Α-amino Acid Esters Research Articles

One-pot synthesis of difluoromethyl-containing 1,2,3,4-tetrahydropyridines

Difluoromethyl-containing diethyl 1,2,3,4-tetrahydropyridine-3,5-dicarboxylate derivatives were synthesized in up to 90% yields by the Mannich reaction of ethyl 4,4-difluoroacetoacetate with formaldehyde and primary amine hydrochlorides. The effects of the reactant structure and reaction conditionson the efficiency of formation of 1,2,3,4-tetrahydropyridines and hexahydropyrimidines was studied. In the presence of NaCl in an acetate buffer (рН 4), the 1,2,3,4-tetrahydropyridine structure is formed selectively. When 4-aminophenol hydrochloride is used, the 3,4,5,6-tetrahydropyrimidin-1-ium difluoroacetate salt is produced, apart from the target product. The reactions with (S)-α-amino acid ester hydrochlorides afford mixtures of two diastereomeric 1,2,3,4-tetrahydropyridines.

Screening of α-amino acid ester acyl transferase variant with improved activity by combining rational and random mutagenesis.

Random and rational mutagenesis of an α-amino acid ester acyl transferase from Sphingobacterium siyangensis AJ2458 (SAET) was conducted to examine the production of aspartame, an α-l-aspartyl-l-phenylalanine methyl ester. We previously reported aspartame production via combination of enzymatic and chemical methods. However, the productivity of the aspartame intermediate by SAET was approximately one-fifth that of l-alanyl-l-glutamine (Ala-Gln), whose production method has already been established. Here, to improve the enzymatic activity of SAET, we performed random mutagenesis in the gene encoding SAET and obtained 10 mutations that elevated the enzymatic activity (1.2- to 1.7-fold increase) relative to that of wild-type SAET. To further improve the activity, we performed mutagenesis to optimize the combination of the obtained mutations and finally selected one SAET variant with 10 amino acid substitutions (M35-4 SAET). An Escherichia coli strain overexpressing M35-4 SAET displayed a 5.7-fold higher activity than that of the wild-type SAET, which was almost equal to that of Ala-Gln by an E. coli strain overexpressing wild-type SAET. The Vmax value of M35-4 SAET was 2.0-fold greater, and its thermostability was higher than those of wild-type SAET. These results suggest that the obtained SAET variants contribute to improvement in aspartame production.

Umpolung Reactivity of Imine Ester: Visible-Light Mediated Transfer Hydrogenation of α-Aryl Imino Esters by Phenylsilane and Water.

A visible-light mediated chemoselective transfer hydrogenation of α-aryl imino esters was demonstrated. The methodology allowed the efficient and practical preparation of α-amino acid esters. The mechanism of the reaction was probed by DFT calculations, and deuteration experiments indicated deuterium was introduced into amino acid esters efficiently (up to 99 % D ratio), enabling a feasible way to obtain deuterated amino acids using D2 O as a cheap deuterium source.

Synthesis of alkyl isothiazolidine-1,1-dioxide 3-carboxylates via the intramolecular carbo-Michael reaction strategy

Herein we present short and cost-effective synthesis of alkyl isothiazolidine-1,1-dioxide 3-carboxylates starting from commercially available α-amino acid ester hydrochlorides. These compounds were designed as sulfonamide-containing bioisosteres of known pharmacological template – pyroglutamic acid (pGlu). Specifically, α-amino acid ester hydrochlorides were sulfonylated with (2-chloroethyl)sulfonyl chloride providing in one-pot manner the corresponding alkyl 2-((vinylsulfonyl)amino)carboxylates. The obtained vinyl sulfonamides possessing SO2NH functionality were alkylated with either MeI or MeOCH2Cl (MOMCl) prior to cyclization step. At the same time, vinyl sulfonamides derived from N-monosubstituted and cyclic amino acid esters were directly involved in NaH-mediated intramolecular carbo-Michael reaction affording the target alkyl isothiazolidine-1,1-dioxide 3-carboxylates. Further acid-promoted cleavage of MOM-protecting group led to NH-unsubstituted target compounds.

Enantioselective Three-Component Photochemical 1,4-Bisalkylation of 1,3-Butadiene with Pd/Cu Catalysis.

Catalysis by excited-state palladium has emerged as an active area of research, but controlling the enantioselectivity remains a challenge. Herein, we report the use of synergistic Pd/Cu catalysis to accomplish the first three-component photochemical 1,4-bisalkylation reactions of 1,3-butadiene. Consequently, α-amino acid esters bearing quaternary stereocenters were expeditiously synthesized from three simple starting materials: an alkyl bromide, butadiene, and an aldimine ester. Experimental and computational investigation of the reaction mechanism confirmed a radical pathway involving catalysis by an excited-state palladium species. The stereochemistry is mainly controlled by the chiral Cu catalyst.

Palladium-Catalyzed Aminocarbonylation of (Hetero)aryl Iodides with α-Amino Acid Esters as Nucleophiles.

We report palladium-catalyzed aminocarbonylation of (hetero)aryl iodides with α-amino acid esters as nucleophiles. The synthesized N-capped α-amino acids are biologically important building blocks. The mild conditions provide products with high enantioselectivity at 80 °C in 35 min. The reactions are performed under air in a sealed vessel using chloroform as an in situ CO source. For the first time, regioselective carbonylation of histidine is also presented.

Application of partially aromatic ortho-quionone-methides for the synthesis of novel naphthoxazines with improved antibacterial activity

Starting from naphthols and morpholine and using ethyl glyoxylate as the aldehyde component in the modified Mannich reaction, new aminonaphthol derivatives substituted with 2- and 1-naphthol were synthesised. The stabilization of precursor bifunctional compounds via partially aromatic ortho-quinone methide intermediate was tested with different cyclic imines in [4 + 2] cycloaddition. Based on 1H NMR analysis, in the case of new α-amino acid esters the formation of a single product has been assumed. The NOE spectrum proved that the relative configuration of the newly formed stereogenic centres was trans. The compounds have also been tested in bacteria in order to reduce or reverse antibiotic resistance. Compounds 13 and 14 could inhibit the efflux pump system in susceptible and methicillin-resistant Staphylococcus aureus strains.

Copper-Catalyzed Decarboxylative Propargylic Alkylation of Enol Carbonates: Stereoselective Synthesis of Quaternary α-Amino Acids

A copper-catalyzed asymmetric decarboxylative propargylic alkylation of enol carbonates has been realized, allowing for the highly stereoselective formation of acyclic vicinal tri- and tetrasubstituted stereocenters. With this strategy, a series of optically active quaternary α-amino acid esters with an adjunct chiral tertiary propargylic moiety have been prepared from propargyl azlactone-enol carbonates in high yields and with good to excellent diastereo- and enantioselectivities. The success of this reaction exemplifies the high potential of the decarboxylative strategy to resolve unmet challenges present in traditional catalytic propargylic alkylation.

Kinetic model development for α-amino ester hydrolase (AEH)-catalyzed synthesis of β-lactam antibiotics

α-Amino ester hydrolases (AEH) are a class of enzymes highly specific for catalyzing the synthesis and hydrolysis of amides and esters of α-amino acids. They are particularly promising catalyst candidates as an alternative to penicillin G acylase (PGA) for synthesis of a variety of β-lactam antibiotics, including cephalexin, cefadroxil, amoxicillin, and ampicillin. In this study, X. campestris pv. campestris AEH and two previously established quadruple variants designed for enhanced stability (N186D/A275P/V622I/E143G termed QVG and N186D/A275P/V622I/E143H termed QVH) were characterized in terms of their kinetic properties. AEH appears to have highest substrate specificity for cephalosporins, particularly cephalexin. The optimum pH value for activity was found to be between pH 6.5 – 6.75 for synthesis of amoxicillin, cephalexin, and cefadroxil, while synthesis selectivity consistently increased with decreasing pH value. Evidence for substrate inhibition preventing the β-lactam nucleus from binding and forming the corresponding amide is discussed. Time-course kinetic data across a wide range of substrate concentrations was found to corroborate the presence of substrate inhibition, and five possible kinetic models are derived to explain AEH-catalyzed cephalexin synthesis kinetic profiles. A best fit model that incorporates both competitive substrate inhibition and partial substrate inhibition was selected based on the Akaike Information Criterion (AIC) and quality of fit at high substrate concentration. Finally, progress of the synthesis of beta-lactams in a single CSTR was simulated using the best fit kinetic model and a Pareto optimal front was constructed for fractional yield, productivity, and substrate conversion to evaluate potential reactor configurations.

Synthesis and kinetic characterization of hyperbolic inhibitors of human cathepsins K and S based on a succinimide scaffold

Cathepsins K and S are closely related papain-like cysteine peptidases and potential therapeutic targets for metabolic and inflammatory diseases such as osteoporosis and arthritis. Here we describe the reduction of a previously characterized succinimide (2,5-dioxopyrrolidine)-containing hyperbolic inhibitor of cathepsin K (methyl (RS)-N-[1-(4-methoxyphenyl)-2,5-dioxopyrrolidin-3-yl]glycinate), to obtain a better and more selective compound (compound 4a - methyl (2,5-dioxopyrrolidin-3-yl)glycinate), which acted as a hyperbolic mixed inhibitor/activator similar to already known allosteric effectors of cathepsin K. We then investigated the potential of the succinimide scaffold as inhibitors of cathepsins K and/or S and synthesized a library of such compounds by 1,4-addition of α-amino acid esters and related compounds to N-substituted maleimides. From the generated library, we identified the first small molecule hyperbolic inhibitors of cathepsin S (methyl ((R)-2,5-dioxopyrrolidin-3-yl)-l-threoninate (compound R-4c) and 3-{[(1S,2R,3′S)-2-hydroxycyclohexyl]amino}pyrrolidine-2,5-dione (compound (1S,2R,3′S-10)). The former acted via a similar mechanism to compound 4a, while the latter was a hyperbolic specific inhibitor of cathepsin S. Given the versatility of the scaffold, the identified compounds will be used as the basis for the development of high-affinity hyperbolic inhibitors of the individual peptidases and to explore the potential of hyperbolic inhibitors for the inhibition of cysteine cathepsins in in vitro models.

Enantiomer Separation of Chiral Amines and Amino Acid Esters on Polysaccharide Phenylcarbamates Derived Chiral Stationary Phases

We have developed an efficient chiral HPLC method for enantiomeric resolution of some chiral amines and α- amino acid esters as nitrobenzoxadiazole (NBD) derivatives on amylose and cellulose phenylcarbamates derived chiral stationary phases (CSPs) under simultaneous ultraviolet (UV) and fluorescence (FL) detection. The observed enantioselectivities were affected by the type of the analyte (amines or α-amino acid esters), backbone structure (cellulose or amylose) of the CSP used, and substituents of phenyl moiety on the chiral selector of CSP. Further, for same chiral selectors, coated type CSPs showed better enantiomeric separation than those observed for the covalently bonded type CSPs. In general, for the enantiomeric resolution of chiral amines, Chiralpak IE and Chiralcel OD-H columns showed the highest enantioselectivities. However, for resolution of α-amino acid esters, the performances of Chiralpak IA and Chiralpak AD-H (or Lux Amylose-1) columns were superior to those of other CSPs used. In general, the degrees of enantioselectivity for α-amino acid ethyl esters are greater than those for chiral amines. The developed analytical method was applied to determine the enantiomeric purity of two commercially available chiral amine and α-amino acid ester; the enantiomeric impurities were observed to be 0.35 and 0.05% for (S)-α-methylbenzylamine and (S)-leucine ethyl ester, respectively. The validation data obtained from intra- and inter-day accuracy assays for (S)-3,3-dimethyl-2-butylamine and (S)-leucine ethyl ester were 99.92-101.46 and 100.61-101.78%; and 100.05-102.12 and 101.25-102.73%, respectively; the intra- and interday precision assays in terms of relative standard deviation (% RSD) were found to be 0.96-1.57 and 0.81- 1.91%; and 0.24-1.01% and 0.65-1.35%, respectively. Owing to the high accuracy and precision results, the developed analytical method can prove to be useful for the enantiomeric separation of various chiral amines and amino acid esters as NBD derivatives using polysaccharide derived CSPs.

Asymmetric Reduction of Aromatic α-Dehydroamino Acid Esters with Water as Hydrogen Source.

The asymmetric reduction of aromatic α-dehydroamino acid esters with water as the hydrogen source was developed by a Rh/Cu co-catalytic system. The reaction tolerates various functional groups, providing a valuable synthetic tool to access chiral α-amino acid esters readily. Moreover, the present methodology also was applied in the cost-effective and easy to handle preparation of chiral deuterated α-amino esters by using D2O.

Direct Catalytic N-Alkylation of α-Amino Acid Esters and Amides Using Alcohols with High Retention of Stereochemistry.

The direct functionalization of naturally abundant chiral scaffolds such as α‐amino acid esters or amides with widely abundant alcohols, without any racemization, is a demanding transformation that is of central importance for the synthesis of bio‐active compounds. Herein a robust and general method was developed for the direct N‐alkylation of α‐amino acid esters and amides with alcohols. This powerful ruthenium‐catalyzed methodology is atom‐economic, base‐free, and allowed for excellent retention of stereochemical integrity. The use of diphenylphosphate as additive was crucial for significantly enhancing reactivity and product selectivity. Notably, the only by‐product was water and both substrates could be potentially derived from renewable resources.

Synthesis of novel pregnane-based 20-carboxamides via palladium-catalysed aminocarbonylation

20-Carboxamidopregnene derivatives, such as 3β-acetoxy-5α-pregn-20-ene-20-carboxamides and 5α-pregn-20-ene-20-carboxamides were synthesized from the widely accessible 3β-acetoxy-pregn-5,16-dien-20-one (PDA) using selective hydrogenation, hydrazine and iodoalkene formation, as well as palladium-catalysed aminocarbonylation. The 20-iodo-20-ene derivatives, obtained from the corresponding 20-keto derivatives via their hydrazones, served as substrates. 23 new 20-carboxamides were obtained using various N-nucleophiles ranging from simple primary amines to α-amino acid esters. The novelty of this methodology lies in the application of facile, moderate or high-yielding reactions to obtain otherwise hardly accessible steroidal 20-carboxamides of pharmaceutical importance. In other words, instead of the enzymatic or synthetic degradation of e.g., sterols or cholanic acids, functionalization of the basic skeleton (a ‘building-up’ approach) was used.

Access to highly functionalized imidazolones bearing α-amino acid esters via KOH-promoted annulation of amidines, nitrosoarenes and malonic esters.

An efficient approach to obtain highly functionalized imidazolones bearing α-amino acid esters through KOH-mediated one-pot three-component annulation of amidines, nitrosoarenes and malonic esters is reported. This reaction features broad substrate scope, a cheap and readily available promoter, good to high yields for most substrates and mild reaction conditions. The mechanism study shows that the KOH-mediated formation of the imine intermediate via the reaction of nitrosoarenes with malonic esters is a key step.

A novel route for aspartame production by combining enzymatic and chemical reactions for industrial use.

Here, we report a novel industrial aspartame production route, involving the enzymatic production of α-l-aspartyl-l-phenylalanine β-methylester from l-aspartic acid dimethylester and l-phenylalanine by α-amino acid ester acyl transferase. The route also involves the chemical transformation of α-l-aspartyl-l-phenylalanine β-methylester to α-l-aspartyl-l-phenylalanine methylester hydrochloride (aspartame hydrochloride) in an aqueous solution with methanol and HCl, followed by HCl removal to form aspartame.

Enantioselective Nucleophilic Aromatic Substitution Reaction of Azlactones to Synthesize Quaternary α-Amino Acid Derivatives

AbstractAn asymmetric organocatalytic nucleophilic aromatic substitution reaction of azlactones with electron-deficient aryls was established. A variety of α-aryl α-alkyl α-amino acid esters and peptides were obtained in decent yields and stereoselectivities. A new bifunctional catalytic mode involving charge-transfer interaction and hydrogen bonding is proposed to explain the enantioselectivity.

Nano Aggregate Formation Through Self-Assembly of Poly(L-lysine)-Block-Poly(γ-benzyl-L-glutamate)-Graft-Poly(ethylene glycol) Copolymer.

Polymeric nano aggregates based on poly(L-lysine)-block-PBLG-graft-poly(ethylene glycol) (PLL-b-PBLG-g-PEG) copolymers were prepared by a dialysis method in deionized water. PLL-b-PBLG-g-PEG copolymers with different degrees of PEG substitution were synthesized by combining the ring-opening polymerization of α-amino acid N-carboxyanhydrides and ester exchange reactions. Proton nuclear magnetic resonance spectroscopy and gel permeation chromatography were employed to confirm the polymer structures and molecular weights. Transmission electron microscopy and dynamic light scattering were used to observe the self-assembly behavior. The experimental results revealed that the volume content of deionized water in the mixture significantly affects the morphology and size of the aggregates formed by PLL-b-PBLG-g-PEG copolymers. Spherical, spindle-like, needle-like, and daisy-like aggregates were observed with an increase in the volume content of deionized water in the mixture.

Synthesis of Fluorinated Quaternary α-Amino Acid Esters

Key words amino acid esters - fluorinated amino acids - aza-Friedel–Crafts alkylation - silver catalysis

Ionic liquids derived from α-amino acid ester salts as potent green corrosion inhibitors for mild steel in 1M HCl

In 1 M HCl solution, three selected amino acid ester salt based ionic liquids ([AAE][Sac] ILs), namely L-Phenyl Alanine methyl ester saccharinate ([PheME][Sac]), L-Leucine methyl ester saccharinate ([LeuME][Sac]), and L-Alanine methyl ester saccharinate ([AlaME][Sac]) under static conditions were examined as potent green corrosion inhibitors for mild steel by means of electrochemical measurements, weight loss, FT-IR spectroscopy, contact angle measurement, UV–vis spectroscopy, SEM/EDAX study, quantum chemical calculations and Monte Carlo (MC) simulation studies. 1H NMR, and FTIR spectroscopy has confirmed the structure of obtained ILs. The investigations were done in the temperature range of 303–353 K. [AAE][Sac] ILs are assessed as an efficient steel corrosion inhibitors in 1 M HCl up to 333 K but have less inhibiting properties above 333 K i.e., 343 and 353 K. Among the [AAE][Sac] ILs analysed, [PheME][Sac] showed the greatest inhibition efficiency and obey the order as: [PheME][Sac] > [LeuME][Sac] > [AlaME][Sac]. Polarization measurements showed all the [AAE][Sac] ILs tested to be mixed-type inhibitors. The adsorption of the examined [AAE][Sac] ILs obeyed the Langmuir adsorption isotherm perfectly. The theoretical descriptors provided by quantum chemical calculations and advanced MC simulation also reinforced the experimental conclusions adequately.