Synthesis Of Unnatural Amino Acids Research Articles

Flavin-Catalyzed, Photochemical Conversion of Dehydroalanine into 4,5-Dihydroxynorvaline.

The chemical synthesis of unnatural amino acids (UAA) is a key strategy for preparing designed peptides, including pharmaceutically active compounds. Alterations of existing amino acid residues such as dehydroalanine (Dha) are particularly important since selected positions can be addressed without the necessity of a complete de novo synthesis. The intriguing UAA 4,5-dihydroxynorvaline (Dnv) is found in a variety of naturally occurring peptides and biologically active compounds. However, no method is currently available to modify an existing peptide with this residue. We report the use of flavin catalysts and visible light irradiation for this challenge, which serves as a versatile strategy for converting Dha into Dnv. Our study shows that excited flavins are competent hydrogen atom abstraction catalysts for ethers and acetals, which allows masked 1,2-dihydroxyethylene functionalization from 2,2-dimethyl-1,3-dioxolane. The masked diol was successfully coupled to Dha residues, and a series of Dnv-containing products is reported. A mild and orthogonal protocol for deprotection of the acetal group was also identified, allowing free Dnv-modified peptides to be obtained. This method provides a straightforward strategy for Dnv functionalization, which is envisioned to be crucial for accessing natural products and synthetic analogues with pharmaceutical activity.

Flavin‐Catalyzed, Photochemical Conversion of Dehydroalanine into 4,5‐Dihydroxynorvaline

The chemical synthesis of unnatural amino acids (UAA) is a key strategy for preparing designed peptides, including pharmaceutically active compounds. Alterations of existing amino acid residues such as dehydroalanine (Dha) are particularly important since selected positions can be addressed without the necessity of a complete de novo synthesis. The intriguing UAA 4,5‐dihydroxynorvaline (Dnv) is found in a variety of naturally occurring peptides and biologically active compounds. However, no method is currently available to modify an existing peptide with this residue. We report the use of flavin catalysts and visible light irradiation for this challenge, which serves as a versatile strategy for converting Dha into Dnv. Our study shows that excited flavins are competent hydrogen atom abstraction catalysts for ethers and acetals, which allows masked 1,2‐dihydroxyethylene functionalization from 2,2‐dimethyl‐1,3‐dioxolane. The masked diol was successfully coupled to Dha residues, and a series of Dnv‐containing products is reported. A mild and orthogonal protocol for deprotection of the acetal group was also identified, allowing free Dnv‐modified peptides to be obtained. This method provides a straightforward strategy for Dnv functionalization, which is envisioned to be crucial for accessing natural products and synthetic analogues with pharmaceutical activity.

Enantioselective Synthesis of Unnatural Amino Acids by N–H Bond Insertion of Anilines

Enantioselective Synthesis of Unnatural Amino Acids by N–H Bond Insertion of Anilines

Organophotoredox-Catalyzed Synthesis of Unnatural α/β Amino Acids and Peptides via Deaminative Three-Component Coupling.

Herein, we disclose an expedient visible-light-mediated, organophotoredox-catalyzed multicomponent synthesis of unnatural amino acids using a Katritzky salt, glyoxal derivatives, and substituted anilines. Mechanistically, an alkyl radical is generated from the Katritzky salt via a deaminative process that undergoes addition to the in situ-generated imine to furnish α-amino acids in a moderate diastereoisomeric ratio. For the first time, we have demonstrated this deaminative protocol to access substituted β-amino acids from α-amino acid-derived Katritzky salts. Furthermore, α-amino amides are also generated from the corresponding 2-oxoacetamide derivatives.

Dual Metal-Catalyzed Electrocatalytic Synthesis of Unnatural Amino Acids

Dual Metal-Catalyzed Electrocatalytic Synthesis of Unnatural Amino Acids

Photocatalytic Functionalization of Dehydroalanine-Derived Peptides in Batch and Flow.

Unnatural amino acids, and their synthesis by the late-stage functionalization (LSF) of peptides, play a crucial role in areas such as drug design and discovery. Historically, the LSF of biomolecules has predominantly utilized traditional synthetic methodologies that exploit nucleophilic residues, such as cysteine, lysine or tyrosine. Herein, we present a photocatalytic hydroarylation process targeting the electrophilic residue dehydroalanine (Dha). This residue possesses an α,β-unsaturated moiety and can be combined with various arylthianthrenium salts, both in batch and flow reactors. Notably, the flow setup proved instrumental for efficient scale-up, paving the way for the synthesis of unnatural amino acids and peptides in substantial quantities. Our photocatalytic approach, being inherently mild, permits the diversification of peptides even when they contain sensitive functional groups. The readily available arylthianthrenium salts facilitate the seamless integration of Dha-containing peptides with a wide range of arenes, drug blueprints, and natural products, culminating in the creation of unconventional phenylalanine derivatives. The synergistic effect of the high functional group tolerance and the modular characteristic of the aryl electrophile enables efficient peptide conjugation and ligation in both batch and flow conditions.

Photocatalytic Functionalization of Dehydroalanine‐Derived Peptides in Batch and Flow

AbstractUnnatural amino acids, and their synthesis by the late‐stage functionalization (LSF) of peptides, play a crucial role in areas such as drug design and discovery. Historically, the LSF of biomolecules has predominantly utilized traditional synthetic methodologies that exploit nucleophilic residues, such as cysteine, lysine or tyrosine. Herein, we present a photocatalytic hydroarylation process targeting the electrophilic residue dehydroalanine (Dha). This residue possesses an α,β‐unsaturated moiety and can be combined with various arylthianthrenium salts, both in batch and flow reactors. Notably, the flow setup proved instrumental for efficient scale‐up, paving the way for the synthesis of unnatural amino acids and peptides in substantial quantities. Our photocatalytic approach, being inherently mild, permits the diversification of peptides even when they contain sensitive functional groups. The readily available arylthianthrenium salts facilitate the seamless integration of Dha‐containing peptides with a wide range of arenes, drug blueprints, and natural products, culminating in the creation of unconventional phenylalanine derivatives. The synergistic effect of the high functional group tolerance and the modular characteristic of the aryl electrophile enables efficient peptide conjugation and ligation in both batch and flow conditions.

Synthesis of Unnatural Amino Acids via Ni/Ag Electrocatalytic Cross-Coupling.

A simple protocol is outlined herein for rapid access to enantiopure unnatural amino acids (UAAs) from trivial glutamate and aspartate precursors. The method relies on Ag/Ni-electrocatalytic decarboxylative coupling and can be rapidly conducted in parallel (24 reactions at a time) to ascertain coupling viability followed by scale-up for the generation of useful quantities of UAAs for exploratory studies.

Electrochemical Synthesis of Unnatural Amino Acids Embedding 5- and 6-Membered Heteroaromatics.

Using a commercially available potentiostat, the electrochemical synthesis of unnatural amino acids bearing heteroaromatics on the lateral chain has been accomplished. This strategy exploits the side-chain decarboxylative arylation of aspartic/glutamic acid, a reaction that becomes challenging with electron-rich coupling partners such as 5- and 6-membered heteroaromatics. These rings are underrepresented in unnatural amino acids, therefore allowing a wider exploration of the chemical space, given the abundance of the aryl bromides employable in this reaction.

Application of the LADA Strategy for the Synthesis of Unnatural Amino Acids through 1,2-Aryl Migration of Allylic Alcohols.

Unnatural amino acids are versatile building blocks. Herein, we report the application of the LADA strategy for the direct synthesis of unnatural amino acids through 1,2-aryl migration of allylic alcohols. This reaction proceeds under mild conditions, tolerates diverse functionalities, and works smoothly on different thiols.

Redesigning transamination and decarboxylation characteristics of L-aspartate aminotransferase by site directed mutation of non-active site

Aspartate aminotransferase (L-AspAT) is a highly substrate-specific biocatalyst for chiral amino acid splitting and unnatural amino acid synthesis, with both transamination and decarboxylation functions, but it is frequently interfered with each other in the catalytic process. The characterized mutant strains for the isolation of transamination and decarboxylation were obtained by bioinformatics analysis and site-directed mutagenesis in this research. The results showed that the mutants T296D and C180I enhanced decarboxylation by hydrogen bonding to α-ketoglutarate. In contrast, the mutants W130S and W130P increased the transamination activities to 157 % and 144 % of the WT respectively, which improved the binding efficiency through the expansion of the substrate binding pocket of the mutations. In addition, the catalytic efficiency of W130P for o-chlorobenzoylformate was also increased to 226 % of the WT, and the size of the binding pocket with o-chlorobenzoylformate was increased from 9.2 Å to 11.5 Å, a big change improved the probability of the substrate's entry. These results provided an extremely important idea and theoretical basis for changing the preference of bifunctional enzymes by mutating.

Benzylic Lithiation Reaction for the Synthesis of Unnatural Amino Acids

Benzylic Lithiation Reaction for the Synthesis of Unnatural Amino Acids

Electrochemical Synthesis of Unnatural Amino Acids via Anodic Decarboxylation of N-Acetylamino Malonic Acid Derivatives.

Broad application of α,α-disubstituted cyclic amino acid derivatives in medicinal chemistry urges for analogue design with improved pharmacokinetic properties. Herein, we disclose an electrochemical approach toward unnatural THF- and THP-containing amino acid derivatives that relies on anodic decarboxylation-intramolecular etherification of inexpensive and readily available N-acetylamino malonic acid monoesters under Hofer-Moest reaction conditions. The decarboxylative cyclization proceeds under constant current conditions in an undivided cell in an aqueous medium without any added base. A successful bioisosteric replacement of the 1-aminocyclohexane-1-carboxylic acid subunit by the THP-containing amino acid scaffold in cathepsin K inhibitor balicatib helped to reduce lipophilicity while retaining low nanomolar enzyme inhibitory potency and comparable microsomal stability.

Synthesis of Unnatural Amino Acids from in situ Generated Glycine Cation Equivalents

Synthesis of Unnatural Amino Acids from in situ Generated Glycine Cation Equivalents

Direct synthesis of unnatural amino acids and modifications of peptides via LADA strategy

Unnatural amino acids (UAAs) have broad applications in pharmaceutical sciences and biological studies. Current synthetic methods for UAAs mainly rely on asymmetric catalysis and often require several steps. There is a lack of direct and simple methods. To address this challenge, we designed the LADA (labeling-activation-desulfurization-addition) strategy: selective labeling and activation of cysteine residues, the photocatalytic desulfurization and the subsequent radical addition to alkenes. Although composed of two steps, it is one-pot synthesis and has advantages such as high functional group tolerance, biocompatible reaction condition, and retained stereochemistry. This highly efficient strategy was successfully applied in the direct synthesis of unnatural amino acids and modifications of peptides with more than 50 examples.

LADA strategy for the synthesis of unnatural amino acids and direct modifications of peptides

LADA strategy for the synthesis of unnatural amino acids and direct modifications of peptides

Photochemical Synthesis of Unnatural Amino Acids through CF3 Radical Addition to Michael Acceptors

Key words photochemistry - carbocation - Michael acceptor - umpolung

Synthesis of Unnatural Amino Acids from Glycinates

Synthesis of Unnatural Amino Acids from Glycinates

Front Cover: Katritzky Salts for the Synthesis of Unnatural Amino Acids and Late‐Stage Functionalization of Peptides (Eur. J. Org. Chem. 12/2023)

The Front Cover shows chalkboard drawings of recent advances in the use of Katritzky salts as intermediates for the synthesis of unnatural amino acids, late-stage functionalization of peptides, and macrocyclization. Thanks to the progress made in deaminative strategies using Katritzky salts, a variety of radical alkylation methods have been developed in the peptide chemistry field. Peptide drug development will greatly benefit from the novel methodologies to expand the chemical space explored around peptides and biomolecules. Cover design realized by Yousif. More information can be found in the Review by A. M. Yousif et al.

Glycosyl Radical-Based Synthesis of C-Glycoamino Acids and C-Glycopeptides.

Radical-based reactions usually exhibit excellent functional-group compatibilities due to their mild initiation conditions. Glycosyl radical involved C-glycosylation modifications are important strategies to achieve highly regio- and chemoselective constructions of C-glycosidic bonds or C-glycoside linkages of peptides and proteins. In this Concept, we cover recent developments in glycosyl radical-based synthesis of unnatural amino acids and late-stage modification of peptides and proteins, and provide a preliminary outlook on the possible development of this direction in the future.