Methods for 2-Deoxyglycoside Synthesis

Abstract

Deoxy-sugars often play a critical role in modulating the potency of many bioactive natural products. Accordingly, there has been sustained interest in methods for their synthesis over the past several decades. The focus of much of this work has been on developing new glycosylation reactions that permit the mild and selective construction of deoxyglycosides. This Review covers classical approaches to deoxyglycoside synthesis, as well as more recently developed chemistry that aims to control the selectivity of the reaction through rational design of the promoter. Where relevant, the application of this chemistry to natural product synthesis will also be described.

Figure 1

Representative deoxyglycoside-containing natural products.

Figure 2

Examples of different approaches to deoxy-sugar synthesis. (A) Direct glycosylation; (B) indirect synthesis; (C) the use of glycals as electrophiles; (D) de novo synthesis; and (E) the anomeric alkylation approach.

Scheme 1. Models for Selectivity in Additions to Oxocarbenium Cations of 2-Deoxy-sugars

Scheme 2. Effect of Nucleophile Reactivity on Selectivity in C-Glycoside Synthesis

Scheme 3. Zorbach’s Synthesis of Digitoxin Analogues Using Deoxy-sugar Bromides (PNB = p-Nitrobenzoyl)

Scheme 4. Thiem’s Synthesis of the Chromomycin A₃ Disaccharide

Scheme 5. Takeuchi’s Convergent Glycosylation for the Synthesis of a Protected 2-Hydroxyaclacinomycin A

Scheme 6. Giuliano’s Study on the Effects of Acceptor Structure on Glycosylation Reactions with Oliose Bromide Donors

Scheme 7. AgOTf-Mediated Synthesis of the Cororubicin Trisaccharide

Scheme 8. Binkley’s Study on the Effect of Acceptor Protecting Group on Selectivity in Glycosylations with Olivose Donors

Scheme 9. Paterson’s Studies on the Glycosylation of the C19–C28 Fragment of Concanamycin A Using Bromides

Scheme 10. Crimmins’ Synthesis of the Apoptolidin Disaccharide

Scheme 11. Herzon’s Explanation for β-Selectivity in Glycosylations with C-3 Benzoate-Protected Bromide Donors

Scheme 12. Ramiliarison and Monneret’s Synthesis of the Musettamycine Disaccharide under Helferich Conditions

Scheme 13. Verma and Wang’s Use of Thioglycosides as Latent Glycosyl Chlorides

Scheme 14. Lam and Gervay-Hague’s Synthesis of Aryl 2-Deoxyglycosides by S_N2-Displacement on Glycosyl Iodides

Scheme 15. Planas’ Synthesis of a 4-Nitrophenyl (PNP) Glycoside via S_N2 Displacement of a Glycosyl Iodide

Scheme 16. Yu’s Approach to Attaching the Core Sugar to the Landomycin Family of Natural Products

Scheme 17. Nicolaou’s Use of Glycosyl Fluorides in the Synthesis of Avermectin B_1a

Scheme 18. Synthesis of a Deoxyfucose Containing Sialyl Lewis-X Mimetic by De Frees and Co-workers

Scheme 19. Synthesis of the Glycosylated C19–28 Fragment of Concanamycin by Tatsuta, Kinoshita, and Co-workers

Scheme 20. Nicolaou’s Use of an Evernitrose Fluoride in the Synthesis of the ABC Subunit of Everninomicin

Scheme 21. Nicolaou’s Synthesis of the Vancomycin Disaccharide through BF₃·OEt₂-Mediated Activation of a Vancosamine Fluoride

Scheme 22. Suzuki’s Synthesis of the C-Glycoside Core of Vineomycinone B₂

Scheme 23. Glycosyl Fluorides in Herzon’s Synthesis of the Lomaiviticin Cyclohexenone Core

Scheme 24. Woodward’s (A) and Martin’s (B) Use of Pyridyl Thioglycosides in the Synthesis of Erythromycins

Scheme 25. Hanessian’s Use of Pyridyl Glycosides in the Synthesis of Avermectin B_1a

Scheme 26. NBS Activation of 2-Deoxythioglycosides in Oligosaccharide Synthesis

Scheme 27. Use of AgPF₆ for Thioglycoside Activation As Applied to Hirama’s Synthesis of the Kedarcidin Chromophore (PMBM = p-Methoxybenzyloxymethyl)

Scheme 28. Toshima’s UV-Mediated Glycosylation of Unprotected Deoxythioglycosides in the Presence of 4-Methoxyphenylboronic Acid

Scheme 29. Bower’s Visible-Light-Promoted Glycosylation

Scheme 30. Use of Constrained Donors with Isopropylidene Acetals (A) or Cyclic Carbonates (B) in Selective Glycosylation Reactions

Scheme 31. Mong’s Use of the Pico Directing Group in the Synthesis of the Landomycin E Trisaccharide

Scheme 32. Sugimura and Watanabe’s Use of Intermolecular Aglycone Delivery in Their Synthesis of Cytosaminomycin C

Scheme 33. Mong’s Use of DMF as a Modulator in the α-Selective Synthesis of 2-Deoxyglycosides

Scheme 34. Kahne’s One-Pot Synthesis of the Ciclamycin Trisaccharide Using Glycosyl Sulfoxides

Scheme 35. Terashima’s Use of a 2-Deoxyglycosyl Acetate for the Synthesis of 4-Demethoxydaunorubicin

Scheme 36. Myers’ Use of 2-Deoxyglycosyl Acetates in the Synthesis of Trioxacarin A Analogues

Scheme 37. Glycosyl Acetates in O- to C-Rearrangements

Scheme 38. Kim’s α-Selective Glycosylation Using a 2-Deoxyglycosylbenzyl Phthalate Donor

Scheme 39. Murphy’s Use of Constrained Glucuronic Acid Derivatives for α-Selective Glycosylation Reactions

Scheme 40. Hirama’s Synthesis of a Glycosylated Kedarcidin Intermediate Using Polymer-Bound DBU To Synthesize the Trichloroacetimidate Donor

Scheme 41. Boons’ Use of Chiral Auxiliaries (A) and Allyl Glycosides (B) for α-Selective Glycosylations

Scheme 42. Tanaka, Yoshizawa, and Takahashi’s Use of the Benzylsulfonate Protecting Group for β-Selective Glycosylations

Scheme 43. Installation of the epi-Vancosamine in Danishefsky’s Synthesis of Pluraflavin A

Scheme 44. Tanaka and Takahashi’s α-Selective Glycosylation Controlled by a C-4 Sulfonate on the Donor

Scheme 45. Schmidt’s Use of Glycosyl Phosphates in 2-Deoxy-sugar Glycoside Synthesis

Scheme 46. Sulikowski’s Use of Glycosyl Phosphates in the Synthesis of the Landomycin A Hexasaccharide

Scheme 47. Sulikowski’s Use of Differential Glycosyl Phosphite Reactivity in the One-Pot Synthesis of a Trisaccharide

Scheme 48. Yu’s Use of the Mitsunobu Glycosylation in Their Synthesis of Jadomycin S

Scheme 49. Burke’s Use of the Gin Glycosylation in the Synthesis of 2-Deoxy-sugar Analogues of Amphotericin B

Scheme 50. Activation of Glycals for the Construction of the Core Tetrasaccharide of Kijanimicin

Scheme 51. Activation of Glycals for Glycosylation Using TolS(STol)₂SbCl₆

Scheme 52. Use of C-2 Thioethers to Promote Selectivity with Glycosyl Fluorides (A), Trichloroacetimidates (B), and N,N,N′,N′-Tetramethylphosphoramidate Donors (C)

Scheme 53. Glycosylations Proceeding through the Intermediacy of an epi-Sulfonium Cation for the Construction of β-Linked Deoxy-sugars

Scheme 54. Roush’s Use of 2-Iodoglycosides for β-Specific Glycosylation Reactions

Scheme 55. Galan and McGarrigle’s Thiourea-Catalyzed Glycosylation of Galactals to Furnish 2-Deoxyglycosides

Scheme 56. Urea-Catalyzed Koenigs–Knorr Glycosylation

Scheme 57. Glycosylation of 2-Nitroglycals Using Thiourea/Cinchona Bifunctional Organocatalyst

Scheme 58. Glycosylation of 2-Nitroglycals Using Thiourea/Pyrrolidine Bifunctional Organocatalyst

Scheme 59. NHC-Catalyzed Stereoselective Glycosylation of 2-Nitrogalactals with Alcohols and Phenol

Scheme 60. Glycosylation of Glycosyl Chlorides Using a Macrocyclic Bisthiourea Organocatalyst

Scheme 61. Matched/Mismatched Catalyst/Substrate Glycosylation To Yield 2-Deoxyglycosides

Scheme 62. Glycosylation of Glycals Using Thiourea/Brønsted Acid Cooperative Catalysis

Scheme 63. Iterative Tungsten-Catalyzed Alkynol Cycloisomerization (A) and Stereoselective Acid-Catalyzed Glycosyation Reactions (B)

Scheme 64. NOBF₄ As a Lewis Acid for the Glycosylation of Trichloroacetimidates

Scheme 65. Regioselective Glycosylation Using Diphenylborinic-Derived Ethanolamine Adduct

Scheme 66. Choice of Lewis Base and/or Organoboron Catalyst Is Important To Facilitate Challenging Glycosylations

Scheme 67. In Situ Formation of Glycosyl Mesylate Donors and Subsequent Glycosylation Using a Diarylorganoboron Catalyst

Scheme 68. Electron-Deficient Pyridinium Salt-Catalyzed 2-Deoxyglycosylation and Proposed Intermolecular (A) and Intramolecular (B) Mechanisms

Scheme 69. α-Selective Dehydrative Glycosylation Protocols for the Synthesis of β-Deoxyglycosidic Linkages

Scheme 70. Glycosylation of C6-Bromo 2-Deoxy-2-iodo-β-glucopyranosyl Fluorides

Scheme 71. Castillon’s Synthesis of 2-Deoxy-2-iodoglycosides

Scheme 72. Hypervalent Iodine-Mediated Synthesis of Amino Acid 2-Deoxyglycoside Conjugates

Scheme 73. Polymer-Assisted Activation of Glycals and Subsequent Glycosidation

Scheme 74. Visible-Light-Mediated Tin-Free Reductive Deiodination of 2-Iodo-2-deoxyglycosides

Scheme 75. NIS/Phosphorus Compound-Catalyzed Synthesis of (A) 2-Deoxy-2-iodoglycosides and (B) 2-Deoxyglycosides and Proposed Mechanism of Glycosylation Using NIS and P(OPh)₃

Scheme 76. N-Sulfonylimidazole-Catalyzed Synthesis of 2-Deoxy-β-glycosides

Scheme 77. N-Tosyl-4-nitroimidazole-Catalyzed Synthesis of 2-Deoxy-β-glycosides

Scheme 78. Synthesis of 2-Deoxy-β-glycosides Using Anomeric O-Alkylation/Arylation

Scheme 79. Anomeric Alkylation Involving Triflates As Leaving Groups

Scheme 80. Synthesis of α-d-Boivinoside 283

Scheme 81. Glycosylation of Unprotected Sugars Using PPh₃/CBr₄ under Neutral Conditions

Scheme 82. Stereoselective Synthesis of Conformationally Constrained 2-Deoxy-β-glucosides

Scheme 83. Synthesis of 2-Deoxy-β-galactosides from 2-Deoxy-2-halogalactopyranosyl Donors

Scheme 84. Stereoselective Glycosylations with Trans-Fused Cyclic 3,4-O-Disiloxane Protected Glucals

Scheme 85. Pd(0)-Catalyzed Glycosylation for the De Novo Synthesis of α-Mannoheptasaccharide

Scheme 86. Pd-Catalyzed O-Glycosylation

Scheme 87. Palladium-Catalyzed Synthesis of 2-Deoxyglycosides from Glycals

Scheme 88. Palladium-Catalyzed Synthesis of 2,3-Unsaturated Deoxyglycosides from Glycals

Scheme 89. Au(I)-Catalyzed Synthesis of 2-Deoxyglycosides Using S-But-3-ynyl Thioglycosides and Proposed Catalytic Cycle

Scheme 90. Au(III)/Phenylacetylene-Catalyzed Glycosylation of Glycals, Glycosyl Acetates, and Trichloroacetimidates

Scheme 91. Au(I)-Catalyzed Synthesis of 2-Deoxyglycosides from Glycals

Scheme 92. Direct Synthesis of Digitoxin

Scheme 93. Ruthenium-Catalyzed Synthesis of 2,3-Dideoxy-d-ribosides

Scheme 94. Synthesis of 2-Deoxy-C-glycosyl Compounds via Stille Cross-couplings

Scheme 95. Synthesis of β-C-Glycosyl Compounds by Intramolecular Palladium-Catalyzed Decarboxylative Coupling

Scheme 96. Cu(I)-Catalyzed Synthesis of C-Glycosyl Alkynes and Proposed Mechanism

Scheme 97. Synthesis of C-Glycosyl Aromatic Compounds via “Ring-Opening–Ring-Closure” Methodology of Functionalized Alcohols

Scheme 98. Lewis Acid-Catalyzed Synthesis of 2-Thio-2-deoxy-C-glycosyl Compounds

Scheme 99. Synthesis of C-Glycosides by Glycosyl Cross-coupling of Anomeric Stannates and Simplified Proposed Mechanism

Scheme 100. Synthesis of 2-Nitro-2-deoxyglycosides by Stetter Reaction

Scheme 101. Total Synthesis of Vineomycinone B₂ Methyl Ester

Scheme 102. De Novo Synthesis of C-Glycosides by Prins-Cyclization and Oxidation of Silyl-Protected Alchohols

Scheme 103. Synthesis of S-Linked 2-Deoxyglycosides via Glycosyl Lithium Intermediates