Asymmetric Synthesis of Merck's Potent hNK1 Antagonist and Its Stereoisomers via Tandem Acylation/[3,3]-Rearrangement of 1,2-Oxazine N-Oxides

J Org Chem. 2020 Sep 4;85(17):11060-11071. doi: 10.1021/acs.joc.0c01322. Epub 2020 Aug 20.

Abstract

An asymmetric total synthesis of Merck's hNK1 antagonist and three of its stereoisomers was accomplished in 10 steps. The synthesis involves a stereoselective assembly of 1,2-oxazine N-oxide by the [4 + 2]-cycloaddition, site-selective C-H oxygenation using a novel tandem acylation/[3,3]-rearrangement process and the reductive 1,2-oxazine ring contraction into a pyrrolidine ring as key stages. Using this strategy, the fused pyrrolidine subunit was constructed with exceptionally high regio- and stereoselectivities. The approach described here can be used to access enantiopure 3,4-disubstituted prolinols, which are frequently found in pharmaceutically relevant molecules and organocatalysts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Cycloaddition Reaction
  • Oxazines*
  • Oxides*
  • Stereoisomerism

Substances

  • Oxazines
  • Oxides