Activation of Carbon-Heteroatom Bonds: Transition Metal-Catalyzed Coupling of Strained Rings

Abstract

Epoxides and aziridines are invaluable substrates for complex molecule synthesis due to their accessibility and proclivity toward ring opening. Generally, C-C bond formation with these substrates is uncatalyzed and requires either harsh stoichiometric organometallic reagents or a narrow set of stabilized carbanions, thereby limiting the generality of these transformations. To address these drawbacks, we have investigated the transition metal-catalyzed cross coupling of epoxides and aziridines. Conditions for the coupling of styrenyl epoxides with boronic acids were developed; a variety of alpha-substituted alcohols are generated with good reaction efficiency. Mechanistic studies support a multi-catalytic sequence involving Csp3-O bond activation. This methodology was extended to include the cross coupling of simple aliphatic aziridines with zinc nucleophiles. Crucial to the success of this transformation was the development of a novel protecting group capable of coordinating the catalyst, activating the aziridine toward oxidative addition, and assisting in reductive elimination. This transformation represents the first use of a non-benzylic or allylic Csp3-N bond as an electrophile in a catalytic cross-coupling reaction and affords medicinally relevant beta-substituted amines.