A general iridium-catalyzed reductive dienamine synthesis allows a five-step synthesis of catharanthine via the elusive dehydrosecodine Yaseen A. Almehmadi 1,2 , Darren J. Dixon 1 * 1 Department of Chemistry, University of Oxford, UK, 2 Department of Chemistry, Rabigh College of Science and Arts, Saudi Arabia We developed a new catalytic, highly stereo- and regioselective approach towards the rapid construction of highly functionalized isoquinuclidines (ISQs). These bridged bicycles are abundant in active principle ingredients and natural products, 1 such as catharanthine, 18-methoxycoronaridine, cononusine, and caldaphinidine D (figure 1, a). Our new methodology relies on the use of an iridium (I) complex to hydrosilylate β,γ-unsaturated δ-lactams, which can lead to the downstream formation of a reactive dienamine intermediate, before undergoing a concerted [4+2] cycloaddition reaction with a wide range of dienophiles (figure 1, b). This remarkable transformation proceeds with high stereocontrol, low catalyst loading, and from readily available starting materials, resulting in the formation of complex isoquinuclidine polycyclic products. This robust synthetic approach was also extended to acyclic, aliphatic starting materials, enabling the formation of cyclohexene-substituted amine products and has enables the shortest (five-step) synthetic route to access catharanthine (figure 1, c) to date, an alkaloid that also happens to be a building block for vinblastine 2 (a widely used anticancer drug approved by the World Health Organization for several aggressive cancers such as brain, lung, testicular, bladder, and melanoma cancer).
Figure 1. (a) The prevalence of isoquinuclidines; (b) our work; (c) 5-step biomimetic total synthesis of catharanthine. References 1. Silva, E. M.; Rocha, D. H.; Silva, A. M. Diels−Alder Reactions of 1,2-Dihydropyridines: An Efficient Tool for the Synthesis of Isoquinuclidines. Synthesis 2018 , 50 , 1773−1782. 2. Caputi, L.; Franke, J.; Farrow, S. C.; Chung, K.; Payne, R. M. E.; Nguyen, T.-D.; Dang, T.-T. T.; Soares Teto Carqueijeiro, I.; Koudounas, K.; Dugé de Bernonville, T.; Ameyaw, B.; Jones, D. M.; Vieira, I. J. C.; Courdavault, V.; O’Connor, S. E. Missing Enzymes in the Biosynthesis of the Anticancer Drug Vinblastine in Madagascar Periwinkle. Science 2018 , 360 , 1235−1239.
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