Diastereospecific arylation and cascade deconstructive amidation/thioesterification of readily available lactam-fused bromolactones

Abstract

An intrinsic goal when designing synthetic methodology is to identify approaches whereby readily accessible precursors are converted into an array of products, which efficiently tap into new 3D-chemical space. In these studies, readily available bicyclic lactam-bromolactones have been interrogated in several fragment growth protocols by utilizing the halogen and lactone motifs as versatile linchpins for strategic construction of C–C, C–N, C–O, and C–S bonds. Diastereospecific C(sp³)–C(sp²) Kumada coupling of sterically imposing [5,5]-bicyclic lactam-bromolactones with several aryl Grignard reagents, under palladium catalysis, furnishes diarylmethane-tethered lactam-lactones in synthetically attractive yields, stereoinvertive fashion, and with a tolerance for many functional groups. When [5,6]-bicyclic lactam-bromolactones, which are prone to β-hydride elimination are employed, efficient arylation is observed only under Co(acac)₃-catalyzed conditions. Importantly, these [5,6]-bicyclic lactam-bromolactones undergo retentive arylation, independent of the transition metal catalyst. A base-mediated cascade deconstructive amidation of the [5,6]-bicyclic lactam-bromolactones with primary aliphatic amines proceeds efficiently to afford epoxide-tethered lactam carboxamides, which bear four contiguous stereocenters. Furthermore, an unusual route to homoallylic thioesters has been uncovered through deconstructive contra-thermodynamic thioesterification of the lactam-fused bromolactone precursors.