Cortistatin A is a marine steroid with highly selective and perhaps mechanistically unique antiangiogenic activity. Herein we report a synthesis of this natural product by way of “cortistatinone”, an intermediate ideally suited for investigating the key pharmacophore of the cortistatin family. The synthesis begins with a terrestrial steroid and traverses a route to cortistatin A through the discovery of unique chemical reactivity. Specifically, we demonstrate the first example of a directed, geminal C−H bisoxidation, a new fragmentation cascade to access expanded B-ring steroid systems, a chemoselective cyclization to install the hallmark oxabicycle of the cortistatin family, and a remarkably selective hydrogenation reaction, which should find extensive use in future syntheses of the cortistatins and designed analogues. The synthesis displays a level of brevity, efficiency, and practicality that will be crucial in evaluating the medicinal potential of this fascinating class of marine steroids.
Convergent approach: the total syntheses of (-)-flueggine A and (+)-virosaine B have been accomplished in a concise and convergent manner. Key steps in these approaches were relay ring-closing metathesis reactions for rapid construction of the key intermediates, and 1,3-dipolar cycloaddition reactions for the formation of the natural products.
Natural products containing eight-membered carbocycles constitute a class of structurally intriguing and biologically important molecules such as the famous diterpenes taxol and vinigrol. Such natural products are being increasingly investigated because of their fascinating architectural features and potent medicinal properties. However, synthesis of natural products with cyclooctane moieties has proved to be highly challenging. This review highlights the recently completed total syntheses of natural products with eight-membered carbocycles with a focus on strategic considerations. A collection of 27 representative studies from the literature covering the decade from 2009 to 2019 is described in chronological order with relevant studies grouped together, including syntheses of the same natural product by different research groups using different strategies. Finally, a summary and outlook including a discussion of the major features of each strategy used in the syntheses are presented. This review illustrates the diversity and creativity in the elegant synthetic designs of eight-membered carbocycles. We hope this review will provide timely illumination and beneficial guidance for future synthetic efforts for organic chemists who are interested in this area.
A concise first total synthesis of (±) maoecrystal V (1) is reported. The synthesis features a Wessely oxidative dearomatization of a phenol, an intramolecular Diels-Alder reaction, and a Rh-catalyzed O-H bond insertion as key steps.
Development of a gold-catalyzed tandem reaction of 1,7-diynes with both internal and external nucleophiles was realized, which constructed five chemical bonds, two rings, and two stereogenic centers in a single step. Based on the novel cascade transformation, we achieved a unified strategy toward the stereoselective total syntheses of C-15 oxygenated drimane-type sesquiterpenoids and their analogues, which provided the natural products kuehneromycin A, antrocin, anhydromarasmone, and marasmene as a proof-of-concept study.
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