Asymmetric transfer hydrogenation (ATH) of ketones using ([(arene)Ru(TsDPEN)Cl]-type catalysts is now a well-established method for the enantioselective synthesis of alcohols. In most cases, formic acid / triethylamine azeotrope (FA:TEA, 5:2) is used as the hydrogen source. ATH of some simple ketones such as, acetophenone and benzophenone derivatives, using Noyori-Ikariya catalysts has been reported and often gives the corresponding alcohol products with high enantioselectivities. But the ATH of hindered and challenging ketones is less well studied.

Hence, herein we report the results of two systematic studies. The first is of substrates containing the o-hydroxyphenyl group. ATH was carried out using various catalysts out of which (R,R)-C3-tethered catalyst was found to be the most active. The enantioselectivity is influenced by a combination of steric and electronic factors. We demonstrate how the correct choice of substituents can be used to deliver products with very high enantiomeric excess, including examples that would otherwise be very difficult to access by other methods. The directing effect of the o-OH group can provide the products with high enantioselectivity. The methodology was applied to the synthesis if challenging targets, including a sphingosine 1-phosphate receptor inhibitor. In another application, the ATH of a range of ketones flanked by a combination of an aromatic and a heterocyclic ring (furan, thiophene, N-methylimidazole) was also studied. The reduction enantioselectivity was high (up to 99% ee) in cases where the aromatic ring contained an ortho-substituent.