Enantioselective Total Synthesis of (+)-Alstilobanine C, (+)-Undulifoline, and (-)-Alpneumine H

Nicolas David Gaeng, Guang Li, Cyril Piemontesi, Qian Wang, Jieping Zhu
WILEY-V C H VERLAG GMBH, 2021
Journal paper

We report herein the enantioselective total synthesis of three monoterpene indole alkaloids, namely, (+)-alstilobanine C, (+)-undulifoline, and (-)-alpneumine H. The key features of our synthesis include: a) introduction of chirality via enantioselective deprotonation of a prochiral 4-substituted cyclohexanone; b) use of methoxymethyl (MOM) ether as both a hydroxyl protective group and a latent oxonium species for the formation of bridged oxepane and c) domino double reductive cyclization to build both the indole and the piperidine ring at the end of the synthesis. The synthesis confirmed the absolute configuration of these natural products assigned based on the biogenetic hypothesis.

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Nicolas David Gaeng, Guang Li, Cyril Piemontesi, Qian Wang, Jieping Zhu
WILEY-V C H VERLAG GMBH, 2021
Journal paper

Abstract

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https://infoscience.epfl.ch/record/285500?ln=en

About this result

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Natural product

A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural p

Protecting group

A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important

Indole

Indole is an aromatic, heterocyclic, organic compound with the formula . It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely

Towards the Sarpagine-Ajmaline-Macroline Family of Indole Alkaloids: Enantioselective Synthesis of an N-Demethyl Alstolactone Diastereomer

Dylan Jean Robert Dagoneau, Qian Wang, Jieping Zhu

the strategy involving the use of functionalized tetrahydro-6H-cycloocta[b]indol-6-one is reported as a key intermediate for synthesis of members of the sarpagine-ajmaline-macroline family of monoterpene indole alkaloids. The desired tricycle was synthesized through the following key steps: 1) Evans' syn-selective aldolization; 2) Liebeskind-Srogl cross-coupling using the phenylthiol ester of 3-chloropropanoic acid as a surrogate of acrylic thioester for the synthesis of 2,3-disubstituted indoles; and 3) ring-closing metathesis (RCM) for the formation of the eight-membered ring. An N-allylation followed by intramolecular 1,4-addition was planned for synthesis of the vobasine class of natural products. However, attempted cyclizations under a diverse set of conditions involving anionic, radical, and organopalladium/organonickel species failed to produce the bridged ring system. On the other hand, esterification of the pendant primary alcohol function with acetoacetic acid, followed by intramolecular Michael addition, afforded the desired tetracycle with excellent diastereoselectivity. Subsequent functional group manipulation and transannular cyclization of the amino alcohol afforded the N(1)-demethyl-3,5-diepi-alstolactone. We believe that the same synthetic route would afford the alstolactone should the amino alcohol with appropriate stereochemistry be used as the starting material.

WILEY-V C H VERLAG GMBH2020

Total Synthesis of Alstilobanine C, Undulifoline and Alstilobanine B

Nicolas David Gaeng

The total synthesis of pentacyclic monoterpene indole alkaloids is the focus of this thesis. Total syntheses of (±)-alstilobanine C, (±)-undulifoline and (±)-alstilobanine B, three natural products from the Ulean family of alkaloids, were accomplished. The characteristic features of our synthesis included: a) a domino sequence involving a highly diastereoselective Michael addition followed by chemoselective C-acylation of the resulting enolate by Mander¿s ester; b) an unprecedented Lewis acid mediated intramolecular addition of enolate to oxonium, generated in situ from MOM protective group; c) a sequence of chemoselective reduction/indolization/intramolecular aza-Michael addition. This domino process afforded directly the (±)-alstilobanine C, a pentacyclic monoterpene indole alkaloid in 87% yield. Reductive N-methylation of (±)-alstilobanine C provided (±)-undulifoline which, upon N-oxidation, was further converted to (±)-alstilobanine B. Enantioselective total synthesis of the same natural products through a different synthetic route is presented. After exploring different unsuccessful strategies, an enzymatic desymmetrization of a meso compound was adopted for the synthesis of enantioenriched cyclopentenone intermediate. Applying the two domino sequence developed previously, namely, Michael addition/C-acylation and oxepane formation, an efficient synthesis of the oxobicyclo[4.2.1]nonane was realized. A palladium-catalyzed decarboxylative cross-coupling, a methodology developed in our group, afforded an advanced bicyclic intermediate with all the carbon and functional groups needed to accomplish the total synthesis. However, conversion of the vinyl group to alkylazide or its synthetic equivalent proved to be difficult in spite of the efforts dedicated to this seemingly trivial transformation.

EPFL2018

Isocyanoacetates as Synthetic Platform Towards Natural Products and Biologically Relevant Scaffolds

Thomas Bertrand Pascal Marie Buyck

My PhD work started with the development of a racemic access to trigonoliimine B, an hexacyclic alkaloid isolated in 2010. After having explored different strategies, we reported a 7-step synthesis of this natural product. This synthesis features a challenging and unprecedented Bischler-Napieralski reaction for the formation of a 7-membered ring with the concurrent creation of an exocyclic imine at the last step. The choice of sulfolane as solvent for this transformation was critical to the success. Aiming at upgrading our synthesis towards an enantioselective version, we developed an enantioselective synthesis of α-quaternary α-amino acids. The Michael addition between α-aryl isocyanoacetates and phenyl vinyl selenone catalyzed by a quinine derivative affords enantioenriched Michael adducts. Due to the nature of the functional groups, these adducts are easily transformed to useful scaffolds such as pyrrolidinones and oxindoles. We also demonstrated the synthetic utility of this transformation by using it for the enantioselective total synthesis of (+)- and (-)-trigonoliimine A. With the idea to further demonstrate the efficiency of this reaction for natural product synthesis, we are trying to develop the first total synthesis of (+)-hinckdentine A. Finally, during our investigations on the Michael adduct, we observed the formation of 1,3-oxazinan-2-one. We implemented an integrated one-pot process to access biologically relevant 1,3-oxazinan-2-one. We also studied the reaction mechanism demonstrating an unprecedented triple role of phenyl selenonyl group as an electron withdrawing group, a leaving group and a latent oxidant.

EPFL2014