Cationic Bis(phosphine) Cobalt(I) Arene Complexes as Precatalysts for the Asymmetric Synthesis of Sitagliptin

Connor S. MacNeil, Hongyu Zhong, Tyler P. Pabst, Michael Shevlin, Paul J. Chirik

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The cobalt-catalyzed asymmetric hydrogenation of dehydro-sitagliptin was studied and applied to the synthesis of sitagliptin (Januvia). Catalyst discovery efforts were accelerated by the application of a general method for the synthesis of cationic bis(phosphine) cobalt η6-arene complexes. One-electron oxidation of bis(phosphine) cobalt(II) dialkyl complexes in the presence of arenes furnished the corresponding, bench-stable cobalt precatalysts, [(P-P)Co(η6-C6H6)][BAr4F]. Asymmetric hydrogenation utilized 0.5 mol % of the optimal catalyst, [(R,R)-(iPrDuPhos)Co(η6-C6H6)][BAr4F], in THF solution and produced sitagliptin in >99% yield with 97% ee. Cobalt catalysts were compatible with a range of solvents and maintained excellent activity and selectivity after standing in air in the solid state for 2 weeks. Deuterium labeling studies support an enamine-imine tautomerization process resulting in the reduction of the metalated imine. Notably, state-of-the-art neutral bis(phosphine) cobalt precatalysts were ineffective, emphasizing the utility of a class of cationic cobalt precatalysts.

Original languageEnglish (US)
Pages (from-to)4680-4687
Number of pages8
JournalACS Catalysis
Volume12
Issue number8
DOIs
StatePublished - Apr 15 2022

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)

Keywords

  • asymmetric catalysis
  • cobalt
  • deuterium labeling
  • hydrogenation
  • pharmaceuticals

Fingerprint

Dive into the research topics of 'Cationic Bis(phosphine) Cobalt(I) Arene Complexes as Precatalysts for the Asymmetric Synthesis of Sitagliptin'. Together they form a unique fingerprint.

Cite this