Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5'-alkynylation.

Raja Ben Othman,Christine Gravier-Pelletier,Sandrine Calvet-Vitale,Laurent Le Corre,Mickaël J Fer

doi:10.3762/bjoc.13.153

Abstract

The 5’-alkynylation of uridine-derived aldehydes is described. The addition of alkynyl Grignard reagents on the carbonyl group is significantly influenced by the 2’,3’-di-O-protecting groups (R1): O-alkyl groups led to modest diastereoselectivities (65:35) in favor of the 5’R-isomer, whereas O-silyl groups promoted higher diastereoselectivities (up to 99:1) in favor of the 5’S-isomer. A study related to this protecting group effect on the diastereoselectivity is reported.

Highlights

Nucleoside and nucleotide derivatives or analogues are biologically active compounds of major interest [1,2]
Intrigued by the moderate diastereomeric ratio reported for the addition or organometallic reagents onto nucleoside aldehyde (Table 1), we decided to investigate the influence of the protecting groups of the uridine aldehyde on the stereochemical outcome of the nucleophilic addition of a Grignard reagent and we wish to report the results of our study
Vasella’s group devoted a huge amount of work to the synthesis and characterization of these compounds and notably reported that TES was better than TMS for efficient separation of both isomers, resulting in an improved 42% yield for the isolated major diastereomer (5’R)-11ab [12]

Summary

Introduction

Nucleoside and nucleotide derivatives or analogues are biologically active compounds of major interest [1,2]. Intrigued by the moderate diastereomeric ratio reported for the addition or organometallic reagents onto nucleoside aldehyde (Table 1), we decided to investigate the influence of the protecting groups of the uridine aldehyde on the stereochemical outcome of the nucleophilic addition of a Grignard reagent and we wish to report the results of our study. To unambiguously determine the ratio of diastereomers and the C-5’ configuration of the major one for the synthesized propargylic alcohols 11–15, their partial or complete deprotection was carried out to take advantage of an unequivocal 1H NMR comparison with known compounds, or reliable derivatives.

Results

Conclusion