Asymmetric Diels–Alder and Inverse‐Electron‐Demand Hetero‐Diels–Alder Reactions of β,γ‐Unsaturated α‐Ketoesters with Cyclopentadiene Catalyzed by N,N′‐Dioxide Copper(II) Complex

Highly enantioselective Diels–Alder (DA) and inverse‐electron‐demand hetero‐Diels–Alder (HDA) reactions of β,γ‐unsaturated α‐ketoesters with cyclopentadiene catalyzed by chiral N,N′‐dioxide–Cu(OTf)₂ (Tf=triflate) complexes have been developed. Quantitative conversion of β,γ‐unsaturated α‐ketoesters and excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to >99 % ee) were observed for a broad range of substrates. Both aromatic and aliphatic β,γ‐unsaturated α‐ketoesters were found to be suitable substrates for the reactions. Moreover, the chemoselectivity of the DA and HDA adducts were improved by regulating the reaction temperature. Good to high chemoselectivity (up to 94 %) of the DA adducts were obtained at room temperature, and moderate chemoselectivity (up to 65 %) of the HDA adducts were achieved at low temperature. The reaction also featured mild reaction conditions, a simple procedure, and remarkably low catalyst loading (0.1–1.5 mol %). A strong positive nonlinear effect was observed.     

Bimetallic Catalytic Asymmetric Tandem Reaction of β‐Alkynyl Ketones to Synthesize 6,6‐Spiroketals

The enantioselective tandem reaction of β,γ‐unsaturated α‐ketoesters with β‐alkynyl ketones was realized by a bimetallic catalytic system of achiral Au^ΙΙΙ salt and chiral N,N′‐dioxide‐Mg^ΙΙ complex. The cycloisomerization of β‐alkynyl ketone and asymmetric intermolecular [4+2] cycloaddition with β,γ‐unsaturated α‐ketoesters subsequently occurred, providing an efficient and straightforward access to chiral multifunctional 6,6‐spiroketals in up to 97 % yield, 94 % ee and >19/1 d.r. Besides, a catalytic cycle was proposed based on the results of control experiments.     

Asymmetric Synthesis of Oxa‐Bridged Oxazocines through a Catalytic RhII/ZnII Relay [4+3] Cycloaddition Reaction

Oxa‐bridged oxazocines bearing three chiral carbon centers were synthesized efficiently through a bimetallic catalytic asymmetric tandem reaction of β,γ‐unsaturated α‐ketoesters with diazoimides. The process contained a rhodium‐promoted in situ generation of isomünchnone from diazoimide decomposition, and a [4+3]‐cycloaddition of β,γ‐unsaturated α‐ketoester catalyzed by a chiral N,N′‐dioxide‐Zn^II complex. Ligand‐accelerated catalysis was found, and a possible transition‐state model was proposed to explain the origin of stereoselectivity.     

Stereoselective Synthesis of Highly Functionalized Nitrocyclopropanes through the Organocatalyic Michael‐Addition‐Initiated Cyclization of Bromonitromethane and β,γ‐Unsaturated α‐Ketoesters

A highly diastereo‐ and enantioselective cyclopropanation of β,γ‐unsaturated α‐ketoesters with bromonitromethane has been successfully developed through a domino Michael‐addition/intramolecular‐alkylation strategy. Acceptable yields (up to 89 %) and enantioselectivities (up to 96 % ee) have been obtained.     

Enantioselective Copper(I/II)‐Catalyzed Conjugate Addition of Nitro Esters to β,γ‐Unsaturated α‐Ketoesters

A highly enantioselective Michael addition of nitroacetates to β,γ‐unsaturated α‐ketoesters was developed by using chiral copper catalysts. The Michael addition products can be obtained in high yields with up to 99 % ee. With these densely functionalized products, the chiral cyclic nitrones, which are important synthetic intermediates, can be obtained in one step.     

Cy‐SaBOX/Copper(II)‐Catalyzed Highly Diastereo‐ and Enantioselective Synthesis of Bicyclic N,O Acetals

Facile and effective access for the asymmetric construction of the useful and important skeleton of the bicyclic N,O‐acetals is described. Cu^II/SaBOX could catalyze the reaction of β,γ‐unsaturated α‐ketoesters with cyclic enamines efficiently, thus affording the desired products in excellent yields with excellent stereoselectivities (21 examples; up to 99 % yields; up to >95:5 d.r.; and 95–99 % ee). This reaction can be well performed on gram scale, even with only 1 mol % catalyst loading. The single‐crystal structures of the copper complexes lead to a good understanding of the stereo‐synergistic effects of the sidearm.     

Asymmetric Catalytic Formal 1,4‐Allylation of β,γ‐Unsaturated α‐Ketoesters: Allylboration/Oxy‐Cope Rearrangement

A highly enantioselective formal conjugate allyl addition of allylboronic acids to β,γ‐unsaturated α‐ketoesters has been realized by employing a chiral Ni^II/N,N′‐dioxide complex as the catalyst. This transformation proceeds by an allylboration/oxy‐Cope rearrangement sequence, providing a facile and rapid route to γ‐allyl‐α‐ketoesters with moderate to good yields (65–92 %) and excellent ee values (90–99 % ee). The isolation of 1,2‐allylboration products provided insight into the mechanism of the subsequent oxy‐Cope rearrangement reaction: substrate‐induced chiral transfer and a chiral Lewis acid accelerated process. Based on the experimental investigations and DFT calculations, a rare boatlike transition‐state model is proposed as the origin of high chirality transfer during the oxy‐Cope rearrangement.     

N,N′‐Dioxide/Nickel(II)‐Catalyzed Asymmetric Inverse‐Electron‐Demand Hetero‐Diels–Alder Reaction of β,γ‐Unsaturated α‐Ketoesters with Enecarbamates

N,N′‐Dioxide/nickel(II) complexes have been developed to catalyze the inverse‐electron‐demand hetero‐Diels–Alder reaction of β,γ‐unsaturated α‐ketoesters with acyclic enecarbamates. After detailed screening of the reaction parameters, mild optimized reaction conditions were established, affording 3,4‐dihydro‐2H‐pyranamines in up to 99 % yield, 99 % ee and more than 95:5 d.r. The catalytic system was also efficient for β‐substituted acyclic enecarbamates, affording more challenging 2,3,4‐trisubstituted 3,4‐dihydro‐2H‐pyranamine with three contiguous stereogenic centers in excellent yields, diastereoselectivities, and enantioselectivities. The reaction could be scaled up to a gram scale with no deterioration of either enantioselectivity or yield. Based on these experiments and on previous reports, a possible transition state was proposed.     

Controlling the α/γ‐Reactivity of Vinylogous Ketone Enolates in Organocatalytic Enantioselective Michael Reactions

The first regio‐, diastereo‐, and enantioselective direct Michael reaction of β,γ‐unsaturated ketones with nitroolefins is enabled by Brønsted base/hydrogen‐bonding bifunctional catalysis. A squaramide‐substituted tertiary amine catalyzes the reaction of a broad range of β,γ‐unsaturated ketones to proceed at the α‐site exclusively, giving rise to adducts with two consecutive tertiary carbon stereocenters in diastereomeric ratios of up to >20:1 and enantioselectivities generally in the 90–98 % ee range.     

Catalytic Regio‐ and Enantioselective [4+2] Annulation Reactions of Non‐activated Allenes by a Chiral Cationic Indium Complex

Regio‐ and enantioselective [4+2] annulation between β,γ‐unsaturated α‐keto esters and non‐activated allenes was achieved by using a chiral cationic indium(III)/phosphate catalyst. The reaction affords the corresponding C3‐selective dihydropyrans in good yields and with high enantioselectivity (up to 99 % ee ).     

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.     

Rhodium‐Catalyzed Asymmetric Arylation of β,γ‐Unsaturated α‐Ketoamides for the Construction of Nonracemic γ,γ‐Diarylcarbonyl Compounds

A highly regio‐ and enantioselective rhodium‐catalyzed 1,4‐addition of arylboronic acids to β,γ‐unsaturated α‐ketoamides using a simple new chiral sulfinylphosphine ligand is described. This transformation provides an attractive approach to construct chiral nonracemic γ,γ‐diarylsubstituted carbonyl compounds, as exemplified in the concise syntheses of sertraline and tetrahydroquinoline‐2‐carboxylamide.     

A Facile Approach to Optically Active Hydroquinoline‐2‐carboxylates by a One‐Pot Asymmetric Michael/Transamination/Cyclization Process

An efficient one‐pot synthesis of optically active hydroquinoline‐2‐carboxylates from 1,3‐cyclohexanediones, β,γ‐unsaturated α‐keto ester, and benzylamine in the presence of a chiral base catalyst and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) with good diastereoselectivity and high enantioselectivity is described. The reaction proceeds by a sequential asymmetric Michael/transamination/cyclization process.     

Efficient synthesis of 3‐arylaminopyrroline‐2‐ones by the tandem reaction of anilines and β,γ‐unsaturated α‐ketoesters

A concise and efficient synthetic approach to 3‐arylaminopyrroline‐2‐ones from anilines and β,γ‐unsaturated α‐ketoesters in boiling dichloromethane has been developed. This protocol possesses many advantages such as short reaction time, high isolated yields, and expanding substrate scopes. According to the isolated intermediates and controlled reactions, the reaction was tentatively proposed to involve the Michael addition/condensation and subsequent intramolecular cyclization. The structures of the title compounds were unambiguously confirmed by various spectral data such as X‐ray crystallographic analysis.     

PPh3⋅HBr‐DMSO Mediated Expedient Synthesis of γ‐Substituted β,γ‐Unsaturated α‐Ketomethylthioesters and α‐Bromo Enals: Application to the Synthesis of 2‐Methylsulfanyl‐3(2 H)‐furanones

An efficient chemoselective general procedure for the synthesis of γ‐substituted β,γ‐unsaturated α‐ketomethylthioesters from α,β‐unsaturated ketones has been achieved through an unprecedented PPh₃?HBr‐DMSO mediated oxidative bromination and Kornblum oxidation sequence. The newly developed reagent system serves admirably for the synthesis of α‐bromoenals from enals. Furthermore, AuCl₃‐catalyzed efficient access to 3(2H)‐furanones from the above intermediates under extremely mild conditions are described.     

Alkenylation of C(sp3)−H Bonds by Zincation/Copper‐Catalyzed Cross‐Coupling with Iodonium Salts

α‐Vinylation of phosphonates, phosphine oxides, sulfones, sulfonamides, and sulfoxides has been achieved by selective C?H zincation and copper‐catalyzed C(sp³)?C(sp²) cross‐coupling reaction using vinylphenyliodonium salts. The vinylation transformation proceeds in high efficiency and stereospecificity under mild reaction conditions. This zincative cross‐coupling reaction represents a general alkenylation strategy, which is also applicable for α‐alkenylation of esters, amides, and nitriles in the synthesis of β,γ‐unsaturated carbonyl compounds.     

Umpolung Reactions of α‐Imino Esters: Useful Methods for the Preparation of α‐Amino Acid Frameworks

This paper summarizes our recent efforts toward the development of tandem reactions utilizing umpolung reactions of α‐imino esters. A highly diastereoselective tandem N‐alkylation–Mannich reaction of α‐imino esters was developed. A tandem N‐alkylation–addition reaction of α‐imino esters derived from ethyl glyoxylate with various aldehydes proceeded to give 1,2‐amino alcohols. The same reaction also proceeded efficiently using a novel flow system comprising two connected microreactors. Novel syntheses of α‐quaternary alkynyl amino esters and allenoates were developed through the use of umpolung N‐addition to β,γ‐alkynyl α‐imino esters, followed by regioselective acylation. In addition, a highly regioselective tandem N‐alkylation–vinylogous aldol reaction of β,γ‐alkenyl α‐imino esters was discovered. N‐Alkylation of α‐iminophosphonates followed by a Horner–Wadsworth–Emmons reaction with aldehydes occurred to afford enamines, which can be used in a four‐component coupling reaction with methyl vinyl ketone. α‐N‐Acyloxyimino esters served as highly efficient substrates for the N,N,C‐trialkylation reaction to introduce various nucleophiles at the imino nitrogen and carbon atoms.     

A New Strategy for Enantioselective Construction of Multisubstituted Five‐Membered Oxygen Heterocycles via a Domino Michael/Hemiketalization Reaction

A new highly enantioselective domino Michael/hemiketalization reaction of α‐hydroxyacetophenone with β,γ‐unsaturated α‐keto esters for the synthesis of 2,2,4,5‐tetrasubstituted chiral tetrahydrofurans is reported. With 2 mol % intramolecular dinuclear zinc‐AzePhenol complex prepared in situ from the reaction of multidentate semi‐azacrown ether ligand with ZnEt₂, the corresponding anti‐multisubstituted tetrahydrofuran products were obtained in up to 90 % yields, and 98 % enantiomeric excess (ee) at 0 °C for 45 min. Moreover, the products were easily converted to 2,3,5‐trisubstituted 2,3‐dihydrofurans without any loss in optical activity.     

Efficient Access to All‐Carbon Quaternary and Tertiary α‐Functionalized Homoallyl‐type Aldehydes from Ketones

β,γ‐Unsaturated aldehydes with all‐carbon quaternary or tertiary α‐centers were rapidly assembled from ketones through a unique synthetic operation consisting of 1) C₁ homologation, 2) Lewis acid mediated epoxide–aldehyde isomerization, and 3) electrophilic trapping. The synthetic equivalence of a vinyl oxirane and a β,γ‐unsaturated aldehyde is the key concept of this previously undisclosed tactic. Mechanistic studies and labeling experiments suggest that an aldehyde enolate is a crucial intermediate. The homologating carbenoid formation plays a critical role in determining the chemoselectivity.     

A Mild Isomerization Reaction for β,γ‐Unsaturated Ketone to α,β‐Unsaturated Ketone

A series of β,γ‐unsaturated ketones were isomerized to their corresponding α,β‐unsaturated ketones by the introduction of DABCO in iPrOH at room temperature. The endo‐cyclic double bond (β,γ‐position) on ketone was rearranged to exo‐cyclic double bond (α,β‐position) under the reaction conditions.