Enamines transition model

Recently, DFT calculations showed that in this proline-catalyzed process an enamine carboxylic acid mediated transition model rules under base-free conditions, giving the expected product stereochemistry, while an enamine carboxylate pathway operates in the presence of base, leading to the opposite enantiomer [23]. 

The (Z)-enamine transition state 31 was proposed as the intermediate in the syn-selective reaction of an acyclic ketone donor with an aldehyde acceptor catalyzed by 22. In this type of reaction, formation of the ( )-enamine of the acyclic ketone is disfavored due to steric repulsion between R and substituents (Figure 28.3) [18]. The (F)-enamine formed by an aldehyde donor with the axially chiral catalyst 23 can react with an aldehyde acceptor that is activated by the proximal acidic proton of 23 via transition model 33, thus affording the syn-aldol product [19],... 

The obtained syn diastereoselectivity with acyclic ketone donors could be explained by Z-enamine transition state (Scheme 5.8), whereas the reactions of cyclic ketones such as protected DHA, which are capable only of forming fi-enamine due to ring size constraints, give preferentially fl h-aldol adducts (Scheme 5.8). These models can be applied to other primary-tertiary diamine catalyzed aldol reactions. 

To rationalize the 5 selectivity, a cyclic transition state model has been proposed which involves the selection of the Re-face of the enolate by the Re-face of the nitro enamine and includes a coordination between the metallic cation and the nitrogen atom of the pyrrolidine ring23. 

The strongly twisted Case 2 molecules should rather be classified as zwitterionic compounds than as enamines. They are of interest as models for the transition states to C=C rotation in Case 1 molecules, and also as carbanions free from a chelating cation. 

The observed absolute configuration of the products is in compliance with a simple transition state model where the phenyl group of the diox-ane moiety shields the Re face of the intermediate formed by addition of the nucleophilic carbene to the aldehyde, therefore, directing the attack of the enoate Michael acceptor to occur with the less hindered face, that is the Si face of the enamine (Fig. 16). The electrophilic part of the intermediate bearing the activated C=C double bond is approached by... 

The originally proposed stereochemical model by Hajos and Parrish" was rejected by M.E. Jung and A. Eschenmoser. They proposed a one-proline aldolase-type mechanism involving a side chain enamine. The most widely accepted transition state model to account for the observed stereochemistry was proposed by C. Agami et al. suggesting the involvement of two (S)-(-)-proline molecules. " " Recently, K.N. Houk and co-workers reexamined the mechanism of the intra- and intermolecular (S)-(-)-proline catalyzed aldol reactions. Their theoretical studies, kinetic, stereochemical and dilution experiments support a one-proline mechanism where the reaction goes through a six-membered chairlike transition state. 

Sevin, A., Tortajada, J., F au, M. Toward a transition-state model in the asymmetric alkylation of chiral ketone secondary enamines by electron-deficient alkenes. Atheoretical MO study. J. Org. Chem. 1986, 51, 2671-2675. 

Two different models were proposed by Ley for the 2b-catalyzed reaction which should also be of application for the cases of proline 1 and proline-tetrazole catalysts 2a, both of them in good agreement with the observed absolute configuration of the final Michael adducts (Figure 2.2). One proposal involved the possibility of the tetrazole moiety acting as a bulky substituent which directed the income of the electrophile by the less hindered face of the enamine intermediate in the most stable pseudo-rrarw conformation. Alternatively, the formation of a hydrogen-bonded transition state was also proposed, in this case with the participation of the pseudo-cj5 enamine conformer. This second pathway was afterwards estimated to be the energetically most favored one by DFT calculations. ... 

The differences of stereoselectivity can be explained by the corresponding transition states (TS), even if the models are amino acid and solvent dependent. ° Unlike the proline-catalysed mechanism, the ability of the C-N bond to rotate does not constrain the enamine intermediate and therefore several transition-state structures could exist. 

The authors propose a reaction mechanism that proceeds via plausible enamine A and iminium ion B formation as well as explaining the observed -diasteroselectivity with a transition state based on Seebach s model (Scheme 13.19). ... 

The group of Moutevelis-Minakakis reported in 2014 the preparation and application of a series of tripeptides containing proline, phenylalanine and tert-butyl esters of different amino acids (see 36, Scheme 13.22c) for the asymmetric aldol reaction of aromatic aldehydes and various substituted ketones in both aqueous and organic medium. The authors assume in the proposed transition-state model, besides the well-known enamine activation, a stabilisation of the aldehyde via hydrogen-bond interactions of the two amide protons of the tripeptide with the carbonyl group of the aldehyde. The desired adducts were isolated in good to excellent yields and with very good diastereoselectivities and enantioselectivities. ... 

FIGURE 2.1. Working transition state models for the electrophilic attack to the enamine intermediate, (a) List-Houk model, (b) Steric model, (c) Seebach-Eschenmoser model. 

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