Mountains to Climb in the Chemistry of Highly Complex Indole Alkaloids: Methodology for Total Synthesis – Mount-Indole

To obtain these very complex natural molecules, we have developed approaches inspired by their biosyntheses, known as the bio-inspired approach. The goal is to try to get closer in the laboratory via organic chemistry to the way nature constructs these molecules in order to simplify the access routes to very complex compounds of potential biological interest. The goal is to control the formation of one chemical bond rather than another to obtain only the desired product after a short sequence of chemical steps.

As a notable result, we performed the biomimetic synthesis of bipleiophylline by oxidation of 2,3-bishydroybenzoic acid in the presence of pleiocarpamine (natural). On the other hand, the synthesis of 16-epi-pleiocarpamine was carried out by total synthesis.
This project gave rise to 16 publications, some of which have a high impact and particularly those reporting the syntheses of bipleiophylline and several molecules of the pleiocarpamine family in the journals «Nature Chemistry« and «Angewandte Chemie« respectively.

Achieve the total synthesis of pleiocarpamine
Fully understand the biosynthetic transformation of geissoschizine into the mavacuran skeleton
Perform the total synthesis of additional natural bis-indoles from pleiocarpamine

Publications multipartenaires
«Unified biomimetic assembly of voacalgine A and bipleiophylline via divergent oxidative couplings« Lachkar, D.; Denizot, N.; Bernadat, G.; Ahamada, K.; Beniddir, M. A.; Dumontet, V.; Gallard, J.-F.; Guillot, R.; Leblanc, K.; Otogo N'nang, E.; Turpin, V.; Kouklovsky, C.; Poupon, E.*; Evanno, L.*; Vincent. G.* Nat. Chem. 2017, 9, 793-798.
«Divergent Oxidative Couplings between Indoles and 1,2-Dihydroxybenzoic Acid Derivatives for the Biomimetic Synthesis of Voacalgine A and Bipleiophylline« Denizot, N.; Lachkar, D.; Poupon, E.*; Evanno, L.*; Vincent, G.* Synthesis 2018, 50, 4229-4242.
«Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for the Total Synthesis of (–)-17-nor-Excelsinidine« Jarret, M.; Tap, A.; Kouklovsky, C.; Poupon, E.; Evanno, L.*; Vincent, G.* Angew. Chem. Int. Ed. 2018, 57, 12294-12298.
«Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for Enantioselective Total Synthesis of Mavacuran Alkaloids« Jarret, M.; Turpin, V.; Tap, A.; Gallard, J.F.; Kouklovsky, C.; Poupon, E.*; Vincent, G.* Evanno, L.* Angew. Chem. Int. Ed. 2019, 58, 9861-9865.
«Bioinspired Divergent Oxidative Cyclizations of Geissoschizine: Total Synthesis of (–)-17-nor-Excelsinidine, (+)-16-epi-Pleiocarpamine, (+)-16-Hydroxymethyl-Pleiocarpamine and (+)-Taberdivarine H« Jarret, M.; Tap, A.; Turpin, V.; Denizot, N.; Kouklovsky, C.; Poupon, E.*; Evanno, L.*; Vincent, G.* Eur. J. Org. Chem. 2020, 6340-6351 (front cover). «YourJOC Talents« special collection
«Bioinspired Early Divergent Oxidative Cyclizations toward Pleiocarpamine, Talbotine, and Strictamine« Jarret, M.; Abou-Hamdan, H.; Kouklovsky, C.; Poupon, E.; Evanno, L.; Vincent, G.* Org. Lett 2021, 23, 1355-1360.
“The Chemistry of Mavacurane Alkaloids, A Rich Source of Bis-Indole Alkaloids” Mauger, A.; Jarret, M.; Kouklovsky, C.; Poupon, E.; Evanno, L.; Vincent, G.; Nat. Prod. Rep. doi:10.1039/D0NP00088D

Nature is able to assemble simple chemical building blocks and increment structural complexity to produce highly refined natural products. In this context, bipleiophylline is one of the more complex indole alkaloid isolated to date and its total synthesis is considered as “a mountain to climb”. Pleiocarpamine is a pivotal intermediate in the biogenesis of bipleiophylline and several other natural substances.

The overall objectives of this project are
1) to elucidate the biosynthesis of pleiocarpamine and by the way bringing answers to fundamental issues in the early stage of monoterpne indole alkaloids
2) achieve the first total synthesis of pleiocarpamine based, in part, on these biosynthetic considerations
3) achieve the first and bio-inspired total synthesis of bipleiophylline and related alkaloids from pleiocarpamine.

This collaborative project at the interplay of biosynthesis, biomimetic total synthesis and synthetic methodology development will be conducted by the teams of G. Vincent (ICMMO, faculty of Sciences) and E. Poupon/L. Evanno (BioCIS, faculty of Pharmacy) at Université Paris-Sud.