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 language | English (US) |
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Pages (from-to) | 4680-4687 |
Number of pages | 8 |
Journal | ACS Catalysis |
Volume | 12 |
Issue number | 8 |
DOIs | |
State | Published - Apr 15 2022 |
All Science Journal Classification (ASJC) codes
- Catalysis
- General Chemistry
Keywords
- asymmetric catalysis
- cobalt
- deuterium labeling
- hydrogenation
- pharmaceuticals