A Desilylative Approach to Alkyl Substituted C(1)-Ammonium Enolates: Application in Enantioselective [2+2] Cycloadditions

Abstract

The catalytic generation of C(1)-ammonium enolates from the corresponding α-silyl-α-alkyl substituted carboxylic acids using the isothiourea HyperBTM is reported. This desilylative approach grants access to α-unsubstituted and α-alkyl substituted C(1)-ammonium enolates, which are typically difficult to access through traditional methods reliant upon deprotonation. The scope and limitations of this process is established in enantioselective [2+2]-cycloaddition processes with perfluoroalkylketones (31 examples, up to 96 % yield and >99 : 1 er), as well as selective [2+2]-cycloaddition with trifluoromethyl enones (4 examples, up to 75 % yield and >99 : 1 er). Preliminary mechanistic studies indicate this process proceeds through an initial kinetic resolution of an in situ prepared (±)-α-silyl-α-alkyl substituted anhydride, while the reaction process exhibits overall pseudo zero-order kinetics.

Keywords: Cycloaddition; Desilylation; Enolate; Isothiourea; β-Lactone.

Figure 1

a) Traditional method of C(1)‐ammonium enolate generation from carboxylic acids. b) Chi's desilylative functionalisation of benzylic substituents. c) Proposed desilylative generation of C(1)‐ammonium enolates from carboxylic acids using isothioureas.