Enantioselective Organocatalytic Domino Michael/Aldol Reactions: An Efficient Procedure for the Stereocontrolled Construction of 2H‐Thiopyrano[2,3‐b]quinoline Scaffolds

An efficient procedure for the stereocontrolled construction of 2H‐thiopyrano[2,3‐b]quinoline scaffolds has been developed, starting from simple compounds. The domino Michael/aldol reactions between 2‐mercaptobenzaldehydes and enals, promoted by chiral diphenylprolinol TMS ether, proceed with excellent chemo‐ and enantioselectivity to give the corresponding synthetically useful and pharmaceutically valuable 2H‐thiopyrano[2,3‐b]quinolines in high yields with 90–99 % ee.     

Organocatalytic Domino Oxa‐Michael/1,6‐Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds

An asymmetric organocatalytic domino oxa‐Michael/1,6‐addition reaction of ortho‐hydroxyphenyl‐substituted para‐quinone methides and isatin‐derived enoates has been developed. In the presence of 5 mol % of a bifunctional thiourea organocatalyst, this scalable domino reaction affords 4‐phenyl‐substituted chromans bearing spiro‐connected oxindole scaffolds and three adjacent stereogenic centers in good to excellent yields (up to 98 %) and with very high stereoselectivities (up to >20:1 d.r., >99 % ee).     

Chiral Amine Catalyzed Reductive Aldol/Reductive Michael Addition Cascade Towards Enantioselective Synthesis of Benzannulated Diquinanes

Disclosed here an amine-catalyzed reductive aldol-condensation followed by an intramolecular reductive Michael-addition cascade employing Hantzsch ester as hydride source to a keto-bis-enone to provide enantio- and diastereoselective benzannulated diquinanes having three consecutive stereocenters, one of which is an all-carbon quaternary formyl stereocenter. Interestingly, on changing a tether connecting the ketone and an enone moiety from an aliphatic to an aromatic, a change in reactivity is observed. In this case, instead of the above-mentioned reductive aldol condensation, an asymmetric aldol reaction occurs, followed by an iminium/enamine isomerization and, finally diastereoselective Michael addition reaction occurs. As a result, a bis-benzannulated diquinane is obtained with vicinal congested quaternary chiral centers.     

Enantioselective Aldol Reactions Catalyzed by Chiral Phosphine Oxides

The development of enantioselective aldol reactions catalyzed by chiral phosphine oxides is described. The aldol reactions presented herein do not require the prior preparation of the masked enol ethers from carbonyl compounds as aldol donors. The reactions proceed through a trichlorosilyl enol ether intermediate, formed in situ from carbonyl compounds, which then acts as the aldol donor. Phosphine oxides activate the trichlorosilyl enol ethers to afford the aldol adducts with high stereoselectivities. This procedure was used to realize a directed cross‐aldol reaction between ketones and two types of double aldol reactions (a reaction at one/two α position(s) of a carbonyl group) with high diastereo‐ and enantioselectivities.     

Enantioselective Synthesis of 3,4‐Dihydropyran‐2‐ones by Domino Michael Addition and Lactonization with New Asymmetric Organocatalysts: Cinchona‐Alkaloid‐Derived Chiral Quaternary Ammonium Phenoxides

Chiral quaternary ammonium phenoxides were readily prepared from commercially available cinchona alkaloids and proved to be useful new asymmetric organocatalysts. Among various chiral quaternary ammonium phenoxides, a cinchonidine‐derived catalyst that bears both a sterically hindered N1‐9‐anthracenylmethyl group and a strongly electron withdrawing 9‐O‐3,5‐bis(trifluoromethyl)benzyl group were found to be highly effective for the Michael addition of ketene silyl acetals (derived from phenyl carboxylates) and α,β‐unsaturated ketones followed by lactonization. Optically active 3,4‐dihydropyran‐2‐one derivatives were obtained in high yields with excellent control of enantio‐ and diastereoselectivity. This catalyst can be handled in air and stored at room temperature in a sealed bottle without decomposition for at least one month.     

Asymmetric Organocatalytic Addition Reactions of Maleimides: A Promising Approach Towards the Synthesis of Chiral Succinimide Derivatives

Recent progress in asymmetric organocatalysis has led to the development of several asymmetric transformations that employ various substrates. Among these substrates, maleimides have emerged as excellent Michael acceptors, dienophiles, and dipolarophiles. In this Focus Review we highlight the advances in the asymmetric synthesis of succinimide derivatives through asymmetric organocatalytic addition reactions of maleimides.     

Organocatalytic Atroposelective Aldol Condensation: Synthesis of Axially Chiral Biaryls by Arene Formation

Axially chiral compounds are of significant importance in modern synthetic chemistry and particularly valuable in drug discovery and development. Nonetheless, current approaches for the preparation of pure atropisomers often prove tedious. We demonstrate here a synthetic method that efficiently transfers the stereochemical information of a secondary amine organocatalyst into the axial chirality of tri‐ortho‐substituted biaryls. An aromatic ring is formed during the dehydration step of the described aldol condensation cascade, leading to highly enantioenriched binaphthyl derivatives. The fundamental course of the reaction is related to the biosynthesis of aromatic polyketides.     

Catalytic Asymmetric Synthesis of Benzobicyclo[3.2.1]octanes

Lawsone aldehydes were directly transformed into the biologically important, unique carbon skeleton of chiral methanobenzo[f]azulenes/methanodibenzo[a,d][7]annulenes in high dr and ee and in very good yields by using quinine-thiourea-catalyzed tandem Wittig/intramolecular Michael/intramolecular aldol reactions. This asymmetric catalytic tandem protocol will be highly useful because these final molecules are basic skeletons of important antibiotics.     

Asymmetric Synthesis of Fully Substituted Cyclopentane‐Oxindoles through an Organocatalytic Triple Michael Domino Reaction

An efficient, highly stereoselective asymmetric synthesis of fully functionalized cyclopentanes bearing an oxindole moiety and several other functional groups in one pot has been developed. Key step is an organocatalytic triple Michael domino reaction forming three C?C bonds and six stereocenters, including a quaternary one. Starting from equimolar amounts of simple substrates, a high molecular complexity can be reached after a Wittig olefination in one pot. The new protocol can easily be scaled up to gram amounts.     

Organocatalytic Enantioselective Synthesis of Chiral Allenes: Remote Asymmetric 1,8-Addition of Indole Imine Methides

An organocatalytic enantioconvergent synthesis of chiral tetrasubstituted allenes is disclosed. With suitable chiral phosphoric acid catalysts, a range of racemic indole-substituted propargylic alcohols reacted with nucleophiles to provide efficient access to a series of enantioenriched allenes with high enantioselectivities. Control experiments suggested a mechanism involving remotely controlled asymmetric 1,8-addition of the in situ generated indole imine methide via a bifunctional transition state.     

One‐Pot Organocatalytic Enantioselective Michael/Povarov Domino Strategy for the Construction of Spirooctahydroacridine‐3,3′‐oxindole Scaffolds

An asymmetric organocatalytic one‐pot strategy for the construction of spirooctahydroacridine‐3,3′‐oxindole scaffolds has been successfully developed by means of a domino Michael/Povarov reaction sequence. The one‐pot protocol affords the chiral spirocyclohexaneoxindoles bearing an octahydroacridine motif with five stereocenters in good to high yields (up to 89 % yield) with excellent to perfect diastereoselectivities (up to >20:1 d.r.) and enantioselectivities (up to >99 % ee). This highly efficient one‐pot domino procedure will allow diversity‐oriented syntheses of this intriguing class of compounds with potential biological activities.