Synthesis Of Unnatural Α-amino Acids Research Articles

Asymmetric synthesis of unnatural α-amino acids through photoredox-mediated C–O bond activation of aliphatic alcohols

A practical protocol for the stereoselective synthesis of unnatural α-amino acids is disclosed, using ubiquitous aliphatic alcohols as radical precursors to form the α-amino acid backbone under redox-neutral photoredox-mediated conditions.

Engineering of Dual-Function Vitreoscilla Hemoglobin: A One-Pot Strategy for the Synthesis of Unnatural α-Amino Acids.

Despite a well-developed and growing body of work on the directed evolution of hemoproteins, the potential of hemoproteins to catalyze non-natural reactions remains underexplored. This paper reports a new biocatalytic strategy for the one-pot synthesis of unnatural α-amino acids. Engineered variants of dual-function Vitreoscilla hemoglobin were found to efficiently catalyze N-H insertion and C-H sp3 alkylation, providing moderate to excellent yields (57%-95%) of unnatural α-amino acid derivatives and turnover numbers (1425-2375).

Synthesis of Unnatural α-Amino Acids from (Pyridin-2-yl) Carbamate via CIPE-Induced Carbonyl Migration.

Synthetic methods of unnatural α-amino acids have always been the focus of extensive research due to their significant bioactivities. However, convenient transition-metal-free catalyzed methods are still in demand. Herein, we report a novel strategy for the construction of an unnatural α-amino acid skeleton via intramolecular rearrangement of carbamates, which are readily available from amines and their common protecting groups. This rearrangement could afford a variety of amino ester products in up to 98% yield, even in gram-scale reaction. The reaction mechanism was studied in detail through experiments and theoretical calculations. The complex-induced proximity effect (CIPE) from the 2-pyridyl group is shown to be indispensable for this transformation.

Synthesis of Unnatural α-Amino Acids Mediated by Visible Light

Synthesis of Unnatural α-Amino Acids Mediated by Visible Light

Photoredox-Enabled Decarboxylative Synthesis of Unnatural α-Amino Acids

AbstractRecently, development of general synthetic routes to unnatural α-amino acids has gained significant momentum, driven by the high demand for such building blocks in fundamental research within molecular and structural biology, as well as for development of new pharmaceuticals. Herein, we highlight the recent progress in employing photoredox-mediated synthetic methods for accessing unnatural α-amino acids with a focus on various decarboxylative radical-based strategies.

Biocompatible Photoinduced Alkylation of Dehydroalanine for the Synthesis of Unnatural α-Amino Acids.

A site-selective alkylation of dehydroalanine to access protected unnatural amino acids is described. The protocol is characterized by the wide nature of alkyl radicals employed, mild conditions, and functional group compatibility. This protocol is further extended to access peptides, late-stage functionalization of pharmaceuticals, and enantioenriched amino acids.

Synthesis of Unnatural α-Amino Acids via Photoinduced Decatungstate-Catalyzed Giese Reactions of Aldehydes.

Synthesis of unnatural amino acids has long been a focus of chemistry research. Here, we present an efficient, general method that furnishes γ-carbonyl α-amino acids via photoinduced decatungstate-catalyzed Giese reactions of readily available aldehydes as radical precursors. This mild, robust method is compatible with a wide array of functional groups and has a broad substrate scope. We demonstrated the utility of the method by modifying several amino acid bearing drugs and natural products.

Stereoselective synthesis of unnatural α-amino acid derivatives through photoredox catalysis.

A protocol for stereoselective C-radical addition to a chiral glyoxylate-derived N-sulfinyl imine was developed through visible light-promoted photoredox catalysis, providing a convenient method for the synthesis of unnatural α-amino acids. The developed protocol allows the use of ubiquitous carboxylic acids as radical precursors without prior derivatization. The protocol utilizes near-stoichiometric amounts of the imine and the acid radical precursor in combination with a catalytic amount of an organic acridinium-based photocatalyst. Alternative mechanisms for the developed transformation are discussed and corroborated by experimental and computational studies.

Synthesis of Unnatural α-Amino Acids under Visible-Light Irradiation

Synthesis of Unnatural α-Amino Acids under Visible-Light Irradiation

Stereoselective Synthesis of Unnatural α-Amino Acids

Key words amino acids - palladium catalysis - asymmetric catalysis - hydroalkylation - azlactones - dienes

A general synthesis of unnatural α-amino acids by iron-catalysed olefin–olefin coupling via generated radicals

A general protocol for the asymmetric synthesis of unnatural α-amino acids with γ-tertiary and quaternary carbon centers via generated radicals is reported.

One-pot, two-step synthesis of unnatural α-amino acids involving the exhaustive aerobic oxidation of 1,2-diols.

Herein, we report the nor-AZADO-catalyzed exhaustive aerobic oxidations of 1,2-diols to α-keto acids. Combining oxidation with transamination using dl-2-phenylglycine led to the synthesis of free α-amino acids (AAs) in one pot. This method enables the rapid and flexible preparation of a variety of valuable unnatural AAs, such as fluorescent AAs, photoactivatable AAs, and other functional AAs for bioorthogonal reactions.

Synthesis of Unnatural α-Amino Acids and Heterocycles as New Bases of Nucleoside Moiety

The treatment of 4-(3,4-Dichlorophenyl)-4-oxobut-2-enoic acid with ethylglycinate, anthranilic, and phenylene diamine, can be afforded butanoic acid derivatives 1 as unnatural α-amino acid. The aza-Michael adducts 1 are used as a key starting materials to synthesize some heterocycles include furanone, benzoxazapindione, pyridazinone and quinoxaline deriva- tives via treatment of the adducts 1 with electrophilic and nucleophilic reagents to synthesize new bases of nucleoside moieties. The acid chloride of dibasic adduct 1b can be afforded regioselective heterocycles indolone 9, and quinolone 10 depending on pH medium.

Scalable organocatalytic asymmetric Strecker reactions catalysed by a chiral cyanide generator

The Strecker synthesis is one of the most facile methods to access racemic α-amino acids. However, feasible catalytic asymmetric Strecker reactions for the large-scale production of enantioenriched α-amino acids are rare. Here we report a scalable catalytic asymmetric Strecker reaction that uses an accessible chiral variant of oligoethylene glycol as the catalyst and KCN to generate a chiral cyanide anion. Various α-amido sulphone substrates (alkyl, aryl and heteroaryl) can be transformed into the optically enriched Strecker products, α-aminonitriles, with excellent yields and enantioselectivities. Moreover, the robust nature of the catalyst enables a 'one-pot' synthesis of enantiomerically pure α-amino acids starting from α-amido sulphones and simple catalyst recycling. These features can make this protocol easily adaptable to the practical synthesis of unnatural α-amino acids.

Recent Advances in the Synthesis of Unnatural α-Amino Acids - An Updated Version

The synthesis of unnatural α-amino acids is an area of research that has gained a lot of attention in recent years. The availability of synthetic methods for novel unnatural α-amino acids derivatives and related compounds will be critical in the de novo design of molecules that mimic the conformation of natural, active peptides. These molecules - peptidomimetics - are designed to display high receptor affinity and selectivity, in addition to enhanced bioavailability and metabolic stability. This review presents and discusses selected synthetic methodologies leading to unnatural α-amino acids, including chiral catalysts that enable enantioselective synthesis and microwave-assisted synthesis. Solid phase synthesis and construction of organometallic α-amino acids reveal the scope of influence that this field has in organic chemistry. Additionally, the article is aimed to provide a brief insight into biosynthetic approaches to the synthesis of α-amino acid derivatives, thus providing the reader with an overall appreciation of the field. For the purpose of this issue our previous review on the unnatural α-amino acids synthesis [Perdih A. and Sollner Dolenc M. Curr Org. Chem. 2007, 11, 801-832] has been revised and updated and discusses also selected contributions covering the period from 2007-2010. Keywords: Unnatural α-amino acids, peptidomimetics, amino acid derivatives, synthesis, neurotransmitters, neuromodulators, hormones, paracrine factors, cytokines, antigens, Peptide molecules, photolytic degradation, stereo-electronic, covalent or noncovalent, glycomimetics field

Recent Advances in the Synthesis of Unnatural α-Amino Acids

The synthesis of unnatural α-amino acids is an area of research that has gained a lot of attention in recent years. The availability of synthetic methods for novel unnatural αamino acid derivatives and related compounds will be a critical point in the de novo design of molecules that mimic the conformation of the natural, active peptides. These molecules (peptidomimetics) are designed to display high receptor affinity and selectivity, in addition to enhanced bioavailability and metabolic stability. This review focuses on selected recent synthetic methodologies leading to unnatural α-amino acids including chiral catalysts that enable enantioselective synthesis and microwave-assisted synthesis. Solid phase synthesis and construction of organometallic αamino acids reveal the scope of influence that this field has in organic chemistry. Additionally, the article is aimed to provide a brief insight into the biosynthetic approaches to the synthesis of α-amino acid derivatives, and to give the reader an appreciation of the field. Keywords: Arylglycine derivatives, Dehydroamino Acid Derivatives, N-Methylation, USP methodology, Hydrogenation, Proline Derivatives

Hydrogen-Mediated Reductive Coupling of Conjugated Alkynes with Ethyl (N-Sulfinyl)iminoacetates: Synthesis of Unnatural α-Amino Acids via Rhodium-Catalyzed C−C Bond Forming Hydrogenation [J. Am. Chem. Soc. 2005, 127, 11269−11276

Hydrogen-Mediated Reductive Coupling of Conjugated Alkynes with Ethyl (<i>N</i>-Sulfinyl)iminoacetates: Synthesis of Unnatural α-Amino Acids via Rhodium-Catalyzed C−C Bond Forming Hydrogenation [<i>J. Am. Chem. Soc.</i> <b>2005</b>, <i>127</i>, 11269−11276

Hydrogen-Mediated Reductive Coupling of Conjugated Alkynes with Ethyl (N-Sulfinyl)iminoacetates: Synthesis of Unnatural α-Amino Acids via Rhodium-Catalyzed C−C Bond Forming Hydrogenation

Rhodium-catalyzed hydrogenation of 1,3-enynes 1a-8a and 1,3-diynes 9a-13a at ambient temperature and pressure in the presence of ethyl (N-tert-butanesulfinyl)iminoacetate and ethyl (N-2,4,6-triisopropylbenzenesulfinyl)iminoacetates, respectively, results in reductive coupling to afford unsaturated alpha-amino acid esters 1b-13b in good to excellent yields with exceptional levels of regio- and stereocontrol. Further hydrogenation of the diene containing alpha-amino acid esters 1b-8b using Wilkinson's catalyst at ambient temperature and pressure results in regioselective reduction to afford the beta,gamma-unsaturated alpha-amino acid esters 1c-8c in good to excellent yields. Exhaustive hydrogenation of the unsaturated side chains of the Boc- and Fmoc-protected derivatives of enyne and diyne coupling products 14b-16b occurs in excellent yield using Crabtree's catalyst at ambient temperature and pressure providing the alpha-amino acid esters 14d-16d, which possess saturated side chains. Finally, cross-metathesis of the Boc-protected reductive coupling product 14b with cis-1,4-diacetoxy-2-butene proceeds readily to afford the allylic acetate 14e. Isotopic labeling studies that involve reductive coupling of enyne 1a and diyne 9a under an atmosphere of elemental deuterium corroborate a catalytic mechanism in which oxidative coupling of the alkyne and imine residues is followed by hydrogenolytic cleavage of the resulting metallacycle. A stereochemical model accounting for the observed sense of asymmetric induction is provided. These studies represent the first use of imines as electrophilic partners in hydrogen-mediated reductive carbon-carbon bond formation.

A new strategy for the stereoselective synthesis of unnatural α-amino acids

A new method for the synthesis of racemic non-proteinogenic α-amino acids has been developed, which involves (i) hetero-Diels–Alder addition of ethyl 2-nitrosoacrylate to electron rich alkenes such as enol ethers, enamines and allylsilanes, (ii) NaCNBH 3 reduction of the C N bond in the oxazines thus generated, the stereochemistry of the products being controlled by epimerisation of the thermodynamically less stable isomer to the more stable one, (iii) protection of the N–H group as N-Boc and (iv) finally, N–O bond cleavage of both free and protected products to give proline or bis-homoserine derivatives, respectively. An example with concomitant reduction of the carboxylate group, resulting in the formation of the respective amino alcohol is reported. Applying this methodology to a homochiral enol ether, the protected parent d-proline was prepared in enantiomerically pure form, whereas the asymmetric synthesis of the respective bis-homoserine was unsuccessful.

Catalysis of highly stereoselective Mannich-type reactions of ketones with α-imino esters by a pyrrolidine-sulfonamide. Synthesis of unnatural α-amino acids

The novel pyrrolidine-sulfonamide I has been prepared and used successfully to catalyze Mannich-type reactions between ketones and α-imino esters. The process is used to efficiently synthesize functionalized α-amino acid derivatives with excellent levels of regio-, diastereo-, and enantio-selectivity.