Synthesis of novel 3 '-C-methyl-apionucleosides: an asymmetric construction of a quaternary carbon by Claisen rearrangement

The synthesis of 2,3-dideoxy-3-C-(hydroxymethyl)-3-C-methyl-D-glycero-tetro furanosyl nucleosides was accomplished in high enatiomeric purity (98.5% ee ) via [3,3]-sigmatropic Claisen rearrangement of (E)(S)-5-benzyloxy-1-tert- butyldimethylsilanyloxy-4-methyl prepared from 2,3-O-isopropylidene-D-glyce raldehyde. The synthesized nucleosides were assayed against human immunodef iciency virus (HIV) and hepatitis B virus in human peripheral blood mononuc lear (PBM) and 2.2.15 cells, respectively. 6-Amino-9-[2,3-dideoxy-3-C-(hydr oxymethyl)-3-C-methyl-beta-D-glycero-tetrofuranosyl]-2-fluoropurine shows m oderate antiviral activity (EC50 = 2.55 mu M) against HIV-1 strains and 6-a mino-9-[3-deoxy-3-C-(hydroxymethyl)-3-methyl-alpha-D-glycero-tetrofuranosyl ]-2-fluoropurine exhibits potent anti-HIV activity (EC50=0.073 mu M) with s ignificant cytotoxity (IC50 = 1.0 mu M). (C) 2000 Elsevier Science Ltd. All rights reserved.