The effect of silyl substituents in diphenylprolinol silyl ether catalysts was investigated. Mechanistically, reactions catalyzed by diphenylprolinol silyl ether can be categorized into three types: two that involve an iminium ion intermediate, such as for the Michael-type reaction (type A) and the cycloaddition reaction (type B), and one that proceeds via an enamine intermediate (type C). In the Michael-type reaction via iminium ions (type A), excellent enantioselectivity is realized when the catalyst with a bulky silyl moiety is employed, in which efficient shielding of a diastereotopic face of the iminium ion is directed by the bulky silyl moiety. In the cycloaddition reaction of iminium ions (type B) and reactions via enamines (type C), excellent enantioselectivity is obtained even when the silyl group is less bulky and, in this case, too much bulk reduces the reaction rate. In other cases, the yield increases when diphenylprolinol silyl ethers with bulky substituents are employed, presumably by suppressing side reactions between the nucleophilic catalyst and the reagent. The conformational behaviors of the iminium and enamine species have been determined by theoretical calculations. These data explain the effect of the bulkiness of the silyl substituent on the enantioselectivity and reactivity of the catalysts.

Michael reaction of carbon nucleophile is one of the most important carbon-carbon bond forming reactions in organic synthesis. [1] In the nucleophilic addition to a,b-g,d-diunsaturated carbonyl compounds, there are three possible reaction paths such as 1,2-, 1,4-, and 1,6-addition reactions. As for the asymmetric catalytic method, there are several successful selective 1,4-and 1,6-addition reactions catalyzed by transition-metal catalysts. [1,2] Recently the field of organocatalysis has been developing rapidly [3] and organocatalysts have been successfully employed in the asymmetric, catalytic Michael reaction, in which most of the reactions are those of a,b-unsaturated electron withdrawing group. [4] As for the organocatalyst-mediated asymmetric 1,4-and 1,6-addition reactions, [5] Jørgensen and coworkers reported the selective 1,6-addition reaction of a,b-g,d-diunsaturated ketones with b-keto ester and benzophenone imine using cinchona alkaloids under phase transfer conditions. [6] Although the same nucleophile was employed, a chiral enamine derived from aldehyde and diphenylprolinol silyl ether, [7] the 1,6-addition proceeds between aldehyde to dienic sulfones, [8] whereas the 1,4-addition occurs between aldehyde and nitrodiene, [9] both of which are reported by Alexakis and coworkers. Ma reported 1,4-addition of dibenzyl malonate and a,b-g,ddiunsaturated aldehyde catalyzed by diphenylprolinol silyl [**]

Diphenylprolinol silyl ether was found to be an effective organocatalyst in the enantioselective and direct Michael reaction of nitroethanol and alpha,beta-unsaturated aldehydes, affording the 1-hydroxy-trans-3,4-disubstituted tetrahydropyrans after isomerization. The generated Michael addition products are useful synthetic intermediates, which can be converted into chiral tetrahydropyran with a quaternary stereocenter, 3-substituted cis- and trans-prolines, and alpha-amino acid derivatives.

Direct and enantioselective: Diphenylprolinol silyl ether was found to catalyze the direct, asymmetric Michael reaction of 4-substituted 2-aryl-2-oxazoline-5-one and alpha,beta-unsaturated aldehydes, affording the chiral alpha,alpha-disubstituted alpha-amino acid derivatives with excellent enantioselectivity.