Direct Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated Butyrolactones to α,β‐Unsaturated Thioamides

Soft Lewis acid/Brønsted base cooperative catalysts have enabled direct catalytic asymmetric vinylogous conjugate addition of α,β‐ and β,γ‐unsaturated butyrolactones to α,β‐unsaturated thioamides with perfect atom economy. When using α‐angelica lactone and its derivatives as pronucleophiles, as little as 0.5 mol % catalyst loading was sufficient to complete the reaction necessary to construct consecutive tri‐ and tetrasubstituted stereogenic centers in a highly diastereo‐ and enantioselective fashion.     

Catalytic Michael/Ring‐Closure Reaction of α,β‐Unsaturated Pyrazoleamides with Amidomalonates: Asymmetric Synthesis of (−)‐Paroxetine

A highly enantioselective tandem Michael/ring‐closure reaction of α,β‐unsaturated pyrazoleamides and amidomalonates has been accomplished in the presence of a chiral N,N′‐dioxide–Yb(OTf)₃ complex (Tf: trifluoromethanesulfonyl) to give various substituted chiral glutarimides with high yields and diastereo‐ and enantioselectivities. Moreover, this methodology could be used for gram‐scale manipulation and was successfully applied to the synthesis of (?)‐paroxetine. Further nonlinear and HRMS studies revealed that the real catalytically active species was a monomeric L ‐PMe₂ –Yb³⁺ complex. A plausible transition state was proposed to explain the origin of the asymmetric induction.     

Diphenylprolinol Silyl Ether Catalyzed Asymmetric Michael Reaction of Nitroalkanes and β,β‐Disubstituted α,β‐Unsaturated Aldehydes for the Construction of All‐Carbon Quaternary Stereogenic Centers

The asymmetric Michael reaction of nitroalkanes and β,β‐disubstituted α,β‐unsaturated aldehydes was catalyzed by diphenylprolinol silyl ether to afford 1,4‐addition products with an all‐carbon quaternary stereogenic center with excellent enantioselectivity. The reaction is general for β‐substituents such as β‐aryl and β‐alkyl groups, and both nitromethane and nitroethane can be employed. The addition of nitroethane is considered a synthetic equivalent of the asymmetric Michael reaction of ethyl and acetyl substituents by means of radical denitration and Nef reaction, respectively. The short asymmetric synthesis of (S)‐ethosuximide with a quaternary carbon center was accomplished by using the present asymmetric Michael reaction as the key step. The reaction mechanism that involves the E/Z isomerization of α,β‐unsaturated aldehydes, the retro‐Michael reaction, and the different reactivity between nitromethane and nitroethane is discussed.     

Direct Asymmetric Michael Reaction of α,β‐Unsaturated Aldehydes and Ketones Catalyzed by Two Secondary Amine Catalysts

A direct asymmetric Michael reaction of α,β‐unsaturated aldehydes and ketones proceeded in the presence of two pyrrolidine‐type catalysts, a diphenylprolinol silyl ether and hydroxyproline, to afford synthetically useful δ‐keto aldehydes with excellent diastereo‐ and enantioselectivity. Although there are several iminium ions and enamines in the reaction mixture, the iminium ion generated by the former catalyst reacts preferentially with the enamine generated by the latter catalyst.     

Direct Catalytic Asymmetric Doubly Vinylogous Michael Addition of α,β‐Unsaturated γ‐Butyrolactams to Dienones

An asymmetric doubly vinylogous Michael addition (DVMA) of α,β‐unsaturated γ‐butyrolactams to sterically congested β‐substituted cyclic dienones with high site‐, diastereo‐, and enantioselectivity has been achieved. An unprecedented DVMA/vinylogous Michael addition/isomerization cascade reaction affords chiral fused tricyclic γ‐lactams with four newly formed stereocenters.     

Highly Enantioselective Synthesis of α‐Stereogenic Esters through Catalytic Asymmetric Michael Addition of 4‐Oxo‐4‐arylbutenoates

Highly enantioselective Michael addition of 1,3‐dicarbonyl compounds and nitromethane to 4‐oxo‐4‐arylbutenoates catalyzed by N,N′‐dioxide–Sc(OTf)₃ complexes has been developed. Using 0.5–2 mol % catalyst loading, various α‐stereogenic esters were obtained regioselectively with excellent yields (up to 97 %) and enantioselectivities (up to >99 % ee). Moreover, the reaction performed well under nearly solvent‐free conditions. The products with functional groups are ready for further transformation, which showed the potential value of the catalytic approach. According to the experimental results and previous reports, a plausible working model has been proposed to explain the origin of the activation and the asymmetric induction.     

Base‐Dependent Stereodivergent Intramolecular Aza‐Michael Reaction: Asymmetric Synthesis of 1,3‐Disubstituted Isoindolines

The nucleophilic addition (A_N) / intramolecular aza‐Michael reaction (IMAMR) process on Ellman’s tert‐butylsulfinyl imines, bearing a Michael acceptor in the ortho position, is studied. This reaction affords 1,3‐disubstituted isoindolines with a wide range of substituents in good yields and diastereoselectivities. Interestingly, careful choice of the base for the aza‐Michael step allows either the cis or the trans diastereoisomers to be exclusively obtained. This stereodivergent cyclization has enabled the synthesis of C₂‐symmetric bisacetate‐substituted isoindolines. In addition, bisacetate isoindolines bearing two well‐differentiated ester moieties are also noteworthy because they may allow for the orthogonal synthesis of β,β′‐dipeptides using a single nitrogen atom as a linchpin.     

Cinchonamine Squaramide Catalyzed Asymmetric aza‐Michael Reaction: Dihydroisoquinolines and Tetrahydropyridines

The first example of a chiral cinchona‐squaramide catalyzed enantioselective intramolecular aza‐Michael addition for the synthesis of dihydroisoquinolines and tetrahydropyridines has been developed. In general, good yields and excellent enantioselctivities were observed. Broad classes of Michael acceptors, such as enones, esters, thioesters, and Weinreb amides, were successful substrates. The possibility of recycling the catalysts has also been demonstrated. An oxidation of combined enamine and keto functionalities on chiral dihydroisoquinolines leads to a single diastereomer of an architecturally unprecedented tetracyclic core without loss in enantioselectivity.     

Electrophilic Activation of α,β‐Unsaturated Amides: Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated γ‐Butyrolactones

Although catalytic asymmetric conjugate addition reactions have remarkably advanced over the last two decades, the application of less electrophilic α,β‐unsaturated carboxylic acid derivatives in this useful reaction manifold remains challenging. Herein, we report that α,β‐unsaturated 7‐azaindoline amides act as reactive electrophiles to participate in catalytic diastereo‐ and enantioselective vinylogous conjugate addition of γ‐butyrolactones in the presence of a cooperative catalyst comprising of a soft Lewis acid and a Brønsted base. Reactions mostly reached completion with as little as 1 mol % of catalyst loading to give the desired conjugate adducts in a highly stereoselective manner.     

Catalytic Asymmetric Epoxidation of α,β‐Unsaturated Esters with Chiral Yttrium–Biaryldiol Complexes

The full details of the asymmetric epoxidation of α,β‐unsaturated esters catalyzed by yttrium complexes with biaryldiol ligands are described. An yttrium–biphenyldiol catalyst, generated from Y(OiPr)₃–biphenyldiol ligand–triphenylarsine oxide (1:1:1), is suitable for the epoxidation of various α,β‐unsaturated esters. With this catalyst, β‐aryl α,β‐unsaturated esters gave high enantioselectivities and good yields (≤99 % ee). The reactivity of this catalyst is good, and the catalyst loading could be decreased to as little as 0.5–2 mol % (the turnover number was up to 116), while high enantiomeric excesses were maintained. For β‐alkyl α,β‐unsaturated esters, an yttrium–binol catalyst, generated from Y(OiPr)₃–binol ligand–triphenylphosphine oxide (1:1:2), gave the best enantioselectivities (≤97 % ee). The utility of the epoxidation reaction was demonstrated in an efficient synthesis of (?)‐ragaglitazar, a potential antidiabetes agent.     

α,β‐Double Electrophilic Addition of Allene‐1,3‐Dicarboxylic Esters for the Construction of Polysubstituted Furans by KI/tert‐Butyl Hydroperoxide (TBHP)‐Promoted Oxidative Annulation

An unprecedented KI/tert‐butyl hydroperoxide promoted tandem Michael addition/oxidative annulation of allene‐1,3‐dicarboxylic esters and 1,3‐dicarbonyl compounds has been developed. This procedure provides a new, facile, and transition‐metal‐free synthetic approach to afford polysubstituted furans in moderate to excellent yields (up to 93 %). This method first establishes a α,β‐double electrophilic reaction mode of allene‐1,3‐dicarboxylic esters to form 1,3‐dicarbonyl compounds.     

The Catalytic Asymmetric Mukaiyama–Michael Reaction of Silyl Ketene Acetals with α,β‐Unsaturated Methyl Esters

α,β‐Unsaturated esters are readily available but challenging substrates to activate in asymmetric catalysis. We now describe an efficient, general, and highly enantioselective Mukaiyama–Michael reaction of silyl ketene acetals with α,β‐unsaturated methyl esters that is catalyzed by a silylium imidodiphosphorimidate (IDPi) Lewis acid.     

Bifunctional Guanidine via an Amino Amide Skeleton for Asymmetric Michael Reactions of β‐Ketoesters with Nitroolefins: A Concise Synthesis of Bicyclic β‐Amino Acids

Two activations are better than one : The chiral bifunctional guanidine 1 , which features an amino amide backbone, catalyzes the asymmetric Michael addition of a range of substrates and gives products with excellent stereoselectivities. The method also allows the efficient synthesis of optically pure β‐amino acid esters. Both the guanidine group and the NH proton of the amide were important for the dual activation.