Synthesis Of Unnatural Amino Acids Research Articles

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.

Katritzky Salts for the Synthesis of Unnatural Amino Acids and Late‐Stage Functionalization of Peptides

AbstractPeptide drug discovery often benefits from the large structural diversity permitted by unnatural amino acids (UAAs). Indeed, numerous approved peptide drugs include UAAs in their sequences. Therefore, innovative chemical approaches either to synthesize UAAs or to allow late‐stage functionalization of peptides are emerging themes in peptide drug discovery. Thanks to the recent advances in deaminative strategies using alkylpyridiniums salts, often referred to as Katritzky salts, a variety of radical alkylation methods have been developed. In recent years the use of Katritzky salts have become popular in peptide chemistry due to their ease of preparation from a primary amine, which is a predominant functional group in amino acids. This review highlights the progress that has been made by using Katritzky salts in the synthesis of UAAs, late‐stage peptide functionalization, and peptide macrocyclization.

Radical‐Mediated C−H Alkylation of Glycine Derivatives: A Straightforward Strategy for Diverse α‐Unnatural Amino Acids

AbstractUnnatural amino acids are important scaffolds for novel drug candidates, and especially α‐alkyl amino acids have emerged as a valuable variant. This is due to the ubiquity of alkyl groups, which are pervasive as key motifs in natural products, biological and pharmaceutical molecules. The development of radical‐based approaches in organic synthesis has expanded dramatically in recent years. It has enabled site‐ and region‐specific installation of a variety of functionalities in small molecules, which has been spontaneously applied in the preparation of versatile amino acid building blocks. The glycine motif in the backbone of amino acids has gained significant attention for allowing access to a variety of complex α‐unnatural amino acids via radical‐mediated α‐C−H alkylation. This review summarizes the last decade's development of radical‐based α‐C−H alkylation of glycine derivatives to provide unnatural α‐amino acids. The advantages, current limitations, and perspectives of glycine‐based unnatural amino acid synthesis are also discussed.

Nickel-Catalyzed Enantioselective Synthesis of Unnatural Amino Acids

Nickel-Catalyzed Enantioselective Synthesis of Unnatural Amino Acids

Ruthenium-Catalyzed Synthesis of Unnatural Amino Acids through Transfer Hydrogenation of Enamides

Key words ruthenium catalysis - transfer hydrogenation - enamides - amino acid derivatives - isopropyl alcohol

A New Method for Undruggable Targets: Amino Acids as Fragments of Inhibitors

Over the last decade, protein‐protein interactions (PPIs) have emerged as promising targets in the precise treatment of serious diseases. Many essential cellular pathways that are implicated in human diseases are controlled by intracellular PPIs. Such PPIs could be potential drug targets, and thus the ability of molecules to inhibit specific PPIs has remarkable therapeutic value. Unfortunately, PPI interfaces are generally large and present great difficulty for small molecule inhibitor design. Alternate strategies are being developed towards drug design and discovery for this type of target. For example, the synthesis of unnatural amino acids allows production of extremely large libraries of highly modified peptides, which may be screened against a PPI target. Peptide hits are a potential source of lead compounds in the search for new pharmaceutical agents and are promising for PPI inhibition. It is in this context that selection of the right unnatural amino acid becomes crucial.For this reason, developing new strategies to solve this problem is a key factor to find more efficient and specific inhibitors to PPI’s.In this study, we introduce a simple, Nuclear Magnetic Resonance (NMR) based methodology that screens natural and unnatural amino acids as “fragments” for development of new peptide‐based inhibitors for specific PPI’s. We validate this new method against MDM2, a well‐characterized and important negative regulator of the p53 tumor suppressor with known small peptides that inhibit its interaction with p53. A central tryptophan is the largest contributor to binding in this interface, and the corresponding MDM2 binding pocket is where we focused our efforts. Using this methodology, we screened non‐natural tryptophan derivatives, and several displayed a better binding affinity compared with the natural counterpart. Our simplified method allows priority ranking of amino acids according to their affinity to the protein. The highest‐ranking amino acids will be incorporated into peptides synthetically to confirm that improved free amino acid affinity translates to enhanced peptide binding and inhibition. In addition, this serves as a convenient and robust method to ‘pre‐screen’ amino acids for incorporation into in vitro peptide selection via mRNA display.