Direct and efficient synthesis of nucleosides through the ortho-(tert-butylethynyl)phenyl thioglycosides (BEPTs) protocol

Abstract

Nucleosides are highly biologically relevant compounds, and are widely clinically used as drugs for the treatment of virus/bacteria infections and cancers. However, efficient chemical synthesis of nucleoside is highly difficult due to the low reactivity of nucleobases acceptors, challenging the existing synthetic protocols. Here we show an alternative synthetic protocol with judiciously designed o-(tert-butylethynyl)phenyl thioglycosides (BEPTs) as donors. The protocol is featured by stable glycosylation donors and high efficiency, direct glycosylation without the need for preactivation/silylation of nucleobases, broad substrate scope, capacity in furnishing 2-deoxy-nucleosides, cost efficiency, scalability, and significantly improved reaction speed, and exhibits favorable and profound solvent effects for hexafluoroisopropanol (HFIP). To check the practicality of the protocol, efficient preparation of angustmycin A and dJ is accomplished. The reaction mechanisms are systematically investigated, providing deep insights to the BEPT protocol.

Fig. 1. Existing strategies for nucleoside synthesis and the BEPT protocol.

A N-glycosylation strategy via either ionic or radical mechanisms (LG leaving group, o-ABz ortho-alkynylbenzoyl, EPP 3,5-dimethyl-4-(2′-phenylethnylhenyl)phenyl, PVB ortho-(1-phenylvinyl)benzyl, EGC ethynylcyclohexyl glycosyl carbonate). B Sugar-ring construction strategy (LG leaving group, NB nucleobase). C Enzymatic transglycosylation strategy (NB nucleobase). D The BEPT protocol (BEP o-tert-butylethynylphenyl).

Fig. 2. Mechanism elucidation of the BEPT protocol in nucleoside synthesis.

A Glycosylation of 2a with MCEPT and BEPT donors (MCEPT o-(methoxycarbonylethynylphenyl)thio). B Isolation of the key catalyst intermediate II. C The chemical shift migration of H-8 of 2a’ with the increment of Au(I) catalyst amounts. D Titration of 2a’ and Au(I) catalyst (0.5 equiv) with III. E Comparison of the chemical shifts of H-8 in 2a in the presence of the same amount of III and IV (2.0 equiv). F DFT calculations (The calculations were conducted using Gaussian 09D).

Fig. 3. Direct synthesis of purine-type N-glycosides through the PG procedure of the BEPT protocol.

Boc-protected purine derivatives were selected as acceptors. Boc butoxylcarbonyl.

Fig. 4. Direct synthesis of pyrimidine-type glycosides through the BEPT protocol.

A Direct glycosylation of pyrimidine bases through the protecting group (PG) procedure of the BEPT protocol (PMB-protected pyrimidine bases were selected as acceptors. PMB p-methoxybenzyl. B Direct glycosylation of pyrimidine bases through the solvent procedure of the BEPT protocol (A mixture of DCM and HFIP (v/v = 4:1) was used as reaction media. DCM dichloromethane, HFIP hexafluoroisopropanol.

Fig. 5

DFT calculations (The calculations were performed with B3LYP/def2-SVP//M06-2X/def2-TZVP).

Fig. 6

Synthesis of 2′-deoxynucleoside derivatives by the combination of BEPT protocol and photocatalyzed C–O bond editing techniques (1,4-dihydroisonicotinoyl (DHIN) was used as a stereo-controlling and deoxygenation-initiating group, and the direct saturation of the DHIN group to isonicotinoyl (IN) group was found to be the major side reaction).

Fig. 7. Examination of the practicality of the BEPT protocol.

A Comparison of the BEPT protocol with ABz and EGC protocols (ABz o-alkynylbenzoyl, EGC ethynylcyclohexyl glycosyl carbonate). B Glycosylation of other N-nucleophiles (the chemical structures were unequivocally determined by 1D and 2D NMR). C Scalable synthesis of nucleoside drugs (the N-glycosylation steps were conducted on a gram-scale).

Fig. 8. Synthesis of augustmycin A (19), dJ (24), and dJ analog (24′).

A Convergent synthesis of angustmycin A (N-glycosidic linkage construction after exo-glycal fabrication). B Synthesis of dJ 24 (the glycosidic linkage construction sequence is O-glycosidic linkage first and then N-glycosidic linkage). C Divergent synthesis of dJ 24 and its analog 24′ (the glycosidic linkage construction sequence is N-glycosidic linkage first, followed by O-glycosidic linkage).