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. 2012 May 18;14(10):2488-91.
doi: 10.1021/ol300777p. Epub 2012 May 3.

Efficient synthesis of exo-N-carbamoyl nucleosides: application to the synthesis of phosphoramidate prodrugs

Jong Hyun Cho  1 , Steven J Coats, Raymond F Schinazi
Affiliations

Efficient synthesis of exo-N-carbamoyl nucleosides: application to the synthesis of phosphoramidate prodrugs

Jong Hyun Cho et al. Org Lett. .

Abstract

An efficient protection protocol for the 6-exo-amino group of purine nucleosides with various chloroformates was developed utilizing N-methylimidazole (NMI). The reaction of an exo-N(6)-group of adenosine analogue 1 with alkyl/and aryl chloroformates under optimized conditions provided the N(6)-carbamoyl adenosines (2a-j) in good to excellent yields. The reaction of N(6)-Cbz-protected nucleosides (5a-c) with phenyl phosphoryl chloride (7) using t-BuMgCl followed by catalytic hydrogenation afforded the corresponding phosphoramidate pronucleotides (8a-c) in excellent yield.

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Figures

Figure 1
Figure 1
Benzyloxycarbonyl N-alkylimidazolium salts
Scheme 1
Scheme 1
Synthesis of purine phenyl phosphoramidates (8a-c)a aProduct was a diastereomeric mixture in which RP/SP or SP/RP ratio ranged from 1:1 to 1:1.5.
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