| Summary: | Xanthone natural products are a diverse class of structurally interesting and biologically active molecules most commonly isolated from plants. The tricyclic framework of a xanthone can be found in a number of complex natural products. Previous efforts have mostly focused on the synthesis of polycyclic xanthone natural products, thereby leaving dimeric xanthones an unexplored realm. Herein, we report an efficient methodology to construct the dimeric natural product griffipavixanthone and related congeners.
We first explored the racemic synthesis of griffipavixanthone (GPX). The key step utilizes a novel, intermolecular [4+2] cycloaddition–cyclization cascade between a vinyl p-quinone methide (p-QM) and an in situ generated 1,3-diene promoted by either Lewis or Brønsted acids. Experimental and computational studies reveal that the reaction pathway operates via a stepwise, cationic Diels–Alder cycloaddition. With an interest in harnessing the inherent cationic nature of the cascade reaction, we became interested in achieving an asymmetric synthesis of GPX. Synthesis of the natural product was accomplished via dimerization of a p-quinone methide using a specific chiral phosphoric acid (CPA) catalyst to afford a protected precursor in excellent diastereo- and enantioselectivity. Mechanistic studies, including an unbiased computational investigation of chiral ion-pairs using parallel tempering (PT) methods, were performed in order to probe the mode of asymmetric induction. This methodology enabled the absolute stereochemistry determination and prompted biological investigations to probe its efficacy as an anticancer agent. Finally, we report a divergent reaction of the xanthone p-QM monomers to form a novel limonene-type bis-xanthone architecture. A Hammett study designed to probe the mechanism revealed that the electronics of the xanthone carbonyl dictate regioselectivity; the overall process allows for initial bond construction tunability and ultimately new chemotypes. === 2023-11-04T00:00:00Z
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