Collective Total Synthesis of Mavacuran Alkaloids through Intermolecular 1,4-Addition of an Organolithium Reagent.

We report a synthetic endeavor towards the highly strained pentacyclic caged framework of the mavacuran alkaloids which culminated with the concise total synthesis of C-fluorocurine, C-profluorocurine, C-mavacurine, normavacurine, 16-epi-pleiocarpamine and taberdivarine H. We designed a strategy involving late-stage construction of the D ring by Michael addition of a vinylic nucleophile to a 2-indolyl acrylate moiety. While the intramolecular Michael addition did not succeed, we were able to perform a diastereoselective unusual intermolecular 1,4-addition of a functionalized vinyl lithium reagent to a readily accessible Michael acceptor with the assistance of the piperidine nitrogen atom through the formation of a complex as suggested by DFT computations. Final cyclization was achieved by nucleophilic substitution to form an ammonium intermediate. The first total syntheses of C-profluorocurine and C-fluorocurine were finalized by the dihydroxylation of C-mavacurine and a pinacol rearrangement, respectively.

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

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.

Diastereoselective Synthesis of an Advanced Intermediate of Thapsigargin and Other 6,12-Guaianolides Using a RCEYM Strategy.

A new and flexible approach toward the synthesis of 6,12-guaianolide anticancer drugs such as trilobolides or thapsigargin has been developed that could be applied to the preparation of analogues with a modified ring system. The synthesis starts from commercial 2-methylcyclopentane-1,3-dione, only relying on diastereoselective reactions for the construction of the stereogenic centers at C1, C3, C6, and C10 and features a high-yielding ring-closing enyne metathesis (RCEYM) step for the formation of the [5,7] bicyclic core.

Bioinspired Oxidative Cyclization of the Geissoschizine Skeleton for the Total Synthesis of (-)-17-nor-Excelsinidine.

We report the first total synthesis of (-)-17-nor-excelsinidine, a zwitterionic monoterpene indole alkaloid that displays an unusual N4-C16 connection. Inspired by the postulated biosynthesis, we explored an oxidative coupling approach from the geissoschizine framework to forge the key ammonium-acetate connection. Two strategies allowed us to achieve this goal, namely an intramolecular nucleophilic substitution on a 16-chlorolactam with the N4 nitrogen atom or a direct I2 -mediated N4-C16 oxidative coupling from the enolate of geissoschizine.

A General Catalytic Asymmetric Prins Cyclization.

A new class of highly acidic confined imino-imidodiphosphate (iIDP) Brønsted acids catalyze the asymmetric Prins cyclization of both aliphatic and aromatic aldehydes. Diverse functionalized 4-methylenetetrahydropyrans are obtained in good to excellent yields and with good to excellent regio- and enantioselectivities. Our iIDP catalysts provide an efficient and scalable enantioselective approach to various fragrances, including rose oxide and doremox.

Chiral Allenes via Alkynylogous Mukaiyama Aldol Reaction.

Herein we describe the development of a catalytic enantioselective alkynylogous Mukaiyama aldol reaction. The reaction is catalyzed by a newly designed chiral disulfonimide and delivers chiral allenoates in high yields and with excellent regio-, diastereo-, and enantioselectivity. Our process tolerates a broad range of aldehydes in combination with diverse alkynyl-substituted ketene acetals. The reaction products can be readily derivatized to furnish a variety of highly substituted enantiomerically enriched building blocks.

Alkoxyallene-ynes: Selective Preparation of Bicyclo[5.3.0] Ring Systems Including a δ-Alkoxy Cyclopentadienone.

The development of an intramolecular rhodium(I)-catalyzed Pauson-Khand reaction of alkoxyallene-ynes with a proximal alkoxy group is reported. This reaction, in the presence of a [Rh(cycloocta-1,5-diene)Cl]2/propane-1,3-diylbis(diphenylphosphane) system under a CO atmosphere, constitutes a powerful tool for selectively accessing carbo- and heterobicyclo[5.3.0] frameworks featuring an enol ether moiety. Through this procedure, a straightforward access to guaiane skeletons with a tertiary hydroxy group at the C10 position was achieved.

Asymmetric synthesis of a highly functionalized enantioenriched system close to thapsigargin framework.

A straightforward approach to a highly functionalized enantioenriched bicyclo[5.3.0]decadienone system close to the thapsigargin framework has been achieved. The developed synthetic route involves two main stages: installation of the chains on either side of the quaternary center at C7 starting from a central enantiopure epoxide and formation of the bicyclic octahydroazulene through subsequent Pauson-Khand annelation.