Nonlinear effects aldol reactions

SCHEME 44. Nonlinear effect in intramolecular aldol reaction. 

Enantioselective addition of (C2//5)2Z/i to CJlsCHOIn the presence of (— )-l, diethylzinc adds to C6H5CHO to provide the (R)-adduct. The optical purity of the catalyst (1) has a marked effect on the rate and also on the optical purity of the adduct. Thus (-)-PDB of only 10-20% ee provides (R)-l-phenylpropanol in 80-90% ee and about 95% chemical yield. This nonlinear effect in catalyzed asymmetric oxidations and aldolizations has been noted previously.2 It may be a result of the molecularity of the reaction or of the aggregation or ligand exchange of the catalyst. 

Puchot, C. SamueL O. Dunach, E. Zhao, S. Agami, C. Kagan, H. B. Nonlinear effects in asymmetric synthesis. Examples in asymmetric oxidations and aldolization reactions, J. Am. Chem. Soc. 1986,108, 2353-2357. 

The formation of 64 using catalyst (S,S)-62 exhibits a positive nonlinear effect, fitting well with Kagan s two ligand model [78] whereas the more hindered catalyst (S,S)-63 led to a perfect linear asymmetric induction suggesting that the product arose from a transition structure involving only one chiral phosphoramide. The kinetic study of this aldol reaction is in accordance with these re-... 

Another important fact was reported in the 1980s Agami and co-workers studied the application of proline in an enolendo aldolization reaction. Their mechanistic studies showed nonlinear and dilution effects that suggested the involvement of two molecules of proline in the transition state (Scheme 1.6) [18]. 

It is worth noting, however, that nonlinear effects are actually observed in aldol and in other proline (or amino acid)-catalyzed reactions when proline is not completely solubilized in the reaction medium this phenomenon, which is due to the differential solubility of racemic and of enantiopure solid proline, was independently uncovered by Hayashi, Blackmond, and Breslow [21] and has been proposed as one of the possible mechanisms that led to biomolecular homochirality in prebiotic chemistry [22]. 

This process, like the proline-catalyzed nitroso aldol reaction, has been shown to exhibit the unusual characteristics of a rising reaction rate and a positive nonlinear effect [31]. An autoinductive reaction resulting in selective formation of a proline-product species in the catalytic cycle, analogous to that depicted in Scheme 2.3, has been invoked by Blackmond [32] to account for these results. 

The mechanism of the amino acid-catalyzed Mannich reactions is depicted in Scheme 4.14. Accordingly, the ketone or aldehyde donor reacts with the amino acid to give an enamine. Next, the preformed or in situ- generated imine reacts with the enamine to give after hydrolysis the enantiomerically enriched Mannich product, and the catalytic cycle can be repeated. It is important to bear in mind that N-Chz-, N- Boc-, or A-benzoyl-protected imines are water-sensitive. Thus, they can hydrolyze and thereby decrease the yield of the transformation. Moreover, in the case of cross-Mannich-type addition with aldehydes as nucleophiles the catalytic self-aldolization pathway can compete with the desired pathway and lead to nonlinear effects [63]. 

In 1986, we discovered the first three cases of nonlinear effects in asymmetric synthesis the Shaipless epoxidation of geraniol ((+)-NLE), the asymmetric oxidation of p-tolyl methyl sulfide by our titanium reagent ((-)-NLE), and the proline catalyzed asymmetric aldolization of a triketone ( (-)-NLE). The mechanism of the last reaction was studied by Agami et al and found to be second-order with respect to proline. ... 

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