Enantioselective Organocatalytic Michael Addition Research Articles

Organocatalytic Diastereo‐ and Enantioselective Michael Addition of α‐Aryl Isocyanoacetates to Aurone‐Derived Azadienes

AbstractA highly diastereo‐ and enantioselective organocatalytic Michael addition of α‐aryl isocyanoacetates to aurone‐derived azadienes under mild conditions has been developed. This efficient methodology enables access to chiral α,α‐disubstituted α‐amino ester derivatives with two adjacent stereocenters, one of them quaternary, bearing a benzofuran scaffold in their structure in high yields and stereocontrol. Furthermore, the reaction product can be readily converted into an α,α‐disubstituted α‐amino acid in high yield via hydrolysis of the isocyano group without compromising enantioselectivity.

Enantioselective Michael Addition/Cyclization/Desymmetrization Sequence of Prochiral Cyclic Hemiacetals and Nitroolefins: Synthesis of Chiral Oxygen-Bridged Bicyclic Compounds.

The organocatalytic enantioselective Michael addition of functionalized prochiral cyclic hemiacetals and nitroolefins has been developed under cooperative enamine and hydrogen bond catalysis. The obtained chiral hemiacetal intermediates could be used in the subsequent diastereocontrolled cyclization/desymmetrization divergent process to access (1) 9-oxabicyclo[3.3.1]nonane or 8-oxabicyclo[3.2.1]octane frameworks via oxocarbenium ion-mediated Friedel-Crafts cyclization, and (2) 2,9-dioxabicyclo[3.3.1]nonane frameworks via intramolecular nucleophilic cyclization. Experimental results suggest that there is neighboring group participation controlling the diastereoselectivities of the desymmetrization process.

Enantioselective Organocatalytic Michael Addition Reactions Catalyzed by Proline/Prolinol/Supported Proline based Organocatalysts: An Overview

AbstractEver since the discovery of enantioselective organocatalytic Michael addition reactions, it has emerged as a significant path for synthesizing a variety of stereochemical products under mild conditions, also a prominent C−X (X=C, O, N, S) bond formation reaction in organic chemistry. Over time, substantial progress has been accomplished in diversity‐ and target‐ oriented asymmetric Michael addition reactions. This review provides a brief overview of the results, scope, and limitations of several influential strategies involving enantio‐selective Michael addition reactions promoted by mono‐functional proline/prolinol/supported‐proline‐based chiral organocatalysts. Furthermore, we also sincerely believe that the various synthetic strategies documented in this review will pave a pathway to improve the status of Michael addition reactions for synthesizing various drug molecules involving complex intermediates.

Organocatalytic Enantioselective Michael Addition of Pyrazol‐5‐ones to β‐Silylmethylene Malonates: Synthesis of Chiral Organosilanes Under Metal‐ free Conditions

AbstractHerein, we report a Michael addition reaction of pyrazolin‐5‐ones with β‐silylmethylene malonates using a squaramide catalyst derived from quinidine under mild reaction conditions. This protocol delivered chiral organosilanes appendage with pyrazole moiety in high yields (up to 90%) and good to excellent enantioselectivities (up to 98 : 2 er). A quinine derived thiourea catalyst deliver corresponding antipode for enantiomers with almost similar level of yields (up to 93%) and good to excellent enantioselectivities (up to 2 : 98 er). The scale‐up reaction for synthesis of two chiral organosilanes confirmed the practical reliability of this protocol.

Enantioselective Organocatalytic Michael Addition to Unsaturated Indolyl Ketones.

An efficient enantioselective organocatalytic method for the synthesis of N-alkylated indoles with α-branched alkyl substituents from the corresponding unsaturated indolyl ketones via a Michael addition has been developed. The resulting products were obtained in high enantioselectivities and in good yields. Various nucleophiles (nitroalkanes, malononitrile, malonic esters) can be used. The substitution pattern of the indole ring had no significant impact on the reaction outcome. Both electron-withdrawing and electron-donating substituents in any position of the heteroaromatic ring were well-tolerated.

Enantioselective Construction of Vicinal Sulfur‐functionalized Quaternary and Tertiary Stereocenters via Organocatalytic Michael Addition of 5H‐Thiazol‐4‐ones to 1‐Azadienes

AbstractAn organocatalytic enantioselective Michael addition of 5H‐thiazol‐4‐ones to 1‐azadienes has been developed. In the presence of chiral phosphoric acid, a series of optically active benzofuran derivatives featured by vicinal sulfur‐containing quaternary and tertiary stereocenters were obtained in high yields (71‐99%) with high stereoselectivities (70–96% ee and 8 : 1–20 : 1 d.r.).

Organocatalytic Enantioselective Michael Addition between 3-(3-hydroxy-1H-pyrazol-1-yl)Oxindole and β-Nitrostyrene for the Preparation of Chiral Disubstituted Oxindoles.

A new enantioselective Michael addition between 3-(3-hydroxy-1H-pyrazol-1-yl)oxindole, a new synthon generated from isatin N,N'-cyclic azomethine imine 1,3-dipole, and β-nitrostyrene has been disclosed. A series of chiral 3-(3-oxo-2,3-dihydro-1H-pyrazol-1-yl) disubstituted oxindoles were obtained in excellent results (up to 97% yield, up to 94% ee) with moderate to good diastereoselectivities (up to 4.3:1 dr).

Enantioselective Organocatalytic Michael Addition and Ring Closure Cascade Reaction of o‐Quinone Methides with Nitriles

A convenient way to prepare chiral 2-amino-3-substituted-4H-chromen derivatives.

Organocatalytic Enantioselective Michael Addition of Oxazolones to 2‐Enoylpyridine N‐Oxides for Assembling of Pyridine N‐Oxides Featuring Vicinal Oxygen‐Containing Tetrasubstituted Stereocenters

AbstractThe thiourea catalyzed enantioselective Michael addition of 5H‐oxazol‐4‐ones to 2‐enoylpyridine N‐oxides is described. Under mild conditions, a series of optically active pyridine N‐oxides inlaid with oxazolone motif were obtained in high yields (62–99%) with excellent stereoselectivities (84–>99% ee and >20:1 dr). Notably, the method offers a direct synthetic approach to enantioenriched pyridine N‐oxides featured by vicinal oxygen‐containing tetrasubstituted stereocenters.magnified image

An organic-base catalyzed asymmetric 1,4-addition of tritylthiol to in situ generated aza-o-quinone methides at the H2O/DCM interface.

Based on an efficient method for in situ generation of N-o-QM species in the presence of a base, enantioselective catalytic conjugated additions of tritylthiol to in situ generated N-o-QMs are reported. Acid-base bifunctional organocatalyst 4c (10 mol%) enables these transformations with high stereoselectivities (up to 94% ee) using H2O/DCM as a solvent under mild conditions.

Organocatalytic atropo- and E/Z-selective Michael addition reaction of ynones with α-amido sulfones as sulfone-type nucleophile

We describe herein the first enantioselective organocatalytic Michael addition reaction of α-amido sulfones to ynones to access axially chiral styrenes.

Asymmetric Total Synthesis of (+)-Strychnine.

A synthetic strategy for the catalytic asymmetric total synthesis of (+)-strychnine is disclosed. Key features of this synthesis include an organocatalytic enantioselective Michael addition to establish the chirality of the starting building block, a photoinduced radical cascade reaction to access the Corynanthe alkaloid intermediate, and a bioinspired cascade rearrangement to generate the core of the Strychnos alkaloids.

Studies on the Organocatalytic Enantioselective Michael Addition of Cyclic Ketones and α,α-Disubstituted Aldehydes to α-Nitrostyrenes

Studies on the Organocatalytic Enantioselective Michael Addition of Cyclic Ketones and α,α-Disubstituted Aldehydes to α-Nitrostyrenes

Organocatalytic Enantioselective Michael Addition of 3‐Indolinone‐2‐Carboxylates to Maleimides

An organocatalyzed asymmetric conjugate addition of 2‐substituted 3‐indolinones to maleimides has been developed by using a chiral bifunctional squaramide derived from quinidine to promote the reaction. This method provides easy access to 3‐indolinone‐2‐carboxylate‐succinimide adducts in high yields with excellent diastero and entantioselectivities and is a useful approach for the construction of vicinal quaternary‐tertiary chiral centers. In addition, product 4l was successfully converted into a chiral indoline‐pyrrolidine adduct.

Enantioselective organocatalytic Michael additions of N,N'-dialkylbarbituric acids to enones.

N,N'-Dialkylbarbituric acids as cyclic malonamide donors were successfully used in the enantioselective Michael addition reaction of enones. Using cinchona alkaloid-based bifunctional squaramide as an organocatalyst, this Michael reaction of N,N'-di-tert-butylbarbituric acid with various enones features a highly enantioselective (91-99% ee) production of the corresponding optically active 5-substituted barbituric acid derivatives. The transformations of the Michael product for the barbituric acid structural unit were realized in two ways, deprotection to remove the N-tert-butyl group and alkylation to produce 5,5-disubstituted barbituric acid derivatives.

Synthesis of pyrrolidine-3-carboxylic acid derivatives via asymmetric Michael addition reactions of carboxylate-substituted enones.

To concisely synthesize highly enantiomerically enriched 5-alkyl-substituted pyrrolidine-3-carboxylic acids, organocatalytic enantioselective Michael addition reactions of 4-alkyl-substituted 4-oxo-2-enoates with nitroalkanes have been developed. Using the developed reaction method, 5-methylpyrrolidine-3-carboxylic acid with 97% ee was obtained in two steps.

2-Carboxythioester-1,3-dithiane: A Functionalized Masked Carbonyl Nucleophile for the Organocatalytic Enantioselective Michael Addition to Enones

An S-(2,2,2-trifluoroethyl) 1,3-dithiane-2-carbothioate has been successfully employed as acyl anion synthon in the organocatalytic enantioselective addition to enones promoted by quinine- and quinidine-derived tertiary/primary diamines. By proper selection of a co-catalyst and by optimization of the reaction parameters, convenient experimental conditions were found that allowed to obtain the highly functionalized products in up to 90% yield and 98% ee in short reaction times. These compounds, featuring selectively removable functionalities, proved to be versatile synthetic intermediates, which could be transformed into different derivatives without any erosion of the stereochemical integrity of the molecules.

Organocatalytic Enantioselective Decarboxylative Michael Addition of β‐Keto Acids to Dicyanoolefins and Disulfonylolefins

AbstractA convenient organocatalytic enantioselective decarboxylative Michael addition of β‐keto acids to dicyanoolefins and disulfonylolefins is realized. In the presence of saccharide‐derived chiral amino thioureas, the reaction proceeded smoothly to afford a wide range of the Michael adducts in 62–99% yield with 70–94% ee. Moreover, one of the chiral adducts obtained could be readily converted into the monofluorinated product in a total 68% yield over four steps with 85% ee.magnified image

ChemInform Abstract: Enantioselective Organocatalytic Michael Addition of Isorhodanines to α,β‐Unsaturated Aldehydes.

AbstractVarious isorhodanine derivatives react with 3‐aryl or 3‐alkyl substituted acryl aldehydes to form 4,5‐disubstituted isorhodanine adducts in high yields.

ChemInform Abstract: Combining Organocatalysis with Central‐to‐Axial Chirality Conversion: Atroposelective Hantzsch‐Type Synthesis of 4‐Arylpyridines.

AbstractOrganocatalytic enantioselective Michael addition provides 4‐aryl‐1,4‐dihydropyridines.