A convenient synthesis of (3S,3aR,5R,7aS,8S)-Hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-ol, a high-affinity nonpeptidyl ligand for highly potent HIV-1 protease inhibitors

We describe a practical synthesis of optically active (3S,3aR,5R,7aS,8S)-hexahydro-4H-3,5-methanofuro [2,3-b]pyran-8-ol. This stereochemically defined 6-5-5 tricyclic heterocycle is an important high-affinity P2 ligand for a variety of highly potent HIV-1 protease inhibitors that show clinical potential. The key steps involve an enantioselective ring opening of meso carbic anhydride mediated by the cinchona alkaloid. The resulting optically active acid was reduced to optically active bicyclo[2.2.1]hept-5-ene derivative which was converted to the ligand alcohol by ozonolysis, reduction, and dehydration of the resulting primary alcohol followed by ozonolytic cleavage and reduction. Optically active ligand alcohol was obtained in high enantiomeric purity (99 % ee). (C) 2022 Elsevier Ltd. All rights reserved.

Automated summary

We described a practical synthesis and key steps for the preparation of optically active compounds, which are important for HIV-1 protease inhibitors.