KETONE SYNTHESIS AND APPLICATIONS
20230357286 · 2023-11-09
Assignee
Inventors
Cpc classification
C07D207/08
CHEMISTRY; METALLURGY
B01J2231/4205
PERFORMING OPERATIONS; TRANSPORTING
C07D317/26
CHEMISTRY; METALLURGY
B01J31/1815
PERFORMING OPERATIONS; TRANSPORTING
C07D519/00
CHEMISTRY; METALLURGY
C07F7/1892
CHEMISTRY; METALLURGY
International classification
C07F7/18
CHEMISTRY; METALLURGY
Abstract
Provided are new nickel./zirconium-mediated coupling reactions useful in the synthesis of ketone-containing compounds, e.g., halichondrin natural products and related molecules. A feature of the present disclosure is the use of a nickel(I) catalyst in tandem with a nickel (II) catalyst in the Ni/Zr-mediated coupling reactions. Without wishing to be bound by any particular theory, the nickel (I) catalyst selectively activates the electrophilic coupling partner (i.e., the compound of Formula (A)), and the nickel(ll) catalyst selectively activates the nucleophilic coupling partner (i.e., a thioester of Formula (B)). This dual catalyst system leads to improved coupling efficiency and eliminates the need for a large excess of one of the coupling partners (i.e., a compound of Formula (A) or (B)).
Claims
1. A method for preparing a compound of Formula (C): ##STR00208## or a salt thereof, the method comprising coupling a compound of Formula (A): ##STR00209## or a salt thereof, with a compound of Formula (B): ##STR00210## or a salt thereof, in the presence of a nickel(I) complex, a nickel(II) complex, and a zirconium complex; wherein: X.sup.1 is halogen or a leaving group; R.sup.S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R.sup.A is optionally substituted alkyl; and R.sup.B is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; optionally wherein R.sup.A and R.sup.B are joined together via a linker, wherein the linker is selected from the group consisting of optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted acylene, and combinations thereof.
2. The method of claim 1, wherein the compound of Formula (A) is of Formula (A-1): ##STR00211## or a salt thereof; the compound of Formula (B) is of Formula (B-1): ##STR00212## or a salt thereof; and the compound of Formula (C) is of Formula (C-1): ##STR00213## or a salt thereof, wherein: R.sup.S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; each instance of R.sup.A1, R.sup.A2, R.sup.B1, and R.sup.B2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; optionally wherein R.sup.A1 and R.sup.B1 are joined together via a linker.
3. The method of claim 2 comprising reacting a compound of Formula (A-B): ##STR00214## or a salt thereof, to prepare a compound of Formula (C-2): ##STR00215## or salt thereof; wherein: ##STR00216## represents a linker.
4. The method of claim 1 or 2, wherein the compound of Formula (B) is of Formula (L-2-6): ##STR00217## or a salt or stereoisomer thereof; the compound of Formula (A) is of Formula (R-2-I): ##STR00218## or a salt or stereoisomer thereof; and the compound of Formula (C) is of Formula (H3-2-II): ##STR00219## or a salt or stereoisomer thereof, wherein: R.sup.1, R.sup.2, R.sup.3, and R.sup.5 are each independently hydrogen, halogen, or optionally substituted alkyl; each instance of R.sup.4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R.sup.4 groups are taken together to form: ##STR00220## each instance of R.sup.6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R.sup.6 groups are taken together to form: ##STR00221## R.sup.P4, R.sup.P5, and R.sup.P6 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally wherein two R.sup.P6 are joined with the intervening atoms to form optionally substituted heterocyclyl; R.sup.X is hydrogen or -OR.sup.Xa, wherein R.sup.Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and R.sup.Y is hydrogen or -OR.sup.Ya, wherein R.sup.Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally wherein R.sup.Xa and R.sup.Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
5. The method of claim 4, wherein the compound of Formula (B) is of Formula (E-L): ##STR00222## or a salt or stereoisomer thereof; the compound of Formula (A) is of Formula (E-R): ##STR00223## or a salt or stereoisomer thereof; and the compound of Formula (C) is of Formula (E-1): ##STR00224## or a salt or stereoisomer thereof.
6. The method of claim 5, wherein the compound of Formula (B) is the following: ##STR00225## or a salt or stereoisomer thereof; the compound of Formula (A) is the following: ##STR00226## or a salt or stereoisomer thereof; and the compound of Formula (C) is the following: ##STR00227## or a salt or stereoisomer thereof.
7. The method of any one of claims 1-6, wherein the nickel(I) complex is of the formula: NiX•(ligand); wherein X is halogen, and “ligand” is a tridentate ligand.
8. The method of claim 7, wherein the nickel(I) complex is used after being formed by complexation of a nickel source and the “ligand” in solution.
9. The method of claim 8, wherein the nickel source is of the formula: NiX.sub.2.
10. The method of claim 8 or 9, wherein the nickel source is NiI.sub.2.
11. The method of any one of claims 1-10, wherein the nickel(I) complex is of the formula: ##STR00228## wherein: X is a halogen; each instance of p is independently 0 or an integer from 1-4, inclusive; each instance of R.sup.c is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —N(R.sup.N).sub.2, -OR.sup.O, or -SR.sup.S1; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.
12. The method of any one of claims 1-11, wherein the nickel(I) complex is of the formula: ##STR00229## .
13. The method of any one of claims 1-12, wherein the nickel(I) complex is present in a catalytic amount.
14. The method of claim 13, wherein the nickel(I) complex is present in from about 0.1-10 mol% with respect to the compound of Formula (A) or the compound of Formula (B); preferably wherein the nickel(I) complex is present in about 1 mol% with respect to the compound of Formula (A) or the compound of Formula (B).
15. The method of claim 13, wherein the nickel(I) complex is present in from about 1-30 mol% the compound of Formula (A) or the compound of Formula (B).
16. The method of claim 13, wherein the nickel(I) complex is present in about 20 mol% with respect to the compound of Formula (A) or the compound of Formula (B).
17. The method of any one of claims 1-16, wherein the nickel(II) complex is of the formula: NiX.sub.2•(ligand); wherein X is halogen, and “ligand” is a bidentate ligand.
18. The method of claim 17, wherein the nickel(II) complex is used after being formed by complexation of a nickel source and the “ligand” in solution.
19. The method of claim 18, wherein the nickel source is of the formula: NiX.sub.2.
20. The method of claim 18 or 19, wherein the nickel source is NiCl.sub.2.
21. The method of any one of claims 1-20, wherein the nickel(II) complex is of the formula: ##STR00230## wherein: each instance of X is a halogen; p is 0 or an integer from 1-4, inclusive; s is 0, 1, or 2; each instance of R.sup.c is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —N(R.sup.N).sub.2, -OR.sup.O, or -SR.sup.S1; each instance of R.sup.c′ is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —N(R.sup.N).sub.2, -OR.sup.O, or -SR.sup.S1; each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.
22. The method of any one of claims 1-21, wherein the nickel(II) complex is of the formula: ##STR00231## .
23. The method of any one of claims 1-22, wherein the nickel(II) complex is present in a catalytic amount.
24. The method of claim 23, wherein the nickel(II) complex is present in from about 0.1-10 mol% with respect to the compound of Formula (A) or the compound of Formula (B).
25. The method of claim 23, wherein the nickel(II) complex is present in from about 1 mol% with respect to the compound of Formula (A) or the compound of Formula (B).
26. The method of claim 23, wherein the nickel(II) complex is present in from about 1-20 mol% with respect to the compound of Formula (A) or the compound of Formula (B).
27. The method of claim 23, wherein the nickel(II) complex is present in about 5 mol% with respect to the compound of Formula (A) or the compound of Formula (B).
28. The method of any one of claims 1-27, wherein the zirconium complex is Cp.sub.2ZrCl.sub.2.
29. The method of any one of claims 1-28, wherein the zirconium complex is present in stoichiometric or excess amount.
30. The method of claim 29, wherein the zirconium complex is present in about 1 to about 4 equivalents with respect to the compound of Formula (A) or the compound of Formula (B).
31. The method of claim 29, wherein the zirconium complex is present in about 1 equivalent with respect to the compound of Formula (A) or the compound of Formula (B).
32. The method of any one of claims 1-31, wherein the step of coupling is carried out in the presence of zinc or manganese.
33. The method of claim 32 or 33, wherein the zinc or manganese is present in a stoichiometric or excess amount.
34. The method of claim 33, wherein the zinc or manganese is present in about 1-10 equivalents with respect to the compound of Formula (A) or the compound of Formula (B).
35. The method of claim 33, wherein the zinc or manganese is present in about 6 equivalents with respect to the compound of Formula (A) or the compound of Formula (B).
36. The method of any one of claims 32-35, wherein the reaction is carried out in the presence of zinc metal.
37. The method of any one of claims 1-36, wherein the step of coupling is carried out in the presence of a base or proton scavenger.
38. The method of claim 37, wherein the base or proton scavenger is di-tert-butylmethylpyridine (dtbmpy).
39. The method of any one of claims 1-38, wherein the reaction is carried out in the presence of the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; the zirconium complex: Cp.sub.2ZrCl.sub.2; and zinc or manganese metal.
40. The method of any one of claims 1-38, wherein the reaction is carried out in the presence of the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; the zirconium complex: Cp.sub.2ZrCl.sub.2; zinc metal; and 2,6-di-tert-butyl-4-methylpyridine.
41. The method of any one of claims 1-40, wherein the step of coupling is carried out in a solvent.
42. The method of claim 41, wherein the solvent comprises one or more of N,N-dimethylacetamide (DMA), 1,2-dimethoxyethane (DME), and 1,3-dimethyl-2-imidazolidinone (DMI).
43. The method of claim 41, wherein the solvent comprises a DMA/DME mixture.
44. The method of claim 41, wherein the solvent comprises a DMI/DME mixture.
45. The method of any one of claims 1-44, wherein the step of coupling is carried out at or around room temperature.
46. The method of any one of claims 1-45, wherein the compound of Formula (A) is present in in a range from about 1 equivalent to less than 1.3 equivalents with respect to the compound of Formula (B).
47. The method of any one of claims 1-46, wherein the compound of Formula (A) and the compound of Formula (B) are present in approximately 1:1 ratio.
48. The method of any one of claims 1-5 and 7-47, wherein X.sup.1 is a halogen.
49. The method of any one of claims 1-5 and 7-48, wherein X.sup.1 is —I.
50. The method of any one of claims 1-5 and 7-49, wherein R.sup.S is optionally substituted heteroaryl.
51. The method of any one of claims 1-5 and 7-50, wherein R.sup.S is optionally substituted pyridyl.
52. The method of any one of claims 1-5 and 7-51, wherein R.sup.S is optionally substituted 2-pyridyl.
53. The method of any one of claims 1-5 and 7-52, wherein R.sup.S is of the formula: ##STR00232## .
54. The method of any one of claims 4 and 7-53, wherein R.sup.1 is optionally substituted C.sub.1-6 alkyl.
55. The method of any one of claims 4 and 7-54, wherein R.sup.1 is unsubstituted C.sub.1-6 alkyl.
56. The method of any one of claims 4 and 7-55, wherein R.sup.1 is methyl.
57. The method of any one of claims 4 and 7-56, wherein R.sup.2 is optionally substituted C.sub.1-6 alkyl.
58. The method of any one of claims 4 and 7-57, wherein R.sup.2 is unsubstituted C.sub.1-6 alkyl.
59. The method of any one of claims 4 and 7-58, wherein R.sup.2 is methyl.
60. The method of any one of claims 4 and 7-59, wherein R.sup.3 is optionally substituted C.sub.1-6 alkyl.
61. The method of any one of claims 4 and 7-60, wherein R.sup.3 is unsubstituted C.sub.1-6 alkyl.
62. The method of any one of claims 4 and 7-61, wherein R.sup.3 is methyl.
63. The method of any one of claims 4 and 7-61, wherein R.sup.5 is optionally substituted C.sub.1-6 alkyl.
64. The method of any one of claims 4 and 7-61, wherein R.sup.5 is unsubstituted C.sub.1-6 alkyl.
65. The method of any one of claims 4 and 7-64, wherein R.sup.5 is methyl.
66. The method of any one of claims 4 and 7-65, wherein two R.sup.4 groups are taken together to form: ##STR00233## .
67. The method of any one of claims 4 and 7-66, wherein two R.sup.6 groups are taken together to form: ##STR00234## .
68. The method of any one of claims 4 and 7-67, wherein R.sup.X and R.sup.Y are both hydrogen.
69. The method of any one of claims 4 and 7-68, wherein R.sup.X is hydrogen; and R.sup.Y is –OR.sup.Ya.
70. The method of any one of claims 4 and 7-69, wherein R.sup.X is –OR.sup.Xa; and R.sup.Y is –OR.sup.Ya.
71. The method of any one of claims 4, 5, and 7-70, wherein R.sup.P4 is an oxygen protecting group.
72. The method of any one of claims 4, 5, and 7-71, wherein R.sup.P4 is a silyl protecting group.
73. The method of any one of claims 4, 5, and 7-72, wherein R.sup.P4 is TES.
74. The method of any one of claims 4, 5, and 7-73, wherein R.sup.P5 is an oxygen protecting group.
75. The method of any one of claims 4, 5, and 7-74, wherein R.sup.P5 is a silyl protecting group.
76. The method of any one of claims 4, 5, and 7-75, wherein R.sup.P5 is TES.
77. The method of any one of claims 4, 5, and 7-76, wherein two R.sup.P6 are joined together with the intervening atoms to form: ##STR00235## wherein each instance of R is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, or optionally substituted hydroxyl.
78. The method of any one of claims 4, 5, and 7-77, wherein two R.sup.P6 are joined together with the intervening atoms to form: ##STR00236## .
Description
BRIEF DESCRIPTION OR THE DRAWINGS
[0079] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.
[0080]
[0081]
[0082]
[0083]
[0084]
[0085]
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0086] Provided herein are Ni/Zr-mediated coupling reactions useful in the preparation of ketone-containing compounds. As described herein, a feature of the present disclosure is the use of a nickel(I) catalyst in tandem with a nickel(II) catalyst in the Ni/Zr-mediated coupling reactions. Without wishing to be bound by a particular theory, the nickel(I) catalyst selectively activates the electrophilic coupling partner (i.e., the compound of Formula (A)), and the nickel(II) catalyst selectively activates the nucleophilic coupling partner (i.e., a thioester of Formula (B)). In certain embodiments, this dual catalyst system leads to improved coupling efficiency and eliminates the need for a large excess of one of the coupling partners (i.e., a compound of Formula (A) or (B)). The Ni/Zr-mediated coupling reactions provided herein are therefore particularly useful for reactions involving complex coupling partners, e.g., in the synthesis of complex natural products such as halichondrins and analogs thereof.
[0087] Therefore, also provided herein are methods for the preparation of halichondrins (e.g., halichondrin A, B, C; homohalichondrin A, B, C; norhalichondrin A, B, C) and analogs thereof. For example, in certain embodiments, methods provided herein are useful in the synthesis of compounds described in, e.g., International Publication Nos. WO 2019/010363, published Jan. 10, 2019; WO 2018/187331, published Oct. 11, 2018; and WO 2019/099646, published May 23, 2019; the entire contents of each of which is incorporated herein by reference.
[0088] The present disclosure also provides compounds (i.e., intermediates) useful in the methods provided herein. In certain embodiments, the compounds provided herein are useful as synthetic intermediates en route to halichondrins and analogs thereof. All compounds described herein are included as emodiments of the invention. Furthermore, the present disclosure provides reagents and catalysts useful in the methods described herein. All reagents and catalysts described herein are included as embodiments of the invention.
[0089] The present disclosure also provides reaction mixtures comprising one or more compounds, reagents, catalysts, and/or solvents described herein. All reaction mixtures described herein are included as embodiments of the invention. The present disclosure also provides kits comprising one or more reagents, catalysts, and/or compounds described herein.
Ni/Zr-Mediated Coupling Reactions
[0090] In one aspect, provided herein are nickel/zirconium-mediated coupling reactions (“Ni/Zr-mediated coupling reactions”) involving coupling of a thioester and an alkyl halide (e.g., alkyl iodide, alkyl bromide, alkyl chloride, etc.) or alkyl-leaving group (e.g., alkyl sulfonate) (Scheme 1A).
[0091] The coupling reactions may be intermolecular or intramolecular (i.e., in Scheme 1A, R.sup.A and R.sup.B are optionally joined by a linker). In certain embodiments, the compound of Formula (A) is a primary or secondary alkyl halide (X.sup.1 = halogen), and the compound of Formula (B) is an alkyl thioester (R.sup.B = optionally substituted alkyl), as shown in Scheme 1B.
##STR00007##
##STR00008##
[0092] As represented in Scheme 1A, provided herein are methods for preparing a compound of Formula (C):
##STR00009##
or a salt thereof, the methods comprising reacting a compound of Formula (A):
##STR00010##
or a salt thereof, with a compound of Formula (B):
##STR00011##
or a salt thereof, in the presence of a nickel(I) complex, a nickel(II) complex, and a zirconium complex; wherein: [0093] R.sup.A is optionally substituted alkyl; [0094] R.sup.B is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; [0095] optionally wherein R.sup.A and R.sup.B are joined together via a linker, wherein the linker is selected from the group consisting of optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted acylene, and combinations thereof, [0096] X.sup.1 is halogen or a leaving group; and [0097] R.sup.S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.
[0098] In certain embodiments, R.sup.A is a small molecule or part of a small molecule. In certain embodiments, R.sup.B is a small molecule or part of a small molecule. Small molecules encompass complex small molecules, such as natural products, pharmaceutical agents, and fragments thereof, and intermediates thereto.
[0099] As generally defined herein, a “linker” is a group comprising optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted acylene, optionally substituted heteroatoms, or any combination thereof.
[0100] In certain embodiments, the compound of Formula (A) is of Formula (A-1):
##STR00012##
or a salt thereof; the compound of Formula (B) is of Formula (B-1):
##STR00013##
or a salt thereof; and the compound of Formula (C) is of Formula (C-1):
##STR00014##
or a salt thereof, wherein: [0101] X.sup.1 is halogen or a leaving group; [0102] R.sup.S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; [0103] each instance of R.sup.A1, R.sup.A2, R.sup.B1, and R.sup.B2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; optionally wherein R.sup.A1 and R.sup.B1 are joined together via a linker.
[0104] In certain embodiments, R.sup.A1 is a small molecule or part of a small molecule. In certain embodiments, R.sup.B1 and R.sup.B2 are independently small molecules or parts of small molecules. Small molecules encompass complex small molecules, such as natural products, pharmaceutical agents, and fragments thereof, and intermediates thereto.
[0105] The Ni/Zr-mediated coupling reactions provided herein may be performed in an intramolecular fashion to yield cyclic ketones as shown in Scheme 1C.
##STR00015##
[0106] As shown in Scheme 1C, provided herein are methods for preparing a compound of Formula (C-2):
##STR00016##
or salt thereof, comprising reacting a compound of Formula (A-B):
##STR00017##
or a salt thereof, in the presence of a nickel(I) complex, a nickel(II) complex, and a zirconium complex; wherein: [0107] R.sup.A1 and R.sup.B2 are optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; [0108] X.sup.1 is halogen or a leaving group; [0109] R.sup.S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; and represents a linker.
[0111] As described herein, a feature of the present disclosure is the use of a nickel(I) catalyst in conjunction with a nickel(II) catalyst. Without wishing to be bound by any particular theory, the nickel(I) catalyst selectively activates the compound of Formula (A) and the nickel(II) catalyst selectively activates the compound of Formula (B). In certain embodiments, this dual catalyst system leads to improved coupling efficiency and eliminates the need for an excess of one of the coupling partners (i.e., a compound of Formula (A) or (B)). This improvement can be important for reactions involving coupling partners that are structurally complex, expensive, and/or difficult to access (e.g., in the synthesis of halichondrins and analogs thereof).
[0112] In certain embodiments, in a Ni/Zr-mediated coupling described herein, the compound of Formula (A) is present in a range from about 1 equivalent to about 1.3 equivalents with respect to the compound of Formula (B). In certain embodiments, the compound of Formula (A) is present in about 1, 1.05, 1.1, 1.15, 1.2, 1.25, or 1.3 equivalents with respect to the compound of Formula (B). In certain embodiments, the compound of Formula (A) and the compound of Formula (B) are present in approximately 1:1 molar ratio.
[0113] In certain embodiments, the compound of Formula (C) is isolated in 80% yield or greater when any of the aforementioned ratios of coupling partners is used. In certain embodiments, the compound of Formula (C) is isolated in approximately 85% yield or greater. In certain embodiments, the compound of Formula (C) is isolated in approximately 90% yield or greater. In certain embodiments, the compound of Formula (C) is isolated in approximately 95% yield or greater. In certain embodiments, the compound of Formula (C) is isolated in approximately 98% yield or greater.
[0114] As described herein, the Ni/Zr-mediated coupling reactions are carried out in the presence of a nickel(I) complex, a nickel(II) complex, and a zirconium complex. The nickel(I) and nickel(II) complexes (e.g., nickel salt, nickel complex, nickel catalyst, or nickel pre-catalyst) may be any known or available complexes in the art.
[0115] In certain embodiments, the nickel(I) complex is of the formula: NiX•(ligand); wherein X is halogen. In certain embodiments, “ligand” is a tridentate ligand. In certain embodiments, the ligand is a tripyridyl ligand. In certain embodiments, the nickel(I) complex is of the formula:
##STR00019##
wherein: [0116] X is a halogen; [0117] each instance of p is independently 0 or an integer from 1-4, inclusive; [0118] each instance of R.sup.c is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —N(R.sup.N).sub.2, —OR.sup.O, or —SR.sup.S1; [0119] each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0120] each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and [0121] each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.
[0122] In certain embodiments, the nickel(I) complex is of the formula:
##STR00020##
[0123] For example, in certain embodiments, the nickel(I) complex is of the formula:
##STR00021##
[0124] In certain embodiments, the nickel(I) complex is of one of the following formulae:
##STR00022##
##STR00023##
##STR00024##
[0125] In certain embodiments, the nickel(I) complex is used after being formed by complexation of a nickel source and the “ligand” in solution. In certain embodiments, the nickel source is of the formula: NiX.sub.2; wherein X is halogen. In certain embodiments, the nickel source is NiBr.sub.2, NiI.sub.2, or NiCl.sub.2. In certain embodiments, the nickel source is NiI.sub.2. In certain embodiments, the “ligand” is of the following formula:
##STR00025##
or a salt thereof.
[0126] In certain embodiments, the “ligand” is of the formula:
##STR00026##
[0127] For example, in certain embodiments, the “ligand” is of the formula:
##STR00027##
[(Me).sub.3tpy], or a salt thereof.
[0128] In certain embodiments, the “ligand” is of one of the following formulae:
##STR00028##
##STR00029##
##STR00030##
[0129] In certain embodiments, the “ligand” is one of the following tridentate ligands:
##STR00031##
##STR00032##
##STR00033##
[0130] In certain embodiments, the ligand is a bidentate ligand. In certain embodiments, the “ligand” is one of the following bidentate ligands:
##STR00034##
##STR00035##
##STR00036##
##STR00037##
[0131] In certain embodiments, the “ligand” is of the formula:
##STR00038##
. For example, in certain embodiments, the “ligand” is of the formula:
##STR00039##
[(py-(Me)imid)].
[0132] In certain embodiments, the nickel(I) complex is present in a catalytic amount. In certain embodiments, the nickel(I) complex is present at approximately 0.001-0.1 mol%, 0.1-1 mol%, 1-5 mol%, 5-10 mol%, 1-10 mol%, 5-20 mol%, 10-20 mol%, 20-30 mol%, 20-40 mol%, 30-40 mol%, 40-50 mol%, 50-60 mol%, 60-70 mol%, 70-80 mol%, or 80-90 mol% with respect to a compound of Formula (A) and/or (B) in the reaction mixture. In certain embodiments, the nickel(I) complex is present in from about 0.1-10 mol% with respect to the compound of Formula (A) and/or the compound of Formula (B). In certain embodiments, the nickel(I) complex is present in about 1 mol% with respect to the compound of Formula (A) and/or the compound of Formula (B). In certain embodiments, the nickel(I) complex is present in from about 1-30 mol% the compound of Formula (A) and/or the compound of Formula (B). In certain embodiments, the nickel(I) complex is present in about 20 mol% with respect to the compound of Formula (A) and/or the compound of Formula (B). In certain embodiments, the nickel(I) complex is present in a stoichiometric or excess amount relative to a compound of Formula (A) and/or (B) in the reaction mixture. In certain embodiments, approximately 1 equivalent of nickel(I) complex is present (i.e., stoichiometric). In other embodiments, greater than 1 equivalent of nickel(I) complex is present (i.e., excess).
[0133] In certain embodiments, the nickel(I) complex is present in a catalytic amount. In certain embodiments, the nickel(I) complex is present at approximately 0.001-0.1 mol%, 0.1-1 mol%, 1-5 mol%, 5-10 mol%, 1-10 mol%, 5-20 mol%, 10-20 mol%, 20-30 mol%, 20-40 mol%, 30-40 mol%, 40-50 mol%, 50-60 mol%, 60-70 mol%, 70-80 mol%, or 80-90 mol% with respect to a compound of Formula (A) in the reaction mixture. In certain embodiments, the nickel(I) complex is present in from about 0.1-10 mol% with respect to the compound of Formula (A). In certain embodiments, the nickel(I) complex is present in about 1 mol% with respect to the compound of Formula (A). In certain embodiments, the nickel(I) complex is present in from about 1-30 mol% the compound of Formula (A). In certain embodiments, the nickel(I) complex is present in about 20 mol% with respect to the compound of Formula (A). In certain embodiments, the nickel(I) complex is present in a stoichiometric or excess amount relative to a compound of Formula (A) in the reaction mixture. In certain embodiments, approximately 1 equivalent of nickel(I) complex is present (i.e., stoichiometric). In other embodiments, greater than 1 equivalent of nickel(I) complex is present (i.e., excess).
[0134] In certain embodiments, the nickel(II) complex is of the formula: NiX.sub.2•(ligand); wherein X is halogen. In certain embodiments, “ligand” is a bidentate ligand. In certain embodiments, the nickel(II) complex is of the formula:
##STR00040##
wherein: [0135] each instance of X is a halogen; [0136] p is 0 or an integer from 1-4, inclusive; [0137] s is 0, 1, or 2; [0138] each instance of R.sup.c is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —N(R.sup.N).sub.2, -OR.sup.O, or -SR.sup.S1; [0139] each instance of R.sup.c′ is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —N(R.sup.N).sub.2, -OR.sup.O, or -SR.sup.S1; [0140] each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; [0141] each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group; and [0142] each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group.
[0143] For example, in certain embodiments, the nickel(II) complex is of the formula:
##STR00041##
[(py-(Me)imid)•Ni.sup.IICl.sub.2].
[0144] In certain embodiments, the nickel(II) complex is of one of the following formulae:
##STR00042##
##STR00043##
##STR00044##
##STR00045##
[0145] In certain embodiments, the nickel(II) complex is of one of the following formulae:
##STR00046##
##STR00047##
##STR00048##
[0146] In certain embodiments, the nickel(II) complex is used after being formed by complexation of a nickel source and the “ligand” in solution. In certain embodiments, the nickel source is of the formula: NiX.sub.2; wherein X is halogen. In certain embodiments, the nickel source is NiBr.sub.2, NiI.sub.2, or NiCl.sub.3. In certain embodiments, the nickel source is NiCl.sub.2. In certain embodiments, the “ligand” is of the formula:
##STR00049##
. For example, in certain embodiments, the “ligand” is of the formula:
##STR00050##
[(py-(Me)imid)].
[0147] In certain embodiments, the “ligand” is a tridentate ligand. In certain embodiments, the “ligand” is a tripyridyl ligand. In certain embodiments, the “ligand” is of the following formula:
##STR00051##
or a salt thereof.
[0148] In certain embodiments, the “ligand” is of the formula:
##STR00052##
or a salt thereof.
[0149] For example, in certain embodiments, the “ligand” is of the formula:
##STR00053##
[(Me).sub.3tpy], or a salt thereof.
[0150] In certain embodiments, the “ligand” is one of the following tridentate ligands:
##STR00054##
##STR00055##
##STR00056##
[0151] In certain embodiments, the “ligand” is one of the following tridentate ligands:
##STR00057##
##STR00058##
##STR00059##
[0152] In certain embodiments, the “ligand” is one of the following bidentate ligands:
##STR00060##
##STR00061##
##STR00062##
##STR00063##
[0153] In certain embodiments, the nickel(II) complex is present in a catalytic amount. In certain embodiments, the nickel(II) complex is present at approximately 0.001-0.1 mol%, 0.1-1 mol%, 1-5 mol%, 5-10 mol%, 1-10 mol%, 5-20 mol%, 10-20 mol%, 20-30 mol%, 20-40 mol%, 30-40 mol%, 40-50 mol%, 50-60 mol%, 60-70 mol%, 70-80 mol%, or 80-90 mol% with respect to a compound of Formula (A) and/or (B) in the reaction mixture. In certain embodiments, the nickel(II) complex is present at from about 0.1-10 mol% with respect to the compound of Formula (A) and/or the compound of Formula (B). In certain embodiments, the nickel(II) complex is present at about 1 mol% with respect to the compound of Formula (A) and/or the compound of Formula (B). In certain embodiments, the nickel(II) complex is present at from about 1-20 mol% with respect to the compound of Formula (A) and/or the compound of Formula (B). In certain embodiments, the nickel(II) complex is present at about 5 mol% with respect to the compound of Formula (A) and/or the compound of Formula (B). In certain embodiments, the nickel(II) complex is present in a stoichiometric or excess amount relative to a compound of Formula (A) and/or (B) in the reaction mixture. In certain embodiments, approximately 1 equivalent of nickel(II) complex is present (i.e., stoichiometric). In other embodiments, greater than 1 equivalent of nickel(II) complex is present (i.e., excess).
[0154] In certain embodiments, the nickel(II) complex is present in a catalytic amount. In certain embodiments, the nickel(II) complex is present at approximately 0.001-0.1 mol%, 0.1-1 mol%, 1-5 mol%, 5-10 mol%, 1-10 mol%, 5-20 mol%, 10-20 mol%, 20-30 mol%, 20-40 mol%, 30-40 mol%, 40-50 mol%, 50-60 mol%, 60-70 mol%, 70-80 mol%, or 80-90 mol% with respect to a compound of Formula (B) in the reaction mixture. In certain embodiments, the nickel(II) complex is present at from about 0.1-10 mol% with respect to the compound of Formula (B). In certain embodiments, the nickel(II) complex is present at about 1 mol% with respect to the compound of Formula (B). In certain embodiments, the nickel(II) complex is present at from about 1-20 mol% with respect to the compound of Formula (B). In certain embodiments, the nickel(II) complex is present at about 5 mol% with respect to the compound of Formula (B). In certain embodiments, the nickel(II) complex is present in a stoichiometric or excess amount relative to a compound of Formula (B) in the reaction mixture. In certain embodiments, approximately 1 equivalent of nickel(II) complex is present (i.e., stoichiometric). In other embodiments, greater than 1 equivalent of nickel(II) complex is present (i.e., excess).
[0155] As described above, the Ni/Zr-mediated coupling reactions are carried out in the presence of a zirconium complex. In certain embodiments, the zirconium complex is a zirconium(IV) complex. In certain embodiments, the zirconium complex is of the formula (ligand).sub.nZrX.sub.2; wherein n is the number of ligands (e.g., 0, 1, 2, 3, 4); and X is halogen (e.g., Cl, Br, I, or F). In certain embodiments, n is 2; and each ligand is independently optionally substituted cyclopentadienyl. In certain embodiments, n is 2; and each ligand is cyclopentadienyl. In certain embodiments, each X is chlorine.
[0156] In certain embodiments, the zirconium complex is Cp.sub.2ZrX.sub.2. In certain embodiments, the zirconium complex is Cp.sub.2ZrCl.sub.2.
[0157] In certain embodiments, the zirconium complex is Bis(cyclopentadienyl)zirconium(IV) dichloride (Cp.sub.2ZrCl.sub.2), Bis(cyclopentadienyl)dimethylzirconium(IV), Bis(cyclopentadienyl)zirconium(IV) chloride hydride, Bis(butylcyclopentadienyl)zirconium(IV) dichloride, Dimethylbis(pentamethylcyclopentadienyl)zirconium(IV), Bis(methylcyclopentadienyl)zirconium(IV) dichloride, Dichloro[rac-ethylenebis(indenyl)]zirconium(IV), Bis(cyclopentadienyl)zirconium(IV) dihydride, or Dichloro[rac-ethylenebis(4,5,6,7-tetrahydro-1-indenyl)]zirconium(IV).
[0158] In certain embodiments, the zirconium complex is present in a catalytic amount. In certain embodiments, the zirconium complex is present in between 0.001-0.1 mol%, 0.1-1 mol%, 1-5 mol%, 5-10 mol%, 1-10 mol%, 5-20 mol%, 10-20 mol%, 20-30 mol%, 30-40 mol%, 40-50 mol%, 50-60 mol%, 60-70 mol%, 70-80 mol%, or 80-90 mol% with respect to a compound of Formula (A) or (B) in the reaction mixture. In certain embodiments, the zirconium complex is present in a stoichiometric or excess amount relative to a compound of Formula (A) or (B) in the reaction mixture. In certain embodiments, approximately 1 equivalent of zirconium complex is present (i.e., stoichiometric). In other embodiments, greater than 1 equivalent of zirconium complex is present (i.e., excess). In certain embodiments, the zirconium complex is present in about 1 to about 5 equivalents with respect to the compound of Formula (A) or the compound of Formula (B). In certain embodiments, the zirconium complex is present in about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 equivalents with respect to the compound of Formula (A) or the compound of Formula (B). In certain embodiments, the zirconium complex is present in about 1 equivalent with respect to the compound of Formula (A) or the compound of Formula (B).
[0159] In certain embodiments, a Ni/Zr-mediated coupling reaction provided herein is performed in the presence of one or more additional reagents or catalysts, such as a reducing metal. Any reducing metal can be used in the coupling described herein. In certain embodiments, the reducing metal is zinc or manganese. The zinc or manganese may be present in a catalytic, stoichiometric, or excess amount. In certain embodiments, the zinc or manganese is present in excess (i.e., greater than 1 equivalent) with respect to a compound of Formula (A) or Formula (B). In certain embodiments, between 1 and 10 equivalents of zinc or manganese is used. In certain embodiments, approximately 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 equivalents of zinc or manganese is present. In certain embodiments, approximately 6 equivalents of zinc or manganese is used. In certain embodiments, approximately 3 equivalents of zinc or manganese is used.
[0160] In certain embodiments, the reducing metal is zinc. In certain embodiments, the reducing metal is manganese. In certain embodiments, zinc metal is used (i.e., zinc(0)). In certain embodiments, manganese metal is used (i.e., manganese(0)). In certain embodiments, the reaction is carried out in the presence of zinc powder, zinc foil, zinc beads, or any other form of zinc metal. In certain embodiments, a zinc salt is employed such as zinc acetate, zinc sulfate, zinc chloride, zinc bromide, zinc iodide, zinc fluoride, zinc sulfide, or zinc phosphate.
[0161] In certain embodiments, the coupling reaction is carried out in the presence of one or more reagents which help activate zinc metal in the reaction (e.g., by clearing the surface of zinc oxide). In certain embodiments, the reaction is carried out in the presence of a trialkylsilyl halide (e.g., triethylsilyl chloride (TESCl)). This reagent may be present in a catalytic, stoichiometric, or excess amount with respect to a compound of Formula (A) or Formula (B). In certain embodiments, approximately 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, or 10 equivalents of this reagent is present with respect to a compound of Formula (A) or Formula (B). In certain embodiments, approximately 1.5 equivalents of this reagent is present with respect to a compound of Formula (A) or Formula (B).
[0162] In certain embodiments, the Ni/Zr-mediated coupling is carried out in the presence of one or more additional reagents (i.e., in addition to nickel, zirconium, and zinc; or in addition to nickel, zirconium, and manganese).
[0163] In certain embodiments, the Ni/Zr-mediated coupling reaction is carried out in the presence of a base or proton scavenger. In certain embodiments, the base is a pyridine base. In certain embodiments, the base is 2,6-di-tert-butyl pyridine. In certain embodiments, the base is 2,6-lutidine. In certain embodiments, the base is 2,6-di-tert-butyl-4-methylpyridine. In certain embodiments, the base is used in a stoichiometric or excess amount with respect to a compound of Formula (A) or Formula (B). In certain embodiments, approximately 1 equivalent to 10 equivalents of the base or proton scavenger is employed with respect to a compound of Formula (A) or Formula (B). In certain embodiments, approximately 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, or 10 equivalents of the base or proton scavenger is present with respect to a compound of Formula (A) or Formula (B). In certain embodiments, approximately 2.5 equivalents of the base or proton scavenger is employed with respect to a compound of Formula (A) or Formula (B).
[0164] In certain embodiments, the Ni/Zr-mediated coupling described herein is carried out in a solvent. Any solvent may be used, and the scope of the method is not limited to any particular solvent or mixture of solvents. The solvent may be polar or non-polar, protic or aprotic, or a combination of solvents (e.g., co-solvents). Examples of useful organic solvents are provided herein. In certain embodiments, the solvent comprises N,N-dimethylacetamide (DMA). In certain embodiments, the solvent comprises 1,2-dimethoxyethane (DME). In certain embodiments, the solvent is a DMA/DME mixture (e.g., 1:1).
[0165] In certain embodiments, the solvent comprises 1,3-dimethyl-2-imidazolidinone (DMI). In certain embodiments, the coupling reaction is carried out in a DMI/tetrahydrofuran (THF) mixture. In certain embodiments, the coupling reaction is carried out in a DMI/ethyl acetate (EtOAc) mixture.
[0166] In certain embodiments, the coupling reaction is carried out in a DMI/DME mixture (e.g., 1:1). In certain embodiments, the coupling reaction is carried out in approximately 1:1 DMI/DME.
[0167] The Ni/Zr-mediated coupling reactions described herein may be carried out at any concentration in solvent. Concentration refers to the molar concentration (mol/L) of a coupling partners (e.g., compounds of Formula (A) or (B)) in a solvent. In certain embodiments, the concentration is approximately 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 M. In certain embodiments, the concentration is about 0.2 M. In certain embodiments, the concentration is approximately 0.5 M. In certain embodiments, the concentration is greater than 1 M. In certain embodiments, the concentration is less than 0.1 M.
[0168] The Ni/Zr-mediated coupling reactions described herein can be carried out at any temperature. In certain embodiments, the reaction is carried out at around room temperature (i.e., between 18 and 24° C.). In certain embodiments, the reaction is carried out below room temperature (e.g., between 0° C. and room temperature). In certain embodiments, the reaction is carried out at above room temperature (e.g., between room temperature and 100° C.). In certain embodiments, the reaction is carried out at a temperature ranging from approximately room temperature to approximately 100° C. In certain embodiments, the reaction is carried out at a temperature ranging from approximately room temperature to approximately 50° C.
[0169] In certain embodiments, the reaction is carried out in the presence of a nickel(I) complex, a nickel(II) complex, a zirconium complex, and a reducing metal.
[0170] In certain embodiments, the reaction is carried out in the presence of a nickel (I) complex of the formula: NiX•(ligand); a nickel (II) complex of the formula: NiX.sub.2•(ligand); a zirconium complex of the formula: (ligand).sub.nZrX.sub.2; and zinc or manganese metal.
[0171] In certain embodiments, the reaction is carried out in the presence of the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; the zirconium complex: Cp.sub.2ZrCl.sub.2; and zinc or manganese metal.
[0172] In certain embodiments, the reaction is carried out in the presence of the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; the zirconium complex: Cp.sub.2ZrCl.sub.2; and zinc metal.
[0173] In certain embodiments, the reaction is carried out in the presence of approximately 1 mol% the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; approximately 1 mol% of the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; approximately 1 equivalent of the zirconium complex: Cp.sub.2ZrCl.sub.2; and approximately 3 equivalents of zinc metal. In certain embodiments, the reaction is carried out in a mixture of DMA/DME. In certain embodiments, the reaction is carried out at around room temperature.
[0174] In certain embodiments, the reaction is carried out in the presence of approximately 1 mol% the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; approximately 1 mol% of the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; approximately 1 equivalent of the zirconium complex: Cp.sub.2ZrCl.sub.2; and approximately 3 equivalents of zinc metal, in a mixture of DMA/DME (e.g., 1:1 DMA/DME; 0.5 M) at around room temperature.
[0175] In certain embodiments, the reaction is carried out in the presence of a nickel(I) complex, a nickel(II) complex, a zirconium complex, a reducing metal, and a base or proton scavenger.
[0176] In certain embodiments, the reaction is carried out in the presence of a nickel (I) complex of the formula: NiX•(ligand); a nickel (II) complex of the formula: NiX.sub.2•(ligand); a zirconium complex of the formula: (ligand).sub.nZrX.sub.2; zinc or manganese metal; and a base or proton scavenger.
[0177] In certain embodiments, the reaction is carried out in the presence of the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; the zirconium complex: Cp.sub.2ZrCl.sub.2; zinc or manganese metal; and a base or proton scavenger.
[0178] In certain embodiments, the reaction is carried out in the presence of the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; the zirconium complex: Cp.sub.2ZrCl.sub.2; zinc metal; and 2,6-di-tert-butyl-4-methylpyridine.
[0179] In certain embodiments, the reaction is carried out in the presence of approximately 20 mol% the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; approximately 5 mol% of the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; approximately 1 equivalent of the zirconium complex: Cp.sub.2ZrCl.sub.2; approximately 6 equivalents of zinc metal; and approximately 2.5 equivalents of 2,6-di-tert-butyl-4-methylpyridine. In certain embodiments, the reaction is carried out in a mixture of DMA/DME. In certain embodiments, the reaction is carried out at around room temperature.
[0180] In certain embodiments, the reaction is carried out in the presence of approximately 20 mol% the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; approximately 5 mol% of the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; approximately 1 equivalent of the zirconium complex: Cp.sub.2ZrCl.sub.2; approximately 6 equivalents of zinc metal; and approximately 2.5 equivalents of 2,6-di-tert-butyl-4-methylpyridine, in a mixture of DMA/DME (e.g., 1:1 DMA/DME; 0.2 M) at around room temperature.
Synthesis of Halichondrins and Analogs
[0181] The Ni/Zr-mediated coupling reactions provided herein can be applied to the synthesis of halichondrins (e.g., halichondrin A, B, C; homohalichondrin A, B, C, norhalichondrin A, B, C) and analogs thereof. In certain embodiments, methods are useful in the synthesis of compounds of Formula (H3-A), such as Compound (1). In certain embodiments, the methods comprise the steps of: (1) coupling a “left half” building block with a “right half” building block via a Ni/Zr-mediated coupling reaction provided herein; optionally followed by (2) cyclizing the resulting coupling product (e.g., acid-mediated cyclization); and optionally followed by any necessary synthetic transformations to arrive at a desired product.
Synthesis of Halichondrins
[0182] The Ni/Zr-mediated coupling reactions provided herein can be applied to the preparation of halichondrins (e.g., halichondrin A, B, C) and analogs thereof. For example, as shown in Scheme 2A, coupling of a left half of Formula (L-2-14) with a right half of Formula (R-2-I) via a Ni/Zr-mediated coupling yields a ketone of Formula (H-2-II), cyclization of which provides a compound of Formula (H-2-I), which is a halichondrin or an analog thereof, or an intermediate thereto.
##STR00064##
[0183] In certain embodiments, the compound of Formula (A) is of Formula (R-2-I); the compound of Formula (B) is of Formula (L-2-14); and the compound of Formula (C) is of the Formula (H-2-II). Accordingly, provided herein is a method of preparing a compound of Formula (H-2-II):
##STR00065##
or a salt or stereoisomer thereof, the method comprising coupling a compound of Formula (L-2-14):
##STR00066##
or a salt or stereoisomer thereof, with a compound of Formula (R-2-I):
##STR00067##
or a salt or stereoisomer thereof, in the presence of a nickel(I) complex, a nickel(II) complex, and a zirconium complex, wherein: [0184] R.sup.S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; [0185] X.sup.1 is halogen or a leaving group; [0186] R.sup.1, R.sup.2, R.sup.3, and R.sup.5 are each independently hydrogen, halogen, or optionally substituted alkyl; [0187] each instance of R.sup.4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R.sup.4 groups are taken together to form: [0188] each instance of R.sup.6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R.sup.6 groups are taken together to form: [0189] R.sup.P1, R.sup.P2, R.sup.P3, R.sup.P4, and R.sup.P5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; [0190] R.sup.X is hydrogen or -OR.sup.Xa, wherein R.sup.Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and [0191] R.sup.Y is hydrogen or -OR.sup.Ya, wherein R.sup.Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; [0192] optionally wherein R.sup.Xa and R.sup.Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
[0193] In certain embodiments, the step of coupling to provide a compound of Formula (H-2-II) is a Ni/Zr-mediated coupling reaction provided herein. Any reagents or conditions provided herein for the Ni/Zr-mediated coupling may be used in the coupling.
[0194] Additional methods for converting compounds of Formula (H-2-II) into compounds of Formula (H-2-I) (e.g., halichondrins and analogs thereof) can be found in International Publication No. WO 2019/010363, published Jan. 10, 2019, which is incorporated herein by reference. For example, in certain embodiments, the method described above may further comprise a step of cyclizing a compound of Formula (H-2-II):
##STR00070##
or a salt or stereoisomer thereof, to yield a compound of Formula (H-2-I):
##STR00071##
or a salt or stereoisomer thereof.
Synthesis of Homohalichrondrins
[0195] The Ni/Zr-mediated coupling reactions provided herein can be applied to the preparation of homohalichondrins (e.g., homohalichondrin A, B, C), and analogs thereof. For example, as shown in Scheme 2B, coupling of a left half of Formula (L-2-16) with a right half of Formula (R-2-I) via a Ni/Zr-mediated coupling yields a ketone of Formula (HH-2-II), cyclization of which provides a compound of Formula (HH-2-I), which is a homohalichondrin natural product or an analog thereof, or an intermediate thereto.
##STR00072##
[0196] In certain embodiments, the compound of Formula (A) is of Formula (R-2-I); the compound of Formula (B) is of Formula (L-2-16); and the compound of Formula (C) is of the Formula (HH-2-II). Provided herein is a method of preparing a compound of Formula (HH-2-II):
##STR00073##
or a salt or stereoisomer thereof, the method comprising coupling a compound of Formula (L-2-16):
##STR00074##
or a salt or stereoisomer thereof, with a compound of Formula (R-2-I):
##STR00075##
or a salt or stereoisomer thereof, in the presence of a nickel(I) complex, a nickel(II) complex, and a zirconium complex, wherein: [0197] R.sup.S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; [0198] X.sup.1 is halogen or a leaving group; [0199] R.sup.1, R.sup.2, R.sup.3, and R.sup.5 are each independently hydrogen, halogen, or optionally substituted alkyl; [0200] each instance of R.sup.4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R.sup.4 groups are taken together to form: [0201] each instance of R.sup.6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R.sup.6 groups are taken together to form: [0202] R.sup.P1, R.sup.P3, R.sup.P4, and R.sup.P5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; [0203] R.sup.x is hydrogen or -OR.sup.Xa, wherein R.sup.Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and [0204] R.sup.Y is hydrogen or -OR.sup.Ya, wherein R.sup.Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; [0205] optionally wherein R.sup.Xa and R.sup.Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
[0206] In certain embodiments, the step of coupling to provide a compound of Formula (HH-2-II) is a Ni/Zr-mediated coupling as provided herein. Any reagents or conditions provided herein for the Ni/Zr-mediated coupling may be used in the coupling.
[0207] Additional methods for converting compounds of Formula (HH-2-II) into compounds of Formula (HH-2-1) (e.g., homohalichondrins and analogs thereof) can be found in International Publication No. WO 2019/010363, published Jan. 10, 2019, which is incorporated herein by reference. For example, in certain embodiments, the method described above may further comprise a step of cyclizing a compound of Formula (HH-2-II):
##STR00078##
or a salt or stereoisomer thereof, to yield a compound of Formula (HH-2-I):
##STR00079##
or a salt or stereoisomer thereof.
Synthesis of Norhalichondrlns
[0208] The Ni/Zr-mediated coupling reactions provided herein can be applied to the preparation of norhalichondrins (e.g., norhalichondrin A, B, C) and analogs thereof. For example, as shown in Scheme 2C, coupling of a left half of Formula (L-2-15) with a right half of Formula (R-2-I) via a Ni/Zr-mediated coupling yields a ketone of Formula (NH-2-II), cyclization of which provides a compound of Formula (NH-2-I), which is a norhalichondrin or an analog thereof, or intermediate thereto.
##STR00080##
[0209] In certain embodiments, the compound of Formula (A) is of Formula (R-2-I); the compound of Formula (B) is of Formula (L-2-15); and the compound of Formula (C) is of the Formula (NH-2-II). Provided herein is a method of preparing a compound of Formula (NH-2-II):
##STR00081##
or a salt or stereoisomer thereof, the method comprising coupling a compound of Formula (L-2-15):
##STR00082##
or a salt or stereoisomer thereof, with a compound of Formula (R-2-I):
##STR00083##
or a salt or stereoisomer thereof, in the presence of a nickel(I) complex, a nickel(II) complex, and a zirconium complex, wherein: [0210] R.sup.s is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; [0211] X.sup.1 is halogen or a leaving group; [0212] R.sup.1, R.sup.2, R.sup.3, and R.sup.5 are each independently hydrogen, halogen, or optionally substituted alkyl; [0213] each instance of R.sup.4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R.sup.4 groups are taken together to form: [0214] each instance of R.sup.6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R.sup.6 groups are taken together to form: [0215] R.sup.P3 R.sup.P4, and R.sup.P5 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; [0216] R.sup.7 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; [0217] R.sup.X is hydrogen or -OR.sup.Xa, wherein R.sup.Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and [0218] R.sup.Y is hydrogen or -OR.sup.Ya, wherein R.sup.Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; [0219] optionally wherein R.sup.Xa and R.sup.Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
[0220] In certain embodiments, the step of coupling to provide a compound of Formula (NH-2-II) is a Ni/Zr-mediated coupling provided herein. Any reagents or conditions provided herein for the Ni/Zr-mediated coupling may be used in the coupling.
[0221] Additional methods for converting compounds of Formula (NH-2-II) into compounds of Formula (NH-2-I) (e.g., norhalichondrins and analogs thereof) can be found in International Publication No. WO 2019/010363, published Jan. 10, 2019, which is incorporated herein by reference. For example, in certain embodiments, the method described above may further comprise a step of cyclizing a compound of Formula (NH-2-II):
##STR00086##
or a salt or stereoisomer thereof, to yield a compound of Formula (NH-2-I):
##STR00087##
or a salt or stereoisomer thereof.
Synthesis of Additional Halichondrin Analogs
[0222] Methods for the preparation of additional halichondrin analogs are provided herein. The Ni/Zr-mediated coupling reactions provided herein can be applied to the preparation of additional halichondrin analogs. For example, as shown in Scheme 2D, coupling of a left half of Formula (L-2-6) with a right half of Formula (R-2-I) via a Ni/Zr-mediated coupling yields a ketone of Formula (H3-2-II), cyclization of which provides a compound of Formula (H3-2-I). The compound of Formula (H3-2-I) can be subjected to further synthetic transformation to yield a desired compound.
##STR00088##
[0223] In certain embodiments, the compound of Formula (A) is of Formula (R-2-I); the compound of Formula (B) is of Formula (L-2-6); and the compound of Formula (C) is of the Formula (H3-2-I). Provided herein is a method of preparing a compound of Formula (H3-2-II):
##STR00089##
or a salt or stereoisomer thereof, the method comprising coupling a compound of Formula (L-2-6):
##STR00090##
or a salt or stereoisomer thereof, with a compound of Formula (R-2-I):
##STR00091##
or a salt or stereoisomer thereof, in the presence of a nickel(I) complex, a nickel(II) complex, and a zirconium complex, wherein: [0224] R.sup.s is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; [0225] X.sup.1 is halogen or a leaving group; [0226] R.sup.1, R.sup.2, R.sup.3, and R.sup.5 are each independently hydrogen, halogen, or optionally substituted alkyl; [0227] each instance of R.sup.4 is independently hydrogen, halogen, or optionally substituted alkyl, or two R.sup.4 groups are taken together to form: [0228] each instance of R.sup.6 is independently hydrogen, halogen, or optionally substituted alkyl, or two R.sup.6 groups are taken together to form: [0229] R.sup.P4, R.sup.P5, and R.sup.P6 are each independently hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally wherein two R.sup.P6 are joined with the intervening atoms to form optionally substituted heterocyclyl; [0230] R.sup.X is hydrogen or -OR.sup.Xa, wherein R.sup.Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; and [0231] R.sup.Y is hydrogen or -OR.sup.Ya, wherein R.sup.Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; [0232] optionally wherein R.sup.Xa and R.sup.Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl.
[0233] In certain embodiments, the method comprises coupling a compound of Formula (EL):
##STR00094##
or a salt or stereoisomer thereof, with a compound of the formula (E-R):
##STR00095##
or a salt or stereoisomer thereof, in the presence of a nickel(I) complex, a nickel(II) complex, and a zirconium complex, to yield a compound of the formula (E-1):
##STR00096##
or a salt or stereoisomer thereof.
[0234] In certain embodiments, the step of coupling to provide a compound of Formula (H3-2-II), (E-1), or a salt or stereoisomer thereof, is a Ni/Zr-mediated coupling provided herein. Any reagents or conditions provided herein for the Ni/Zr-mediated coupling may be used in the coupling. For example, in certain embodiments, the reaction is carried out in the presence of a nickel(I) complex, a nickel(II) complex, a zirconium complex, a reducing metal, and a base or proton scavenger.
[0235] In certain embodiments, the reaction is carried out in the presence of a nickel (I) complex of the formula: NiX•(ligand); a nickel (II) complex of the formula: NiX.sub.2•(ligand); a zirconium complex of the formula: (ligand).sub.nZrX.sub.2; zinc or manganese metal; and a base or proton scavenger.
[0236] In certain embodiments, the reaction is carried out in the presence of the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; the zirconium complex: Cp.sub.2ZrCl.sub.2; zinc or manganese metal; and a base or proton scavenger.
[0237] In certain embodiments, the reaction is carried out in the presence of the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; the zirconium complex: Cp.sub.2ZrCl.sub.2; zinc metal; and 2,6-di-tert-butyl-4-methylpyridine.
[0238] In certain embodiments, the reaction is carried out in the presence of approximately 20 mol% the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; approximately 5 mol% of the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; approximately 1 equivalent of the zirconium complex: Cp.sub.2ZrCl.sub.2; approximately 6 equivalents of zinc metal; and approximately 2.5 equivalents of 2,6-di-tert-butyl-4-methylpyridine. In certain embodiments, the reaction is carried out in a mixture of DMA/DME. In certain embodiments, the reaction is carried out at around room temperature.
[0239] In certain embodiments, the reaction is carried out in the presence of approximately 20 mol% the nickel (I) complex: (Me).sub.3tpy•Ni.sup.II; approximately 5 mol% of the nickel(II) complex: (py-(Me)imid)•Ni.sup.IICl.sub.2; approximately 1 equivalent of the zirconium complex: Cp.sub.2ZrC1.sub.2; approximately 6 equivalents of zinc metal; and approximately 2.5 equivalents of 2,6-di-4ert-butyl-4-methylpyridine, in a mixture of DMA/DME (e.g., 1:1 DMA/DME; 0.2 M) at around room temperature.
[0240] Additional methods for converting compounds of Formula (H3-2-II) into compounds of Formula (H3-2-I) can be found in International Publication No. WO 2019/010363, published Jan. 10, 2019, which is incorporated herein by reference. For example, in certain embodiments, the method described above may further comprise a step of cyclizing a compound of Formula (H3-2-II):
##STR00097##
or a salt or stereoisomer thereof, to yield a compound of Formula (H3-2-I):
##STR00098##
or a salt or stereoisomer thereof
[0241] In certain embodiments, the method is a method of preparing Compound (2):
##STR00099##
or a salt or stereoisomer thereof, the method comprising cyclizing a compound of the formula:
##STR00100##
or a salt or stereoisomer thereof.
General Reaction Parameters
[0242] The following embodiments apply to all synthetic methods described herein.
[0243] The reactions provided and described herein may involve one or more reagents. In certain embodiments, a reagent may be present in a catalytic amount. In certain embodiments, a catalytic amount is from 0.001-0.1 mol%, 0.1-1 mol%, 0-5 mol%, 0-10 mol%, 1-5 mol%, 1-10 mol%, 5-10 mol%, 10-20 mol%, 20-30 mol%, 30-40 mol%, 40-50 mol%, 50-60 mol%, 60-70 mol%, 70-80 mol%, 80-90 mol%, or 90-99 mol%. In certain embodiments, a reagent may be present in a stoichiometric amount (i.e., about 1 equivalent). In certain embodiments, a reagent may be present in excess amount (i.e., greater than 1 equivalent). In certain embodiments, the excess amount is about 1.1, 1.2, 1.3, 1.4, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 15, or 20 equivalents. In certain embodiments, the excess amount is from about 1.1-2, 2-3, 3-4, 4-5, 1.1-5, 5-10, 10-15, 15-20, or 10-20 equivalents. In certain embodiments, the excess amount is greater than 20 equivalents.
[0244] A reaction described herein may be carried out at any temperature. In certain embodiments, a reaction is carried out at or around room temperature (rt) (around 21° C. or 70° F.). In certain embodiments, a reaction is carried out at below room temperature (e.g., from -100° C. to 21° C.). In certain embodiments, a reaction is carried out at or around -78° C. In certain embodiments, a reaction is carried out at or around -10° C. In certain embodiments, a reaction is carried out at around 0° C. In certain embodiments, a reaction is carried out at above room temperature. In certain embodiment, a reaction is carried out at 30, 40, 50, 60, 70, 80, 110, 120, 130, 140, or 150° C. In certain embodiments, a reaction is carried out at above 150° C.
[0245] A reaction described herein may be carried out in a solvent, or a mixture of solvents (i.e., cosolvents). Solvents can be polar or non-polar, protic or aprotic. Any solvent may be used in the reactions described herein, and the reactions are not limited to particular solvents or combinations of solvents. Common organic solvents useful in the methods described herein include, but are not limited to, acetone, acetonitrile, benzene, benzonitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methyl ether, carbon disulfide carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N.N-dimethylacetamide N,N-dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethylether, 2-ethoxyethyl ether, ethyl acetate, ethyl alcohol, ethylene glycol, dimethyl ether, heptane, n-hexane, hexanes, hexamethylphosphoramide (HMPA), 2-methoxyethanol, 2-methoxyethyl acetate, methyl alcohol, 2-methylbutane, 4-methyl-2-pentanone, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-methyl-2-pyrrolidinone, dimethylsulfoxide (DMSO), nitromethane, 1-octanol, pentane, 3-pentanone, 1-propanol, 2-propanol, pyridine, tetrachloroethylene, tetrahyrdofuran (THF), 2-methyltetrahydrofuran, toluene, trichlorobenzene, 1,1,2-trichlorotrifluoroethane, 2,2,4-trimethylpentane, trimethylamine, triethylamine, N,N-diisopropylethylamine, diisopropylamine, water, o-xylene, and p-xylene.
[0246] A reaction described herein may be carried out over any amount of time. In certain embodiments, a reaction is allowed to run for seconds, minutes, hours, or days. In certain embodiments, the Ni/Zr-mediated coupling reaction is allowed to run for seconds, minutes, hours, or days.
[0247] Methods described herein can be used to prepare compounds in any chemical yield. In certain embodiments, a compound is produced in from 1-10%, 10-20% 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100% yield. In certain embodiments, the yield is the percent yield after one synthetic step (e.g., after the Ni/Zr-mediated coupling reaction). In certain embodiments, the yield is the percent yield after more than one synthetic step (e.g., 2, 3, 4, or 5 synthetic steps).
[0248] Methods described herein may further comprise one or more purification steps. For example, in certain embodiments, a compound produced by a method described herein may be purified by chromatography, extraction, filtration, precipitation, crystallization, or any other method known in the art. In certain embodiments, a compound or mixture is carried forward to the next synthetic step without purification (i.e., crude).
[0249] In certain embodiments, a compound or reaction mixture produced by a method described herein is purified by aqueous extraction. In certain embodiments, a compound produced by a method described herein is purified by chromatography (e.g., silica gel chromatography). In certain embodiments, a compound produced by a method described herein is purified by aqueous extraction followed by chromatography (e.g., silica gel chromatography).
[0250] Metals (e.g., Ni, Zr, Zn, and/or Mn) used in the methods described herein can be removed from the reaction mixtures by one or more step of extraction, chromatography, precipitation, filtration, or any other method known in the art. In certain embodiments, a method described herein yields a product that is substantially free of metals.
[0251] The synthetic method provided herein can be carried out on any scale (i.e., to yield any amount of product). In certain embodiments, the methods are applicable to small-scale synthesis or larger-scale process manufacture. In certain embodiments, a reaction provided herein is carried out on a scale to yield less than 1 g of product. In certain embodiments, a reaction provided herein is carried out to yield greater than 1 g, 2 g, 5 g, 10 g, 15 g, 20 g, 25 g, 30 g, 40 g, 50 g, 100 g, 200 g, 500 g, or 1 kg of a product.
Chemical Groups
[0252] The following chemical group definitions apply to all compounds and methods described herein.
Group R.SUP.S
[0253] As defined herein, R.sup.S is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In certain embodiments, R.sup.s is optionally substituted alkyl. In certain embodiments, R.sup.s is optionally substituted C.sub.1-6alkyl. In certain embodiments, R.sup.s is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.S is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.S is optionally substituted carbocyclyl. In certain embodiments, R.sup.S is optionally substituted aryl. In certain embodiments, R.sup.S is optionally substituted heterocyclyl. In certain embodiments, R.sup.S is optionally substituted heteroaryl. In certain embodiments, R.sup.S is optionally substituted 6-membered heteroaryl. In certain embodiments, R.sup.S is optionally substituted 6-membered heteroaryl comprising 1, 2, or 3 nitrogen atoms. In certain embodiments, R.sup.S is optionally substituted pyridyl. In certain embodiments, R.sup.S is unsubstituted pyridyl (Py). In certain embodiments, R.sup.S is optionally substituted 2-pyridyl. In certain embodiments, R.sup.S is unsubstituted 2-pyridyl (2-Py). In certain embodiments, R.sup.S is selected from the group consisting of:
##STR00101##
##STR00102##
##STR00103##
In certain embodiments, R.sup.S is
##STR00104##
(abbreviated herein as “2-Py” or “Py”).
Group X.SUP.1
[0254] As defined herein, X.sup.1 is halogen or a leaving group. In certain embodiments, X.sup.1 is a halogen. In certain embodiments, X.sup.1 is —Cl (i.e., chloride). In certain embodiments, X.sup.1 is -Br (i.e., bromide). In certain embodiments, X.sup.1 is —I (i.e., iodide). In certain embodiments, X.sup.1 is —F (i.e., fluoride). In certain embodiments, X.sup.1 is a leaving group.
Groups R′, R.SUP.2., R.SUP.3., R.SUP.4., R.SUP.3., R.SUP.6., and R.SUP.7
[0255] As defined herein, R.sup.1 is hydrogen, halogen, or optionally substituted alky. In certain embodiments, R.sup.1 is hydrogen. In certain embodiments, R.sup.1 is halogen. In certain embodiments, R.sup.1 is optionally substituted alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.1 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.1 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, see-butyl, and tert-butyl. In certain embodiments, R.sup.1 is methyl.
[0256] As defined herein, R.sup.2 is hydrogen, halogen, or optionally substituted alky. In certain embodiments, R.sup.2 is hydrogen. In certain embodiments, R.sup.2 is halogen. In certain embodiments, R.sup.2 is optionally substituted alkyl. In certain embodiments, R.sup.2 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.2 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.2 is methyl.
[0257] As defined herein, R.sup.3 is hydrogen, halogen, or optionally substituted alky. In certain embodiments, R.sup.3 is hydrogen. In certain embodiments, R.sup.3 is halogen. In certain embodiments, R.sup.3 is optionally substituted alkyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.3 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.3 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.3 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.3 is methyl.
[0258] As defined herein, each instance of R.sup.4 is independently hydrogen, halogen, or optionally substituted alkyl; and optionally two R.sup.4 groups are taken together to form:
##STR00105##
In certain embodiments, R.sup.4 is hydrogen. In certain embodiments, R.sup.4 is halogen. In certain embodiments, R.sup.4 is optionally substituted alkyl. In certain embodiments, R.sup.4 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.4 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.4 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.4 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.4 is methyl. In certain embodiments, two R.sup.4 groups are taken together to form:
##STR00106##
[0259] As defined herein, R.sup.5 is hydrogen, halogen, or optionally substituted alky. In certain embodiments, R.sup.5 is hydrogen. In certain embodiments, R.sup.5 is halogen. In certain embodiments, R.sup.5 is optionally substituted alkyl. In certain embodiments, R.sup.5 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.5 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.5 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.5 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.5 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.5 is methyl.
[0260] As defined herein, each instance of R.sup.6 is independently hydrogen, halogen, or optionally substituted alkyl; and optionally two R.sup.6 groups are taken together to form:
##STR00107##
In certain embodiments, R.sup.6 is hydrogen. In certain embodiments, R.sup.6 is halogen. In certain embodiments, R.sup.6 is optionally substituted alkyl. In certain embodiments, R.sup.6 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.6 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.6 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.6 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.6 is methyl. In certain embodiments, two R.sup.6 groups are taken together to form:
##STR00108##
[0261] As defined herein, R.sup.7 is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.7 is hydrogen. In certain embodiments, R.sup.7 is optionally substituted alkyl. In certain embodiments, In certain embodiments, R.sup.7 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.7 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.7 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.7 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.7 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.7 is methyl. In certain embodiments, R.sup.7 is ethyl. In certain embodiments, R.sup.7 is optionally substituted carbocyclyl. In certain embodiments, R.sup.7 is optionally substituted aryl. In certain embodiments, R.sup.7 is optionally substituted heterocyclyl. In certain embodiments, R.sup.7 is optionally substituted heteroaryl. In certain embodiments, R.sup.7 is optionally substituted acyl. In certain embodiments, R.sup.7 is an oxygen protecting group. In certain embodiments, R.sup.7 is an optionally substituted benzyl protecting group. In certain embodiments, R.sup.7 is benzyl (-CH.sub.2Ph; “Bn”).
Groups R.SUP.X and R.SUP.Y
[0262] As defined herein, R.sup.X is hydrogen or -OR.sup.Xa. In certain embodiments, R.sup.X is hydrogen. In certain embodiments, R.sup.X is -OR.sup.Xa.
[0263] As generally defined herein, R.sup.Xa is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.Xa is hydrogen. In certain embodiments, R.sup.Xa is optionally substituted alkyl. In certain embodiments, R.sup.Xa is optionally substituted acyl. In certain embodiments, R.sup.Xa is or an oxygen protecting group. In certain embodiments, R.sup.Xa is optionally substituted allyl. In certain embodiments, R.sup.Xa is
##STR00109##
(allyl).
[0264] As defined herein, R.sup.Y is hydrogen or -OR.sup.Ya. In certain embodiments, R.sup.Y is hydrogen. In certain embodiments, R.sup.Y is -OR.sup.Ya.
[0265] As generally defined herein, R.sup.Ya is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.Ya is hydrogen. In certain embodiments, R.sup.Ya is optionally substituted alkyl. In certain embodiments, R.sup.Ya is optionally substituted acyl. In certain embodiments, R.sup.Ya is or an oxygen protecting group. In certain embodiments, R.sup.Ya is optionally substituted allyl. In certain embodiments, R.sup.Ya is
##STR00110##
(allyl).
[0266] In certain embodiments, R.sup.Xa and R.sup.Ya are joined together with their intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.Xa and R.sup.Ya are joined together with their intervening atoms to form optionally substituted 5-membered heterocyclyl. In certain embodiments, R.sup.Xa and R.sup.Ya are joined together with their intervening atoms to form optionally substituted 1,3-dioxolane ring. In certain embodiments, R.sup.Xa and R.sup.Ya are joined together with their intervening atoms to form the following:
##STR00111##
In certainembodiments, R .sup.Xa and R.sup.Ya′ are joined together with their intervening atoms to form the following:
##STR00112##
[0267] In certain embodiments, R.sup.X and R.sup.Y are both hydrogen.
[0268] In certain embodiments, R.sup.X is hydrogen, and R.sup.Y is -OR.sup.Ya. In certain embodiments, R.sup.x is hydrogen; and R.sup.Y is —OH.
[0269] In certain embodiments, R.sup.X is -OR.sup.Xa; and R.sup.Y is -OR.sup.Ya. In certain embodiments, R.sup.x is —OH; and R.sup.Y is —OH.
Groups R.SUP.P1., R.SUP.P2., R.SUP.P3., R.SUP.P4., R.SUP.P5.and R.SUP.P6
[0270] As defined herein, R.sup.P1 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.P1 is hydrogen. In certain embodiments, R.sup.P1 is optionally substituted alkyl. In certain embodiments, In certain embodiments, R.sup.P1 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P1 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P1 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P1 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.P1 is optionally substituted acyl. In certain embodiments, R.sup.P1 is an oxygen protecting group. In certain embodiments, R.sup.P1 is optionally substituted allyl. In certain embodiments, R.sup.P1 is allyl. In certain embodiments, R.sup.P1 is optionally substituted silyl. In certain embodiments, R.sup.P1 is trialkylsilyl. In certain embodiments, R.sup.P1 is triethylsilyl (-SiEt.sub.3; “TES”). In certain embodiments, R.sup.P1 is trimethylsilyl (—SiMe.sub.3; “IMS”). In certain embodiments, R.sup.P1 is tert-butyl dimethylsilyl (—Sit—BuMe.sub.2; “TBS”). In certain embodiments, R.sup.P1 is tert-butyl diphenylsilyl (—Sit—BuPh.sub.2; “TBDPS”). In certain embodiments, R.sup.P1 is an optionally substituted benzyl protecting group. In certain embodiments, R.sup.P1 is benzyl (—CH.sub.2Ph; “Bn”). In certain embodiments, R.sup.P1 is a methoxybenzyl protecting group. In certain embodiments, R.sup.P1 is para-methoxybenzyl:
##STR00113##
(“MPM” or “PMB”).
[0271] In certain embodiments, R.sup.P1 and R.sup.P2 are joined with the intervening atoms to form optionally substituted heterocyclyl.
[0272] As defined herein, R.sup.P2 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.P2 is hydrogen. In certain embodiments, R.sup.P2 is optionally substituted alkyl. In certain embodiments, R.sup.P2 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P2 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P2 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.P2 is optionally substituted acyl. In certain embodiments, R.sup.P2 is an oxygen protecting group. In certain embodiments, R.sup.P2 is optionally substituted allyl. In certain embodiments, R.sup.P2 is allyl. In certain embodiments, R.sup.P2 is optionally substituted silyl. In certain embodiments, R.sup.P2 is trialkylsilyl. In certain embodiments, R.sup.P2 is triethylsilyl (—SiEt.sub.3; “TES”). In certain embodiments, R.sup.P2 is trimethylsilyl (—SiMe.sub.3; “TMS”). In certain embodiments, R.sup.P2 is tert-butyl dimethylsilyl (—Sit—BuMe.sub.2; “TBS”). In certain embodiments, R.sup.P2 is tert-butyl diphenylsilyl (—Sit—BuPh.sub.2; “TBDPS”). In certain embodiments, R.sup.P2 is an optionally substituted benzyl protecting group. In certain embodiments, R.sup.P2 is benzyl (—CH.sub.2Ph; “Bn”). In certain embodiments, R.sup.P2 is a methoxybenzyl protecting group. In certain embodiments, R.sup.P2 is para-methoxybenzyl:
##STR00114##
(“MPM” or “PMB”).
[0273] In certain embodiments, R.sup.P3 and R.sup.P3 are joined with the intervening atoms to form optionally substituted heterocyclyl.
[0274] As defined herein, R.sup.P3 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.P3 is hydrogen. In certain embodiments, R.sup.P3 is optionally substituted alkyl. In certain embodiments, R.sup.P3 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P3 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P3 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P3 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, see-butyl, and tert-butyl. In certain embodiments, R.sup.P3 is optionally substituted acyl. In certain embodiments, R.sup.P3 is an oxygen protecting group. In certain embodiments, R.sup.P3 is optionally substituted allyl. In certain embodiments, R.sup.P3 is allyl. In certain embodiments, R.sup.P3 is optionally substituted silyl. In certain embodiments, R.sup.P3 is trialkylsilyl. In certain embodiments, R.sup.P3 is triethylsilyl (—SiEt.sub.3; “TES”). In certain embodiments, R.sup.P3 is trimethylsilyl (—SiMe.sub.3; “TMS”). In certain embodiments, R.sup.P3 is tert-butyl dimethylsilyl (—Sit—BuMe.sub.2; “TBS”). In certain embodiments, R.sup.P3 is tert-butyl diphenylsilyl (—Sit—BuPh.sub.2; “TBDPS”). In certain embodiments, R.sup.P3 is an optionally substituted benzyl protecting group. In certain embodiments, R.sup.P3 is benzyl (—CH.sub.2Ph; “Bn”). In certain embodiments, R.sup.P3 is a methoxybenzyl protecting group. In certain embodiments, R.sup.P1 is para-methoxybenzyl:
##STR00115##
(“MPM” or “PMB”).
[0275] As defined herein, R.sup.P4 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R.sup.P4 is hydrogen. In certain embodiments, R.sup.P4 is optionally substituted alkyl. In certain embodiments, R.sup.P4 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P4 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P4 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P4 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P4 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.P4 is optionally substituted acyl. In certain embodiments, R.sup.P4 is an oxygen protecting group. In certain embodiments, R.sup.P4 is optionally substituted allyl. In certain embodiments, R.sup.P4 is allyl. In certain embodiments, R.sup.P4 is optionally substituted silyl. In certain embodiments, R.sup.P4 is trialkylsilyl. In certain embodiments, R.sup.P4 is triethylsilyl (—SiEt.sub.3; “TES”). In certain embodiments, R.sup.P4 is trimethylsilyl (—SiMe.sub.3; “TMS”). In certain embodiments, R.sup.P4 is tert-butyl dimethylsilyl (—Sit—BuMe.sub.2; “TBS”). In certain embodiments, R.sup.P4 is tert-butyl diphenylsilyl (—Sit—BuPh.sub.2; “TBDPS”). In certain embodiments, R.sup.P4 is an optionally substituted benzyl protecting group. In certain embodiments, R.sup.P4 is benzyl (—CH.sub.2Ph; “Bn”). In certain embodiments, R.sup.P4 is a methoxybenzyl protecting group. In certain embodiments, R.sup.P4 is para-methoxybenzyl:
##STR00116##
(“MPM” or “PMB”).
[0276] As defined herein, R.sup.P5 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally wherein two R.sup.P5 are joined with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.P5 is hydrogen. In certain embodiments, R.sup.P5 is optionally substituted alkyl. In certain embodiments, R.sup.P5 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P5 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P5 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P5 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P5 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.P5 is optionally substituted acyl. In certain embodiments, R.sup.P5 is an oxygen protecting group. In certain embodiments, R.sup.P5 is optionally substituted allyl. In certain embodiments, R.sup.P5 is allyl. In certain embodiments, R.sup.P5 is optionally substituted silyl. In certain embodiments, R.sup.P5 is trialkylsilyl. In certain embodiments, R.sup.P5 is triethylsilyl (—SiEt.sub.3; “TES”). In certain embodiments, R.sup.P5 is trimethylsilyl (—SiMe.sub.3; “TMS”). In certain embodiments, R.sup.P5 is tert-butyl dimethylsilyl (—Sit—BuMe.sub.2; “TBS”). In certain embodiments, R.sup.P5 is tert-butyl diphenylsilyl (—Sit—BuPh.sub.2; “TBDPS”). In certain embodiments, R.sup.P5 is an optionally substituted benzyl protecting group. In certain embodiments, R.sup.P5 is benzyl (—CH.sub.2Ph; “Bn”). In certain embodiments, R.sup.P5 is a methoxybenzyl protecting group. In certain embodiments, R.sup.P5 is para-methoxybenzyl:
##STR00117##
(“MPM” or “PMB”). In certain embodiments, two R.sup.P5 are joined with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two R.sup.P5 are joined with the intervening atoms to form optionally substituted six-membered heterocyclyl. In certain embodiments, two R.sup.P5 are joined with the intervening atoms to form a ring of the formula:
##STR00118##
In certain embodiments, two R.sup.P5 are joined with the intervening atoms to form a ring of the formula:
##STR00119##
In certain embodiments, two R.sup.P5 are joined with the intervening atoms to form a ring of the formula:
##STR00120##
In certain embodiments, two R.sup.P5 are joined with the intervening atoms to form a ring of the formula:
##STR00121##
[0277] As defined herein, R.sup.P6 is hydrogen, optionally substituted alkyl, optionally substituted acyl, or an oxygen protecting group; optionally wherein two R.sup.P6 are joined with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R.sup.P6 is hydrogen. In certain embodiments, R.sup.P6 is optionally substituted alkyl. In certain embodiments, R.sup.P6 is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P6 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.P6 is optionally substituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P6 is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.P6 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, R.sup.P6 is optionally substituted acyl. In certain embodiments, R.sup.P6 is an oxygen protecting group. In certain embodiments, R.sup.P6 is optionally substituted allyl. In certain embodiments, R.sup.P6 is allyl. In certain embodiments, R.sup.P6 is optionally substituted silyl. In certain embodiments, R.sup.P6 is trialkylsilyl. In certain embodiments, R.sup.N is triethylsilyl (—SiEt.sub.3; “TES”). In certain embodiments, R.sup.P6 is trimethylsilyl (—SiMe.sub.3; “TMS”). In certain embodiments, R.sup.P6 is tert-butyl dimethylsilyl (—Sit—BuMe.sub.2; “TBS”). In certain embodiments, R.sup.P6 is tert-butyl diphenylsilyl (—Sit—BuPh.sub.2; “TBDPS”). In certain embodiments, R.sup.P6 is an optionally substituted benzyl protecting group. In certain embodiments, R.sup.P6 is benzyl (—CH.sub.2Ph; “Bn”). In certain embodiments, R.sup.P6 is a methoxybenzyl protecting group. In certain embodiments, R.sup.P6 is para-methoxybenzyl:
##STR00122##
(“MPM” or “PMB”). In certain embodiments, two R.sup.P6 are joined with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two R.sup.P6 are joined with the intervening atoms to form optionally substituted six-membered heterocyclyl. In certain embodiments, two R.sup.P6 are joined with the intervening atoms to form a ring of the formula:
##STR00123##
In certain embodiments, two R.sup.P6 are joined with the intervening atoms to form a ring of the formula:
##STR00124##
[0278] In certain embodiments, R.sup.P1, R.sup.P2, R.sup.P3, R.sup.P4 and R.sup.P5 are silyl protecting groups. In certain embodiments, R.sup.P1 and R.sup.P2 are TBS; and R.sup.P3, R.sup.P4, and R.sup.P5 are TES.
[0279] In certain embodiments, R.sup.P3 is a silyl protecting group; R.sup.7 is optionally substituted alkyl, and R.sup.P4 and R.sup.P5 are silyl protecting groups. In certain embodiments, R.sup.P3 is TES; R.sup.7 is methyl; and R.sup.P4 and R.sup.P5 are TES.
[0280] In certain embodiments, two R.sup.P6 are joined to form:
##STR00125##
and R.sup.P4 and R.sup.P5 are silyl protecting groups. In certain embodiments, two R.sup.P6 are joined to form:
##STR00126##
and R.sup.P4 and R.sup.P5 are TES.
Group R
[0281] As generally defined herein, each R is independently hydrogen or optionally substituted alkyl. In certain embodiments, at least one instance of R is hydrogen. In certain embodiments, at least one instance of R is optionally substituted alkyl. In certain embodiments, at least one instance of R is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R is optionally substituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R is unsubstituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiments, each R is tert-butyl.
Group X, R.SUP.c., R.SUP.c′., R.SUP.N., p, and s
[0282] As defined herein, each instance of X is independently halogen. In certain embodiments, each X is —Cl. In certain embodiments, each X is —Br. In certain embodiments, each X is —I. In certain embodiments, each X is —F.
[0283] As defined herein, each instance of p is independently 0 or an integer from 1-4, inclusive. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5.
[0284] As defined herein, s is 0, 1, or 2. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2.
[0285] As defined herein, each instance of R.sup.c is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —N(R.sup.N).sub.2, -OR.sup.O, or -SR.sup.S1. In certain embodiments, at least one instance of R.sup.c is hydrogen. In certain embodiments, at least one instance of R.sup.c is halogen In certain embodiments, at least one instance of R.sup.c is —CN. In certain embodiments, at least one instance of R.sup.c is —NO.sub.2. In certain embodiments, at least one instance of R.sup.c is —N.sub.3. In certain embodiments, at least one instance of R.sup.c is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.c is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.c is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.c is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.c is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.c is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.c is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.c is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.c is —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.c is -OR.sup.O. In certain embodiments, at least one instance of R.sup.c is or -SR.sup.S1. In certain embodiments, at least one instance of R.sup.c is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.c is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.c is optionally substituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.c is unsubstituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.c is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, see-butyl, and tert-butyl. In certain embodiment, at least one instance of R.sup.c is methyl. In certain embodiment, each instance of R.sup.c is methyl.
[0286] As defined herein, each instance of R.sup.c′ is independently hydrogen, halogen, —CN, —NO.sub.2, —N.sub.3, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, —N(R.sup.N).sub.2, -OR.sup.O, or -SR.sup.S1. In certain embodiments, at least one instance of R.sup.c′ is hydrogen. In certain embodiments, at least one instance of R.sup.c′ is halogen In certain embodiments, at least one instance of R.sup.c′ is —CN. In certain embodiments, at least one instance of R.sup.c′ is —NO.sub.2. In certain embodiments, at least one instance of R.sup.c′ is —N.sub.3. In certain embodiments, at least one instance of R.sup.c′ is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.c′ is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.c′ is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.c′ is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.c′ is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.c′ is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.c′ is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.c′ is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.c′ is —N(R.sup.N).sub.2. In certain embodiments, at least one instance of R.sup.c′ is -OR.sup.O. In certain embodiments, at least one instance of R.sup.c′ is or -SR.sup.S1.
[0287] As defined herein, each instance of R.sup.N is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a nitrogen protecting group; or two R.sup.N bonded to the same nitrogen atom are taken together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.N is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.N is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.N is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.N is a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.N is optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.N is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.N is optionally substituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.N is unsubstituted C.sub.1-3 alkyl. In certain embodiments, at least one instance of R.sup.N is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In certain embodiment, at least one instance of R.sup.N is methyl.
[0288] each instance of R.sup.O is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, at least one instance of R.sup.O is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.O is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.O is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.O is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.O is an oxygen protecting group.
[0289] each instance of R.sup.S1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted acyl, or a sulfur protecting group. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted alkyl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted alkenyl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted alkynyl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted aryl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted heteroaryl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.S1 is optionally substituted acyl. In certain embodiments, at least one instance of R.sup.S1 is a sulfur protecting group.
EXAMPLES
Ni./Zr-Mediated Coupling Reactions
[0290] A new Ni/Zr-mediated one-pot ketone synthesis was developed with use of a mixture of (Me).sub.3tpy—Ni.sup.II— and py-(Me)imid.Math.N.sup.IICl.sub.2-catalysts. The Ni.sup.I-catalyst selectively activates alkyl halides, whereas the Ni.sup.II-catalyst activates thioesters. An adjustment of a relative loading of the two catalysts allows to tune the relative rate of the two activations and trap a short-lived radical intermediate(s) efficiently. Thus, the new method makes one-pot ketone synthesis highly effective even with a 1:1 mixture of the coupling partners. The synthetic value of the new method is demonstrated with the C—C bond formation at the final stage of a convergent halichondrin-synthesis.
[0291] Recently, a Ni/Zr-mediated one-pot ketone synthesis was reported, which was successfully applied to a unified total synthesis of the halichondrin class of marine natural products..sup.1,2 During a study of extending the one-pot ketone synthesis to macroketocyclization, it was observed that the efficiency of cyclization was noticeably improved with use of a mixture of (dtbbpy).Math.NiBr.sub.2 and (tpy)-NiCl.sub.2 (
[0292] With the hope of identifying better catalysts, various NiX.sub.2-complexes with bidentate- and tridentate-ligands were first screened. Through this screen, 2-(1-methyl-1H-imidazol-2-yl)pyridine (abbreviated as py-(Me)imid) and 4,4′,4″-trimethyl-2,2′:6′,2″-terpyridine (abbreviated as (Me).sub.3-tpy) emerged as the best-performing ligands (
[0293] The coupling was effected by either Zn— or Mn-metal in the presence of Cp.sub.2ZrCl.sub.2 (0.7-1.0 equiv), although the coupling with Mn-metal is slower than that with Zn-metal. A 1:1 mixture of N.N-dimethylacetamide (DMA) and 1,2-dimethoxyethane (DME) at C ~0.5 M was used as a solvent, and the coupling was typically completed within 3 hours at RT..sup.5,6
[0294] The ketone coupling of 1 + 2 .fwdarw. 3 requires the activation of the iodide in 1 as well as the thiopyridine ester in 2. In the previous method, (dtbbpy).Math.NiBr.sub.2 activates obviously both iodide and thiopyridine ester. The results in Table 1 demonstrate that (Me)3tpy.Math.Ni.sup.II selectively activates the iodide 1, whereas py-(Me)imid.Math.Ni.sup.IICl.sub.2 activates thiopyridine ester 2. However, it should be noted that the Ni.sup.II-catalyst also activates 1, but the rate of activation with the Ni.sup.II-catalyst is significantly slower than that with the Ni.sup.II-catalyst.
TABLE-US-00001 Studies to determine the primary role of the two catalysts. 1 + 2 .fwdarw. 3 (Ar = C.sub.8H.sub.4OM.sub.e-P) (1.0 equiv) (1.0 equiv) (Me).sub.3tpy.Math. Ni (py-(Me)imid).Math. NiCl.sub.2 time (h) recovered 1 recovered 2 isolated 3 entry 1 1 mol% 1 mol% 3 0% 0% 96% entry 2 2 mol% 0 0.5 0% 70% 22% entry 3 2 mol% 0 3 0% 65% 22% entry 4 0 2 mol% 0.5 51% 44% 21% entry 5 0 2 mol% 3 26% 12% 46% Reactions were carried out with or without Ni— and Ni — catalysts in the presence of Cp.sub.2ZrCl.sub.2 (1 equiv) and Zn (3 equiv) in DMA/DME (1/1, 0 0.5 M) at RT. The amounts indicated for 1-3 are based on the materials isolated chromatographically.
[0295] In the absence of Zn-metal, 1 is stable against (Me).sub.3tpy.Math.Ni.sup.II, thereby indicating that the activation of 1 requires a Ni.sup.0-species generated from (Me).sub.3terpy-Ni.sup.II in situ. Indeed, the coupling of 1 + 2 - 3 with Ni.sup.0-species, prepared from Ni.sup.0(COD).sub.2 and (Me).sub.2tpy ligand, gave ketone 3..sup.6 It is worth noting that iodide 1 gave two products 4 and 5 under the condition of (Me).sub.3tpy.Math.Ni.sup.II/Zn (Entry 3) but only 4 under the condition of Ni.sup.0(Me).sub.2tpy, showing that 4 is formed via dimerization of the radical, whereas 5 via the reductive ring-opening 1 with Zn-metal.
[0296] Overall, (Me).sub.3tpy.Math.Ni.sup.I—I is first reduced by Zn— or Mn-metal to the corresponding (Me).sub.3tpy.Math.Ni.sup.0 and then serves as a radical initiator for the ketone coupling (
[0297] The primary role of py-(Me)imid.Math.Ni.sup.IICl.sub.2 is the activation of 2 via the well-precedent oxidative addition with the Ni.sup.0-species generated from the Ni.sup.II-complex and Zn-metal in situ (
[0298] Interestingly, the activation of both 1 and 2 is affected by a Ni.sup.0-species, yet in a different mode. The observed selectivity is attributed to the structural difference between py-(Me)imid.Math.Ni— and (Me).sub.3tpy.Math.Ni-complexes; it is known that the Ni-complex with a bidentate ligand adopts a tetrahedral structure, whereas the Ni-complex with a terpyridine ligand adopts a squire-planar structure..sup.9
[0299] Among Ni.sup.IIBr.sub.2- or Ni.sup.IICl.sub.2-complexes with bidentate-ligands, py-(Me)imid.Math.Ni.sup.IICl.sub.2 was found to be the fastest and cleanest catalyst thus far. In addition, the activated species generated from 2 was found stable at least 0.5-1 hours in the reaction system..sup.10
[0300] As reported previously, zirconocene greatly accelerates the rate of coupling. .sup.2a A remarkable rate-enhancement is not observed with Cp.sub.2Zr.sup.IVCl.sub.2 alone, but with Cp.sub.2Zr.sup.IVCl.sub.2 with Zn-metal, thereby suggesting that it is caused by a reduced form of Cp.sub.2Zr.sup.IVCl.sub.2, and it is speculated to be Cp.sub.2Zr.sup.IIICl..sup.11
[0301] Obviously, a ligand-exchange is required to form ketone 3 from the initially formed oxidative-addition intermediate, i.e., A .fwdarw. B (
[0302] This new method has great synthetic value. As mentioned, the ketone coupling of 1 + 2 .fwdarw. 3 requires the activation of iodide 1 and thiopyridine ester 2. In the previous method, (dtbbpy).Math.NiBr.sub.2 activates both iodide and thiopyridine ester. Therefore, the relative rate of two activations is inherent to a given pair of coupling partners. In the new method, the two activations are independently effected by two catalysts (Me).sub.3tpy.Math.Ni.sup.II and py-(Me)imid.Math.Ni.sup.IICl.sub.2, thereby allowing us to tune the relative rates of the two activations by adjusting a relative loading of two catalysts.
[0303] A number of substrates tested in this laboratory show that activation of an iodide by (Me).sub.3tpy.Math.Ni.sup.II is uniformly fast, but the generated radicals are short-lived..sup.13 Contrarily, it has been observed that the rate of thiopyridine-ester activation widely varies, depending on substrate structure. Fortunately, generated intermediates are relatively long-lived..sup.10 Therefore, it is now possible to tune the relative rate of the two activations by simply adjusting the relative loading of the two catalysts to trap the short-lived radical intermediates by A. In order to trap the radical intermediate without waste, it is necessary to keep the relative rate of activation of an iodide slower than that of a thiopyridine ester. For the case of 1 + 2 .fwdarw. 3, the isolated yield reaches a plateau at around 3/1 ratio of the Ni.sup.I— and Ni.sup.II-catalyst-loadings, cf., Entry 5 vs. Entries 1-4 (Table 2). Interestingly, it has been observed that this ratio varies widely, depending on substrate structure. In general, as the rate of thiopyridine-ester activation is slower for a complex substrate, a lower ratio of Ni.sup.I-over Ni.sup.II-catalyst-loadings gives a better coupling yield. For example, the Ni.sup.I/Ni.sup.II = ¼ was used for the halichondrin case (
TABLE-US-00002 Ratio of Ni.sup.I— and Ni.sup.II-catalyst-loadings and coupling yields. 1 + 2 .fwdarw. 3 (1.0 equiv) (1.0 equiv) (Me).sub.3tpy•Ni.sup.Il py-(Me)imid-Ni.sup.IICl.sub.2 isolated ketone entry 1 1 mol% 5 mol% 96% entry 2 1 mol% 3 mol% 96% entry 3 1 mol% 1 mol% 96% entry 4 3 mol% 1 mol% 96% entry 5 5 mol% 1 mol% 91% Ketone-coupling was done with (Me).sub.3tpy•Nil, py-(Me)imid• NiCl.sub.2, Cp.sub.2ZrCl.sub.2 (1 equiv), and Zn (3 equiv) in DMA-DME (1:1, C 0.5 M) at RT, 3 h.
[0304] With this knowledge, it is now possible to realize the one-pot ketone synthesis efficiently even with a 1:1 ratio of the coupling partners. The results summarized in Table 3 and
TABLE-US-00003 Ratio of substrates 1 and 3 and coupling yields. 1 + 2 .fwdarw. 3 1 (equiv) 2 (equiv) isolated ketone entry 1 1.1 1.0 96% entry 2 1.0 1.0 96% entry 3 1.0 1.1 94% Ketone-coupling was done with (Me).sub.3tpy•Ni.sup.II (1 mol%), py(Me)imid• Ni.sup.IICl.sub.2 (1 mol%), Cp.sub.2ZrCl.sub.2 (1 equiv), and Zn (3 equiv) in DMA-DME (1:1, C 0.5 M) at RT, 3 h.
[0305] In addition, the overall coupling-rate can be controlled by the loading of the two catalysts. For example, the coupling of 1 + 2 .fwdarw. 3 was completed in ~3 hours, with 1 mol % loading of the two catalysts.
[0306] The new method shows the scope and limitation very similar to those observed for the previous method (Table 4)..sup.14 However, it should be noted that comparable, or even slightly better, yields were achieved with the new method with use of a 1:1 mixture of the iodide and thiopyridine ester, as opposed to a 1.2:1 mixture in the previous method.
TABLE-US-00004 Selected examples of ketone couplings
[0307] It is well appreciated that a convergent approach is the choice for a synthesis of a complex molecule over a linear approach. In order to carry out a convergent synthesis effectively, an efficient coupling reaction(s) is required. However, only a limited number of coupling reactions are shown to be useful at the late stage of a complex molecule synthesis; ideal coupling reactions need to meet a number of demanding criteria, including functional group tolerance, coupling efficiency with a ~1:1 molar ratio of coupling partners, coupling rate, stereoselectivity, and others. The previous one-pot ketone synthesis was successfully applied to the final C—C bond formation in the unified synthesis of halichondrins, although 1.0:1.3 molar ratio of coupling partners were required to achieve >80% yields..sup.2b As shown in
[0308] In summary, a new Ni/Zr-mediated one-pot ketone synthesis has been developed, with use of a mixture of (Me).sub.3tpy.Math.Ni.sup.II- and py-(Me)imid.Math.Ni.sup.IICl.sub.2-catalysts. The Ni.sup.I-catalyst selectively activates iodides, whereas the Ni.sup.II-catalyst activates thiopyridine esters. An adjustment of the relative loading of the two catalysts allows us to tune the relative rate of the two activations and trap a short-lived radical intermediate(s) efficiently. The new method is efficient, even with use of a 1:1 mixture of the coupling partners. The synthetic value of the new method is demonstrated with the C—C bond formation at the final stage of a convergent halichondrin synthesis.
General Experimental Information
[0309] Unless otherwise noted, all reagents and solvents were obtained from commercial suppliers and used without further purification. Reactions involving air or moisture sensitive reagents or intermediates were performed under an inert atmosphere of nitrogen or argon in glassware that was oven dried. Analytical thin layer chromatography (TLC) was performed with E. Merck precoated TLC plates, silica gel 60F-254, layer thickness 0.25 mm. TLC plates were visualized by staining with AMCAN (ammonium molybdate/cerium ammonium nitrate), PMA (phosphomolybdic acid hydrate), or p-anisaldehyde. Flash chromatography separations were performed on E. Merck Silica Gel 60 (40-63 .Math.m), Kanto Chemical Silica Gel 60N (spherical, neutral, 40-50 .Math.m), or Wako Pure Chemical Industry Wakogel 50NH.sub.2 (38-63 .Math.m). Medium pressure column chromatography was performed with YAMAZEN Smart Flash. NMR spectra were recorded on a Varian Inova 600 MHz or Varian Inova 500 MHz. Chemical shifts were reported in parts per million (ppm). The residual solvent peak was used as an internal reference (for .sup.1H NMR spectra: 7.26 ppm in CDCl.sub.3, 7.16 ppm in C.sub.6D.sub.6; for .sup.13C NMR: 77.0 ppm in CDCl.sub.3 and 128.0 ppm in C.sub.6D.sub.6). Coupling constants (J) are reported in Hz and the splitting abbreviations used are: s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, and br for broad. Optical rotations were measured at 20° C. using Perkin-Elmer 241 polarimeter. IR spectra were recorded on Bruker Alpha FT-IR spectrometer. Electrospray ionization experiments were performed on Micromass Inc., Platform II Atmospheric Pressure Ionization Mass Spectrometer.
Preparation of Nickel Catalysts
Py-(Me)imid-Ni.SUP.II.Cl.SUB.2
[0310] ##STR00140##
To a stirred solution of 2-(1H-imidazol-2-yl)pyridine (Aldrich; 4.00 g, 27.6 mmol) in DMSO (40 mL) was added KOH fine powder (4.64 g, 82.8 mmol) at room temperature. After stirring for 30 minutes, MeI (1.90 mL, 30.4 mmol) was added to a mixture at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 3 hours. The reaction mixture was poured into water (160 mL), and the resulting mixture was extracted with CH.sub.2Cl.sub.2 (80 mL) three times. The combined organic extracts were washed with water (120 mL) five times and brine, dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (CH.sub.2Cl.sub.2/MeOH = 20:1) to afford 2—(Me—imidazol-2-yl)pyridine (3.91 g, 24.3 mmol, 88%) as a colorless oil.
##STR00141##
[0311] To a stirred solution of 2—(Me—imidazol-2-yl)pyridine (5.85 g, 36.3 mmol) in dry THF (Baker; 160 mL, 0.2 M) was added NiCl.sub.2•DME (Stream; 7.98 g, 36.3 mmol) under inert atmosphere in glove box. The heterogeneous mixture was stirred at reflux for 24 hours out of glove box. The resulting mixture was cooled to room temperature and filtered through a glass filter funnel to collect the green solid. The resulting green solid was washed with Et.sub.2O. ground to fine powder, and dried under reduced pressure using drying pistol technique at 140° C. (xylenes) for 15 hours to afford py-(Me)imid.Math.Ni(II)Cl.sub.2 complex (9.27 g, 32.3 mmol, 89%).
Py-(Me)imid-NiBr2
[0312] ##STR00142##
To a stirred solution of 2-(Me-imidazol-2-yl)pyridine (546 mg, 3.38 mmol) in dry THF (Baker; 15.4 mL, 0.2 M) was added NiBr.sub.2•DME (Stream; 950 mg, 3.07 mmol) under inert atmosphere in glove box. The heterogeneous mixture was stirred at room temperature for 20 hours in glove box. The resulting mixture was filtered through a glass filter funnel to collect the yellow solid. The resulting solid was washed with Et.sub.2O, ground to fine powder, and dried under reduced pressure using drying pistol technique at 140° C. (xylenes) for 15 hours to afford py-(Me)imid.Math.Ni(II)Br.sub.2 complex (1.15 g, 3.07 mmol, quant.).
(Me).SUB.3.tpy.Math.Ni(II)Cl.SUB.2
[0313] ##STR00143##
To a stirred solution of 4,4′,4″-trimethyl-2,2′:6′,2″-terpyridine (Stream; 2.06 g, 7.49 mmol) in dry THF (Baker; 34 mL, 0.2 M) was added NiCl.sub.2•DME (Stream; 1.65 g, 7.49 mmol) under inert atmosphere in glove box. The heterogeneous mixture was stirred at reflux for 24 hours out of glove box. The resulting mixture was cooled to room temperature and filtered through a glass filter funnel to collect the blue solid. The resulting blue solid was washed with Et.sub.2O, ground to fine powder, and dried under reduced pressure using drying pistol technique at 140° C. (xylenes) for 15 hours to afford (Me)3tpy.Math.Ni(II)Cl.sub.2 complex (3.00 g, 7.44 mmol, 99%).
(dtbbpy)•NiCl.SUB.2
[0314] ##STR00144##
To a stirred solution of 4,4′-di-tert-butyl-2,2′-dipyridyl (Aldrich: 200 mg, 0.745 mmol) in dry THF (Baker; 3.4 mL, 0.2 M) was added NiCl.sub.2•DME (Stream; 164 mg, 0.745 mmol) under inert atmosphere in glove box. The heterogeneous mixture was stirred at reflux for 24 hours out of glove box. The resulting mixture was cooled to room temperature and filtered through a glass filter funnel to collect the blue solid. The resulting blue solid was washed with Et.sub.2O, ground to fine powder, and dried under reduced pressure using drying pistol technique at 140° C. (xylenes) for 15 hours to afford (dtbbpy).Math.NiCl.sub.2 complex (260 mg, 0.653 mmol, 88%).
(dtbbpy).Math.NiBr.SUB.2
[0315] ##STR00145##
To a stirred solution of 4,4′-di-tert-butyl-2,2′-dipyridyl (Aldrich: 957 mg, 3.56 mmol) in dry THF (Baker; 16 mL, 0.2 M) was added NiBr.sub.2•DME (Stream; 1.00 g, 3.24 mmol) under inert atmosphere in glove box. The heterogeneous mixture was stirred at room temperature for 24 hours in glove box.
[0316] The resulting mixture was cooled to room temperature and filtered through a glass filter funnel to collect the yellow solid. The resulting solid was washed with Et.sub.2O, ground to fine powder, and dried under reduced pressure using drying pistol technique at 140° C. (xylenes) for 15 hours to afford (dtbbpy).Math.NiBr.sub.2 complex (1.50 g, 3.08 mmol, 95%).
(Me).SUB.3.tpy•Ni(I)I
[0317] ##STR00146##
According to a procedure reported by Vicic.sup.15, to a stirred solution of 4,4′,4″-trimethyl-2,2′:6′,2″-terpyridine (Stream; 1.00 g, 3.63 mmol) in dry THF (Baker; 31 mL, 0.2 M) was added Ni(cod).sub.2 (Stream; 1.00 g, 3.63 mmol) under inert atmosphere in glove box. After stirring for 30 minutes, a solution of MeI (0.230 mL, 3.63 mmol) and THF (8 mL) was added slowly to the mixture. After further stirring for 5 hours, the mixture was diluted with dry pentane (Aldrich, 90 mL) out of glove box and stored in refrigerator overnight. The mixture was filtered through a glass filter funnel to collect the brown solid. The resulting solid was washed with hexane and Et.sub.2O, ground to fine powder, and dried under reduced pressure using drying pistol technique at 140° C. (xylenes) for 15 hours to afford (Me).sub.3tpy-Ni(I)I complex (1.67 g, 3.63 mmol, quant.).
Optimization Studies
[0318] The optimization of coupling condition was been started with the mixture of bidentate-ligand.Math.NiX.sub.2, (Me).sub.3tpy.Math.Ni(II)Cl.sub.2, and (Me).sub.3tpy-Ni(I)I. The tables below summarize the reaction optimization.
Evaluation of Nickel Catalysts
[0319] ##STR00147##
TABLE-US-00005 entry (dtbppy).Math.NiBr.sub.2 (mol%) py-(Me)imid.Math.Ni(II)Cl.sub.2 (mol%) (Me).sub.3tpy.Math.Ni(II)Cl.sub.2 (mol%) (Me).sub.3tpy.Math.Ni(I)I (mol%) yield′ (%) 1 20 none none none 58 2 20 none 5 none 69 3 none 20 none none 48 4 none 20 5 none 86 5 none 20 none 5 88 DMA = N,N-Dimethytacetemide DME = 1.2-Dimethoxyethane *Isolated yields.
Evaluation of Substrate Ratios for 3
[0320] ##STR00148##
TABLE-US-00006 entry 1 (equiv) 2 (equiv) yield* (%) 1 1.2 1.0 92 2 1.1 1.0 89 3 1.0 1.0 86 4 1.0 1.1 87 5 1.0 1.2 88 *Isolated yields.
Evaluation of Solvents and Concentrations for 3
[0321] ##STR00149##
TABLE-US-00007 entry solvents (1/1) concentration [C] yield (%)* 1 DMF/DME 0.5 M 65 2 DMI/DME 0.5 M 80 3 DMA/THF 0.5 M 75 4 DMA/1,4-dioxane 0.5 M 82 5 DMA/DME DMA/ 0.5 M 86 6 DME DMA/DME 0.2 M 82 7 0.1 M 77 DMF = N,N-Dimethyliomamide DMI = 1,8-Dimethyl-2-imidazolidinone Isolated yields.
Evaluation of Catalytic Loadings
[0322] ##STR00150##
TABLE-US-00008 entry py-(Me)imid.Math.Ni(II)Cl.sub.2 (mol%) (Me).sub.3tpy.Math.Ni(II)Cl.sub.2 (mol%) (Me).sub.3tpy.Math.Ni(II) (mol%) time (h) yield* (%) 1 20 5 none 1 86 2 20 none 5 1 88 3 27 none 5 1 71 4 5 none 5 1 90 5 5 none 1 3 96 6 1 none 5 3 91 7 1 none 1 3 96 8 1 1 none 3 87 9 2 none none 3 46 10 none none 2 3 22 *Isolated yields.
[0323] From the above screens, it was found that (Me).sub.3tpy.Math.Ni(I)I was better than (Me).sub.3tpy.Math.Ni(H)Cl.sub.2 in obtaining higher yields.
Comparison of Zinc and Manganese as Reductant
[0324] ##STR00151##
TABLE-US-00009 entry reductant X (equiv) Y (equiv) yield* (%) 1 Zn 1.1 1.0 96 2 Zn 1.0 1.0 96 3 Zn 1.0 1.1 94 4 Mn 1.1 1.0 85 5 Mn 1.0 1.0 85 6 Mn 1.0 1.1 84 *Isolated yleids.
Relationship of Catalyst Loadings and Concentrations for S2
[0325] ##STR00152##
TABLE-US-00010 entry [C] M X mol% Y mol% yield (%)* 1 05 1 1 85 2 0.2 1 1 poor conversion 3 0.2 5 5 87 4 0.1 10 10 76 5 0.1 20 10 79 6 0.1 20 5 85 7 0.1 25 5 86 *Isolated yields.
Evaluation of Substrate Ratios for S2
[0326] ##STR00153##
TABLE-US-00011 entry 1 (equiv) 81 (equiv) yield * (%) 1 1.1 1.0 91 2 1.0 1.0 85 3 1.0 1.1 83 *Isolated yields.
Evaluation of Bidentate Ligand.Math.Ni(II) Complexes
[0327] ##STR00154##
TABLE-US-00012 entry (bidentate)NiX.sub.2 yield (%)* 1 py-(Me)imid-Ni(II)Cl.sub.2 96 2 py-(Me)imid.Math.Ni(II)Br.sub.2 69 3 (dtbbpy).Math.NiCl.sub.2 79 4 (dtbbpy).Math.NiBr.sub.2 63 *Isolated yields.
Evaluation of Terpyridine.Math.Ni Complexes
[0328] ##STR00155##
TABLE-US-00013
Evaluation of Additives
[0329] ##STR00162##
TABLE-US-00014 entry additive yield (%) * 1 Cp.sub.2ZrCl.sub.2 96 2 Cp.sub.2TiCl.sub.2 complex mixture 3.sup.b (Cp.sub.2ZrCl).sub.2 62 .sup.a Isolated yields. .sup.b THF was used instead of DME. Reaction was carried out for 8 h.
Preparation of (Cy.SUB.2.ZrCl).SUB.2
[0330] According to a procedure reported by Schwartz.sup.16, to a stirred colorless solution of Cp.sub.2ZrCl.sub.2 (145 mg, 0.500 mmol) in dry THF (Baker; 0.5 mL) was added 20% Na(Hg) (60.0 mg, 0.525 mmol) under inert atmosphere in glove box and the mixture was stirred for 14 hours. The resulting deep red mixture was used for the ketone-coupling in entry 3 without further purification.
Effects of Cp.SUB.2.ZrCl.SUB.2 for 3
[0331] ##STR00163##
[0332] It was discovered that the Cp.sub.2ZrCl.sub.2 enhanced the coupling rate and decreased the productions of ester S3 and dimer 4.
Procedure for the Reaction in Entry 5
[0333] To a solution of iodide 1 (37.3 mg, 0.165 mmol, 1.0 equiv) and thiopyridine ester 2 (45.0 mg, 0.165 mmol, 1.0 equiv) in DMA (0.17 mL) and DME (0.17 mL) were added py-(Me)imid.Math.Ni(II)Cl.sub.2 (0.50 mg, 1.65 .Math.mol, 1 mol%) and (Me).sub.3tpy.Math.Ni(I)I (0.80 mg, 1.65 .Math.mol, 1 mol%) in the absence of Cp.sub.2ZrCl.sub.2. After stirring for 1 minute, Zn powder (32.4 mg, 0.495 mmol, 3.0 equiv) was added at room temperature. After being stirred at the same temperature for 6 hours, the reaction mixture was diluted with Et.sub.2O and sat. NaHCO.sub.3 aq. The organic layer was separated and the aqueous layer was extracted with Et.sub.2O five times. The combined organic layer was washed with water three times and brine one time, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography on silica gel to give ketone 3 (31.6 mg, 0.121 mmol, 73%), ester S3 (6.00 mg, 0.023 mmol, 14%), and dimer 4 (0.70 mg, 0.007 mmol, 4%).
Effects of Cp.SUB.2.ZrCl.SUB.2 with Different Acyl Derivatives
[0334] ##STR00164##
TABLE-US-00015 entry x = time (h) Cp.sub.2ZrCl.sub.2 (X mol%) 3 (%) S3 (%) 4 (%) 1
##STR00169##
Mechanistic Studies
Hydrozirconation/Ketone Coupling
[0335] ##STR00170##
##STR00171##
[0336] In a glove box, to a solution of olefin (i or ii) in THF was added Cp.sub.2ZrHCl (1.0-1.1 equiv). After stirring for 20 hours, a mixture of thiopyridine ester 2, catalysts, and Zn in DMA (0.42 mL) were added. After being stirred at the same temperature for 4 hours, the reaction mixture was removed from glove box and diluted with Et.sub.2O and sat. NaHCO.sub.3 aq. (1 mL). The organic layer was separated and the aqueous layer was extracted with Et.sub.2O five times. The combined organic layer was washed with water three times and brine one time, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The no ketone formations were detected from .sup.1H-NMR analysis of the crude materials.
Consumption Rate of Thiopyridine Ester 2
[0337] ##STR00172##
TABLE-US-00016 entry catalyst time (h) recovered yield.sup.1 of 2 (%) 1 none 14 97 2 (dtbbpy).Math.NiBr.sub.2 0.5 93 3 3 85 4 14 72 5 py-(Me)imid.Math.Ni(II)Cl.sub.2 0.5 89 6 3 64 7 14 11 8 .sup.2 14 79 9 .sup.3 14 87 10 (Me).sub.3tpy.Math.(II)I 0.5 99 11 3 96 12 14 78 13 .sub.4 py-(Me)imid.Math.Ni(COD).sub.2 0.5 0 14 .sub.4 dtbby.Math.Ni(COD).sub.2 0.5 0 15 .sub.4 (Me).sub.3ipy.Math.Ni(COD).sub.2 0.5 0 .sup.1 *Isolated yields. .sup.2 Without Cp.sub.2ZrCl.sub.2.sup.3 Without Zn. .sup.4 1 Equivalent of ligand.Math.Ni(COD).sub.2 was used without Zn. The reactions were carried out at 0.2 M.
Coupling of Bromide
[0338] ##STR00173##
TABLE-US-00017 entry py-(Me)imid.Math.Ni(II)Cl.sub.2 (mol%) (dtbbpy.Math.NiBr.sub.2 (mol%) (Me).sub.3tpy.Math.Ni(II)I (mol%) yield(%).sup.* 1 2 none none <1 2 none 2 none <1 3 none none 2 9 4 1 none 1 24 5 1 none 5 28 .sup.*Isolated yields.
##STR00174##
β-Elimination and Dimerization of Bromide
[0339] ##STR00175##
TABLE-US-00018 entry catalyst time (h) bromide 4 .sup.1 (%) 5 .sup.2 (%) 1 none 18 no conversion 0 0 2 py-(Me)imid.Math.Ni(II)Cl.sub.2 9 poor conversion <1 <1 3 (dtbbpy).Math.NiBr.sub.2 poor conversion <1 <1 4 (Me).sub.3tpy.Math.Ni(II)I 9 9 consumed poor 19 detected 5 .sup.3 py-(Me)imid.Math.Ni(COD).sub.2 1 conversion poor <1 <1 6 .sup.3 dtbbpy.Math.Ni(COD).sub.2 1 conversion <1 <1 7 .sup.3 (Me).sub.3tpy.Math.Ni(COD).sub.2 1 consumed 33 detedcted .sup.1 Isolated yields. .sup.2 Not *Isolated .sup.3 1 Equivalent of ligand.Math.Ni(COD).sub.a was used without Zn. The reactions were carried out at 0.2 M.
β-Elimination and Dimerization of Iodide
[0340] ##STR00176##
TABLE-US-00019 entry reductant catalyst (mol%) time (h) 1, lodide (%) 4 .sup.1 (%) 5 .sup.2 (%) 1 Zn none 2 0 0 only detectable 2 Zn (Me).sub.3tpy.Math.Ni(I)I 2 0 20 ∼80 3.sup.3 Zn (Me).sub.3tpy.Math.Ni(I)I 2 0 72 ∼28 4 Mn none 4 no conversion 0 0 5 Mn (Me).sub.3tpy.Math.M(I)I 14 0 66 ∼34 6.sup.3 none (Me).sub.3tpy.Math.Ni(I)I 8 no conversion 0 0 7.sup.3 none (Me).sub.3tpy.Math.Ni(COD).sub.2 1.5 0 55 ∼45 .sup.1 *Isolated yield. .sup.2Not Isolated. .sup.3 1 Equivalent of ligand.Math.Ni was used. Reactions were carried out at 0.2 M.
Stoichiometric Ni(COD).SUB.2 mediated-Coupling
[0341] ##STR00177##
TABLE-US-00020 entry ligand 1 .sup.1 (%) 2 .sup.1 (%) 3 .sup.2 (%) 4 .sup.2 (%) 1 py-(Me)imid 40 0 55 <1 2 dtbppy 50 0 46 <1 3 (Me).sub.3tpy 0 18 26 40 .sup.1Recovered yields. .sup.2isolated yields.
##STR00178##
In a glove box, to a solution of ligand (1.0 equiv) in DMA (0.42 mL) was added Ni(COD).sub.2 (45.1 mg, 0.165 mmol, 1.0 equiv). After stirring for 30 minutes, a mixture of iodide 1 (37.3 mg, 0.165 mmol, 1.0 equiv) and thiopyridine ester 2 (45.0 mg, 0.165 mmol, 1.0 equiv) in DME (0.42 mL) were added. After being stirred at the same temperature for 30 minutes, the reaction mixture was removed from glove box and diluted with Et.sub.2O and sat. NaHCO.sub.3 aq. (1 mL). The organic layer was separated and the aqueous layer was extracted with Et.sub.2O five times. The combined organic layer was washed with water three times and brine one time, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography on silica gel to give products and starting materials.
Evaluation of Negishi-Coupling Pathway
[0342] ##STR00179##
##STR00180##
TABLE-US-00021 entry reactants time (n) 3* (%) 7e* (%) 1
Experimental Evidence of a Radical Pathway
Radical Ring-Opening/Ketone Coupling
[0343] ##STR00182##
In a glove box, to a solution of iodomethylcyclopropane S5 (30.0 mg, 0.165 mmol, 1.0 equiv) and thiopyridine ester 2 (45.0 mg, 0.165 mmol, 1.0 equiv) in DMA (0.17 mL) and DME (0.17 mL) were added py-(Me)imid.Math.Ni(II)Cl.sub.2 (0.50 mg, 1.65 .Math.mol, 1 mol%), (Me).sub.3tpy.Math.Ni(I)I (0.80 mg, 1.65 .Math.mol, 1 mol%), and Cp.sub.2ZrCl.sub.2 (48.2 mg, 0.165 mmol, 1.0 equiv). After stirring for 1 minute, Zn powder (32.4 mg, 0.495 mmol, 3.0 equiv) was added at room temperature. After being stirred at the same temperature for 3 hours, the reaction mixture was removed from glove box and diluted with Et.sub.2O (1 mL) and sat. NaHCO.sub.3 aq. (1 mL). The organic layer was separated and the aqueous layer was extracted with Et.sub.2O (1 mL) five times. The combined organic layer was washed with water (1 mL) three times and brine (1 mL) one time, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography on silica gel to give S6 (21.4 mg, 0.098 mmol, 59%) as colorless oil.
Radical 5-exo-trig Cyclization/Ketone Coupling.SUP.17
[0344] ##STR00183##
In a glove box, to a solution of iodide S7 (41.9 mg, 0.165 mmol, 1.0 equiv) and thiopyridine ester 2 (45.0 mg, 0.165 mmol, 1.0 equiv) in DMA (0.17 mL) and DME (0.17 mL) were added py-(Me)imid.Math.Ni(II)Cl.sub.2 (0.50 mg, 1.65 .Math.mol, 1 mol%), (Me).sub.3tpy.Math.Ni(l)I (0.80 mg, 1.65 .Math.mol, 1 mol%), and Cp.sub.2ZrCl.sub.2 (48.2 mg, 0.165 mmol, 1.0 equiv). After stirring for 1 minute, Zn powder (32.4 mg, 0.495 mmol, 3.0 equiv) was added at room temperature. After being stirred at the same temperature for 3 hours, the reaction mixture was removed from glove box and diluted with Et.sub.2O (1 mL) and sat. NaHCO.sub.3 aq. (1 mL). The organic layer was separated and the aqueous layer was extracted with Et.sub.2O (1 mL) five times. The combined organic layer was washed with water (1 mL) three times and brine (1 mL) one time, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography on silica gel to give S8 (27.1 mg, 0.923 mmol, 57%) as colorless oil.
Ketone Coupling in the Halichondrin Synthesis
[0345] ##STR00184##
General Procedure for 3
[0346] ##STR00185##
In a glove box, to a solution of iodide 1 (37.3 mg, 0.165 mmol, 1.00 equiv) and thiopyridine ester 2 (45.0 mg, 0.165 mmol, 1.00 equiv) in DMA (0.17 mL) and DME (0.17 mL) were added py-(Me)imid-Ni(II)Cl.sub.2 (0.50 mg, 1.65 .Math.mol, 1 mol%), (Me).sub.3tpy.Math.Ni(I)I (0.80 mg, 1.65 .Math.mol, 1 mol%), and Cp.sub.2ZrCl.sub.2 (48.2 mg, 0.165 mmol, 1.0 equiv). After stirring for 1 minute, Zn powder (32.4 mg, 0.495 mmol, 3.0 equiv Sigma-aldrich, used without any activation) was added at room temperature. After being stirred at the same temperature for 3 hours, (monitored by TLC), the reaction mixture was removed from glove box and diluted with Et.sub.2O (1 mL) and sat. NaHCO.sub.3 aq. (1 mL). The organic layer was separated and the aqueous layer was extracted with Et.sub.2O (1 mL) five times. The combined organic layer was washed with water (1 mL) three times and brine (1 mL) one time, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The obtained crude material was purified by flash column chromatography (hexanes/AcOEt = 5:1) on silica gel to afford ketone 3 (41.6 mg, 0.159 mmol, 96°fo) as colorless oil.
Final Ketone Coupling in the Halichondrin Synthesis
[0347] ##STR00186##
In a glove box, to a solution of iodide 8 (100 mg, 0.101 mmol, 1.00 equiv), thiopyridine ester 9 (72.0 .Math.g, 0.101 .Math.mol, 1.00 equiv), and DTBMP (51.9 mg, 0.253 mmol, 2.5 equiv) in DMA (0.26 mL) and DME (0.26 mL) were added py-(Me)imid.Math.Ni(II)Cla (5.8 .Math.g, 0.0202 .Math.mol, 20 mol%), (Me).sub.3tpy.Math.Ni(I)I (2.3 .Math.g, 0.00505 .Math.mol, 5 mol%), and Cp.sub.2ZrCl.sub.2 (29.5 mg, 0.101 mmol, 1 equiv) at room temperature. After stirring for 1 minute, Zn (39.6 mg, 0.606 mmol, 6.0 equiv Sigma-aldrich, used without any activation) was added to a mixture. After further stirring for 90 minutes, the reaction was quenched with a mixture of saturated aqueous NaHCO.sub.3 and water (1/1), and the resulting mixture was extracted with EtOAc five times. The combined organic extracts were dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using YAMAZEN (hexanes/AcOEt = 3:1) to afford ketone 10 (119 mg, 0.0818 mmol, 81%) as a colorless amorphous solid.
Characterization Data
2-Methyl-1H-imidazol-2-yl)pyridine
[0348] ##STR00187##
IR (film) 3105, 1588, 1490, 1462, 1278, 1034, 790, 742, 707 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 8.66-8.49 (m, 1H), 8.18 (dt, J = 8.1, 1.2 Hz, 1H), 7.75 (ddd, J = 9.5, 7.1, 1.7 Hz, 1H), 7.21 (ddd, J = 7.6, 4.9, 1.3 Hz, 1H), 7.12 (d, J = 1.4 Hz, 1H), 6.97 (s, 1H), 4.13 (d, J= 1.2 Hz, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 150.79, 148.19, 144.96, 136.55, 128.18, 124.37, 122.64, 122.33, 36.28; HRMS (ESI) m/z calc. for C.sub.9H.sub.10O.sub.3 [M+H]+ 160.0875; found 160.0864.
4-Methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)butan-2-one, 3
[0349] ##STR00188##
3 was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 5:1) to afford 3 (41.6 mg, 0.159 mmol, 96%) as a colorless oil. IR (film) 2934, 2849, 1712, 1612, 1513, 1441, 1300. 1246, 1178, 1087, 1043, 828 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.09 (d, J= 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 3.91 (d,J=11.4 Hz, 1H), 3.78 (s, 3H), 3.77-3.72 (m, 1H), 3.41 (t, J =1 0.8 Hz, 1 H), 2.83 (t,J=7.8 Hz, 2H), 2.74 (q, J = 5.4 Hz, 2H), 2.64 (dd, J =15.6 Hz, 7.8 Hz, 1H), 2.36 (dd, J = 15.6 Hz, 5.2 Hz, 1H), 1.80 (d, J = 5.2 Hz, 1H), 1.58 (d, J=12.6 Hz, 1H), 1.53-1.46 (m, 3H), 1.29-1.21 (m, 1H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 210.2, 158.1, 135.7, 133.9, 133.3, 129.8, 129.3, 127.8, 114.0, 63.1, 55.4, 44.7, 39.5, 29.1, 27.0, 26.7, 19.3; HRMS (ESI) m/z calc. for C.sub.16H.sub.23O.sub.3 [M+H]+ 263.1642; found 263.1649.
1,2-Bis(tetrahydro-2H-pyran-2-yl)ethane, 4
[0350] ##STR00189##
Colorless oil. IR (film) 2930, 2838, 1086, 1047, 897 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 4.14-3.86 (m, 2H), 3.42 (td, J = 11.6, 2.3 Hz, 2H), 3.32-3.08 (m, 2H), 1.82 (dt, J = 13.2, 2.9 Hz, 2H), 1.54 (dddd, J= 49.2, 16.8, 7.2, 3.7 Hz, 11H), 1.34-1.15 (m, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 78.14, 77.26, 68.47, 32.91, 32.10, 31.99, 31.76, 26.23, 23.60, 23.58; HRMS (ESI) m/z calc. for C.sub.12H.sub.23O.sub.2 [M+H].sup.+ 199.1698; found 199.1687.
1-(2,2-Dimethyl-1,3-dioxolan-4-yl)-4-(4-methoxyphenyl)butan-2-one, 7a
[0351] ##STR00190##
7a was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 5:1) to afford 7a (44.0 mg, 0.158 mmol, 96%) as a colorless oil. IR (film) 3035, 2988, 2935, 1711, 1612, 1513, 1478, 1370, 1246, 1178, 1058, 1036, 829, 669 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.09 (d, J= 8.5 Hz, 2H), 6.81 (d, J= 8.5 Hz, 2H), 4.44 (quin, J= 6.0 H, 1H), 4.15 (dd, J= 8.5 Hz, 8.0 Hz, 1H), 3.77 (s, 3H), 3.50 (dd, J = 8.5 Hz, 8.0 Hz, 1H), 2.88-2.80 (m, 3H), 2.76-2.71 (m, 2H), 2.52 (dd, J= 16.5 Hz, 7.0 Hz, 1H) 1.38 (s, 3H), 1.33 (s, 3H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 207.8, 158.0, 132.8, 129.2, 113.9, 108.8, 71.7, 69.4, 55.2, 47.2, 45.2, 28.7, 26.9, 25.5; HRMS (ESI) m/z calc. for C.sub.16H.sub.22NaO.sub.4 [M+Na]+ 301.1410; found 301.1425.
tert-Butyl(S)-2-(4-(4-methoxyphenyl)-2-oxobutyl)pyrrolidine-1-carboxylate, 7b
[0352] ##STR00191##
7b was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 4:1) to afford 7b (51.6 mg, 0.149 mmol, 90%) as a colorless oil.
IR (film) 2971, 1685, 1512, 1391, 1364, 1243, 1166, 1107, 1034, 827, 772 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.10 (d,J= 8.5 Hz, 2H), 6.82 (d, J= 8.6 Hz, 2H), 4.14 (d, J = 10.3 Hz, 1H), 3.79 (s, 3H), 3.32 (d, J= 6.6 Hz, 2H), 2.78 (dt, J = 60.4, 7.6 Hz, 2H), 2.69 (dd, J = 16.1, 9.7 Hz, 2H), 2.37 (dd, J = 16.1, 9.7 Hz, 1H), 2.03 (dq, J = 12.7, 8.1 Hz, 1H), 1.78 (ddd, J= 9.1, 6.4, 3.9 Hz, 2H), 1.59 (dtd, J = 12.6, 5.6, 3.3 Hz, 1H), 1.45 (s, 10H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 208.71, 157.94, 154.27, 133.03, 129.23, 113.87, 79.33, 55.25, 53.43, 47.34, 46.33, 44.97, 31.09, 28.83, 28.53, 23.28; HRMS (ESI) m/z calc. for C.sub.20H.sub.30NO.sub.4 [M+H].sup.+ 348.2175; found 348.2240.
tert-Butyl(RH5-(4-methoxyphenyl)-3-oxo-1-phenylpentyl)carbamate, 7c
[0353] ##STR00192##
7c was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 5:1) to afford 7c (60.5 mg, 0.158 mmol, 96%) as a white solid.
[a]t2= 14.7 (c 0.3, CHCl.sub.3); IR (film) 3376, 2979, 2932, 1707, 1612, 1513, 1455, 1366, 1247, 1175, 1037, 819, 701 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.33-7.29 (m, 2H), 7.27-7.22 (m, 3H), 7.00 (d, J= 8.4 Hz, 2H), 6.78 (d, J= 8.4 Hz, 2H), 5.46 (brs, 1H), 5.07 (brs, 1H), 3.78 (s, 3H), 3.00 (brs, 1H), 2.85 (dd, J = 17.4 Hz, 4.3 Hz, 1H), 2.73 (t, J =7.8 Hz, 2H), 2.69-2.62 (m, 1H), 2.59-2.52 (m, 1H), 1.41 (s, 9H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 208.5, 158.1, 155.3, 141.7, 132.9, 129.3, 128.8, 127.5, 126.4, 114.0, 79.9, 55.4, 51.3, 48.8, 45.4, 28.7, 28.5; HRMS (ESI) m/z calc. for C.sub.23H.sub.29NNaO.sub.4 [M+Na].sup.+ 406.1989; found 406.1980.
tert-Butyl(S)-(6-(4-methoxyphenyl)-oxo-1-phenylhexan-2-yl)carbamate, 7d
[0354] ##STR00193##
7d was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes: EtOAc = 5.1) to afford 7d (60.9 mg, 0.153 mmol, 93%) as a white solid.
-5.7 (c 1.1, CHCl.sub.3); IR (film) 3360, 2977, 2931, 1708, 1612, 1513, 1455, 1391, 1366, 1301, 1247, 1174, 1109, 1077, 1037, 824, 778, 702 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.29-7.25 (m, 2H), 7.21 (t, J= 7.2 Hz, 1H), 7.10 (d, J = 7.2 Hz, 2H), 7.08 (d,J= 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 5.04 (brs, 1H), 4.11 (brs, 1H), 3.78 (s, 3H), 2.91 (brs, 1H), 2.84-2.75 (m, 3H), 2.71-2.58 (m, 2H), 2.54 (d, J =4.9 Hz, 2H), 1.40 (s, 9H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 209.5, 158.1, 155.4, 138.2, 132.9, 129.4, 129.3, 128.7, 126.7, 114.1, 79.5, 55.4, 48.9, 45.6, 45.1, 40.4, 28.8, 28.5; HRMS (ESI) m/z calc. for C.sub.24H.sub.32NO.sub.4 [M+H].sup.+ 398.2331; found 398.2326.
1-Methoxyphenyl)-5-phenylpentan-3-one, 7e
[0355] ##STR00194##
7e was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 10:1) to afford 7e (40.9 mg, 0.152 mmol, 92%) as a colorless oil. IR (film) 3061, 3027, 2932, 2835, 1712, 1611, 1512, 1247, 1035, 823 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.35-7.25 (m, 2H), 7.25-7.14 (m, 3H), 7.10 (dd, J = 8.4, 1.5 Hz, 2H), 6.91-6.74 (m, 2H), 3.80 (s, 3H), 2.88 (dt,J = 25.9, 7.6 Hz, 4H), 2.79-2.55 (m, 4H); .sup.13C NMR (126 MHz,CDCl.sub.3) δ = 209.26, 157.97, 141.04, 133.03, 129.24, 128.49, 128.31, 126.10, 113.91, 55.26, 44.78, 44.55, 29.73, 28.91; HRMS (ESI) m/z calc. for C.sub.18H.sub.21O.sub.2 [M+H].sup.+ 269.1542; found 269.1503.
1-(1H-Indol-3-yl)-5-(4-methoxyphenyl)pentan-3-one, 7f
[0356] ##STR00195##
7f was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 4:1) to afford 7f (45.6 mg, 0.148 mmol, 90%) as a white solid. IR (film) 3409, 2930, 1706, 1511, 1456, 1244, 1178, 1092, 1033, 822, 743 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.98 (br, 1H), 7.57 (dq, J= 7.9, 1.0 Hz, 1H), 7.35 (dt, J= 8.2, 0.9 Hz, 1H), 7.21 (ddd, J= 8.1, 7.0, 1.3 Hz, 1H), 7.13 (ddd, J= 8.0, 7.0, 1.1 Hz, 1H), 7.10-7.00 (m, 2H), 6.94 (dd, J= 2.3, 1.1 Hz, 1H), 6.86-6.67 (m, 2H), 3.79 (s, 3H), 3.05 (ddd, J= 7.6, 6.9, 0.9 Hz, 2H), 2.82 (dt, J= 20.0, 7.4 Hz, 4H), 2.69 (dd, J= 8.1, 7.0 Hz, 2H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 210.13, 157.91, 136.27, 133.09, 129.25, 127.14, 122.03, 121.52, 119.29, 118.68, 115.16, 113.86, 111.16, 55.27, 44.74, 43.46, 28.93, 19.33; HRMS (ESI) m/z calc. for C.sub.20H.sub.22NO.sub.2 [M+H].sup.+ 308.1651; found 308.1620.
1-Methoxyphenyl)-5,5-dimethylhexan-3-one, 7 g
[0357] ##STR00196##
7 g was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc =10:1) to afford 7 g (34.8 mg, 0.149 mmol, 90%) as a colorless oil. IR (film) 2953, 1708, 1512, 1363, 1244, 1177, 1035, 824 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.09 (d, J= 8.6 Hz, 2H), 6.82 (d, J= 8.6 Hz, 2H), 3.78 (s, 3H), 2.81 (t, J = 7.6 Hz, 2H), 2.74-2.57 (m, 2H), 2.28 (s, 2H), 0.99 (s, 9H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 210.17, 157.95, 133.35, 129.34, 113.90, 55.33, 55.28, 46.98, 31.13, 29.81, 28.90; HRMS (ESI) m/z calc. for C.sub.15H.sub.23O.sub.2 [M+H].sup.+ 235.1698; found 235.1959.
1-Cyclohexyl-3(4-methoxyphenyl)propan-1-one, 7h
[0358] ##STR00197##
7h was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 10:1) to afford 7h (36.6 mg, 0.149 mmol, 90%) as a colorless oil. IR (film) 2927, 2852, 1703, 1511, 1243, 1176, 1034, 822 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.11 (d,J= 8.6 Hz, 2H), 6.83 (dd,J= 8.5, 1.3 Hz, 2H), 3.80 (d, J = 1.2 Hz, 3H), 2.84 (t, J = 7.5 Hz, 2H), 2.79-2.62 (m, 2H), 2.44-2.14 (m, 1H), 1.94-1.72 (m, 4H), 1.67 (dp, J= 11.8, 4.1, 2.7 Hz, 1H), 1.50-1.01 (m, 5H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 213.27, 157.89, 133.47, 129.24, 113.84, 55.25, 50.99, 42.50, 28.87, 28.40, 25.86, 25.66; HRMS (ESI) m/z calc. for C.sub.16H.sub.23O.sub.2 [M+H].sup.+ 247.1698; found 247.1744.
4-(4-Methoxyphenyl)-3-oxopentyl)phenyl-trifluoromethanesulfonate, 7i
[0359] ##STR00198##
7i was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 5:1) to afford 7i (57.8 mg, 0.139 mmol, 84%) as a colorless oil. IR (film) 1713, 1512, 1417, 1247, 1208, 1137, 885, 728, 608 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.26-7.20 (m, 2H), 7.21-7.14 (m, 2H), 7.13-6.99 (m, 2H), 6.91-6.70 (m, 2H), 3.80 (s, 3H), 2.92 (t, J= 7.4 Hz, 2H), 2.85 (t, J= 7.5 Hz, 2H), 2.71 (td, J= 7.4, 4.9 Hz, 4H), .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 208.55, 158.01, 147.90, 141.73, 132.81, 130.14, 129.23, 121.26, 120.01, 117.46, 113.92, 113.88, 55.24, 44.71, 44.06, 28.90, 28.81; HRMS (ESI) m/z calc. for C.sub.19H.sub.20F.sub.3NaO.sub.5S [M+H].sup.+ 439.0803; found 439.0832.
1-Bromophenyl)-5-methoxyphenyl)pentan-3-one, 7j
[0360] ##STR00199##
7j was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 10:1) to afford 7j (47.3 mg, 0.136 mmol, 83%) as a colorless oil. IR (film) 2931, 1711, 1511, 1487, 1243, 1177, 1034, 1010, 814, 516 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.45-7.31 (m, 2H), 7.06 (dd, J = 19.4, 8.1 Hz, 4H), 6.83 (d, J = 8.3 Hz, 2H), 3.80 (d, J = 1.2 Hz, 3H), 2.84 (t. J = 7.5 Hz, 4H), 2.68 (t, J = 7.5 Hz, 4H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 208.83, 157.98, 140.04, 132.89, 131.50, 130.13, 129.23, 119.84, 113.91, 55.27, 44.76, 44.21, 29.01, 28.89; HRMS (ESI) m/z calc. for C.sub.18H.sub.20BrO.sub.2 [M+H].sup.+ 347.0647; found 347.0601.
1-Lodophenyl)-5-methoxyphenyl)pentan-3-one, 7k
[0361] ##STR00200##
7k was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 10:1) to afford 7k (40.0 mg, 0.101 mmol, 61%) as a colorless oil. IR (film) 2929, 1710, 1510, 1242, 1176, 1033, 1005, 809, 513 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.59 (d, J= 7.9 Hz, 2H), 7.15 - 7.00 (m, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H), 3.80 (s, 3H), 2.84 (td, J= 7.6, 4.4 Hz, 4H), 2.68 (t,J= 7.4 Hz, 4H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 208.82, 157.98, 140.72, 137.49, 132.89, 130.48, 129.23, 113.91, 91.15, 55.28, 44.76, 44.18, 29.11, 28.89; HRMS (ESI) m/z calc. for C.sub.18H.sub.20IO.sub.2 [M+H].sup.+ 395.0508; found 395.0535.
1-Hydroxyphenyl)-5-methoxyphenyl)pentan-3-one, 71
[0362] ##STR00201##
71 was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 10:1) to afford 71 (39.8 mg, 0.139 mmol, 85%) as a colorless oil. IR (film) 3380, 2931, 1701, 1611, 1511, 1442, 1243, 1177, 1033, 825, 542 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.08 (d,J= 8.6 Hz, 2H), 7.02 (d,J= 8.4 Hz, 2H), 6.83 (d,J= 8.5 Hz, 2H), 6.75 (d, J= 8.4 Hz, 2H), 5.30 (br, 1H), 3.80 (s, 3H), 2.83 (q, J= 7.1 Hz, 4H), 2.69 (td, J= 7.5, 3.0 Hz, 4H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 210.20, 157.91, 154.02, 133.00, 132.90, 129.41, 129.25, 115.34, 113.93, 55.30, 44.82, 28.90 (Two signals are missing due to overlap); HRMS (ESI) m/z calc. for C.sub.18H.sub.20NaO.sub.3 [M+Na].sup.+ 307.1310; found 307.1320.
Ketone, 10
[0363] ##STR00202##
All analytical data for 10 was in accordance with our previous literature.sup.18.
1,3-Bis(tetrahydro-2H-pyran-2-yl)propan-2-one, S2
[0364] ##STR00203##
S2 was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 4:1) to afford S2 (31.7 mg, 0.140 mmol, 85%) as a colorless oil. IR (film) 2933, 2487, 1713, 1440, 1378, 1356, 1203, 1175, 1088 cm.sup.-1; .sup.1M NMR (500 MHz, CDCl.sub.3) δ = 3.91 (d, J= 9.2 Hz, 2H), 3.79-3.73 (m, 2H), 3.43 (dd, J= 11.2, 10.8 Hz, 2H), 2.67 (dd, J= 14.8, 5.8 Hz, 2H), 2.44 (dd, J= 14.8, 5.8 Hz, 2H), 1.80 (d, J= 7.2 Hz, 2H), 1.62-1.58 (m, 3H), 1.52-1.46 (m, 5H), 1.30-1.21 (m, 2H), .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 207.7, 74.1, 68.7, 50.6, 50.4, 31.9, 25.9, 23.5; HRMS (ESI) m/z calc. for C.sub.13H.sub.22NaO.sub.3 [M+Na].sup.+ 249.1467; found 249.1460.
Hexen-1-yl 3-(4-methoxyphenyl)propanoate, S3
[0365] ##STR00204##
Colorless oil. IR (film) 2935, 1729, 1512, 1244, 1175, 1034, 911, 824 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ= 7.14 (dd, J= 8.8, 0.7 Hz, 2H), 6.84 (d, J= 8.5 Hz, 2H), 5.80 (ddt, J= 16.9, 10.2, 6.7 Hz, 1H), 5.15-4.88 (m, 2H), 4.08 (t, J = 6.6 Hz, 2H), 3.80 (d, J= 0.6 Hz, 3H), 2.91 (t, J= 7.8 Hz, 2H), 2.61 (dd, J= 8.2, 7.3 Hz, 2H), 2.20-1.94 (m, 2H), 1.73-1.55 (m, 2H), 1.43 (tt,J= 9.9, 6.5 Hz, 2H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 173.04, 158.05, 138.34, 132.61, 129.22, 114.80, 113.87, 64.35, 55.23, 36.22, 33.27, 30.16, 28.06, 25.17; HRMS (ESI) m/z calc. for C.sub.16H.sub.23O.sub.3 [M+H].sup.+ 263.1647; found 263.1683.
1-Methoxyphenyl)hept-6-en-3-one, S6
[0366] ##STR00205##
S6 was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 20:1 ) to afford S6 (21.4 mg, 0.098 mmol, 59%) as a colorless oil. IR (film) 2926, 1753, 1612, 1513, 1442, 1365,1301, 1246, 1178, 1109, 1036, 911, 829 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.09 (d, J= 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 5.83-5.73 (m, 1H), 5.01 (dd, J= 17.5 Hz, 1.4 Hz, 1H), 4.97 (dd, J= 10.0 Hz, 1.4 Hz, 1H), 3.78 (s, 3H), 2.84 (t,J=7.5 Hz, 2H), 2.70 (t,J= 7.5 Hz, 2H), 2.48 (t, J=7.5 Hz, 2H), 2.31 (q, J=7.5 Hz, 2H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 209.4, 158.0, 137.1, 133.1, 129.2, 115.2, 114.0, 55.3, 44.6, 42.0, 28.9, 27.7; HRMS (ESI) m/z calc. for C.sub.14H.sub.19O.sub.2 [M+H].sup.+ 219.1380; found 219.1374.
1-(Hexahydrofuro[2,3-b]furan-3-yl)-4-(4-methoxyphenyl)butan-2-one, S8
[0367] ##STR00206##
S8 was synthesized according to the general procedure. The crude product was purified by flash silica gel column chromatography (hexanes:EtOAc = 2:1) to afford S8 (27.1 mg, 0.093 mmol, 57%) as a colorless oil. IR (film) 2951, 1710, 1611, 1512, 1244, 1030, 1001, 828 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl.sub.3) δ = 7.10 (d, J= 8.2 Hz, 2H), 6.94-6.73 (m, 2H), 5.83-5.59 (m, 1H), 3.99 (t, J= 7.9 Hz, 1H), 3.91-3.69 (m, 5H), 3.45-3.27 (m, 1H), 2.97-2.80 (m, 3H), 2.79-2.64 (m, 3H), 2.55 (dd, J = 17.6, 7.6 Hz, 1H), 2.45 (dd, J= 17.6, 7.0 Hz, 1H), 1.90-1.72 (m, 1H), 1.66 (dq, J= 12.2, 5.9 Hz, 1H); .sup.13C NMR (126 MHz, CDCl.sub.3) δ = 208.10, 158.06, 132.70, 129.23, 113.95, 109.47, 71.69, 68.91, 55.27, 45.08, 44.64, 41.13, 36.89, 28.96, 25.48; HRMS (ESI) m/z calc. for C .sub.17H.sub.23O.sub.4 [M+H].sup.+ 291.1596; found 291.1584.
REFERENCES
[0368] 1) For Ni-mediated one-pot ketone syntheses, see: [0369] a) Mukaiyama group: M. Onaka, Y. Matsuoka, T. Mukaiyama, Chem. Lett. 1981, 10, 531. [0370] b) Weix group: A. C. Wotal, D. J. Weix, Org. Lett. 2012, 14, 1476; A. C. Wotal, R. D. Ribson, D. J. Weix, Organometallics 2014, 33, 5874; D. J. Weix, Acc. Chem. Res. 2015, 48, 1767. [0371] c) Gong group: H. Yin, C. Zhao, H. You, K. Lin, H. Gong, Chem. Commun. 2012, 48, 7034; C. Zhao, X. Jia, X. Wang, H. Gong, J. Am. Chem. Soc. 2014, 136, 17645. [0372] d) Reisman group: A. H. Cherney, N. T. Kadunce, S. E. Reisman, J. Am. Chem. Soc. 2013, 135, 7442. [0373] e) Baran group: S. Ni, N. M. Padial, C. Kingston, J. C. Vantourout, D. C. Schmitt, J. T. Edwards, M. M. Kruszyk, R. R. Merchant, P. K. Mykhailiuk, B. B. Sanchez, S. Yang, M. A. Perry, G. M. Gallego, J. J. Mousseau, M. R. Collins, R. J. Cherney, P. S. Lebed, J. S. Chen, T. Qin, P. S. Baran, J. Am. Chem. Soc. 2019, 141, 6726. Link, CAS [0374] 2) [0375] a) Y. Ai, N. Ye, Q. Wang, K. Yahata, Y. Kishi, Angew. Chem., Int. Ed. 2017, 56, 10791. [0376] b) K. Yahata, N. Ye, Y. Ai, K. Iso, Y. Kishi, Angew. Chem., Int. Ed. 2017, 56, 10796. Crossref, Medline, CAS [0377] 3) A. Umehara, K. Umihara, Y. Kishi, unpublished results. [0378] 4) [0379] a) T. J. Anderson, G. D. Jones, D. A. Vicic, J. Am. Chem. Soc. 2004, 126, 8100, [0380] b) G. D. Jones, C. McFarland, T. J. Anderson, D. A. Vicic, Chem. (Commun. 2005, 4211. [0381] c) G. D. Jones, J. L. Martin, C. McFarland, O. R. Allen, R. E. Hall, A. D. Haley, R. J. Brandon, T. Konovalova, P. J. Desrochers, P. Pulay, D. A. Vicic, J. Am. Chem. Soc. 2006, 128, 13175. [0382] d) J. T. Ciszewski, D. Y. Mikhaylov, K. V. Holin, M. K. Kadirov, Y. H. Budnikova, O. Sinyashin, D. A. Vicic, Inorg. Chem. 2011, 50, 8630. [0383] e) D. Mikhaylov, T. Gryaznova, Y. Dudkina, M. Khrizanphorov, S. Latypov, O. Kataeva, D. A. Vicic, O. G. Sinyashin, Y. Budnikova, Dalton Trans. 2012, 41, 165. Crossref, Medline, CAS [0384] 5) The coupling smoothly proceeded in a 1:1 mixture of DMA-DME, DMA-dioxane, and DMA-THF. DMA can be replaced with 1,3-dimethylimidazolidin-2-one (DMI) and DMA. [0385] 6) For the details, see Supporting Information. [0386] 7) Experiments with commonly-used radical probes support an involvement of a radical(s) in the ketone coupling, cf. i .fwdarw. ii and iii .fwdarw. iv. [0387] 8) For selected papers and reviews on Ni.sup.I, see for example: [0388] a) X. Lin, D. L. Phillips, J. Org. Chem. 2008, 73, 3680. [0389] b) K. M. Arendt, A. G. Doyle, Angew. Chem., Int. Ed. 2015, 54, 9876. [0390] c) C.-Y. Lin, P. P. Power, Chem. Soc. Rev. 2017, 46, 5347. [0391] d) Y. H. Budnikova, D. A. Vicic, A. Klein, Inorganics 2018, 6, 18. Crossref, Medline, CAS [0392] 9) For example, see: M. T. Quirós, D. Collado-Sanz, E. Buñuel, D. J. Cárdenas, J. Phys. Chem. A 2018, 122, 2250. Crossref, Medline, CAS [0393] 10) Experimentally, this was shown from the following experiment; 2 was first treated with py-(Me)imid.Math.Ni.sup.IICl.sub.2 (1 mol %), Cp.sub.2Zr.sup.IVC.sub.2 (1 equiv), Zn (3 equiv) in 1:1 DMA/DME at RT for 1 hour. Then, 1 (1 equiv) and (Me).sub.3tpy-Ni.sup.II (1 mol %) in DMA/DME were added, and 3 was isolated in a yield comparable to the standard condition. [0394] 11) For Cp.sub.2Zr.sup.IIICl and its dimeric form (prepared by reduction of Cp.sub.2Zr.sup.IVCl.sub.2 with Na/Hg), see: d) M. C. Barden, J. Schwartz, J. Org. Chem. 1997, 62, 7520. However, to our best knowledge, Cp.sub.2Zr.sup.IVCl.sub.2/Zn or Mn system is unknown. Crossref, Medline, CAS [0395] a) G. M. Williams, K. I. Gell, J. Schwartz, J. Am. Chem. Soc. 1980, 102, 3660. [0396] b) G. M. Williams, J. Schwartz, J. Am. Chem. Soc. 1982, 104, 1122. [0397] c) K. Fujita, T. Nakamura, H. Yorimitsu, K. Oshima, J. Am. Chem. Soc. 2001, 123, 3137. [0398] 12) At an early stage of study, we were interested in an alternative possibility: Cp.sub.2Zr.sup.IIICl could have a high reactivity towards R°, to form Cp.sub.2Zr.sup.IV(R)Cl, which might be involved in the ketone coupling. However, the experiment using hydrozirconation-products showed this possibility unlikely. [0399] 13) Experimentally, this was shown from the following experiment; 1was first treated with (Me).sub.3tpy•Ni.sup.II (1 mol %), Cp.sub.2Zr.sup.IVCl.sub.2 (1 equiv), Zn (3 equiv) in 1:1 DMA/DME at RT for 30 minutes. Then, 2 (1 equiv) and py-(Me)imid.Math.Ni.sup.IICl.sub.2 (1 mol %) in DMA/DME were added, but no ketone formation was observed. [0400] 14) The thiopyridine ester 2 was used for the study. Knowing that the activation of 2 is fast (see the text), we chose Ni.sup.I/Ni.sup.II = 1 mol %/1 mol %. [0401] 15) T. J. Anderson, G. D. Jones, D. A. Vicic, J. Am. Chem. Soc. 2004, 126, 8100. [0402] 16) M. C. Barden, J. Schwartz, J. Org. Chem. 1997, 62, 7520. [0403] 17) F. Wu, W. Lu, Q. Qian, Q. Ren, H. Gong, Org. Lett. 2012, 14, 3044. [0404] 18) K. Yahata, N. Ye, Y. Ai, K. Iso, Y. Kishi, Angew. Chem. Int. Ed. 2017, 56, 10796.
EQUIVALENTS AND SCOPE
[0405] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
[0406] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein.
[0407] It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
[0408] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
[0409] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.