Asymmetric induction

Résumé

Asymmetric induction (also enantioinduction) describes the preferential formation in a chemical reaction of one enantiomer or diastereoisomer over the other as a result of the influence of a chiral feature present in the substrate, reagent, catalyst or environment. Asymmetric induction is a key element in asymmetric synthesis. Asymmetric induction was introduced by Hermann Emil Fischer based on his work on carbohydrates. Several types of induction exist. Internal asymmetric induction makes use of a chiral center bound to the reactive center through a covalent bond and remains so during the reaction. The starting material is often derived from chiral pool synthesis. In relayed asymmetric induction the chiral information is introduced in a separate step and removed again in a separate chemical reaction. Special synthons are called chiral auxiliaries. In external asymmetric induction chiral information is introduced in the transition state through a catalyst of chiral ligand. This me

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https://en.wikipedia.org/wiki/Asymmetric_induction

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This thesis is divided in seven main chapters including an introduction about the state of the art in the field, four main chapters describing the main part of the work, a short insight on the implications of the presented results for other research projects and a conclusion. The experimental procedures as well as spectroscopic data are grouped in a special section at the end of the thesis. Acetylenes are versatile intermediates in chemistry, biochemistry and material sciences. The functionalization of alkynes by addition reactions to carbonyl compounds, cycloaddition or coupling reactions using metal catalysis for example make them excellent building blocks for the construction of organic molecules. Furthermore, there are several examples of natural products and drugs containing an acetylene group. Usually, they are synthesized by addition of an acetylide anion to an electrophile. However, the reverse approach (Umpolung of the reactivity) via an electrophilic acetylene synthon has been more rarely used. This constitutes a serious limitation, in particular when considering that "classical" C-C bond formation is not adequate for the synthesis of quaternary centers containing an acetylene. The subject of this thesis is the development of a new class of alkynylation reactions to access propargylic quaternary centers by using hypervalent iodine reagents for the Umpolung of the normal reactivity of alkynes. We started our studies examining the alkynylation reaction with different β-keto esters using the hypervalent iodine reagent TMS-Ethynyl BenziodoXone (TMS-EBX). The excellent reactivity of this cyclic iodine reagent as alkynylation reagent led to the formation of free acetylene products even in the presence of sterically hindered ester groups. The ethynylation reaction proceeded in good yield using TBAF both as a base and fluoride source with TMS-EBX as alkynylation reagent for cyclic and non-cyclic keto esters. Different hypervalent iodine compounds have been tested for the alkynylation of cyclic keto esters. EBX reagents have shown to be generally more efficient than the established iodonium salts. Based on these first results, we next examined the alkynylation of nitro and cyano esters as well as β-keto amides, which have never been used in the past. We were pleased to see that the developed method was also applicable for these classes of compounds affording the corresponding ethynylated products in good yield. The synthetic potential of propargylic nitro compounds bearing free acetylenes was demonstrated by their transformation into propargylic triazoles, hydroxylamines and protected amines, as well as into allyl amines in good yield. We have investigated next, the asymmetric version of the alkynylation reaction under organocatalytic phase-transfer conditions. An enantiomeric excess of 40% has been obtained for cyclic keto esters using cinchona-derived catalysts. Phosphonium catalysts gave an improved enantiomeric excess (51% ee). Higher asymmetric induction has been obtained using the binaphthyl-derived catalysts developed by Maruoka, which has been tested for different substrates to give 12-79% ee. Finally, we have conducted preliminary mechanistic investigations. In situ NMR experiments, isotope labeling and structure-activity relationship studies have allowed us to propose a first crude picture of the catalytic cycle for the alkynylation reaction. In summary, we have reported the first truly general approach for the alkynylation of soft nucleophiles using hypervalent iodine reagents. The developed reaction conditions led to high yields of unprotected acetylenes with cyclic, nitro and linear keto esters as well as keto amides. Furthermore, asymmetric induction was observed using cinchona or binaphthyl derived phase-transfer catalysts (up to 79% ee). This allows a new direct access to chiral acetylene compound in high yields under operationally simple reaction conditions. Future work will be dedicated to the improvement of the enantiomeric excess as well as the scope of the reaction.

EPFL2011

Chargement

Le réarrangement [1,2] de Wittig

Frédéric Bailly

The importance of catalysis in chemistry has not to be proved anymore. Be it homogeneous or heterogeneous catalysis, the constant progresses observed in that field proves its obvious interest. The asymmetric homogeneous catalysis is a method of choice to synthesize chiral substances. Indeed, it allows the obtention of these compounds in an enantioselective way. During transition metal mediated catalytic asymmetric reactions, the chirality is induced by the presence of organic monodentate or bidentate chiral ligand, directly linked to the metal. Very good results were obtained in this kind of reaction with chiral ligands based on binaphthyl skeleton. Initially, this thesis work consisted in the study of the double [1,2] Wittig rearrangement of binaphthyl ethers. It was shown, for allyl carbanion, that only one diastereoisomer is formed during the rearrangement among the three possible one. This diastereoisomer has a C2 symmetry axis and the absolute configuration of the two new asymmetric centers created was assigned. On the other hand, for benzyl or benzhydril carbanions, the results are differents. For the former, the three possible diastereisomer are formed with the unsymmetrical one as the major compound. In the latter case, no rearrangement takes place and only starting material is recovered after neutralization of the reaction mixture. Then, the potential of double [1,2] Wittig rearrangements applied to allyl binaphthyl ethers was evaluate in order to synthesize homochiral compounds usable in asymmetric homogeneous catalysis. It was shown that this transformation could be used to give access to the enantiopur acid 1,1'-binaphtyl-2,2'-dicarboxylic which finds applications in the field of the asymmetric catalysis. The high diastereoselectivity observed during this double rearrangement allowed to develop the kinetic resolution of the binaphthyl skeleton by means of the asymmetric epoxidation according to the conditions described by K.B Sharpless and T Katsuki. Finally, taking profit of the high diastereoselectivity already mentioned, it was possible to elaborate out a new phosphorus ligand whose stereoinduction capacity was evaluated for catalytic asymmetric hydrosilylation.

EPFL2005

Chargement

Formal Homo-Nazarov and Other Cyclization Reactions of Activated Cyclopropanes

Fides Benfatti, Filippo De Simone, Tanguy Jean Daniel Saget, Jérôme Waser

The Nazarov cyclization of divinyl ketones gives access to cyclopentenones. Replacing one of the vinyl groups by a cyclopropane leads to a formal homo-Nazarov process for the synthesis of cyclohexenones. In contrast to the Nazarov reaction, the cyclization of vinyl-cyclopropyl ketones is a stepwise process, often requiring harsh conditions. Herein, we describe two different approaches for further polarization of the three-membered ring of vinyl-cyclopropyl ketones to allow the formal homo-Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group α to the carbonyl on the cyclopropane gave a more than tenfold increase in reaction rate, allowing us to extend the scope of the reaction to non-electron-rich aryl donor substituents in the β position to the carbonyl on the cyclopropane. In this case, a proof of principle for asymmetric induction could be achieved using chiral Lewis acid catalysts. In the second approach, heteroatoms, especially nitrogen, were introduced β to the carbonyl on the cyclopropane. In this case, the reaction was especially successful when the vinyl group was replaced by an indole heterocycle. With a free indole, the formal homo-Nazarov cyclization on the C3 position of indole was observed using a copper catalyst. In contrast, a new cyclization reaction on the N1 position was observed with Brønsted acid catalysts. Both reactions were applied to the synthesis of natural alkaloids. Preliminary investigations on the rationalization of the observed regioselectivity are also reported.

2011

Chargement

Le réarrangement [1,2] de Wittig

Frédéric Bailly

EPFL2005

EPFL2011