Diarylprolinol‐Mediated Asymmetric Direct Cross‐Aldol Reaction of α,β‐Unsaturated Aldehyde as an Electrophilic Aldehyde

The diarylprolinol‐mediated asymmetric direct cross‐aldol reaction of α,β‐unsaturated aldehyde as an electrophilic aldehyde was developed. The reaction becomes accelerated by an acid when a carbonyl group is introduced at the γ‐position of the α,β‐unsaturated aldehyde. Synthetically useful γ,δ‐unsaturated β‐hydroxy aldehydes were obtained with high anti‐selectivity and excellent enantioselectivity.     

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.     

Access to Cyclic β‐Amino Acids by Amine‐Catalyzed Enantioselective Addition of the γ‐Carbon Atoms of α,β‐Unsaturated Imines to Enals

Disclosed herein is a new catalytic approach for an efficient access to cyclic β‐amino acids widely found in bioactive small molecules and peptidic foldamers. Our method involves addition of the remote γ‐carbon atoms of α,β‐unsaturated imines to enals by iminium organic catalysis. This highly chemo‐ and stereo‐selective reaction affords cyclic β‐amino aldehydes that can be converted to amino acids bearing quaternary stereocenters with exceptional optical purities. Our study demonstrates the unique power of organic catalytic remote carbon reactions in rapid synthesis of functional molecules.     

Organocatalyzed Cyclopropanation of α‐Substituted α,β‐Unsaturated Aldehydes: Enantioselective Synthesis of Cyclopropanes Bearing a Chiral Quaternary Center

An enantioselective cyclopropanation of α‐substituted α,β‐unsaturated aldehydes with bromomalonate has been successfully developed through a domino Michael/α‐alkylation strategy. The method allows the efficient formation of cyclopropanes bearing a quaternary carbon stereocenter at the α‐position of the aldehydes by using iminium/enamine catalysis and gives a nice extension on the organocatalytic cyclopropanation of bromomalonate and α,β‐unsaturated aldehydes previously reported by other groups. Very good yields (up to 81 %) and enantioselectivities (up to 97 % ee) have been obtained. The optically active cyclopropane derivatives are of high synthetic interest as useful targets for further elaboration into more complex structures.     

Asymmetric Diels–Alder Reaction of α‐Substituted and β,β‐Disubstituted α,β‐Enals via Diarylprolinol Silyl Ether for the Construction of All‐Carbon Quaternary Stereocenters

The asymmetric Diels–Alder reaction of α‐substituted acrolein proceeds in the presence of the trifluoroacetic acid salt of trifluoromethyl‐substituted diarylprolinol silyl ether to afford the exo‐isomer with both excellent diastereoselectivity and high enantioselectivity. In the Diels–Alder reaction of a β,β‐disubstituted α,β‐unsaturated aldehyde, good exo‐selectivity and excellent enantioselectivity was obtained when the perchloric acid salt of the bulky triisopropyl silyl ether of trifluoromethyl substituted diarylprolinol was employed as an organocatalyst in the presence of water. In both cases, all‐carbon quaternary stereocenters are constructed enantioselectively.     

Catalytic Asymmetric Michael Reaction of 5H‐Oxazol‐4‐Ones with α,β‐Unsaturated Acyl Imidazoles

The asymmetric Michael reaction between 5H‐oxazol‐4‐ones and α,β‐unsaturated acyl imidazoles is reported. A novel 2‐benzo[b]thiophenyl‐modified chiral ProPhenol species is synthesized and used as a ligand, leading to good enantioselectivities in this asymmetric conjugate addition reaction. Furthermore, the introduction of phenol additives as achiral co‐ligands is found to improve the reaction’s chemical yields, diastereoselectivities, and enantioselectivities.     

Light‐Driven Enantioselective Organocatalytic β‐Benzylation of Enals

A photochemical organocatalytic strategy for the direct enantioselective β‐benzylation of α,β‐unsaturated aldehydes is reported. The chemistry capitalizes upon the light‐triggered enolization of 2‐alkyl‐benzophenones to afford hydroxy‐o ‐quinodinomethanes. These fleeting intermediates are stereoselectively intercepted by chiral iminium ions, transiently formed upon condensation of a secondary amine catalyst with enals. Density functional theory (DFT) studies provided an explanation for why the reaction proceeds through an unconventional Michael‐type addition manifold, instead of a classical cycloaddition mechanism and subsequent ring‐opening.     

Synthesis of Functionalized Indoles with a Trifluoromethyl‐Substituted Stereogenic Tertiary Carbon Atom Through an Enantioselective Friedel–Crafts Alkylation with β‐Trifluoromethyl‐α,β‐enones

Chiral complexes of BINOL‐based ligands with zirconium tert‐butoxide catalyze the Friedel–Crafts alkylation reaction of indoles with β‐trifluoromethyl‐α,β‐unsaturated ketones to give functionalized indoles with an asymmetric tertiary carbon center attached to a trifluoromethyl group. The reaction can be applied to a large number of substituted α‐trifluoromethyl enones and substituted indoles. The expected products were obtained with good yields and ees of up to 99 %.     

Amidation of Aldehydes and Alcohols through α‐Iminonitriles and a Sequential Oxidative Three‐Component Strecker Reaction/Thio‐Michael Addition/Alumina‐Promoted Hydrolysis Process to Access β‐Mercaptoamides from Aldehydes,Amines, and Thiols

Mild and general alumina‐promoted hydrolysis conditions for converting α‐iminonitriles into carboxamides have been developed. In combination with the oxidative three‐component Strecker reaction, the one‐pot direct amidation of aldehydes and alcohols is reported. Subsequently, an Yb(OTf)₃‐catalyzed Michael addition of thiols to α,β‐unsaturated α‐iminonitriles is reported for the synthesis of β‐mercapto‐α‐iminonitriles. The successful integration of an oxidative Strecker reaction, thio‐Michael addition, and neutral‐alumina‐promoted hydrolysis of β‐mercapto‐α‐iminonitriles into a three‐component one‐pot process allowed us to develop the direct conversion of amines, aldehydes, and thiols into β‐mercaptoamides. All of these procedures were applicable to aromatic and aliphatic amines and aldehydes.     

Asymmetric Dearomatization of β‐Naphthols through a Bifunctional‐Thiourea‐Catalyzed Michael Reaction

An intermolecular asymmetric dearomatization reaction of β‐naphthols with nitroethylene through a chiral‐thiourea‐catalyzed Michael reaction is described. Enantioenriched functionalized β‐naphthalenones with an all‐carbon quaternary stereogenic center could thus be easily constructed from simple naphthol derivatives in good yields and excellent enantioselectivity (up to 79 % yield, 98 % ee).     

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.     

Synthesis of β‐Haloketones by β‐Addition Reactions of α,β‐Unsaturated Ketones with BX3 (X = Br,Cl) as Halide Source

A series of β‐bromoketones and β‐chloroketones were synthesized by the addition reactions of α,β‐unsaturated ketones under BX₃ (X = Br, Cl) and ethylene glycol reaction system. The α,β‐unsaturated ester also was successfully converted to its corresponding β‐bromoester under the reaction condition.     

A Novel Approach to Synthesis of α，β－Unsaturated Ketones

A new approach to the synthesis of α，β-unsaturated ketones from 1,2,3-trimethyl benzimidazolium salt via the condensation reaction with aldehydes followed by the addition reaction of Grignard reagents with quaternary C=N bond was provided.     

Direct Oxidation of β‐Aryl Substituted Aldehydes to α,β‐Unsaturated Aldehydes Promoted by an o‐Anisidine–Pd(OAc)2 Co‐catalyst

An o‐anisidine‐Pd(OAc)₂ catalytic system for the direct co‐catalytic Saegusa oxidation of β‐aryl substituted aldehydes to α,β‐unsaturated aldehydes has been developed. The use of o‐anisidine in place of (S)‐diphenylprolinol made the process more simply and cost‐effective. The process not only features the use of unmodified aldehydes rather than enol silyl ethers, but also gives moderate to good yields (44–72 %).     

Enantioselective Synthesis of Spirocyclohexadienones by NHC‐Catalyzed Formal [3+3] Annulation Reaction of Enals

The enantioselective synthesis of pyrazolone‐fused spirocyclohexadienones was demonstrated by the reaction of α,β‐unsaturated aldehydes with α‐arylidene pyrazolinones under oxidative N‐heterocyclic carbene (NHC)catalysis. This atom‐economic and formal [3+3] annulation reaction proceeds through a vinylogous Michael addition/spiroannulation/dehydrogenation cascade to afford spirocyclic compounds with an all‐carbon quaternary stereocenter in moderate to good yields and excellent ee values. Key to the success of the reaction is the cooperative NHC‐catalyzed generation of chiral α,β‐unsaturated acyl azoliums from enals, and base‐mediated tandem generation of dienolate/enolate intermediates from pyrazolinones.     

Enantioselective Palladium‐Catalyzed Oxidative β,β‐Fluoroarylation of α,β‐Unsaturated Carbonyl Derivatives

The site‐selective palladium‐catalyzed three‐component coupling of deactivated alkenes, arylboronic acids, and N‐fluorobenzenesulfonimide is disclosed herein. The developed methodology establishes a general, modular, and step‐economical approach to the stereoselective β‐fluorination of α,β‐unsaturated systems.     

New Types of Reactivity of α,β‐Unsaturated N,N‐Dimethylhydrazones: Chemodivergent Diastereoselective Synthesis of Functionalized Tetrahydroquinolines and Hexahydropyrrolo[3,2‐b]indoles

The indium trichloride‐catalyzed reaction between aromatic imines and α,β‐unsaturated N,N‐dimethylhydrazones in acetonitrile afforded 1,2,3,4‐tetrahydroquinolines bearing a hydrazone function at C4 through a one‐pot diastereoselective domino process that involves the formation of two C? C bonds and the controlled generation of two stereocenters, one of which is quaternary. This reaction constitutes the first example of an α,β‐unsaturated dimethylhydrazone that behaves as a dienophile in a hetero Diels–Alder reaction. The related reaction between anilines, aromatic aldehydes, and methacrolein dimethylhydrazone in CHCl₃ with BF₃?Et₂O as catalyst afforded polysubstituted 1,2,3,3a,4,8b‐hexahydropyrrolo[3,2‐b]indoles as major products through a fully diastereoselective ABB′C four‐component domino process that generates two cycles, three stereocenters, two C? C bonds, and two C? N bonds in a single operation.     

Remote Sulfonamido Group Enhances Reactivity and Selectivity for Asymmetric Michael Addition of Nitroalkanes to α,β‐Unsaturated Aldehydes

The pyrrolidine–camphorsulfonamide‐based catalyst 1 a catalyzes the enantioselective conjugate addition of nitroalkanes to α,β‐unsaturated aldehydes in the presence of five equivalents of water in iPrOH to give the corresponding chiral Michael adducts in good yields and high enantioselectivities (up to 99 % ee) with a catalyst loading as low as 1 mol %.     

Asymmetric Conjugate Addition of Malonate Esters to α,β‐Unsaturated N‐Sulfonyl Imines: An Expeditious Route to Chiral δ‐Aminoesters and Piperidones

The asymmetric conjugate addition of malonate esters to α,β‐unsaturated N‐sulfonyl imines is catalyzed by PyBOX/La(OTf)₃ complexes in the presence of 4 Å MS. The reaction gives the corresponding E enamines bearing a stereogenic center at the allylic position with good yields and enantiomeric ratios up to 97:3. This reaction provides a synthetic entry to chiral δ‐aminoesters and piperidones.     

Efficient Synthesis of 9H‐Pyrrolo[1,2‐α]Indoles via Michael Addition–Condensation of 3‐Substituted Indoles with α,β‐Unsaturated Ketimines

By employing copper dibromide as a catalyst, Michael addition–condensation of 3‐substituted indoles with α,β‐unsaturated ketimines was realized. The reactions afforded a large variety of 9H‐pyrrolo[1,2‐α ]indoles with good yields (up to 99 %). In addition, a plausible reaction mechanism was proposed.