Synthesis of a Bicyclic Analogue of AZT Restricted in an Unusual O4‘-<i>Endo</i> Conformation

Abstract

The [3.2.0]bicyclic beta-nucleoside analogue 5 has been designed as a conformationally restricted analogue of the anti-HIV drug AZT. The synthesis of 5 as well as its alpha-anomer 29 is hereby described. The synthesis was accomplished from D-arabinose via a modified Corey-Link procedure stereoselectively incorporating the azide moiety as well as a methyl ester function. When the tert-butyldiphenylsilyl group was used as a permanent protecting group, a selective formation of an oxetane ring failed. When using the p-methoxyphenyl group as a permanent protecting group, 5 and 29 were efficiently obtained via a selective reduction of the ester, a nucleobase coupling followed by separation of the anomers and ring-closing procedures. The nucleoside 5 is conformationally restricted in an unusual O4'-endo (East) conformation, which is an intermediate between the North- and South-type conformations. Nevertheless, neither 5 nor 29 displayed any anti-HIV activity.