Houk -List model Aldol reaction

The preference for the amine-catalyzed aldol reaction to go through a TS having the features of 53a or 55a is now called the Houk-List model. This type of TS has three major characteristics (1) proton transfer from the carboxylic acid to the incipient alcohol concomitant with the formation of the C-C bond (TS D of Scheme 6.8) (2) the enamine is in the anti orientation and (3) the aldehyde substituent is anti to the enamine carbon. 

An interesting twist in the amino-acid-catalyzed aldol reaction is the use of histidine as catalyst. The key element of the Houk-List model is the proton transfer that accompanies the C-C bond formation. Histidine in aqueous solution can supply two sites for the proton transfer the carboxylic acid group (analogous to proline) or the imidazole. Experimental studies of the histidine-catalyzed aldol reaction demonstrates appreciable selectivity as shown in Reactions 6.22 and 6.23. ... 

The Houk-List model was also applied to explain the origin of stereoselectivity in proline-catalyzed intermolecular aldol reactions [19c, 24]. Contrary to the Hajos-Parrish reaction, there is no restriction on the approach of the electrophile. Interestingly enough, theoretical calculations strongly favour an anti proline enamine... 

FIGURE 2.7. The Houk List model for intermolecular proline-catalyzed aldol reactions. 

Houk s involvement in proline-catalyzed asymmetric induction began in a similar way. Occasionally something very interesting appears in the literature, especially so if it is amendable to elucidation by computational methods, Houk recalls. We are especially interested in synthetic methods where the experimentalist is unclear of just how things work. This was Ihe case with the proline work. We saw the work of Barbas and List on the aldol reaction, and we were aware of the Hajos-Parrish reaction. So we started computations on simple models, and then looked at the Hajos-Parrish reaction, and we came upon an explanation for its stereoselectivity. This was all done without communicating with any of the experimentalists. ... 

Agami s model was subsequently challenged by List, Lerner, and Barbas III in 2000 [8a], when they proposed a one-proline enamine mechanism for the proline-catalyzed intermolecular aldol reaction between ketones and aldehydes. Shortly afterwards, on the basis of DFT calculations, Houk and co-workers proposed a very similar mechanism for the Hajos-Parrish intramolecular aldol [19]. Using the B3LYP/6-31H-G(2df,p) level of DFT theory, Houk and co-workers [20] have seen that the energy difference between the two possible chair Zimmermann-Traxler-like transition states, which differ in the orientation of the enamine with... 

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