A novel organocatalytic activation mode of cyclopropanes is presented. The reaction concept is based on a design in which a reactive donor-acceptor cyclopropane intermediate is generated by in situ condensation of cyclopropylacetaldehydes with an aminocatalyst. The mechanism of this enamine-based activation of cyclopropylacetaldehydes is investigated by the application of a combined computational and experimental approach. The activation can be traced to a favorable orbital interaction between the π-orbital of the enamine and the σ*C-C orbital of the cyclopropyl ring. Furthermore, the synthetic potential of the developed system has been evaluated. By the application of a chiral secondary amine catalyst, the organocatalytically activated cyclopropanes show an unexpected and highly stereoselective formation of cyclobutanes, functionalizing at the usually inert sites of the donor-acceptor cyclopropane. By the application of 3-olefinic oxindoles and benzofuranone, biologically relevant spirocyclobutaneoxindoles and spirocyclobutanebenzofuranone can be obtained in good yields, high diastereomeric ratios, and excellent enantiomeric excesses. The mechanism of the reaction is discussed and two mechanistic proposals are presented.

The enantioselective inverse-electron-demand hetero-Diels-Alder reaction of the remote olefin functionality in dienamines has been developed by the simultaneous activation of α,β-unsaturated aldehydes and acyl phosphonates. The dual activation is based on an organocatalyst that activates both the α,β-unsaturated aldehyde, through dienamine formation, and the acyl phosphonate by hydrogen-bonding. The enantioselective reaction results in the formation of dihydropyran frameworks with three contiguous stereogenic centers. Different substitution patterns are possible for both the heterodiene and the dienophile, and the target products are obtained in good yields and up to 92% ee. The potential of the reaction is demonstrated by transformation of the products into valuable and complex synthons.

We report a new process to access highly enantioenriched sulfur-based heterocycles by an asymmetric catalytic thio-Diels-Alder reaction. Thiocarbonyls are challenging heterodienophiles in enantioselective Diels-Alder reactions, due to their inherent high reactivity and their poor ability to coordinate to chiral catalysts. We successfully circumvented these problems by employing a different strategy, which explores the use of in situ generated catalyst-bound dienes. Synthetically useful dihydrothiopyrans as well as other bi- and tricyclic sulfur-containing heterocycles are formed in high yields and high to excellent selectivities. DFT calculations were performed to examine the mechanism of the developed reaction. Furthermore, a series of synthetic transformations of the optically active sulfur-based heterocycles are presented.

Fine-tuning: Three types of optically active trans-2,3-disubstituted-2,3-dihydrobenzofurans having three contiguous stereogenic centers can be efficiently accessed by one-pot reaction cascades (see scheme; TMS = trimethylsilyl). High substitution diversity of the final products can be achieved from the same common precursors by fine-tuning of their reactivity through simple structural modifications.

A novel reaction that provides chiral allenes by amino catalytic activation of either aldehydes or α,β-unsaturated aldehydes for reaction with alkynyl-substituted enones is presented. The reaction forms a variety of trisubstituted allenes in high yields and with excellent stereoselectivities. The utility of the reaction concept is demonstrated by the synthesis of chiral furan derivatives in high yields and stereoselectivities.