An asymmetric domino reaction was developed utilizing readily available cyclic N-sulfonylimines and simple aldehydes to construct biologically important and synthetically challenging piperidine derivatives consisting of three contiguous stereocenters. trans-Perhydroindolic acid proved to be an efficient organocatalyst in this reaction (up to 89% yield, 80:20 dr, and 99% ee). The absolute configuration of the catalytic product was determined by X-ray crystallography studies. The product could be conveniently converted to synthetically useful intermediates, such as (3R,4S)-4-ethyl-3-methyl-6-phenylpiperidinyridin-2-one (8), via a simple transformation.

A highly enantioselective Pd-catalyzed asymmetric allylic substitution cascade of cyclic N-sulfonylimines with an accompanying asymmetric desymmetrization has been developed for the construction of fused tetrahydroindole derivatives bearing two chiral centers. Mechanistic studies confirmed that the cascade reaction proceeds by initial allylic alkylation and subsequent allylic amination. The first alkylation is a chirality-control step and represents an asymmetric desymmetrization of cis-cyclic allyl diacetates. The reaction has been performed on a gram scale, and the desired products can take part in several transformations.

A Pd-catalyzed asymmetric allylic alkylation of azlactones with 4-arylvinyl-1,3-dioxolan-2-ones was developed, providing "branched" chiral α-amino acids with vicinal tertiary and quaternary stereocenters, in high yields and with excellent selectivities. Mechanistic studies revealed that the formation of a hydrogen bond between the Pd-allylic complex and azlactone isomer is responsible for the excellent regioselectivities. This asymmetric alkylation can be carried out on a gram scale without a loss of catalytic efficiency, and the resulting product can be further transformed to a chiral azetidine in two simple steps.

An organocatalyzed asymmetric tandem reaction of cyclic N-sulfonylimines and α,β-unsaturated aldehydes was developed. These substrates follow an alternative reaction pathway to that of reactions involving saturated aldehydes, affording similar piperidine derivatives.

(2S,3aR,7aS)-Perhydroindolic acid, the key intermediate in the synthesis of trandolapril, and its trans-isomers, were readily prepared. These prolinelike molecules are unique in that they contain a rigid bicyclic structure, with two hydrogen atoms trans to each other at the bridgehead carbon atoms. These molecules were used successfully as chiral organocatalysts in asymmetric domino Michael addition/cyclization reactions of aldehyde esters with b,g-unsaturated a-keto esters. They proved to have excellent catalytic behavior, allowing for the synthesis of multi-substituted, enantiomerically enriched hemiacetal esters. Under optimal conditions (using 10 mol% catalyst loading), a series of b,g-unsaturated a-keto esters was examined with up to 99% de, ee and yield, respectively. Additionally, the enantiomerically enriched hemiacetal esters could be readily transformed into their corresponding bioactive pyranoA C H T U N G T R E N N U N G [2,3-b]pyrans (possessing a multi-substituted bicyclic backbone).