Biomimetic dehydrogenative Diels-Alder cycloadditions: total syntheses of brosimones A and B.

Nature creates an intriguing array of molecular architectures that has attracted extensive investigations on natural product identification, origin, biological activities, and chemical synthesis. In particular, biosynthetic studies have inspired elegant biomimetic total synthesis of natural products. Herein, we report biomimetic syntheses of the natural products brosimones A and B featuring multicatalytic, dehydrogenative Diels–Alder (DHDA) cycloadditions of 2’-hydroxychalcones. Prenylflavonoid Diels–Alder natural products, mainly isolated from the root bark of mulberry trees (Morus alba), are biosynthetically derived from electron-rich 2’-hydroxychalcone dienophiles and flavonoid dienes. Pioneering studies by Nomura and co-workers have determined that the requisite diene subunits arise from prenyl groups in nature. In one key experiment, the natural product artonin I (1) was isolated from Morus alba cell extract after both prenylated flavone 2 and chalcone 3 were fed to cell culture (Scheme 1). As part of our continuing interest in the total synthesis of prenylflavonoid Diels–Alder and related natural products, we have recently reported silica-supported silver nanoparticles (AgNPs) as a highly efficient catalyst for [4+2] cycloadditions of 2’-hydroxychalcones. Inspired by the aforementioned biosynthesis studies, further investigation was directed to the development of catalysts that enable biomimetic DHDA cycloadditions employing prenyl groups as diene precursors. In this regard, we envisioned tandem reactions that employ one catalyst system to promote dehydrogenation of prenyl groups to 1,3-substituted dienes in combination with silica-supported AgNPs to catalyze Diels–Alder cycloadditions of chalcone dienophiles and in situ-generated dienes. Brosimones A (4) and B (5) were both isolated from the plant Brosimopsis oblongifolia in Brazil and feature dimeric structures derived from prenyl chalcone 7 (Scheme 2). The intriguing biosynthetic relationship and structures of the brosimones, in particular the [3.3]metacyclophane core of 4, underscores the compounds as attractive targets for further development of DHDA cycloadditions. Our initial studies began with model reactions using prenyl chalcone 8. After screening a number of catalysts and oxidants, we observed that the desired dehydrogenative cycloaddition was catalyzed by a mixture of platinum on activated carbon (Pt/C) and silica-supported AgNPs in an ambient air atmosphere (Table 1, entry 1), which afforded cycloadducts exo-9 and endo-10 in 52% combined yield. We also examined hydrogen scavengers for transfer dehydrogenation, including cyclopentene (entry 3) and norbornene (entry 6). Use of cyclopentene afforded the best yield and mass balance and was chosen as the optimal hydrogen Scheme 1. Proposed biosynthesis of artonin I (1).