Catalytic Enantioselective Additions of Allyl Moieties to α-Halomethyl Ketones, Trifluoromethyl Substituted NH-Ketimines, and Nitriles

Abstract

Homoallylic alcohols and amines are commonly used building blocks for synthesis of biologically active molecules, yet a survey of the methods for their synthesis reveals a plague of limitations. Notably, the use of toxic reagents (Cr-, Mn-, and Sn-containing), precious metal catalysts (Ir- and In-based), non-ambient reaction temperatures (–78 to 140 °C), and extended reaction times (up to 240 hours), limit application on larger scale. The protection/deprotection sequences required to install directing/activating groups for reaction efficiency and enantioselectivity not only add synthetic steps but the conditions required for removal of such entities are not amenable to more complex and sensitive molecules. The development of catalytic enantioselective methods for addition of allyl moieties to readily available substrates including halomethyl ketones, trifluoromethyl-substituted ketimines, and nitriles have been developed. In the first two cases, an aminophenol-based boryl catalyst is utilized for enantioselective additions of allyl moieties through transition states controlled by either electrostatic attraction between a C–X bond and the catalyst’s ammonium moiety or minimization of steric and dipolar repulsion. In the latter, multicomponent additions to nitriles have been developed for synthesis of cyclic amines. In all cases, application is demonstrated through synthesis of otherwise difficult-to-access derivatives or biologically active molecules.