Chiral Α-amino Research Articles

Enantioselective Synthesis of Azatricycles via Post-Ugi Cyclizations.

We report a new method to create enantioenriched azatricycles using chiral α-amino acids in a two-step process after an Ugi reaction. Amino acids are great building blocks for making pure chiral molecules. Using chiral natural molecules in multicomponent reactions (MCRs) helps increase their variety by adding new chiral centers. The Ugi reaction, discovered by Ivar Karl Ugi in 1959, is a versatile MCR that helps create complex molecular structures and natural products through additional transformations called post-Ugi modifications. Designing these modifications requires selecting the right amine, acid, aldehyde/ketone, and isocyanide. Amino acids, with their primary amine and carboxylic acid groups and a pre-existing chiral center, are ideal for making diverse and selective post-Ugi modifications. Our method uses ipso-cyclization and aza-Michael cyclization with hypervalent iodine to create various azaspirotricyclic structures with high stereocontrol. This approach works well with different substrates and shows promise for further development in drug discovery.

Enantioselective Deoxygenative Amino-Cyanation of Carboxylic Acids via Ti-Multicatalysis.

Carboxylic acids are valued synthetic building blocks that offer shelf life stability, structural diversity, and wide commercial availability. Despite the remarkable synthetic utility of carboxylic acids, a direct enantioselective deoxygenative functionalization of carboxylic acids remains rare. We present enantioselective deoxygenative amino-cyanation of carboxylic acids using a novel TiIV-multicatalytic system that catalytically modified each C-O bond of carboxylic acid to C-C, C-N, and C-H bonds, generating enantio-enriched chiral α-amino nitriles (up to 98:2 er).

Synthesis of chiral α-amino acids via Pd(ii)-catalyzed enantioselective C-H arylation of α-aminoisobutyric acid.

Non-natural chiral α,α-disubstituted α-amino acids (α,α-AAs) constitute an attractive α-aminoisobutyric acid (Aib) replacement for improving bioavailability of linear peptides as therapeutics due to the ability of these amino acids to induce the peptides to form helical structures. Enantioselective β-C(sp3)-H arylation of Aib could potentially provide a versatile one-step strategy for accessing diverse α,α-AAs, but the installation and removal of external directing groups was found in our previously reported work to reduce the efficiency of this approach. Herein we report a Pd(ii)-catalyzed enantioselective C-H arylation of N-phthalyl-protected Aib enabled by a N-2,6-difluorobenzoyl aminoethyl phenyl thioether (MPAThio) ligand, affording α,α-AAs with up to 72% yield and 98% ee. Use of this newly developed chiral catalyst has also significantly improved enantioselective C(sp3)-H arylation of cyclopropanecarboxylic acids by expanding the substrate scope to heterocyclic coupling partners and increasing enantioselectivity to 99% ee.

Enantioselective α-Amination of Amides by One-Pot Organo-/Iodine Sequential Catalysis.

An one-pot organo- and iodine sequential catalysis strategy for reactions of amides with pyrazole-based primary amines was described to synthesize chiral α-amino amides with a quaternary stereocenter. This methodology exhibited strong asymmetric induction, resulting in a typical enantiomeric excess value exceeding 99% and diastereoselectivity up to >99:1 dr. Moreover, the reaction was conducted without the use of any metals or strong bases.

T3P®-Assisted cascade synthesis of N-acyl α-cyanoamines, cyanoaryl amides and N-acyl cyanoarylamines: Application in making three pharmaceutically important molecules

Organic compounds possessing N-acyl α-cyanoamine function shows numerous pharmaceutical and medicinal properties, however, their synthesis require multiple steps. This article describes a novel and sustainable one-pot construction of N-acyl α-cyanoamines from α-amino amides and acids via propanephosphonic acid anhydride (T3P®)-assisted cascade strategy. A variety of chiral α-amino amides were conveniently transformed to N-acyl α-cyanoamine derivatives (15) by reacting with carboxylic acids using current protocol. The products are formed in 81–94% in 12 h at room temperature. Additionally, this method was also extended to the synthesis of cyanoaryl amides (18) (from 4-((aminooxy)carbonyl)benzoic acid and primary/secondary amines) and N-acyl cyanoarylamines (20) (from 3-aminobenzamide and carboxylic acids) with 83–95% yields in 2 h at 70 °C. The developed strategy has also been utilized successfully for the synthesis of DPP-4 inhibition agent, 2, intermediate, 4 of SphK1 inhibitor, and clinical agent of COVID-19, 10. These procedures are step-as well as pot-economic, which saves the reagents, solvents and separation agents required for the multiple steps that are associated with the reported routes.

Photoinduced C(sp3)-H Functionalization of Glycine Derivatives: Preparation of Unnatural α-Amino Acids and Late-Stage Modification of Peptides.

ConspectusPeptides are essential components of living systems and contribute to critical biological processes, such as cell proliferation, immune defense, tumor formation, and differentiation. Therefore, peptides have attracted considerable attention as targets for the development of therapeutic products. The incorporation of unnatural amino acid residues into peptides can considerably impact peptide immunogenicity, toxicity, side effects, water solubility, action duration, and distribution and enhance the peptides' druggability. Typically, the direct modification of natural amino acids is a practical and effective approach for promptly obtaining unnatural amino acids. However, selective functionalization of multiple C(sp3)-H bonds with comparable chemical reactivities in the peptide side chains remains a formidable challenge. Furthermore, chemical modifications aimed at highly reactive (nucleophilic and aromatic) groups on peptide side chains can interfere with the biological activity of peptides.In recent years, the rapid advancement of photoinduced radical reactions has made photoredox radical-radical cross-coupling a practical approach for constructing C(sp3)-C(sp3) bonds under mild conditions. Glycine, a naturally occurring amino acid and the fundamental skeleton of all α-amino acids, provides a basis for the alkylated modification of its own α-C(sp3)-H bond under mild conditions. This Account describes our recent research endeavors for systematically investigating the photocatalytic α-C(sp3)-H alkylation of glycine derivatives via radical-radical coupling between N-aryl glycinate-derived radicals and various alkyl radicals. In 2018, we disclosed the photoinduced Cu-catalyzed decarboxylative α-C(sp3)-H alkylation of glycine derivatives. Subsequently, we developed a catalyst-free method for alkylating glycine derivatives and glycine residues in peptides via electron donor-acceptor (EDA)-complex-promoted single electron transfer. Moreover, we developed a photoinduced method for the radical alkylation of N-aryl glycinate α-C(sp3)-H bonds using unactivated alkyl chlorides (iodides) under photocatalyst-free conditions. Notably, by building on racemic alkylations of glycine derivatives and glycine-residue-containing peptides, we recently stereoselectively alkylated the N-aryl glycinate α-C(sp3)-H bond using a dual-functional Cu catalyst generated in situ for synthesizing a series of unnatural chiral α-amino and C-glycoamino acids.We have developed a series of methods for synthesizing unnatural amino acids through the α-C(sp3)-H alkylation of glycine derivatives using photoredox-promoted radical coupling as a key strategy. These methods are efficient and versatile and can be used for the late-stage modification of peptides in various contexts. Our work builds on the fundamental importance of glycine as the basic scaffold of all α-amino acids and highlights the potential of radical-based chemistry for developing chemical transformations in peptide synthesis. These findings have broad implications for chemical biology and may open doors for discovering peptide drugs and developing therapeutics.

Synthesis of protected 1,4-trans-1,5-cis-4,5-diamino-2-cyclopenten-1-ol via stereoselective vinylation of α-amino aldimine

We report the synthesis of diaminocyclitol, protected 1,4-trans-1,5-cis-4,5-diamino-2-cyclopenten-1-ol. The key strategy was stereoselective vinylation of an acyclic chiral α-amino aldimine to construct syn-diamine moiety. The 1,5-cis-amino alcohol moiety was established by stereoselective reduction, and the cyclopentene structure was secured through a ring-closing metathesis reaction.

Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines.

Chiral amines are commonly used in the pharmaceutical and agrochemical industries1. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods1,2. Although the N-alkylation of aliphatic amines with alkyl halides has been widely adopted for over 100 years, catalyst poisoning and unfettered reactivity have been preventing the development of a catalyst-controlled enantioselective version3-5. Here we report the use of chiral tridentate anionic ligands to enable the copper-catalysed chemoselective and enantioconvergent N-alkylation of aliphatic amines with α-carbonyl alkyl chlorides. This method can directly convert feedstock chemicals, including ammonia and pharmaceutically relevant amines, into unnatural chiral α-amino amides under mild and robust conditions. Excellent enantioselectivity and functional-group tolerance were observed. The power of the method is demonstrated in a number of complex settings, including late-stage functionalization and in the expedited synthesis of diverse amine drug molecules. The current method indicates that multidentate anionic ligands are a general solution for overcoming transition-metal-catalyst poisoning.

A Spiro Phosphamide Catalyzed Enantioselective Proton Transfer of Ylides in a Free Carbene Insertion into N-H Bonds.

Free carbene readily causes multiple side reactions due to its high energy, thus its asymmetric transformation is very difficult. We present here our findings of high-pKa Brønsted acid catalysts that enable free carbene insertion into N-H bonds of amines to prepare chiral α-amino acid derivatives with high enantioselectivity. Under irradiation with visible light, diazo compounds produce high-energy free carbenes that are captured by amines to form free ylide intermediates, and then the newly designed high-pKa Brønsted acids, chiral spiro phosphamides, promote the proton transfer of ylides to afford the products. Computational and kinetic studies uncover the principle for the rational design of proton-transfer catalysts and explain how the catalysts accelerate this transformation and provide stereocontrol.

Chiral phosphoric acid-catalyzed enantioselective phosphinylation of 3,4-dihydroisoquinolines with diarylphosphine oxides

Chiral phosphorous-containing compounds are playing a more and more significant role in several different research fields. Here, we show a chiral phosphoric acid-catalyzed enantioselective phosphinylation of 3,4-dihydroisoquinolines with diarylphosphine oxides for the efficient and practical construction of a family of chiral α-amino diarylphosphine oxides with a diverse range of functional groups. The phosphine products are suitable for transforming to several kinds of chiral (thio)ureas, which might be employed as chiral ligands or catalysts with potential applications in asymmetric catalysis. Control and NMR tracking experiments show that the reaction proceeds via the tert-butyl 1-(tert-butoxy)-3,4-dihydroiso-quinoline-2(1H)-carboxylate intermediate, followed by C-P bond formation. Furthermore, computational studies elucidated that the hydrogen bonding strength between the phosphonate and isoquinolinium determines the stereoselectivity of the phosphinylation reaction.

A synthetic route to artificial chiral α-amino acids featuring a 3,4-dihydroisoquinolone core through a Rh(III)-catalyzed functionalization of allyl groups in chiral Ni(II) complexes.

Currently, non-proteinogenic α-amino acids (α-AAs) have attracted increasing interest in bio- and medicinal chemistry. In this context, the first protocol for the asymmetric synthesis of artificial α-AAs featuring a 3,4-dihydroisoquinolone core with two stereogenic centers was successfully elaborated. A straightforward Rh(III)-catalysed C-H activation/annulation reaction of various aryl hydroxamates with a set of robust and readily available chiral Ni(II) complexes, which have allylic appendages derived from glycine (Gly), alanine (Ala) and phenylalanine (Phe), allowed incorporation of a 3,4-dihydroisoquinolone scaffold into the chiral amino acid residue. The reaction was performed in methanol and under mild conditions (at room temperature under air atmosphere), providing separable diastereomeric complexes with up to 94% total yield. The target α-AA with a 3,4-dihydroisoquinolone core in an enantiopure form was subsequently released from the obtained chiral Ni(II) complexes via an acidic decomposition in aqueous HCl, along with the recovery of the chiral auxiliary ligand.

Enantiodetermining processes in the synthesis of alanine, serine, and isovaline.

In this study, quantum chemical calculations were used to explore the synthesis of three chiral α-amino acids, specifically alanine, serine, and isovaline, from reactants found in interstellar space. Our focus is on the crucial step in the synthesis pathway that determines the chirality of the amino acids. The results indicate that in the case of alanine, the determination of enantiomer is primarily influenced by the direction of the collision of molecules or functional groups, which leads to the formation of a chirality center in a crucial intermediate. However, contrary to chemical expectations, the enantiodetermining/enantioselection step for serine and isovaline synthesis occurs prior to the creation of a chirality center.

Synthesis of α-amino acid derived (1,2,3-triazol-4-yl)-picolinamide (tzpa) ligands and their corresponding luminescent Tb(iii) complexes

The synthesis of chiral α-amino acid derived (1,2,3-triazol-4-yl)-picolinamide (tzpa) ligands 4–6 designed by combining the coordination properties of two well-known ligand structures within a single unit is described.

Ammonia to chiral α-amino acid

Ammonia to chiral α-amino acid

C(sp3)-Arylation by Conformationally Accelerated Intramolecular Nucleophilic Aromatic Substitution (SNAr).

ConspectusThe asymmetric synthesis of heavily substituted benzylic stereogenic centers, prevalent in natural products, therapeutics, agrochemicals, and catalysts, is an ongoing challenge. In this Account, we outline our contribution to this endeavor, describing our discovery of a series of new reactions that not only have synthetic applicability but also present significant mechanistic intrigue. The story originated from our longstanding interest in the stereochemistry and reactivity of functionalized organolithiums. While investigating the lithiation chemistry of ureas (a “Cinderella” sister of the more established amides and carbamates), we noted an unexpected Truce–Smiles (T-S) rearrangement involving the 1,4-N → C transposition of a urea N′-aryl group to the α-carbanion of an adjacent N-benzyl group. Despite this reaction formally constituting an SNAr substitution, we found it to be remarkably tolerant of the electronic properties of the migrating aryl substituent and the degree of substitution at the carbanion. Moreover, in contrast to classical SNAr reactions, the rearrangement was sufficiently rapid that it took place under conditions compatible with configurational stability in an organolithium intermediate, enabling enantiospecific arylation at benzylic stereogenic centers. Experimental and computational studies confirmed a low kinetic barrier to the aryl migration arising from the strong preference for a trans arrangement of the urea N′-aryl and carbonyl groups, populating a reactive conformer in which spatial proximity was enforced between the carbanion and N′-aryl group, hugely accelerating ipso-substitution.This discovery led us to uncover a whole series of conformationally accelerated intramolecular N → C aryl transfers using different anilide-based functional groups, including a diverse range of urea, carbamate, and thiocarbamate-substituted anions. Products included enantioenriched α-tertiary amines (including α-arylated N-heterocycles) and alcohols, as well as rare α-tertiary thiols. Synthetically challenging diarylated centers with differentiated aryl groups featured heavily in all product sets. The absolute enantiospecificity (retention versus inversion) of the reaction was dependent on the heteroatom α to the lithiation site: the origin of this stereodivergence was probed both experimentally and computationally. Asymmetric variants of the rearrangement were realized by enantioselective deprotonation, and connective strategies were developed in which an intermolecular C–C bond-forming event preceded the anionic rearrangement. Substrates where the N′-nucleofuge (at the aryl ipso position) was tethered to the migrating arene allowed us to use the rearrangement as a ring expansion method to generate 8- to 12-membered medium-ring N-heterocycles from very simple precursors. Stabilized carbon nucleophiles such as alkali metal enolates also readily promoted intramolecular N → C aryl transfer in N′-arylureas, opening up access to biologically relevant hydantoins, and enabling a “chiral memory” approach for the (hetero)arylation of chiral α-amino acids with programmable retention or inversion of configuration. Collectively, our studies of electronically versatile T-S rearrangements in anilide-based systems have culminated in a practical and general strategy for transition metal-free C(sp3)-arylation. More broadly, our results highlight the power of conformational activation to achieve unprecedented reactivity in the construction of challenging C–C bonds.

Recent Advances in the Asymmetric Synthesis of Αlpha-Amino Acids via Radical Reactions

Chiral α-amino acids rank among the most important building blocks in living organisms and find wide application in synthetic chemistry, biochemistry, catalysis, and development of new drugs. This review highlights recent advances in the synthesis of chiral α-amino acids and their derivatives via radical reactions.

Stereocontrolled 1,3-nitrogen migration to access chiral α-amino acids.

α-Amino acids are essential for life as building blocks of proteins and components of diverse natural molecules. In both industry and academia, the incorporation of unnatural amino acids is often desirable for modulating chemical, physical, and pharmaceutical properties. We here report a protocol for the economical and practical synthesis of optically active α-amino acids based on an unprecedented stereocontrolled 1,3-nitrogen shift. Our method employs abundant and easily accessible carboxylic acids as starting materials, which are first connected to a nitrogenation reagent, followed by a highly regio- and enantioselective ruthenium- or iron-catalyzed C(sp3)−H amination. This straightforward method displays a very broad scope, providing rapid access to optically active α-amino acids with aryl, allyl, propargyl, and alkyl side chains, and also permits stereocontrolled late-stage amination of carboxylic acid-containing drugs and natural products.

Copper-Catalyzed Asymmetric Conjugated Addition to Form Chiral α-Amino Acids

Copper-Catalyzed Asymmetric Conjugated Addition to Form Chiral α-Amino Acids

Chiral Primary Amine Catalyzed Enantioselective Tandem Reactions Based on Heyns Rearrangement: Synthesis of α-Tertiary Amino Ketones

Herein, we disclose a new catalytic asymmetric tandem reaction based on the Heyns rearrangement for the synthesis of chiral α-amino ketones with readily available substrates. The rearrangement is different from the Heyns rearrangement in that the α-amino ketones were obtained without the shift of the carbonyl group. The key to success is using chiral primary amine as a catalyst by mimicking glucosamine-6-phosphate synthase in catalyzing the efficient Heyns rearrangement in organisms.

Monitoring of the yogurt fermentation process based on a rapid bio-luminescent chiral pattern recognition of amino acids.

The analysis of chiral α-amino acids is of great significance in asymmetric synthesis, nutrition, food science, and microbiology. However, the ability of chiral recognition is difficult to achieve. Due to the demand for expensive equipment and skilled operators, traditional methods such as high-performance liquid chromatography are limited. The previously reported methods based on chemical sensor arrays usually cannot carry out the chiral analysis. Here, we developed a novel biosensor array based on the interaction between a suite of host-based luminescent bacteria and amino acids and used linear discriminant analysis to reflect their luminescence response patterns. This biosensor array could effectively discriminate chiral amino acids, including 19 L-amino acids, their corresponding D-enantiomers, and the achiral glycine. In addition, the determination of enantiomeric purity and quantitative ability has been proved. The successful identification of a complex system containing multiple chiral amino acids further demonstrates the superiority of the bioluminescent sensor array. Moreover, this sensor array could efficiently monitor the dynamic composition of free amino acids in the process of milk fermentation. Finally, the bioluminescence response mechanism of the luminescent bacteria for the recognition of chirality was clarified. This approach possessed the advantages of facile construction, high throughput, easy operation, high accuracy and fast response.