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

The cobalt-catalyzed asymmetric hydrogenation of dehydro-sitagliptin was studied and applied to the synthesis ofsitagliptin (Januvia). Catalyst discovery efforts were accelerated by the application of a general method for the synthesis of cationicbis(phosphine) cobalt eta 6-arene complexes. One-electron oxidation of bis(phosphine) cobalt(II) dialkyl complexes in the presence ofarenes furnished the corresponding, bench-stable cobalt precatalysts, [(P-P)Co(eta 6-C6H6)][BAr4F]. Asymmetric hydrogenationutilized 0.5 mol % of the optimal catalyst, [(R,R)-(iPrDuPhos)Co(eta 6-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 selectivityafter standing in air in the solid state for 2 weeks. Deuterium labeling studies support an enamine-imine tautomerization processresulting 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.

Automated summary

The cobalt-catalyzed asymmetric hydrogenation of dehydro-sitagliptin was studied and applied to the synthesis of sitagliptin. The discovery of catalysts was accelerated by the synthesis of cationic bis(phosphine) cobalt eta 6-arene complexes. The optimal catalyst showed high yield and enantioselectivity, and maintained excellent activity and selectivity after standing in air for 2 weeks.