Organocatalytic kinetic resolution cascade reactions: new mechanistic and stereochemical manifold in diphenyl prolinol silyl ether catalysis.

A new cascade reaction involving an iminium-catalyzed intramolecular oxa-Michael addition followed by an enamine-catalyzed intermolecular Michael addition is reported herein. This cascade reaction generates enantiopure, highly functionalized tetrahydropyrans and tetrahydrofurans in a one-pot reaction and in up to 89 % combined yield and up to 99 % ee. This cascade reaction is catalyzed by diaryl prolinol silyl ethers, which are a privileged class of catalysts. The stereochemical outcome of these cascade reactions is unprecedented. Computational studies indicate that this stereochemical outcome arises from nonclassical hydrogen-bonding interactions between the electrophile and the substrate, and from entropic considerations of preorganization. The unprecedented configurations of the cascade products, combined with the computational models, reveal for the first time that asymmetric induction by diaryl prolinol silyl ether catalysts is not always exclusively reagent controlled. The stereochemical outcome also arises from a kinetic resolution or dynamic kinetic resolution of the ß-stereocenter through an enamine-catalyzed intermolecular reaction. This unprecedented organocascade reaction mechanism may be adaptable to diaryl prolinol silyl ether-catalyzed cascade reactions, in which both the iminium- and enamine-catalyzed steps are intermolecular, an underdeveloped type of cascade reaction.

An organocascade kinetic resolution.

Products of a novel iminium-catalyzed oxa-Michael addition undergo a kinetic resolution by a subsequent enamine-catalyzed intermolecular reaction. This is a rare example of kinetic resolution by enamine catalysis and the first organocascade kinetic resolution. This resolution produces enantioenriched 2,6-cis-tetrahydropyrans and, notably, cascade products with absolute and relative configurations normally not observed using this diphenyl prolinol silyl ether. This resolution thus provides new insight into asymmetric induction in reactions employing this catalyst.

A general organocatalyzed Michael-Michael cascade reaction generates functionalized cyclohexenes.

Although ß-dicarbonyl compounds are regularly employed as Michael donors, intermediates arising from the Michael addition of unsaturated ß-ketoesters to α,ß-unsaturated aldehydes are susceptible to multiple subsequent reaction pathways. We designed cyclic unsaturated ß-ketoester substrates that enabled the development of the first diphenyl prolinol silyl ether catalyzed Michael-Michael cascade reaction initiated by a ß-dicarbonyl Michael donor to form cyclohexene products. The reaction conditions we developed for this Michael-Michael cascade reaction were also amenable to a variety of linear unsaturated ß-ketoester substrates, including some of the same linear unsaturated ß-ketoester substrates that were previously ineffective in Michael-Michael cascade reactions. These studies thus revealed that a change in simple reaction conditions, such as solvent and additives, enables the same substrate to undergo different cascade reactions, thereby accessing different molecular scaffolds. These studies also culminated in the development of a general organocatalyzed Michael-Michael cascade reaction that generates highly functionalized cyclohexenes with up to four stereocenters, in up to 97% yield, 32:1 dr, and 99% ee, in a single step from a variety of unsaturated ß-ketoesters.

A new organocatalyzed Michael-Michael cascade reaction generates highly substituted fused carbocycles.

While beta-ketoesters are useful Michael donors, they were previously ineffective in Michael-Michael cascade reactions using alpha,beta-unsaturated aldehydes in conjunction with diphenylprolinol silyl ether organocatalysts. However, through rational modification of substrates and manipulation of the catalytic cycle, we developed an efficient Michael-Michael cascade reaction using beta-ketoesters of type 9. In this transformation, highly substituted fused carbocycles are generated in a single step in up to 87% yield and 99% ee.

Novel bifunctional sulfonamides catalyze an enantioselective conjugate addition.

A new bifunctional organocatalyst with a novel structural and functional motif has been developed. This bifunctional sulfonamide organocatalyst was used in the conjugate addition of 1,3-dicarbonyl compounds (13) to ß-nitrostyrenes (12). Yields up to 91% and enantiomeric excesses up to 79% were obtained in this reaction. This catalyst activates both 13 via its basic moiety and 12 through hydrogen bonding.