The first example of an intramolecular asymmetric reductive amination of a 
dialkyl ketone with an aliphatic amine has been developed for the synthesis of 
Suvorexant (MK-4305), a potent dual Orexin antagonist under development for the 
treatment of sleep disorders. This challenging transformation is mediated by a 
novel Ru-based transfer hydrogenation catalyst that provides the desired 
diazepane ring in 97% yield and 94.5% ee. Mechanistic studies have revealed that 
CO(2), produced as a necessary byproduct of this transfer hydrogenation 
reaction, has pronounced effects on the efficiency of the Ru catalyst, the form 
of the amine product, and the kinetics of the transformation. A simple kinetic 
model explains how product inhibition by CO(2) leads to overall first-order 
kinetics, but yields an apparent zero-order dependence on initial substrate 
concentration. The deleterious effects of CO(2) on reaction rates and product 
isolation can be overcome by purging CO(2) from the system. Moreover, the rate 
of ketone hydrogenation can be greatly accelerated by purging of CO(2) or 
trapping with nucleophilic secondary amines.