Nickel‐Promoted Highly Regioselective Carboxylation of Aryl Ynol Ether and Its Application to the Synthesis of Chiral β‐Aryloxypropionic Acid Derivatives

Nickel(0)‐promoted carboxylation of aryl ynol ether proceeded in a highly regioselective manner to produce α‐substituted‐β‐aryloxyacrylic acid derivatives. The α‐substituted‐β‐aryloxyacrylic acids were transformed into the corresponding β‐aryloxypropionic acid derivative as an optically active form via rhodium‐catalyzed asymmetric hydrogenation.     

Nickel‐Catalyzed Direct Carboxylation of Olefins with CO2: One‐Pot Synthesis of α,β‐Unsaturated Carboxylic Acid Salts

The nickel‐catalyzed direct carboxylation of alkenes with the cheap and abundantly available C₁ building block carbon dioxide (CO₂) in the presence of a base has been achieved. The one‐pot reaction allows for the direct and selective synthesis of a wide range of α,β‐unsaturated carboxylates (TON>100, TOF up to 6 h^?1, TON=turnover number, TOF=turnover frequency). Thus, it is possible, in one step, to synthesize sodium acrylate from ethylene, CO₂, and a sodium salt. Acrylates are industrially important products, the synthesis of which has hitherto required multiple steps.     

Highly Efficient Synthesis of Heterocyclic and Alicyclic β2‐Amino Acid Derivatives by Catalytic Asymmetric Hydrogenation

A valuable class of new heterocyclic and alicyclic prochiral α‐aminomethylacrylates has been conveniently synthesized through a three‐step transformation involving a Baylis–Hillman reaction, O‐acetylation, and a subsequent allylic amination. The corresponding novel β²‐amino acid derivatives were prepared with excellent enantioselectivities and high yields by catalytic asymmetric hydrogenation using the catalyst rhodium(Et‐Duphos) (Et‐Duphos=2′,5′,2′′,5′′‐tetraethyl‐1,2‐bis(phospholanyl)benzene)) under mild reaction conditions (up to 99 % ee and S/C=1000). The influence of the substrate on the enantioselectivity and reactivity is investigated, and the most suitable substrate configuration for the highly efficient enantioselective hydrogenation of β‐substituted α‐aminomethylacrylates under the Rh–Duphos system is reported. The current protocol provides a very practical, facile, and scalable method for the preparation of heterocyclic and alicyclic β²‐amino acids and their derivatives.     

Enantioselective Synthesis of Chiral Cyclopent‐2‐enones by Nickel‐Catalyzed Desymmetrization of Malonate Esters

The enantioselective synthesis of highly functionalized chiral cyclopent‐2‐enones by the reaction of alkynyl malonate esters with arylboronic acids is described. These desymmetrizing arylative cyclizations are catalyzed by a chiral phosphinooxazoline/nickel complex, and cyclization is enabled by the reversible E/Z isomerization of alkenylnickel species. The general methodology is also applicable to the synthesis of 1,6‐dihydropyridin‐3(2H)‐ones.     

ZnCl2‐Promoted Asymmetric Hydrogenation of β‐Secondary‐Amino Ketones Catalyzed by a P‐Chiral Rh–Bisphosphine Complex

A new catalytic system has been developed for the asymmetric hydrogenation of β‐secondary‐amino ketones using a highly efficient P‐chiral bisphosphine–rhodium complex in combination with ZnCl₂ as the activator of the catalyst. The chiral γ‐secondary‐amino alcohols were obtained in 90–94 % yields, 90–99 % enantioselectivities, and with high turnover numbers (up to 2000 S/C; S/C=substrate/catalyst ratio). A mechanism for the promoting effect of ZnCl₂ on the catalytic system has been proposed on the basis of NMR spectroscopy and HRMS studies. This method was successfully applied to the asymmetric syntheses of three important drugs, (S)‐duloxetine, (R)‐fluoxetine, and (R)‐atomoxetine, in high yields and with excellent enantioselectivities.     

Efficient Synthesis of β‐Hydroxy‐α‐Amino Acid Derivatives via Direct Catalytic Asymmetric Aldol Reaction of α‐Isothiocyanato Imide with Aldehydes

An easily available and efficient chiral N,N′‐dioxide–nickel(II) complex catalyst has been developed for the direct catalytic asymmetric aldol reaction of α‐isothiocyanato imide with aldehydes which produces the products in morderate to high yields (up to 98 %) with excellent diastereo‐ (up to >99:1 d.r.) and enantioselectivities (up to >99 % ee). A variety of aromatic, heteroaromatic, α,β‐unsaturated, and aliphatic aldehydes were found to be suitable substrates in the presence of 2.5 mol % L ‐proline‐derived N,N′‐dioxide L5 –nickel(II) complex. This process was air‐tolerant and easily manipulated with available reagents. Based on experimental investigations, a possible transition state has been proposed to explain the origin of reactivity and asymmetric inductivity.     

Synthesis of β‐Substituted γ‐Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis

β‐Substituted chiral γ‐aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of β‐substituted γ‐aminobutyric acid derivatives through visible‐light‐induced photocatalyst‐free asymmetric radical conjugate additions is reported. Various β‐substituted γ‐aminobutyric acid analogues, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (42–89 %) and with excellent enantioselectivity (90–97 % ee). Synthetically valuable applications were demonstrated by providing straightforward synthetic access to the pharmaceuticals or related bioactive compounds (S)‐pregabalin, (R)‐baclofen, (R)‐rolipram, and (S)‐nebracetam.     

Expedient Synthesis of Chiral α‐Amino Acids through Nickel‐Catalyzed Reductive Cross‐Coupling

A novel method for the synthesis of non‐natural L ‐ and D ‐amino acids by a Ni‐catalyzed reductive cross‐coupling reaction is described. This strategy enables the racemization‐free cross‐coupling of serine/homoserine‐ derived iodides with aryl/acyl/alkyl halides. It provides convenient access to varieties of enantiopure and functionalized amino acids, which are important building blocks in bioactive compounds and pharmaceuticals.