Natural Products are an important source for the invention of new drugs, yet natural products of with pivotal biological functions are usually complex compounds with numerous stereogenic centers. The efficient and scalable asymmetric syntheses of these crucial natural products are a long-standing challenge for synthetic chemists. Monoterpene indole alkaloids are a class of natural products with divergent chemical structures and biological functions. Such features of these alkaloids have drawn strong attention from the synthetic community. (-)-Goniomitine is an Apsidosperma type monoterpene indole alkaloid isolated in 1987 from the Madagascar plant Gonioma Malagasy. This alkaloid shows promising anti-tumor activity. Although not the most complicated member of the monoterpene indole alkaloids, the asymmetric construction of two contiguous stereocenters of which one is an all-carbon quaternary center still poses significant challenges. Reported synthesis of this alkaloid mainly used chiral reagents (Jia and co-workers, Org. Lett. 2014, 16, 3416) or chiral auxiliaries (Zu and co-workers, Angew. Chem. Int. Ed. 2017, 56, 2754). In 2016, Stoltz et al first demonstrated the first catalytic asymmetric synthesis of (-)-goniomitine utilizing a Pd-catalyzed allylation reaction. Recently, Prof. Jianhua Xie reported a gram-scale scalable synthesis of (-)-goniomitine featuring an Ir-catalyzed asymmetric hydrogenation of an exocyclic enone ester.
The Xie group is long engaged in using highly efficient asymmetric hydrogenations in the catalytic asymmetric synthesis of natural products. In their synthesis of (-)-goniomitine, they envisioned to control the absolute stereochemistry via asymmetric hydrogenation of 5a. The all-carbon quaternary center on the cyclopentane system could then be stereoselectively installed via alkylation. A Johnson-Claisen rearrangement was envisaged for the introduction of the side chain of the tryptophol. The tetracyclic structure could then be accessed by applying Zhu’s iORC strategy (Angew. Chem., Int. Ed. 2013, 52, 3272; J. Am. Chem. Soc. 2014, 136, 15102).
During their studies on the hydrogenation, they discovered the spiro iridium catalyst Ir-SpiroPAP ((S)-10b) gave optimal catalytic activity and enantioselectivity. Gram scale preparation of enantioenriched 6a took only 0.01 mol% catalyst loading. The subsequent alkylation reaction for the construction of the all-carbon quaternary center could be conducted on gram scale with 80% yield. They then cleverly used a Johnson-Claisen rearrangement for the synthesis of 8a. A 6-step protocol including introduction of the aryl amino group via palladium coupling chemistry forged key intermediate 9. 9 then underwent oxidative cleavage/deprotection of amino and hydroxyl groups/cyclization cascade, leading to (-)-goniomitine in a one-pot procedure. The whole synthetic sequence was concise and efficient; each step could be conducted on gram-scale. The synthesis of (-)-goniomitine took 11 steps with 27% overall yield. Based on this strategy, they also succeeded in the syntheses of pentacyclic Aspidosperma alkaloids (+)-1, 2-drhydroaspidospermidine (2), (+)-aspidospermidine (3) and (+)-vincadifformine (4).
This work was published on Angew. Chem. Int. Ed., the first author of the article was Huaiyu Bin（DOI: 10.1002/ange.201812822）
