Asymmetric Catalytic Access to Piperazin-2-ones and Morpholin-2-ones in a One-Pot Approach: Rapid Synthesis of an Intermediate to Aprepitant

J Org Chem. 2023 Jun 16;88(12):7888-7892. doi: 10.1021/acs.joc.2c02491. Epub 2023 Feb 21.

Abstract

A one-pot Knoevenagel reaction/asymmetric epoxidation/domino ring-opening cyclization (DROC) has been developed from commercial aldehydes, (phenylsulfonyl)acetonitrile, cumyl hydroperoxide, 1,2-ethylendiamines, and 1,2-ethanol amines to provide 3-aryl/alkyl piperazin-2-ones and morpholin-2-ones in yields of 38 to 90% and up to 99% ee. Two out of the three steps are stereoselectively catalyzed by a quinine derived urea. The sequence has been applied for a short enantioselective entry to a key intermediate, in both absolute configurations, involved in the synthesis of the potent antiemetic drug Aprepitant.

MeSH terms

  • Aldehydes*
  • Amines*
  • Aprepitant
  • Catalysis
  • Cyclization

Substances

  • Aprepitant
  • Aldehydes
  • Amines