MNBA-mediated β-lactone formation: mechanistic studies and application for the asymmetric total synthesis of tetrahydrolipstatin

J Org Chem. 2012 Jun 1;77(11):4885-901. doi: 10.1021/jo300139r. Epub 2012 May 14.

Abstract

Various β-lactones were prepared from β-hydroxycarboxylic acids by intramolecular dehydration condensation using MNBA, an effective coupling reagent, along with a nucleophilic catalyst. The transition state that provides the desired 4-membered ring model system is disclosed by density functional theory (DFT) calculations, and the structural features of the transition form are discussed. This method was successfully applied to the asymmetric total synthesis of tetrahydrolipstatin (THL), an antiobestic drug used in clinical treatment to inhibit the activity of pancreatic lipase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anhydrides / chemistry*
  • Anti-Obesity Agents / chemical synthesis*
  • Anti-Obesity Agents / chemistry*
  • Anti-Obesity Agents / pharmacology
  • Cross-Linking Reagents / chemistry*
  • Humans
  • Lactones / chemical synthesis*
  • Lactones / chemistry*
  • Lactones / pharmacology
  • Lipase / antagonists & inhibitors*
  • Lipase / metabolism*
  • Nitrobenzoates / chemistry*
  • Pancreas / drug effects*
  • Pancreas / enzymology*

Substances

  • 2-methyl-6-nitrobenzoic anhydride
  • Anhydrides
  • Anti-Obesity Agents
  • Cross-Linking Reagents
  • Lactones
  • Nitrobenzoates
  • lipstatin
  • Lipase