Asymmetric aminocatalysis exploits the potential of chiral primary and secondary amines to catalyze asymmetric reactions. It has greatly simplified the functionalization of carbonyl compounds while ensuring high enantioselectivity. Recent advances in cinchona-based primary amine catalysis have provided new synthetic opportunities and conceptual perspectives for successfully attacking major challenges in carbonyl compound chemistry, which traditional approaches have not been able to address. This Review outlines the historical context for the development of this catalyst class while charting the landmark discoveries and applications that have further expanded the synthetic potential of aminocatalysis.

Cinchona-based primary amine catalysis in the asymmetric functionalization of carbonyl compounds.

The discovery of a novel activation mode provided by organocatalysis is presented. It is demonstrated that the merger of optically active secondary amines and polyenals generates reactive trienamine intermediates, which readily participate in Diels-Alder reactions with different classes of dienophiles, hence, providing a facile entry to highly complex molecular frameworks with excellent stereocontrol. For the Diels-Alder reactions with 3-olefinic oxindoles, spirocyclic oxidoles are formed in high yields, and with enantioselectivities in the range of 94-98% ee. It is demonstrated, that some of these products can be transformed into the hexahydrofuro[2,3-b]indole fragment. The organocatalytic trienamine concept has been extended to also include Diels-Alder reactions of olefins substituted with cyanoacetates providing multifunctional cyclohexenes with three contiguous stereocenters in high yield and good stereocontrol. The novelty of this activation strategy lies within the perfect chirality relay over a distance of up to eight bonds. Moreover, we also present the first trienamine tandem reaction by combining trienamine catalysis with enamine activation. In addition to the experimental results, a detailed mechanistic survey is also provided including NMR spectroscopic studies and calculations of the reactive trienamine intermediates, rationalizing the origin of stereochemistry.

Trienamines in asymmetric organocatalysis: Diels-Alder and tandem reactions.

An oxidative γ-functionalization of enals under N-heterocyclic carbene (NHC) catalysis to give unsaturated δ-lactones is disclosed. Enantioselectivity control involving the relatively remote enal γ-carbon was achieved via Lewis acid [Sc(OTf)3 or combined Sc(OTf)3/Mg(OTf)2] and NHC cooperative catalysis.

Oxidative γ-addition of enals to trifluoromethyl ketones: enantioselectivity control via Lewis acid/N-heterocyclic carbene cooperative catalysis.

A new concept in organocatalysis allowing for the construction of cyclobutanes with four contiguous stereocenters with complete diastereo- and enantiomeric control by a formal [2 + 2]-cycloaddition is presented. The concept is based on simultaneous dual activation of α,β-unsaturated aldehydes and nitroolefins by amino- and hydrogen-bonding catalysis, respectively. A new bifunctional squaramide-based aminocatalyst has been designed and synthesized in order to enable such an activation strategy. The potential and scope of the reaction are demonstrated, and computational studies which account for the stereochemical outcome are presented.

Asymmetric organocatalytic formal [2 + 2]-cycloadditions via bifunctional H-bond directing dienamine catalysis.

The organocatalytic asymmetric α-alkylation of aldehydes by 1,6-conjugated addition of enamines to p-quinone methides is described. Employing a newly developed class of chiral secondary amine catalysts, α-diarylmethine-substituted aldehydes with two contiguous stereocenters have been synthesized in a simple manner with good diastereocontrol and excellent enantioselectivity.

Julian Stiller

Papers

Enantioselective α- and γ-alkylation of α,β-unsaturated aldehydes using dienamine activation.

Enantioselective α‐ and γ‐Alkylation of α,β‐Unsaturated Aldehydes Using Dienamine Activation.