Synthesis Of Non-proteinogenic Amino Acids Research Articles

Stereo-divergent Synthesis of Nonproteinogenic Amino Acids and Synthetic Study for Biologically Active Cyclopeptides

Naturally occurring cyclopeptides are potential middle-molecule drug candidates beyond Lipinski's rule of five. This paper focuses on the structural determination and structure-activity relationship (SAR) study of two cyclopeptides: asperterrestide A and decatransin. The proposed asperterrestide A was synthesized by solution-phase peptide elongation, followed by macrolactamization. NMR analysis and molecular modeling studies revealed the stereochemistry at the two α-positions of amino acid residues as opposite to each other. This was further confirmed by the total synthesis of the revised asperterrestide A. SAR study of synthetic products revealed that the β-hydroxy group in the nonproteinogenic amino acid residue was not essential for its cytotoxicity. In addition, N-alkyl-enriched peptide fragments of decatransin were synthesized in solution-phase without diketopiperadine formation. The putative candidates of decatransin was synthesized by convergent peptide coupling, followed by macrocyclization under modified Mitsunobu conditions. The structure of the natural decatransin, including its absolute configuration, was determined through a comparison of spectral data and the cytotoxicity exhibited by the synthetic products.

Simplifying the Synthesis of Nonproteinogenic Amino Acids via Palladium-Catalyzed δ-Methyl C-H Olefination of Aliphatic Amines and Amino Acids.

Transition metal-catalyzed directing group assisted C-H functionalizations provide a straightforward access to a wide variety of nonproteinogenic amino acids. While altering the side chain of an existing natural amino acids is one way, introducing a functional group to an aliphatic amine to synthesize versatile unnatural amino acids is another exciting avenue. In this work, we explore both the possibilities by the palladium-catalyzed δ-C(sp3)-H olefination of aliphatic amines and amino acids. A diverse substrate scope including sequential difunctionalizations followed by post synthetic transformations were achieved to understand the applicability of the current protocol. An in-depth mechanistic study was carried out to learn the mode of the reaction pathway.

Analysis of FR901379 Biosynthetic Genes in Coleophoma empetri by Clustered Regularly Interspaced Short Palindromic Repeats/Cas9-Based Genomic Manipulation.

The compound FR901379, a sulfated echinocandin produced by the filamentous fungus Coleophoma empetri F-11899, is an important intermediate for the synthesis of the antifungal drug micafungin. In this study, we established an efficient clustered regularly interspaced short palindromic repeats/Cas9-based gene editing tool for the industrial production strain C. empetri SIPI1284. With this method, the efficiency of gene mutagenesis in the target locus is up to 84%, which enables the rapid gene disruption for the analysis of FR901379 biosynthetic genes. Next, we verified the putative functional genes of the FR901379 biosynthetic gene cluster via gene disruption and gene complementation in vivo. These core functional genes included the nonribosomal peptide synthetase gene (CEnrps), the fatty-acyl-AMP ligase gene (CEligase) responsible for the formation of the activated form of palmitic acid and its transfer to CEnrps, four nonheme mononuclear iron oxygenase genes (CEoxy1, CEoxy2, CEoxy3, and CEoxy4) responsible for the synthesis of nonproteinogenic amino acids, l-homotyrosine biosynthesis genes (CEhtyA-D), two cytochrome P450 enzyme genes (CEp450-1 and CEp450-2), and a transcription regulator gene (CEhyp). In addition, by screening the whole genome, we identified two unknown genes (CEp450-3 and CEsul) responsible for the sulfonyloxy group of FR901379, which were separated from the core FR901379 biosynthetic cluster. Furthermore, during gene disruptions in the research, we obtained a series of FR901379 analogues and elucidated the relationship between the groups and antifungal activities.

Recent Advances in Rapid Synthesis of Non-proteinogenic Amino Acids from Proteinogenic Amino Acids Derivatives via Direct Photo-Mediated C-H Functionalization.

Non-proteinogenic amino acids have attracted tremendous interest for their essential applications in the realm of biology and chemistry. Recently, rising C–H functionalization has been considered an alternative powerful method for the direct synthesis of non-proteinogenic amino acids. Meanwhile, photochemistry has become popular for its predominant advantages of mild conditions and conservation of energy. Therefore, C–H functionalization and photochemistry have been merged to synthesize diverse non-proteinogenic amino acids in a mild and environmentally friendly way. In this review, the recent developments in the photo-mediated C–H functionalization of proteinogenic amino acids derivatives for the rapid synthesis of versatile non-proteinogenic amino acids are presented. Moreover, postulated mechanisms are also described wherever needed.

A novel, enantioselective, thermostable recombinant hydantoinase to aid the synthesis of industrially valuable non-proteinogenic amino acids

Overexpression of a novel hydantoinase (hyuH) from P. aeruginosa (MCM B-887) in E. coli yielded optically pure carbamoyl amino acids. The use of optically pure carbamoyl amino acids as substrates facilitates the synthesis of non-proteinogenic amino acids. The enzyme hyuH shared a maximum of 92 % homology with proven hydantoinase protein sequences from the GenBank database, highlighting its novelty. Expression of hydantoinase gene was improved by >150 % by overexpressing it as a fusion protein in specialized E. coli CODON + host cells, providing adequate machinery for effective translation of the GC-rich gene. The presence of distinct residues in the substrate binding and active site of MCM B-887 hydantoinase enzyme explained its unique and broad substrate profile desirable for industrial applications. The purified enzyme, with a specific activity of 53U/mg of protein, was optimally active at 42 °C and pH 9.0 with a requirement of 2 mM Mn2+ ions. Supplementation of 500 mM of Na-glutamate enhanced the thermostability of the enzyme by more than 200 %.

Preparation of Chiral Contiguous Epoxyaziridines and Their Regioselective Ring-Opening for Drug Syntheses.

Synthetically valuable chiral (aziridin-2-yl)oxirane-3-carbaldehydes bearing three consecutive functional groups including aziridine, epoxide, and aldehyde were prepared from the stereoselective epoxidation of (aziridin-2-yl)acrylaldehydes with H2 O2 using organocatalyst (2R)- or (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as organocatalyst. The regioselective ring opening of aziridines and epoxides enabled us to achieve the highly efficient asymmetric synthesis of the antibiotic edeine D fragment 3-hydroxy-4,5-diaminopenatanoic acid, an intermediate for the formal synthesis of non-proteinogenic amino acid (-)-galantinic acid, and for potent antifungal agent (+)-preussin, and the medicinally important framework 3-hydroxy-2-hydroxymethylpyrrolidine.

Production of non‐proteinogenic amino acids from α‐keto acid precursors with recombinant Corynebacterium glutamicum

In the present work, Corynebacterium glutamicum was metabolically engineered for the enantioselective synthesis of non-proteinogenic amino acids as valuable building blocks for pharmaceuticals and agrochemicals. The novel bio-catalytic activity of C. glutamicum was obtained by heterologous expression of the branched chain aminotransferase IlvE from Escherichia coli. Upon this modification, the recombinant cells converted the α-keto acid precursor 2-(3-hydroxy-1-adamantyl)-2-oxoethanoic acid (HOAE) into the corresponding amino acid 2-(3-hydroxy-1-adamantyl)-(2S)-amino ethanoic acid (HAAE). Similarly, also L-tert-leucine could be obtained from trimethyl pyruvate indicating a broader applicability of the novel strategy. In both cases, the amino group donor glutamate was supplied from the endogenous metabolism of the recombinant producer. Hereby, the uptake of the precursor and secretion of the product was supported by an enhanced cell permeability through treatment of ethambutol, which inhibits arabinosyl transferases involved in cell wall biosynthesis. The excretion of HAAE into the reaction medium was linked to the secretion of glutamate, indicating a similar mechanism for the export of both compounds. On the other hand, the efflux of L-tert-leucine appeared to be driven by active transport. Subsequent bioprocess engineering enabled HAAE and L-tert-leucine to be produced at a rate of 0.21 and 0.42 mmol (g dry cells)⁻¹ h⁻¹, respectively up to a final product titer of 40 mM. Beyond the given examples, integrated metabolic and cell envelop engineering might extend the production of a variety of other non-proteinogenic amino acids as well as chiral amines by C. glutamicum.

Developments in the Synthesis of Organometallic Amino Acids and Analogues

Structure and function of synthetic amino acids with side chain metal complexes have particular importance for extending our understanding of organometallic compounds under physiological conditions and mimic protein folding and stabilization. Chemists are now designing biomimetic organo-metallic amino acids that can form both secondary and tertiary structures. An overview of the design and synthesis of non-proteinogenic amino acids containing metal ions in the side chain is discussed. Keywords: Amino acid analogues, side chain metal complex, synthesis, structure

Structure Elucidation of Dimethylformamide-Solvated Alkylzinc Cations in the Gas Phase

Organozinc iodides, useful for the synthesis of nonproteinogenic amino acids, are investigated in the gas phase by a combination of electrospray (ESI)-MS/MS, accurate ion mass measurements, and infrared multiphoton dissociation (IRMPD) spectroscopy employing a free electron laser. ESI allowed the full characterization of a set of dimethylformamide (DMF)-solvated alkylzinc cations formed by formal loss of I(-) in the gas phase. Gas phase ion structures of the organozinc cations were identified and optimized by computations at the B3LYP/6-311G** level of theory. The calculations indicate that the zinc cation in gas phase alkylzinc-DMF species preferentially adopts a tetrahedral coordination sphere with four ligands, namely the alkyl group, any internal coordinating group, and DMF (the number of which depends on the number of internal coordinating groups present). Besides the sequential loss of coordinated DMF, collision-induced dissociation (CID) patterns demonstrate that the zinc-DMF interaction in tetrahedral four-coordinate mono-DMF-zinc complex ions can be even stronger than covalent bonds. The IRMPD spectra of the alkylzinc-DMF species examined show a rich pattern of indicative bands in the range of 1000-1800 cm(-1). All major features of the recorded IRMPD spectra are consistent with the computed IR spectra of the respective gas phase ion structures predicted by theory, allowing identification and assignment.

Kolbe Electrolysis as a Novel Way of Generating Non-Proteinogenic Amino Acids

By using Kolbe electrolysis [1], an anodic oxidation, carboxylic acids are able to form dimers through precent decarboxylation and generation of radicals. The scope of the Kolbe reaction can be considerably enhanced by cross-reaction of two different carboxylic acids. L-glutamic acid (Glu), which is blocked at the α-carboxyl and the amino group by protective groups, opens a new way for the synthesis of non-proteinogenic amino acids with defined stereochemistry. As examples Z-L-norleucine and amino acids containing a second amino group at its side chain were synthesized.

Synthesis of non-proteinogenic amino acids using Michael addition to unsaturated orthopyroglutamate derivative

Stereoselective synthesis of non-proteinogenic amino acids via Michael addition to 3,4-didehydropyroglutamate derivative in which the carboxyl function is protected as a 2,7,8-trioxabicyclo[3.2.1]octane (ABO ester) group is described. The obtained 3-substituted pyroglutamic ABO ester was directly converted to 3-substituted glutamic acids such as chlorpheg by acidic hydrolysis, whereas 3-substituted proline derivatives were obtained by chemoselective reduction of the lactam carbonyl group. A formal total synthesis of baclofen, a γ-aminobutyric acid (GABA) analogue, is also described.

Asymmetric synthesis of nonproteinogenic amino acids with l-amino acid transaminase: synthesis of (2 S)-2-amino-4-oxo-4-phenylbutyric and (3 E,2 S)-2-amino-4-phenylbutenoic acids

2,4-Dioxo-4-phenylbutyric acid and 2-oxo-4-phenylbut-3-enoic acid are converted to the corresponding ( S)-2-amino acids by recombinant Escherichia coli whole cells over-expressing aromatic transaminase from Enterobacter sp. BK2K-1 (AroAT Es) in high yields (68–78%) and high enantiomeric purity (>99%) using l-aspartic acid as an amino donor.

A New Stereocontrolled Approach to a Key Intermediate in the Synthesis of (2S,3R)-Capreomycidine

A new stereocontrolled approach to the synthesis of advanced intermediate in the synthesis of nonproteinogenic amino acid (2S,3R)-capreomycidine via the novel domino reaction has been developed.

Design and Synthesis of Non-proteinogenic Amino Acids and Secondary Structures of Their Peptides

Replacement of the alpha-hydrogen atom of L-alpha-amino acids with an alkyl substituent results in alpha,alpha-disubstituted amino acids. The modification changes the properties of the amino acids. Incorporation of alpha,alpha-disubstituted amino acids into oligopeptides restricts the conformational freedom of their peptides. The author developed a synthetic route for optically active alpha-ethylated alpha,alpha-disubstituted amino acids using chiral cyclic 1,2-diol, and disclosed that the preferred conformation of peptides composed of chiral alpha-ethylated disubstituted amino acids is a fully planar conformation, whereas that of chiral alpha-methylated disubstituted amino acids is a 3(10)-helical structure. Furthermore, the author designed and synthesized two chiral cyclic alpha,alpha-disubstituted amino acids, i.e., (3S,4S)-1-amino-3,4-di(methoxy)cyclopentanecarboxylic acid {(S,S)-Ac5cdOM}, and (1R,6R)-8-aminobicyclo-[4.3.0]non-3-ene-8-carboxylic acid {(R,R)-Ab5,6=c}. They do not have a chiral center at the alpha-position, but do have chiral centers on the side-chain cyclopentane or the bicyclic skeleton. The preferred secondary structure of the (S,S)-Ac5cdOM homopeptides was the left-handed (M) 3(10)-helical structure (hexapeptide) and the left-handed (M) alpha-helical structure (octa- and decapeptides), while that of the (R,R)-Ab5,6=c hexapeptide was both the right-handed (P) and left-handed (M) 3(10)-helices. These results indicate that the side-chain chiral centers affect the secondary structure of their peptides, and the side-chain chiral environment is important for the control of the helical-screw direction of peptides.

Synthesis of nonproteinogenic amino acids to probe lantibiotic biosynthesis.

The synthesis of six nonproteinogenic amino acids appropriately protected for Fmoc-based solid-phase peptide synthesis is described. These amino acids are (2S,3R)-vinylthreonine, (2S)-(E)-2-amino-5-fluoro-pent-3-enoic acid (fluoroallylglycine), (S)-beta(2)-homoserine, (S) and (R)-beta(3)-homocysteine, and (2R,3R)-methylcysteine. Once incorporated into peptides, these compounds were envisioned to serve as alternative substrates for the lantibiotic synthases that dehydrate serine and threonine residues in their peptide substrates and catalyze the subsequent intramolecular Michael-type addition of cysteines to the dehydroamino acids.

Synthesis of non-proteinogenic amino acids from N-(4-toluenesulfonyl)dehydroamino acid derivatives

By treating N-(4-toluenesulfonyl)- N-( tert-butyloxycarbonyl)-dehydroamino acid derivatives with different reactants under different conditions, a variety of new amino acids are obtained, viz. (i) α-alcoxy-α-amino acids, (ii) α,α-diamino acids and (iii) novel β-substituted dehydroamino acids.

ChemInform Abstract: Formation of Functional Cyclic Nitrones via a New Reaction Intermediate, Nitrosoketene and Its Development for the Synthesis of Nonproteinogenic Amino Acids

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Stereoselective synthesis of non-proteinogenic amino acids

Abstract The lactam enolate of the protected pyroglutamic acid ester (1) has been shown to react with activated imines to yield optically pure derivatives of non-proteinogenic amino acids.

ChemInform Abstract: Synthesis of Chiral Cyclic Nitrones via a Nitrosoketene Intermediate and Their Use for the Complete EPC Synthesis of Nonproteinogenic Amino Acids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of chiral cyclic nitrones via a nitrosoketene intermediate and their use for the complete EPC synthesis of nonproteinogenic amino acids

New cyclic chiral nitrones constituting two diastereomers were synthesized by the reaction of isonitroso Meldrum's acid with l-menthone via a nitrosoketene intermediate. Both nitrones reacted with allyltrimethylsilane diastereoselectively to give the corresponding isoxazolidine derivatives as sole products, which converted to ( S)- and ( R)-allylglycines in ca. 100% ee, respectively.