Enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine: the key to an efficient and practical synthesis of a glucokinase activator

J Org Chem. 2008 Jul 4;73(13):4986-93. doi: 10.1021/jo8006804. Epub 2008 May 29.

Abstract

A short and practical synthesis of glucokinase activator 1 was achieved utilizing a convergent strategy involving S(N)Ar coupling of activated aryl fluoride 11 with hydroxypyridine 9. The key to the success of the synthesis was the development of a novel method for enantioselective formation of alpha-arylpyrrolidines during the course of the project. In this method, (-)-sparteine-mediated enantioselective lithiation of N-Boc-pyrrolidine was followed by in situ transmetalation to zinc and Pd-catalyzed coupling with aryl bromide 3, proceeding in 92% ee. This transformation allowed the preparation of compound 1 in a 31% overall yield over six steps.

MeSH terms

  • Enzyme Activators / chemical synthesis*
  • Glucokinase / metabolism*
  • Molecular Structure
  • Palladium / chemistry*
  • Pyrrolidines / chemistry*

Substances

  • Enzyme Activators
  • N-Boc-pyrrolidine
  • Pyrrolidines
  • Palladium
  • Glucokinase