Houk List model

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. ... 

Figure 5.3 Generalised cataljtic cycle for proline-catal3 ed additions reactions based on the Houk-List model.

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. 

Figure 17.7 (a) Syn-face addition in Houk-List models (b) onti-face addition in Seebach-Eschenmoser transition state models. 

Houk employed SMD(water)/M06-2x/6-31-l-G(d,p) computations to model these histidine-catalyzed reactions. For the reaction of isobutyraldehyde with formaldehye, eight TSs were located, four with the carboxylic acid group as the proton donor and fonr with the imidazole as the proton donor. The lowest energy TS for each case has the Houk-List geometry with the proton transfer occurring with the C-C formation. In this case, the two lowest TSs are of equal energy. 

Thus, a unified model for proline-catalyzed asymmetric a-functionalization of carbonyl compoimds by electrophiles uncovered in the period 1971-2006 is provided by the Houk-List transition state and its analogs, which embody three important and... 

Horeau principle 1286,1294 Horner-Wadsworth-Emmons (HWE) sequence 1309 host-guest complexes 687 Houk-List transition state model 475, 477, 478... 

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. ... 

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. 

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... 

The enantioselectivity of a closely related reaction, the proline-catalyzed a-ami-nation of aldehydes with diazodicarboxylic esters, independently disclosed by List and by Jprgensen in 2002 [30], can also be accounted for by a List-Houk transition state model (Figure 2.10). 

The proline-catalyzed intermolecular Michael reaction of unactivated ketones with nitroalkenes [33] can also be fitted in a mechanistic scenario involving the List-Houk transition state model (Figpre 2.11). 

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