Enantio- and diastereo-convergent synthesis of (2 R,5 R)- and (2 R,5 S)-Pityol through enzyme-triggered ring closure

Abstract

A short chemoenzymatic synthesis of the (2 R,5 S)- and (2 R,5 R)-stereoisomer of the bark beetle pheromone Pityol 1 was achieved from (±)-Sulcatol 2 in an enantio- and diastereo-convergent fashion without the formation of any ‘unwanted’ stereoisomer. The key steps include: (i) lipase-catalyzed deracemization of (±)- 2 using kinetic resolution coupled to an in-situ inversion or, alternatively, dynamic resolution using combined lipase- and Ru-catalysis; and (ii) creation of the second stereogenic center by an epoxide hydrolase-catalyzed diastereo-convergent hydrolysis of a haloalkyl oxirane, followed by spontaneous ring closure to form 1 in a stereoselective fashion.