Pd(II)-Catalyzed Synthesis of Bicyclo[3.2.1] Lactones via Tandem Intramolecular ?-C(sp3)-H Olefination and Lactonization of Free Carboxylic Acids

ABSTRACT: Bicyclo[3.2.1] lactones are chemical scaffolds found in numerous bioactive natural products. Herein, we detail the development of a novel palladium(II)-catalyzed tandem intramolecular ??-C(sp3)???H olefination and lactonization reaction that rapidly transforms linear carboxylic acid possessing a tethered olefin into the bicyclo[3.2.1] lactone motif. This transformation features a broad substrate scope, shows excellent functional group compatibility, and can be extended to the preparation of the related seven-membered bicyclo[4.2.1] lactones. Additionally, we demonstrate the synthetic potential of this annulation by constructing the 6,6,5-tricyclic lactone core structure of the meroterpenoid cochlactone A. We anticipate that this compelling reaction may provide a novel synthetic disconnection that can be broadly applied toward the preparation of a variety of bioactive natural products.

Automated summary

In this study, a novel reaction has been developed to convert carboxylic acids with olefin into bicyclo[3.2.1] lactone motifs. This reaction shows a broad substrate scope, excellent functional group compatibility, and can be extended to the synthesis of related lactone compounds.