Synthesis of 2′- and 3′-Amino-Substituted Uridine,Thymidine and Adenosine,and Their Inhibitions of HIV Replication

Abstract

Reactions of primary and secondary amines with appropriately protected 2′-O-mesyl-3′-deoxynucleosides 1, 5, and 18 gave 2′,3′-dideoxy-2′-alkylaminonucleosides 2a-d, 6a-c and 19a-d, f, n-q (35–40%) as well as a small amount of 2′,3′-glyceropentofuranosyl nucleoside 3, 7 or 11 (∼15%). Displacement of the 3′-O-mesyl group in 9b with amines gave mainly the elimination product 11, except in the reaction with morpholine and benzylamine which gave 3′-amino-substituted products 10c and 10d at a yield of 52% and 24%, respectively. The ring-opening reactions of appropriately protected 2′, 3′,-O-lyxoanhydro-adenosine 13 by a variety of primary and secondary amines gave isomeric mixtures of 2′-alkylamino nucleosides 15a-k (∼20%) and 3′-alkylamino nucleosides 14a-m (∼60%). These alkylamino nucleosides have been subsequently deprotected under acidic conditions to give the parent nucleosides in good yields; their biological activities as inhibitors of human immunodeficiency virus (HIV) replication have been also evaluated. The 2′,3′-dideoxy-2′-substituted and 2′,3′-dideoxy-3′-substituted nucleosides described herein are not available through any other known routes.