No abstract

Enantioselective [2 + 2] cycloaddition of C(1)ammonium enolates generated catalytically using the isothiourea HyperBTM with N-alkyl isatins gives spirocyclic β-lactones. In situ ring opening with an amine nucleophile generates isolable highly enantioenriched products in up to 92:8 dr and in >99:1 er.β-Lactones are versatile synthetic building blocks and significant components of many bioactive natural products. 1,2 As a consequence, a range of enantioselective synthetic methods for their preparation has been developed, with both Lewis acid and Lewis base catalyzed approaches common. 3 In terms of Lewis base catalysis using tertiary amines, the use of cinchona alkaloids and chiral DMAP derivatives has been extensively used to promote β-lactone formation through the generation of an intermediate C(1)-ammonium enolate. 4 Although versatile, these methods typically rely on the generation of reactive monosubstituted ketenes (formed in situ from acyl chlorides) or isolable but sensitive disubstituted ketenes as starting materials. 5 In an alternative approach, Romo introduced the NCAL (nucleophile-catalyzed aldollactonization) process to prepare β-lactones from keto-acids (Scheme 1a). 6 Key to this protocol was the development of carboxylic acids as the C(1)-ammonium enolate precursor, with a modified Mukaiyama reagent used for in situ generation of a reactive ester. Addition of either a cinchona alkaloid or isothiourea catalyst was used to generate the desired C(1)ammonium enolate, with subsequent intramolecular formal [2 + 2]-cycloaddition onto the pendant carbonyl giving highly enantioenriched β-lactones. Building on this work, we previously demonstrated the use of symmetric arylacetic anhydrides as alternative C(1)-ammonium enolate precursors. 7 These anhydrides are generally readily prepared from the parent carboxylic acid, are easy to handle, and can be used in conjunction with isothiourea catalysts without requiring the excess base that is a recognized limitation of alternative protocols using carboxylic acids as starting materials. This approach was applied to the HyperBTM-catalyzed enantioselective intermolecular formation of β-lactones with perfluoroalkyl ketones and arylacetic anhydrides (Scheme 1b). Mechanistic studies using natural abundance 13 C kinetic isotope effect experiments, together with computational analyses, indicated the operation of a concerted asynchronous