Rhodium-Catalyzed Homogeneous Asymmetric Hydrogenation of Naphthol Derivatives

Abstract

Due to their strong aromaticity and difficulties in chemo-, regio-, and enantioselectivity control, asymmetric hydrogenation of naphthol derivatives to 1,2,3,4-tetrahydronaphthols has remained a long-standing challenge. Herein, we report the first example of homogeneous asymmetric hydrogenation of naphthol derivatives catalyzed by tethered rhodium–diamine catalysts, affording a wide array of optically pure 1,2,3,4-tetrahydronaphthols in high yields with excellent regio-, chemo-, and enantioselectivities (up to 98% yield and >99% ee). Mechanistic studies with experimental and computational approaches reveal that fluorinated solvent 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) plays vital roles in the control of reactivity and selectivity, and 1-naphthol is reduced via a cascade reaction pathway, including dearomative tautomerization, 1,4-hydride addition, and 1,2-hydride addition in sequence. A novel synergistic activation mode was proposed in which HFIP assists a synergistic activation of both the hydrogen molecule and naphthol in the presence of a base, and the in situ-generated fleeting keto tautomer is immediately trapped and reduced by the Rh(III)–H species before it escapes from the solvent cage. This protocol provides a straightforward and practical pathway for the synthesis of key intermediates for several chiral drugs. Particularly, optically pure Nadolol, a drug for the treatment of hypertension, angina pectoris, congestive heart failure, and certain arrhythmias, is enantioselectively synthesized for the first time.