Industrially Viable Syntheses of Highly Enantiomerically Enriched 1-Aryl Alcohols via Asymmetric Hydrogenation

The practicalities of the asymmetric hydrogenation of acetophenone derivatives are addressed. The catalysts used, derived from the precatalysts [(xylylPhanePhos)RuCl2(DPEN)] (S)-(R,R)-1 and (R)-(S,S)-1, were shown to possess very high reactivity. 4‘-Fluoroacetophenone was hydrogenated at a molar substrate-to-catalyst ratio (S/C) of 100,000 with complete conversion effected in as little as 80 min (average turnover ∼1200 min-1, peak turnover ∼2500 min-1). The catalysts are tolerant of a range of commercial grade substrates, in most cases a S/C of 5000−10000 was achieved without the need to purify the ketone. Using precatalyst 1 enantioselectivities of 95 → 99% ee were achieved. The high selectivity and catalyst activity, plus the simplicity of the process, offers significant advantages over other enantioselective ketone reductions.