Prolines tetrazole

Figure 3.38 a The general enamine catalytic cycle in the presence of L-proline b an example of an asymmetric Mannich-type addition of cyclohexanone to iminoethyl glyoxalate, catalyzed by a proline tetrazole derivative. 

Scheme 2.5 Enantioselective Michael reactions of ketones with nitroalkenes catalyzed by proline and proline-tetrazole analogues.

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. ... 

Once in the modern organocatalysis era and with the mechanistic rationale for the iminium activation concept in hand, many different and more efficient methodologies have been developed for this particular reaction. For example, and still focused on the use of secondary amines as catalysts, imidazolidine 53a and proline-tetrazole 2a catalysts have been developed for the conjugate addition of malonates to acyclic enones (Scheme 3.17). For the 53a-catalyzed reaction, this proceeded well in terms of yields and enantioselectivities for a wide range of differently substituted arylideneacetones and for cyclohexenone but yields tend to decrease when more bulky substituents were placed around the carbonyl moiety. Importantly, the enantioselectivity of the reaction was very dependent upon the nature of the malonate reagent, observing that dibenzyl malonate and diethylmalonate furnished the best results. The most... 

Scheme 3.21 Enantioselective Michael addition of nitroalkanes to acyclic enones catalyzed by imidazolidines 53a and 53c, proline tetrazole 2a and amine-thiourea ent-37b.

Remarkably, no reaction occurred when proline, hydroxyproline or proline-tetrazole that did not exhibit surfactant properties were employed as organocatalysts in the presence of water. 

In 2004, Yamamoto and Arvidsson independently reported the catalytic activity of the L-proline tetrazole catalyst 30 in asymmetric aldol reactions of ketones with aldehydes [161-163]. At the same time. Ley and coworkers reached similar conclusions by applying this system to asymmetric Mannich and Michael addition reactions (Scheme 1.8) [164]. Since then, the scope of this chemistry has been expanded by several research groups [165-174]. 

Scheme 24.4 Proline-tetrazole catalyzed aldol reactions.

Knudsen KR, Mitchell GET, Ley SV. Asymmetric organo-catalytic conjugate addition of malonates to enones using a proline tetrazole catalyst. Chem. Commun. 2006 1 66-68. 

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