An enantioselective enzymatic desymmetrization route to hexahydro-4 H-furopyranol, a high-affinity ligand for HIV-1 protease inhibitors

Abstract

An enantioselective synthesis of (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-ol, a high-affinity nonpeptide ligand for a variety of potent HIV-1 protease inhibitors is described. The key steps involved a highly enantioselective enzymatic desymmetrization of meso-diacetate, an efficient transacetalization, and a highly diastereoselective reduction of a ketone. This route is amenable to large-scale synthesis using readily available starting materials.

Keywords: Desymmetrization; Enantioselective; Enzymatic hydrolysis; HIV-1 Protease Inhibitors; Ligand.

Figure 1

Structures of protease inhibitors 1–4

Figure 2

The key hydrogen bonding interactions of hexahydro-4 H-furopyranol ligand of inhibitor 4 with Asp29 and Asp30.

Scheme 1

An enzymatic desymmetrization strategy for hexahydro-4H-furopyranol

Scheme 2

Synthesis of bicyclic acetal 14

Scheme 3

Synthesis of ligand alcohol 6

Scheme 4

Synthesis of HIV-1 protease inhibitor 20