Recyclable Ligands for the Non‐Enzymatic Dynamic Kinetic Resolution of Challenging α‐Amino Acids

Structurally simple and inexpensive chiral tridentate ligands were employed for substantially advancing the purely chemical dynamic kinetic resolution (DKR) of unprotected racemic tailor‐made α‐amino acids (TM‐α‐AAs), enabling the first DKR of TM‐α‐AAs bearing tertiary alkyl chains as well as multiple unprotected functional groups. Owing to the operationally convenient conditions, virtually complete stereoselectivity, and full recyclability of the source of chirality, this method should find wide applications for the preparation of TM‐α‐AAs, especially on large scale.     

Chemical Dynamic Kinetic Resolution and S/R Interconversion of Unprotected α‐Amino Acids

Reported herein is the first purely chemical method for the dynamic kinetic resolution (DKR) of unprotected racemic α‐amino acids (α‐AAs), a method which can rival the economic efficiency of the enzymatic reactions. The DKR reaction principle can be readily applied for S/R interconversions of α‐AAs, the methodological versatility of which is unmatched by biocatalytic approaches. The presented process features a virtually complete stereochemical outcome, fully recyclable source of chirality, and operationally simple and convenient reaction conditions, thus allowing its ready scalability. A quite unique and novel mode of the thermodynamic control over the stereochemical outcome, including an exciting interplay between axial, helical, and central elements of chirality is proposed.     

Enantioselective C−H Olefination of α‐Hydroxy and α‐Amino Phenylacetic Acids by Kinetic Resolution

Significant progress has been made in the past decade regarding the development of enantioselective C?H activation reactions by desymmetrization. However, the requirement for the presence of two chemically identical prochiral C?H bonds represents an inherent limitation in scope. Reported is the first example of kinetic resolution by a palladium(II)‐catalyzed enantioselective C?H activation and C?C bond formation, thus significantly expanding the scope of enantioselective C?H activation reactions.     

Isothiourea‐Catalyzed Acylative Kinetic Resolution of Tertiary α‐Hydroxy Esters

A highly enantioselective isothiourea‐catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently‐developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure was also translated to a continuous‐flow process using a polymer‐supported variant of the catalyst.     

Enantio‐ and Chemoselective Differentiation of Protected α‐Amino Acids and β‐Homoamino Acids with a Single Copper(II) Host

The association between an achiral copper(II)‐containing host 1 and chiral carboxylates has been expanded beyond previous studies to new chiral carboxylate guests, both α‐amino acids and β‐homoamino acids. The observed exciton‐coupled circular dichroism (ECCD) signals for the enantiomers of each carboxylate were equal and opposite, and these signals differed in size and shape between the individual amino acids. Linear discriminant analysis (LDA) was applied as a statistical analysis technique to differentiate the amino acids, both enantioselectively and chemoselectively, giving the absolute configuration and identity of the amino acid. The identity of each of the α‐amino acids and β‐homoamino acids were determined independently by LDA, and then the two were considered together. Each of these analyses showed good differentiation of the amino acid guests with the use of only one host molecule.     

Synthesis of a new Class of Chiral β—Mercaptoalcohols from Amino Acids

The syntheses of three new optically active β-mercaptoalcohols,(R)-1,1-diphenyl-2-mercapto-3-methyl-1-butanol,(R)-1,1-diphenyl-2-mercapto-4-methyl-1-pentanol,and (R)-1,1-diphenyl-2-mercapto-1-benzenepropanol from the corresponding amino acids are described.The enantiomeric excesses of these β-mercaptoalcohols were determined by ^1H NMR as their (S)-mandeloyl derivatives.     

Stereoarrayed CF3‐Substituted 1,3‐Diols by Dynamic Kinetic Resolution: Ruthenium(II)‐Catalyzed Asymmetric Transfer Hydrogenation

CF₃‐substituted 1,3‐diols were stereoselectively prepared in excellent enantiopurity and high yield from CF₃‐substituted diketones by using an ansa‐ruthenium(II)‐catalyzed asymmetric transfer hydrogenation in formic acid/triethylamine. The intermediate mono‐reduced alcohol was also obtained in very high enantiopurity by applying milder reaction conditions. In particular, CF₃C(O)‐substituted benzofused cyclic ketones underwent either a single or a double dynamic kinetic resolution during their reduction.     

Chiral Amino Acids‐Derived Catalysts and Ligands

Transforming amino acids into novel catalysts and ligands is a remarkable subset of new catalyst development in order to imitate enzymatic efficiencies. Their ability to perform a variety of asymmetric catalytic reactions is complimented by their ready availability, rich transformations, stability and easy procedure. Herein, we focused on describing our endeavor of developing new catalysts and ligands from primary and secondary amino acids. It includes C₂‐symmetric N,N'‐dioxides, guanidine‐amides, bispidine‐based diamines, and other organic salts. The account covered a brief introduction about their discovery, representative applications and related mechanisms.     

Kinetic Resolution of the Racemic 2‐Hydroxyalkanoates Using the Enantioselective Mixed‐Anhydride Method with Pivalic Anhydride and a Chiral Acyl‐Transfer Catalyst

A variety of optically active 2‐hydroxyalkanoates and the corresponding 2‐acyloxyalkanoates are produced by the kinetic resolution of racemic 2‐hydroxyalkanoates by using achiral 2,2‐diarylacetic acid with hindered carboxylic anhydrides as the coupling reagents. The combined use of diphenylacetic acid, pivalic anhydride, and (+)‐(R)‐benzotetramisole ((R)‐BTM) effectively produces (S)‐2‐hydroxyalkanoates and (R)‐2‐acyloxyalkanoates from the racemic 2‐hydroxyalkanoates (s‐values=47–202). This protocol directly provides the desired chiral 2‐hydroxyalkanoate derivatives from achiral diarylacetic acid and racemic secondary alcohols that do not include the sec‐phenethyl alcohol moiety by using the transacylation process to generate the mixed anhydrides from the acid components with bulky carboxylic anhydrides under the influence of the chiral acyl‐transfer catalyst. The transition state that provides the desired (R)‐2‐acyloxyalkanoate from (R)‐2‐hydroxyalkanoate included in the racemic mixture is disclosed by DFT calculations, and the structural features of the transition form are also discussed.     

Nickel‐Catalyzed Asymmetric Transfer Hydrogenation of Olefins for the Synthesis of α‐ and β‐Amino Acids

The field of asymmetric (transfer) hydrogenation of prochiral olefins has been dominated by noble metal catalysts based on rhodium, ruthenium, and iridium. Herein we report that a simple nickel catalyst is highly active in the transfer hydrogenation using formic acid. Chiral α‐ and β‐amino acid derivatives were obtained in good to excellent enantioselectivity. The key toward success was the use of the strongly donating and sterically demanding bisphosphine Binapine.     

Quaternary Chiral β2,2‐Amino Acids with Pyridinium and Imidazolium Substituents

The reactions of cyclic sulfamidates as electrophiles with a variety of nitrogen‐containing aromatic heterocycle nucleophiles, such as pyridines, N‐alkylimidazoles and N‐methylbenzimidazol, was explored. In all cases, although the nucleophilic substitution reactions occurred on quaternary centres, elimination products were not detected. The inversion of configuration at this quaternary centre was determined by X‐ray diffraction analysis and the enantiomeric excess of the reactions was checked by chiral HPLC. This synthetic approach allowed us to obtain a new family of chiral charged β^2,2‐amino acids, including a new bisamino acid that incorporates an imidazolium salt as a cross‐linker. In this context, the treatment of these chiral imidazolium salts with Ag₂O opens the way to new chiral N‐heterocyclic carbenes, which are important substrates in the fields of organometallic and organocatalytic chemistry. Additionally, we have done a thorough conformational analysis of these β‐amino acid derivatives, both in the solid state and in solution. The most important conformational feature of these acyclic systems is the rigidity of the N‐CH₂‐C‐N⁺ dihedral angle, which is essentially due to the gauche effect.