Highly efficient synthesis of chiral beta-amino acid derivatives via asymmetric hydrogenation

The Rh-TangPhos complex is an efficient hydrogenation catalyst for making chiral beta-amino acid derivatives. With the Rh-TangPhos system, high enantioselectivities (up to 99.6%) and turnover numbers have been obtained in the hydrogenation of E/Z isomeric mixtures of both beta-alkyl and beta-aryl beta-(acylamino)acrylates. [reaction: see text]     

Highly efficient synthesis of beta-amino acid derivatives via asymmetric hydrogenation of unprotected enamines

A direct asymmetric hydrogenation of unprotected enamino esters and amides is described. Catalyzed by Rh complexes with Josiphos-type chiral ligands, this method gives beta-amino esters and amides in high yield and high ee (93-97% ee). No acyl protection/deprotection is required.     

4,4'-Disubstituted BINAPs for highly enantioselective Ru-catalyzed asymmetric hydrogenation of ketones

A family of tunable precatalysts Ru(4,4'-BINAP)(chiral diamine)Cl2 was synthesized and used for highly enantioselective hydrogenation of aromatic ketones. This result differs from previous chiral diphosphines that rely on the bis(xylyl)phosphino groups to control enantioselectivity. An X-ray structural study reveals that the bulky substituents on the 4,4'-positions of BINAP can effectively create a suitable chiral pocket in the transition state and thus provide a new mechanism for the enantiocontrol in such a remarkable asymmetric catalytic process.     

Synthesis of enantiopure β2-homoalanine derivatives via rhodium catalyzed asymmetric hydrogenation

The stereoselective synthesis of chiral β²-homoalanine derivatives with 99% ee by the Rh-catalyzed enantioselective hydrogenation of prochiral 2-aminomethyl acrylates is described. The subsequent transformation to chiral 3-amino-2-methylpropanols is also demonstrated.     

Catalytic stereoselective synthesis of α-Amino phosphonic acid derivatives by asymmetric hydrogenation

The phosphonate analogue of α-N-benzoyl protected phenylalanine methylester has been prepared by catalytic synthesis. Commonly used Rh-complexes has been applied in asymmetric hydrogenation to check their usefulness in the standard reaction.     

A novel chiral phosphinediamine ligand and asymmetric hydrogenation of acrylic acid derivatives

A novel chiral phosphinediamine ligand (PN₂) was prepared from (S)-1-phenylethylamine and dichloroisopropylphosphine. The rhodium-PN₂ catalyst utilizing selective ligation of the amino unit and electrostatic interaction between the ligand and a substrate gave high enantioselectivities up to 92% ee in asymmetric hydrogenations of acrylic acid derivatives.     

Efficient enantioselective synthesis of 3-aminochroman derivatives through ruthenium-Synphos catalyzed asymmetric hydrogenation

A highly enantioselective asymmetric hydrogenation of various trisubstituted enamides derived from chroman-3-ones promoted by cationic Ru-Synphos catalysts is reported. This atom-economical and clean method provides an efficient route to optically active 3-aminochroman derivatives, which are important pharmacophores found in numerous drug candidates, in high chemical yields and enantiomeric excesses up to 96%.     

Asymmetric synthesis of chiral glutaric acid derivatives via Rh-catalyzed enantioselective hydrogenation

The first Rh-catalyzed enantioselective hydrogenation of dimethyl 2-methyleneglutarate and its derivatives has been reported. For the hydrogenation of dimethyl 2-methyleneglutarate with a chiral ferrocene-based monodentate phosphoramidite ligand (FAPhos), good enantioselectivity (over 90% ee) with full conversions was achieved. In contrast, the hydrogenation of substrates bearing an aryl substituent at a methylene moiety proved to be more difficult, in which the best enantioselectivity of up to 81% ee was obtained by the use of a P-stereogenic BoPhoz-type ligand.     

Synthesis of new chiral 2-functionalized-1,2,3,4-tetrahydroquinoline derivatives via asymmetric hydrogenation of substituted quinolines

The asymmetric hydrogenation of a series of quinolines substituted by a variety of functionalized groups linked to the C2 carbon atom is providing access to optically enriched 2-functionalized 1,2,3,4-tetrahydroquinolines in the presence of in situ generated catalysts from [Ir(cod)Cl]₂, a bisphosphine, and iodine. The enantioselectivity levels were as high as 96% ee.     

An enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid via asymmetric hydrogenation

A concise enantioselective synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (1, Pregabalin) has been developed. The key step is the asymmetric hydrogenation of a 3-cyano-5-methylhex-3-enoic acid salt 2 with a rhodium Me-DuPHOS catalyst, providing the desired (S)-3-cyano-5-methylhexanoate 3 in very high ee. Subsequent hydrogenation of the nitrile 3 with a heterogeneous nickel catalyst provides Pregabalin 1 in excellent overall yield and purity.     

Highly enantioselective asymmetric hydrogenation of beta-acetamido dehydroamino acid derivatives using a three-hindered quadrant rhodium catalyst

[reaction: see text] A previously reported three-hindered quadrant chiral ligand and its corresponding rhodium complex provide high enantioselectivity for the asymmetric hydrogenation of beta-acetamido dehydroamino acid substrates. Both (E)- and (Z)-substrates are hydrogenated with high enantioselectivity in all of the reported examples. Asymmetric hydrogenation of a cyclic beta-acetamido dehydroamino acid substrate in 85% ee is also reported.     

Highly enantioselective synthesis of alpha,beta-diaminopropanoic acid derivatives using a catalytic asymmetric hydrogenation approach

Rh-DuPhos-catalyzed asymmetric hydrogenation of alpha,beta-diamidoacrylates provides a highly efficient and enantioselective route to chiral alpha,beta-diaminopropanoic acid derivatives. The mechanistic course of the hydrogenation was studied using isotopically enriched enamide complexes and phosphorus and carbon NMR. Addition of methyl alpha-N-benzoyl-beta-N-acetyl-diaminopropenoate to the solvated catalyst gave a single 1:1 enamide complex and demonstrated the binding of the olefin and alpha-amide carbonyl group; the carboxylate and beta-N-acyl groups did not bind to the metal. Changes to the electronic and steric properties of the beta-N-acyl group were well tolerated; however, small changes to the binding alpha-N-acyl group were found to significantly affect hydrogenation yields.     

Unusual deactivation in the asymmetric hydrogenation of itaconic acid

The formation of unusual Rh(III) substrate complexes from [Rh(DIPAMP)(MeOH)₂]BF₄ and itaconic acid has been detected which leads to the deactivation of the catalyst. The influence of different parameters on the formation of such complexes, namely substrate concentration, reaction time, temperature, acidic and basic additives, was investigated with different NMR methods. Two different Rh(III) substrate complexes are formed whose ratio is strongly dependent on substrate concentration and reaction time. The pH value of the solution shows a strong influence on the chemical shifts of the ³¹P NMR signals of such complexes. A catalyst-mediated esterification of itaconic acid in methanol was detected. Extended investigations provide detailed ¹H, ¹³C and ³¹P NMR data for the Rh(III) complexes and information about their stability in solution.     

联萘衍生物作为手性配体在不对称氢化中的应用

综述了近年来联萘衍生物作为手性配体构成的金属络合物在前手性烯、酮及亚胺的不对称氢化反应中的应用。     

Efficient rhodium-catalyzed asymmetric hydrogenation for the synthesis of a new class of N-aryl beta-amino acid derivatives

[reaction: see text] N-Aryl beta-amino esters were obtained by asymmetric hydrogenation of a new class of N-aryl beta-enamino esters. High conversions and up to 96.3% ee values were achieved with a Rh-TangPhos catalyst.     

Primary trifluoroborate-iminiums enable facile access to chiral α-aminoboronic acids via Ru-catalyzed asymmetric hydrogenation and simple hydrolysis of the trifluoroborate moiety

This work describes the first preparation and application of primary trifluoroborate-iminiums (pTIMs) as a new, easily accessible and valuable class of organoboron derivatives. An array of structurally diverse pTIMs was prepared from potassium acyltrifluoroborates in excellent yields. Highly efficient and enantioselective [(R,R)-TethTsDpen-RuCl] complex-catalyzed hydrogenation of pTIMs provided direct access to chiral primary trifluoroborate-ammoniums (pTAMs). Moreover, facile synthesis of a series of structurally diverse chiral α-aminoboronic acids from chiral pTAMs was accomplished through novel, operationally simple and efficient conversion using hexamethyldisiloxane/aqueous HCl. Using no chromatography at any point, this work allowed easy access to chiral α-aminoboronic acids, as exemplified by the synthesis of optically pure anti-cancer drugs bortezomib and ixazomib.

Starting with potassium acyltrifluoroborates (KATs), N-unprotected chiral α-aminoboronic acids are prepared in three simple steps without chromatography. This facile methodology will tap the broad potential of these valuable compounds.     

Synthesis of chiral hydantoin derivatives by homogeneous Pd-catalyzed asymmetric hydrogenation

5-Aryl substituted chiral hydantoin derivatives were synthesized via asymmetric hydrogenation of prochiral exocyclic alkenes using a Pd/BINAP catalyst. Moderate to good enantioselectivity were obtained (21–90% ee). A chiral Brönsted acid additive was found to be a key factor to obtain high enantioselectivity.