Catalytic prenyl conjugate additions for synthesis of enantiomerically enriched PPAPs
Shawn Voon Hwee Ng, Casey Howshall, T. Ho, Binh Khanh, Yuebiao Zhou, Can Qin, Kai Ze Tee, Peng Liu, Filippo Romiti, Amir H. Hoveyda
Abstract
Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of >400 natural products with a broad spectrum of bioactivity, ranging from antidepressant and antimicrobial to anti-obesity and anticancer activity. Here, we present a scalable, regio-, site-, and enantioselective catalytic method for synthesis of cyclic β-prenyl ketones, compounds that can be used for efficient syntheses of many PPAPs in high enantiomeric purity. The transformation is prenyl conjugate addition to cyclic β-ketoesters promoted by a readily accessible chiral copper catalyst and involving an easy-to-prepare and isolable organoborate reagent. Reactions reach completion in just a few minutes at room temperature. The importance of this advance is highlighted by the enantioselective preparation of intermediates previously used to generate racemic PPAPs. We also present the enantioselective synthesis of nemorosonol (14 steps, 20% yield) and its one-step conversion to another PPAP, garcibracteatone (52% yield).