Triarylaminium Radical Cation Promoted Coupling of Catharanthine with Vindoline: Diastereospecific Synthesis of Anhydrovinblastine and Reaction Scope

Abstract

A new triarylaminium radical cation promoted coupling of catharanthine with vindoline is disclosed, enlisting tris(4-bromophenyl)aminium hexachlororantimonate (BAHA, 1.1 equiv) in aqueous 0.05 N HCl/trifluoroethanol (1−10:1) at room temperature (25 °C), that provides anhydrovinblastine in superb yield (85%) with complete control of the newly formed quaternary C16′ stereochemistry. A definition of the scope of aromatic substrates that participate with catharanthine in the BAHA-mediated diastereoselective coupling reaction and simplified indole substrates other than catharanthine that participate in the reaction are disclosed that identify the key structural features required for participation in the reaction, providing a generalized indole functionalization reaction that bears little structural relationship to catharanthine or vindoline.

A microbial supply chain for production of the anti-cancer drug vinblastine

“…Despite the vast repertoire of MIAs with documented bioactivities, obtaining requisite amounts of MIAs needed for further development and clinical applications is often challenging because of the low yields observed in extracts from natural plant resources, as exemplified by the chemotherapeutic drugs vinblastine and vincristine requiring 500 and 2,000 kg of Catharanthus roseus dried leaves, respectively, to obtain 1 g of products 3 , 7 , 8 . Likewise, owing to the numerous stereo centres found in MIAs, multi-step synthetic chemistry holds little promise for bulk production of complex MIA therapeutics 2 , 9 , and thus the current vinblastine supply chains rely on extraction from C. roseus and subsequent condensation of the catharanthine and vindoline precursors 10 . As vincristine and vinblastine were listed as being drugs with a shortage in 2019–2020 by the US Food and Drug Administration 11 , there is a growing awareness of the importance of refactoring the biosynthesis of MIAs in genetically tractable heterologous hosts.…”

Biologically Significant and Recently Isolated Alkaloids from Endophytic Fungi

“…Many attempts were made to enhance the availability of VLB ( 5 ) through semisynthesis from the two monoterpene indole alkaloid precursors, vindoline ( 7 ) and catharanthine ( 8 ), − two of the more prevalent alkaloids in the leaves of C . roseus . , These and related synthetic efforts resulted in new anticancer drug analogues of the alkaloids, such as vindesine, vinflunine, and vinorelbine and led to successful efforts to enhance the activity and reduce side effects through structure modification .…”

The quest for supernatural products: the impact of total synthesis in complex natural products medicinal chemistry

“…Because of their clinical importance, structural complexity, low natural abundance and unique mechanism of action, vinblastine and vincristine continue to be the subject of extensive total synthesis, semisynthetic and biosynthetic studies. [109][110][111][112][113][114][115][116][117] In efforts to develop analogues with further improved tubulin binding properties and antitumor activity, Boger et al developed a tandem intramolecular [4 + 2]/[3 + 2] oxadiazole cycloaddition cascade for the concise total synthesis of vindoline 118 as well as a biomimetic Fe(III)-promoted coupling of vindoline with catharanthine [119][120][121][122][123] and in situ C20' oxidation. This has allowed not only the convergent total synthesis of vinblastine itself but related analogues with deep-seated modifications.…”