A new diagnostic tool for elucidating the mechanism of enantioselective reactions. Application to the Hajos–Parrish reaction

Agami, Claude; Levisalles, J.; Puchot, C.

doi:10.1039/c39850000441

Cited by 37 publications

(13 citation statements)

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“…The initial proposed mechanism [29] for the intramolecular aldol reaction involved the presence of two proline molecules, one forming the enamine nucleophile and other being a proton relay based on an observed small dilution effect [30] and a small nonlinear effect [31]. However, a careful repetition of those experiments showed that neither a dilution nor a nonlinear effect was present [32].…”

Section: Intramolecular Proposed Mechanismmentioning

confidence: 99%

Organocatalyzed Aldol Reactions

Guillena¹

2013

Modern Methods in Stereoselective Aldol Reactions

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The use of catalytic enantioselective methods to perform an aldol reaction provides a direct entry for the synthesis of chiral compounds and is probably the most attractive way to achieve this goal with high control of the chemo-, regio-, diastereo-, and enantioselectivity. The application of biochemical methods based on enzyme aldolases or antibodies, which are discussed in other chapters, avoid the use of preformed enolates or their equivalents for enhancing the global atom efficiency of the process [1] for which the narrow substrate scope is a major drawback. The discovery of methodologies to carry out the enantioselective direct aldol reaction [2] has eluded the production of stoichiometric by-products increasing the substrate scope. This task could be accomplished by using small molecules as catalysts, such as metal complexes (which are covered along this book) and organic molecules, also known as organocatalysts [3]. The growth of this last research area and the direct aldol reaction are closely linked [4], with the report on the use of (S)-proline as catalyst for the intermolecular aldol [5] definitely being the push for the development of the organocatalytic methods as a competitive methodology for the synthesis of chiral compounds.In a strict sense, an organocatalyzed reaction is a process in which all the involved reagents and catalysis are purely organic compounds of low-molecular weight, excluding boron-and silicon-containing derivatives. However, in some cases, the presence of a silyl group only plays a steric role and therefore can also be considered as an organocatalyzed process. Also, if the organocatalyst involved in a reaction is immobilized in a polymer, a dendrimer, or even an inorganic material that serves only as a support to facilitate its recovery [6], it could still be considered as an organocatalyst, although those types of derivatives have been scarcely used in the natural product synthesis and therefore will be excluded from this chapter. Therefore, a comprehensive overview of the direct aldol reaction [7], emphasizing the reactivity, scope, selectivity, and limitations of the methodology and giving several examples of their application to the synthesis of biologically active compounds, is discussed in this chapter.

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Section: Intramolecular Proposed Mechanismmentioning

confidence: 99%

Organocatalyzed Aldol Reactions

Guillena¹

2013

Modern Methods in Stereoselective Aldol Reactions

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“…[1 -7] Indeed, since the famous asymmetric annulation catalyzed by l-proline in 1970s, [8,9] reported by Hajos et al and Wiechert et al, almost nothing new was published, except some examples of intramolecular Michael additions catalyzed by a stoichiometric amount of l-proline. [10,11] In the 1980s, Agami [12,13] postulated a mechanism involving two molecules of l-proline based on non-linear effects in the formation of the Wielands ketone, but recent works of Houk and List 14 have contradict his results. Only recently, many examples of reactions catalyzed by l-proline were reported, such as aldol reactions, [14 -34] Mannich reactions, [35 -46] conjugate additions, [47 -50] a-aminations, [51 -54] a-aminooxylations, [55][56][57] a-alkylations [58] and related reactions.…”

Section: Introductionmentioning

confidence: 99%

The Use of N‐Alkyl‐2,2′‐bipyrrolidine Derivatives as Organocatalysts for the Asymmetric Michael Addition of Ketones and Aldehydes to Nitroolefins

Andrey¹,

Alexakis²,

Tomassini³

et al. 2004

Adv Synth Catal

255

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Abstract:The direct Michael addition of aldehydes and ketones to nitroolefins, catalyzed by N-i-Pr-2,2'-bipyrrolidine, is described. The desired 1,4-adducts are obtained in excellent yields with enantioselectivities up to 95% ee and dr up to 95 : 5 of the syn aldehyde addition product. An unexpected inversion of diastereoselectivity was observed for the addition of a-hydroxy ketones to b-arylnitroolefins with enantioselectivities up to 98% ee. The formation of an internal hydrogen bond between the OH group of the ahydroxy ketone and the tertiary nitrogen of the catalyst leads to the formation of a rigid cis enamine intermediate that accounts for the inversion of the expected diastereoselectivity and the very high ees.

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“…176,177 As the computational chemistry is developed, the mechanism for (S)-proline-catalyzed aldol reaction is investigated. The Houk group shows evidence for the involvement of only one proline molecule in the transition states of intramolecular aldol reactions, which are based on kinetic measurements and the absence of nonlinear and dilution effects.…”

Section: Mechanistic Studiesmentioning

confidence: 99%