Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467, USA.
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Science. 2024 Oct 11;386(6718):167-175. doi: 10.1126/science.adr8612. Epub 2024 Oct 10.
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).
多环聚多烯基酰基间苯三酚（PPAPs）是一类具有广泛生物活性的>400 种天然产物，具有抗抑郁、抗菌、抗肥胖和抗癌等活性。在这里，我们提出了一种可规模化、区域选择性、位点选择性和对映选择性的催化方法，用于合成环状β-烯基酮，这些化合物可用于高效合成多种 PPAPs，具有高对映体纯度。该转化是由一种易于获得的手性铜催化剂促进的环状β-酮酯的烯丙基共轭加成反应，涉及一种易于制备和分离的有机硼酸酯试剂。反应在室温下只需几分钟即可完成。通过对以前用于生成外消旋 PPAPs 的中间体进行对映选择性制备，突出了这一进展的重要性。我们还展示了 nemorosonol（14 步，20%产率）的对映选择性合成及其一步转化为另一种 PPAP，garcibracteatone（52%产率）。
