Ru-catalyzed asymmetric transfer hydrogenation of α-acyl butyrolactone via dynamic kinetic resolution: Asymmetric synthesis of bis-THF alcohol intermediate of darunavir

The Ru-catalyzed enantio- and diastereoselective dynamic kinetic resolution of alpha-(benzyloxy/benzoyloxy)acyl-gamma-butyrolactones has been examined via transfer hydrogenation. Employing the in situ prepared (R,R)-Ru-FsDPEN catalyst, the transfer hydrogenation of using formic acid/triethylamine at rt gave the corresponding (S)-3-((S)-2-(benzyloxy/benzoyloxy)-1-hydroxyethyl)dihydrofuran-2(3H)-one with good to excellent diastereo- and enantioselectivity. One of the resulting hydrogenation product prepared on gram scales was utilized for the synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (1), a key synthetic intermediate of various HIV protease inhibitors such as darunavir with excellent enantio-(95% ee) and diastereoselectivities (dr 95:5). (C) 2021 Elsevier Ltd. All rights reserved.

Automated summary

This study demonstrates the Ru-catalyzed enantio- and diastereoselective dynamic kinetic resolution of alpha-(benzyloxy/benzoyloxy)acyl-gamma-butyrolactones via transfer hydrogenation. Excellent diastereo- and enantioselectivities were achieved with the in situ prepared (R,R)-Ru-FsDPEN catalyst, leading to the synthesis of important organic molecules with good efficiency.