Manganese Pentacarbonyl Bromide as Regeneration Catalyst Enabled Biomimetic Asymmetric Reduction.

Using readily available manganese pentacarbonyl bromide as a regeneration catalyst, biomimetic asymmetric reduction of imines including quinoxalinones, benzoxazinones, and benzoxazine has been successfully developed in the presence of transfer catalyst chiral phosphoric acids, providing the chiral amines with high yields and enantioselectivities.

Iridium-Catalyzed Asymmetric Hydrogenation of Heteroaromatics with Multiple N Atoms via Substrate Activation: An Entry to 4,5,6,7-Tetrahydropyrazolo[1,5-]pyrimidine-3-carbonitrile Core of a Potent BTK Inhibitor.

The chiral 4,5,6,7-tetrahydropyrazolo[1,5-]pyrimidine is the key core skeleton of potent Bruton's tyrosine kinase (BTK) inhibitor Zanubrutinib, and the catalyst-controlled asymmetric hydrogenation of planar multinuclear pyrimidine heteroarenes with multiple N atoms could provide an efficient route toward its synthesis. Owing to the strong aromaticity and poisoning effect toward chiral transition metal catalyst, asymmetric hydrogenation of pyrazolo[1,5-]pyrimidines with multiple nitrogen atoms is still a challenge for synthesizing the chiral 4,5,6,7-tetrahydropyrazolo[1,5-]-pyrimidine. Herein, an efficient iridium-catalyzed asymmetric hydrogenation of pyrazolo[1,5-]pyrimidines has been developed using substrate activation strategy, with up to 99% ee.

Biomimetic Asymmetric Reduction Based on the Regenerable Coenzyme NAD(P)H Models.

ConspectusIn nature, the coenzyme NAD(P)H is utilized for the transfer of hydrogen and electrons in biocatalytic reduction, which involves the process of recycling, coenzyme usage, and reduction. Inspired by the biological system, a series of nonregenerable achiral and chiral NAD(P)H models were synthesized and employed. However, this approach faced intractable limitations, such as the need for an equivalent amount of mimics, accompanied by the production of byproducts, which resulted in poor atom economy and difficult separation of products.

Palladium-Catalyzed Asymmetric Hydrogenation of Unprotected 3-Substituted Indoles.

A palladium-catalyzed asymmetric hydrogenation of unprotected 3-substituted indoles was developed, providing a series of 3-substituted indolines in excellent yields with ≤94.4:5.6 er.

Rhodium-Catalyzed Asymmetric Hydrogenation of All-Carbon Aromatic Rings.

Compared with heteroarenes, homogeneous asymmetric hydrogenation of all-carbon aromatic rings is a longstanding challenge in organic synthesis due to the strong aromaticity and difficult enantioselective control. Herein, we report the rhodium/diphosphine-catalyzed asymmetric hydrogenation of all-carbon aromatic rings, affording a series of axially chiral cyclic compounds with high enantioselectivity through desymmetrization or kinetic resolution. In addition, the central-chiral cyclic compounds were also obtained by asymmetric hydrogenation of phenanthrenes bearing a directing group.

Enantioselective Synthesis of 2-Functionalized Tetrahydroquinolines through Biomimetic Reduction.

Biomimetic asymmetric reduction of 2-functionalized quinolines has been successfully developed with the chiral and regenerable NAD(P)H model CYNAM in the presence of transfer catalyst simple achiral phosphoric acids, providing the chiral 2-functionalized tetrahydroquinolines with up to 99% ee. Using this methodology as a key step, a chiral and potent opioid analgesic containing a 1,2,3,4-tetrahydroquinoline motif was synthesized with high overall yield.

α-Keto Acids as Triggers and Partners for the Synthesis of Quinazolinones, Quinoxalinones, Benzooxazinones, and Benzothiazoles in Water.

A general and efficient method for the synthesis of quinazolinones, quinoxalinones, benzooxazinones, and benzothiazoles from the reactions of α-keto acids with 2-aminobenzamides, benzene-1,2-diamines, 2-aminophenols, and 2-aminobenzenethiols, respectively, is described. The reactions were conducted under catalyst-free conditions, using water as the sole solvent with no additive required, and successfully applied to the synthesis of sildenafil. More importantly, these reactions can be conducted on a mass scale, and the products can be easily purified through filtration and washing with ethanol (or crystallized).

Chiral Phosphoric Acid-Catalyzed Pictet-Spengler Reactions for Synthesis of 5',11'-Dihydrospiro[indoline-3,6'-indolo[3,2-]qui-nolin]-2-ones Containing Quaternary Stereocenters.

Chiral phosphoric acid-catalyzed Pictet-Spengler reactions of 2-(1-indolyl)aniline derivatives and isatins by the condensation/cyclization process have been realized. A series of enantioenriched 5',11'-dihydrospiro[indoline-3,6'-indolo[3,2-]quinolin]-2-ones bearing quaternary stereogenic centers were obtained with excellent yields and up to >99% ee. This protocol was suitable for the Pictet-Spengler reactions of 2-(1-benzyl-5-methyl-1-pyrrol-2-yl)aniline, and a variety of 1',5'-dihydro-spiro[indoline-3,4'-pyrrolo[3,2-]quinolin]-2-ones could also be obtained in good yields and up to 88% ee.

Biomimetic asymmetric reduction of benzoxazinones and quinoxalinones using ureas as transfer catalysts.

Using ureas as transfer catalysts through hydrogen bonding activation, biomimetic asymmetric reduction of benzoxazinones and quinoxalinones with chiral and regenerable NAD(P)H models was described, giving chiral dihydrobenzoxazinones and dihydroquinoxalinones with high yields and excellent enantioselectivities. A key dihydroquinoxalinone intermediate of a BRD4 inhibitor was synthesized using biomimetic asymmetric reduction.

Palladium-catalyzed asymmetric hydrogenation of 2-aryl cyclic ketones for the synthesis of trans cycloalkanols through dynamic kinetic resolution under acidic conditions.

The first efficient palladium-catalyzed asymmetric hydrogenation of 2-aryl cyclic ketones has been described through dynamic kinetic resolution under acidic conditions, providing a facile access to chiral trans cycloalkanol derivatives with excellent enantioselectivities.

Synthesis of Chiral β-Fluoroalkyl β-Amino Acid Derivatives via Palladium-Catalyzed Hydrogenation.

An enantioselective palladium-catalyzed hydrogenation of β-fluoroalkyl β-amino acrylic acid derivatives has been successfully developed, providing the corresponding chiral β-fluoroalkyl β-amino acid derivatives in good yields with excellent enantioselectivities. In addition, chiral γ-fluoroalkyl γ-amino alcohol could be synthesized by a simple reduction of the corresponding hydrogenated product. The mechanism of the reaction was explored by deuterium-labeling experiments.

Chiral Phosphoric Acid-Catalyzed Synthesis of Fluorinated 5,6-Dihydroindolo[1,2- c]quinazolines with Quaternary Stereocenters.

A chiral phosphoric acid-catalyzed enantioselective synthesis of fluorinated 5,6-dihydroindolo[1,2- c]quinazolines has been developed by a condensation/amine addition cascade from 2-(1 H-indolyl)anilines and fluorinated ketones, giving the fluorinated aminals with quaternary stereogenic centers with excellent yields and up to 97% ee. A series of the fluorinated aromatic, aliphatic ketones, and ethyl trifluoropyruvate are suitable.

Catalytic Asymmetric Synthesis of Isoindolinones.

As important reactive species, isoindolinones represent a cluster of valuable building blocks for the construction of natural-product-like compounds. In particular, chiral isoindolinones are the key structural feature of naturally occurring bioactive molecules. During the past decade, great advances have been made in the asymmetric synthesis of isoindolinone skeleton compounds.

Catalytic Biomimetic Asymmetric Reduction of Alkenes and Imines Enabled by Chiral and Regenerable NAD(P)H Models.

The development of biomimetic chemistry based on the NAD(P)H with hydrogen gas as terminal reductant is a long-standing challenge. Through rational design of the chiral and regenerable NAD(P)H analogues based on planar-chiral ferrocene, a biomimetic asymmetric reduction has been realized using bench-stable Lewis acids as transfer catalysts. A broad set of alkenes and imines could be reduced with up to 98 % yield and 98 % ee, likely enabled by enzyme-like cooperative bifunctional activation.

Iridium-Catalyzed Asymmetric Hydrogenation of 4,6-Disubstituted 2-Hydroxypyrimidines.

An efficient iridium-catalyzed hydrogenation of 4,6-disubstituted 2-hydroxypyrimidines has been achieved, giving chiral cyclic ureas with excellent diastereoselectivities and up to 96% ee of enantioselectivities. In the presence of the in situ generated hydrogen halide, the equilibrium of the lactame-lactime tautomerism of 2-hydroxypyrimidine is more toward the oxo form with lower aromaticity, which effectively improves the reactivity to facilitate hydrogenation. Moreover, the cyclic ureas could be readily converted into chiral 1,3-diamine derivatives without loss of optical purity.

Organocatalytic Asymmetric Reduction of Fluorinated Alkynyl Ketimines.

Highly chemoselective catalytic transfer hydrogenation of fluorinated alkynyl ketimines has been achieved by employing chiral phosphoric acid as a catalyst with benzothiazoline as a hydride source, providing the corresponding chiral fluorinated propargylamines in good yields and excellent enantioselectivities. In addition, iodocyclization of fluorinated propargylamine affords chiral 3-iodo-2-(trifluoromethyl)-1,2-dihydroquinoline, which can be easily converted to 2-(trifluoromethyl)- 1,2-dihydroquinoline derivatives with the selective COX-2 inhibitory activity.

Facile Synthesis of Chiral Cyclic Ureas through Hydrogenation of 2-Hydroxypyrimidine/Pyrimidin-2(1H)-one Tautomers.

A facile access to optically active cyclic ureas was developed through palladium-catalyzed asymmetric hydrogenation of pyrimidines containing tautomeric hydroxy group with up to 99 % ee. Mechanistic studies indicated that reaction pathway proceed through hydrogenation of C=N of the oxo tautomer pyrimidin-2(1H)-one, acid-catalyzed isomerization of enamine-imine, and hydrogenation of imine pathway. In addition, the chiral cyclic ureas are readily converted into useful chiral 1,3-diamine and thiourea derivatives without loss of optical purity.

Asymmetric Hydrogenation of Isoquinolines and Pyridines Using Hydrogen Halide Generated in Situ as Activator.

By employing halogenide trichloroisocyanuric acid as a traceless activation reagent, a general iridium-catalyzed asymmetric hydrogenation of isoquinolines and pyridines is developed with up to 99% ee. This method avoids tedious steps of installation and removal of the activating groups. The mechanism studies indicated that hydrogen halide generated in situ acted as an activator of isoquinolines and pyridines.

Synthesis of chiral sultams via palladium-catalyzed intramolecular asymmetric reductive amination.

A novel palladium-catalyzed intramolecular reductive amination of ketones with weakly nucleophilic sulfonamides has been developed in the presence of a Brønsted acid, giving a wide range of chiral γ-, δ-, and ε-sultams in high yields and up to 99% of enantioselectivity.

Synthesis of Chiral Fluorinated Propargylamines via Chemoselective Biomimetic Hydrogenation.

A highly enantioselective synthesis of chiral fluorinated propargylamines was developed through phosphoric acid and ruthenium-catalyzed chemoselective biomimetic hydrogenation of the carbon-nitrogen double bond of fluorinated alkynyl ketimines in the presence of a carbon-carbon triple bond. This reaction features high chemoselectivity and slow background reaction. In addition, selective transformations of the chiral fluorinated propargylamines were also reported.

Kinetic Resolution of Axially Chiral 5- or 8-Substituted Quinolines via Asymmetric Transfer Hydrogenation.

An efficient kinetic resolution of axially chiral 5- or 8-substituted quinoline derivatives was developed through asymmetric transfer hydrogenation of heteroaromatic moiety, simultaneously obtaining two kinds of axially chiral skeletons with up to 209 of selectivity factor. This represents the first successful application of asymmetric transfer hydrogenation of heteroaromatics in kinetic resolution of axially chiral biaryls.

Synthesis of Chiral Fluorinated Hydrazines via Pd-Catalyzed Asymmetric Hydrogenation.

An enantioselective hydrogenation of fluorinated hydrazones has been achieved by employing [Pd(R)-DTBM-SegPhos(OCOCF3)2] as the catalyst, providing a general and convenient method toward chiral fluorinated hydrazines. A broad substrate scope including β-aryl-, γ-aryl-, and alkyl-chain-substituted hydrazones worked efficiently in high yields and up to 94% of enantioselectivity. The reductive amination between trifluoromethyl-substituted ketones and benzohydrazides could also proceed smoothly.

Enantioselective Synthesis of α-Amino Phosphonates via Pd-Catalyzed Asymmetric Hydrogenation.

A highly enantioselective palladium-catalyzed hydrogenation of a series of linear and cyclic α-iminophosphonates has been achieved, providing efficient access to optically active α-aminophosphonates with up to 99% ee.

C-H Oxidation/Michael Addition/Cyclization Cascade for Enantioselective Synthesis of Functionalized 2-Amino-4H-chromenes.

A streamlined method for the enantioselective synthesis of 2-amino-4H-chromenes from readily available 2-alkyl-substituted phenols and active methylene compounds bearing a cyano group with up to 97% ee is presented. This reaction is a cascade procedure including manganese dioxide mediated C-H oxidation for the generation of o-quinone methides and bifunctional squaramide-catalyzed Michael addition/cyclization.