Asymmetric total synthesis of Gelsemium alkaloids

Plants from the genus Gelsemium are recognized as poisonous species and have been widely used in traditional Asian medicine to treat skin ulcers, dermatitis, and various ailments over a thousand years. Because of the interesting biological activities and the densely-packed, polycyclic architectures, Gelsemium alkaloids isolated from various Gelsemium elegans have received great attention from the synthetic community. Gelsedine-type alkaloids, as the largest subfamily of the Gelsemium alkaloids (>60 members isolated to date), have received the interest of a number of organic chemists, such as Fukuyama, Carreira, Farreira and Zhao, to achieved total synthesis of gelsedine-type alkaloids.

Recently, Ma group has developed and implemented a divergent route to synthesize gelsedine-type alkaloids (J. Am. Chem. Soc. 2018, 140 (37), 11608–11612). The gelsedine-type alkaloids possess an common oxabicyclo[3.2.2]-nonane core and spiro-N-methoxy indolinone moiety, along with a diversely functionalized heterocycle embedded in the compact framework. Ma and coworkers constructed the core structure of the gelsedine-type alkaloids with grams scale by a smart strategy, which hinges on the rapid assembly of the common core from the known fragments by asymmetric Michael addition, tandem oxidation/aldol cyclization and pinacol rearrangement. Then via a late-stage heterocyclization process the versatile intermediates were transformed a diversely functionalized heterocycle (such as pyrrolidine, pyrroline, pyrrolidinone or azetidine ring), which culminated in total syntheses of (–)-gelsedilam, (–)-gelsedine, (–)-gelsenicine and (–)-gelsemoxonine in 7-9 steps from known fragments without using any protecting group.

 

These projects were sponsored by Chinese Academy of Sciences Strategic Priority Research Program  and National Natural Science Foundation of China.

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