Catalytic Asymmetric Construction Research Articles

Catalytic Asymmetric Construction of Tertiary Carbon Centers Featuring an α-Difluoromethyl Group with CF2H-CH2-NH2 as the “Building Block”

We report here for the first time a novel difluoromethylated ketimine building block condensed by thioisatin and difluoroethylamine, offering efficient access to a broad range of enantioenriched products bearing difluoroethylamine units (27 examples, ≤98% yield, >99% ee) in the presence of quinine-derived squaramide. Further transformation of the intermediate would generate a variety of versatile functional blocks like α-difluoromethyl amines, β-amino acid, and β-diamine with retention of the enantiomeric excess at the difluoromethyl-bound carbon.

Catalytic Asymmetric Construction of a 1,2,4-Benzotriazepine Skeleton via Diastereo- and Enantioselective Decarboxylative [4 + 3] Cyclization.

We have developed a protocol for palladium-catalyzed decarboxylative [4 + 3] cycloaddition reactions between 4-vinyl benzoxazinanones and azomethine imines to generate moderate to good yields of structurally diverse 1,2,4-benzotriazepines bearing two stereogenic centers with good to excellent stereoselectivities. This protocol not only addresses the challenge of asymmetrically constructing compounds with a 1,2,4-benzotriazepine skeleton but also demonstrates the utility of decarboxylative cycloadditions for the synthesis of enantioenriched polycyclic compounds.

Catalytic asymmetric construction of C-4 alkenyl substituted pyrazolone derivatives bearing multiple stereoelements.

An organocatalytic asymmetric process was reported for the sterically precise construction of C-4 alkenyl substituted pyrazolone derivatives bearing multiple stereoelements. A series of interesting products featuring the union of a centrally chiral pyrazolone moiety and an axially chiral styrene unit were obtained in high yield with excellent diastereoselectivity and enantioselectivity (up to 99% ee, >20 : 1 dr). The process has the characteristics of mild reaction conditions, simple operation and broad substrate scope. The result of gram-scale reaction indicates that the reaction has good practicability.

Frontispiece: Catalytic Asymmetric Construction of Axially Chiral Indole‐Based Frameworks: An Emerging Area

Frontispiece: Catalytic Asymmetric Construction of Axially Chiral Indole‐Based Frameworks: An Emerging Area

Catalytic Asymmetric Construction of Axially Chiral Indole-Based Frameworks: An Emerging Area.

Axially chiral indole-based frameworks have been recognized as a class of important five-membered heterobiaryls and developing catalytic asymmetric approaches for constructing these frameworks in an enantioselective manner is highly desirable. In recent years, synthetic chemists have paid much attention to this research field, and rapid developments have occurred. At this point, a range of axially chiral indole-based scaffolds have been constructed via various catalytic asymmetric reactions based on different strategies. Thus, the catalytic asymmetric construction of axially chiral indole-based frameworks has become an emerging area. This minireview summarizes the rapid advances in this field and gives some insights into future developments, which will help this research field to thrive.

Cover Picture

The cover picture shows that a new class of axially chiral aryl‐alkene‐indole frameworks has been constructed by the strategy of designing 3‐alkynyl‐2‐indolylmethanols as versatile reactants for catalytic asymmetric cyclizations. This approach represents the first catalytic asymmetric construction of axially chiral alkene‐heteroaryl scaffolds, which will add a nascent member to the atropisomeric family. The authors devised the innovative strategy to construct the intriguing axially chiral frameworks, just like Nuwa used the 'five‐colored stone' to mend the sky in the mythology of ancient China. More details are discussed in the article by Shi and Jiao et al. on page 543—552.image

Axially Chiral Aryl‐Alkene‐Indole Framework: A Nascent Member of the Atropisomeric Family and Its Catalytic Asymmetric Construction

Summary of main observation and conclusionA new class of axially chiral aryl‐alkene‐indole frameworks have been designed, and the first catalytic asymmetric construction of such scaffolds has been established by the strategy of organocatalytic (Z/E)‐selective and enantioselective (4+3) cyclization of 3‐alkynyl‐2‐indolylmethanols with 2‐naphthols or phenols (all >95 : 5 E/Z, up to 98% yield, 97% ee). This reaction also represents the first catalytic asymmetric construction of axially chiral alkene‐heteroaryl scaffolds, which will add a new member to the atropisomeric family. This approach has not only confronted the great challenges in constructing axially chiral alkene‐heteroaryl scaffolds but also provided a powerful strategy for the enantioselective construction of axially chiral aryl‐alkene‐indole frameworks.

Catalytic Asymmetric Construction of All-Carbon Quaternary Stereocenters via Coupling of CO2 with 1,3-Dienes

Catalytic Asymmetric Construction of All-Carbon Quaternary Stereocenters via Coupling of CO₂ with 1,3-Dienes

Design and Catalytic Asymmetric Construction of Axially Chiral Aryl-Alkene-Indole Frameworks

Design and Catalytic Asymmetric Construction of Axially Chiral Aryl-Alkene-Indole Frameworks

Catalytic Asymmetric Synthesis of Diketopiperazines by Intramolecular Tsuji-Trost Allylation.

We report the intramolecular Tsuji–Trost reaction of Ugi adducts to give spiro-diketopiperazines in high yield and with high enantioselectivity. This approach allows the catalytic asymmetric construction of a broad range of these medicinally important heterocycles under mild conditions, in two steps from cheap, commercially available starting materials.

The Catalytic Asymmetric Construction of Trifluoromethylated Quaternary Carbon-Containing Thiochromans

Trifluoromethylated chiral quaternary stereogenic carbon center at 2-position of thiochromans has been constructed through organocatalyzed Michael-aldol reaction. With quinine squaramide as catalyst, the reaction of 2-mercaptobenzaldehyde with β-aryl-β-CF3 enones or β-alkyl-β-CF3 enones gave 2-CF3-thiochromans bearing three contiguous stereogenic centers in good to excellent diastereoselectivities, enantioselectivities, and yields.

Frontispiece: Design and Catalytic Asymmetric Construction of Axially Chiral 3,3′‐Bisindole Skeletons

Chiral Bisindole Skeletons. Organocatalytic asymmetric addition reactions of 2-substituted 3,3′-bisindoles and electrophiles create interesting structural skeletons, as described by F. Shi et al. in their Communication on page 3014 ff.

Enantioselective Synthesis of Atropisomers Featuring Pentatomic Heteroaromatics by Pd-Catalyzed C–H Alkynylation

Due to the lower rotational barriers, the catalytic asymmetric construction of atropisomeric species featuring a five-membered ring remains a formidable challenge. Herein, we describe a Pd-catalyzed atroposelective C–H alkynylation to synthesize such atropisomers. A wide range of atropisomers displaying either a stereogenic C–N or C–C bond featuring one or even two five-membered rings were obtained (up to 98% yield and up to >99% ee). Various five-membered heteroarenes, including pyrroles, thiophenes, benzothiophenes, and benzofurans were compatible with this protocol. Notably, this strategy offers the catalytic asymmetric synthesis of axially chiral 3,3′-bisbenzothiophene with good ee (93% ee). Computational studies revealed the key structural elements that differentiate the rotational barriers of benzothiophene and benzofuran moieties.

Catalytic Asymmetric Construction of β-Azido Amides and Esters via Haloazidation.

A catalytic regio- and enantioselective haloazidation reaction with a chiral iron(II) complex catalyst under mild reaction conditions was reported. By this approach, the stereoselective α-halo-β-azido difunctionalization of both α,β-unsaturated amides and α,β-unsaturated esters was achieved. This method enabled the construction of a broad spectrum of valuable functionalized amides and esters, including enantiomerically enriched β-azido amides, aziridine amides, α-amino amide derivatives, β-triazole amides, functionalized peptide derivatives, and α-halo-β-azido-substituted esters.

Ligand-controlled switch in diastereoselectivities: catalytic asymmetric construction of spirocyclic pyrrolidine-azetidine/oxe(thie)tane derivatives.

An efficient catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with four-membered ring-containing exocyclic alkenes has been developed, and either the exo or endo spirocyclic pyrrolidine-azetidine/oxe(thie)tane derivatives were diastereodivergently generated by employing Cu(i)/tBu-Phosferrox and a Cu(i)/N,O-ligand complex, respectively. Notably, various heteroatom-containing (N, O, S) exocyclic alkenes were found to be well-tolerated in this transformation.

Design and Catalytic Asymmetric Construction of Axially Chiral 3,3′‐Bisindole Skeletons

AbstractThe first catalytic asymmetric construction of 3,3′‐bisindole skeletons bearing both axial and central chirality has been established by organocatalytic asymmetric addition reactions of 2‐substituted 3,3′‐bisindoles with 3‐indolylmethanols (up to 98 % yield, all >95:5 d.r., >99 % ee). This reaction also represents the first highly enantioselective construction of axially chiral 3,3′‐bisindole skeletons, and utilizes the strategy of introducing a bulky group to the ortho‐position of prochiral 3,3′‐bisindoles. This reaction not only provides a good example for simultaneously controlling axial and central chirality in one operation, but also serves as a new strategy for catalytic enantioselective construction of axially chiral 3,3′‐bisindole backbones from prochiral substrates.

Design and Catalytic Asymmetric Construction of Axially Chiral 3,3'-Bisindole Skeletons.

The first catalytic asymmetric construction of 3,3'-bisindole skeletons bearing both axial and central chirality has been established by organocatalytic asymmetric addition reactions of 2-substituted 3,3'-bisindoles with 3-indolylmethanols (up to 98 % yield, all >95:5 d.r., >99 % ee). This reaction also represents the first highly enantioselective construction of axially chiral 3,3'-bisindole skeletons, and utilizes the strategy of introducing a bulky group to the ortho-position of prochiral 3,3'-bisindoles. This reaction not only provides a good example for simultaneously controlling axial and central chirality in one operation, but also serves as a new strategy for catalytic enantioselective construction of axially chiral 3,3'-bisindole backbones from prochiral substrates.

Catalytic Asymmetric Construction of Halogenated Stereogenic Carbon Centers by Direct Vinylogous Mannich-Type Reaction.

A catalytic asymmetric vinylogous Mannich-type reaction of γ-halo-α,β-unsaturated N-acylpyrazoles and N-Boc-aldimines was disclosed, which afforded an array of halogenated (F-, Cl-, and Br-) allylic stereogenic carbon centers in high yields with good to high regio-, diastereo-, and enantioselectivities. The brominated product served as a suitable electrophile for common SN2 nucleophilic substitution and copper-mediated SN2' allylic alkylation with metal reagents. The utility of present methodology was demonstrated by the asymmetric synthesis of a common intermediate toward the synthesis of two chiral 2,3-disubstituted piperidine pharmaceuticals.

Enantioselective Construction of Silicon-Stereogenic Silanes by Scandium-Catalyzed Intermolecular Alkene Hydrosilylation.

The catalytic asymmetric construction of silicon-stereogenic silanes is of great interest and significance, but has met with only limited success to date. We herein report the enantioselective hydrosilylation of alkenes with dihydrosilanes by a chiral half-sandwich scandium catalyst, which constitutes an efficient and general route for the synthesis of a wide range of enantioenriched silicon-stereogenic silanes from easily accessible starting materials. This reaction features a broad substrate scope, high yields, and high enantioselectivity. Some of the chiral tertiary silane products were also converted into valuable derivatives, such as chiral silanol, quaternary silane, and benzosilole compounds.

Enantioselective Construction of Silicon‐Stereogenic Silanes by Scandium‐Catalyzed Intermolecular Alkene Hydrosilylation

AbstractThe catalytic asymmetric construction of silicon‐stereogenic silanes is of great interest and significance, but has met with only limited success to date. We herein report the enantioselective hydrosilylation of alkenes with dihydrosilanes by a chiral half‐sandwich scandium catalyst, which constitutes an efficient and general route for the synthesis of a wide range of enantioenriched silicon‐stereogenic silanes from easily accessible starting materials. This reaction features a broad substrate scope, high yields, and high enantioselectivity. Some of the chiral tertiary silane products were also converted into valuable derivatives, such as chiral silanol, quaternary silane, and benzosilole compounds.