Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Myrtoidine and malagashanine, highly complex indole alkaloids, are effective adjuvants in developing cures for plasmodium malaria and potent multi-drug resistant agents. Despite nearly 30 years of progress, myrtoidine and the related family of Malagasy alkaloids still present formidable challenges for synthetic chemists. Here, we developed a diastereoselective [2+2+2] tandem cyclization reaction with alkyl-substituted methylene malonate, enabling highly efficient collective total synthesis of four Malagasy alkaloids from commercially available tryptamines within 10–13 steps. The synthetic strategy included rapid and highly stereoselective assembly of the tetracyclic indoline core containing 5–7 contiguous stereogenic carbon centers, rarely seen in indole alkaloids. Among the four natural products, (±)-myrtoidine, (±)-11-demethoxymyrtoidine, and (±)-12-hydroxymalagashanine were synthesized for the first time, and the work on (±)-malagashanine represented the shortest synthetic route so far. Our current study should enable further explorations of chemical and biological spaces based on myrtoidine, malagashanine, and related natural products.