Abstract
α‐Substituted chiral ketones that have small steric and electronic differences around the reaction sites are difficult substrates to reduce with high diastereoselectivity. Metal hydride reduction of 2‐(4‐benzoylmorpholinyl) phenyl ketone and 3‐(1‐tert‐butoxycarbonylpiperidinyl) phenyl ketone using sodium borohydride, zinc borohydride, and potassium tri‐sec‐butylborohydride as reducing agents affords the syn‐ and anti‐alcohols in a lower than 80:20 ratio. Hydrogenation of these ketones with a catalyst system of RuCl~2~(BIPHEP)(DMEN) and potassium tert‐butoxide in 2‐propanol results in the syn‐alcohols with ≥ 99:1 selectivity [BIPHEP=2,2′‐bis(diphenylphosphino)biphenyl, DMEN=N,N‐dimethylethylenediamine]. The marked difference in the diastereoselectivity suggests that the stereoselection in this hydrogenation is primarily regulated by the structure of the catalyst’s reaction field (“catalyst‐controlled diastereoselection”) but not the internal stereocontrol of the substrates. This chemistry is applied to the asymmetric hydrogenation through dynamic kinetic resolution with a RuCl~2~[(S)‐BINAP][(R)‐DMAPEN]/potassium tert‐butoxide catalyst [BINAP=2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl, DMAPEN=2‐dimethylamino‐1‐phenylethylamine]. A series of aryl heterocycloalkyl ketones has been converted to the alcohols in excellent diastereo‐ and enantioselectivities. The modes of catalyst‐controlled diastereoselection and enantioselection are interpreted by using transition‐state molecular models. (S,S)‐Reboxetine, a selective norepinephrine uptake inhibitor, was synthesized from one of product alcohols.