Methods and intermediates for the preparation of fondaparinux
09822140 · 2017-11-21
Assignee
Inventors
Cpc classification
C07H15/04
CHEMISTRY; METALLURGY
C07H1/00
CHEMISTRY; METALLURGY
C07H15/18
CHEMISTRY; METALLURGY
C07H23/00
CHEMISTRY; METALLURGY
C07H15/203
CHEMISTRY; METALLURGY
International classification
C07H1/00
CHEMISTRY; METALLURGY
C07H3/06
CHEMISTRY; METALLURGY
C07H23/00
CHEMISTRY; METALLURGY
C07H15/04
CHEMISTRY; METALLURGY
C07H15/18
CHEMISTRY; METALLURGY
Abstract
The present invention relates to methods for the synthesis of fondaparinux and intermediates thereto.
Claims
1. A compound of Formula (I): ##STR00121## wherein: X.sub.1 is —OR.sup.A or —SR.sup.A, wherein R.sup.A is hydrogen, an oxygen or sulfur protecting group, optionally substituted C.sub.1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; R.sup.2 and R.sup.11 are independently optionally substituted arylalkyl; R.sub.N1, R.sub.N2, and R.sub.N3 are independently —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group; R.sup.3 and R.sup.6 are independently —C(O)R.sup.D, wherein each occurrence of R.sup.D is independently optionally substituted alkyl or optionally substituted aryl; R.sup.1, R.sup.5, and R.sup.9 are independently selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl; R.sup.10 is optionally substituted arylalkyl; R.sub.Y and R.sub.Z are independently hydrogen or an oxygen protecting group; R.sup.7 is selected from the group consisting of —Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and R.sup.4 and R.sup.8 are independently optionally substituted arylalkyl; or a salt thereof.
2. The compound of claim 1, wherein the compound is of Formula (I-a) or (I-b): ##STR00122## ##STR00123##
3. The compound of claim 1, wherein the compound is of the formula: ##STR00124##
4. The compound of claim 1, wherein X.sub.1 is in the alpha configuration or the beta configuration.
5. The compound of claim 1, wherein X.sub.1 is C.sub.1-10 alkoxy.
6. The compound of claim 1, wherein R.sub.N1, R.sub.N2, and R.sub.N3 are independently selected from the group consisting of —N.sub.3, —NH(Cbz), —NH(Boc), —NH(Fmoc), —NHC(O)CCl.sub.3, —NHC(O)CH.sub.3, and —N(C(O)CH.sub.3).sub.2.
7. The compound of claim 1, wherein R.sup.1, R.sup.5, and R.sup.9 are each —Si(R.sup.B).sub.3.
8. The compound of claim 7, wherein R.sup.1, R.sup.5 and R.sup.9 are t-butyldiphenylsilyl.
9. The compound of claim 1, wherein R.sup.2 and R.sup.11 are each substituted benzyl.
10. The compound of claim 1, wherein R.sup.1, R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sup.2 and R.sup.11 are p-bromobenzyl.
11. The compound of claim 1, wherein R.sup.3 and R.sup.6 are levulinyl.
12. The compound of claim 1, wherein R.sup.1, R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sup.3 and R.sup.6 are levulinyl.
13. The compound of claim 1, wherein R.sup.7 is —Si(R.sup.B).sub.3 or —C(O)R.sup.C; wherein R.sup.C is optionally substituted alkyl or optionally substituted aryl.
14. The compound of claim 1, wherein R.sup.1, R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sup.7 is benzoyl.
15. The compound of claim 1, wherein R.sub.Y and R.sub.Z are each hydrogen or each an oxygen protecting group.
16. The compound of claim 1, wherein R.sup.1, R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sub.Y and R.sub.Z are acetyl.
17. The compound of claim 1, wherein X.sub.1 is selected from the group consisting of alpha-thiomethyl, beta-thiomethyl, alpha-thiocresyl, beta-thiocresyl, alpha-t-butyldiphenylsilyloxy, beta-t-butyldiphenylsilyloxy, and alpha-methoxy.
18. A compound of Formula (II): ##STR00125## wherein: X.sub.2 is —OR.sup.A or —SR.sup.A, wherein R.sup.A is hydrogen, an oxygen or sulfur protecting group, optionally substituted C.sub.1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; R.sup.11 is optionally substituted arylalkyl; R.sub.N2 and R.sub.N3 are independently —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group; R.sup.3 and R.sup.6 are independently —C(O)R.sup.D, wherein each occurrence of R.sup.D is independently optionally substituted alkyl or optionally substituted aryl; R.sup.5 and R.sup.9 are independently selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl; R.sup.10 is optionally substituted arylalkyl; R.sub.Y and R.sub.Z are independently hydrogen or an oxygen protecting group; R.sup.7 is selected from the group consisting of —Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and R.sup.4 and R.sup.8 are independently optionally substituted arylalkyl; or a salt thereof.
19. The compound of claim 18, wherein X.sub.2 is selected from the group consisting of halogen, optionally substituted thioalkyl, optionally substituted thioaryl, —OC(═N)CCl.sub.3, —OP(O)(OR.sup.F).sub.2, and n-pentenyl, wherein R.sup.F is hydrogen, optionally substituted alkyl, or optionally substituted acyl.
20. The compound of claim 18, wherein X.sub.2 is —S-tolyl, —OH, or —OAc.
21. The compound of claim 18, wherein R.sub.N2 and R.sub.N3 are independently selected from the group consisting of —N.sub.3, —NH(Cbz), —NH(Boc), —NH(Fmoc), —NHC(O)CCl.sub.3, —NHC(O)CH.sub.3, and —N(C(O)CH.sub.3).sub.2.
22. The compound of claim 18, wherein R.sup.5 and R.sup.9 are each —Si(R.sup.B).sub.3.
23. The compound of claim 18, wherein R.sup.11 is optionally substituted benzyl.
24. The compound of claim 18, wherein R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sup.11 is p-bromobenzyl.
25. The compound of claim 18, wherein R.sup.3 and R.sup.6 are levulinyl.
26. The compound of claim 18, wherein R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sup.3 and R.sup.6 are levulinyl.
27. The compound of claim 18, wherein R.sup.7 is —Si(R.sup.B).sub.3.
28. The compound of claim 18, wherein R.sup.7 is —C(O)R.sup.D, wherein R.sup.C is optionally substituted alkyl or optionally substituted aryl.
29. The compound of claim 18, wherein R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sup.7 is benzoyl.
30. The compound of claim 18, wherein R.sub.Y and R.sub.Z are each hydrogen or each an oxygen protecting group.
31. The compound of claim 18, wherein R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sub.Y and R.sub.Z are acetyl.
32. The compound of claim 18, wherein the compound is of Formula (II-a) or Formula (II-b): ##STR00126## ##STR00127##
33. The compound of claim 18, wherein the compound is of the formula: ##STR00128##
34. A compound of Formula (III): ##STR00129## wherein: R.sub.N2 is —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group; R.sup.3 and R.sup.6 are independently —C(O)R.sup.D, wherein each occurrence of R.sup.D is independently optionally substituted alkyl or optionally substituted aryl; R.sup.5 is selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl; R.sub.Y is hydrogen or an oxygen protecting group; R.sup.7 is selected from the group consisting of —Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and R.sup.4 and R.sup.8 are independently optionally substituted arylalkyl; or a salt thereof.
35. The compound of claim 34, wherein R.sub.N2 is selected from the group consisting of —N.sub.3, —NH(Cbz), —NH(Boc), —NH(Fmoc), —NHC(O)CCl.sub.3, —NHC(O)CH.sub.3, and —N(C(O)CH.sub.3).sub.2.
36. The compound of claim 34, wherein R.sup.5 is a silyl protecting group.
37. The compound of claim 34, wherein R.sup.5 is t-butyldiphenylsilyl; and R.sup.3 and R.sup.6 are levulinyl.
38. The compound of claim 34, wherein R.sup.7 is —Si(R.sup.B).sub.3 or —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl or optionally substituted aryl.
39. The compound of claim 34, wherein R.sup.5 is t-butyldiphenylsilyl; and R.sup.7 is benzoyl.
40. The compound of claim 34, wherein R.sub.Y is hydrogen or an oxygen protecting group.
41. The compound of claim 34, wherein R.sup.5 is t-butyldiphenylsilyl; and R.sub.Y is acetyl.
42. The compound of claim 34, wherein the compound is of the formula: ##STR00130##
43. A method for for synthesizing fondaparinux 25: ##STR00131## or a salt thereof; the method comprising: (a) deprotecting a pentasaccharide of formula (I) or a salt thereof: ##STR00132## wherein: X.sub.1 is alpha-methoxy; R.sup.2 and R.sup.11 are independently optionally substituted arylalkyl; R.sub.N1, R.sub.N2, and R.sub.N3 are independently —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group; R.sup.3 and R.sup.6 are independently —C(O)R.sup.D, wherein each occurrence of R.sup.D is independently optionally substituted alkyl or optionally substituted aryl; R.sup.1, R.sup.5, and R.sup.9 are independently selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl; R.sup.10 is optionally substituted arylalkyl; R.sub.Y and R.sub.Z are independently hydrogen or an oxygen protecting group; R.sup.7 is selected from the group consisting of —Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and R.sup.4 and R.sup.8 are independently optionally substituted arylalkyl; under suitable conditions to form a compound of formula (IX): ##STR00133## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.N1, R.sub.N2, and R.sub.N3 are as defined above; (b) oxidizing, deprotecting, and esterifying the compound of formula (IX) under suitable conditions to form a compound of formula (X): ##STR00134## wherein R′ is C.sub.1-6 alkyl or optionally substituted benzyl; and wherein R.sup.2, R.sup.4, R.sup.7, R.sup.8, R.sup.10, R.sup.11, R.sub.N1, R.sub.N2, and R.sub.N3 are as defined above; (c) sulfonating the compound of formula (X) under suitable conditions to form a compound of formula (XI): ##STR00135## wherein R.sup.2, R.sup.4, R.sup.7, R.sup.8, R.sup.10, R.sup.11, R.sub.N1, R.sub.N2, and R.sub.N3 are as defined above; (d) converting the compound of formula (XI) to a compound of formula (XII) under suitable conditions: ##STR00136## (e) deprotecting the compound of formula (XII) under suitable conditions to form a compound of formula (XIII): ##STR00137## and (f) sulfonating the compound of formula (XIII) under suitable conditions to form fondaparinux 25 or a salt thereof.
44. The method of claim 43, further comprising a second process for synthesizing the pentasaccharide of formula (I), the second process comprising: reacting a tetrasaccharide of formula (II): ##STR00138## wherein X.sub.2 is —OR.sup.A or —SR.sup.A, in which R.sup.A is hydrogen, an oxygen or sulfur protecting group, optionally substituted C.sub.1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; and R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, R.sub.Z, R.sub.N2, and R.sub.N3 are as defined in claim 43; with monosaccharide E: ##STR00139## under suitable conditions to form a pentasaccharide of formula (I), wherein X.sub.1, R.sup.1, R.sup.2, and R.sub.N1 are as defined in claim 43.
45. The method of claim 44, further comprising a third process for synthesizing the tetrasaccharide of formula (II): the process comprising: (a) reacting a trisaccharide of formula (III): ##STR00140## wherein R.sup.N2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8, and R.sup.Y are as defined in claim 44; with a monosaccharide of formula A: ##STR00141## wherein X.sub.5 is a leaving group and R.sub.N3, R.sup.9, R.sup.11, and R.sup.12 are as defined in claim 44; in the presence of an activating agent under suitable conditions to form a compound of formula (VIIIa): ##STR00142## wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, R.sub.N2, and R.sub.N3 are as defined in claim 44; (b) ring-opening and protecting the compound of formula (VIIIa) under suitable conditions to form a compound of formula (VIII): ##STR00143## wherein R.sup.14 is an oxygen protecting group and R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.14, R.sub.Y, R.sub.Z, R.sub.N2, and R.sub.N3 are as defined in claim 44; and (c) converting the —OR.sup.14 group of the compound of formula (VIII) to the group X.sub.2 under suitable conditions to form the compound of formula (II).
46. A method of synthesizing fondaparinux 25 ##STR00144## or a salt thereof, the method comprising: (1) a first process for synthesizing a trisaccharide of formula (III): ##STR00145## in which R.sub.N2 is —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group; R.sup.3 and R.sup.6 are independently —C(O)R.sup.D, wherein each occurrence of R.sup.D is independently optionally substituted alkyl or optionally substituted aryl; R.sup.5 is selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl; R.sub.Y is hydrogen or an oxygen protecting group; R.sup.7 is selected from the group consisting of —Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and R.sup.4 and R.sup.8 are independently optionally substituted arylalkyl; or a salt thereof; the first process comprising: (a) reacting monosaccharides of formulae C and D; ##STR00146## wherein R.sup.12 and R.sup.13 are each independently an oxygen protecting group; X.sub.3 is a leaving group; and R.sup.4, R.sup.5, and R.sub.N2 are as defined above; in the presence of an activating agent under suitable conditions to form a disaccharide of formula (IV): ##STR00147## wherein R.sup.N2, R.sup.4, R.sup.5, R.sup.12, and R.sup.13 are as defined above; (b) deprotecting the disaccharide of formula (IV) under suitable conditions to form a compound of formula (V): ##STR00148## wherein R.sup.N2, R.sup.4, R.sup.5, and R.sup.12 are as defined above; (c) protecting and deprotecting the compound of formula (V) under suitable conditions to form a compound of formula (VI): ##STR00149## wherein R.sup.N2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are as defined above; (d) reacting the compound of formula (VI) with a monosaccharide of formula B: ##STR00150## wherein R.sup.15 and R.sup.16 are independently hydrogen, alkyl or aryl, wherein at least one of R.sup.15 and R.sup.16 is not hydrogen; X.sub.4 is a leaving group; and R.sup.7 and R.sup.8 are as defined above; in the presence of an activating agent under suitable conditions to form a trisaccharide of formula (VII): ##STR00151## wherein R.sup.N2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are as defined above; (e) protecting the trisaccharide of formula (VII) under suitable conditions to form the trisaccharide of formula (III); (2) a second process for synthesizing a tetrasaccharide of formula (II): ##STR00152## or a salt thereof; wherein: X.sub.2 is —OR.sup.A or —SR.sup.A, wherein R.sup.A is hydrogen, an oxygen or sulfur protecting group, optionally substituted C.sub.1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; R.sup.11 is optionally substituted arylalkyl; R.sub.N3 is —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group; R.sup.9 is selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl; R.sup.10 is optionally substituted arylalkyl; R.sub.Z is hydrogen or an oxygen protecting group; and R.sub.N2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sub.Y are as defined above; the second process comprising: (a) reacting the trisaccharide of formula (III): with a monosaccharide of formula A: ##STR00153## wherein X.sub.5 is a leaving group; and R.sup.N3, R.sup.9, R.sup.11, and R.sup.12 are as defined above; in the presence of an activating agent under suitable conditions to form a compound of formula (VIIIa): ##STR00154## wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, R.sub.N2, and R.sub.N3 are as defined above; (b) ring-opening and protecting the compound of formula (VIIIa) under suitable conditions to form a compound of formula (VIII): ##STR00155## wherein R.sup.14 is an oxygen protecting group; and R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.14, R.sub.Y, R.sub.Z, R.sub.N2, and R.sub.N3 are as defined above; and (c) converting the —OR.sup.14 group of the compound of formula (VIII) to the group X.sub.2 under suitable conditions to form the tetrasaccharide of formula (II); (3) a third process for synthesizing a pentasaccharide of formula (I): ##STR00156## or a salt thereof; wherein: X.sub.1 is alpha-methoxy; R.sup.2 is optionally substituted arylalkyl; R.sub.N1 is —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group; R.sup.1 is selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl; and R.sub.N2, R.sub.N3, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.Y, and R.sub.Z are as defined above; the third process comprising: reacting the tetrasaccharide of formula (II): ##STR00157## wherein X.sub.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, R.sub.Z, R.sub.N2, and R.sub.N3 are as defined above; with monosaccharide E: ##STR00158## under suitable conditions to form the pentasaccharide of formula (I); wherein X.sub.1, R.sup.1, R.sup.2 and R.sub.N1 are as defined above; (4) a fourth process for synthesizing fondaparinux 25: or a salt thereof; the fourth process comprising: (a) deprotecting the pentasaccharide of formula (I): under suitable conditions to form a compound of formula (IX): ##STR00159## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.N1, R.sub.N2, and R.sub.N3 are as defined above; (b) oxidizing, deprotecting, and esterifying the compound of formula (IX) under suitable conditions to form a compound of formula (X): ##STR00160## wherein R′ is C.sub.1-6 alkyl or optionally substituted benzyl; and wherein R.sup.2, R.sup.4, R.sup.7, R.sup.8, R.sup.10, R.sup.11, R.sub.N1, R.sub.N2, and R.sub.N3 are as defined above; (c) sulfonating the compound of formula (X) under suitable conditions to form a compound of formula (XI): ##STR00161## wherein R.sup.2, R.sup.4, R.sup.7, R.sup.8, R.sup.10, R.sup.11, R.sub.N1, R.sub.N2, and R.sub.N3 are as defined above; (d) converting the compound of formula (XI) to a compound of formula (XII) under suitable conditions: ##STR00162## wherein R.sup.2, R.sup.4, R.sup.8, R.sup.10, R.sup.11, R.sub.N1, R.sub.N2, and R.sub.N3 are as defined above; (e) deprotecting the compound of formula (XII) under suitable conditions to form a compound of formula (XIII): ##STR00163## and (f) sulfonating the compound of formula (XIII) under suitable conditions to form fondaparinux 25, or a salt thereof.
47. The method of claim 46, wherein the trisaccharide of formula (III) is compound 16: ##STR00164##
48. The method of claim 46, wherein the disaccharide of formula (IV) is compound 12: ##STR00165##
49. The method of claim 46, wherein the compound of formula (V) is compound 13: ##STR00166##
50. The method of claim 46, wherein the compound of formula (VI) is compound 14: ##STR00167##
51. The method of claim 46, wherein the trisaccharide of formula (VII) is compound 15: ##STR00168##
52. The method of claim 46, wherein the deprotection step (b) comprises treating the disaccharide of (IV) with base.
53. The method of claim 46, wherein R.sub.Y is acetyl.
54. The method of claim 46, wherein R.sup.3 is levulinyl.
55. The method of claim 46, wherein step (c) comprises protecting the compound of formula (V) with EDC, DMAP, and 4-oxopentanoic acid.
56. The method of claim 46, wherein R.sup.12 is 2-napththylmethyl.
57. The method of claim 56, wherein step (c) comprises deprotecting the compound of formula (V) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).
58. The method of claim 46, wherein R.sup.4 and R.sup.8 are benzyl.
59. The method of claim 46, wherein R.sub.N2 is —N.sub.3.
60. A method of synthesizing a tetrasaccharide of formula (II): ##STR00169## or a salt thereof; wherein: X.sub.2 is —OR.sup.A or —SR.sup.A, wherein R.sup.A is hydrogen, an oxygen or sulfur protecting group, optionally substituted C.sub.1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; R.sup.11 is optionally substituted arylalkyl; R.sub.N2 and R.sub.N3 are independently —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group; R.sup.3 and R.sup.6 are independently —C(O)R.sup.D, wherein each occurrence of R.sup.D is independently optionally substituted alkyl or optionally substituted aryl; R.sup.5 and R.sup.9 are independently selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl; R.sup.10 is optionally substituted arylalkyl; R.sub.Y and R.sub.Z are independently hydrogen or an oxygen protecting group; R.sup.7 is selected from the group consisting of —Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and R.sup.4 and R.sup.8 are independently optionally substituted arylalkyl; the method comprising: (a) reacting a trisaccharide of formula (III): ##STR00170## wherein R.sup.N2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8, and R.sup.Y are as defined above; with a monosaccharide of formula A: ##STR00171## wherein X.sub.5 is a leaving group; and wherein R.sub.N3, R.sup.9, R.sup.11, and R.sup.12 are as defined above; in the presence of an activating agent under suitable conditions to form a compound of formula (VIIIa): ##STR00172## wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, R.sub.N2, and R.sub.N3 are as defined above; (b) ring-opening and protecting the compound of formula (VIIIa) under suitable conditions to form a compound of formula (VIII): ##STR00173## wherein R.sup.14 is an oxygen protecting group; and wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.14, R.sub.Y, R.sub.Z, R.sub.N2, and R.sub.N3 are as defined above; and (c) converting the —OR.sup.14 group of the compound of formula (VIII) to the group X.sub.2 under suitable conditions to form the tetrasaccharide of formula (II), or a salt thereof.
61. The method of claim 60, wherein the tetrasaccharide of formula (II) is compound 18: ##STR00174##
62. The method of claim 60, wherein the trisaccharide of formula (III) is compound 16: ##STR00175##
63. The method of claim 60, wherein the trisaccharide of formula (III) is prepared by a process comprising: (a) reacting monosaccharides of formulae C and D; ##STR00176## wherein R.sup.12 and R.sup.13 are each independently an oxygen protecting group; X.sub.3 is a leaving group; and R.sup.4, R.sup.5, and R.sub.N2 are as defined above in claim 60; in the presence of an activating agent under suitable conditions to form a disaccharide of formula (IV): ##STR00177## wherein R.sup.N2, R.sup.4, R.sup.5, R.sup.12, and R.sup.13 are as defined above in claim 60; (b) deprotecting the disaccharide of formula (IV) under suitable conditions to form a compound of formula (V): ##STR00178## wherein R.sup.N2, R.sup.4, R.sup.5, and R.sup.12 are as defined above in claim 60; (c) protecting and deprotecting the compound of formula (V) under suitable conditions to form a compound of formula (VI): ##STR00179## wherein R.sup.N2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are as defined above in claim 60; (d) reacting the compound of formula (VI) with a monosaccharide of formula B: ##STR00180## wherein R.sup.15 and R.sup.16 are independently hydrogen, alkyl or aryl, wherein at least one of R.sup.15 and R.sup.16 is not hydrogen; X.sub.4 is a leaving group; and R.sup.7 and R.sup.8 are as defined above in claim 60; in the presence of an activating agent under suitable conditions to form a trisaccharide of formula (VII): ##STR00181## wherein R.sup.N2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are as defined above in claim 60; (e) protecting the trisaccharide of formula (VII) under suitable conditions to form the trisaccharide of formula (III).
64. The method of claim 60, wherein the compound of formula (VIII) is compound 17: ##STR00182##
65. The method of claim 60, wherein R.sup.14, R.sub.Y, and R.sub.Z are acetyl.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
(14) Fondaparinux is a linear octasulfated pentasaccharide having five O-sulfated moieties and three N-sulfated moieties. In addition, fondaparinux contains six hydroxyl groups that are not sulfated. Fondaparinux contains three glucosamine derivatives, one glucuronic acid, and one L-iduronic acid. The five saccharides are connected to each other in alternate α and β linkages (
(15) The monosaccharide units that form the building blocks for the fondaparinux molecule are labeled with the glucosamine unit on the left referred to as monosaccharide A and the next, an uronic acid unit to its right as B and subsequent monosaccharide units, C, D and E respectively as shown in
(16) In certain embodiments, the present invention relates to a new synthetic route to fondaparinux. In the synthesis of fondaparinux, the monosaccharides of formulae A, B, C, D and E described herein can be made either by methods described in the art or by methods described herein. In other embodiments, the present invention relates to intermediates useful for the synthesis of fondaparinux. In some embodiments, an compound described herein is also useful as an antithrombotic agent. In certain embodiments, the present invention provides compounds or compositions comprising provided compounds, for use in inhibiting factor Xa.
(17) In some embodiments, the present invention provides a compound of Formula (I):
(18) ##STR00032## wherein: X.sub.1 is —OR.sup.A or —SR.sup.A, wherein R.sup.A is hydrogen, a oxygen or sulfur protecting group, optionally substituted C.sub.1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; R.sup.2 and R.sup.11 are independently optionally substituted arylalkyl; R.sub.N1, R.sub.N2, and R.sub.N3 are independently —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or an amino protecting group; R.sup.3 and R.sup.6 are independently —C(O)R.sup.D, wherein each occurrence of R.sup.D is independently optionally substituted alkyl or optionally substituted aryl; R.sup.1, R.sup.5, and R.sup.9 are independently selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl; R.sup.10 is optionally substituted arylalkyl; R.sub.Y and R.sub.Z are independently hydrogen or an oxygen protecting group; R.sup.7 is selected from the group consisting of —Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and R.sup.4 and R.sup.8 are independently optionally substituted arylalkyl;
or a salt thereof.
(19) In some embodiments, for the formulae described herein, X.sub.1 is —OR.sup.A or —SR.sup.A, wherein R.sup.A is hydrogen, an oxygen or sulfur protecting group, optionally substituted C.sub.1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl.
(20) In certain embodiments, X.sub.1 is in the alpha configuration. In certain embodiments, X.sub.1 is in the beta configuration.
(21) In some embodiments, X.sub.1 is —OR.sup.A. In some embodiments, X.sub.1 is —OH. In some embodiments, X.sub.1 is —O(protecting group). In some embodiments, X.sub.1 is —OR.sup.A, wherein R.sup.A is unsubstituted C.sub.1-10 alkyl. In some embodiments, X.sub.1 is —OR.sup.A, wherein R.sup.A is substituted C.sub.1-10 alkyl. In some embodiments, X.sub.1 is —OR.sup.A, wherein R.sup.A is unsubstituted aryl. In some embodiments, X.sub.1 is —OR.sup.A, wherein R.sup.A is substituted aryl. In some embodiments, X.sub.1 is —OR.sup.A, wherein R.sup.A is unsubstituted acyl. In some embodiments, X.sub.1 is OR.sup.A, wherein R.sup.A is substituted acyl. In some embodiments, X.sub.1 is OR.sup.A, wherein R.sup.A is unsubstituted imidoyl. In some embodiments, X.sub.1 is —OR.sup.A, wherein R.sup.A is substituted imidoyl.
(22) In some embodiments, X.sub.1 is —SR.sup.A. In some embodiments, X.sub.1 is —SH. In some embodiments, X.sub.1 is —S (protecting group). In some embodiments, X.sub.1 is —SR.sup.A, wherein R.sup.A is unsubstituted C.sub.1-10 alkyl. In some embodiments, X.sub.1 is —SR.sup.A, wherein R.sup.A is substituted C.sub.1-10 alkyl. In certain embodiments, X.sub.1 is —SCH.sub.3. In some embodiments, X.sub.1 is —SR.sup.A, wherein R.sup.A is unsubstituted aryl. In some embodiments, X.sub.1 is —SR.sup.A, wherein R.sup.A is substituted aryl. In some embodiments, X.sub.1 is —SR.sup.A, wherein R.sup.A is unsubstituted acyl. In some embodiments, X.sub.1 is —SR.sup.A, wherein R.sup.A is substituted acyl. In some embodiments, X.sub.1 is —SR.sup.A, wherein R.sup.A is unsubstituted imidoyl. In some embodiments, X.sub.1 is —SR.sup.A, wherein R.sup.A is substituted imidoyl.
(23) In some embodiments, X.sub.1 is C.sub.1-10 alkoxy. In some embodiments, X.sub.1 is C.sub.1-3 alkoxy. In certain embodiments, X.sub.1 is methoxy. In certain embodiments, X.sub.1 is alpha-methoxy.
(24) In some embodiments, X.sub.1 is selected from the group consisting of alpha-thiomethyl, beta-thiomethyl, alpha-thiocresyl, beta-thiocresyl, alpha-t-butyldiphenylsilyloxy, beta-t-butyldiphenylsilyloxy, and alpha-methoxy.
(25) In some embodiments, for the formulae described herein, R.sup.1 is selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl. In some embodiments, R.sup.1 is unsubstituted arylalkyl. In some embodiments, R.sup.1 is substituted arylalkyl. In some embodiments, R.sup.1 is benzyl. In some embodiments, R.sup.1 is —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl. In certain embodiments, R.sup.1 is trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, or triisopropylsilyl. In certain embodiments, R.sup.1 is t-butyldiphenylsilyl.
(26) In some embodiments, for the formulae described herein, R.sup.2 is optionally substituted arylalkyl. In some embodiments, R.sup.2 is substituted arylalkyl. In some embodiments, R.sup.2 is unsubstituted arylalkyl. In some embodiments, R.sup.2 is unsubstituted benzyl. In some embodiments, R.sup.2 is substituted benzyl. In some embodiments, R.sup.2 is bromobenzyl. In certain embodiments, R.sup.2 is p-bromobenzyl.
(27) In some embodiments, for the formulae described herein, R.sup.3 is —C(O)R.sup.D, wherein R.sup.D is optionally substituted alkyl or optionally substituted aryl. In some embodiments, R.sup.D is optionally substituted alkyl. In some embodiments, R.sup.D is optionally substituted aryl. In some embodiments, R.sup.D is substituted alkyl. In some embodiments, R.sup.D is unsubstituted alkyl. In some embodiments, R.sup.D is substituted aryl. In some embodiments, R.sup.D is unsubstituted aryl. In certain embodiments, R.sup.3 is acetyl. In certain embodiments, R.sup.3 is chloroacetyl. In certain embodiments, R.sup.3 is benzoyl. In certain embodiments, R.sup.3 is levulinyl.
(28) In some embodiments, for the formulae described herein, R.sup.4 is optionally substituted arylalkyl. In some embodiments, R.sup.4 is substituted arylalkyl. In some embodiments, R.sup.4 is unsubstituted arylalkyl. In some embodiments, R.sup.4 is unsubstituted benzyl. In some embodiments, R.sup.4 is substituted benzyl.
(29) In some embodiments, for the formulae described herein, R.sup.5 is selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl. In some embodiments, R.sup.5 is unsubstituted arylalkyl. In some embodiments, R.sup.5 is substituted arylalkyl. In some embodiments, R.sup.5 is benzyl. In some embodiments, R.sup.5 is —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl. In certain embodiments, R.sup.5 is trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, or triisopropylsilyl. In certain embodiments, R.sup.5 is t-butyldiphenylsilyl.
(30) In some embodiments, for the formulae described herein, R.sup.6 is C(O)R.sup.D, wherein R.sup.D is optionally substituted alkyl or optionally substituted aryl. In some embodiments, R.sup.D is optionally substituted alkyl. In some embodiments, R.sup.D is optionally substituted aryl. In some embodiments, R.sup.D is substituted alkyl. In some embodiments, R.sup.D is unsubstituted alkyl. In some embodiments, R.sup.D is substituted aryl. In some embodiments, R.sup.D is unsubstituted aryl. In certain embodiments, R.sup.6 is acetyl. In certain embodiments, R.sup.6 is chloroacetyl. In certain embodiments, R.sup.6 is benzoyl. In certain embodiments, R.sup.6 is levulinyl.
(31) In some embodiments, for the formulae described herein, R.sup.7 is selected from the group consisting of —Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C. In some embodiments, R.sup.7 is —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl. In some embodiments, R.sup.7 is optionally substituted arylalkyl. In some embodiments, R.sup.7 is —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl. In some embodiments, R.sup.7 is unsubstituted arylalkyl. In some embodiments, R.sup.7 is substituted arylalkyl. In some embodiments, R.sup.7 is benzyl. In some embodiments, R.sup.7 is —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl. In certain embodiments, R.sup.7 is trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, or triisopropylsilyl. In certain embodiments, R.sup.7 is t-butyldiphenylsilyl. In some embodiments, R.sup.7 is —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl. In some embodiments, R.sup.7 is —C(O)R.sup.C, wherein R.sup.C is unsubstituted alkyl. In some embodiments, R.sup.7 is —C(O)R.sup.C, wherein R.sup.C is substituted alkyl. In some embodiments, R.sup.7 is —C(O)R.sup.C, wherein R.sup.C is haloalkyl. In some embodiments, R.sup.7 is —C(O)R.sup.C, wherein R.sup.C is optionally substituted aryl. In some embodiments, R.sup.7 is —C(O)R.sup.C, wherein R.sup.C is substituted aryl. In some embodiments, R.sup.7 is C(O)R.sup.C, wherein R.sup.C is unsubstituted aryl. In certain embodiments, R.sup.7 is benzoyl. In some embodiments, R.sup.7 is —C(O)R.sup.C, wherein R.sup.C is optionally substituted arylalkyl. In some embodiments, R.sup.7 is —C(O)R.sup.C, wherein R.sup.C is substituted arylalkyl. In some embodiments, R.sup.7 is —C(O)R.sup.C, wherein R.sup.C is unsubstituted arylalkyl.
(32) In some embodiments, for the formulae described herein, R.sup.8 is optionally substituted arylalkyl. In some embodiments, R.sup.8 is substituted arylalkyl. In some embodiments, R.sup.8 is unsubstituted arylalkyl. In some embodiments, R.sup.8 is unsubstituted benzyl. In some embodiments, R.sup.8 is substituted benzyl.
(33) In some embodiments, for the formulae described herein, R.sup.9 is selected from the group consisting of optionally substituted arylalkyl and Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl. In some embodiments, R.sup.9 is unsubstituted arylalkyl. In some embodiments, R.sup.9 is substituted arylalkyl. In some embodiments, R.sup.9 is benzyl. In some embodiments, R.sup.9 is Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl. In certain embodiments, R.sup.9 is trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, or triisopropylsilyl. In certain embodiments, R.sup.9 is t-butyldiphenylsilyl.
(34) In some embodiments, for the formulae described herein, R.sup.10 is optionally substituted arylalkyl. In some embodiments, R.sup.10 is substituted arylalkyl. In some embodiments, R.sup.10 is unsubstituted arylalkyl. In some embodiments, R.sup.10 is unsubstituted benzyl. In some embodiments, R.sup.10 is substituted benzyl. In some embodiments, R.sup.10 is unsubstituted naphthylmethyl. In some embodiments, R.sup.10 is substituted naphthylmethyl. In certain embodiments, R.sup.10 is 2-naphthylmethyl (2-NAP).
(35) In some embodiments, for the formulae described herein, R.sup.11 is optionally substituted arylalkyl. In some embodiments, R.sup.11 is substituted arylalkyl. In some embodiments, R.sup.11 is unsubstituted arylalkyl. In some embodiments, R.sup.11 is unsubstituted benzyl. In some embodiments, R.sup.11 is substituted benzyl. In some embodiments, R.sup.11 is bromobenzyl. In certain embodiments, R.sup.11 is p-bromobenzyl (PBB).
(36) In some embodiments, for the formulae described herein, R.sub.Y is hydrogen or an oxygen protecting group. In some embodiments, R.sub.Y is hydrogen. In some embodiments, R.sub.Y is an oxygen protecting group. In certain embodiments, R.sub.Y is an acyl group. In certain embodiments, R.sub.Y is acetyl. In certain embodiments, R.sub.Y is chloroacetyl. In certain embodiments, R.sub.Y is methoxyacetyl. In certain embodiments, R.sub.Y is trichloroacetyl.
(37) In some embodiments, for the formulae described herein, R.sub.Z is hydrogen or an oxygen protecting group. In some embodiments, R.sub.Z is hydrogen. In some embodiments, R.sub.Z is an oxygen protecting group. In certain embodiments, R.sub.Z is an acyl group. In certain embodiments, R.sub.Z is acetyl. In certain embodiments, R.sub.Z is chloroacetyl. In certain embodiments, R.sub.Z is methoxyacetyl. In certain embodiments, R.sub.Z is trichloroacetyl.
(38) In some embodiments, for the formulae described herein, R.sub.N1 is —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group. In certain embodiments, R.sub.N1 is —N.sub.3. In certain embodiments, R.sub.N1 is —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group. In certain embodiments, R.sub.N1 is —NH.sub.2. In certain embodiments, R.sub.N1 is —NHR.sup.W, wherein R.sup.W is a nitrogen protecting group. In certain embodiments, R.sub.N1 is —N(R.sup.W).sub.2, wherein each R.sup.W is a nitrogen protecting group. In certain embodiments, R.sub.N1 is selected from the group consisting of —N.sub.3, —NH(Cbz), —NH(Boc), —NH(Fmoc), —NHC(O)CCl.sub.3, —NHC(O)CH.sub.3, and —N(C(O)CH.sub.3).sub.2. In certain embodiments, R.sub.N1 is —NH(Cbz). In certain embodiments, R.sub.N1 is —NH(Fmoc). In certain embodiments, R.sub.N1 is —NHC(O)CCl.sub.3. In certain embodiments, R.sub.N1 is —NHC(O)CH.sub.3. In certain embodiments, R.sub.N1 is —N(C(O)CH.sub.3).sub.2.
(39) In some embodiments, for the formulae described herein, R.sub.N2 is —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group. In certain embodiments, R.sub.N2 is —N.sub.3. In certain embodiments, R.sub.N2 is —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group. In certain embodiments, R.sub.N2 is —NH.sub.2. In certain embodiments, R.sub.N2 is —NHR.sup.W, wherein R.sup.W is a nitrogen protecting group. In certain embodiments, R.sub.N2 is —N(R.sup.W).sub.2, wherein each R.sup.W is a nitrogen protecting group. In certain embodiments, R.sub.N2 is selected from the group consisting of —N.sub.3, —NH(Cbz), —NH(Boc), —NH(Fmoc), —NHC(O)CCl.sub.3, —NHC(O)CH.sub.3, and —N(C(O)CH.sub.3).sub.2. In certain embodiments, R.sub.N2 is —NH(Cbz). In certain embodiments, R.sub.N2 is —NH(Fmoc). In certain embodiments, R.sub.N2 is —NHC(O)CCl.sub.3. In certain embodiments, R.sub.N2 is —NHC(O)CH.sub.3. In certain embodiments, R.sub.N2 is —N(C(O)CH.sub.3).sub.2.
(40) In some embodiments, for the formulae described herein, R.sub.N3 is —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group. In certain embodiments, R.sub.N3 is —N.sub.3. In certain embodiments, R.sub.N3 is —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group. In certain embodiments, R.sub.N3 is —NH.sub.2. In certain embodiments, R.sub.N3 is —NHR.sup.W, wherein R.sup.W is a nitrogen protecting group. In certain embodiments, R.sub.N3 is —N(R.sup.W).sub.2, wherein each R.sup.W is a nitrogen protecting group. In certain embodiments, R.sub.N3 is selected from the group consisting of —N.sub.3, —NH(Cbz), —NH(Boc), —NH(Fmoc), —NHC(O)CCl.sub.3, —NHC(O)CH.sub.3, and —N(C(O)CH.sub.3).sub.2. In certain embodiments, R.sub.N3 is —NH(Cbz). In certain embodiments, R.sub.N3 is —NH(Fmoc). In certain embodiments, R.sub.N3 is —NHC(O)CCl.sub.3. In certain embodiments, R.sub.N3 is —NHC(O)CH.sub.3. In certain embodiments, R.sub.N3 is —N(C(O)CH.sub.3).sub.2.
(41) In some embodiments, R.sub.N1, R.sub.N2, and R.sub.N3 are the same. In some embodiments, R.sub.N1, R.sub.N2, and R.sub.N3 are —N.sub.3.
(42) In some embodiments, R.sup.1, R.sup.5, and R.sup.9 are the same. In some embodiments, R.sup.1, R.sup.5, and R.sup.9 are each —Si(R.sup.B).sub.3. In some embodiments, R.sup.1, R.sup.5 and R.sup.9 are t-butyldiphenylsilyl.
(43) In some embodiments, R.sup.2 and R.sup.11 are the same. In some embodiments, R.sup.2 and R.sup.11 are each optionally substituted benzyl. In some embodiments, R.sup.2 and R.sup.11 are p-bromobenzyl.
(44) In some embodiments, R.sup.1, R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sup.2 and R.sup.11 are p-bromobenzyl.
(45) In some embodiments, R.sup.3 and R.sup.6 are the same. In some embodiments, R.sup.3 and R.sup.6 are levulinyl.
(46) In some embodiments, R.sup.1, R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sup.3 and R.sup.6 are levulinyl.
(47) In some embodiments, R.sup.1, R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sup.7 is benzoyl.
(48) In some embodiments, R.sub.Y and R.sub.Z are the same. In some embodiments, R.sub.Y and R.sub.Z are each a protecting group. In some embodiments, R.sub.Y and R.sub.Z are each an acyl protecting group. In some embodiments, R.sub.Y and R.sub.Z are acetyl.
(49) In some embodiments, R.sup.1, R.sup.5 and R.sup.9 are t-butyldiphenylsilyl; and R.sub.Y and R.sub.Z are acetyl.
(50) In some embodiments, a provided compound is of Formula (I-a):
(51) ##STR00033##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, and R.sub.Z are as described herein.
(52) In some embodiments, a provided compound is of Formula (I-b):
(53) ##STR00034##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, R.sub.Z, R.sub.N1, R.sub.N2, and R.sub.N3 are as described herein.
(54) In some embodiments, a provided compound is of the formula:
(55) ##STR00035##
(56) In some embodiments, the present invention provides a compound of Formula (II):
(57) ##STR00036##
(58) wherein: X.sub.2 is selected from the group consisting of a leaving group, —OR.sup.A, or —SR.sup.A, wherein R.sup.A is hydrogen, an oxygen or sulfur protecting group, optionally substituted C.sub.1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl; R.sup.11 K is optionally substituted arylalkyl; R.sub.N2 and R.sub.N3 are independently —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group; R.sup.3 and R.sup.6 are independently —C(O)R.sup.D, wherein each occurrence of R.sup.D is independently optionally substituted alkyl or optionally substituted aryl; R.sup.5 and R.sup.9 are independently selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl; R.sup.10 is optionally substituted arylalkyl; R.sub.Y and R.sub.Z are independently hydrogen or an oxygen protecting group; or R.sub.Z and X.sub.2 are taken together with their intervening atoms to form a five-membered ring; R.sup.7 is selected from the group consisting of —Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and R.sup.4 and R.sup.8 are independently optionally substituted arylalkyl; or a salt thereof.
(59) R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, R.sub.Z, R.sub.N2, and R.sub.N3 are further described in embodiments herein.
(60) In some embodiments, X.sub.2 is selected from the group consisting of a leaving group, —OR.sup.A, or —SR.sup.A, wherein R.sup.A is hydrogen, an oxygen or sulfur protecting group, optionally substituted C.sub.1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl. In some embodiments, X.sub.2 is —OR.sup.A or —SR.sup.A, wherein R.sup.A is hydrogen, an oxygen or sulfur protecting group, optionally substituted C.sub.1-10 alkyl, optionally substituted aryl, optionally substituted acyl, or optionally substituted imidoyl.
(61) In certain embodiments, X.sub.2 is in the alpha configuration. In certain embodiments, X.sub.2 is in the beta configuration. In certain embodiments, X.sub.2 is racemic.
(62) In some embodiments, X.sub.2 is —OR.sup.A. In some embodiments, X.sub.2 is —OH. In some embodiments, X.sub.2 is —O(protecting group). In some embodiments, X.sub.2 is —OR.sup.A, wherein R.sup.A is unsubstituted C.sub.1-10 alkyl. In some embodiments, X.sub.2 is —OR.sup.A, wherein R.sup.A is substituted C.sub.1-10 alkyl. In some embodiments, X.sub.2 is —OR.sup.A, wherein R.sup.A is unsubstituted aryl. In some embodiments, X.sub.2 is —OR.sup.A, wherein R.sup.A is substituted aryl. In some embodiments, X.sub.2 is —OR.sup.A, wherein R.sup.A is unsubstituted acyl. In some embodiments, X.sub.2 is —OR.sup.A, wherein R.sup.A is substituted acyl. In some embodiments, X.sub.2 is —OR.sup.A, wherein R.sup.A is unsubstituted imidoyl. In some embodiments, X.sub.2 is —OR.sup.A, wherein R.sup.A is substituted imidoyl.
(63) In some embodiments, X.sub.2 is —SR.sup.A. In some embodiments, X.sub.2 is —SH. In some embodiments, X.sub.2 is —S(protecting group). In some embodiments, X.sub.2 is —SR.sup.A, wherein R.sup.A is unsubstituted C.sub.1-10 alkyl. In some embodiments, X.sub.2 is —SR.sup.A, wherein R.sup.A is substituted C.sub.1-10 alkyl. In certain embodiments, X.sub.2 is —SCH.sub.3. In some embodiments, X.sub.2 is —SR.sup.A, wherein R.sup.A is unsubstituted aryl. In some embodiments, X.sub.2 is —SR.sup.A, wherein R.sup.A is substituted aryl. In some embodiments, X.sub.2 is —SR.sup.A, wherein R.sup.A is unsubstituted acyl. In some embodiments, X.sub.2 is —SR.sup.A, wherein R.sup.A is substituted acyl. In some embodiments, X.sub.2 is —SR.sup.A, wherein R.sup.A is unsubstituted imidoyl. In some embodiments, X.sub.2 is —SR.sup.A, wherein R.sup.A is substituted imidoyl.
(64) In some embodiments, X.sub.2 is C.sub.1-10 alkoxy. In some embodiments, X.sub.2 is C.sub.1-3 alkoxy. In certain embodiments, X.sub.2 is methoxy. In certain embodiments, X.sub.2 is alpha-methoxy.
(65) In some embodiments, X.sub.2 is selected from the group consisting of alpha-thiomethyl, beta-thiomethyl, alpha-thiocresyl, beta-thiocresyl, alpha-t-butyldiphenylsilyloxy, beta-t-butyldiphenylsilyloxy, and alpha-methoxy.
(66) In some embodiments, X.sub.2 is a leaving group. In some embodiments, X.sub.2 is selected from the group consisting of halogen, optionally substituted thioalkyl, optionally substituted thioaryl, —OC(═N)CCl.sub.3, —OP(O)(OR.sup.F).sub.2, and n-pentenyl, wherein R.sup.F is hydrogen, optionally substituted alkyl, or optionally substituted acyl.
(67) In certain embodiments, X.sub.2 is
(68) ##STR00037##
(abbreviated —S-tolyl). In certain embodiments, X.sub.2 is —OH. In certain embodiments, X.sub.2 is —OAc.
(69) In certain embodiments, a provided compound is of Formula (II-a):
(70) ##STR00038##
wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, and R.sub.Z are as described herein.
(71) In certain embodiments, a provided compound is of Formula (II-b):
(72) ##STR00039##
wherein R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, R.sub.Z, R.sub.N2, and R.sub.N3 are as described herein.
(73) In certain embodiments, a provided compound is of the formula:
(74) ##STR00040##
(75) In another aspect, the present invention provides a compound of Formula (III):
(76) ##STR00041##
(77) wherein: R.sub.N2 is —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group; R.sup.3 and R.sup.6 are independently —C(O)R.sup.D, wherein each occurrence of R.sup.D is independently optionally substituted alkyl or optionally substituted aryl; R.sup.5 is selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl; R.sub.Y is hydrogen or an oxygen protecting group; R.sup.7 is selected from the group consisting of —Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and R.sup.4 and R.sup.8 are independently optionally substituted arylalkyl; or a salt thereof.
(78) R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sub.Y, and R.sub.N2 are further described in embodiments herein.
(79) In certain embodiments, a provided compound is of the formula:
(80) ##STR00042##
(81) In another aspect, the present invention provides methods (Method A) for synthesizing a trisaccharide of formula (III):
(82) ##STR00043##
or a salt thereof;
the method comprising:
(83) (a) reacting monosaccharides of formulae C and D;
(84) ##STR00044##
(85) wherein R.sup.12 and R.sup.13 are each independently an oxygen protecting group; and
(86) X.sub.3 is a leaving group;
(87) in the presence of an activating agent under suitable conditions to form a disaccharide of formula (IV):
(88) ##STR00045##
(89) (b) deprotecting the disaccharide of formula (IV) under suitable conditions to form a compound of formula (V):
(90) ##STR00046##
(91) (c) protecting and deprotecting the compound of formula (V) under suitable conditions to form a compound of formula (VI):
(92) ##STR00047##
(93) (d) reacting the compound of formula (VI) with a monosaccharide of formula B:
(94) ##STR00048##
(95) wherein R.sup.15 and R.sup.16 are independently hydrogen, alkyl or aryl, wherein at least one of R.sup.15 and R.sup.16 is not hydrogen; and
(96) X.sub.4 is a leaving group;
(97) in the presence of an activating agent under suitable conditions to form a trisaccharide of formula (VII):
(98) ##STR00049##
and
(99) (e) protecting the trisaccharide of formula (VII) under suitable conditions to form a trisaccharide of formula (III);
(100) wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sub.Y, and R.sub.N2 are as described herein.
(101) In certain embodiments, the compound of formula (III) is compound 16:
(102) ##STR00050##
(103) In certain embodiments, the compound of formula (IV) is compound 12:
(104) ##STR00051##
(105) In certain embodiments, the compound of formula (V) is compound 13:
(106) ##STR00052##
(107) In certain embodiments, the compound of formula (VI) is compound 14:
(108) ##STR00053##
(109) In certain embodiments, the compound of formula (VII) is compound 15:
(110) ##STR00054##
(111) In certain embodiments, step (a) of Method A takes place in the presence of an electrophile. In certain embodiments, step (a) of Method A takes place in the presence of N-iodosuccinimide. In certain embodiments, step (a) of Method A takes place in the presence of acid. In certain embodiments, step (a) of Method A takes place in the presence of a catalytic amount of acid. In certain embodiments, step (a) of Method A takes place in the presence of triflic acid.
(112) In some embodiments, step (a) of Method A takes place in a polar solvent. In certain embodiments, the solvent is a polar aprotic solvent. In certain embodiments, the solvent is a halogenated solvent. In certain embodiments, step (a) of Method A takes place in dichloromethane.
(113) In some embodiments, the deprotection step (b) of Method A comprises treating the compound of formula (IV) with base. In certain embodiments, the base is an alkoxide. In certain embodiments, the base is a methoxide. In certain embodiments, the deprotection step (b) of Method A comprises treating the compound of formula (IV) with sodium methoxide in methanol. In certain embodiments, R.sub.Y in Method A is acetyl. In certain embodiments, R.sup.3 in Method A is levulinyl.
(114) In certain embodiments, step (c) of Method A comprises protecting the compound of formula (V) using 4-oxopentanoic acid (LevOH). In certain embodiments, step (c) of Method A comprises protecting the compound of formula (V) with EDC, DMAP, and 4-oxopentanoic acid.
(115) In certain embodiments, R.sup.12 of Method A is 2-napththylmethyl.
(116) In certain embodiments, step (c) of Method A comprises deprotecting the compound of formula (V) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).
(117) In certain embodiments, R.sup.4 and R.sup.8 of Method A are benzyl. In certain embodiments, R.sub.N2 of Method A is —N.sub.3.
(118) In certain embodiments, step (d) of Method A takes place in the presence of an electrophile. In certain embodiments, step (d) of Method A takes place in the presence of N-iodosuccinimide. In certain embodiments, step (d) of Method A takes place in the presence of acid. In certain embodiments, step (d) of Method A takes place in the presence of a catalytic amount of acid. In certain embodiments, step (d) of Method A takes place in the presence of triflic acid.
(119) In some embodiments, step (d) of Method A takes place in a polar solvent. In certain embodiments, the solvent is a polar aprotic solvent. In certain embodiments, the solvent is a halogenated solvent. In certain embodiments, step (d) of Method A takes place in dichloromethane.
(120) In some embodiments, the protecting group of step (e) of Method A is an acetyl group.
(121) In some embodiments, the present invention provides methods (Method B) of synthesizing a tetrasaccharide of formula (II):
(122) ##STR00055##
or a salt thereof;
the method comprising:
(123) (a) reacting a trisaccharide of formula (III):
(124) ##STR00056##
(125) with a monosaccharide of formula A:
(126) ##STR00057##
(127) wherein X.sub.5 is a leaving group;
(128) in the presence of an activating agent under suitable conditions to form a compound of formula (VIIIa):
(129) ##STR00058##
(130) (b) ring-opening and protecting the compound of formula (VIIIa) under suitable conditions to form a compound of formula (VIII):
(131) ##STR00059##
wherein R.sup.14 is a protecting group; and
(132) (c) converting the —OR.sup.14 group of the compound of formula (VIII) to a leaving group X.sub.2 under suitable conditions to form a compound of formula (II);
(133) wherein X.sub.2, X.sub.5, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.14, R.sub.Y, R.sub.Z, R.sub.N2, and R.sub.N3 are as described herein.
(134) In certain embodiments, the compound of formula (II) is compound 18:
(135) ##STR00060##
(136) In certain embodiments, the compound of formula (III) is compound 16:
(137) ##STR00061##
(138) In certain embodiments, the compound of formula (VIII) is compound 17:
(139) ##STR00062##
(140) In certain embodiments, the compound of formula (III) used in Method B is prepared by Method A.
(141) In certain embodiments, step (a) of Method B takes place in the presence of an electrophile. In certain embodiments, step (a) of Method B takes place in the presence of N-iodosuccinimide. In certain embodiments, step (a) of Method B takes place in the presence of acid. In certain embodiments, step (a) of Method B takes place in the presence of a catalytic amount of acid. In certain embodiments, step (a) of Method B takes place in the presence of triflic acid.
(142) In some embodiments, step (a) of Method B takes place in a polar solvent. In certain embodiments, the solvent is a polar aprotic solvent. In certain embodiments, the solvent is a halogenated solvent. In certain embodiments, step (a) of Method B takes place in dichloromethane.
(143) In certain embodiments, the R.sup.14, R.sub.Y, and R.sub.Z of Method B are acetyl. In certain embodiments, step (b) of Method B takes place in the presence of acetic anhydride. In certain embodiments, ring-opening is effected by a Lewis acid. In certain embodiments, the Lewis acid is trimethylsilyl trifluoromethanesulfonate (TMSOTf).
(144) In some embodiments, X.sub.2 of Method B is —S-tolyl. In certain embodiments, step (c) of Method B takes place in the presence of trimethyl(4-methylphenylthio)silane (TMSSTol). In certain embodiments, step (c) of Method B takes place in the presence of ZnI.sub.2.
(145) In certain embodiments, Method B further comprises reacting the tetrasaccharide of formula (II) with monosaccharide E:
(146) ##STR00063##
(147) wherein X.sub.1, R.sup.1, R.sup.2, and R.sub.N1 are as described herein;
(148) under suitable conditions to form a pentasaccharide of formula (I) as described herein.
(149) In some embodiments, the present invention provides methods (Method C) of synthesizing a tetrasaccharide of Formula (II):
(150) ##STR00064##
or a salt thereof;
the method comprising:
(151) (a) reacting a disaccharide of formula (VI):
(152) ##STR00065##
(153) with a disaccharide of formula F:
(154) ##STR00066##
(155) wherein X.sub.6 is a leaving group;
(156) in the presence of an activating agent under suitable conditions to form a compound of formula (VIIIa):
(157) ##STR00067##
(158) (b) ring-opening and protecting the compound of formula (VIIIa) under suitable conditions to form a compound of formula (VIII):
(159) ##STR00068##
(160) wherein R.sup.14 is an oxygen protecting group; and
(161) (c) converting the —OR.sup.14 group of the compound of formula (VIII) to a leaving group X.sub.2 under suitable conditions to form a compound of formula (II);
(162) wherein X.sub.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, R.sub.Z, R.sub.N2, and R.sub.N3 are as described herein.
(163) In certain embodiments, the compound of formula (II) is compound 18:
(164) ##STR00069##
(165) In certain embodiments, the compound of formula (VI) is compound 14:
(166) ##STR00070##
(167) In certain embodiments, the compound of formula (VIII) is compound 17:
(168) ##STR00071##
(169) In certain embodiments, R.sup.14, R.sub.Y, and R.sub.Z of Method C are acetyl.
(170) In certain embodiments, the compound of formula F is compound 28:
(171) ##STR00072##
(172) In certain embodiments, the present invention provides methods of synthesizing a tetrasaccharide of formula (VIIIa):
(173) ##STR00073##
or a salt thereof;
wherein:
(174) R.sup.11 is optionally substituted arylalkyl;
(175) R.sub.N2 and R.sub.N3 are independently —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group;
(176) R.sup.3 and R.sup.6 are independently —C(O)R.sup.D, wherein each occurrence of R.sup.D is independently optionally substituted alkyl or optionally substituted aryl;
(177) R.sup.5 and R.sup.9 are independently selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl;
(178) R.sup.10 is optionally substituted arylalkyl;
(179) R.sub.Y is independently hydrogen or an oxygen protecting group; or
(180) R.sub.Z and X.sub.2 are taken together with their intervening atoms to form a five-membered ring;
(181) R.sup.7 is selected from the group consisting of —Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and
(182) R.sup.4 and R.sup.8 are independently optionally substituted arylalkyl; the method comprising:
(183) reacting a disaccharide of formula (VI):
(184) ##STR00074##
(185) with a disaccharide of formula F:
(186) ##STR00075##
(187) wherein X.sub.6 is a leaving group;
(188) in the presence of an activating agent under suitable conditions to form a compound of formula (VIIIa).
(189) In certain embodiments, the compound of formula (VIIIa) is
(190) ##STR00076##
(191) In certain embodiments, step (a) of Method C takes place in the presence of an electrophile. In certain embodiments, step (a) of Method C takes place in the presence of N-iodosuccinimide. In certain embodiments, step (a) of Method C takes place in the presence of acid. In certain embodiments, step (a) of Method C takes place in the presence of a catalytic amount of acid. In certain embodiments, step (a) of Method C takes place in the presence of triflic acid.
(192) In some embodiments, step (a) of Method C takes place in a polar solvent. In certain embodiments, the solvent is a polar aprotic solvent. In certain embodiments, the solvent is a halogenated solvent. In certain embodiments, step (a) of Method C takes place in dichloromethane.
(193) In certain embodiments, the R.sup.14, R.sub.Y, and R.sub.Z of Method C are acetyl. In certain embodiments, step (b) of Method C takes place in the presence of acetic anhydride. In certain embodiments, ring-opening is effected by a Lewis acid. In certain embodiments, the Lewis acid is trimethylsilyl trifluoromethanesulfonate (TMSOTf).
(194) In some embodiments, X.sub.2 of Method C is S-tolyl. In certain embodiments, step (c) of Method C takes place in the presence of trimethyl(4-methylphenylthio)silane (TMSSTol). In certain embodiments, step (c) of Method C takes place in the presence of ZnI.sub.2.
(195) In certain embodiments, Method C further comprises reacting the tetrasaccharide of formula (II) with monosaccharide E:
(196) ##STR00077##
(197) wherein X.sub.1, R.sup.1, R.sup.2, and R.sub.N1 are as described herein;
(198) under suitable conditions to form a pentasaccharide of formula (I) as described herein.
(199) In some embodiments, the present invention provides methods (Method D) for synthesizing a pentasaccharide of formula (I):
(200) ##STR00078##
or a salt thereof;
the method comprising:
(201) reacting a tetrasaccharide of formula (II):
(202) ##STR00079##
(203) with monosaccharide E:
(204) ##STR00080##
under suitable conditions to form a pentasaccharide of formula (I);
(205) wherein X.sub.1, X.sub.2, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, R.sub.Z, R.sub.N1, R.sub.N2, and R.sub.N3 are as described herein.
(206) In some embodiments, Method D described above further comprises a deprotection step.
(207) In certain embodiments, the reaction between the tetrasaccharide of formula (II) and monosaccharide E of Method D takes place in the presence of an electrophile. In certain embodiments, the electrophile is N-iodosuccinimide. In certain embodiments, the reaction between the tetrasaccharide of formula (II) and monosaccharide E of Method D takes place in the presence of an acid. In certain embodiments, the reaction between the tetrasaccharide of formula (II) and monosaccharide E of Method D takes place in the presence of a catalytic amount of acid. In certain embodiments, the reaction between the tetrasaccharide of formula (II) and monosaccharide E of Method D takes place in the presence of triflic acid.
(208) In some embodiments, the reaction between the tetrasaccharide of formula (II) and monosaccharide E of Method D takes place in a polar solvent. In certain embodiments, the solvent is a polar aprotic solvent. In certain embodiments, the solvent is a halogenated solvent. In certain embodiments, the halogenated solvent is dichloromethane.
(209) In another aspect, the present disclosure provides a method (Method E) of synthesizing fondaparinux:
(210) ##STR00081##
or a salt thereof;
the method comprising:
(211) (a) deprotecting a pentasaccharide of formula (I′):
(212) ##STR00082##
wherein:
(213) X.sub.1 is alpha-methoxy;
(214) R.sup.2 and R.sup.11 are independently optionally substituted arylalkyl;
(215) R.sub.N1, R.sub.N2, and R.sub.N3 are independently —N.sub.3 or —N(R.sup.W).sub.2, wherein each R.sup.W is independently hydrogen or a nitrogen protecting group;
(216) R.sup.3 and R.sup.6 are independently —C(O)R.sup.D, wherein each occurrence of R.sup.D is independently optionally substituted alkyl or optionally substituted aryl;
(217) R.sup.1, R.sup.5, and R.sup.9 are independently selected from the group consisting of optionally substituted arylalkyl and —Si(R.sup.B).sub.3, wherein each R.sup.B is independently alkyl or aryl;
(218) R.sup.10 is optionally substituted arylalkyl;
(219) R.sub.Y and R.sub.Z are independently hydrogen or an oxygen protecting group;
(220) R.sup.7 is selected from the group consisting of Si(R.sup.B).sub.3, optionally substituted arylalkyl, and —C(O)R.sup.C, wherein R.sup.C is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and
(221) R.sup.4 and R.sup.8 are independently optionally substituted arylalkyl;
(222) under suitable conditions to form a compound of formula (IX):
(223) ##STR00083##
(224) (b) oxidizing, deprotecting, and esterifying the compound of formula (IX) under suitable conditions to form a compound of formula (X):
(225) ##STR00084##
wherein R′ is C.sub.1-6 alkyl or optionally substituted benzyl;
(226) (c) sulfonating the compound of formula (X) under suitable conditions to form a compound of formula (XI):
(227) ##STR00085##
(228) (d) converting the compound of formula (XI) to a compound of formula (XII) under suitable conditions:
(229) ##STR00086##
(230) (e) deprotecting the compound of formula (XII) under suitable conditions to form a compound of formula (XIII):
(231) ##STR00087##
and
(232) (f) sulfonating the compound of formula (XIII) under suitable conditions to form fondaparinux 25.
(233) X.sub.1, R′, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sub.Y, R.sub.Z, R.sub.N1, R.sub.N2, and R.sub.N3 are further described in embodiments herein.
(234) In certain embodiments, R.sub.N1, R.sub.N2, and R.sub.N3 of formula (I′) of Method E are independently selected from the group consisting of —N.sub.3, —NH(Cbz), —NHC(O)CH.sub.3, and —N(C(O)CH.sub.3).sub.2.
(235) In certain embodiments, the pentasaccharide of formula (I′) is compound 19:
(236) ##STR00088##
(237) In certain embodiments, the compound of formula (IX) is compound 20:
(238) ##STR00089##
(239) In certain embodiments, the compound of formula (X) is compound 21:
(240) ##STR00090##
(241) In certain embodiments, the compound of formula (XI) is compound 22:
(242) ##STR00091##
(243) In certain embodiments, the compound of formula (XII) is compound 23:
(244) ##STR00092##
(245) In certain embodiments, the compound of formula (I′) is prepared by Method B, C, or D.
(246) In some embodiments, the deprotection step (a) of Method E comprises treating the compound of formula (I′) with base. In certain embodiments, the base is an alkoxide. In certain embodiments, the base is a methoxide. In certain embodiments, the deprotection step (a) of Method E comprises treating the compound of formula (I′) with Mg(OMe).sub.2. In certain embodiments, R.sub.Y in Method A is acetyl.
(247) In certain embodiments, the oxidizing of step (b) of Method E comprises using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). In certain embodiments, the oxidizing of step (b) of Method E comprises using bisacetoxyiodobenzene (BAIB). In certain embodiments, the oxidizing of step (b) of Method E comprises using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)/bisacetoxyiodobenzene (BAIB).
(248) In certain embodiments, the esterifying of step (b) of Method E comprises using diazomethane. In certain embodiments, the esterifying of step (b) of Method E comprises using hydrazine. In certain embodiments, the esterifying of step (b) of Method E comprises transesterification with an alcohol. In certain embodiments, the esterifying of step (b) of Method E comprises using t-butylene. In certain embodiments, the esterifying of step (b) of Method E comprises using an alkyl halide. In certain embodiments, the deprotection of step (b) of Method E comprises using a fluoride reagent. In certain embodiments, the deprotection of step (b) of Method E comprises using HF.
(249) In certain embodiments, the sulfonating step (c) of Method E comprises using SO.sub.3-pyridine complex. In certain embodiments, the sulfonating step (c) of Method E comprises using SO.sub.3 and triethylamine. In certain embodiments, the sulfonating step (f) of Method E comprises using SO.sub.3-pyridine complex. In certain embodiments, the sulfonating step (e) of Method E comprises using SO.sub.3 and triethylamine. In certain embodiments, the sulfonating step (c) of Method E comprises using SO.sub.3 and triethylamine in DMF. In certain embodiments, the sulfonating step (f) of Method E comprises using SO.sub.3-pyridine complex in aqueous sodium hydroxide.
(250) In certain embodiments, step (d) of Method E comprises using a base. In certain embodiments, the base is hydroxide. In certain embodiments, the base is sodium hydroxide. In certain embodiments, the base is lithium hydroxide. In certain embodiments, step (d) of Method E employs a peroxide in addition to a base. In certain embodiments, the peroxide is hydrogen peroxide.
(251) In certain embodiments, the deprotecting step (e) of Method E comprises using PdOH/carbon and hydrogen gas. In certain embodiments, the deprotecting step (e) of Method E takes place in a buffer. In certain embodiments, the buffer is a phosphate buffer.
(252) In certain embodiments, the present invention provides a method of synthesizing fondaparinux comprising Methods A, B, D, and E. In certain embodiments, the present invention provides a method of synthesizing fondaparinux comprising Methods C, D, and E.
EXAMPLES
(253) ##STR00093##
3,4,6-tri-O-acetyl-2-azido-2-deoxy-D-glucopyranosyl acetate (2)
(254) Trifluoromethanesulfonic anhydride (0.94 mL, 5.57 mmol) was slowly added dropwise from an addition funnel to a solution of sodium azide (1.80 g, 27.8 mmol) in a mixture of water (4.7 mL) and dichloromethane (7.6 mL) at 0° C. After stirring at the same temperature for 2 h, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were neutralized with saturated NaHCO3(aq). The generated trifluoromethanesulfonicazide (TfN.sub.3) was directly used without further purification for the ensuing reaction. Sodium carbonate (0.59 g, 5.57 mmol) was added to a solution of D-glucosamine hydrochloride 1 (1.00 g, 4.60 mmol) in water (10 mL) until the pH value was around 10-11. After immersing this mixture in an ice-bath, CuSO4.5H2O (12.0 mg, 0.05 mmol) and the TfN3 solution in dichloromethane were added sequentially. MeOH (10 mL) was added to the mixture until the phase became homogeneous. The ice-bath was then removed and the reaction was kept stirring at room temperature for 2 d. After that, acetic anhydride (4.0 mL), DMAP (0.01 g, 0.09 mmol) were added and stirred for 1 d. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Hex=1/1) to afford the azido compound 2.
(255) ##STR00094##
p-Methylphenyl 2-azido-2-deoxy-1-thio-D-glucopyranoside (3)
(256) To a solution of 2 (1.00 g, 2.68 mmol) and p-thiocresol (0.41 g, 3.30 mmol) in BF.sub.3/OEt.sub.2 (5.0 mL) was stirred for 8 h at room temperature, and the reaction was added with MeOH (5.0 mL), and refluxed for 16 h. Et.sub.3N was added to quench the reaction, and was evaporated at reduced pressure. The residue was purified by flash column chromatography (MeOH/CH.sub.3Cl=1/9) to afford compound 3 in 78% yield.
(257) ##STR00095##
p-Methylphenyl 2-azido-2-deoxy-4-O-(2-naphthylmethyl)-1-thio-D-glucopyranoside (4)
(258) TMSOTf (58.0 μL, 0.32 mmol) was added at room temperature under nitrogen to a suspension of 3 (1.00 g, 3.20 mmol) and HMDS (1.14 mL, 5.12 mmol) in CH.sub.2Cl.sub.2 (10 mL). After the system had been stirred for 1 h, CH.sub.2Cl.sub.2 (10 mL), 4 Å molecular sieves (1.00 g) and 2-NAPCHO (0.56 g, 3.36 mmol) were added and stirred for 1 h. The mixture was then cooled to 0° C. and TMSOTf (0.12 mL, 0.64 mmol) was added. After the system had been stirred for 2 h, BH.sub.3/THF (17.0 mL, 16.0 mmol), and TMSOTf (0.3 mL, 1.6 mmol) were added. After the reaction had been stirred at 0° C. for another 8 h, TBAF (3.20 mL) was added. The mixture was stirred at room temperature for 16 h and filtered through a pad of celite. The filtrate was washed with saturated NaHCO.sub.3(aq), extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Hex=1/3) to afford compound 4 (1.27 g, 88%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.84-7.75 (m, 9H, Ar—H), 7.48-7.45 (m, 5.6H, Ar—H), 7.42 (t, J=6.3 Hz, 3.5H, Ar—H), 7.35 (d, J=7.9 Hz, 3H, Ar—H), 7.12 (dd, 4.6H, J=11.9, 8.0 Hz, Ar—H), 5.43 (d, J=5.5 Hz, 1.2H, H-1), 4.95 (d, J=11.5 Hz, 1.2H, CH.sub.2Ph), 4.91 (d, J=11.5 Hz, 1.2H, CH.sub.2Ph), 4.89 (d, J=8.5 Hz, 1H, CH.sub.2Ph), 4.84 (d, J=8.5 Hz, 1H, CH.sub.2Ph), 4.38 (d, J=9.7 Hz, 1H, H-1), 4.25 (d, J=9.4 Hz, 1.2H, H-5), 3.96 (t, J=9.6 Hz, 1.2H, H-3), 3.91 (d, J=10.4 Hz, 1H, H-6a), 3.83-3.80 (m, 2.4H, H-6ab), 3.76-3.71 (m, 2.2H, H-2, H-6b), 3.60 (t, J=9.7 Hz, 1H, H-3), 3.56 (t, J=9.4 Hz, 1.2H, H-4), 3.44 (t, J=9.7 Hz, 1H, H-4), 3.33-3.31 (m, 1H, H-5), 3.21 (t, J=9.7 Hz, 1H, H-2), 2.93 (brs, 2H, OH), 2.33 (s, 3H), 2.31 (s, 3.6H).
(259) ##STR00096##
p-Methylphenyl 2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-4-O-(2-naphthylmethyl)-1-thio-D-glucopyranoside (C)
(260) Compound 4 (5.00 g, 10.9 mmol), Et.sub.3N (4.6 mL, 21.8 mmol) and DMAP (0.13 g, 1.1 mmol) were dissolved in CH.sub.2Cl.sub.2 (50.0 mL) under nitrogen and the reaction flask was immersed in an ice-water bath. TBDPSCl (2.9 mL, 12.0 mmol) was added to the solution, the ice-water bath was removed, and the mixture was kept stirring for 1 day. The reaction was quenched by adding MeOH and the solvents were evaporated under reduced pressure. The reaction was extracted with ethyl acetate and water. The combined organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo to give a residue, which was further purified by flash column chromatography (EtOAc/Hex=1/7) to afford compound C (6.88 g, 90%).
(261) ##STR00097##
p-Methylphenyl 2-azido-3-O-(p-bromobenzyl)-6-O-tert-butyldiphenylsilyl-2-deoxy-4-O-(2-naphthylmethyl)-1-thio-D-glucopyranoside (A)
(262) To a solution of C (10.00 g, 14.5 mmol) in THF (100.0 mL) was consecutively added with parabromobenzylbromide (4.75 g, 15.23 mmol) and NaH (0.56 g, 17.4 mmol) at 0° C. under nitrogen. After stirring for 8 h at room temprature, the reaction was quenched with MeOH, and the solvent was evaporated at reduced pressure. The mixture was dissolved in EtOAc, and the solution was sequentially washed with water, and brine. The organic layer was dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo. The mixture was further purified by flash column chromatography (EtOAc/Hex=1/9) to afford compound A (11.8 g, 90%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94-7.89 (m, 5.5H, Ar—H), 7.86-7.76 (m, 18.0H, Ar—H), 7.69-7.65 (m, 3.6H, Ar—H), 7.59-7.55 (m, 6.2H, Ar—H), 7.54-7.44 (m, 19.3H, Ar—H), 7.42-7.34 (m, 12.3H, Ar—H), 7.31-7.26 (m, 4.8H, Ar—H), 7.14-7.12 (m, 5.4H, Ar—H), 5.68 (d, J=5.3 Hz, 1.6H, αH-1), 5.10 (d, J=11.1 Hz, 1.7H, ArCH.sub.2), 5.05-5.00 (m, 2.7H, ArCH.sub.2), 4.98 (s, 1.0H, ArCH.sub.2), 4.95 (s, 3.3H, ArCH.sub.2), 4.89 (s, 2.0H, ArCH.sub.2), 4.48 (d, J=10.1 Hz, 1.0H, βH-1), 4.43 (d, J=9.4, 1.5H, αH-5), 4.18-4.14 (m, 2.7H, αH-6a, βH-6a), 4.10-3.91 (m, 8.7H, αH-2, αH-6b, αH-3, αH-4, βH-2, βH-6b), 3.65-3.60 (m, 1.4H, βH-3), 3.50-3.45 (m, 2.1H, βH-4, βH-5), 2.40 (s, 7.6H, CH.sub.3), 1.22 (s, 9.9H, t-Bu), 1.18 (s, 13.7H, t-Bu).
(263) ##STR00098##
Methyl 2-azido-3-O-(p-bromobenzoyl)-6-O-tert-butyldiphenylsilyl-2-deoxy-α-D-glucopyranoside (E)
(264) A mixture of the thioglycoside A (2.00 g, 2.33 mmol) and MeOH (0.13 mL, 2.8 mmol) in dry Et.sub.2O (20.0 mL) was added to a reaction flask containing freshly dried 3 Å molecular sieves under nitrogen. The mixture was stirred at room temperature for 1 h, and the solution was cooled to −60° C. N-Iodosuccinimide (NIS, 0.64 g, 2.8 mmol) and trifluoromethanesulfonic acid (100.0 μL, 1.17 mmol) were added to the reaction flask, and the mixture was gradually warmed up to −40° C. The resulting solution was kept stirring for 3 h, and DDQ (1.61 g, 11.65 mmol), CH.sub.3CN (20.0 mL) were added to the reaction. The mixture was stirred for 2 days and the whole mixture was filtered through Celite followed by washing with CH.sub.2Cl.sub.2, and the filtrate was sequentially washed with 10% Na.sub.2S.sub.2O.sub.3(aq) and brine. The organic layer was dried over anhydrous MgSO.sub.4. The residue was filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography (EtOAc/Hex=1/8) to give the compound E (0.83 g, 57%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.70-7.65 (m, 6H, Ar—H), 7.48-7.35 (m, 11H, Ar—H), 7.27 (d, J=8.2 Hz, 1H, Ar—H), 4.82 (d, J=11.4 Hz, 1H, ArCH.sub.2), 4.79 (d, J=11.4 Hz, 1H, ArCH.sub.2), 4.72 (d, J=3.2 Hz, 1H, H-1), 3.86-3.85 (m, 2H, H-6a, H-6b), 3.79 (t, J=9.3 Hz, 1H, H-3), 3.71 (t, J=9.3 Hz, 1H, H-4), 3.64-3.62 (m, 1H, H-5), 3.34 (s, 3H, CH.sub.3), 3.31 (dd, J=9.3, 3.2 Hz, 1H, H-2), 2.62 (s, 1H, OH), 1.05 (s, 9H, t-Bu).
(265) ##STR00099##
p-Methylphenyl 1-thio-β-D-glucopyranoside (6)
(266) To a solution of 5 (1.00 g, 2.56 mmol) and p-thiocresol (0.41 g, 3.30 mmol) in BF.sub.3/OEt.sub.2 (5.0 mL) was stirred for 8 h at room temperature, and the reaction was added with MeOH (5.0 mL), and refluxed for 16 h. Et.sub.3N was added to quench the reaction, and was evaporated at reduced pressure. The residue was purified by flash column chromatography (MeOH/CH.sub.3Cl=1/9) to afford compound 6 in 72% yield.
(267) ##STR00100##
p-Methylphenyl 2,3,4,6-tri-O-methylsilyl-1-thio-β-D-glucopyranoside (6a)
(268) Compound 6 (29.0 g, 101 mmol) was dissolved in CH.sub.2Cl.sub.2 (300 mL) under N.sub.2 atmosphere, the reaction flask was immersed in an ice bath, Et.sub.3N (140 mL, 1.01 mol) and TMSCl (64.7 mL, 506 mmol) were sequentially added to the solution, and the mixture was stirred at room temperature for 16 h. The reaction was quenched with water, and the crude target material was extracted with ethyl acetate. The combined organic layer was dried over MgSO.sub.4, filtered and concentrated in vacuo to give a residue, which was further recrystallized via vapor diffusion method to provide 6a (56.00 g, 97%) as colorless crystals.
(269) ##STR00101##
p-Methylphenyl 2-O-benzoyl-3-O-benzyl-4,6-O-benzylidene-1-thio-β-D-glucopyranoside (B)
(270) TMSOTf (47.0 μL, 0.26 mmol) was added at 0° C. under nitrogen to a solution of 6a (1.00 g, 1.74 mmol), 4 Å molecular sieves (1.00 g) and benzaldehyde (0.18 mL, 1.77 mmol) in CH.sub.2Cl.sub.2 (10 mL). After the system had been stirred for 2 h, triethylsilane (0.30 mL, 1.91 mmol), benzaldehyde (0.18 mL, 1.77 mmol) and TMSOTf (30.0 μL, 0.17 mmol) were added. After the reaction had been stirred for another 4 h, benzoic anhydride (1.00 mL, 8.70 mmol) and TMSOTf (0.12 mL, 0.7 mmol) were successively added at 0° C. The mixture was stirred at room temperature for 16 h and filtered through a pad of celite. The filtrate was washed with saturated NaHCO.sub.3(aq), extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Hex=1/8) to afford compound B (0.62 g, 63%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.05 (dd, J=8.4, 1.3 Hz, 2H, Bz-H), 7.63 (tt, J=7.4, 1.3 Hz, 1H, Ar—H), 7.53-7.47 (m, 4H, Ar—H), 7.44-7.35 (m, 5H, Ar—H), 7.16-7.06 (m, 7H, Ar—H), 5.62 (s, 1H, PhCH), 5.29 (dd, J=10.0, 8.6 Hz, 1H, H-2), 4.83 (d, J=12.0 Hz, 1H, CH.sub.2Ph), 4.81 (d, J=10.0 Hz, 1H, H-1), 4.68 (d, J=12.0 Hz, 1H, CH.sub.2Ph), 4.44 (dd, J=10.3, 5.0 Hz, 1H, H-6a), 3.90 (dd, J=9.2, 8.6 Hz, 1H, H-3), 3.86 (t, J=10.3 Hz, 1H, H-6b), 3.82 (t, J=9.2 Hz, 1H, H-4), 3.57 (ddd, J=10.3, 9.2, 5.0 Hz, 1H, H-5), 2.34 (s, 3H, CH.sub.3).
(271) ##STR00102##
3-O-Benzyl 1,2:5,6,-di-O-isopropylidene-α-D-glucofuranose (8)
(272) To a solution of 7 (1,2:5,6,-di-O-isopropylidene-α-
(273) ##STR00103##
3-O-Benzyl 1,2-O-isopropylidene-α-D-glucofuranose (9)
(274) To a solution of 8 in 64% AcOH (250 mL) was stirred for 16 h at room temperature and the reaction was quenched with saturated NaHCO.sub.3(aq). The mixture was dissolved in EtOAc, and the solution was sequentially washed with water, and brine. The organic layer was dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Hex=1/5) to afford compound 9. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 7.33-7.21 (m, 1H, Ar—H), 5.87 (d, J=3.8 Hz, 1H, H-1), 4.64, 4.56 (ABq, J=11.7 Hz, 2H, CH.sub.2Ph), 4.56 (d, J=3.8 Hz, 1H, H-2), 4.12-4.04 (m, 2H, H-3, H-4), 4.02-3.94 (m, 1H, H-5), 3.76 (dd, 1H, J=11.6, 2.9 Hz, H-6a), 3.64 (dd, 1H, J=11.6, 5.5 Hz, H-6b), 3.34 (brs, 2H, OH-5, OH-6), 1.44 (s, 3H, CH.sub.3), 1.26 (s, 3H, CH.sub.3).
(275) ##STR00104##
6-O-Benzoyl-3-O-benzyl-5-O-methylsulfonyl-1,2-O-isopropylidene-α-D-glucofuranose (10)
(276) Compound 9 was dissolved in CH.sub.2Cl.sub.2 (500 mL) under N.sub.2 atmosphere, the reaction flask was immersed in an ice bath, Et.sub.3N (90.0 mL, 644 mmol) and benzoyl chloride (14.2 mL, 122 mmol) were sequentially added to the solution, and the mixture was stirred at the same temperature for 2 h. Methyl chloride (9.48 mL, 122 mmol) was added to the solution, the ice bath was removed, and then, the mixture was stirred at room temperature for 16 h. The reaction was quenched with water, and the crude target material was extracted with ethyl acetate. The combined organic layer was sequentially washed with 1 N HCl.sub.(aq), saturated NaHCO.sub.3(aq) and brine. The organic phase was dried over MgSO.sub.4, filtered and concentrated in vacuo to get a residue, which was purified by flash column chromatography on silica gel (EtOAc/Hex=1/3) to provide 10 (70.9 g, 75% in three steps) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.06 (dd, J=7.5, 1.5 Hz, 2H, Bz-H), 7.56 (t, J=7.5 Hz, 1H, Bz-H), 7.45-7.26 (m, 7H, Ar—H), 5.91 (d, J=3.4 Hz, 1H, H-1), 5.40 (ddd, J=8.0, 6.2, 2.0 Hz, 1H, H-5), 4.91 (dd, J=12.8, 2.0 Hz, 1H, H-6a), 4.70 (d, J=11.0 Hz, 1H, CH.sub.2Ph), 4.60 (d, J=3.4 Hz, 1H, H-2), 4.599 (d, J=11.0 Hz, 1H, CH.sub.2Ph), 4.49 (dd, J=12.8, 6.2 Hz, 1H, H-6b), 4.46 (dd, J=8.0, 3.4 Hz, 1H, H-4), 4.13 (d, J=3.4 Hz, 1H, H-3), 2.98 (s, 3H, CH.sub.3), 1.49 (s, 3H, CH.sub.3), 1.31 (s, 3H, CH.sub.3).
(277) ##STR00105##
3-O-Benzyl-1,6-anhydro-β-L-idopyranose (11)
(278) To a solution of 10 (1.20 g, 2.44 mmol) in a mixed solvent of CH.sub.2Cl.sub.2 and t-BuOH (2/1 ratio, 18 mL) was added potassium t-butoxide (0.60 g, 5.36 mmol) at 0° C. under nitrogen. After stirring for 16 h, the reaction was acidified with 0.6 N H.sub.2SO.sub.4(aq) (ca. 4.5 mL) and the flask was equipped with a simple distillation head to evaporate CH.sub.2Cl.sub.2 and t-BuOH under reduced pressure. 0.6 N H.sub.2SO.sub.4(aq) (5 mL) and diglyme (10 mL) were added to the resulting solution, and the mixture was kept stirring at 160° C. for another 16 h. After cooling to room temperature, the reaction was neutralized with 3 N NaOH.sub.(aq) (2 mL), and the solvent was removed on rotary evaporator under vacuum. Water (10 mL) was added to the residue, and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over MgSO.sub.4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Hex=1/1) to give a white solid, which was further recrystallized via vapor diffusion method to provide 11 (0.32 g, 52%) as colorless crystals. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.36-7.28 (m, 5H, Ar—H), 5.27 (d, J=1.8 Hz, 1H, H-1), 4.93 (d, J=11.7 Hz, 1H, CH.sub.2Ph), 4.72 (d, J=11.7 Hz, 1H, CH.sub.2Ph), 4.41 (t, J=4.9 Hz, 1H, H-5), 4.01 (d, J=7.8 Hz, 1H, H-6a), 3.85 (ddd, J=7.8, 4.9, 3.3 Hz, 1H, H-4), 3.71 (dd, J=7.8, 4.9 Hz, 1H, H-6b), 3.64 (td, J=7.8, 1.8 Hz, 1H, H-2), 3.37 (t, J=7.8 Hz, 1H, H-3), 2.09 (d, J=3.3 Hz, 1H, OH-4), 1.89 (d, J=7.8 Hz, 1H, OH-2).
(279) ##STR00106##
2-O-Benzoyl-3-O-benzyl-1,6-anhydro-β-L-idopyranose (D)
(280) To a solution of 11 (3.00 g, 11.9 mmol) in dichloromethane (35 mL) was consecutively added pyridine (3.0 mL, 35.7 mmol) and benzoyl chloride (1.4 mL, 12.5 mmol) at 0° C. under nitrogen. After stirring for 4 h, the reaction was quenched with MeOH, and the solvent was evaporated at reduced pressure. The mixture was dissolved in EtOAc, and the solution was sequentially washed with 2 N HCl.sub.(aq), saturated NaHCO.sub.3(aq), water, and brine. The organic layer was dried over anhydrous MgSO.sub.4, filtered, and concentrated in vacuo. The residue was recrystallized from EA/Hex=1/4 to afford the 4-alcohol D (3.60 g, 85%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.08 (dd, J=7.6, 1.3 Hz, 2H, Bz-H), 7.59 (tt, J=7.6, 1.3 Hz, 1H, Bz-H), 7.46 (t, J=7.6 Hz, 2H, Bz-H), 7.29-7.24 (m, 5H, Ar—H), 5.53 (d, J=1.6 Hz, 1H, H-1), 5.07 (dd, J=8.2, 1.6 Hz, 1H, H-2), 4.80 (d, J=11.6 Hz, 1H, CH.sub.2Ph), 4.65 (d, J=11.6 Hz, 1H, CH.sub.2Ph), 4.51 (t, J=4.6 Hz, 1H, H-5), 4.15 (d, J=7.5 Hz, 1H, H-6a), 4.00 (ddd, J=8.2, 4.6, 3.0 Hz, 1H, H-4), 3.87 (t, J=8.2 Hz, 1H, H-3), 3.76 (dd, J=7.5, 4.6 Hz, 1H, H-6b), 2.22 (d, J=3.0 Hz, 1H, OH-4).
(281) ##STR00107##
1,6-Anhydro-4-O-(2-azido-6-O-tertbutyldiphenylsilyl-2-deoxy-4-O-(2-naphthylmethyl)-α-D-glucopyranosyl)-2-O-benzoyl-3-O-benzyl-β-L-idopyranose (12)
(282) A mixture of the thioglycoside C (4.30 g, 6.23 mmol) and acceptor D (3.33 g, 9.34 mmol) in dry CH.sub.2Cl.sub.2 (70.0 mL) was added to a reaction flask containing freshly dried 4 Å molecular sieves under nitrogen. The mixture was stirred at room temperature for 1 h, and the solution was cooled to −60° C. N-Iodosuccinimide (NIS, 1.74 g, 8.10 mmol) and trifluoromethanesulfonic acid (TfOH, 220.0 μL, 2.49 mmol) were added to the reaction flask, and the mixture was gradually warmed up to −40° C. The resulting solution was kept stirring for 3 h, and Et.sub.3N was added to quench the reaction. The whole mixture was filtered through Celite followed by washing with CH.sub.2Cl.sub.2, and the filtrate was sequentially washed with 10% Na.sub.2S.sub.2O.sub.3(aq) and brine. The organic layer was dried over anhydrous MgSO.sub.4. The residue was filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography (EtOAc/Hex=1/5) to give the disaccharide 12 (4.00 g, 70%).
(283) ##STR00108##
1,6-Anhydro-4-O-(2-azido-6-O-tertbutyldiphenylsilyl-2-deoxy-4-O-(2-naphthylmethyl)-α-D-glucopyranosyl)-3-O-benzyl-β-L-idopyranose (13)
(284) NaOMe (6.00 mg, 0.11 mmol) was added to a solution of compound 12 (0.10 g, 0.11 mmol) in MeOH (5 mL) ar room temperature under nitrogen atomsphere. After stirring for 3 h, the reaction was neutralized by adding DOWEX 50WX4-200 resin. The mixture was filtered, and the filtrate was concentrated under reduced pressure, purified by flash column chromatography (EtOAc/Hex=1/2) to give the disaccharide 13 (0.08 g, 92%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.82 (dd, J=3.4, 6.0 Hz, 1H, Ar—H), 7.79-7.76 (m, 2H, Ar—H), 7.70-7.67 (m, 5H, Ar—H), 7.51-7.48 (m, 2H, Ar—H), 7.44-7.40 (m, 4H, Ar—H), 7.39-7.30 (m, 8H, Ar—H), 5.27-5.24 (m, 2H, H-1, H-1′), 4.94 (d, J=11.2 Hz, 1H, CH.sub.2Ph), 4.90 (s, 2H, CH.sub.2Ph), 4.83 (d, J=11.2 Hz, 1H, CH.sub.2Ph), 4.51 (t, J=4.6 Hz, 1H, H-5), 4.11 (dd, J=10.1, 8.3 Hz, 1H, H-3′), 3.98 (d, J=7.7 Hz, 1H, H-6a), 3.90-3.85 (m, 3H, H-6′a, H-6′b, H-4), 3.65-3.56 (m, 5H, H-2, H-3, H-6b, H-4′, H-5′), 3.24 (dd, J=3.8, 10.1 Hz, 1H, H-2′), 1.09 (s, 9H, t-Bu).
(285) ##STR00109##
1,6-Anhydro-4-O-(2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-levulinyl-α-D-glucopyranosyl)-3-O-benzyl-2-O-levulinyl-β-L-idopyranose (14)
(286) Disaccharide 13 (0.23 g, 0.28 mmol) and the residue, EDC (0.27 g, 1.40 mmol) and DMAP (4.0 mg, 0.03 mmol) were dissolved in CH.sub.2Cl.sub.2 (4 mL) and the reaction flask was cooled to 0° C. LevOH (0.32 g, 2.80 mmol) was slowly added to the solution and the mixture was stirred for another 16 h. After that, DDQ (0.2 g, 0.84 mmol) in three equal portions in half-hour intervals and H.sub.2O (0.2 ml) was added. After 4 h of stirring, the reaction was quenched by sat. NaHCO.sub.3(aq) followed by extraction with CH.sub.2Cl.sub.2. The combined organic layer was sequentially washed with saturated NaHCO.sub.3(aq), brine, dried over anhydrous MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc/Hex=1/2) on silica gel to provide 4′-alcohol 14 (0.17 g, 70%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.65-7.62 (m, 4H, Ar—H), 7.42-7.23 (m, 11H, Ar—H), 5.34-5.31 (m, 2H, H-1, H-3′), 5.29 (d, J=3.5 Hz, 1H, H-1′), 4.81-4.78 (m, 2H, H-2, ArCH.sub.2), 4.71 (d, J=11.1 Hz, 1H, ArCH.sub.2), 4.54 (t, J=4.1 Hz, 1H, H-5), 4.10 (d, J=7.8 Hz, 1H, H-6a), 3.94-3.89 (m, 3H, H-3, H-5′, H-6′a), 3.82-3.80 (m, 1H, H-6′b), 3.70-3.66 (m, 3H, H-4, H-4′, H-6b), 3.27 (s, 1H, OH), 3.22 (dd, J=10.8, 3.5 Hz, 1H, H-2′), 2.95-2.89 (m, 1H), 2.81-2.76 (m, 1H), 2.72-2.61 (m, 3H), 2.58-2.45 (m, 3H), 2.17 (s, 3H, CH.sub.3), 2.16 (s, 3H, CH.sub.3), 1.03 (s, 9H, t-Bu).
(287) ##STR00110##
O-[2-O-Benzoyl-3-O-benzyl-β-D-glucopyranosyl]-(1→4)-O-[2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-levulinyl-α-D-glucopyranosyl]-(1→4)-O-1,6-anhydro-3-O-benzyl-2-O-levulinyl-β-L-idopyranose (15)
(288) A mixture of the thioglycoside B (0.16 g, 0.28 mmol) and acceptor 14 (0.19 g, 0.21 mmol) in dry CH.sub.2Cl.sub.2 (3.0 mL) was added to a reaction flask containing freshly dried 3 Å molecular sieves under nitrogen. The mixture was stirred at room temperature for 1 h, and the solution was cooled to −60° C. N-Iodosuccinimide (NIS, 0.23 g, 0.32 mmol) and trifluoromethanesulfonic acid (TfOH, 4.0 μL, 42.0 μmol) were added to the reaction flask, and the mixture was gradually warmed up to −40° C. The resulting solution was kept stirring for 3 h and warmed up to 0° C. TFA (0.5 mL), H.sub.2O (0.1 mL) was added and stirred for 1 h. Saturated NaHCO.sub.3(aq) was added to quench the reaction and the whole mixture was filtered through Celite followed by washing with CH.sub.2Cl.sub.2, and the filtrate was sequentially washed with 10% Na.sub.2S.sub.2O.sub.3(aq) and brine. The organic layer was dried over anhydrous MgSO.sub.4. The residue was filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography (EtOAc/Hex=1/3) to give the disaccharide 15 (0.15 g, 58%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.73-7.71 (m, 4H, Ar—H), 7.64-7.62 (m, 2H, Ar—H), 7.49-7.40 (m, 5H, Ar—H), 7.36-7.25 (m, 6H, Ar—H), 7.71-7.14 (m, 5H, Ar—H), 5.32 (t, J=10.0 Hz, 1H, H-3′), 5.28-5.26 (m, 2H, H-1, H-1′), 5.12 (dd, J=9.2, 8.5 Hz, 1H, H-2″), 4.79-4.76 (m, 2H, H-1″, ArCH2), 4.74 (dd, J=8.1, 1.5 Hz, 1H, H-2), 4.70-4.63 (m, 3H, ArCH.sub.2), 4.10-4.07 (m, 2H, H-5, H-4′), 3.99-3.91 (m, 4H, H-4″, H-6″a, H-6″b, H-6a), 3.86-3.78 (m, 3H, H-3, H-6′a, OH), 3.63 (d, J=11.3 Hz, 1H, H-6′b), 3.51 (m, 2H, H-3″, OH), 3.40-3.38 (m, 2H, H-4, H-6b), 3.33-3.31 (m, 1H, H-5), 3.26-3.24 (m, 1H, H-5′), 3.23 (dd, J=10.0, 3.6 Hz, 1H, H-2′) 2.93-2.87 (m, 1H), 2.81-2.76 (m, 1H), 2.71-2.63 (m, 2H), 2.56-2.44 (m, 4H), 2.22 (s, 3H, CH.sub.3), 2.14 (s, 3H, CH.sub.3), 1.07 (s, 9H, t-Bu).
(289) ##STR00111##
O-[6-O-Acetyl-2-O-benzoyl-3-O-benzyl-β-D-glucopyranosyl]-(1→4)-O-[2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-levulinyl-α-D-glucopyranosyl]-(1→4)-O-1,6-anhydro-3-O-benzyl-2-O-levulinyl-β-L-idopyranose (16)
(290) A solution of compound 15 (0.20 g, 0.16 mmol) in dichloromethane (4.0 mL) were sequentially added Et.sub.3N (0.30 mL, 2.08 mmol), Ac.sub.2O (0.03 mL, 0.32 mmol) and at 0° C. under nitrogen and warmed up to room temperature. After 16 h, MeOH was added and stirred for 10 min to quench the reaction and the solvents were evaporated under reduced pressure. EtOAc and water were added to the residue, and the desired material was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc/Hex=1/3) on silica gel to furnish the desired product 16 (0.17 g, 82%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.76-7.71 (m, 4H, Ar—H), 7.63-7.62 (m, 2H, Ar—H), 7.49-7.39 (m, 5H, Ar—H), 7.35-7.24 (m, 9H, Ar—H), 7.18-7.13 (m, 5H, Ar—H), 5.33 (t, J=10.1 Hz, 1H, H-3′), 5.30 (d, J=3.5 Hz, 1H, H-1′), 5.27 (m, 1H, H-1), 5.14 (t, J=8.8 Hz, 1H, H-2″), 4.81-4.54 (m, 7H, ArCH.sub.2, H-1″, H-2, H-6″a), 4.23-4.21 (m, 1H, H-6″b), 4.10-4.07 (m, 2H, H-5, H-4′), 3.95 (d, J=7.9 Hz, 1H, H-6a), 3.87 (t, J=8.1 Hz, 1H, H-3), 3.80-3.79 (m, 2H, H-4, H-6′a), 3.64 (d, J=11.6 Hz, 1H, H-6′b), 3.60 (t, J=9.3 Hz, 1H, H-4″), 3.48-3.42 (m, 2H, H-3″, H-6b), 3.35-3.34 (m, 1H, H-5″), 3.28-3.26 (m, 1H, H-5′), 3.20 (dd, J=10.1, 3.5 Hz, 1H, H-2′), 3.01 (brs, 1H, OH), 2.83-2.63 (m, 6H), 2.56-2.44 (m, 2H), 2.20 (s, 3H, CH.sub.3), 2.14 (s, 3H, CH.sub.3), 2.12 (s, 3H, CH.sub.3), 1.06 (s, 9H, t-Bu).
(291) ##STR00112##
O-[2-Azido-3-O-(p-bromobenzyl)-6-O-tert-butyldiphenyl-2-deoxy-4-O-(2-naphthylmethyl)-α-D-glucopyranosyl]-(1→4)-O-[6-O-acetyl-2-O-benzoyl-3-O-benzyl-β-D-glucopyranosyl]-(1→4)-O-[2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-levulinyl-α-D-glucopyranosyl]-(1→4)-O-6-O-acetyl-3-O-benzyl-2-O-levulinyl-α,β-L-idopyranosyl acetate (17)
(292) A mixture of the thioglycoside A (0.15 g, 0.17 mmol) and acceptor 16 (0.11 g, 0.08 mmol) in dry CH.sub.2Cl.sub.2 (3 mL) was added to a reaction flask containing freshly dried AW 300 molecular sieves under nitrogen. The mixture was stirred at room temperature for 1 h, and the solution was cooled to −78° C. N-Iodosuccinimide (NIS, 47.0 mg, 0.20 mmol) and trifluoromethanesulfonic acid (1.50 μL, 17.0 μmol) were added to the reaction flask, and the mixture was gradually warmed up to −20° C. The resulting solution was kept stirring for 4 h and acetic anhydride (3 mL), trimethylsilyltrifluoromethanesulfonate (8.00 μL, 42.5 μmol) were added and stirred for another 8 h. Et.sub.3N was added to quench the reaction. The whole mixture was filtered through celite followed by washing with CH.sub.2Cl.sub.2, and the filtrate was sequentially washed with 10% Na.sub.2S.sub.2O.sub.3(aq) and brine. The organic layer was dried over anhydrous MgSO.sub.4. The residue was filtered and concentrated in vacuo to get the crude product which was purified by flash column chromatography (EtOAc/Hex=1/2) to get the tetrasaccharide 17 (0.12 g, 65%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.82-7.80 (m, 2.2H, Ar—H), 7.76-7.75 (m, 8.3H, Ar—H), 7.70-7.67 (m, 4.8H, Ar—H), 7.65-7.60 (m, 15.6H, Ar—H), 7.49-7.45 (m, 13.8H, Ar—H), 7.41-7.13 (m, 71.5H, Ar—H), 6.03 (d, J=2.2 Hz, 1H), 5.84 (s, 1H), 5.56-5.54 (m, 1.9H), 5.28-5.17 (m, 4.4H), 5.03 (s, 1.3H), 4.94-4.85 (m, 9.9H), 4.81-4.68 (m, 10.6H), 4.58-4.54 (m, 3.5H), 4.30-4.28 (m, 2.6H), 4.17-3.87 (m, 23.4H), 3.80-3.67 (m, 10.6H), 3.61-3.60 (m, 3.3H), 3.52-3.46 (m, 4.4H), 3.30-3.28 (m, 1.2H), 3.23-3.22 (m, 2.9H), 2.76-2.52 (m, 18.1H), 2.17 (s, 3.9H), 2.14 (s, 3.2H), 2.10 (s, 6.2H), 2.07 (s, 3.6H), 2.00 (s, 3.7H), 1.85 (s, 3.5H), 1.75 (s, 10.2H), 1.07 (s, 21.3H), 1.02 (s, 19.3H).
(293) ##STR00113##
p-Methylphenyl [2-azido-3-O-(p-bromobenzyl)-6-O-tert-butyldiphenyl-2-deoxy-4-O-(2-naphthylmethyl)-α-D-glucopyranosyl]-(1→4)-O-[6-O-acetyl-2-O-benzoyl-3-O-benzyl-β-D-glucopyranosyl]-(1→4)-O-[2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-levulinyl-α-D-glucopyranosyl]-(1→4)-O-6-O-acetyl-3-O-benzyl-2-O-levulinyl-α-L-idopyranose (18)
(294) Trimethyl(p-tolylthio)silane (TMSSTo1, 0.26 g, 0.81 mmol) and ZnI.sub.2 (92.0 mg, 0.48 mmol) were added to a solution of compound 17 (0.33 g, 0.16 mmol) in dry CH.sub.2Cl.sub.2 (6.0 mL). After 1 h of stirring at room temperature, the mixture was diluted with CH.sub.2Cl.sub.2 (15 mL). The organic layer was washed with saturated NaHCO.sub.3(aq), dried over anhydrous MgSO.sub.4, filtered and concentrated in vacuo. Purification of the residue via flash column chromatography (EtOAc/Hex=1/5) provided the product 18 (0.29 g, 85%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.82-7.80 (m, 1H, Ar—H), 7.76-7.74 (m, 4H, Ar—H), 7.70-7.60 (m, 10H, Ar—H), 7.51-7.45 (m, 5H, Ar—H), 7.41-7.39 (m, 4H, Ar—H), 7.38-7.30 (m, 10H, Ar—H), 7.29-7.24 (m, 6H, Ar—H), 7.23-7.17 (m, 6H, Ar—H), 7.16-7.13 (m, 2H, Ar—H), 7.05 (d, J=8.0 Hz, 2H, Ar—H), 5.56 (d, J=3.8 Hz, 1H, H-1″′), 5.52-5.16 (m, 3H, H-2″, H-3′, H-1), 5.10 (t, J=2.5 Hz, 1H, H-2), 4.95-4.91 (m, 2H, ArCH.sub.2), 4.86 (d, J=11.1 Hz, 1H, ArCH.sub.2), 4.82-4.80 (m, 3H, H-1′, ArCH.sub.2), 4.76 (d, J=10.0 Hz, 1H, ArCH.sub.2), 4.72 (d, J=8.1 Hz, 1H, H-1″), 4.66-4.58 (m, 1H, H-5), 4.56-4.53 (m, 2H, ArCH.sub.2), 4.30-4.28 (m, 1H, H-6″a), 4.16 (dd, J=12.0, 4.9 Hz, 1H, H-6″b), 4.10-3.99 (m, 4H, H-4′, H-6a, H-6b, H-6′a), 3.96-3.92 (m, 2H, H-4, H-3′″), 3.90-3.86 (m, 2H, H-3, H-4″), 3.79-3.72 (m, 4H, H-3″, H-6′b, H-6′″a, H-6″′b), 3.62-3.60 (m, 1H, H-4″), 3.55 (m, 1H, H-5″′), 3.52-3.49 (m, 1H, H-5′), 3.47-3.44 (m, 1H, H-5″), 3.33 (dd, J=10.6, 3.4 Hz, 1H, H-2′), 3.24 (dd, J=9.7, 3.8 Hz, 1H, H-2″), 2.78-2.68 (m, 3H), 2.63-2.58 (m, 2H), 2.54-2.49 (m, 3H), 2.29 (s, 3H, CH.sub.3), 2.17 (s, 3H, CH.sub.3), 2.10 (s, 3H, CH.sub.3), 1.78 (s, 3H, CH.sub.3), 1.76 (s, 3H, CH.sub.3), 1.08 (s, 9H, t-Bu), 1.03 (s, 9H, t-Bu).
(295) ##STR00114##
Methyl [2-azido-3-O-(p-bromobenzyl)-6-O-tert-butyldiphenyl-2-deoxy-4-O-(2-naphthylmethyl)-α-D-glucopyranosyl]-(1→4)-O-[6-O-acetyl-2-O-benzoyl-3-O-benzyl-β-D-glucopyranosyl]-(1→4)-O-[2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-levulinyl-α-D-glucopyranosyl]-(1→4)-O-[6-O-acetyl-3-O-benzyl-2-O-levulinyl-α-L-idopyranosyl]-(1→4)-2-azido-3-O-(p-bromobenzyl)-6-O-tert-butyldiphenylsilyl-2-deoxy-α-D-glucopyranoside (19)
(296) A mixture of the tetrasaccharide 18 (0.16 g, 74.0 μmol) and acceptor E (55.0 mg, 88.0 μmol) in dry CH.sub.2Cl.sub.2 (4.0 mL) was added to a reaction flask containing freshly dried AW 300 molecular sieves under nitrogen. The mixture was stirred at room temperature for 1 h, and the solution was cooled to −20° C. N-Iodosuccinimide (NIS, 22.0 mg, 96.0 μmol) and trifluoromethanesulfonic acid (TfOH, 2.00 μL, 15.0 μmol) were added to the reaction flask, and the mixture was gradually warmed up to 0° C. The resulting solution was kept stirring for 4 h and Et.sub.3N was added to quench the reaction. The whole mixture was filtered through Celite followed by washing with CH.sub.2Cl.sub.2, and the filtrate was sequentially washed with 10% Na.sub.2S.sub.2O.sub.3(aq) and brine. The organic layer was dried over anhydrous MgSO.sub.4. The residue was filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography (EtOAc/Hex=1/3) to give the pentasaccharide 19 (0.11 g, 61%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.82-7.77 (m, 3H, Ar—H), 7.76-7.72 (m, 5H, Ar—H), 7.68-7.64 (m, 7H, Ar—H), 7.62-7.59 (m, 6H, Ar—H), 7.50-7.46 (m, 6H, Ar—H), 7.41-7.24 (m, 31H, Ar—H), 7.23-7.17 (m, 7H, Ar—H), 7.15-7.13 (m, 2H, Ar—H), 7.06-7.05 (m, 2H, Ar—H), 6.92-6.91 (m, 2H, Ar—H), 5.55-5.54 (m, 1H), 5.26 (t, J=10.0 Hz, 1H), 5.21 (t, J=8.7 Hz, 1H), 5.01 (s, 1H), 4.95-4.90 (m, 3H), 4.87-4.86 (m, 1H), 4.84 (s, 1H), 4.80-4.75 (m, 3H), 4.68-4.63 (m, 3H), 4.56 (d, J=10.7 Hz, 1H), 4.40 (d, J=11.1 Hz, 1H), 4.29 (d, J=11.7 Hz, 1H), 4.17 (dd, J=11.8, 4.5 Hz, 1H), 4.07 (t, J=9.8 Hz, 1H), 4.01-3.99 (m, 2H), 3.97-3.81 (m, 9H), 3.78-3.66 (m, 7H), 3.61-3.56 (m, 2H), 3.53-3.51 (m, 1H), 3.49-3.45 (m, 2H), 3.30-3.27 (m, 4H), 3.24-3.21 (m, 1H), 3.18-3.16 (m, 1H), 2.76-2.70 (m, 1H), 2.65-2.58 (m, 3H), 2.55-2.52 (m, 2H), 2.50-2.45 (m, 1H), 2.30-2.26 (m, 1H), 2.10-2.09 (m, 6H), 1.76 (s, 3H, CH.sub.3), 1.57-1.55 (m, 4H), 1.07 (s, 9H, t-Bu), 1.02 (s, 9H, t-Bu), 0.97 (s, 9H, t-Bu).
(297) ##STR00115##
Methyl O-[2-azido-3-O-(p-bromobenzyl)-2-deoxy-4-O-(2-naphthylmethyl)-6-O-tert-butyldiphenyl-α-D-glucopyranosyl]-(1→4)-O-[2-O-benzoyl-3-O-benzyl-β-D-glucopyranosyl]-(1→4)-O-[2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-levulinyl-α-D-glucopyranosyl]-(1→4)-O-[3-O-benzyl-2-O-levulinyl-α-L-idopyranosyl]-(1→4)-2-azido-3-O-(p-bromobenzyl)-6-O-tert-butyldiphenylsilyl-2-deoxy-α-D-glucopyranoside (20)
(298) Mg(OMe).sub.2 (1 mL) was added to a solution of compound 19 (0.13 g, 48.6 μmol) in CH.sub.2Cl.sub.2 (2 mL) at room temperature under nitrogen atomsphere. After stirring for 16 h, the reaction was neutralized by adding acetic acid. The mixture was concentrated under reduced pressure to give the crude product which was purified by flash column chromatography (EtOAc/Hex=1/3) to give the pentasaccharide 20 (0.11 g, 88%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.82-7.80 (m, 2H, Ar—H), 7.78-7.76 (m, 3H, Ar—H), 7.74-7.72 (m, 3H, Ar—H), 7.69-7.761 (m, 19H, Ar—H), 7.57-7.55 (m, 1H, Ar—H), 7.49-7.45 (m, 8H, Ar—H), 7.42-7.16 (m, 59H, Ar—H), 7.15-7.13 (m, 6H, Ar—H), 7.02-6.98 (m, 3H, Ar—H), 5.61 (d, J=3.8 Hz, 1H), 5.25 (t, J=10.0 Hz, 1H), 5.20 (dd, J=9.3, 8.3 Hz, 1H), 5.05 (d, J=2.7 Hz, 1H), 5.02 (d, J=3.7 Hz, 1H), 4.91-4.75 (m, 11H), 4.70-4.66 (m, 3H), 4.64 (d, J=11.1 Hz, 1H), 4.59-4.57 (m, 3H), 4.46 (d, J=11.1 Hz, 1H), 4.13-4.05 (m, 4H), 4.00-3.86 (m, 14H), 3.85-3.75 (m, 9H), 3.72-3.65 (m, 4H), 3.60-3.56 (m, 2H), 3.55-3.54 (m, 1H), 3.45 (d, J=9.9 Hz, 1H), 3.36-3.29 (m, 4H), 3.25-3.21 (m, 3H), 3.20-3.10 (m, 3H), 2.78-2.66 (m, 3H), 2.61-2.45 (m, 8H), 2.30-2.25 (m, 1H), 2.10 (s, 3H, CH.sub.3), 2.07 (s, 3H, CH.sub.3), 1.07 (s, 9H, t-Bu), 1.03 (s, 9H, t-Bu), 0.97 (s, 9H, t-Bu).
(299) ##STR00116##
Methyl O-[2-azido-3-O-(p-bromobenzyl)-2-deoxy-4-O-(2-naphthylmethyl)-α-D-glucopyranosyl]-(1→4)-O-[methyl 2-O-benzoyl-3-O-benzyl-β-D-glucopyranosiduronate]-(1→4)-O-[2-azido-2-deoxy-β-D-glucopyranosyl]-(1→4)-O-[methyl 3-O-benzyl-α-L-idopyranosiduronate]-(1→4)-2-azido-3-O-(p-bromobenzyl)-2-deoxy-α-D-glucopyranoside (21)
(300) BAIB (32.0 mg, 0.10 mmol) was added to a solution of the compound 20 (50.0 mg, 19.0 μmol) in a mixed solvent (CH.sub.2Cl.sub.2/H.sub.2O=2/1, 0.75 mL) at room temperature. After 5 min, TEMPO (1.22 mg, 7.60 μmol) was placed into the mixture which was then kept stirring for 24 h. To quench the reaction, 10% Na.sub.2S.sub.2O.sub.3(aq) was added, and the desired material was extracted with CH.sub.2Cl.sub.2. The combined organic layer was washed with brine, dried over anhydrous MgSO.sub.4, filtered, and concentrated under reduced pressure. Then, hydrazine monohydrate (1 M solution in pyridine/AcOH=1.4/1, 0.2 mL, 0.06 mmol) was added to a solution of the residue in CH.sub.2Cl.sub.2 (1.0 mL) at room temperature. After stirring for 2 h, the reaction was quenched by acetone, and the solvents were evaporated under reduced pressure. To the crude uronate solution in CH.sub.2Cl.sub.2 (1.0 mL) was added an ethereal solution of diazomethane (0.6 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction solution was quenched by acetic acid and the resulting mixture was concentrated in vacuo to yield the crude residue. A 70% solution of HF in pyridine (0.25 mL) was added to an ice-cooled solution of the crude residue in pyridine (1.0 mL). The mixture was allowed to warm to room temperature and stirred for 3 days. The mixture solution was concentrated in vacuo, and the residue was purified by flash column chromatography (MeOH/CH.sub.2Cl.sub.2=1/9) to afford the desilylated compound 21 (28.0 mg, 82%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.91-7.90 (m, 2H, Ar—H), 7.73-7.67 (m, 4H, Ar—H), 7.58-7.56 (m, 1H, Ar—H), 7.51-7.48 (m, 1H, Ar—H), 7.40-7.34 (m, 5H, Ar—H), 7.32-7.30 (m, 2H, Ar—H), 7.28-7.19 (m, 12H, Ar—H), 7.16 (s, 1H, Ar—H), 7.10-7.04 (m, 10H, Ar—H), 6.92-6.89 (m, 2H), 5.37 (d, J=3.7 Hz, 1H), 5.22 (t, J=6.9 Hz, 1H), 5.11 (m, 1H), 4.81-4.66 (m, 10H), 4.60-4.57 (m, 6H), 4.46-4.39 (m, 4H), 4.28 (dd, J=9.0, 8.4 Hz, 1H), 4.15-4.13 (m, 2H), 3.86 (t, J=7.5 Hz, 1H), 3.82-3.68 (m, 16H), 3.66-3.61 (m, 5H), 3.59-3.50 (m, 7H), 3.42 (s, 2H), 3.38-3.34 (m, 3H), 3.31-3.25 (m, 8H), 3.15-3.12, (m, 1H), 3.00 (s, 3H, CH.sub.3), 2.33 (brs, 2H, OH), 1.79-1.73 (m, 3H, OH).
(301) ##STR00117##
Methyl O-[2-azido-3-O-(p-bromobenzyl)-2-deoxy-4-O-(2-naphthylmethyl)-6-O-sulfonato-α-D-glucopyranosyl]-(1→4)-O-[methyl 2-O-benzoyl-3-O-benzyl-β-D-glucopyranosiduronate]-(1→4)-O-[2-azido-2-deoxy-3,6-di-O-sulfonato-α-D-glucopyranosyl]-(1→4)-O-[methyl 3-O-benzyl-2-O-sulfonato-α-L-idopyranosiduronate]-(1→4)-2-azido-3-O-(p-bromobenzyl)-2-deoxy-6-O-sulfonato-α-D-glucopyranoside (22)
(302) A solution of the pentaol 21 (40.0 mg, 23.0 μmol) and sulfur trioxide-triethylamine complex (0.21 g, 1.15 mmol) in DMF (2 mL) was kept stirring at 60° C. under nitrogen for 3 d. The reaction flask was cooled down to room temperature, a solution of phosphate buffer (pH=7, 2.0 mL) was added and the mixture was kept stirring for another 30 min. The resulting solution was concentrated in vacuo and the residue was purified by flash column chromatography (MeOH/CH.sub.2Cl.sub.2=1/7) to give the O-sulfonated compound 22 (36.0 mg, 73%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.22 (d, J=7.8 Hz, 2H, Bz-H), 7.80-7.76 (m, 3H, Ar—H), 7.73 (s, 1H, Ar—H), 7.69-7.65 (m, 1H, Ar—H), 7.57-7.54 (m, 2H, Ar—H),7.45-7.42 (m, 5H, Ar—H), 7.36-7.27 (m, 8H, Ar—H), 7.17 (d, J=8.2 Hz, 1H, Ar—H), 7.11-7.10 (m, 3H, Ar—H), 7.05-7.04 (m, 2H, Ar—H), 6.94 (d, J=8.2 Hz, 1H, Ar—H), 5.42-5.39 (m, 2H), 5.33 (s, 1H), 5.14 (d, J=8.1 Hz, 1H), 5.11 (d, J=3.5 Hz, 1H), 4.99 (d, J=11.0 Hz, 1H), 4.91-4.86 (m, 3H), 4.82-4.77 (m, 4H), 4.71 (s, 1H), 4.62-4.52 (m, 4H), 4.40-4.12 (m, 13H), 3.91-3.79 (m, 7H), 3.75-3.60 (m, 6H), 3.48-3.34 (m, 7H), 3.16 (d, J=9.9 Hz, 1H), 2.73 (s, 2H).
(303) ##STR00118##
Methyl O-(2-deoxy-2-sulfamido-6-O-sulfonato-α-D-glucopyranosyl)-(1→4)-O-(β-D-glucopyranosyluronic acid)-(1→4)-O-(2-deoxy-2-sulfamido-3,6-di-O-sulfonato-α-D-glucopyranosyl)-(1→4)-O-(2-O-sulfonato-α-L-idopyranosyluronic acid)-(1→4)-2-deoxy-2-sulfamido-6-O-sulfonato-α-D-glucopyranoside decasodium salt (25)
(304) 1.0 M solution of LiOH in water (1.2 mL, 1.2 mmol) and 37% H.sub.2O.sub.2 (0.21 mL, 2.5 mmol) were added to a solution of the compound 22 (10.0 mg, 4.5 μmol) in THF (0.3 mL) and MeOH (0.3 mL) at room temperature. The mixture was kept stirring at 37° C. for 5 days, and the reaction solution was neutralized by acetic acid. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on Sephadex LH-20 using MeOH as an eluent. The appropriate fractions were pooled and passed through a column of Bio-rad 50×8 Na.sup.+ resin with MeOH to give the uronate compound 23. A solution of the uronate compound and 20% Pd(OH).sub.2 on carbon (100 mg) in phosphate buffer (pH=7.0, 2 mL) was equipped with a hydrogen balloon, and the mixture was stirred at room temperature for 2 d. The whole mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was dissolved in H.sub.2O (1 mL), and purified through a Sephadex G-25 column eluted with water. After concentration, the residue was passed through a column of Bio-rad 50×8 Na.sup.+ resin using water as eluent to give the amino-alcohol compound 24. The above amino-alcohol residue was dissolved in water (2 mL), and the solution was adjusted to pH=9.5 through addition of 1.0 N NaOH.sub.(aq). Sulfur trioxide-pyridine complex (0.1 g) was added to the mixture in four equal portions with half-hour intervals at room temperature, and the pH value was maintained at 9.5 via calibration of 1.0 N NaOH.sub.(aq). After stirring for 18 h, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on Sephadex G-25 using water as an eluent. The appropriate fractions were pooled and passed through a column of Dowex 50WX8-Na.sup.+ with water. The product portion was lyophilized to give the target molecule 25 (4.5 mg, 60%). .sup.1H NMR (600 MHz, CDCl.sub.3) δ 5.64 (d, J=3.7 Hz, 1H), 5.55 (d, J=3.4 Hz, 1H), 5.19 (d, J=4.0 Hz, 1H), 5.04 (d, J=3.5 Hz, 1H), 4.76-4.74 (m, 1H), 4.63 (d, J=7.8 Hz, 1H), 4.50-4.49 (m, 2H), 4.43-4.35 (m, 7H), 4.32-4.30 (m, 2H), 4.28-4.26 (m, 2H), 4.18-4.15 (m, 7H), 4.00-3.96 (m, 4H), 3.91-3.89 (m, 2H), 3.86-3.82 (m, 2H), 3.80-3.77 (m, 4H), 3.68-3.57 (m, 5H), 3.47-3.41 (m, 8H), 3.30-3.25 (m, 3H).
(305) ##STR00119##
p-Methylphenyl 4-O-[2-azido-3-O-(p-bromobenzyl)-6-O-tert-butyl-diphenylsilyl-2-deoxy-4-O-(2-naphthylmethyl)-α-D-glucopyranosyl]-2-O-benzoyl-3,6-di-O-benzyl-1-thio-β-D-glucopyranoside
(306) A mixture of the compound 27 (2.20 g, 2.64 mmol) and acceptor 26 (1.25 g, 2.20 mmol) in dry CH.sub.2Cl.sub.2 (60 mL) was added to a reaction flask containing freshly dried 4 Å molecular sieves under nitrogen. The mixture was stirred at room temperature for 1 h, and the solution was cooled to −40° C. and AgOTf (2.80 g, 11.0 mmol) were added to the reaction flask, and the mixture was gradually warmed up to −20° C. The resulting solution was kept stirring for 4 h, and Et.sub.3N was added to quench the reaction. The whole mixture was filtered through celite followed by washing with CH.sub.2Cl.sub.2, and the filtrate was sequentially washed with brine. The organic layer was dried over anhydrous MgSO.sub.4. The residue was filtered and concentrated in vacuo to give the crude product which was purified by flash column chromatography (EtOAc/Hex=1/7) to give the disaccharide 28 (2.01 g, 72%).
(307) ##STR00120##
O-[2-Azido-3-O-(p-bromobenzyl)-6-O-tert-butyldiphenyl-2-deoxy-4-O-(2-naphthylmethyl)-α-D-glucopyranosyl]-(1→4)-O-[6-O-acetyl-2-O-benzoyl-3-O-benzyl-β-D-glucopyranosyl]-(1→4)-O-[2-azido-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-levulinyl-α-D-glucopyranosyl]-(1→4)-O-1,6-anhydro-3-O-benzyl-2-O-levulinyl-β-L-idopyranose xy-4-O-(2-naphthylmethyl)-α-D-glucopyranosyl]-2-O-benzoyl-3,6-di-O-benzyl-1-thio-β-D-glucopyranoside
(308) A mixture of the thioglycoside 28 (80.0 mg, 0.06 mmol) and acceptor 14 (44.0 g, 0.05 mmol) in dry CH.sub.2Cl.sub.2 (2 mL) was added to a reaction flask containing freshly dried AW 300 molecular sieves under nitrogen. The mixture was stirred at room temperature for 1 h, and the solution was cooled to −40° C. N-Iodosuccinimide (17.0 mg, 0.08 mmol) and trifluoromethanesulfonic acid (1.00 μL, 10.0 μmol) were added to the reaction flask, and the mixture was gradually warmed up to −20° C. The resulting solution was kept stirring for 4 h and Et.sub.3N was added to quench the reaction. The whole mixture was filtered through celite followed by washing with CH.sub.2Cl.sub.2, and was sequentially washed with 10% Na.sub.2S.sub.2O.sub.3(aq) and brine. The organic layer was dried over anhydrous MgSO.sub.4. The residue was filtered and concentrated in vacuo to get the crude product which was purified by flash column chromatography (EtOAc/Hex=1/3) to get the tetrasaccharide 29 (150 mg, 60%).
Other Embodiments
(309) This application refers to various issued patents, published patent applications, journal articles, books, manuals, and other publications, all of which are incorporated herein by reference.
(310) The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The present invention is not to be limited in scope by examples provided, since the examples are intended as a single illustration of one aspect of the invention and other functionally equivalent embodiments are within the scope of the invention. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims. The advantages and objects of the invention are not necessarily encompassed by each embodiment of the invention.