Catalytic prenyl conjugate additions for synthesis of enantiomerically enriched PPAPs

• 成果类型: Article
• 署名作者: Ng, Shawn; Howshall, Casey; Ho, Thanh Nhat; Mai, Binh Khanh; Zhou, Yuebiao; Qin, Can; Tee, Kai Ze; Liu, Peng; Romiti, Filippo; Hoveyda, Amir H.
• 署名单位: Boston College; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Universites de Strasbourg Etablissements Associes; Universite de Strasbourg; University of Texas System; University of Texas Dallas
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8947
• DOI: 10.1126/science.adr8612
• 发表日期: 2024-10-01
• 页码: 167-175
• 关键词: polycyclic polyprenylated acylphloroglucinols; enantioselective total-synthesis; orbital coupled-cluster; natural-products; benzophenones; allylation; 1; 4-addition; clusianone; lithiation; hyperforin

摘要

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 beta-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 beta-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).