Bipleiophylline is a highly complex monoterpene indole alkaloid composed of two pleiocarpamine units anchored on an aromatic spacer platform. The synthesis of bipleiophylline is considered as a mountain to climb by the organic chemistry community. Here, a unified oxidative coupling protocol between indole derivatives and 2,3-dihydroxybenzoic acid, mediated by silver oxide, has been developed to produce the core of bipleiophylline. This method also allows the independent preparation of benzofuro[2,3-b]indolenine and isochromano[3,4-b]indolenine scaffolds, depending only on the nature of the aromatic platform used. The procedure has been applied to simple indole derivatives and to more challenging monoterpene indole alkaloids, thereby furnishing natural-product-like structures. The use of scarce pleiocarpamine as the starting indole allows the first syntheses of bipleiophylline and of its biosynthetic precursor, voacalgine A. The structure of the latter has been reassigned in the course of our investigations by 2D NMR and displays an isochromano[3,4-b]indolenine motif instead of a benzofuro[2,3-b]indolenine.

We report a full account of our efforts towards bioinspired oxidative cyclizations of geissochizine and analogs to mimic the biosynthesis of the mavacuran, akuammilan, and excelsinidine groups of monoterpene indole alkaloids. The construction of the A,B,C,D ring system of geissoschizine was first achieved by merging two known syntheses of this alkaloid. Modified Ma's oxidative conditions (KHMDS/I2) applied directly to geissoschizine induced formation of the N4–C16 bond encountered in the excelsinidines core. Identical conditions applied to C16‐dimethylmalonate‐containing N4‐quaternized substrates ended in the formation of the mavacurans core (N1–C16 bond). With this unified oxidative cyclization strategy: (–)‐17‐nor‐excelsinidine, (+)‐16‐epi‐pleiocarpamine, (+)‐16‐hydroxymethyl‐pleiocarpamine, 16‐formyl‐pleiocarpamine and (+)‐taberdivarine H were synthetized. We also report a shortened total synthesis of 16‐epi‐pleiocarpamine compared to our preliminary communication from a C16‐monoester analog. Alternatively, 17‐nor‐excelsinidine was synthesized via an intramolecular nucleophilic substitution of a 7‐membered ring α‐chlorolactam prepared from 16‐desformyl‐geissoschizine.

Reported is the enantioselective total syntheses of mavacuran alkaloids,( + +)-taberdivarine H, (+ +)-16-hydroxymethyl-pleiocarpamine,a nd (+ +)-16-epi-pleiocarpamine,a nd their postulated biosynthetic precursor 16-formyl-pleiocarpamine.This family of monoterpene indole alkaloids is atarget of choice since some of its members are subunits of intricate bisindole alkaloids such as bipleiophylline.I nspired by the biosynthetic hypothesis,a no xidative coupling approach from the geissoschizine framework to form the N1ÀC16 bond was explored. Quaternization of the aliphatic nitrogen center was key to achieving the oxidative coupling induced by KHMDS/I 2 as it masks the nucleophilicity of the aliphatic nitrogen center and locksi nt he required cis conformation.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.Zuschriften Scheme 3. Synthesis of (+ +)-16-deformyl-geissoschizine [(+ +)-22], (+ +)-geissoschizine [(+ +)-1], and the geissoschizine malonate (À)-23 according to our previous work. [13] AIBN = 2,2'-azobisisobutyronitrile, Boc = tert-butoxycarbonyl, COD = 1,5-cyclooctadiene, DMAP = 4-(N,Ndimethylamino)pyridine, LDA = lithium diisopropylamide, TFA = trifluoroacetica cid.Scheme 4. Total synthesis of (+ +)-16-epi-pleiocarpamine [(+ +)-5]a nd (+ +)-16-hydroxymethyl pleiocarpamine[(+ +)-3]byN 1 ÀC16 oxidative cyclization from N4-PMB-geissoschizinium derivatives. DIBAL-H = diisobutylaluminum hydride, DMF = N,N-dimethylformamide, PMB = pmethoxybenzyl, TMS = trimethylsilyl.

Camellimidazoles A–C were recently reported as natural substances in Keemun black tea. Although a “biosynthetic” route to these intriguing imidazole dimers was proposed from caffeine by the authors in this seminal report, we envisioned that a artefactual scenario, consisting of alkaline hydrolysis of caffeine and spontaneous cascade reactions with a methylene donor such as formaldehyde or methylene chloride, could also have led to their formation. To capture the diversity of molecules obtained under these conditions (i.e. alkaline treatment of caffeine/formaldehyde), an in silico MetWork‐based pipeline was implemented, highlighting the sought‐after camellimidazoles B and C. A wealth of further compounds were also tagged, notably comprising the herein newly described and unnatural camellimidazoles D–F that were subsequently confirmed as anticipated in silico upon extensive spectroscopic analyses. Likewise, camellimidazoles B and C could also be obtained using methylene chloride as an alternative methylene donor which may also have occurred in the initial phytochemical pipeline that implied this solvent. The current investigation emphasizes the fitness of MetWork tagging to extend the logic of in silico anticipation of metabolic pathways to organic chemistry reactions.

Melonine is a basic monoterpene indole alkaloid (MIA) skeleton from Melodinus philliraeoides that was reported in 1983. The scarcity of its spectroscopic data questioned the validity of its structure. This prompted us to reisolate this molecule and to revise its structure into an unprecedented MIA scaffold. DFT-validated biosynthetic paths to both this new core and the originally reported form are proposed. The pathway to the original structure of melonine seems to be thermodynamically feasible, and that compound may exist as a natural product.

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.

We report the enantioselective total syntheses of mavacurans alkaloids, (+)-taberdivarine H, (+)-16-hydoxymethyl-pleiocarpamine, (+)-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, we explored an oxidative coupling approach from the geissoschizine framework to form the N1-C16 bond. Quaternization of the aliphatic nitrogen was key to achieve the oxidative coupling induced by KHMDS/I₂sinceit hides the nucleophilicity of the aliphatic nitrogen and locks the required cis conformation.

Polyneuridine aldehyde is a key intermediate in the biosynthetic routes of monoterpene indole alkaloids family of natural products. The molecule is the first biosynthetic member of the sarpagan-type alkaloids and is an entry to the ajmalantype and alstophyllan-type alkaloids. Complementary to the recent description of polyneuridine aldehyde, its reactivity was Scheme 1. Place of polyneuridine aldehyde (3) in the biosynthetic pathways.