Engineering an enantioselective amine oxidase for the synthesis of pharmaceutical building blocks and alkaloid natural products

Research output: Contribution to journalArticle

  • External authors:
  • Diego Ghislieri
  • Marta Pontini
  • Simon C Willies
  • Ian Rowles
  • Annika Frank
  • Gideon Grogan

Abstract

The development of cost-effective and sustainable catalytic methods for the production of enantiomerically pure chiral amines is a key challenge facing the pharmaceutical and fine chemical industries. This challenge is highlighted by the estimate that 40-45% of drug candidates contain a chiral amine, fueling a demand for broadly applicable synthetic methods that deliver target structures in high yield and enantiomeric excess. Herein we describe the development and application of a "toolbox" of monoamine oxidase variants from Aspergillus niger (MAO-N) which display remarkable substrate scope and tolerance for sterically demanding motifs, including a new variant, which exhibits high activity and enantioselectivity toward substrates containing the aminodiphenylmethane (benzhydrylamine) template. By combining rational structure-guided engineering with high-throughput screening, it has been possible to expand the substrate scope of MAO-N to accommodate amine substrates containing bulky aryl substituents. These engineered MAO-N biocatalysts have been applied in deracemization reactions for the efficient asymmetric synthesis of the generic active pharmaceutical ingredients Solifenacin and Levocetirizine as well as the natural products (R)-coniine, (R)-eleagnine, and (R)-leptaflorine. We also report a novel MAO-N mediated asymmetric oxidative Pictet-Spengler approach to the synthesis of (R)-harmicine.

Bibliographical metadata

Original languageEnglish
Pages (from-to)10863-9
Number of pages7
JournalJournal of the American Chemical Society
Volume135
Issue number29
DOIs
Publication statusPublished - 24 Jul 2013