Chiral Α-amino Acid Derivatives Research Articles

A Spiro Phosphamide Catalyzed Enantioselective Proton Transfer of Ylides in a Free Carbene Insertion into N-H Bonds.

Free carbene readily causes multiple side reactions due to its high energy, thus its asymmetric transformation is very difficult. We present here our findings of high-pKa Brønsted acid catalysts that enable free carbene insertion into N-H bonds of amines to prepare chiral α-amino acid derivatives with high enantioselectivity. Under irradiation with visible light, diazo compounds produce high-energy free carbenes that are captured by amines to form free ylide intermediates, and then the newly designed high-pKa Brønsted acids, chiral spiro phosphamides, promote the proton transfer of ylides to afford the products. Computational and kinetic studies uncover the principle for the rational design of proton-transfer catalysts and explain how the catalysts accelerate this transformation and provide stereocontrol.

Iridium-catalyzed asymmetric double allylic alkylation of azlactone: efficient access to chiral α-amino acid derivatives.

An unprecedented Ir-catalyzed enantioselective double allylic alkylation of less bulky cyclic imine glycinate (azlactone) was rationally designed and developed, providing various bisallylated chiral amino acid derivatives. Control experiments revealed that this transformation proceeds in a sequential manner featuring quasi-dynamic kinetic resolution of the initially-formed monoallylation intermediates.

Copper(I)-Catalyzed Asymmetric Synthesis of Unnatural α-Amino Acid Derivatives and Related Peptides Containing γ-(aza)Aryls

Chiral α-amino acids are indispensable compounds in organic chemistry, biochemistry, and medicinal chemistry. Herein, by means of copper(I)-catalyzed asymmetric conjugate addition of derivatives of glycine, serine, cysteine, and β-amino-alanine to electron-deficient vinyl(aza)arenes, an array of novel unnatural chiral α-amino acid derivatives bearing a γ-(aza)aryl is prepared in moderate to high yields with high enantioselectivity. Various azaarenes, such as pyrimidine, 1,3,5-triazine, pyridine, pyridine-N-oxide, quinoline, quinoxaline, purine, benzo[d]imidazole, benzothiazole, and 1,2,4-oxadiazole, are well tolerated. Moreover, the electrophiles are nicely extended to (Z)/(E) mixtures of electron-deficient butadienylpyridine and benzene, which are transformed to the corresponding chiral α-amino acid derivatives in high (E)/(Z) ratio and high enantioselectivity. More importantly, the present methodology is successfully applied in the catalytic asymmetric functionalization of Schiff bases derived from peptides, which finally afforded a new chiral tripeptide bearing two electron-deficient azaaryls and one electron-deficient aryl in high total yield with high diastereo- and excellent enantioselectivities.

Nitrogen-Doped Carbon Enables Heterogeneous Asymmetric Insertion of Carbenoids into Amines Catalyzed by Rhodium Nanoparticles.

Development of stable heterogeneous catalyst systems is a crucial subject to achieve sustainable society. Though metal nanoparticles are robust species, the study of asymmetric catalysis by them has been restricted because methods to activate metal nanoparticles without causing metal leaching were limited. We developed Rh nanoparticle catalysts (NCI-Rh) supported on nitrogen-doped carbon as a solid ligand to interact with metals for asymmetric insertion of carbenoids into N-H bonds cocatalyzed by chiral phosphoric acid. Nitrogen dopants played a crucial role in both catalytic activity and enantioselectivity while almost no catalysis was observed with Rh nanoparticles immobilized on supports without nitrogen dopants. Various types of chiral α-amino acid derivatives were synthesized in high yields with high enantioselectivities and NCI-Rh could be reused in seven runs. Furthermore, we demonstrated the corresponding continuous-flow reaction using a column packed with NCI-Rh. The desired product was obtained efficiently for over 90 h through the reactivation of NCI-Rh and the chiral source could be recovered.

Transition metal-catalyzed asymmetric carbene insertion for synthesis of chiral amines

Chiral amines are an important class of organic compounds. They are ubiquitous in organic chemistry and often serve as fundamental building blocks, versatile synthons, efficient chiral catalysts, ligands or auxiliaries in asymmetric synthesis and medicinal chemistry. During the past few decades, there has been remarkable progress in the development of efficient asymmetric methods. Accordingly, asymmetric synthesis, particularly catalytic enantioselective synthesis of chiral amines has received considerable attention from both academia and industry. Among them, transition metal-catalyzed asymmetric carbene insertion has emerged as one of the most useful and powerful methods for synthesis of various chiral amines through the efficient construction of the C−N bonds. In this review, we present the progress and advances that have been made using copper, rhodium, palladium, and iron catalysts to perform enantioselective N−H insertion reactions with diazo compounds. An overview of early examples of Cu(I) and Ag(I)-bisoxazoline-catalyzed asymmetric N−H insertion and the subsequent developments by using copper(I) complexes with chiral spiro bisoxazolines, bipyridines and binol derivatives, as well as with rhodium(II)-, palladium(II)-, iron(II)-carbene chemistry is provided. In these work, catalytic asymmetric metal-carbene insertion into the N−H bond of aromatic amines, amides (BocNH2, CbzNH2), substituted carbazoles and indoles, and benzophenone imines were achieved under mild reaction conditions, allowing access to a wide variety of structurally important chiral amines in enantiomerically enriched form. In particular, with the use of α-aryl or α-alkyl α-diazoesters as carbene precusors, both aryl and alkyl substituted α-amino esters could be prepared in good yields with high enantioselectivities. A recent major breakthrough in enantioselective transition-metal-catalyzed N−H insertion reactions with aliphatic amines is also discussed. By using a combination of an achiral copper complex and chiral amino-thiourea catalyst, highly enantioselective carbene insertion into N−H bonds of aliphatic amines was achieved to produce various chiral α-alkyl α-amino acid derivatives bearing secondary and tertiary amino substituents in good yields. Overall, this review summarizes the most prominent work on transition-metal-catalyzed asymmetric carbene N−H insertion and their applications in chiral amines and natural or unnatural chiral α-amino acid derivatives synthesis.

A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives via a bicyclic imidazole-catalyzed direct enantioselective C-acylation.

Cα-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient synthesis of chiral Cα-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords the corresponding Cα-tetrasubstituted α-amino acid derivatives with excellent enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic chemistry.

Catalytic asymmetric propargyl- and allylboration of hydrazonoesters: a metal-free approach to sterically encumbered chiral α-amino acid derivatives.

A new asymmetric catalytic propargyl- and allylboration of hydrazonoesters is reported. The reactions utilize allenyl- and allylboronic acids in the presence of the inexpensive parent BINOL catalyst. The reactions can be performed under mild conditions (0 °C) without any metal catalyst or other additives affording sterically encumbered chiral α-amino acids. This is the first metal-free method for the asymmetric propargyl- and allylboration of hydrazonoesters.

Formamide Synthesis through Borinic Acid Catalysed Transamidation under Mild Conditions.

A highly efficient and mild transamidation of amides with amines co-catalysed by borinic acid and acetic acid has been reported. A wide range of functionalised formamides was synthesized in excellent yields, including important chiral α-amino acid derivatives, with minor racemisation being observed. Experiments suggested that the reaction rely on a cooperative catalysis involving an enhanced boron-derived Lewis acidity rather than an improved Brønsted acidity of acetic acid.

Nonenzymatic, Enantioconvergent Dynamic Kinetic Resolution (DKR) of Racemic 2-(1H-Pyrrol-1-yl)alkanoic Acids as α-Amino Acid Equivalents

Abstract We report an effective dynamic kinetic resolution (DKR) system of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which consists of a rapid racemization step via an activating substrate and an enantio-discriminating step via catalytic esterification. The combination of pivalic anhydride as an activating agent, bis(α-naphthyl)methanol as an achiral alcohol, (R)-BTM as a chiral acyl-transfer catalyst, and Hünig’s base converted racemic 2-(1H-pyrrol-1-yl)alkanoic acids to the corresponding chiral carboxylates, which can be transformed into chiral α-amino acid derivatives with maintained high enantiopurity.

ChemInform Abstract: C‐Selective and Diastereoselective Alkyl Addition to β,γ‐Alkynyl‐α‐imino Esters with Zinc(II)ate Complexes.

Since umpolung α-imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α-amino acid derivatives. An unusual C-alkyl addition to α-imino esters using a Grignard reagent (RMgX)-derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX](+) moiety, a nucleophilic [R3 Zn](-) moiety, and 2 [MgX2 ]. Therefore, the ionically separated [R3 Zn](-) selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX](+) . In particular, chiral β,γ-alkynyl-α-imino esters can strongly promote highly regio- and diastereoselective C-alkylation because of structural considerations, and the corresponding optically active α-quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.

C-selective and diastereoselective alkyl addition to β,γ-alkynyl-α-imino esters with zinc(II)ate complexes.

Since umpolung α-imino esters contain three electrophilic centers, regioselective alkyl addition with traditional organometallic reagents has been a serious problem in the practical synthesis of versatile chiral α-amino acid derivatives. An unusual C-alkyl addition to α-imino esters using a Grignard reagent (RMgX)-derived zinc(II)ate was developed. Zinc(II)ate complexes consist of a Lewis acidic [MgX](+) moiety, a nucleophilic [R3 Zn](-) moiety, and 2 [MgX2 ]. Therefore, the ionically separated [R3 Zn](-) selectively attacks the imino carbon atom ,which is most strongly activated by chelation of [MgX](+) . In particular, chiral β,γ-alkynyl-α-imino esters can strongly promote highly regio- and diastereoselective C-alkylation because of structural considerations, and the corresponding optically active α-quaternary amino acid derivatives are obtained within 5 minutes in high to excellent yields.

Enantioselective synthesis of arylglycine derivatives by direct C-H oxidative cross-coupling.

A new method for the synthesis of chiral α-amino acid derivatives by enantioselective C-H arylation of N-aryl glycine esters with aryl boric acids in the presence of a chiral Pd(II)-catalyst has been developed. This work successfully integrates the direct C-H oxidation with asymmetric arylation and exhibits excellent enantioselectivity.

Catalytic asymmetric Michael addition of α,β-unsaturated aldehydes to Ni(ii) complexes of the Schiff base of glycine

The conjugate addition of Ni(II) complexes of glycine Schiff base to α,β-unsaturated aldehydes catalyzed by (S)-2-(diphenyl(trimethylsilyloxy)methyl)pyrrolidine afforded adducts in excellent yields with up to 49:1 dr and 95% ee. This method enables the construction of two adjacent chiral centers in one step, and offers an alternative route to chiral α-amino acid derivatives.

Synthesis of chiral N-(2-(1-oxophthalazin-2(1H)-yl) ethanoyl)-α-amino acid derivatives as antitumor agents

A series of chiral α-amino acid derivatives conjugated with 1-oxophthalazine moiety 5a-e were synthesized by coupling of various L-acylated amino acid derivatives with 2-(1-oxophthalazin- 2(1H)-yl)acetic acid in the presence of 1-hydroxybenzotriazole (HOBt) and N,N`- dicyclohexylcarbodiimide (DCC) as coupling reagent. Alternatively, compounds 5a-e were prepared by the reaction of the corresponding aizde 4, via the azide-coupling method, with L- acylated amino acid derivatives. The peptide esters 5a-d were converted into their corresponding amides 6a-d by treating with methanolic ammonia. Moreover, 5a was boiled with hydrazine hydrate to afford the corresponding hydrazide 7. Finally, the dipeptides 8a-c were prepared by coupling of 5a with the appropriate L-amino acid methyl ester. The synthesized compounds were tested against Caucasian breast adenocarcinoma MCF7 cell line.

Stable organogels derived from triazines functionalized with chiral α-amino acid derivatives

Triazines functionalized with three stereogenic α-amino-acidic appendages having at least one amide or hydroxamate function give highly stable organogels in haloalkanes and aromatic solvents, and their gelating ability depends on both structural and stereochemical properties.

Asymmetric hydrogenation in a membrane reactor: recycling of the chiral catalyst by using a retainable micellar system

A micellar enlarged Rh-(2 S,4 S)- N- tert-butoxycarbonyl-4-diphenylphosphino-2-diphenyl-phosphino-methyl-pyrrolidine (BPPM) catalyst was used for the enantioselective hydrogenation of α-amino acid precursors in a membrane reactor, equipped with an ultrafiltration membrane. The chiral α-amino acid derivatives were obtained with good enantioselectivity and space–time yields. The catalyst, embedded in micelles, obtained from triblock copolymers as surfactants, was retained and reused several times without loss of activity and enantioselectivity. Only a minimal leaching of the catalyst components was found.