New synthesis of 2',3'-dideoxy-3'-C-cyano-2'-substituted thymidines by michael addition reactions

Abstract

A new high-yielding preparation of appropriately protected 3'-enenitrile of thymidine 5 has been devised directly from the 3'-keto thymidine 2. The 3'-enenitrile 5 has been subsequently subjected to various Michael addition reactions with ammonia, primary amines (methylamine and benzylamine), secondary amines (pyrrolidine, piperidine and morpholine) and carbon-nucleophiles (sodium dimethylmalonate and conjugate base of nitromethane) as means to synthesize new 2',3'-dideoxy-3'-C-cyano-2'-substituted thymidine derivatives which can not be prepared using any known procedure. Most of these nucleophilic addition reactions gave either the trans-isomer as the sole product, such as 7d–7g, or as the major product 7a–7c & h along with the cis-isomer 8a–8c & h, except for the reaction of 5 with ammonia where the cis-isomer 9e was the major product formed. The Michael adducts have been finally 5'-deprotected to give nucleosides 9a–9h, 10a–10c & h in good yields. Compounds described herein, with free 5'-hydroxyl function, are potential inhibitors of the HIV-reverse transcriptase promoted c-DNA synthesis