A new Synthesis of 1-(2,3-Dideoxy-β-D-Glycero-Pent-2-Enofuranosyl)- Thymine. A Highly Potent and Selective Anti-Hiv Agent

Abstract

A high yielding, straightforward synthesis of 1-(2,3-dideoxy-β-D-glyceropent-2-enofuranosyl)thymine (d4T) (10) is reported through a simple oxidation step of key intermediates such as, 1-(5-O-pivaloyl-3-deoxy-3(R)-phenylseleno-β-D-glyceropentofuranosyl)thymine (7) [1 → 3 → 5 → 7 → 9 → 10], or 1-(5-O-(4-methoxytrityl)-3-deoxy-3(R)-phenylseleno-β-D-glycero pentofuranosyl)thymine (6) [1 → 2 → 4 → 6 → 8 → 10]. The scope of this synthesis is also demonstrated by a simple preparation of a potential prodrug of d4T, 1-(2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)-5-methylcytosine (d4C^5me) (15), both from 1-(5-O-MMTr-2,3-dideoxy- β-D-glyceropent-2-enofuranosyl)thymine (8), and 1-(5-O-pivaloyl-2,3-dideoxy-β-D-glycero-pent-2-enofuranosyl)thymine (9)., Furthermore, 3′, 5′-dideoxy-3′, 5′-bis(phenylselenyl)thymidine (19) produced only 2-methylene-5-(R)-(thymin-1-yl)-2,5-dihydrofuran (22) through an oxidation followed by mild alkali treatment.