Hydrazone Activation in the Aminocatalytic Cascade Reaction for the Synthesis of Tetrahydroindolizines.

In this Letter, we demonstrate the usefulness of hydrazone activation for the synthesis of biologically relevant tetrahydroindolizines. A pyrrol-derived hydrazone bearing a Michael acceptor moiety in the N-alkyl side chain has been designed with the aim of participating in the aminocatalytic cascade reaction leading to the annulation of the new six-membered heterocyclic scaffold. The application of (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the aminocatalyst allows for the iminium ion-enamine-mediated cascade to proceed in a fully stereoselective manner.

Pentaenolate activation in the organocatalytic allylic alkylation of indene-2-carbaldehydes.

In this manuscript, the application of pentaenolate intermediates in the allylic alkylation of indene-2-carbaldehydes with Morita-Baylis-Hillman (MBH) carbonates is described. The reaction has been carried out in a highly enantio- and diastereoselective manner due to the use of a chiral tertiary amine as a nucleophilic catalyst. The developed reactivity constitutes the first application of organocatalytic pentaenolate activation in asymmetric synthesis, expanding the arsenal of catalytic methods.

Differentiating Catalysis in the Dearomative [4 + 2]-Cycloaddition Involving Enals and Heteroaromatic Aldehydes.

In this paper, the application of differentiating catalysis in the [4 + 2]-cycloaddition between 2-alkyl-3-formylheteroarenes and α,ß-unsaturated aldehydes is described. Within the developed approach, the same aminocatalyst is employed for the independent activation of both starting materials, differentiating their properties via LUMO-lowering and HOMO-rising principles. By the combination of dearomative dienamine activation with iminium ion chemistry high enantio- and diastereoselectivity of the doubly asymmetric process was accomplished. Selected transformations of products were also demonstrated.

Asymmetric Dearomative (3+2)-Cycloaddition Involving Nitro-Substituted Benzoheteroarenes under H-Bonding Catalysis.

In our studies, the organocatalytic 1,3-dipolar cycloaddition between 2-nitrobenzofurans or 2-nitrobenzothiophene and N-2,2,2-trifluoroethyl-substituted isatin imines has been developed. The reaction has been realized by employing bifunctional organocatalysis, with the use of squaramide derivative being crucial for the stereochemical efficiency of the process. The usefulness of the cycloadducts obtained has been confirmed in selected transformations, including aromative and non-aromative removal of the nitro group.

Vinylogous hydrazone strategy for the organocatalytic alkylation of heteroaromatic derivatives.

A new umpolung approach for the asymmetric Friedel-Crafts-type alkylation of electron-poor heteroaromatic systems has been developed. It is based on the vinylogous reactivity of hydrazones derived from heteroaromatic aldehydes. The donating effect of the hydrazone moiety can be efficiently transferred over the heteroaromatic system activating it towards an asymmetric Friedel-Crafts reaction with α,ß-unsaturated aldehydes realized under aminocatalytic conditions. Excellent enantioselectivities have been obtained owing to the application of a MacMillan imidazolidinone catalyst. Unmasking of the hydrazone moiety has also been realized resulting in the development of a unique strategy for the asymmetric functionalization of electron-poor heteroaromatic systems.

Pyridylacetic acids and related systems as alkylheteroarene surrogates in asymmetric decarboxylative Michael addition.

In this manuscript, a novel method for the preparation of enantiomerically enriched pyridine derivatives has been described. It is based on the utilization of readily available 2-pyridylacetic acids as valuable synthons for the introduction of a pyridine ring in an asymmetric fashion. They have been used as pronucleophiles in asymmetric decarboxylative Michael addition to α,ß-unsaturated aldehydes. The synthesis based on iminium activation using a chiral aminocatalyst that controlled the stereochemical outcome of the transformation has been successfully accomplished.

Enantioselective H-bond-directed vinylogous iminium ion strategy for the functionalization of vinyl-substituted heteroaryl aldehydes.

In this work the first H-bond-directed vinylogous iminium ion strategy has been developed as a convenient strategy for the γ,δ-functionalization of vinyl-substituted heteroaromatic aldehydes. Their reaction with α-mercaptoketones proceeds in a cascade manner involving 1,6-addition followed by intramolecular aldol reaction. Excellent stereoselectivities have been obtained as a result of the H-bond interactions controlling the outcome of the cyclization step. The application of the strategy for the synthesis of tricyclic compounds bearing furan, tetrahydrothiophene and dihydropyran moieties has also been demonstrated.

The Game of Electrons: Organocatalytic Higher-Order Cycloadditions Involving Fulvene- and Tropone-Derived Systems.

The great progress that took place in the field of higher-order cycloadditions involving fulvene- and tropone-derived systems in the last few years is astonishing. By application of organocatalytic activation modes, new higher-order reactivities have been identified and described in the literature. These approaches take advantage of the high reliability of organocatalysis, at the same time expanding its potential and paving new directions for its further evolution. In this Minireview, the progress in the field of organocatalytic higher-order cycloadditions involving fulvene- and tropone-derived systems is summarized and insights into mechanistic aspects of the developed reactivities are provided. Furthermore, the discussion on the nomenclatural issues related to cycloaddition reactions has been conducted and solutions to clarify the picture proposed.

Inverting the reactivity of troponoid systems in enantioselective higher-order cycloaddition.

By the replacement of the oxygen with the sulfur atom in tropone, a novel reactivity pattern of troponoid systems in enantioselective transformation was achieved. It utilizes tropothione as an 8π-component in the [8+2]-cycloaddition involving α,ß-unsaturated aldehydes. The stereochemistry of the process is governed through the aminocatalytic LUMO-activation of the carbonyl reactant. It is in marked contrast to recently developed aminocatalytic higher-order cycloadditions proceeding via HOMO-activation strategies.

Site-Selective and Enantioselective α,ß,γ-Functionalization of 5-Alkylidenefuran-2(5 H)-ones: A Route to Polycyclic γ-Lactones.

A new strategy for a direct α,ß,γ-functionalization of the γ-lactone framework in the corresponding 5-alkylidenefuran-2(5 H)-ones is reported. The developed approach is based on a stereocontrolled cascade reaction with 2-mercaptocarbonyl compounds proceeding in a sequence of thia-Michael/aldol/oxa-Michael reactions. Such a synthetic strategy allows for a construction of a unique polycyclic architecture containing γ-lactone, tetrahydrofuran, and tetrahydrothiophene ring systems. Excellent enantioselectivities and diastereoselectivities have been obtained in the presence of bifunctional catalyst derived from cinchona alkaloids.

Synthesis of γ,γ-Disubstituted Butenolides through a Doubly Vinylogous Organocatalytic Cycloaddition.

A novel organocatalytic approach to γ,γ-disubstituted butenolides is described. It is based on a fully site-selective functionalization of 5-alkylidenefuran-2(5H)-ones via trienamine-mediated [4+2]-cycloaddition with α,ß,γ,δ-diunsaturated aldehydes. The developed methodology proceeds with excellent stereocontrol and constitutes a unique example of trienamine chemistry with vinylogous dienophiles. Importantly, the reaction has very broad scope and allows for the introduction of substituents also in the α- or the ß-position of the butenolide ring. Usefulness of the products obtained has been confirmed in the intramolecular Stetter reaction leading to polycyclic product.

Organocatalytic Synthesis of cis-2,3-Aziridine Aldehydes by a Postreaction Isomerization.

An unprecedented organocatalytic cis-selective aziridination of α,ß-unsaturated aldehydes is described. The strategy utilizes postreaction isomerization as a key step. Our study demonstrates that by a proper choice of structural features of reagents and the catalyst the outcome of well-established reactions can be altered, leading to the formation of normally inaccessible diastereomers. The usefulness of the developed approach has been confirmed in the syn-selective formal aminohydroxylation of α,ß-unsaturated aldehydes.