Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for Enantioselective Total Synthesis of Mavacuran Alkaloids

Abstract

Reported is the enantioselective total syntheses of mavacuran alkaloids, (+)‐taberdivarine H, (+)‐16‐hydroxymethyl‐pleiocarpamine, and (+)‐16‐epi‐pleiocarpamine, and their postulated biosynthetic precursor 16‐formyl‐pleiocarpamine. This family of monoterpene indole alkaloids is a target of choice since some of its members are subunits of intricate bisindole alkaloids such as bipleiophylline. Inspired by the biosynthetic hypothesis, an oxidative coupling approach from the geissoschizine framework to form the N1−C16 bond was explored. Quaternization of the aliphatic nitrogen center was key to achieving the oxidative coupling induced by KHMDS/I2 as it masks the nucleophilicity of the aliphatic nitrogen center and locks in the required cis conformation.

Biosynthetically Relevant Reactivity of Polyneuridine Aldehyde

“…In the context of the bio-inspired synthesis of mavacuran alkaloids [6,7] we first investigated the possibility to convert 3 back into geissoschizine (2) via a retro-biomimetic process (Scheme 2). Stirring 3 in acetic acid at 65°C afforded tetradehydro-geissoschizine (8) with a 75 % yield.…”

“…This spontaneous reaction is biosynthetically relevant as deformylation events are common in the sarpagan-type and related alkaloids biosynthesis. [7,8] Finally, an original reactivity was found when polyneuridine aldehyde (3) was subjected to the action of zinc dust in acetic acid (Scheme 3). These conditions induced a C3-N4 reductive Scheme 3.…”

“…[2,3] Then, divergent routes lead to the large diversity of this family of alkaloids. From corynan-type geissoschizine (2), [4] intramolecular oxidative couplings explain inter-alia the formation of akuammilan-type, [5] mavacuran-type [6,7] and sarpagan-type alkaloids. [3,8] Concerning the latter group, the first biosynthetic member is polyneuridine aldehyde (3).…”

Total Synthesis of Mavacuran Alkaloids via Bioinspired and Non-Bioinspired Strategies

“…25b Oxidative coupling from the C16-malonate 54a was more efficient since a 76% yield of pentacyclic ammonium derivative 82a was obtained over the benzylation and oxidative coupling steps. 25a After removal of the PMB group with BBr 3 , a Krapcho decarboxylation was performed which also delivered (+)-16- epi -pleiocarpamine ( 15 ) (Scheme 7 ). The pseudo -symmetry of the malonate could be broken since the two esters were in different spatial environments induced by the shape of the mavacuran framework.…”