Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

Abstract

Sugar-modified nucleosides have gained considerable attention in the scientific community, either for use as molecular probes or as therapeutic agents. When the methylene group of the ribose ring is replaced with a sulfur atom at the 3'-position, these compounds have proved to be structurally potent nucleoside analogues, and the best example is BCH-189. The majority of methods traditionally involves the chemical modification of nucleoside structures. It requires the creation of artificial sugars, which is accompanied by coupling nucleobases via N-glycosylation. However, over the last three decades, efforts were made for the synthesis of 1,3-oxathiolane nucleosides by selective N-glycosylation of carbohydrate precursors at C-1, and this approach has emerged as a strong alternative that allows simple modification. This review aims to provide a comprehensive overview on the reported methods in the literature to access 1,3-oxathiolane nucleosides. The first focus of this review is the construction of the 1,3-oxathiolane ring from different starting materials. The second focus involves the coupling of the 1,3-oxathiolane ring with different nucleobases in a way that only one isomer is produced in a stereoselective manner via N-glycosylation. An emphasis has been placed on the C-N-glycosidic bond constructed during the formation of the nucleoside analogue. The third focus is on the separation of enantiomers of 1,3-oxathiolane nucleosides via resolution methods. The chemical as well as enzymatic procedures are reviewed and segregated in this review for effective synthesis of 1,3-oxathiolane nucleoside analogues.

Keywords: 1,3-oxathiolane sugar and nucleosides; Lewis acids; N-glycosylation; chiral auxiliaries; enzymes; separation of racemic nucleosides; stereoselectivity.

Figure 1

Representative modified 1,3-oxathiolane nucleoside analogues.

Figure 2

Mechanism of antiviral action of 1,3-oxathiolane nucleosides, 3TC (1) and FTC (2), as chain terminators.

Figure 3

Synthetic strategies for the construction of the 1,3-oxathiolane sugar ring.

Scheme 1

Synthesis of 4 from benzoyloxyacetaldehyde (3a) and 2-mercapto-substituted dimethyl acetal 3na.

Scheme 2

Synthesis of 8 from protected glycolic aldehyde 3b and 2-mercaptoacetic acid (3o).

Scheme 3

Synthesis of 20 from ᴅ-mannose (3c).

Scheme 4

Synthesis of 20 from 1,6-thioanhydro-ᴅ-galactose (3d).

Scheme 5

Synthesis of 8 from 2-(tert-butyldiphenylsilyloxy)methyl-5-oxo-1,2-oxathiolane (3m).

Scheme 6

Synthesis of 20a from ʟ-gulose derivative 3f.

Scheme 7

Synthesis of 31 from (+)-thiolactic acid 3p and 2-benzoyloxyacetaldehyde (3a).

Scheme 8

Synthesis of 35a from 1,4-dithiane-2,5-diol (3q) and glyoxylic acid (3g) hydrate.

Scheme 9

Synthetic routes toward 41 through Pummerer reaction from methyl 2-mercaptoacetate (3j) and bromoacetaldehyde diethyl acetal (36).

Scheme 10

Strategy for the synthesis of 2,5-substituted 1,3-oxathiolane 41a using 4-nitrobenzyl glyoxylate and mercaptoacetaldehyde diethyl acetal (3nb).

Scheme 11

Synthesis of 44 by a resolution method using Mucor miehei lipase.

Scheme 12

Synthesis of 45 from benzoyloxyacetaldehyde (3a) and 2-mercaptoacetaldehyde bis(2-methoxyethyl) acetal (3nc).

Scheme 13

Synthesis of 46 from 2-mercaptoacetaldehyde bis(2-methoxyethyl) acetal (3nc) and diethyl 3-phosphonoaldehyde 3i.

Scheme 14

Synthesis of 48 from 1,3-dihydroxyacetone dimer 3l.

Scheme 15

Approach toward 52 from protected alkene 3rb and lactic acid derivative 51 developed by Snead et al.

Scheme 16

Recent approach toward 56a developed by Kashinath et al.

Scheme 17

Synthesis of 56a from ʟ-menthyl glyoxylate (3h) hydrate by DKR.

Scheme 18

Possible mechanism with catalytic TEA for rapid interconversion of isomers.

Scheme 19

Synthesis of 35a by a classical resolution method through norephedrine salt 58 formation.

Scheme 20

Synthesis of 63 via [1,2]-Brook rearrangement from silyl glyoxylate 61 and thiol 3nb.

Scheme 21

Combined use of STS and CAL-B as catalysts to synthesize an enantiopure oxathiolane precursor 65.

Scheme 22

Synthesis of 1 and 1a from glycolaldehyde dimer 64 and 1,4-dithiane-2,5-diol (3q) using STS and CAL-B, respectively.

Scheme 23

Synthesis of 68 by using Klebsiella oxytoca.

Scheme 24

Synthesis of 71 and 72 using Trichosporon taibachii lipase and kinetic resolution.

Scheme 25

Synthesis of 1,3-oxathiolan-5-ones 77 and 78 via dynamic covalent kinetic resolution.

Figure 4

Pathway for glycosidic bond formation.

Scheme 26

First synthesis of (±)-BCH-189 (1c) by Belleau et al.

Scheme 27

Enantioselective synthesis of 3TC (1).

Scheme 28

Synthesis of cis-diastereomer 3TC (1) from oxathiolane propionate 44.

Scheme 29

Synthesis of (±)-BCH-189 (1c) via SnCl₄-mediated N-glycosylation of 8.

Scheme 30

Synthesis of (+)-BCH-189 (1a) via TMSOTf-mediated N-glycosylation of 20.

Scheme 31

Synthesis of 3TC (1) from oxathiolane precursor 20a.

Scheme 32

Synthesis of 83 via N-glycosylation of 20 with pyrimidine bases.

Scheme 33

Synthesis of 85 via N-glycosylation of 20 with purine bases.

Scheme 34

Synthesis of 86 and 87 via N-glycosylation using TMSOTf and pyrimidines.

Scheme 35

Synthesis of 90 and 91 via N-glycosylation using TMSOTf and purines.

Scheme 36

Synthesis of 3TC (1) via TMSI-mediated N-glycosylation.

Scheme 37

Stereoselective N-glycosylation for the synthesis of 1 by anchimeric assistance of a chiral auxiliary.

Scheme 38

Whitehead and co-workers’ approach for the synthesis of 1 via direct N-glycosylation without an activator.

Scheme 39

ZrCl₄-mediated stereoselective N-glycosylation.

Scheme 40

Plausible reaction mechanism for stereoselective N-glycosylation using ZrCl₄.

Scheme 41

Synthesis of enantiomerically pure oxathiolane nucleosides 1 and 2.

Scheme 42

Synthesis of tetrazole analogues of 1,3-oxathiolane nucleosides 97.

Scheme 43

Synthetic approach toward 99 from 1,3-oxathiolane 45 by Camplo et al.

Scheme 44

Synthesis of 100 from oxathiolane phosphonate analogue 46.

Scheme 45

Synthetic approach toward 102 and the corresponding cyclic thianucleoside monophosphate 102a by Chao and Nair.

Scheme 46

Synthesis of emtricitabine (2) from 1,4-dithiane-2,5-diol (3q) and glyoxylic acid (3g).

Scheme 47

Synthesis of 1 and 2, respectively, from 56a–d using iodine-mediated N-glycosylation.

Scheme 48

Plausible mechanism for silane- and I₂-mediated N-glycosylation.

Scheme 49

Pyridinium triflate-mediated N-glycosylation of 35a.

Scheme 50

Possible pathway for stereoselective N-glycosylation via in situ chelation with a metal ligand.

Scheme 51

Synthesis of novel 1,3-oxathiolane nucleoside 108 from oxathiolane precursor 8 and 3-benzyloxy-2-methylpyridin-4-one (107).

Scheme 52

Synthesis of 110 using T-705 as a nucleobase and 1,3-oxathiolane derivative 8 via N-glycosylation.

Scheme 53

Synthesis of 1 using an asymmetric leaving group and N-glycosylation with bromine and mesitylene.

Scheme 54

Cytidine deaminase for enzymatic separation of 1c.

Scheme 55

Enzymatic resolution of the monophosphate derivative 116 for the synthesis of (−)-BCH-189 (1) and (+)-BCH-189 (1a).

Scheme 56

Enantioselective resolution by PLE-mediated hydrolysis to obtain FTC (2).

Scheme 57

(+)-Menthyl chloroformate as a resolving agent to separate a racemic mixture 120.

Scheme 58

Separation of racemic mixture 1c by cocrystal 123 formation with (S)-(−)-BINOL.