Addition de Michael

L'addition de Michael ou réaction de Michael est une réaction qui permet la création de liaisons carbone-carbone, voire de liaisons carbone-soufre. Il s'agit de l'addition nucléophile d'un carbanion sur un composé carbonylé α,β-insaturé (aldéhyde, cétone et même ester α,β-insaturé, des nitriles et des amides α,β-insaturés pouvant aussi être utilisés). Elle appartient à la famille des additions nucléophiles conjuguées. Cette réaction doit son nom au chimiste américain Arthur Michael. Équation-bilan L'équation-bilan de l'addition de Michael est: : où les substituants R et R' sur le nucléophile (un donneur de Michael) sont des groupes électroattracteurs, comme des acyles ou des nitriles, ce qui rend l'hydrogène acide et entraine la formation d'un carbanion par réaction avec la base B:. Le substituant R'' sur l'alcène, aussi appelée accepteur de Michael, est généralement une cétone, faisant donc de cette molécule une énone, mais peut également être un groupe nitro. N

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This lecture presents the development of catalytic asymmetric reactions in organic chemistry, including important current topics of research in the field.

La première partie du cours décrit les méthodes classiques de synthèse asymétrique. La seconde partie du cours traite des stratégies de rétrosynthèse basées sur l'approche par disconnection.

Complex polycyclic natural products are chosen to illustrate the evolution of the state-of-the-art of the field, the interplay between strategy and new reactions as well as the importance of implementing multi-bond forming processes in a synthesis.

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Séances de cours associées (39)

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Aldolisation

L'aldolisation (appelée aussi cétolisation dans le cadre des cétones) est une réaction de formation de liaisons carbone-carbone importante en chimie organique. Elle implique généralement l'addition nu

Crotonisation

La crotonisation est une réaction de déshydratation d'un bêta-aldol ou d'un bêta-cétol, formant une alpha-énone. Cet aldol/cétol résulte lui-même de l'aldolisation (condensation aldolique) d'un compo

Pyridine

La pyridine ou azine, de formule brute , est un composé hétérocyclique simple et fondamental qui se rapproche de la structure du benzène où un des groupes CH est remplacé par un atome d’azote. Elle

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

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Around isocyanide reactivity

Antonin François Roland Clemenceau

This manuscript covers two main topics. The first part dealt with the organocatalytic conjugate addition of Michael donors to phenyl vinyl selenone. The enantioselective Cinchona alkaloid-catalyzed Michael addition using a-substituted a-nitroacetates has been developed. The synthesis of various a,a-dialkyl a-nitroacetates has been accomplished in excellent yield and good enantioselectivity which were subsequently converted to cyclic and acyclic quaternary a-amino acids, taking advantage of the rich functionalities of the adducts. a-Substituted a-nitroamides have also been utilized as nucleophile. With them, an organocatalytic Michael addition/intermolecular SN2/hydrolysis sequence have been developed for the synthesis of a-lactones in moderate enantioselectivity. The second part of the manuscript focused on the transition-metal-catalysed insertion of isocyanides bearing participating functional group for the synthesis of heterocycles and natural product. On the one hand, the synthesis of 3,5,5-trisubstituted imidazolones using silver-catalyzed reaction of a,a-disubstituted a-isocyanoacetate with primary amine have been developed. To illustrate this methodology, evodiamine and rutaecarpine, two natural products, have been synthesized using methyl o-isocyanobenzoate. The synthesis of 2,3,5,5-tetrasubstituted imidazolones have been also reported using the 3-CR reaction of a,a-dibenzyl a-isocyanoacetate, primary amine and aryl iodide in the presence of a palladium/copper bimetallic system. On the other hand, palladium catalysed isocyanide insertion have been explored. The Pd-catalyzed multicomponent reaction of primary amine, aryl halide and o-cyanobenzonitrile has permitted the construction of 2-substituted quinazolin-4-one. Finally, the Pd-catalyzed domino process isocyanide insertion/C(sp)3-H activation of 3-cyclopropyl-2-isocyanopropanoate furnished C-2 arylated azaspiro[2.4]hept-4-ene.

EPFL2017

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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

Chargement

This lecture presents the development of catalytic asymmetric reactions in organic chemistry, including important current topics of research in the field.

La première partie du cours décrit les méthodes classiques de synthèse asymétrique. La seconde partie du cours traite des stratégies de rétrosynthèse basées sur l'approche par disconnection.

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