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 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.     

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 ).     

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.     

Enantioselective Rhodium‐Catalyzed Allylic Alkylation of β,γ‐Unsaturated α‐Amino Nitriles: Synthetic Homoenolate Equivalents

An enantioselective rhodium‐catalyzed allylic alkylation of β,γ‐unsaturated α‐amino nitriles is described. This protocol provides a novel approach for the construction of β‐stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio‐ and enantioselectivity, in addition to geometrical control. The γ‐stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β‐substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium‐allyl intermediate facilitates the selective formation of the E‐cyanoenamine products, which is critical since the Z‐isomer affords significantly lower enantiocontrol.     

Catalytic Enantioselective Inverse Electron Demand Hetero‐Diels–Alder Reaction with Allylsilanes

The first diastereo‐ and enantioselective inverse electron demand hetero‐Diels–Alder reaction of β,γ‐unsaturated α‐ketoesters with allylsilanes is described. Chiral copper(II) catalysts successfully activate the β,γ‐unsaturated α‐ketoesters and promote the reaction with allylsilanes with excellent enantioselectivities. This process represents a new entry to chiral oxanes.     

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.     

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.     

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.     

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.     

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.     

SpinPhox/Iridium(I)‐Catalyzed Asymmetric Hydrogenation of Cyclic α‐Alkylidene Carbonyl Compounds

Optically active medium‐sized cyclic carbonyl compounds bearing an α‐chiral carbon center are of interest in pharmaceutical sciences and asymmetric synthesis. Herein, SpinPhox/Ir^I catalysts have been demonstrated to be highly enantioselective in the asymmetric hydrogenation of the CC bonds in the exocyclic α,β‐unsaturated cyclic carbonyls, including a broad range of α‐alkylidene lactams, unsaturated cyclic ketones, and lactones. It is noteworthy that the procedure can be successfully used in the asymmetric hydrogenation of the challenging α‐alkylidenelactam substrates with six‐ or seven‐membered rings, thus affording the corresponding optically active carbonyl compounds with an α‐chiral carbon center in generally excellent enantiomeric excesses (up to 98 % ee). Synthetic utility of the protocol has also been demonstrated in the asymmetric synthesis of the anti‐inflammatory drug loxoprofen and its analogue, as well as biologically important ε‐aminocaproic acid derivatives.     

Organocatalytic Enantioselective Vinylogous Pinacol Rearrangement Enabled by Chiral Ion Pairing

An enantioselective pinacol rearrangement of functionalized (E)‐2‐butene‐1,4‐diols was developed. In the presence of a catalytic amount of a chiral BINOL‐derived N‐triflyl phosphoramide, these 1,4‐diols rearranged to β,γ‐unsaturated ketones in excellent yields and enantioselectivities. The formation of a chiral ion pair between the intermediary allylic cation and the chiral phosphoramide anion was postulated to be responsible for the highly efficient chirality transfer. These chiral building blocks were further converted into enantioenriched polysubstituted tetrahydrofuran and tetrahydronaphthalene derivatives.     

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.     

C‐Selective and Diastereoselective Alkyl Addition to β,γ‐Alkynyl‐α‐imino Esters with Zinc(II)ate Complexes

Since umpolung α‐imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α‐amino acid derivatives. An unusual C‐alkyl addition to α‐imino esters using a Grignard reagent (RMgX)‐derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX]⁺ moiety, a nucleophilic [R₃Zn]^? moiety, and 2 [MgX₂]. Therefore, the ionically separated [R₃Zn]^? selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX]⁺. In particular, chiral β,γ‐alkynyl‐α‐imino esters can strongly promote highly regio‐ and diastereoselective C‐alkylation because of structural considerations, and the corresponding optically active α‐quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.     

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.     

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.     

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.     

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.     

Chain Walking of Allylrhodium Species Towards Esters During Rhodium‐Catalyzed Nucleophilic Allylations of Imines

Allylrhodium species derived from δ‐trifluoroboryl β,γ‐unsaturated esters undergo chain walking towards the ester moiety. The resulting allylrhodium species react with imines to give products containing two new stereocenters and a Z‐alkene. By using a chiral diene ligand, products can be obtained with high enantioselectivities, where a pronounced matched/mismatched effect with the chirality of the allyltrifluoroborate is evident.