (4:1 hexanes:ethyl acetate).
##STR00084##
isopropyl 3-(2-(pyridin-4-yl)ethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo [1.1.1]pentane-1-carboxylate (54)
[0419] General Procedure E was followed on a 0.1 mmol scale with BCP bisboronate 23 and 4-vinylpyridine. Purification by flash chromatography (hexanes:ethyl acetate, 2:1) afforded 20.5 mg (53%) of the title compound 54.
[0420] Physical State: pale yellow oil.
[0421] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.49 (br., 2H), 7.14 (br., 2H), 4.97 (hept, J=6.2 Hz, 1H), 2.59 (td, J=7.7, 4.4 Hz, 2H), 2.50 (dd, J=9.9, 2.0 Hz, 1H), 1.90-1.87 (m, 2H), 1.87-1.83 (m, 3H), 1.72 (d, J=8.1 Hz, 1H), 1.240 (s, 6H), 1.238 (s, 6H), 1.21 (d, J=2.8 Hz, 3H), 1.20 (d, J=2.8 Hz, 3H) ppm.
[0422] .sup.13C NMR (151 MHz, CDCl.sub.3): 169.84, 151.88, 149.29, 124.15, 83.28, 67.70, 55.28, 50.27, 42.07, 40.04, 32.25, 32.20, 24.99, 24.92, 21.94 ppm.
[0423] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.50 ppm.
[0424] HRMS (ESI-TOF): calc'd for C.sub.22H.sub.32BNO.sub.4 [M+H].sup.+: 386.2497, found: 386.2498.
[0425] TLC: R.sub.f=0.23 (1:1 hexanes:ethyl acetate).
General Procedure F for Cross-Coupling of BCP Bisboronates
##STR00085##
General Procedure F1:
[0426] A flame-dried screw-capped culture tube was charged with BCP bisboronate (1.0 equiv.), aryl bromide (3.0 equiv.), 4-CzlPn (5 mol %), Ni(dtbbpy)Cl.sub.2 (10 mol %), Zn(OTf).sub.2 (2.0 equiv.) and DMAP (4.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of DMA (0.2 M) solvent via a syringe. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was allowed to stir in a 450-nm PennPhD integrated photoreactor (M2) for 24-60 hours. After it was confirmed that the starting material was totally consumed, the reaction mixture quenched with water, extracted with ethyl acetate or diethyl ether, washed with brine, dried by Na.sub.2SO.sub.4, and concentrated under high vacuum. The crude residue was purified by chromatography on silica gel.
General Procedure F2:
[0427] Preparation of [Ni] catalyst: A flame-dried screw-capped culture tube was charged with Ni(cod).sub.2 (0.2 mmol, 55 mg) and dtbbpy (0.24 mmol, 64.4 mg). The tube was then evacuated and backfilled with argon three times, followed by addition of DMA (4.0 mL) solvent via a syringe. Next, the tube was sonicated for 20 minutes to dissolve the catalyst.
[0428] A flame-dried screw-capped culture tube was charged with BCP bisboronate (1.0 equiv.), aryl bromide (3.0 equiv.), Zn(OTf).sub.2 (2.0 equiv.) and DMAP (4.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of 4-CzlPn solution (0.02 equiv., 0.02 M) in DMA and [Ni] catalyst solution (0.2 equiv., 0.05 M) in DMA via a syringe. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was allowed to stir in a 450-nm PennPhD integrated photoreactor (M2) for 24-60 hours. After it was confirmed that the starting material was totally consumed, the reaction mixture was quenched with water, extracted with ethyl acetate or diethyl ether, washed with brine, dried by Na.sub.2SO.sub.4, and concentrated under high vacuum. The crude residue was purified by chromatography on silica gel.
Scale-Up of Cross-Coupling of BCP Boronate 14 & 23:
[0429] Preparation of [Ni] catalyst: A flame-dried screw-capped culture tube was charged with Ni(cod).sub.2 (0.4 mmol, 110 mg) and dtbbpy (0.48 mmol, 128.8 mg). Then the tube was evacuated and backfilled with argon three times, followed by addition of DMA (8.0 mL) solvent via a syringe. Next, the tube was sonicated for 20 minutes to form a dark purple solution of Ni catalyst.
[0430] Scale-up preparation of BCP boronate 65: A flame-dried screw-capped culture tube was charged with BCP bisboronate 14 (668 mg, 2.0 mmol, 1.0 equiv.), Zn(OTf).sub.2 (1.46 mg, 4.0 mmol, 2.0 equiv.) and DMAP (977.6 mg, 8.0 mmol, 4.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of phenyl bromide (0.62 mL, 6.0 mmol, 3.0 equiv.), 4-CzlPn solution (1.0 mL, 0.05 equiv., 0.05 M) in DMA and [Ni] catalyst solution (8.0 mL, 0.2 equiv., 0.05 M) in DMA via a syringe. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds. The reaction tube was sealed and then irradiated under a 40 W Kessil blue LED lamp (468 nm) for 60 hours with a fan running to cool the reaction down. After it was confirmed that the starting material was totally consumed, the reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (10 mL2) and diethyl ether (10 mL2), washed with brine (10 mL2), dried by Na.sub.2SO.sub.4, and concentrated under high vacuum. The crude residue was purified by chromatography on silica gel which afforded 209.6 mg (37%) product as colorless oil.
[0431] Scale-up preparation of BCP boronate 55: A flame-dried screw-capped culture tube was charged with BCP bisboronate 23 (406 mg, 1.0 mmol, 1.0 equiv.), 4-bromophenyl methyl sulfone (705 mg, 3.0 mmol, 3.0 equiv.), Zn(OTf).sub.2 (732 mg, 2.0 mmol, 2.0 equiv.) and DMAP (488.8 mg, 4.0 mmol, 4.0 equiv.). Then the tube was evacuated and backfilled with argon for three times, followed by addition of 4-CzlPn solution (1.0 mL, 0.02 equiv., 0.02 M) in DMA and [Ni] catalyst solution (4.0 mL, 0.2 equiv., 0.05 M) in DMA via a syringe. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was sealed and then irradiated under a 40 W Kessil blue LED lamp (468 nm) for 48 hours with a fan running to cool the reaction down. After it is confirmed that the starting material was consumed totally, the reaction mixture quenched with water (30 mL), extracted with ethyl acetate (10 mL2) and diethyl ether (10 mL2), washed with brine (10 mL2), dried by Na.sub.2SO.sub.4, and concentrated under high vacuum. The crude residue was purified by chromatography on silica gel and that afforded 200.0 mg (46%) product as colorless oil.
##STR00086##
isopropyl 3-(4-(methylsulfonyl)phenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (55)
[0432] General Procedure F2 was followed on a 0.1 mmol scale. BCP bisboronate 23 and 4-bromophenyl methyl sulfone were reacted for 60 hours. Purification by flash chromatography (methylene chloride:ethyl acetate, 50:1 to 20:1) afforded 22.4 mg (52%) of the title compound 55.
[0433] Scale-up of preparation of BCP boronate 55 was followed on a 1.0 mmol scale. BCP bisboronate 23 and 4-bromophenyl methyl sulfone were reacted accordingly for 48 hours. Purification by flash chromatography (methylene chloride:ethyl acetate, 50:1 to 20:1) afforded 200.0 mg (46%) of the title compound 55.
[0434] Physical State: white solid.
[0435] m.p.: 114-116 C.
[0436] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.88-7.84 (m, 2H), 7.49-7.45 (m, 2H), 5.04 (hept, J=6.3 Hz, 1H), 3.05 (dd, J=10.0, 1.9 Hz, 1H), 3.03 (s, 3H), 2.37-2.32 (m, 2H), 2.27 (dd, J=8.1, 2.0 Hz, 1H), 2.15 (d, J=8.0 Hz, 1H), 1.26 (d, J=2.5 Hz, 3H), 1.25-1.24 (m, 15H) ppm.
[0437] .sup.13C NMR (151 MHz, CDCl.sub.3): 169.58, 146.67, 138.89, 127.54, 127.45, 83.68, 68.13, 56.72, 52.42, 44.72, 43.53, 39.60, 24.96, 24.91, 21.98 ppm.
[0438] .sup.11B NMR (128 MHz, CDCl.sub.3): 30.90 ppm.
[0439] HRMS (ESI-TOF): calc'd for C.sub.22H.sub.31BO.sub.6S [M+H].sup.+: 435.2007, found: 435.2000.
[0440] TLC: R.sub.f=0.20 (2:1 hexanes:ethyl acetate).
##STR00087##
2-(1-((benzyloxy)methyl)-3-(4-(methylsulfonyl)phenyl)bicyclo[1.1.1]pentan-2-yl)-4,4,5,5-tetra methyl-1,3,2-dioxaborolane (56)
[0441] General Procedure F1 was followed on a 0.1 mmol scale. BCP bisboronate 25 and 4-bromophenyl methyl sulfone were reacted accordingly for 48 hours. Purification by flash chromatography (methylene chloride:ethyl acetate, 50:1 to 20:1) afforded 19.8 mg (42%) of the title compound 56.
[0442] Physical State: pale yellow oil.
[0443] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.84 (dd, J=8.2, 1.3 Hz, 2H), 7.51-7.46 (m, 2H), 7.40-7.31 (m, 4H), 7.30-7.27 (m, 1H), 4.58 (s, 2H), 3.58 (s, 2H), 3.03 (s, 3H), 2.74-2.69 (m, 1H), 2.09 (d, J=8.9 Hz, 2H), 2.00 (dd, J=8.0, 1.7 Hz, 1H), 1.87 (d, J=8.1 Hz, 1H), 1.20 (s, 12H) ppm.
[0444] .sup.13C NMR (151 MHz, CDCl.sub.3): 147.83, 138.77, 138.35, 128.43, 127.64, 127.59, 127.52, 127.30, 83.37, 73.14, 70.06, 55.30, 50.64, 44.75, 44.42, 40.55, 24.93, 24.91 ppm.
[0445] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.32 ppm.
[0446] HRMS (ESI-TOF): calc'd for C.sub.26H.sub.33BO.sub.5S [M+H].sup.+: 469.2215, found: 469.2222.
[0447] TLC: R.sub.f=0.25 (2:1 hexanes:ethyl acetate).
##STR00088##
2-(1-(4-methoxyphenyl)-3-(4-(methylsulfonyl)phenyl)bicyclo[1.1.1]pentan-2-yl)-4,4,5,5-tetra methyl-1,3,2-dioxaborolane (57)
[0448] General Procedure F2 was followed on a 0.1 mmol scale. BCP bisboronate 27 and 4-bromophenyl methyl sulfone were reacted accordingly for 48 hours. Purification by flash chromatography (methylene chloride:ethyl acetate, 50:1) afforded 22.2 mg (31%) of the title compound 57.
[0449] Physical State: white solid.
[0450] m.p.: 155-157 C.
[0451] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.90-7.85 (m, 2H), 7.56-7.51 (m, 2H), 7.29-7.24 (m, 2H), 6.88-6.83 (m, 2H), 3.80 (s, 3H), 3.11 (dd, J=9.6, 1.9 Hz, 1H), 3.04 (s, 3H), 2.37 (dd, J=9.6, 1.2 Hz, 1H), 2.32 (s, 1H), 2.24 (dd, J=8.1, 1.9 Hz, 1H), 2.16 (d, J=7.9 Hz, 1H), 1.22 (s, 6H), 1.21 (s, 6H) ppm.
[0452] .sup.13C NMR (151 MHz, CDCl.sub.3): 158.57, 147.87, 138.42, 133.02, 127.57 (2C), 127.35, 113.65, 83.49, 57.64, 55.43, 52.84, 44.77, 43.36, 42.82, 25.00, 24.92 ppm.
[0453] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.22 ppm.
[0454] HRMS (ESI-TOF): calc'd for C.sub.25H.sub.31BO.sub.5S [M+H].sup.+: 455.2058, found: 455.2058.
[0455] TLC: R.sub.f=0.28 (2:1 hexanes:ethyl acetate).
##STR00089##
4,4,5,5-tetramethyl-2-(1-methyl-3-(4-(methylsulfonyl)phenyl)bicyclo[1.1.1]pentan-2-yl)-1,3,2-dioxaborolane (58)
[0456] General Procedure F2 was followed on a 0.1 mmol scale. BCP bisboronate 14 and 4-bromophenyl methyl sulfone were reacted accordingly for 48 hours. Purification by flash chromatography (hexanes:methylene chloride, 1:1) afforded 15.7 mg (43%) of the title compound 58.
[0457] Physical State: white solid.
[0458] m.p.: 88-90 C. 1H NMR (600 MHz, CDCl.sub.3): 7.85-7.80 (m, 2H), 7.49-7.44 (m, 2H), 3.02 (s, 3H), 2.55 (dd, J=9.7, 2.0 Hz, 1H), 2.01-1.96 (m, 2H), 1.89 (dd, J=8.3, 2.0 Hz, 1H), 1.77 (d, J=8.3 Hz, 1H), 1.29 (s, 3H), 1.24 (s, 12H) ppm.
[0459] .sup.13C NMR (151 MHz, CDCl.sub.3): 148.14, 138.10, 127.53, 127.24, 83.28, 57.75, 53.02, 44.77, 43.56, 38.54, 25.01, 24.97, 18.36 ppm.
[0460] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.95 ppm.
[0461] MS (GCMS, EI): m/z=347 (3%), 262 (14%), 234 (60%), 141 (40%), 84 (100%).
[0462] TLC: R.sub.f=0.38 (2:1 hexanes:ethyl acetate).
##STR00090##
4,4,5,5-tetramethyl-2-(1-(4-(methylsulfonyl)phenyl)-3-(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)-1,3,2-dioxaborolane (59)
[0463] General Procedure F2 was followed on a 0.1 mmol scale. BCP bisboronate 26 and 4-bromophenyl methyl sulfone were reacted accordingly for 48 hours. Purification by flash chromatography (hexanes:methylene chloride, 1:1) afforded 13.0 mg (31%) of the title compound 59.
[0464] Physical State: white solid.
[0465] m.p.: 95-97 C.
[0466] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.92-7.85 (m, 2H), 7.51-7.44 (m, 2H), 3.08 (dd, J=9.6, 2.1 Hz, 1H), 3.04 (s, 3H), 2.30 (dd, J=9.6, 1.5 Hz, 1H), 2.27 (s, 1H), 2.21 (dd, J=8.1, 2.1 Hz, 1H), 2.11 (d, J=8.1 Hz, 1H), 1.24 (s, 12H) ppm.
[0467] .sup.13C NMR (151 MHz, CDCl.sub.3): 145.53, 139.28, 127.56, 127.54, 123.04 (q, J=276.4 Hz), 83.97, 54.16, 49.22, 44.69, 43.31, 38.91 (q, J=38.5 Hz), 24.83, 24.78 ppm.
[0468] .sup.19F NMR (376 MHz, CDCl.sub.3): 72.73 ppm.
[0469] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.29 ppm.
[0470] HRMS (ESI-TOF): calc'd for C.sub.19H.sub.24BF.sub.3O.sub.4S [M+H].sup.+: 417.1513, found: 417.1510.
[0471] TLC: R.sub.f=0.35 (2:1 hexanes:ethyl acetate).
##STR00091##
isopropyl 3-(4-(ethoxycarbonyl)phenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo [1.1.1]pentane-1-carboxylate (60)
[0472] General Procedure F2 was followed on a 0.1 mmol scale. BCP bisboronate 23 and ethyl 4-bromo-benzoate were reacted accordingly for 48 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 15.0 mg (35%) of the title compound 60.
[0473] Physical State: white solid.
[0474] m.p.: 54-56 C.
[0475] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.98-7.94 (m, 2H), 7.35-7.30 (m, 2H), 5.03 (hept, J=6.3 Hz, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.06 (dd, J=9.9, 2.0 Hz, 1H), 2.32 (d, J=8.8 Hz, 2H), 2.26 (dd, J=8.1, 1.9 Hz, 1H), 2.13 (d, J=7.9 Hz, 1H), 1.38 (t, J=7.1 Hz, 3H), 1.25 (d, J=2.2 Hz, 3H), 1.24 (d, J=2.2 Hz, 3H), 1.24 (s, 6H), 1.23 (s, 6H) ppm.
[0476] .sup.13C NMR (151 MHz, CDCl.sub.3): 169.90, 166.73, 145.44, 129.56, 128.98, 126.47, 83.52, 67.98, 61.01, 56.83, 52.29, 43.87, 39.54, 24.96, 24.89, 22.00, 14.49 ppm.
[0477] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.40 ppm.
[0478] MS (GCMS, EI): m/z=413 (4%), 386 (4%), 371 (7%), 286 (30%), 242 (55%), 169 (100%).
[0479] TLC: R.sub.f=0.66 (3:1 hexanes:ethyl acetate).
##STR00092##
isopropyl 3-(4-acetylphenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (61)
[0480] General Procedure F2 was followed on a 0.1 mmol scale. BCP bisboronate 23 and 4-Bromoacetophenone were reacted accordingly for 48 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) and afforded 12.9 mg (38%) of the title compound 61.
[0481] Physical State: white solid.
[0482] m.p.: 39-41 C.
[0483] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.91-7.86 (m, 2H), 7.38-7.33 (m, 2H), 5.03 (hept, J=6.3 Hz, 1H), 3.06 (dd, J=9.8, 2.0 Hz, 1H), 2.58 (s, 3H), 2.33 (d, J=9.0 Hz, 2H), 2.27 (dd, J=8.1, 2.0 Hz, 1H), 2.13 (d, J=8.0 Hz, 1H), 1.26 (d, J=2.3 Hz, 3H), 1.25-1.23 (m, 15H) ppm.
[0484] .sup.13C NMR (151 MHz, CDCl.sub.3): 198.00, 169.84, 145.82, 135.75, 128.43, 126.72, 83.55, 68.01, 56.81, 52.32, 43.83, 39.57, 26.79, 24.97, 24.89, 21.99 ppm.
[0485] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.88 ppm.
[0486] HRMS (ESI-TOF): calc'd for C.sub.23H.sub.31B.sub.05 [M+H].sup.+: 399.2337, found: 399.2342.
[0487] TLC: R.sub.f=0.50 (3:1 hexanes:ethyl acetate).
##STR00093##
isopropyl 3-(4-cyanophenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (62)
[0488] General Procedure F2 was followed on a 0.1 mmol scale with BCP bisboronate 23 and 4-bromobenzonitrile were reacted accordingly for 48 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 14.7 mg (39%) of the title compound 62.
[0489] Physical State: white solid.
[0490] m.p.: 57-59 C.
[0491] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.58 (d, J=8.3 Hz, 2H), 7.39-7.36 (m, 2H), 5.03 (hept, J=6.3 Hz, 1H), 3.02 (dd, J=9.8, 2.0 Hz, 1H), 2.34-2.30 (m, 2H), 2.25 (dd, J=8.1, 2.0 Hz, 1H), 2.13 (d, J=8.0 Hz, 1H), 1.25 (d, J=2.5 Hz, 3H), 1.24 (d, J=2.6 Hz, 3H), 1.24 (s, 6H) 1.23 (s, 6H) ppm.
[0492] .sup.13C NMR (151 MHz, CDCl.sub.3): 169.58, 145.66, 132.13, 127.33, 119.17, 110.60, 83.65, 68.11, 56.72, 52.24, 43.64, 39.56, 24.95, 24.88, 21.98, 21.97 ppm.
[0493] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.54 ppm.
[0494] MS (GCMS, EI): m/z=381 (6%), 365 (2%), 341 (4%), 283 (5%), 239 (14%), 195 (100%).
[0495] TLC: R.sub.f=0.56 (3:1 hexanes:ethyl acetate).
##STR00094##
isopropyl 3-(4-methoxyphenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (63)
[0496] General Procedure F2 was followed on a 0.1 mmol scale. BCP bisboronate 23 and 4-bromo-anisole were reacted accordingly for 48 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 12.8 mg (33%) of the title compound 63.
[0497] Physical State: white solid.
[0498] m.p.: 38-40 C.
[0499] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.22-7.17 (m, 2H), 6.85-6.80 (m, 2H), 5.07-4.98 (hept, J=6.3 Hz, 1H), 3.78 (s, 3H), 3.01 (dd, J=9.5, 1.9 Hz, 1H), 2.29-2.24 (m, 2H), 2.20 (dd, J=8.1, 1.9 Hz, 1H), 2.07 (d, J=7.9 Hz, 1H), 1.27-1.19 (m, 18H) ppm.
[0500] .sup.13C NMR (151 MHz, CDCl.sub.3): 170.28, 158.61, 132.83, 127.57, 113.63, 83.36, 67.80, 56.76, 55.42, 52.38, 43.67, 39.28, 24.99, 24.89, 22.01 ppm.
[0501] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.64 ppm.
[0502] MS (GCMS, EI): m/z=386 (5%), 343 (5%), 299 (19%), 244 (20%), 199 (100%), 172 (77%).
[0503] TLC: R.sub.f=0.63 (3:1 hexanes:ethyl acetate).
##STR00095##
isopropyl 3-(3,5-dimethoxyphenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo [1.1.1]pentane-1-carboxylate (64)
[0504] General Procedure F2 was followed on a 0.1 mmol scale. BCP bisboronate 23 and 3,5-dimethoxylbromobenzene were reacted accordingly for 48 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 14.2 mg (34%) of the title compound 64.
[0505] Physical State: colorless oil.
[0506] .sup.1H NMR (600 MHz, CDCl.sub.3): 6.46 (d, J=2.3 Hz, 2H), 6.33 (t, J=2.3 Hz, 1H), 5.03 (hept, J=6.3 Hz, 1H), 3.78 (s, 6H), 3.00 (dd, J=9.5, 1.9 Hz, 1H), 2.28 (s, 1H), 2.26 (dd, J=9.5, 1.4 Hz, 1H), 2.20 (dd, J=8.1, 1.9 Hz, 1H), 2.07 (d, J=7.6 Hz, 1H), 1.28-1.23 (m, 18H) ppm.
[0507] .sup.13C NMR (151 MHz, CDCl.sub.3): 170.10, 160.83, 142.92, 104.43, 99.22, 83.41, 67.86, 56.41, 55.42, 52.61, 44.10, 39.22, 25.06, 24.93, 22.01, 21.99 ppm.
[0508] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.75 ppm.
[0509] MS (GCMS, EI): m/z=416 (5%), 358 (6%), 328 (4%), 273 (26%), 229 (100%), 202 (32%).
[0510] TLC: R.sub.f=0.56 (3:1 hexanes:ethyl acetate).
##STR00096##
4,4,5,5-tetramethyl-2-(1-methyl-3-phenylbicyclo[1.1.1]pentan-2-yl)-1,3,2-dioxaborolane (65)
[0511] General Procedure F2 was followed on a 0.1 mmol scale. BCP bisboronate 14 and bromobenzene were reacted accordingly for 48 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 12.0 mg (42%) of the title compound 65.
[0512] Scale-up of preparation of BCP boronate 65 was followed on a 2.0 mmol scale with BCP bisboronate 14 and bromobenzene were reacted accordingly for 60 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 209.6 mg (37%) of the title compound 65. [Note: The protodeborylated side-product (R.sup.3H) was removed by high vacuum.]
[0513] Physical State: colorless oil.
[0514] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.30-7.22 (m, 4H), 7.16 (tt, J=6.6, 1.9 Hz, 1H), 2.56 (dd, J=9.9, 1.9 Hz, 1H), 1.93 (d, J=9.3 Hz, 2H), 1.83 (dd, J=8.2, 1.9 Hz, 1H), 1.72 (d, J=8.2 Hz, 1H), 1.26 (s, 3H), 1.230 (s, 6H), 1.225 (s, 6H) ppm.
[0515] .sup.13C NMR (151 MHz, CDCl.sub.3): 141.89, 128.01, 126.45, 126.12, 83.01, 57.73, 52.75, 44.02, 38.05, 25.00, 24.98, 18.55 ppm.
[0516] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.18 ppm.
[0517] MS (GCMS, EI): m/z=284 (0.4%), 269 (4%), 225 (3%), 156 (100%), 84 (76%).
[0518] TLC: R.sub.f=0.38 (15:1 hexanes:ethyl acetate).
##STR00097##
4,4,5,5-tetramethyl-2-(1-methyl-3-(p-tolyl)bicyclo[1.1.1]pentan-2-yl)-1,3,2-dioxaborolane (66)
[0519] General Procedure F2 was followed on a 0.1 mmol scale. BCP bisboronate 14 and 4-bromo-toluene were reacted accordingly for 48 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 11.2 mg (37%) of the title compound 66. [Note: The deborylated side-product (R.sup.3H) was removed by high vacuum]
[0520] Physical State: colorless oil.
[0521] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.20-7.15 (m, 2H), 7.08 (d, J=7.8 Hz, 2H), 2.55 (dd, J=10.0, 1.9 Hz, 1H), 2.31 (s, 3H), 1.94-1.90 (m, 2H), 1.82 (dd, J=8.2, 1.9 Hz, 1H), 1.71 (d, J=8.1 Hz, 1H), 1.27 (s, 3H), 1.244 (s, 6H), 1.240 (s, 6H) ppm.
[0522] .sup.13C NMR (151 MHz, CDCl.sub.3): 138.96, 135.59, 128.71, 126.36, 82.97, 57.75, 52.79, 43.81, 37.99, 25.01, 24.98, 21.25, 18.56 ppm.
[0523] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.23 ppm.
[0524] MS (GCMS, EI): m/z=298 (2.5%), 283 (6%), 239 (5%), 197 (10%), 183 (32%), 170 (100%).
[0525] TLC: R.sub.f=0.38 (15:1 hexanes:ethyl acetate).
##STR00098##
4,4,5,5-tetramethyl-2-(1-methyl-3-(4-(trifluoromethyl)phenyl)bicyclo[0.1.1]pentan-2-yl)-1,3,2-dioxaborolane (67)
[0526] General Procedure F2 was followed on 0.1 mmol scale, wherein BCP bisboronate 14 and 4-bromo-trifluorotoluene were reacted for 48 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) and afforded 13.7 mg (39%) of the title compound 67. [Note: The deborylated side-product (R.sup.3H) was removed by high vacuum]
[0527] Physical State: colorless crystal.
[0528] m.p.: 31-33 C.
[0529] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.51 (d, J=8.0 Hz, 2H), 7.38 (d, J=7.9 Hz, 2H), 2.56 (dd, J=9.6, 1.9 Hz, 1H), 2.01-1.94 (m, 2H), 1.87 (dd, J=8.2, 1.9 Hz, 1H), 1.76 (d, J=8.3 Hz, 1H), 1.29 (s, 3H), 1.243 (s, 6H), 1.241 (s, 6H) ppm.
[0530] .sup.13C NMR (151 MHz, CDCl.sub.3): 145.76, 128.32 (q, J=32.4 Hz), 127.65, 126.84, 124.98 (q, J=3.9 Hz). 83.18, 57.75, 52.87, 43.60, 38.36, 25.00, 24.98, 18.42 ppm.
[0531] .sup.19F NMR (376 MHz, CDCl.sub.3) 62.28 ppm.
[0532] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.01 ppm.
[0533] MS (GCMS, EI): m/z=337 (1%), 284 (1%), 252 (7%), 224 (33%), 84 (100%).
[0534] TLC: R.sub.f=0.38 (15:1 hexanes:ethyl acetate).
##STR00099##
2-(1-(4-methoxyphenyl)-3-methylbicyclo[1.1.1]pentan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxa borolane (68)
[0535] General Procedure F2 was followed on a 0.1 mmol scale, wherein BCP bisboronate 14 and 4-bromo-anisole were reacted for 48 hours. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) and afforded 7.6 mg (24%) of the title compound 68. [Note: The deborylated side-product (R.sup.3H) was removed by high vacuum]
[0536] Physical State: colorless oil.
[0537] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.23-7.18 (m, 2H), 6.83-6.78 (m, 2H), 3.78 (s, 3H), 2.53 (dd, J=9.7, 1.9 Hz, 1H), 1.94-1.89 (m, 2H), 1.81 (dd, J=8.2, 1.9 Hz, 1H), 1.70 (d, J=8.2 Hz, 1H), 1.26 (s, 3H), 1.243 (3, 6H), 1.238 (3, 6H) ppm.
[0538] .sup.13C NMR (151 MHz, CDCl.sub.3): 158.11, 134.36, 127.53, 113.45, 82.98, 57.76, 55.40, 52.83, 43.57, 37.91, 25.01, 24.99, 18.53 ppm.
[0539] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.15 ppm.
[0540] MS (GCMS, EI): m/z=314 (6%), 299 (11%), 199 (35%), 186 (98%), 133 (100%).
[0541] TLC: R.sub.f=0.31 (15:1 hexanes:ethyl acetate).
##STR00100##
5-3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)-2-fluoropyridine (69)
[0542] General Procedure F1 was followed on a 0.1 mmol scale, wherein BCP bisboronate 25 and 3-bromo-6-fluoropyridine were reacted for 48 hours. Purification by flash chromatography (hexanes:ethyl acetate, 5:1) afforded 9.0 mg (22%) of the title compound 69.
[0543] Physical State: colorless oil.
[0544] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.12 (d, J=2.5 Hz, 1H), 7.72 (td, J=8.1, 2.5 Hz, 1H), 7.35 (d, J=7.0 Hz, 4H), 7.31-7.24 (m, 1H), 6.83 (dd, J=8.4, 2.8 Hz, 1H), 4.57 (s, 2H), 3.57 (s, 2H), 2.66 (dd, J=9.7, 2.0 Hz, 1H), 2.10-2.06 (m, 2H), 1.98 (dd, J=8.2, 2.1 Hz, 1H), 1.85 (d, J=8.1 Hz, 1H), 1.20 (s, 12H) ppm.
[0545] .sup.13C NMR (151 MHz, CDCl.sub.3): 162.61 (d, J=237.1 Hz), 145.89 (d, J=14.5 Hz), 139.60 (d, J=7.7 Hz), 138.80, 134.58, 128.43, 127.64, 127.58, 108.73 (d, J=37.4 Hz), 83.37, 73.12, 70.03, 55.14, 50.74, 41.98, 40.88, 24.94, 24.91 ppm.
[0546] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.62 ppm.
[0547] .sup.19F NMR (376 MHz, CDCl.sub.3): 71.46 ppm.
[0548] MS (GCMS, EI): m/z=394 (0.4%), 356 (0.3%), 303 (4%), 218 (6%), 174 (10%), 91(100%).
[0549] TLC: R.sub.f=0.59 (3:1 hexanes:ethyl acetate).
General Procedure G for Minisci Reaction of BCP Bisboronates
##STR00101##
[0550] A screw-capped culture tube was charged with BCP bisboronate (1.0 equiv.), heteroarene (3.0 equiv.) and Mn(OAc).sub.3 (2.5 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of acetic acid/water (0.1 M, 1:1) solvent via a syringe. Next, trifluoroacetic acid (5.0 equiv.) was added into the reaction. Then, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was stirred at 50 C. for 18 hours. After it was confirmed that the starting material was consumed totally, the reaction mixture was concentrated under high vacuum to remove excess acetic acid, quenched with Na.sub.2CO.sub.3 solution, extracted with ethyl acetate, dried with Na.sub.2SO.sub.4, and concentrated under high vacuum. The crude residue was purified by chromatography on silica gel. (Molander et al., 2011)
##STR00102##
2-(3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)-3-chloroquinoxaline (70)
[0551] General Procedure G was followed on a 0.1 mmol scale with BCP bisboronate 25 and 2-chloroquinoxaline. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 23.2 mg (49%) of the title compound 70.
[0552] Physical State: colorless oil.
[0553] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.06-8.00 (m, 1H), 7.99-7.94 (m, 1H), 7.74-7.68 (m, 2H), 7.41-7.33 (m, 4H), 7.30-7.27 (m, 1H), 4.61 (s, 2H), 3.62 (s, 2H), 2.94 (dd, J=9.5, 1.9 Hz, 1H), 2.56 (s, 1H), 2.53 (dd, J=8.0, 1.9 Hz, 1H), 2.28 (dd, J=9.5, 1.3 Hz, 1H), 2.17 (d, J=7.9 Hz, 1H), 1.22 (s, 6H), 1.18 (s, 6H) ppm.
[0554] .sup.13C NMR (151 MHz, CDCl.sub.3): 152.16, 146.94, 141.17, 141.10, 138.80, 130.21, 129.94, 128.97, 128.44, 128.11, 127.64, 127.56, 83.11, 73.09, 70.19, 56.77, 50.50, 45.40, 42.03, 24.88, 24.81 ppm.
[0555] .sup.11B NMR (128 MHz, CDCl.sub.3): 32.52 ppm.
[0556] MS (GCMS, EI): m/z=476 (0.3%), 394 (0.2%), 355 (0.5%), 315 (2%), 229 (20%), 91 (100%).
[0557] TLC: R.sub.f=0.25 (10:1 hexanes:ethyl acetate).
##STR00103##
8-(3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (71)
[0558] General Procedure G was followed on a 0.1 mmol scale with BCP bisboronate 25 and caffeine. Purification by flash chromatography (hexanes:ethyl acetate, 2:1) afforded 27.7 mg (55%) of the title compound 71.
[0559] Physical State: white solid.
[0560] m.p.: 124-126 C.
[0561] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.34 (d, J=4.4 Hz, 4H), 7.30-7.26 (m, 1H), 4.56 (s, 2H), 4.01 (s, 3H), 3.55 (s, 3H), 3.55 (s, 2H), 3.38 (s, 3H), 2.90 (dd, J=9.6, 2.1 Hz, 1H), 2.33 (dd, J=9.6, 1.5 Hz, 1H), 2.29-2.24 (m, 2H), 2.12 (d, J=8.1 Hz, 1H), 1.200 (s, 6H), 1.196 (s, 6H) ppm.
[0562] .sup.13C NMR (151 MHz, CDCl.sub.3): 155.53, 151.82, 151.10, 147.59, 138.56, 128.45, 127.66, 127.64, 107.55, 83.55, 73.17, 69.63, 56.53, 50.85, 43.43, 38.06, 32.60, 30.03, 28.00, 24.89, 24.85 ppm.
[0563] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.53 ppm.
[0564] HRMS (ESI-TOF): calc'd for C.sub.27H.sub.35BN.sub.4O.sub.5 [M+H].sup.+: 507.2773, found: 507.2778.
[0565] TLC: R.sub.f=0.30 (1:1 hexanes:ethyl acetate).
##STR00104##
2-(3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)-3,5-dichloropyrazine (72)
[0566] General Procedure G was followed on a 0.1 mmol scale with BCP bisboronate 25 and 2,6-dichloropyrazine. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 28.3 mg (61%) of the title compound 72.
[0567] Physical State: colorless oil.
[0568] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.39 (s, 1H), 7.38-7.31 (m, 4H), 7.29-7.26 (m, 1H), 4.57 (s, 2H), 3.58 (s, 2H), 2.81 (dd, J=9.6, 2.0 Hz, 1H), 2.38-2.33 (m, 2H), 2.25 (dd, J=9.5, 1.4 Hz, 1H), 2.09 (d, J=8.0 Hz, 1H), 1.19 (s, 6H), 1.17 (s, 6H) ppm.
[0569] .sup.13C NMR (151 MHz, CDCl.sub.3): 150.83, 146.22, 144.99, 141.56, 138.72, 128.43, 127.64, 127.58, 83.23, 73.11, 69.96, 56.33, 50.17, 43.96, 42.12, 24.84, 24.79 ppm.
[0570] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.26 ppm.
[0571] HRMS (ESI-TOF): calc'd for C.sub.23H.sub.27BCl.sub.2N.sub.2O.sub.3 [M+H].sup.+: 461.1565, found: 461.1558.
[0572] TLC: R.sub.f=0.32 (10:1 hexanes:ethyl acetate).
##STR00105##
4-(3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)-3,6-dichloropyridazine (73)
[0573] General Procedure G was followed on a 0.1 mmol scale with BCP bisboronate 25 and 3,6-dichloropyridazine. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 21.6 mg (47%) of the title compound 73.
[0574] Physical State: colorless oil.
[0575] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.44 (s, 1H), 7.35 (d, J=4.4 Hz, 4H), 7.28 (ddd, J=8.0, 4.9, 3.9 Hz, 1H), 4.58 (d, J=12.0 Hz, 1H), 4.55 (d, J=12.0 Hz, 1H), 3.58 (s, 2H), 2.57 (dd, J=9.6, 2.1 Hz, 1H), 2.39 (t, J=1.2 Hz, 1H), 2.36 (dd, J=8.2, 2.1 Hz, 1H), 2.24 (dd, J=9.5, 1.5 Hz, 1H), 2.07 (dd, J=8.3, 0.9 Hz, 1H), 1.192 (s, 6H), 1.185 (s, 6H) ppm.
[0576] .sup.13C NMR (151 MHz, CDCl.sub.3): 156.06, 155.69, 141.72, 138.54, 129.21, 128.48, 127.70, 127.65, 83.73, 73.22, 69.46, 56.27, 50.19, 42.35 (2C), 24.91, 24.88 ppm.
[0577] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.58 ppm.
[0578] HRMS (ESI-TOF): calc'd for C.sub.23H.sub.27BCl.sub.2N.sub.2O.sub.3 [M+H].sup.+: 461.1565, found: 461.1560.
[0579] TLC: R.sub.f=0.18 (10:1 hexanes:ethyl acetate).
##STR00106##
4-(3-((benzyloxy)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)-2-chloro-8-fluoroquinoline (74)
[0580] General Procedure G was followed on a 0.1 mmol scale with BCP bisboronate 25 and 2,6-dichloropyrazine. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 18.6 mg (38%) of the title compound 74.
[0581] Physical State: red oil.
[0582] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.07 (d, J=8.4 Hz, 1H), 7.46 (td, J=8.1, 5.2 Hz, 1H), 7.42-7.39 (m, 1H), 7.39-7.33 (m, 4H), 7.31 (s, 1H), 7.30-7.28 (m, 1H), 4.60 (s, 2H), 3.63 (s, 2H), 2.91 (dd, J=9.6, 2.2 Hz, 1H), 2.45-2.42 (m, 1H), 2.40 (dd, J=8.2, 2.2 Hz, 1H), 2.36 (dd, J=9.5, 1.6 Hz, 1H), 2.17 (d, J=8.1 Hz, 1H), 1.18 (s, 12H) ppm.
[0583] .sup.13C NMR (151 MHz, CDCl.sub.3): 158.42, 156.72, 151.32, 149.76 (d, J=2.5 Hz), 138.65, 138.43 (d, J=11.5 Hz), 128.49, 128.15, 127.68, 126.21 (d, J=8.1 Hz), 122.77, 121.03, 114.32 (d, J=18.7 Hz), 83.55, 73.23, 69.79, 57.86, 51.30, 44.56, 41.97, 24.91, 24.83 ppm.
[0584] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.32 ppm.
[0585] .sup.19F NMR (376 MHz, CDCl.sub.3): 123.05 ppm.
[0586] HRMS (ESI-TOF): calc'd for C.sub.28H.sub.30BClFNO.sub.3 [M+H].sup.+: 494.2064, found: 494.2063.
[0587] TLC: R.sub.f=0.36 (5:1 hexanes:ethyl acetate).
##STR00107##
isopropyl 3-(3-bromoquinoxalin-2-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo [1.1.1]pentane-1-carboxylate (75)
[0588] General Procedure G was followed on a 0.1 mmol scale with BCP bisboronate 23 and 2-bromoquinoxaline. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 22.5 mg (46%) of the title compound 75.
[0589] Physical State: pale red solid.
[0590] m.p.: 102-103 C.
[0591] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.02-7.97 (m, 2H), 7.76-7.69 (m, 2H), 5.05 (hept, J=6.3 Hz, 1H), 3.24 (dd, J=9.4, 1.9 Hz, 1H), 2.95 (d, J=1.2 Hz, 1H), 2.89 (dd, J=8.0, 1.9 Hz, 1H), 2.51 (dd, J=9.4, 1.4 Hz, 1H), 2.42 (d, J=8.0 Hz, 1H), 1.29-1.26 (m, 9H), 1.26 (d, J=4.0 Hz, 3H), 1.23 (s, 6H) ppm.
[0592] .sup.13C NMR (151 MHz, CDCl.sub.3): 169.74, 152.38, 142.10, 140.93, 138.58, 130.53, 130.31, 129.05, 128.25, 83.36, 68.12, 58.13, 52.77, 45.26, 40.91, 24.94, 24.81, 22.03, 22.01 ppm.
[0593] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.05 ppm.
[0594] HRMS (ESI-TOF): calc'd for C.sub.23H.sub.28BBrN.sub.2O.sub.4[M+H].sup.+: 487.1398, found: 487.1399.
[0595] TLC: R.sub.f=0.36 (5:1 hexanes:ethyl acetate).
##STR00108##
8-(3-(4-methoxyphenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (76)
[0596] General Procedure G was followed on a 0.1 mmol scale with BCP bisboronate 27 and caffeine Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 17.1 mg (35%) of the title compound 76.
[0597] Physical State: yellow solid.
[0598] m.p.: >200 C.
[0599] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.25-7.21 (m, 2H), 6.88-6.83 (m, 2H), 4.06 (s, 3H), 3.80 (s, 3H), 3.57 (s, 3H), 3.40 (s, 3H), 3.26 (dd, J=9.7, 2.0 Hz, 1H), 2.60 (dd, J=9.5, 1.4 Hz, 1H), 2.53-2.52 (m, 1H), 2.51 (dd, J=8.1, 2.0 Hz, 1H), 2.39 (d, J=8.0 Hz, 1H), 1.23 (s, 6H), 1.22 (s, 6H) ppm.
[0600] .sup.13C NMR (151 MHz, CDCl.sub.3): 158.78, 155.54, 151.84, 151.33, 147.66, 132.17, 127.49, 113.73, 107.65, 83.66, 58.63, 55.43, 53.25, 46.17, 36.62, 32.69, 30.04, 28.02, 24.92 ppm.
[0601] .sup.11B NMR (128 MHz, CDCl.sub.3): 30.50 ppm.
[0602] HRMS (ESI-TOF): calc'd for C.sub.26H.sub.33BN.sub.4O.sub.5[M+H].sup.+: 493.2617, found: 493.2597.
[0603] TLC: R.sub.f=0.40 (1:1 hexanes:ethyl acetate).
##STR00109##
3,5-dichloro-2-(3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)pyrazine (77)
[0604] General Procedure G was followed on a 0.1 mmol scale with BCP bisboronate 14 and 2,6-dichloropyrazine. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 26.1 mg (74%) of the title compound 77.
[0605] General Procedure G was followed on 2.0 mmol scale with BCP bisboronate 14 and 2,6-dichloropyrazine. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 465.7 mg (65%) of the title compound 77.
[0606] Physical State: white solid.
[0607] m.p.: 32-33 C.
[0608] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.38 (s, 1H), 2.66 (dd, J=9.6, 2.1 Hz, 1H), 2.25-2.20 (m, 2H), 2.17 (dd, J=9.6, 1.2 Hz, 1H), 2.01 (dd, J=8.1, 1.0 Hz, 1H), 1.29 (s, 3H), 1.22 (s, 6H), 1.21 (s, 6H) ppm.
[0609] .sup.13C NMR (151 MHz, CDCl.sub.3): 151.11, 146.19, 144.73, 141.51, 83.17, 58.64, 52.33, 43.13, 40.18, 24.92, 24.87, 18.35 ppm.
[0610] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.87 ppm.
[0611] MS (GCMS, EI): m/z=355 (4%), 354 (5%), 341 (5%), 319 (7%), 213 (27%), 84 (100%).
[0612] TLC: R.sub.f=0.46 (10:1 hexanes:ethyl acetate).
##STR00110##
3,6-dichloro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)bicyclo [1.1.1]pentan-1-yl)pyridazine (73)
[0613] General Procedure G was followed on a 0.1 mmol scale with BCP bisboronate 20 and 2,6-dichloropyrazine. Purification by flash chromatography (hexanes:ethyl acetate, 20:1) afforded 13.6 mg (33%) of the title compound 73.
[0614] Physical State: white solid.
[0615] m.p.: 77-79 C.
[0616] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.41 (s, 1H), 2.94 (dd, J=9.6, 2.2 Hz, 1H), 2.61-2.59 (m, 1H), 2.57 (dd, J=8.2, 2.2 Hz, 1H), 2.47 (dd, J=9.6, 1.7 Hz, 1H), 2.33 (d, J=8.1 Hz, 1H), 1.24 (s, 6H), 1.23 (s, 6H) ppm.
[0617] .sup.13C NMR (151 MHz, CDCl.sub.3): 156.15, 155.34, 139.82, 129.17, 122.48 (q, J=276.1 Hz), 84.39, 55.23, 49.07, 41.20, 40.38 (q, J=39.1 Hz). 24.80, 24.76 ppm.
[0618] .sup.19F NMR (376 MHz, CDCl.sub.3): 72.73 ppm.
[0619] .sup.11B NMR (128 MHz, CDCl.sub.3): 30.91 ppm.
[0620] MS (GCMS, EI): m/z=410 (1%), 408 (1.5%), 393 (2%), 350 (8%), 315 (16%), 59 (100%).
[0621] TLC: R.sub.f=0.30 (10:1 hexanes:ethyl acetate).
##STR00111##
2-chloro-4-(3-(4-methoxyphenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[1.1.1]pentan-1-yl)-6-(trifluoromethyl)pyrimidine (79)
[0622] General Procedure G was followed on a 0.1 mmol scale with BCP bisboronate 27 and 2-chloro-4-(trifluoromethyl)pyrimidine. Purification by flash chromatography (hexanes:ethyl acetate, 10:1) afforded 17.6 mg (37%) of the title compound 79.
[0623] Physical State: yellow oil.
[0624] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.73 (s, 1H), 7.29-7.24 (m, 2H), 6.90-6.84 (m, 2H), 3.81 (s, 3H), 3.12 (dd, J=9.6, 1.9 Hz, 1H), 2.50 (d, J=1.3 Hz, 1H), 2.48-2.43 (m, 1H), 2.37 (dd, J=8.2, 1.9 Hz, 1H), 2.25-2.21 (m, 1H), 1.27 (s, 6H), 1.26 (s, 6H) ppm.
[0625] .sup.13C NMR (151 MHz, CDCl.sub.3): 174.79, 161.98, 158.83, 157.62 (q, J=37.0 Hz), 132.13, 127.64, 120.06 (q, J=275.3 Hz), 113.76, 113.40 (q, J=2.8 Hz), 83.87, 56.61, 55.45, 54.22, 44.16, 43.12, 25.03, 24.87 ppm.
[0626] .sup.19F NMR (565 MHz, CDCl.sub.3): 69.81 ppm.
[0627] .sup.11B NMR (128 MHz, CDCl.sub.3): 31.28 ppm.
[0628] MS (GCMS, EI): m/z=480 (15%), 465 (8%), 352 (32%), 302 (15%), 133 (60%), 84 (100%).
[0629] TLC: R.sub.f=0.36 (10:1 hexanes:ethyl acetate).
D. Experimental Procedures and Characterization Data of Substrates in 2.SUP.Nd .Functionalization of BCP Bisboronates
##STR00112##
(1-benzyloxy)methy)bicyclo[1.1.1]pentan-2-yl)trifuoro-.SUP.4.-borane, potassium salt (81)
[0630] BCP boronate 36 (1.1 g, 3.3 mmol) was suspended in methanol (6.6 mL), and a saturated aqueous solution of KHF.sub.2 (5 mL, 25 mmol) was added dropwise. The suspended solution was stirred at room temperature for 2 hours and then concentrated to dryness. (Note: removing the pinacol by azeotrope with methanol and water under high vacuum 5 times facilitate the subsequent crystallization). The residue was extracted with hot acetone (330 mL), and the combined filtered extracts were concentrated to approximately 5 mL. Diethyl ether was added, and the resultant precipitate was collected and dried to afford the 750 mg (73%) of the potassium trifluoroborate 81.
[0631] Physical State: white solid.
[0632] m.p.: 88-90 C.
[0633] .sup.1H NMR (600 MHz, acetone-d.sup.6): 7.34 (d, J=7.1 Hz, 2H), 7.31 (t, J=7.6 Hz, 2H), 7.26-7.20 (m, 1H), 4.51 (d, J=12.3 Hz, 1H), 4.47 (d, J=12.3 Hz, 1H), 3.48 (d, J=10.7 Hz, 1H), 3.39 (d, J=10.7 Hz, 1H), 2.49 (d, J=9.4 Hz, 1H), 2.36 (s, 1H), 1.70 (s, 1H), 1.54 (d, J=8.0 Hz, 1H), 1.52 (d, J=9.4 Hz, 1H), 1.23-1.15 (m, 1H) ppm.
[0634] .sup.13C NMR (151 MHz, acetone-d.sup.6): 140.80, 128.88, 128.09, 127.75, 72.91, 72.33, 54.06, 47.92, 46.61, 31.15 (q, J=3.3 Hz) ppm.
[0635] .sup.19F NMR (376 MHz, acetone-d.sup.6): 136.15 ppm.
[0636] .sup.11B NMR (128 MHz, Acetone-d.sup.6): 3.77 (q, J=75.1 Hz) ppm.
##STR00113##
(1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-yl)boronic acid (82)
[0637] A screw-capped culture tube was charged with 81 (294 mg, 1.0 mmol) and water (5.0 mL), followed by addition of silica gel (500 mg) under argon atmosphere. The mixture was stirred at room temperature for 1 hour. Ethyl ether (10 mL) was added, and the suspended solution was filtered by Celite. The organic phase was separated, and the water phase was extracted with diethyl ether (35 mL). The combined organic solvent was washed with brine and dried by anhydrous MgSO.sub.4. The solvent was removed under vacuum to afford the desire boronic acid 82 (230 mg, 99%) without further purification.
[0638] A screw-capped culture tube was charged with 36 (314 mg, 1.0 mmol, 1.0 equiv.) and Na.sub.5IO.sub.6 (855.6 mg, 4.0 mmol, 4.0 equiv.), followed by addition of THF/H.sub.2O (5 mL, 1:1). Then 12 M HCl (0.17 mL, 2.0 mmol, 2.0 equiv.) was added to reaction tube at 0 C. The reaction mixture was allowed to stir at 0 C. for 3 hours. After it was confirmed by TLC analysis that 36 was totally consumed, the suspended reaction mixture was filtered via Celite to remove excess Na.sub.5IO.sub.6, and the organic phase was separated, and the water phase was extracted with diethyl ether (35 mL). The combined organic solvent was washed with brine and dried by anhydrous Na.sub.2SO.sub.4. The solvent was removed under vacuum to afford the desire boronic acid 82 (157.8 mg, 68%) without further purification.
[0639] Physical State: white solid.
[0640] m.p.: 64-66 C.
[0641] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.39-7.35 (m, 2H), 7.34-7.30 (m, 3H), 6.05 (br., 2H), 4.57 (d, J=12.0 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 3.52 (dd, J=9.9, 1.5 Hz, 1H), 3.48 (dd, J=9.7, 1.2 Hz, 1H), 2.71 (s, 1H), 2.12 (dd, J=9.8, 2.5 Hz, 1H), 1.76-1.71 (m, 3H), 1.68 (d, J=8.7 Hz, 1H) ppm.
[0642] .sup.13C NMR (151 MHz, CDCl.sub.3): 136.97, 128.75, 128.31, 128.12, 73.79, 71.83, 52.42, 49.98, 44.48, 31.14 ppm.
[0643] .sup.11B NMR (128 MHz, CDCl.sub.3) 31.19 ppm.
[0644] HRMS (ESI-TOF): calc'd for C.sub.13H.sub.17BO.sub.3 [M+H].sup.+: 233.1344, found: 233.1350.
[0645] TLC: R.sub.f=0.68 (2:1 hexanes:ethyl acetate).
##STR00114##
1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-ol (83)
[0646] To a solution of BCP boronate 36 (314.2 mg, 1.0 mmol) and NaOAc (164 mg, 2.0 mmol) in THE (10 mL) at 0 C. was added H.sub.2O.sub.2 (35 wt. % in water, 1.0 mL) dropwise. The resulting mixture was stirred at 0 C. for 1.5 hours. Na.sub.2S.sub.2O.sub.3 was added and the mixture was stirred at 0 C. for 10 min. Diethyl ether was added, the layers were separated, and the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with water and brine, dried over anhydrous MgSO.sub.4, concentrated, and purified by column chromatography (hexanes:ethyl acetate, 2:1) on silica gel to obtain 150 mg (75%) of the alcohol 83.
[0647] Physical State: colorless oil.
[0648] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.37-7.31 (m, 4H). 7.30-7.27 (m, 1H), 4.51 (s, 2H), 4.08 (d, J=6.2 Hz, 1H), 3.46 (d, J=12.0 Hz, 1H), 3.44 (d, J=12.0 Hz, 1H), 2.65 (dd, J=9.7, 2.6 Hz, 1H), 2.55 (s, 1H), 2.22 (br., 1H), 1.76 (dd, J=6.2, 2.5 Hz, 1H), 1.62 (d, J=2.9 Hz, 1H), 1.25 (dd, J=9.7, 2.9 Hz, 1H) ppm.
[0649] .sup.13C NMR (151 MHz, CDCl.sub.3): 138.52, 128.54, 127.74, 127.66, 82.73, 73.29, 68.76, 49.09, 43.46, 39.48, 35.23 ppm.
[0650] HRMS (ESI-TOF): calc'd for C.sub.13H.sub.1602 [M+H].sup.+: 205.1223, found: 205.1220.
[0651] TLC: R.sub.f=0.41 (2:1 hexanes:ethyl acetate).
##STR00115##
2-((1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-yl)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxa borolane (84)
[0652] BCP boronate 36 (31.4 mg, 0.1 mmol, 1.0 equiv.) and bromoiodomethane (15 L, 0.2 mmol, 2.0 eq.) were dissolved in anhydrous THF (1.0 mL) and cooled to 78 C. n-BuLi (2.5 M in n-hexane, 0.08 mL, 0.2 mmol, 2.0 equiv.) was added dropwise and the solution was stirred 10 minutes at 78 C., and then warmed up to room temperature and stirred overnight. The reaction mixture was quenched with saturated NH.sub.4Cl solution and dissolved in ethyl acetate. The aqueous phase was extracted with ethyl acetate twice. The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to afford the crude residue, which was purified by flash chromatography (hexane:ethyl acetate, 20:1) on silica gel to give 28.0 mg (85%) of the desired product 84. (Kondo et al., 2020)
[0653] Physical State: colorless oil.
[0654] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.35-7.30 (m, 4H), 7.29-7.24 (m, 1H), 4.52-4.46 (m, 2H), 3.34 (s, 2H), 2.36 (s, 1H), 2.32-2.24 (m, 2H), 1.79 (d, J=1.7 Hz, 1H), 1.73 (dd, J=6.3, 2.9 Hz, 1H), 1.60 (dd, J=9.8, 1.7 Hz, 1H), 1.22 (s, 12H), 1.09-10.6 (m, 2H) ppm.
[0655] .sup.13C NMR (151 MHz, CDCl.sub.3): 138.95, 128.39, 127.48, 127.46, 83.04, 72.99, 69.35, 55.93, 49.10, 46.79, 45.04, 32.56, 24.95, 24.94 ppm.
[0656] .sup.11B NMR (128 MHz, CDCl.sub.3): 33.77 ppm.
[0657] MS (GCMS, EI): m/z=328 (0.1%), 313 (0.1%), 219 (1%), 179 (5%), 137 (4%), 91 (100%).
[0658] TLC: R.sub.f=0.50 (10:1 hexanes:ethyl acetate).
##STR00116##
(1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-yl)(phenyl)sulfane (85)
[0659] A flame-dried screw-capped culture tube was charged with BCP boronate 36 (31.4 mg, 0.1 mmol, 1.0 equiv.), PhSO.sub.2SPh (50 mg, 0.2 mmol, 2.0 equiv.), and tert-butyl catechol (4.8 mg, 0.03 mmol, 0.3 equiv.), MeOBcat (6.0 mg, 0.04 mmol, 0.4 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of toluene (0.5 mL, 0.2 M) solvent via a syringe. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was allowed to stir at 100 C. for 36 hours. After it was confirmed that the starting material was consumed totally, the reaction mixture was concentrated under high vacuum and the crude residue was purified by chromatography on silica gel to give 15.8 mg (53%) of the desired product 85. (Andrd-Joyaux et al., 2020)
[0660] Physical State: colorless oil.
[0661] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.40-7.37 (m, 2H), 7.37-7.31 (m, 4H), 7.30-7.27 (m, 1H), 7.23 (dd, J=8.5, 7.0 Hz, 2H), 7.18-7.12 (m, 1H), 4.51 (d, J=12.2 Hz, 1H), 4.48 (d, J=12.2 Hz, 1H), 3.72-3.67 (m, 1H), 3.46 (d, J=10.8 Hz, 1H), 3.42 (d, J=10.7 Hz, 1H), 2.76 (s, 1H), 2.63 (dd, J=10.0, 3.0 Hz, 1H), 2.03 (d, J=2.5 Hz, 1H), 1.89-1.82 (m, 2H) ppm.
[0662] .sup.13C NMR (151 MHz, CDCl.sub.3): 138.51, 137.52, 129.10, 128.92, 128.48, 127.66, 127.61, 125.69, 73.23, 68.36, 64.74, 49.32, 47.80, 47.04, 34.68 ppm.
[0663] MS (GCMS, EI): m/z=296 (2.5%), 252 (2.5%), 207 (4%), 147 (10%), 91 (100%).
[0664] TLC: R.sub.f=0.57 (10:1 hexanes:ethyl acetate).
##STR00117##
2-(1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-yl)-6-methoxypyridine (86)
[0665] A solution of 2-bromo-6-methoxypyridine (17 L, 0.14 mmol, 1.4 equiv.) in THF:diethyl ether:pentane (4:1:1, 0.3 M) was cooled to 78 C. and treated with n-BuLi (0.06 mL, 0.14 mmol, 1.3 eq., 2.32 M in hexanes) and the mixture was stirred at this temperature for 30 min. BCP boronate 36 (31.4 mg, 0.1 mmol, 1.0 equiv.) was added dropwise as a solution in THE (0.5 mL). The mixture was stirred at 78 C. for 30 min. The mixture was warmed to room temperature. and the solvents were removed under high vacuum at room temperature. The crude reaction mixture was redissolved in MeOH (1.0 mL) and the mixture was cooled to 0 C. A solution of 1,3-dibromo-5,5-dimethylhydantoin (56 mg, 0.2 mmol, 2.0 eq.) in MeOH (1.5 ml) was added dropwise. After 1 hour at 0 C. saturated aqueous solution of Na.sub.2S.sub.2O.sub.3 was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate (15 mL) and water (15 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous MgSO.sub.4, filtered and concentrated under vacuum. The crude material was adsorbed on silica and purified by flash column chromatography (hexanes:ethyl acetate, 20:1) on silica gel to give 15.6 mg (53%) of the desired product 81. (Odachowski et al., 2016)
[0666] Physical State: colorless oil.
[0667] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.49 (t, J=7.7 Hz, 1H), 7.37-7.30 (m, 4H), 7.29-7.25 (m, 1H), 6.75 (d, J=7.3 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 4.61 (d, J=12.2 Hz, 1H), 4.58 (d, J=12.2 Hz, 1H), 3.83 (s, 3H), 3.72 (d, J=10.9 Hz, 1H), 3.67 (d, J=10.8 Hz, 1H), 3.40 (d, J=6.9 Hz, 1H), 2.91 (s, 1H), 2.14 (dd, J=9.5, 2.6 Hz, 1H), 1.91-1.84 (m, 2H), 1.83 (dd, J=6.9, 2.6 Hz, 1H) ppm.
[0668] .sup.13C NMR (151 MHz, CDCl.sub.3): 163.37, 157.95, 138.87, 138.70 (br.), 128.43, 127.68, 127.58, 115.95, 107.76, 73.21, 69.46, 63.87 (br.), 53.45, 47.68, 47.49, 46.78, 32.06 ppm.
[0669] MS (GCMS, EI): m/z=295 (1%), 240 (1%), 204 (11%), 186 (16%), 174 (18%), 91 (100%).
[0670] TLC: R.sub.f=0.54 (10:1 hexanes:ethyl acetate).
##STR00118##
1-((benzyloxy)methyl)-2-phenylbicyclo[1.1.1]pentane (87)
[0671] On the benchtop, BCP BF.sub.3K 81 (14.7 mg, 0.05 mmol, 1.0 equiv.), (Ir[dF(CF.sub.3)ppy].sub.2(dtbbpy))PF.sub.6 (2.8 mg, 0.0025 mmol, 0.05 equiv.), Ni(dtbbpy)Cl.sub.2 (4.0 mg, 0.01 mmol, 0.20 equiv.) and Cs.sub.2CO.sub.3 (100 mg, 0.3 mmol, 6.0 equiv.) were added to a flame-dried test tube equipped with a stir bar. The test tube was evacuated and backfilled with argon three times. Then PhBr (26 mL, 0.25 mmol, 5.0 equiv.), and distilled dioxane (0.5 mL) were added into the tube. The tube was purged with a gentle stream of argon for 10 seconds, then sealed and stirred at room temperature in 450-nm photoreactor for 24 hours. Next, the reaction mixture was quenched with water (1.0 mL) and extracted with diethyl ether (1.0 mL) three times. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered through Celite, concentrated under reduced pressure, and purified by pTLC (hexanes:diethyl ether, 10:1) on silica gel to obtain 5.3 mg (40%) of the desired coupling product 87. (Primer et al., 2016)
[0672] Physical State: colorless oil.
[0673] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.38-7.33 (m, 4H), 7.32-7.26 (m, 3H), 7.22-7.18 (m, 1H), 7.16 (dt, J=8.1, 1.1 Hz, 2H), 4.60 (d, J=12.1 Hz, 1H), 4.53 (d, J=12.2 Hz, 1H), 3.53 (d, J=10.7 Hz, 1H), 3.47-3.41 (m, 2H), 2.89 (s, 1H), 2.10 (dd, J=10.1, 2.6 Hz, 1H), 1.86 (dq, J=4.0, 1.9 Hz, 2H), 1.78 (dd, J=6.8, 2.6 Hz, 1H) ppm.
[0674] .sup.13C NMR (151 MHz, CDCl.sub.3): 139.99, 138.66, 128.94, 128.49, 128.09, 127.83, 127.70, 125.94, 73.24, 69.05, 62.79, 47.59, 47.00, 46.50, 31.13 ppm.
[0675] MS (GCMS, EI): m/z=264 (0.2%), 173 (2%), 155 (16%), 115 (30%), 91 (100%).
[0676] TLC: R.sub.f=0.54 (10:1 hexanes:ethyl acetate).
##STR00119##
2-(1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-yl)-3-bromoquinoxaline (88)
[0677] A screw-capped culture tube was charged with BCP BF.sub.3K 81 (29.4 mg, 0.1 mmol, 1.0 equiv.), 2-bromoquinoxaline (62.4 mg, 0.3 mmol, 3.0 equiv.) and Mn(OAc).sub.3.Math.2H.sub.2O (80.4 mg, 0.3 mmol, 3.0 equiv.). Then the tube or the flask was evacuated and backfilled with argon three times, followed by addition of acetic acid/water (1.0 mL, 0.1 M, 1:1) solvent via a syringe. Next, trifluoroacetic acid (23 mL, 0.5 mmol, 5.0 equiv.) was added into the reaction. Then the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was stirred at 50 C. for 18 hours. After it was confirmed that the starting material was consumed totally, the reaction mixture was concentrated under high vacuum to remove excess acetic acid, quenched with K.sub.2CO.sub.3 solution, extracted with ethyl acetate, dried with Na.sub.2SO.sub.4, and concentrated under high vacuum. The crude residue was purified by pTLC (hexanes:diethyl ether, 5:1) on silica gel to obtain 12.1 mg (31%) of the desired coupling product 88. (Molander et al., 2011)
[0678] Physical State: red oil.
[0679] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.00 (dd, J=7.7, 2.0 Hz, 2H), 7.78-7.70 (m, 2H), 7.29-7.27 (m, 4H), 7.23 (dq, J=7.8, 2.6 Hz, 1H), 4.59 (d, J=12.2 Hz, 1H), 4.53 (d, J=12.2 Hz, 1H), 3.93 (d, J=10.6 Hz, 1H), 3.82 (d, J=10.6 Hz, 1H), 3.72 (d, J=6.2 Hz, 1H), 3.16 (s, 1H), 2.38 (dd, J=9.8, 2.9 Hz, 1H), 2.05-1.98 (m, 1H), 1.92 (d, J=1.9 Hz, 1H), 1.87 (dd, J=6.2, 2.9 Hz, 1H) ppm.
[0680] .sup.13C NMR (151 MHz, CDCl.sub.3): 154.97, 141.81, 141.52, 138.75, 130.21, 130.10, 129.27, 128.39, 128.28, 127.82, 127.64, 127.54, 73.19, 69.30, 63.69, 48.32, 48.09, 46.13, 33.54 ppm.
[0681] HRMS (ESI-TOF): calc'd for C.sub.21H.sub.19BrN.sub.2O [M+H].sup.+: 395.0754, found: 395.0750.
[0682] TLC: R.sub.f=0.43 (10:1 hexanes:ethyl acetate).
##STR00120##
di-tert-butyl 1-(2-((benzyloxy)methyl)cyclobutyl)hydrazine-1,2-dicarboxylate (89)
[0683] To a screw-capped culture tube was added boronic acid 82 (116 mg, 0.5 mmol), TBC (30 mol %), DBAD (1.0 mmol) and toluene (2.5 mL). The headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was allowed to stir at 70 C. for 2 h. The solvent was concentrated, and the residue was directly purified by flash column chromatography (hexanes:ethyl acetate, 10:1) on silica gel to give 199 mg (95%) of the desired product 89. (Andrd-Joyaux, et al., 2011)
[0684] Physical State: colorless oil.
[0685] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.35-7.26 (m, 5H), 6.99 (br., 0.5H), 6.51 (br., 0.5H), 4.50 (s, 2H), 3.82 (br., 1H), 3.43 (br., 2H), 2.97-2.60 (m, 1H), 2.39-2.29 (m, 1H), 1.90-1.68 (m, 2H), 1.54-1.38 (m, 19H) ppm.
[0686] .sup.13C NMR (151 MHz, CDCl.sub.3): 138.21, 128.51, 127.92, 127.77, 81.16 (br.), 73.48 (br.), 73.08 (br.), 69.32 (br.), 44.87, 28.40, 28.37 ppm. Note: bridge-head CH and C, bridge NCH and CH.sub.2 and two NC(O) were not observed.
[0687] HRMS (ESI-TOF): calc'd for C.sub.23H.sub.34N.sub.2O.sub.5 [M+H].sup.+: 419.2541, found: 419.2541.
[0688] TLC: R.sub.f=0.39 (2:1 hexanes:ethyl acetate).
##STR00121##
2-(2-(1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-yl)propan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (90)
[0689] A flame-dried screw-capped culture tube was charged with BCP boronic acid 82 (23.2 mg, 0.1 mmol, 1.0 equiv.) and sulfonyl hydrazone SI-21 (30.5 mg, 0.12 mmol, 1.0 equiv.), and cesium carbonate (97.5 mg, 0.3 mmol, 3.0 equiv.) Then the tube was evacuated and backfilled with argon three times, followed by addition of chlorobenzene (1.0 mL) via a syringe. After stirring for at 100 C. for 2 hours, the reaction mixture was cooled to room temperature. Next, pinacol (118 mg, 1.0 mmol, 5.0 equiv.) was added, and the reaction was stirred at 100 C. for another 1 hour. The suspended solution was then filtered over Celite and washed with diethyl ether. The solvent was removed under high vacuum, and the crude residue was purified by chromatography (hexanes:ethyl acetate, 15:1) on silica gel to afford 22.1 mg (62%) of the desired product 90. (Yang, et al., 2021a)
[0690] Physical State: white solid.
[0691] m.p.: 27-29 C.
[0692] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.37-7.31 (m, 4H), 7.29-7.24 (m, 1H), 4.52 (s, 2H), 3.56 (d, J=10.6 Hz, 1H), 3.52 (d, J=10.6 Hz, 1H), 2.51 (s, 1H), 2.07 (dd, J=9.9, 3.3 Hz, 1H), 1.86 (d, J=7.1 Hz, 1H), 1.76 (dd, J=7.2, 3.2 Hz, 1H), 1.71 (d, J=1.6 Hz, 1H), 1.46 (dd, J=9.9, 1.7 Hz, 1H), 1.21 (s, 6H), 1.20 (s, 6H), 0.97 (s, 3H), 0.95 (s, 3H) ppm.
[0693] .sup.13C NMR (151 MHz, CDCl.sub.3): 139.12, 128.39, 127.60, 127.44, 82.96, 73.20, 73.07, 69.87, 48.13, 47.65, 47.08, 31.84, 27.12, 26.43, 24.86, 24.84 ppm.
[0694] .sup.11B NMR (128 MHz, CDCl.sub.3): 34.77 ppm.
[0695] MS (GCMS, EI): m/z=355 (0.1%), 341 (0.1%), 294 (0.1%), 207 (3%), 107 (25%), 91 (100%).
[0696] TLC: R.sub.f=0.50 (10:1 hexanes:ethyl acetate).
##STR00122##
4-((1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-yl)amino)benzonitrile (91)
[0697] A flame dried screw-capped culture tube was charged with boronic acid 82 (23.2 mg, 0.1 mmol), 4-nitrobenzonitrile (14.8 mg, 0.1 mmol) and 1,2,2,3,4,4 hexamethylphosphetane 1-oxide (15 mol %) under argon atmosphere, followed by addition of m-xylene (0.2 mL) and PhSiH.sub.3 (0.2 mmol). The reaction mixture was stirred at 120 C. for 8 hours. The mixture was directly purified by flash column chromatography (hexanes:ethyl acetate, 10:1) on silica gel to give 20.0 mg (66%) of the desired product 91. (Nykaza et al., 2018)
[0698] Physical State: colorless oil.
[0699] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.40-7.35 (m, 4H), 7.32 (td, J=6.7, 6.3, 1.7 Hz, 3H), 6.59-6.54 (m, 2H), 5.29 (br., 1H), 4.50 (s, 2H), 3.60 (d, J=6.3 Hz, 1H), 3.51 (d, J=10.3 Hz, 1H), 3.47 (d, J=10.3 Hz, 1H), 2.77 (s, 1H), 2.56 (dd, J=9.8, 2.9 Hz, 1H), 1.83-1.78 (m, 2H), 1.61 (dd, J=9.7, 2.7 Hz, 1H) ppm.
[0700] .sup.13C NMR (151 MHz, CDCl.sub.3): 151.62, 138.21, 133.76, 128.64, 127.96, 127.64, 120.78, 112.25, 98.53, 73.50, 70.09, 68.50, 47.23, 44.82, 43.47, 33.23 ppm.
[0701] HRMS (ESI-TOF): calc'd for C.sub.20H.sub.20N.sub.2O [M+H].sup.+: 305.1648, found: 305.1684.
[0702] TLC: R.sub.f=0.46 (10:1 hexanes:ethyl acetate).
##STR00123##
1-((benzyloxy)methyl)-N-(p-tolyl)bicyclo[1.1.1]pentan-2-amine (92)
[0703] A flame dried screw-capped culture tube was charged with boronic acid 82 (23.2 mg, 0.1 mmol), 4-nitrotoluene (13.7 mg, 0.1 mmol) and 1,2,2,3,4,4 hexamethylphosphetane 1-oxide (15 mol %) under argon atmosphere, followed by addition of m-xylene (0.2 mL) and PhSiH.sub.3 (0.2 mmol). The reaction mixture was stirred at 120 C. for 8 hours. The mixture was directly purified by flash column chromatography (hexanes:ethyl acetate, 10:1) on silica gel to give 18.0 mg (61%) of the desired product 92. (Nykaza et al., 2018)
[0704] Physical State: red oil.
[0705] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.42-7.28 (m, 5H), 7.01-6.96 (m, 2H), 6.59-6.54 (m, 2H), 4.53 (d, J=12.1 Hz, 1H), 4.50 (d, J=12.1 Hz, 1H), 3.60 (d, J=6.2 Hz, 1H), 3.48 (s, 2H), 2.72 (s, 1H), 2.61 (dd, J=9.7, 2.6 Hz, 1H), 2.25 (s, 3H), 1.79 (dd, J=6.3, 2.6 Hz, 1H), 1.76 (d, J=2.5 Hz, 1H), 1.58 (dd, J=9.7, 2.5 Hz, 1H) ppm.
[0706] .sup.13C NMR (151 MHz, CDCl.sub.3): 146.16, 138.55, 129.94, 129.81, 128.55, 127.73, 127.61, 126.22, 112.66, 73.32, 69.83, 69.76, 47.46, 44.80, 43.54, 33.29, 20.53 ppm.
[0707] HRMS (ESI-TOF): calc'd for C.sub.20H.sub.23NO [M+H].sup.+: 294.1852, found: 294.1856.
[0708] TLC: R.sub.f=0.68 (5:1 hexanes:ethyl acetate).
##STR00124##
ethyl 4-(1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-yl)benzoate (93)
[0709] A flame-dried screw-capped culture tube was charged with BCP boronate 36 (31.4 mg, 0.1 mmol, 1.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of THF (0.5 mL, 0.2 M) solvent via a syringe. Next, PhLi (68 mL, 1.75 M in hexanes, 0.12 mmol, 1.2 equiv.) was added into the reaction mixture at 78 C. and the reaction was allowed to stir at 78 C. for 30 minutes. Then the mixture was allowed to warm up to room temperature and stir for another 30 minutes. A solution of 4-CzlPn (3.9 mg, 0.005 mmol, 0.05 equiv.), Ni(dtbbpy)Cl.sub.2 (8.0 mg, 0.02 mmol, 0.2 equiv.) and ethyl 4-bromobenzoate (49 mL, 0.3 mmol, 3.0 equiv.) in DMA (0.5 mL) was added into the reaction mixture. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was allowed to stir in a 450-nm photoreactor for 12 hours. After it was confirmed that the starting material was consumed totally, the reaction mixture was quenched with water, extracted with diethyl ether, washed by saturated brine, dried with Na.sub.2SO.sub.4 and concentrated under high vacuum and the crude residue was purified by chromatography on silica gel to give 21.2 mg (63%) of the desired product 88.
[0710] Physical State: colorless oil.
[0711] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.95 (d, J=8.3 Hz, 2H), 7.39-7.34 (m, 4H), 7.31 (ddd, J=8.6, 5.5, 2.4 Hz, 1H), 7.23 (d, J=7.9 Hz, 2H), 4.59 (d, J=12.1 Hz, 1H), 4.53 (d, J=12.2 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.50 (d, J=10.7 Hz, 1H), 3.47-3.42 (m, 2H), 2.92 (s, 1H), 2.07-2.02 (m, 1H), 1.88 (dd, J=9.7, 1.9 Hz, 1H), 1.86 (d, J=1.8 Hz, 1H), 1.78 (dd, J=6.9, 2.7 Hz, 1H), 1.39 (t, J=7.1 Hz, 3H) ppm.
[0712] .sup.13C NMR (151 MHz, CDCl.sub.3): 166.88, 145.42, 138.48, 129.35, 128.92, 128.52, 128.23, 127.85, 127.79, 73.28, 68.86, 62.78, 60.93, 47.61, 47.34, 46.51, 31.22, 14.50 ppm.
[0713] MS (GCMS, EI): m/z=336 (0.2%), 291 (1%), 230 (6%), 199 (9%), 155 (19%), 91 (100%).
[0714] TLC: R.sub.f=0.46 (10:1 hexanes:ethyl acetate).
##STR00125##
tert-butyl 3-(1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-yl)propanoate (94)
[0715] A flame-dried screw-capped culture tube was charged with BCP boronate 36 (31.4 mg, 0.1 mmol, 1.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of THF (0.2 mL, 0.5 M) solvent via a syringe. Next, PhLi (68 mL, 1.75 M in hexanes, 0.12 mmol, 1.2 equiv.) was added into the reaction mixture at 78 C. and the reaction was allowed to stir at 78 C. for 30 minutes. Then the mixture was allowed to warm up to room temperature and was stirred for another 30 minutes. A solution of 4-CzlPn (3.9 mg, 0.005 mmol, 0.05 equiv.), tert-butylacrylate (29 mL, 0.2 mmol, 2.0 equiv.) and tert-butanol (28 mL, 0.3 mmol, 3.0 equiv.) in acetonitrile (1.0 mL) was added into the reaction mixture. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was allowed to stir in a 450-nm photoreactor for 12 hours. The reaction mixture was concentrated under high vacuum and the crude residue was purified by chromatography on silica gel to give 28.8 mg (91%) of the desired product 94.
[0716] Physical State: colorless oil.
[0717] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.31-7.16 (m, 5H), 4.42 (s, 2H), 3.27 (s, 2H), 2.32 (s, 1H), 2.23 (dd, J=9.8, 2.9 Hz, 1H), 2.16 (ddd, J=8.4, 6.9, 5.2 Hz, 2H), 2.01 (dt, J=7.8, 6.2 Hz, 1H), 1.87-1.70 (m, 2H), 1.69-1.64 (m, 2H), 1.48 (dd, J=9.8, 1.7 Hz, 1H), 1.37 (s, 9H) ppm.
[0718] .sup.13C NMR (101 MHz, CDCl.sub.3): 173.38, 138.79, 134.87, 128.45, 127.57, 80.10, 73.12, 69.51, 60.31, 48.89, 46.38, 45.36, 34.94, 31.12, 28.26, 21.25 ppm.
[0719] HRMS (ESI-TOF): calc'd for C.sub.20H.sub.28O.sub.3[M+H].sup.+: 317.2111, found: 317.2113.
[0720] TLC: R.sub.f=0.54 (10:1 hexanes:ethyl acetate).
##STR00126##
1-((benzyloxy)methyl)bicyclo[1.1.1]pentane-2-carbonitrile (95)
[0721] A flame-dried screw-capped culture tube was charged with BCP boronate 36 (31.4 mg, 0.1 mmol, 1.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of THE (0.2 mL, 0.5 M) solvent via a syringe. Next, PhLi (68 mL, 1.75 M in hexanes, 0.12 mmol, 1.2 equiv.) was added into the reaction mixture at 78 C. and the reaction was allowed to stir at 78 C. for 30 minutes. Then the mixture was allowed to warm up to room temperature and stir for another 30 minutes. A solution of 4-CzlPn (3.9 mg, 0.005 mmol, 0.05 equiv.) and TsCN (36 mg, 0.2 mmol, 2.0 equiv.) in acetonitrile (1.0 mL) was added into the reaction mixture. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was allowed to stir in a 450-nm photoreactor for 12 hours. The reaction mixture was concentrated under high vacuum and the crude residue was purified by chromatography on silica gel to give 14 mg (66%) of the desired product 95.
[0722] Physical State: colorless oil.
[0723] .sup.1H NMR (400 MHz, CDCl.sub.3): 7.42-7.26 (m, 5H), 4.55 (d, J=12.4 Hz, 1H), 4.51 (d, J=12.4 Hz, 1H), 3.50 (d, J=11.0 Hz, 1H), 3.45 (d, J=11.0 Hz, 1H), 2.91 (s, 1H), 2.76 (d, J=7.6 Hz, 1H), 2.53 (dd, J=9.9, 3.4 Hz, 1H), 1.94 (dd, J=7.6, 3.4 Hz, 1H), 1.87 (dd, J=9.9, 2.7 Hz, 1H), 1.81 (d, J=2.7 Hz, 1H) ppm.
[0724] .sup.13C NMR (101 MHz, CDCl.sub.3): 138.11, 128.58, 127.86, 127.63, 119.43, 73.40, 68.17, 48.49, 48.32, 47.87, 45.90, 33.10 ppm.
[0725] MS (GCMS, EI): m/z=213 (3%), 107 (10%), 91 (100%), 65 (35%).
[0726] TLC: R.sub.f=0.63 (2:1 hexanes:ethyl acetate).
##STR00127##
tert-butyl 3-(1-((benzyloxy)methyl)-3-cyanobicyclo[1.1.1]pentan-2-yl)propanoate (96)
[0727] A flame-dried screw-capped culture tube was charged with BCP boronate 42 (33.9 mg, 0.1 mmol, 1.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of THF (0.2 mL, 0.5 M) solvent via a syringe. Next, PhLi (68 mL, 1.75 M in hexanes, 0.12 mmol, 1.2 equiv.) was added into the reaction mixture at 78 C. and the reaction was allowed to stir at 78 C. for 30 minutes. Then the mixture was allowed to warm up to room temperature and was stirred for another 30 minutes. A solution of 4-CzlPn (3.9 mg, 0.005 mmol, 0.05 equiv.), tert-butylacrylate (29 mL, 0.2 mmol, 2.0 equiv.) and tert-butanol (28 mL, 0.3 mmol, 3.0 equiv.) in acetonitrile (1.0 mL) was added into the reaction mixture. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was allowed to stir in a 450-nm photoreactor for 12 hours. The reaction mixture was concentrated under high vacuum and the crude residue was purified by chromatography on silica gel to give 15 mg (44%) of the desired product 96.
[0728] Physical State: colorless oil.
[0729] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.38-7.32 (m, 2H), 7.32-7.26 (m, 3H), 4.47 (d, J=12.2 Hz, 1H), 4.45 (d, J=12.2 Hz, 1H), 3.39-3.34 (m, 2H), 2.70 (dd, J=9.7, 3.1 Hz, 1H), 2.48 (q, J=6.7 Hz, 1H), 2.43-2.27 (m, 2H), 2.18-2.15 (m, 2H), 2.07-1.83 (m, 3H), 1.45 (s, 9H) ppm.
[0730] .sup.13C NMR (151 MHz, CDCl.sub.3): 172.44, 138.04, 128.58, 127.90, 127.67, 117.47, 80.67, 73.39, 67.76, 64.28, 53.00, 49.28, 45.51, 33.53, 28.25, 26.98, 20.43 ppm.
[0731] HRMS (ESI-TOF): calc'd for C.sub.21H.sub.27NO.sub.3 [M+H].sup.+: 342.2064, found: 342.2061.
[0732] TLC: R.sub.f=0.29 (10:1 hexanes:ethyl acetate).
##STR00128##
isopropyl 2-(3-(tert-butoxy)-3-oxopropyl)-3-(2-(pyridin-4-yl)ethyl)bicyclo[1.1.1]pentane-1-carboxylate (97)
[0733] A flame-dried screw-capped culture tube was charged with BCP boronate 54 (41.9 mg, 0.1 mmol, 1.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of THF (0.2 mL, 0.5 M) solvent via a syringe. Next, PhLi (68 mL, 1.75 M in hexanes, 0.12 mmol, 1.2 equiv.) was added into the reaction mixture at 78 C. and the reaction was allowed to stir at 78 C. for 30 minutes. Then the mixture was allowed to warm up to room temperature and was stirred for another 30 minutes. A solution of 4-CzlPn (3.9 mg, 0.005 mmol, 0.05 equiv.), tert-butylacrylate (29 mL, 0.2 mmol, 2.0 equiv.) and tert-butanol (28 mL, 0.3 mmol, 3.0 equiv.) in acetonitrile (1.0 mL) was added into the reaction mixture. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was allowed to stir in a 450-nm photoreactor for 12 hours. The reaction mixture was concentrated under high vacuum and the crude residue was purified by chromatography on silica gel to give 36 mg (85%) of the desired product 97.
[0734] Physical State: colorless oil.
[0735] .sup.1H NMR (400 MHz, CDCl.sub.3): 8.49-8.43 (m, 2H), 7.13-7.06 (m, 2H), 4.95 (hept, J=6.3 Hz, 1H), 2.56-2.47 (m, 2H), 2.41-2.13 (m, 4H), 1.98-1.77 (m, 4H), 1.75 (ddd, J=8.0, 6.9, 2.5 Hz, 2H), 1.67 (dd, J=9.7, 1.7 Hz, 1H), 1.43 (s, 9H), 1.20 (d, J=6.2 Hz, 6H) ppm.
[0736] .sup.13C NMR (151 MHz, CDCl.sub.3): 172.93, 169.43, 151.09, 149.73, 123.85, 80.34, 67.77, 62.08, 51.21, 46.61, 42.50, 41.04, 34.23, 31.90, 30.07, 28.22, 21.90, 20.40 ppm.
[0737] MS (GCMS, EI): m/z=387 (1%), 373 (1%), 342 (5%), 298 (5%), 207 (11%), 93 (100%).
[0738] TLC: R.sub.f=0.17 (2:1 hexanes:ethyl acetate).
##STR00129##
ethyl 4-(1-((benzyloxy)methyl)bicyclo[1.1.1]pentan-2-yl)benzoate (98)
[0739] A flame-dried screw-capped culture tube was charged with BCP boronate 54 (31.4 mg, 0.1 mmol, 1.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of THF (0.5 mL, 0.2 M) solvent via a syringe. Next, PhLi (68 mL, 1.75 M in hexanes, 0.12 mmol, 1.2 equiv.) was added into the reaction mixture at 78 C. and the reaction was allowed to stir at 78 C. for 30 minutes. Then the mixture was allowed to warm up to room temperature and stir for another 30 minutes. A solution of 4-CzlPn (3.9 mg, 0.005 mmol, 0.05 equiv.), Ni(dtbbpy)Cl.sub.2 (8.0 mg, 0.02 mmol, 0.2 equiv.) and ethyl 4-bromobenzoate (49 mL, 0.3 mmol, 3.0 equiv.) in DMA (0.5 mL) was added into the reaction mixture. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was allowed to stir in a 450-nm photoreactor for 12 hours. After it was confirmed that the starting material was consumed totally, the reaction mixture was quenched with water, extracted with diethyl ether, washed by saturated brine, dried with Na.sub.2SO.sub.4 and concentrated under high vacuum and the crude residue was purified by pTLC on silica gel (hexane:acetone, 3:1) to give 10.2 mg (25%) of the desired product 98.
[0740] On the benchtop, BCP BF.sub.3K SI-25 (18.3 mg, 0.05 mmol, 1.0 equiv.), ethyl 4-bromobenzoate (48 mL, 0.3 mmol, 4.0 equiv.), (Ir[dF(CF.sub.3)ppy].sub.2(dtbbpy))PF.sub.6 (2.8 mg, 0.0025 mmol, 0.05 equiv.), Ni(dtbbpy)Cl.sub.2 (4.0 mg, 0.01 mmol, 0.20 equiv.) and Cs.sub.2CO.sub.3 (100 mg, 0.3 mmol, 6.0 equiv.) were added to a flame-dried test tube equipped with a stir bar. The test tube was evacuated and backfilled with argon three times. Then dried THF (0.5 mL) was added into the tube. Then the tube was purged with a gentle stream of argon for 10 seconds, then sealed and stirred at room temperature in 450-nm photoreactor for 24 hours. Next, the reaction mixture was quenched with water (1.0 mL) and extracted with diethyl ether (1.0 mL) three times. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered through Celite, concentrated under reduced pressure, and purified by pTLC (hexanes:diethyl ether, 1:3) on silica gel to obtain 4.8 mg (24%) of the desired coupling product 98.
[0741] Physical State: colorless oil.
[0742] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.50 (d, J=5.0 Hz, 2H), 7.99 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 7.13 (d, J=5.0 Hz, 2H), 5.06 (hept, J=6.2 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.60 (d, J=6.6 Hz, 1H), 2.63 (qdd, J=14.2, 10.3, 6.1 Hz, 2H), 2.33 (dd, J=9.7, 3.0 Hz, 1H), 2.01-1.94 (m, 3H), 1.94-1.86 (m, 2H), 1.39 (t, J=7.1 Hz, 3H), 1.25 (dd, J=7.7, 6.3 Hz, 6H) ppm.
[0743] .sup.13C NMR (151 MHz, CDCl.sub.3): 169.13, 166.65, 151.19, 149.56, 143.16, 129.57, 128.83, 128.68, 123.98, 68.34, 65.00, 61.08, 51.04, 47.02, 43.75, 41.46, 31.91, 30.20, 21.95, 14.49 ppm.
[0744] HRMS (ESI-TOF): calc'd for C.sub.25H.sub.29NO.sub.4 [M+H].sup.+: 408.2169, found: 408.2167.
[0745] TLC: R.sub.f=0.13 (2:1 hexanes:ethyl acetate).
##STR00130##
ethyl 4-(1-(3,5-dichloropyrazin-2-yl)-3-methylbicyclo[1.1.1]pentan-2-yl)benzoate (99)
[0746] A flame-dried screw-capped culture tube was charged with BCP boronate 77 (35.5 mg, 0.1 mmol, 1.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of THF (0.5 mL, 0.2 M) solvent via a syringe. Next, PhLi (68 mL, 1.75 M in hexanes, 0.12 mmol, 1.2 equiv.) was added into the reaction mixture at 78 C. and the reaction was allowed to stir at 78 C. for 30 minutes. Then the mixture was allowed to warm up to room temperature and was stirred for another 30 minutes. A solution of 4-CzlPn (3.9 mg, 0.005 mmol, 0.05 equiv.), Ni(dtbbpy)Cl.sub.2 (8.0 mg, 0.02 mmol, 0.2 equiv.) and ethyl 4-bromobenzoate (49 mL, 0.3 mmol, 3.0 equiv.) in DMA (0.5 mL) was added into the reaction mixture. Next, the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was allowed to stir in a 450-nm photoreactor for 12 hours. After it was confirmed that the starting material was consumed totally, the reaction mixture was quenched with water, extracted with diethyl ether, washed by saturated brine, dried with Na.sub.2SO.sub.4 and concentrated under high vacuum and the crude residue was purified by chromatography on silica gel to give 8.2 mg (22%) of the desired product 99.
[0747] Physical State: red oil.
[0748] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.46 (s, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H), 3.95 (d, J=6.7 Hz, 1H), 2.59 (dd, J=9.8, 3.0 Hz, 1H), 2.36 (dd, J=9.8, 1.7 Hz, 1H), 2.24 (dt, J=7.4, 3.7 Hz, 1H), 2.14 (d, J=1.6 Hz, 1H), 1.42-1.32 (m, 6H) ppm.
[0749] .sup.13C NMR (151 MHz, CDCl.sub.3): 166.68, 149.87, 146.46, 145.42, 143.96, 141.99, 129.47, 128.59, 128.52, 66.18, 60.99, 54.18, 48.84, 44.58, 41.70, 16.40, 14.47 ppm.
[0750] MS (GCMS, EI): m/z=378 (5%), 376 (8%), 341 (20%), 269 (15%), 213 (35%), 115 (100%).
[0751] TLC: R.sub.f=0.46 (10:1 hexanes:ethyl acetate).
##STR00131##
trifluoro(1-methyl-3-phenylbicyclo[1.1.1]pentan-2-yl)-.SUP.4.-borane, potassium salt (SI-24)
[0752] BCP boronate 65 (284 mg, 1.0 mmol) was suspended in methanol (5 mL), and a saturated aqueous solution of KHF.sub.2 (1 mL, 4 mmol) was added dropwise. The suspended solution was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was extracted with hot acetone (320 mL), and the combined filtered extracts were concentrated. Methylene chloride was added, and the resultant precipitate was collected and dried to afford the 201 mg (76%) of the potassium trifluoroborate SI-24.
[0753] Physical State: white solid.
[0754] m.p.: 191-193 C.
[0755] .sup.1H NMR (600 MHz, Acetone-d.sup.6): 7.34-7.29 (m, 2H), 7.14 (dd, J=8.5, 6.9 Hz, 2H), 7.06-7.00 (m, 1H), 2.74 (d, J=9.5 Hz, 1H), 1.78 (s, 1H), 1.63 (d, J=9.4 Hz, 1H), 1.57 (d, J=8.0 Hz, 1H), 1.27 (dd, J=7.7, 5.7 Hz, 1H), 1.18 (s, 3H) ppm.
[0756] .sup.13C NMR (151 MHz, Acetone-d.sup.6): 145.49, 128.03, 127.66, 125.51, 58.94, 52.08, 44.22 (d, J=2.8 Hz), 37.47 (q, J=2.9 Hz), 18.95 ppm.
[0757] .sup.19F NMR (376 MHz, Acetone-d.sup.6): 134.94 ppm.
[0758] .sup.11B NMR (128 MHz, Acetone-d.sub.6): 4.01 (q, J=65.8 Hz) ppm.
##STR00132##
N-(4-bromophenyl)-1-methyl-3-phenylbicyclo[1.1.1]pentan-2-amine (100)
[0759] A screw-capped culture tube was charged with SI-24 (132 mg, 0.5 mmol) and water (2.5 mL), followed by addition of silica gel (250 mg) under argon atmosphere. The mixture was stirred at room temperature for 1 hour. Ethyl ether (5 mL) was added, and the suspended solution was filtered by Celite. The organic phase was separated, and the water phase was extracted with diethyl ether (32 mL). The combined organic solvent was washed with brine and dried by anhydrous MgSO.sub.4. The solvent was removed under vacuum to afford the desired boronic acid without further purification.
[0760] A flame dried screw-capped culture tube was charged with boronic acid (20.2 mg, 0.1 mmol), 1-bromo-4-nitrobenzene (20.2 mg, 0.1 mmol) and 1,2,2,3,4,4-hexamethylphosphetane-1-oxide (15 mol %) under argon atmosphere, followed by addition of m-xylene (0.2 mL) and PhSiH.sub.3 (0.2 mmol) were added. The reaction mixture was stirred at 120 C. for 8 hours. The mixture was directly purified by flash column chromatography (hexanes:ethyl acetate, 10:1) on silica gel to give 14.1 mg (43%) of the desired product 100. (Nykaza et al., 2018)
[0761] Physical State: red oil.
[0762] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.28 (dd, J=8.1, 6.8 Hz, 2H), 7.25-7.19 (m, 1H), 7.16 (ddd, J=10.2, 7.5, 1.8 Hz, 4H), 6.45-6.40 (m, 2H), 3.64 (d, J=6.3 Hz, 1H), 2.65 (dd, J=9.8, 2.7 Hz, 1H), 1.91 (dd, J=6.3, 2.7 Hz, 1H), 1.89 (d, J=2.4 Hz, 1H), 1.84 (dd, J=9.8, 2.5 Hz, 1H), 1.25 (s, 3H) ppm.
[0763] .sup.13C NMR (151 MHz, CDCl.sub.3): 147.23, 138.46, 131.88, 128.48, 126.93, 126.54, 114.47, 108.89, 72.32, 49.00, 47.00, 46.95, 40.85, 15.98 ppm.
[0764] HRMS (ESI-TOF): calc'd for C.sub.18H.sub.18BrN [M+H].sup.+: 328.0695, found: 328.0694.
[0765] TLC: R.sub.f=0.27 (5:1 hexanes:ethyl acetate).
##STR00133##
1-methyl-2-(4-(methylsulfonyl)phenyl)-3-phenylbicyclo[1.1.1]pentane (101)
[0766] On the benchtop, BCP BF.sub.3K SI-24 (14.7 mg, 0.05 mmol, 1.0 equiv.), 4-bromophenyl methyl sulfone (47 mg, 0.2 mmol, 4.0 equiv.), (Ir[dF(CF.sub.3)ppy].sub.2(dtbbpy))PF.sub.6 (2.8 mg, 0.0025 mmol, 0.05 equiv.), Ni(dtbbpy)Cl.sub.2 (4.0 mg, 0.01 mmol, 0.20 equiv.) and Cs.sub.2CO.sub.3 (100 mg, 0.3 mmol, 6.0 equiv.) were added to a flame-dried test tube equipped with a stir bar. The test tube was evacuated and backfilled with argon three times. Then dried dioxane (0.5 mL) was added into the tube. Then the tube was purged with a gentle stream of argon for 10 seconds, then sealed and stirred at room temperature in 450-nm photoreactor for 24 hours. Next, the reaction mixture was quenched with water (1.0 mL) and extracted with diethyl ether (1.0 mL) three times. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered through Celite, concentrated under reduced pressure, and purified by pTLC (hexanes:diethyl ether, 10:1) on silica gel to obtain 8.1 mg (52%) of the desired coupling product 96. (Primer et al., 2016)
[0767] Physical State: colorless oil.
[0768] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.81-7.77 (m, 2H), 7.35-7.29 (m, 2H), 7.29-7.23 (m, 3H), 7.21-7.16 (m, 2H), 3.52 (d, J=6.7 Hz, 1H), 3.02 (s, 3H), 2.35 (dd, J=9.8, 2.8 Hz, 1H), 2.05 (dd, J=9.8, 1.8 Hz, 1H), 2.02 (dd, J=6.8, 2.8 Hz, 1H), 2.00-1.94 (m, 1H), 1.37 (s, 3H) ppm.
[0769] .sup.13C NMR (151 MHz, CDCl.sub.3): 146.42, 139.35, 138.05, 129.76, 128.53, 127.08, 126.83, 126.59, 65.08, 55.55, 47.75, 45.40, 44.68, 39.71, 16.71 ppm.
[0770] HRMS (ESI-TOF): calc'd for C.sub.19H.sub.20O.sub.2S [M+H].sup.+: 313.1257, found: 313.1258.
[0771] TLC: R.sub.f=0.58 (2:1 hexanes:ethyl acetate).
##STR00134##
isopropyl 3-(2-(pyridin-4-yl)ethyl)-2-(trifluoro-24-boraneyl)bicyclo[1.1.1]pentane-1-carboxyl-ate, potassium salt (SI-25)
[0772] BCP boronate 54 (385 mg, 1.0 mmol) was suspended in methanol (5 mL), and a saturated aqueous solution of KHF.sub.2 (1 mL, 4 mmol) was added dropwise. The suspended solution was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was extracted with hot acetone (340 mL), and the combined filtered extracts were concentrated. Methylene chloride was added, and the resultant precipitate was collected and dried to afford the 274 mg (75%) of the potassium trifluoroborate SI-25.
[0773] Physical State: white solid.
[0774] m.p.: >200 C.
[0775] .sup.1H NMR (600 MHz, DMSO-d.sub.6): 8.42-8.38 (m, 2H), 7.20-7.16 (m, 2H), 4.75 (hept, J=6.3 Hz, 1H), 2.54-2.50 (m, 2H), 2.44 (d, J=9.3 Hz, 1H), 1.69 (td, J=7.2, 1.6 Hz, 2H), 1.57 (s, 1H), 1.53 (d, J=9.3 Hz, 1H), 1.44 (d, J=7.9 Hz, 1H), 1.22 (dq, J=10.3, 5.3 Hz, 1H), 1.10 (d, J=6.3 Hz, 6H) ppm.
[0776] .sup.13C NMR (151 MHz, DMSO-d.sub.6): 170.87, 151.89, 149.37, 123.89, 65.80, 55.34, 46.90, 40.94, 31.96, 31.65, 21.79, 21.76 ppm.
[0777] .sup.19F NMR (376 MHz, DMSO-d.sub.6): 133.29 ppm.
[0778] .sup.11B NMR (128 MHz, DMSO-d.sub.6): 2.99 ppm.
##STR00135##
isopropyl 3-(4-(methylsulfonyl)phenyl)-2-(trifluoro-14-boraneyl)bicyclo[1.1.1]pentane-1-carboxylate, potassium salt (SI-26)
[0779] BCP boronate 56 (217 mg, 0.5 mmol) was suspended in methanol (3 mL), and a saturated aqueous solution of KHF.sub.2 (0.7 mL, 2.8 mmol) was added dropwise. The suspended solution was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was extracted with hot acetone (310 mL), and the combined filtered extracts were concentrated. Methylene chloride was added, and the resultant precipitate was collected and dried to afford the 147 mg (71%) of the potassium trifluoroborate SI-26.
[0780] Physical State: white solid.
[0781] m.p.: >200 C.
[0782] .sup.1H NMR (600 MHz, DMSO-d.sub.6): 7.79-7.75 (m, 2H), 7.50-7.45 (m, 2H), 4.83 (hept, J=6.3 Hz, 1H), 3.14 (s, 3H), 2.91 (d, J=9.2 Hz, 1H), 2.06 (s, 1H), 2.01 (d, J=9.2 Hz, 1H), 1.88 (d, J=7.9 Hz, 1H), 1.64 (dq, J=10.1, 5.2 Hz, 1H), 1.15 (d, J=6.2 Hz, 6H) ppm.
[0783] .sup.13C NMR (151 MHz, DMSO-d.sub.6): 170.71, 148.80, 138.11, 127.59, 126.53, 66.17, 56.94, 48.83, 43.84, 42.87, 21.79, 21.76 ppm.
[0784] .sup.19F NMR (376 MHz, DMSO-d.sub.6): 133.31 ppm.
[0785] .sup.11B NMR (128 MHz, DMSO-d.sub.6): 2.57 ppm.
##STR00136##
isopropyl 2-(4-(ethoxycarbonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)bicyclo[1.1.1]pentane-1-carboxylate (102)
[0786] On the benchtop, BCP BF.sub.3K SI-26 (20.1 mg, 0.05 mmol, 1.0 equiv.), ethyl 4-bromobenzoate (49 mL, 0.3 mmol, 6.0 equiv.), (Ir[dF(CF.sub.3)ppy].sub.2(dtbbpy))PF.sub.6 (2.8 mg, 0.0025 mmol, 0.05 equiv.), Ni(dtbbpy)Cl.sub.2 (4.0 mg, 0.01 mmol, 0.20 equiv.) and Cs.sub.2CO.sub.3 (100 mg, 0.3 mmol, 6.0 equiv.) were added to a flame-dried test tube equipped with a stir bar. The test tube was evacuated and backfilled with argon three times. Then dried THF (0.5 mL) was added into the tube. Then the tube was purged with a gentle stream of argon for 10 seconds, then sealed and stirred at room temperature in 450-nm photoreactor for 24 hours. Next, the reaction mixture was quenched with water (1.0 mL) and extracted with diethyl ether (1.0 mL) three times. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered through Celite, concentrated under reduced pressure, and purified by pTLC (hexanes:diethyl ether, 2:1) on silica gel to obtain 4.1 mg (18%) of the desired coupling product 102. (Primer et al., 2016)
[0787] Physical State: colorless oil.
[0788] .sup.1H NMR (600 MHz, CDCl.sub.3): 7.92 (d, J=3.0 Hz, 2H), 7.90 (d, J=2.9 Hz, 2H), 7.35 (d, J=8.3 Hz, 2H), 7.09 (d, J=8.2 Hz, 2H), 5.11 (hept, J=6.3 Hz, 1H), 4.35 (q, J=7.1 Hz, 2H), 4.03 (d, J=6.7 Hz, 1H), 3.07 (s, 3H), 2.76 (dd, J=9.6, 2.9 Hz, 1H), 2.51 (dd, J=9.6, 1.8 Hz, 1H), 2.40 (dd, J=6.8, 2.8 Hz, 1H), 2.35 (d, J=1.8 Hz, 1H), 1.36 (t, J=7.1 Hz, 3H), 1.30 (d, J=4.1 Hz, 3H), 1.29 (d, J=4.0 Hz, 3H) ppm.
[0789] .sup.13C NMR (151 MHz, CDCl.sub.3): 168.86, 166.52, 144.42, 142.00, 139.50, 129.51, 129.18, 128.66, 127.84, 127.79, 68.73, 67.51, 61.10, 53.78, 47.12, 45.07, 44.67, 41.09, 21.98, 21.96, 14.45 ppm.
[0790] HRMS (ESI-TOF): calc'd for C.sub.25H.sub.28O.sub.6S [M+H].sup.+: 457.1679, found: 457.1677.
[0791] TLC: R.sub.f=0.35 (2:1 hexanes:ethyl acetate).
##STR00137##
3,5-dichloro-2-(3-methyl-2-(trifluoro-24-boraneyl)bicyclo[1.1.1]pentan-1-yl)pyrazine, potassium salt (SI-27)
[0792] BCP boronate 77 (355 mg, 1.0 mmol) was suspended in methanol (5 mL), and a saturated aqueous solution of KHF.sub.2 (1 mL, 4 mmol) was added dropwise. The suspended solution was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was extracted with hot acetone (320 mL), and the combined filtered extracts were concentrated. Methylene chloride was added, and the resultant precipitate was collected and dried to afford the 245 mg (73%) of the potassium trifluoroborate SI-27.
[0793] Physical State: white solid.
[0794] m.p.: >200 C.
[0795] .sup.1H NMR (600 MHz, Acetone-d.sup.6): 8.52 (s, 1H), 2.82 (d, J=9.5 Hz, 1H), 2.09 (dd, J=9.7, 2.6 Hz, 1H), 1.88 (t, J=6.3 Hz, 2H), 1.80 (dq, J=11.2, 5.8 Hz, 1H), 1.19 (s, 3H) ppm.
[0796] .sup.13C NMR (151 MHz, Acetone-d.sup.6): 154.86, 146.56, 143.79, 142.24, 58.90, 50.70, 43.69 (d, J=3.3 Hz), 39.67 (d, J=2.8 Hz), 18.61 ppm.
[0797] .sup.19F NMR (376 MHz, Acetone-d.sup.6): 136.10 ppm.
[0798] .sup.11B NMR (128 MHz, Acetone-d.sub.6): 3.63 ppm.
##STR00138##
2-(1-(3,5-dichloropyrazin-2-yl)-3-methylbicyclo[1.1.1]pentan-2-yl)-4-methylquinoline (103)
[0799] A screw-capped culture tube was charged with BCP BF.sub.3K SI-27 (31.9 mg, 0.1 mmol, 1.0 equiv.), lepidine (40 mL, 0.3 mmol, 3.0 equiv.) and Mn(OAc).sub.3.Math.2H.sub.2O (80.4 mg, 0.3 mmol, 3.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of acetic acid/water (1.0 mL, 0.1 M, 1:1) solvent via a syringe. Next, trifluoroacetic acid (23 mL, 0.5 mmol, 5.0 equiv.) was added into the reaction. Then the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was stirred at 50 C. for 18 hours. Then the reaction mixture was concentrated under high vacuum to remove excess acetic acid, quenched with Na.sub.2CO.sub.3 solution, extracted with ethyl acetate, dried with Na.sub.2SO.sub.4, and concentrated under high vacuum. The crude residue was purified by pTLC (hexanes:diethyl ether, 5:1) on silica gel to obtain 11.0 mg (30%) of the desired coupling product 103. (Molander et al., 2011)
[0800] Physical State: pale yellow solid.
[0801] m.p.: 49-51 C.
[0802] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.47 (s, 1H), 7.92 (dd, J=8.4, 1.3 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 6.95 (s, 1H), 4.08 (d, J=6.8 Hz, 1H), 2.73 (dd, J=9.8, 2.8 Hz, 1H), 2.62 (s, 3H), 2.42 (dd, J=9.8, 1.5 Hz, 1H), 2.26 (dd, J=6.9, 2.8 Hz, 1H), 2.12 (s, 1H), 1.49 (s, 3H) ppm.
[0803] .sup.13C NMR (151 MHz, CDCl.sub.3): 158.81, 150.73, 147.81, 146.56, 144.83, 143.60, 141.63, 130.08, 128.97, 126.91, 125.78, 123.64, 121.85, 68.15, 53.90, 49.43, 44.81, 18.98, 16.66 ppm. MS (GCMS, EI): m/z=370 (21%), 368 (32%), 366 (29%), 243 (35%), 205 (75%), 51 (100%).
[0804] TLC: R.sub.f=0.55 (5:1 hexanes:ethyl acetate).
##STR00139##
3-((benzyloxy)methyl)-2-(trifluoro-2-boraneyl)bicyclo[1.1.1]pentane-1-carbonitrile, potassium salt (SI-28)
[0805] BCP boronate 42 (678 mg, 2.0 mmol) was suspended in methanol (10 mL), and a saturated aqueous solution of KHF.sub.2 (2 mL, 8 mmol) was added dropwise. The suspended solution was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was extracted with hot acetone (330 mL), and the combined filtered extracts were concentrated. Methylene chloride was added, and the resultant precipitate was collected and dried to afford the 517 mg (81%) of the potassium trifluoroborate SI-28.
[0806] Physical State: white solid.
[0807] m.p.: 122-124 C.
[0808] .sup.1H NMR (600 MHz, Acetone-d.sup.6): 7.35-7.29 (m, 4H), 7.28-7.21 (m, 1H), 4.49 (d, J=12.2 Hz, 1H), 4.45 (d, J=12.3 Hz, 1H), 3.50 (d, J=10.8 Hz, 1H), 3.42 (d, J=10.9 Hz, 1H), 2.85 (d, J=9.2 Hz, 1H), 2.09 (s, 1H), 1.95 (d, J=8.1 Hz, 1H), 1.91 (d, J=9.3 Hz, 1H), 1.59 (dq, J=10.2, 5.2 Hz, 1H) ppm.
[0809] .sup.13C NMR (151 MHz, Acetone-d.sup.6): 140.18, 128.92, 128.11, 127.92, 120.54, 73.12, 70.53, 57.40, 51.52, 45.32 (q, J=2.2 Hz), 26.47 (q, J=3.4 Hz) ppm.
[0810] .sup.19F NMR (376 MHz, Acetone-d.sup.6): 137.30 ppm.
[0811] .sup.11B NMR (128 MHz, Acetone-d.sub.6): 2.94 (q, J=62.8 Hz) ppm.
##STR00140##
3-((benzyloxy)methyl)-2-(3,5-dichloropyrazin-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile (104)
[0812] A screw-capped culture tube was charged with BCP BF.sub.3K SI-28 (31.9 mg, 0.1 mmol, 1.0 equiv.), 2,6-dichloropyrazine (44.7 mg, 0.3 mmol, 3.0 equiv.) and Mn(OAc).sub.3.Math.2H.sub.2O (80.4 mg, 0.3 mmol, 3.0 equiv.). Then the tube was evacuated and backfilled with argon three times, followed by addition of acetic acid/water (1.0 mL, 0.1 M, 1:1) solvent via a syringe. Next, trifluoroacetic acid (23 mL, 0.5 mmol, 5.0 equiv.) was added into the reaction. Then the headspace of the tube was purged with a gentle stream of argon for approximately 10 seconds and the reaction was stirred at 50 C. for 18 hours. Then the reaction mixture was concentrated under high vacuum to remove excess acetic acid, quenched with K.sub.2CO.sub.3 solution, extracted with ethyl acetate, dried with Na.sub.2SO.sub.4, and concentrated under high vacuum. The crude residue was purified by pTLC (hexanes:diethyl ether, 5:1) on silica gel to obtain 9.3 mg (28%) of the desired coupling product 104. (Molander et al., 2011)
[0813] Physical State: colorless oil.
[0814] .sup.1H NMR (600 MHz, CDCl.sub.3): 8.51 (s, 1H), 7.36-7.26 (m, 3H), 7.23-7.18 (m, 2H), 4.48 (d, J=12.0 Hz, 1H), 4.41 (d, J=11.9 Hz, 1H), 3.92 (d, J=6.4 Hz, 1H), 3.63 (d, J=10.7 Hz, 1H), 3.59 (d, J=10.7 Hz, 1H), 2.80 (dd, J=9.7, 3.1 Hz, 1H), 2.33 (dd, J=9.8, 2.3 Hz, 1H), 2.29 (d, J=2.3 Hz, 1H), 2.25 (dd, J=6.5, 3.1 Hz, 1H) ppm.
[0815] .sup.13C NMR (151 MHz, CDCl.sub.3): 148.50, 148.32, 146.22, 141.56, 137.80, 128.53, 127.96, 127.77, 116.76, 73.51, 67.83, 64.18, 51.67, 50.03, 48.17, 28.12 ppm.
[0816] HRMS (ESI-TOF): calc'd for C.sub.18H.sub.15C.sub.2N.sub.3O [M+H].sup.+: 360.0665, found: 360.0671.
[0817] TLC: R.sub.f=0.36 (5:1 hexanes:ethyl acetate).
E. Optimization of Synthesis and Functionalizations of BCP Bisboronates
TABLE-US-00011 Scheme 13: Optimization of Synthesis of BCP BisBoronates
TABLE-US-00012 TABLE S4 Optimization of cyanation of BCP 25
TABLE-US-00013 Scheme 14: Optimization of 1.sup.st functionalization of BCP BisBoronates
TABLE-US-00014 Scheme 15: Optimization of 2.sup.nd functionalization of BCP BisBoronates
TABLE-US-00015 Scheme 16: Optimization of C2 control of 1.sup.st Functionalization of BCP Boronates
REFERENCES
[0818] The following references to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference. [0819] WO 2010/085528A1 [0820] Anderson, Practical Process Research & DevelopmentA Guide for Organic Chemists, 2.sup.nd ed., Academic Press, New York, 2012. [0821] Andr-Joyaux et al., Angew. Chem. Int. Ed., 59:13859-64, 2020. [0822] Denisenko et al., Angew. Chem. Int. Ed., 59:20515-21, 2020. [0823] Fawcett, A. et al., Angew. Chem., Int. Ed., 55:14663-67, 2016. [0824] Gutierrez et al., J. Am. Chem. Soc., 137:4896-99, 2015. [0825] Handbook of Pharmaceutical Salts: Properties, and Use, Stahl and Wermuth Eds., Verlag Helvetica Chimica Acta, 2002. [0826] Hazrati & Oestreich, Org. Lett., 20:5367-69, 2018. [0827] Jarret et al., Tetrahedron Lett., 31:171-74, 1990. [0828] Joseph et al., Angew. Chem. Int. Ed., 60:24754-69, 2021. [0829] JosienJohn et al., WO2010085528A1, 2010. [0830] Kaiser et al., J. Am. Chem. Soc., 141:14104-09, 2019. [0831] Katayev et al., Org. Lett., 17:5898-01, 2015. [0832] Kim et al., Angew. Chem. Int. Ed., 59:8225-31, 2020. [0833] Kondo et al., Angew. Chem. Int. Ed., 59:1970-74, 2020. [0834] Li et al., Angew. Chem. Int. Ed., 51:2943-46, 2012. [0835] Lima et al., Angew. Chem. Int. Ed., 56:15136-40, 2017. [0836] Lima et al., Angew. Chem. Int. Ed., 55:14085-89, 2016. [0837] Lima et al., Chem. Commun., 54:5606-09, 2018. [0838] Ma et al., Org. Lett., 22:9133-38, 2020. [0839] Mlynarski et al., Nature, 505:386-90, 2014. [0840] Molander et al., Org. Lett., 13:1852-55, 2011. [0841] Mousseau et al., ACS Catal., 12:600-06, 2022. [0842] Nvoa et al., Angew. Chem., Int. Ed., 60:11763-68, 2021. [0843] Nykaza et al., J. Am. Chem. Soc., 140:15200-05, 2018. [0844] Odachowski et al., J. Am. Chem. Soc., 138:9521-32, 2016. [0845] Pozzi et al., J. Am. Chem. Soc., 127:14204-05, 2005. [0846] Primer et al., J. Am. Chem. Soc., 139:9847-50, 2017. [0847] Renaud et al., Angew. Chem. Int. Ed., 59:13859-64, 2020. [0848] Sadhu & Matteson, Organometallics, 4:1687-89, 1985. [0849] Tellis et al., Science, 345:433-36, 2014. [0850] Wiberg & Williams, J. Org. Chem., 35:369-73, 1970. [0851] Wiberg et al., J. Org. Chem., 58(6):1372-1376, 1993. [0852] Yang et al. J. Am. Soc. Chem, 143:471-80, 2021a. [0853] Yang et al., Angew. Chem., Int. Ed., 50:3904-07, 2011. [0854] Yang, Y.; et al. Nat. Chem., 13:950-55, 2021b. [0855] Yuan et al., J. Am. Chem. Soc., 142:7225-34, 2020. [0856] Zhao et al., Proc. Natl. Acad. Sci., USA 118:e2108881118, 2021.