Transition States of the Asymmetric Michael Reactions of Aldehydes Catalyzed by Trimethylsilyl‐Protected Diphenylprolinol

Zhao, Jian‐Qiang; Gan, Lihua

doi:10.1002/ejoc.200900051

Cited by 22 publications

(26 citation statements)

References 32 publications

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“…Enamine species that were formed via fast condensation reactions between catalyst cat and aldehydes have been characterized structurally by several methods including X-ray 31 and NMR 32 studies as well as computations. 14,15,33 In accordance with previous computational results, the present method predicts the Es-trans form to be the most stable conformer for the propanal-derived enamine (denoted as en), whereas the sterically most hindered Z-s-cis structure is significantly destabilized (see Scheme 4).…”

Section: Resultssupporting

confidence: 88%

Stereocontrol in Diphenylprolinol Silyl Ether Catalyzed Michael Additions: Steric Shielding or Curtin–Hammett Scenario?

et al. 2017

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The enantioselectivity of amine-catalyzed reactions of aldehydes with electrophiles is often explained by simple steric arguments emphasizing the role of the bulky group of the catalyst that prevents the approach of the electrophile from the more hindered side. This standard steric shielding model has recently been challenged by the discovery of stable downstream intermediates, which appear to be involved in the rate-determining step of the catalytic cycle. The alternative model, referred to as the Curtin-Hammett scenario of stereocontrol, assumes that the enantioselectivity is related to the stability and reactivity of downstream intermediates. In our present computational study, we examine the two key processes of the catalytic Michael reaction between propanal and β-nitrostyrene that are relevant to the proposed stereoselectivity models, namely the C-C bond formation and the protonation steps. The free energy profiles obtained for the pathways leading to the enantiomeric products suggest that the rate- and stereodetermining steps are not identical as implied by the previous models. The stereoselectivity can be primarily controlled by C-C bond formation even though the reaction rate is dictated by the protonation step. This kinetic scheme is consistent with all observations of experimental mechanistic studies including those of mass spectrometric back reaction screening experiments, which reveal a mismatch between the stereoselectivity of the back and the forward reactions.

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Section: Resultssupporting

confidence: 88%

Stereocontrol in Diphenylprolinol Silyl Ether Catalyzed Michael Additions: Steric Shielding or Curtin–Hammett Scenario?

et al. 2017

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“…The magnitude of Δ E , Δ G gas , and Δ G sol shows that neither the high enantioselectivity nor the reversal of the enantioselectivity can originate from a stability difference in the s‐ cis and s‐ trans enamines alone. This is in agreement with several other theoretical investigations that also reported small electronic energy difference between s‐ cis and s‐ trans conformers (without extensive conformational analysis) . Our results are also in agreement with experimental studies which detected aldehyde‐ and ketone‐derived enamines in s‐ cis as well as s‐ trans conformations .…”

Section: Resultssupporting

confidence: 93%

Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis

Husch

Seebàch

Beck

et al. 2017

Helvetica Chimica Acta

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It has been suggested that the origin of regio-and stereoselectivity in Michael additions of pyrrolidine enamines is achieved by thermodynamic rather than kinetic control through distinct conformational preferences of the enamines. We assess this proposal by elaboration of a computational protocol that warrants sufficient accuracy. The small energy differences between the conformers necessitate a high accuracy of the electronic structure method which, in addition, must allow for computationally feasible calculations of a large number of conformers. Our protocol is based on density functional theory which we validated against explicitly correlated coupled cluster theory. The results are in agreement with the available experimental data, but illustrate that conformational preferences determined for one enamine are not readily transferable to other types of enamines. We found that an appropriate conformational sampling is inevitable to arrive at meaningful conclusions. Most prominently, s-cis and strans conformers are similarly stable for aldehyde-and ketone-derived enamines. The regio-and stereoselectivity in Michael additions of pyrrolidine-derived enamines can not be explained by pronounced stability differences of the enamine isomers and conformers in general, disproving the thermodynamic-control hypothesis. The elucidation of the origin of regio-and stereoselectivity requires further theoretical investigations of the elementary steps of Michael additions.

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“…However, these approaches may be affected by vacuum calculation artifacts or crystal packing effects. Accordingly, conflicting results concerning the conformational preferences of both the exocyclic N-C bond 39,41, [43][44][45][46] and the exocyclic C-C bond 39b,41,43-45 of diarylprolinol ether enamines have been reported from these studies. Therefore, experimental results in solution are highly desirable to clarify these issues.…”

Section: Introductionmentioning

confidence: 99%

Distinct conformational preferences of prolinol and prolinol ether enamines in solution revealed by NMR

2011

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Transition States of the Asymmetric Michael Reactions of Aldehydes Catalyzed by Trimethylsilyl‐Protected Diphenylprolinol

Cited by 22 publications

References 32 publications

Stereocontrol in Diphenylprolinol Silyl Ether Catalyzed Michael Additions: Steric Shielding or Curtin–Hammett Scenario?

Stereocontrol in Diphenylprolinol Silyl Ether Catalyzed Michael Additions: Steric Shielding or Curtin–Hammett Scenario?

Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis

Distinct conformational preferences of prolinol and prolinol ether enamines in solution revealed by NMR

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