Search

Chiral carboxylic acids bearing an α-stereogenic center constitute the backbone of many natural products and therapeutic reagents as well as privileged chiral ligands and catalysts. Hence, it is not surprising that a large number of elegant catalytic asymmetric strategies have been developed toward the efficient synthesis of α-chiral carboxylic acids, such as α-hydroxy acids and α-amino acids. In this review, the recent advances on asymmetric synthesis of α-stereogenic free carboxylic acids via organocatalysis and transition metal catalysis are summarized (mainly from 2010 to 2020). The content is organized by reaction type of the carboxyl source involved, including asymmetric functionalization of substituted carboxylic acids, cyclic anhydrides, α-keto acids and substituted α,β-unsaturated acids and so on. We hope that this review will motivate further interest on catalytic asymmetric synthesis of chiral α-substituted carboxylic acids.

An efficient and benign iron-catalyzed room-temperature method was developed for direct sequential C(sp3)–H/N–H annulation to construct pyrroloindole scaffolds. This strategy features cheap and rea...

Asymmetric catalytic synthesis of 2,3-allenamides from hydrogen-bond-stabilized enynamides in the presence of quinine-based bifunctional squaramide organocatalysts is described. This protocol forms a variety of 2,3-allenamides in high yields and excellent stereoselectivities, in which the elaborated introduction of intramolecular H-bonds within the N, N-bidentate amide group constitutes one of the keys to this highly enantioselective transformation. The synthetic practicality of this reaction has been demonstrated by the axis-to-center chirality transfer of allenamides to furnish enantiomerically enriched building blocks.

An efficient and benign iron-catalyzed room-temperature method was developed for direct sequential C(sp

An enantioselective inverse-electron-demand aza-Diels–Alder reaction of saccharin-derived 1-azadienes and azlactones was developed using a phenylalanine-derived bifunctional Bronsted base-squaramide catalyst, which furnished the chiral tricyclic architectures bearing a quaternary amino acid moiety in high yields with moderate to excellent selectivities. A gram-scale synthesis and further elaboration of the product were also conducted to further demonstrate the synthetic utility of the reaction.

A dearomative remote activation strategy for the asymmetric functionalization of benzylic C-H bonds of heteroaryl aldehydes under bifunctional Brønsted base catalysis has been developed. The in situ generated o-QDMs-type dienolate intermediates were efficiently and stereoselectively trapped by nitroolefins through an asymmetric Michael/nitro-aldol cascade reaction. Using this strategy, a wide variety of synthetically significant tetrahydrodibenzothiophene and tetrahydrodibenzofuran derivatives were synthesized in good yields with high enantioselectivities.

This work develops a photocatalysis method for the synthesis of γ-spirolactams through a tandem intramolecular 1,5-HAT reaction-cyclization process. A variety of novel γ-spirolactams are prepared in good to excellent yields with this method. This transformation features mild reaction conditions and exceptional functional group tolerance. Additionally, γ-terpinene is applied to this transformation as a hydrogen atom donor for the first time.

A C1-symmetric N-heterocyclic carbene (NHC)-catalysed activation of isatin-derived enals under oxidative conditions was achieved. The in situ generated α,β-unsaturated acyl azolium species was efficiently trapped by 1,3-dicarbonyl compounds via a Michael addition/spiroannualtion cascade, delivering a series of synthetically important spirooxindole δ-lactones with up to 96% enantioselectivity.

An efficient and convenient method enabling direct amination of unactivated methylene C(sp3)–H bonds to form C–N bonds with azodiformates as amino source is described. This method highlights the emerging strategy of unactivated methylene as versatile functional groups in organic synthesis and provides a strategy to construct functionalized C–N bonds for the synthesis of complex molecules.

A C

The first organocatalytic hetero-Diels–Alder reaction of an in situ generated diene with either α-keto esters or β,γ-unsaturated α-keto esters was successfully developed. The densely functionalized dihydropyranones with a highly congested quaternary center were readily obtained in moderate to good yields with excellent enantioselectivities under mild conditions.

Vinylogous reactivity of olefinic azlactones was realized through the development of a chiral amine-catalyzed highly stereoselective allylic-allylic alkylation with Morita-Baylis-Hillman carbonates. The Lewis base activation of electrophile and Brønsted base activation of nucleophile were efficiently combined, giving access to multifunctional acyclic α-amino acid derivatives in a highly stereocontrolled manner. The synthetic utility of these versatile synthons was further demonstrated by the facile synthesis of protected cyclic quaternary α-amino acids.

The first enantioselective NHC-catalyzed activation of α-aryl substituted α,β-disubstituted unsaturated aldehyde is successfully developed via a highly-active acyl azolium intermediate. The new C1-symmetric biaryl-saturated imidazolium exhibits a superior ability to enable previously unavailable transformation, and the corresponding fully functionalized dihydropyranones are efficiently synthesized in high yields with excellent enantioselectivities.

HOMO-raising noncovalent activation of α-aryl α,β-unsaturated aldehydes using a bifunctional Bronsted base catalyst is achieved. The catalytically generated dienolate intermediate undergoes all-carbon [4+2] cyclizations with nitroolefins, leading to chiral cyclohexenes with four contiguous stereocenters in high yields and with excellent enantioseletivity. Furthermore, the diastereodivergent synthesis of the products is realized by introducing a second steric control to the bifunctional catalyst; 4 isomers out of 16 possible stereoisomers of the products were selectively produced by simple use of two catalysts and their (pseudo)enantiomers. The results presented here provide new insights into the remote activation of the carbonyl functionality as well as the stereodivergent synthesis of complex chiral molecules with multiple stereocenters.

An efficient and convenient copper-catalyzed method has been developed to achieve direct ortho-C–H/N-H annulation to synthesize phenanthridinones with arynes. This method highlights an emerging strategy to transform inert C–H bonds into versatile functional groups in organic synthesis and provides a new way to synthesize phenanthridinone alkaloids efficiently.

A novel bifunctional thiourea catalyzed formal [5 + 1] cycloaddition of oxindoles and ester-linked bisenones was successfully developed. This strategy involves two sequential Michael additions, leading to spirooxindole δ-lactones with three contiguous stereocenters including an all-carbon quaternary center with high diastereo- and enantioselectivites. In addition, a remarkable N-substituent effect was observed on the reactivity and selectivity.

The first organocatalytic hetero-Diels–Alder reaction of an in situ generated diene with either α-keto esters or β,γ-unsaturated α-keto esters was successfully developed. The densely functionalized dihydropyranones with a highly congested quaternary center were readily obtained in moderate to good yields with excellent enantioselectivities under mild conditions.

Vinylogous reactivity of olefinic azlactones was realized through the development of a chiral amine-catalyzed highly stereoselective allylic-allylic alkylation with Morita-Baylis-Hillman carbonates. The Lewis base activation of electrophile and Bronsted base activation of nucleophile were efficiently combined, giving access to multifunctional acyclic α-amino acid derivatives in a highly stereocontrolled manner. The synthetic utility of these versatile synthons was further demonstrated by the facile synthesis of protected cyclic quaternary α-amino acids.

The first enantioselective NHC-catalyzed activation of α-aryl substituted α,β-disubstituted unsaturated aldehyde is successfully developed via a highly-active acyl azolium intermediate. The new C1-symmetric biaryl-saturated imidazolium exhibits a superior ability to enable previously unavailable transformation, and the corresponding fully functionalized dihydropyranones are efficiently synthesized in high yields with excellent enantioselectivities.

An organocatalytic Michael-cyclization cascade of aldehydes with 4-oxa-α,β-unsaturated carboxylic acids has been developed, giving functionalized γ-lactols with high yields and enantioselectivities. The products could be easily transformed into complex trisubstituted γ-lactones and γ-lactams.

By application of the presented protocol a large scope of functionalized pyrroloindolones can be obtained with good yields and enantioselectivities and excellent diastereoselectivity.

An organocatalytic Michael-cyclization cascade of aldehydes with 4-oxa-α,β-unsaturated carboxylic acids has been developed, giving functionalized γ-lactols with high yields and enantioselectivities. The products could be easily transformed into complex trisubstituted γ-lactones and γ-lactams.

A highly enantioselective asymmetric hetero-Diels—Alder reaction is achieved through hydrogen-bond directed γ-addition of olefinic azlactones (II) to isatins (I) in the presence of β-isocupreidine as catalyst.

An asymmetric formal [5 + 1] cyclization of oxindoles and ester-tagged bisenones is developed using a bifunctional thiourea catalyst.

A catalytic asymmetric hetero-Diels–Alder (HDA) reaction has been achieved through hydrogen-bond directed γ-addition of olefinic azlactones to isatins. This methodology provides an efficient access to spirooxindole dihydropyranones in moderate to good yields and with excellent enantioselectivities.

An intramolecular, quaternary carbon center forming hydroacylation of α-substituted acrylates has been discovered. This interesting transformation can be readily incorporated into a multicatalytic tandem process enabled by a combination of nucleophilic tertiary amine and N-heterocyclic carbene catalysis. With no additional stoichiometric base required, this transformation affords the quaternary pyrroloindolones with high levels of enantioselectivity.