Synthesis of a bicyclic analogue of AZT restricted in an unusual O4'-endo conformation

The [3.2.0]bicyclic beta -nucleoside analogue 5 has been designed as a conf ormationally restricted analogue of the anti-HIV drug AZT. The synthesis of 5 as well as its a-anomer 29 is hereby described. The synthesis was accomp lished from D-arabinose via a modified Corey-Link procedure stereoselective ly 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-methoxyp henyl group as a permanent protecting group, 5 and 29 were efficiently obta ined 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) conformatio n, which is an intermediate between the North-and South-type conformations. Nevertheless, neither 5 nor 29 displayed any anti-HIV activity.