Chiral Α-amino Acids Research Articles

Selection of Planar Chiral Conformations between Pillar[5,6]arenes Induced by Amino Acid Derivatives in Aqueous Media.

Chiral α-amino acids play critical roles in the metabolic process in nearly all life forms. So far, chiral recognition of α-amino acids has mainly focused on the determination of l/d enantiomers. Herein, selection of planar chiral conformations between water-soluble pillar[5]arene WP5 and pillar[6]arene WP6 was observed due to α-side chain or ethyl ester moieties of l-α-amino acid ethyl ester hydrochlorides binding with WP5 and WP6, respectively. Therefore, α-side chain and ethyl ester moieties of l-α-amino acid ethyl ester hydrochlorides were recognized by observing the induced CD signal and its inversion. This is a rare example of being able to detect the chiral region around α-carbon of a chiral α-amino acid molecule.

Chiral Nonnatural α-Amino Acid Synthesis by Enantio-selective Mannich Reaction and Hydrogenation

Chiral Nonnatural α-Amino Acid Synthesis by Enantio-selective Mannich Reaction and Hydrogenation

Impact of D2O on the peptidization of L-alanine

This is our fifth consecutive study carried out in an order to collect experimental evidence on the impact of heavy water (D2O) on the spontaneous peptidization of proteinogenic α-amino acids and this time its subject matter is L-alanine (L-Ala). Our four earlier studies have been focused on the two sulfur-containing α-amino acids (i.e., L-cysteine (L-Cys) and L-methionine (L-Met)), and on two structurally related α-amino acids (i.e., L-proline (L-Pro) and L-hydroxyproline (L-Hyp)). It seemed interesting to assess the effect exerted by D2O on L-Ala, the simplest chiral (endogenous and proteinogenic) α-amino acid with as low molar weight, as 89.09 g mol−1 only. As analytical techniques, we used high-performance liquid chromatography with the diode array detection (HPLC–DAD), mass spectrometry (MS), and scanning electron microscopy (SEM). The obtained results make it clear that the impact of heavy water on the dynamics of the spontaneous peptidization of L-Ala is even stronger than with the four other α-amino acids discussed earlier (although in all five cases, heavy water significantly hampers spontaneous oscillatory peptidization). Unlike in the four previous cases, though, the solubility of L-Ala in pure D2O is quite low and it takes twice as much time to dissolve it in D2O than in MeOH + X, 70:30 (v/v). Consequently, the peptidization of L-Ala in heavy water is even more obstructed than it was the case with the other investigated α-amino acids and it results in considerable yields of the L-Ala crystals (most probably at least partially deuterated) at the expense of the L-Ala-derived peptides. Perhaps it might be interesting to add that out of five α-amino acids investigated so far, which can be divided into two groups of endogenous and exogenous species, two endogenous species (L-Cys and L-Pro) undergo spontaneous oscillatory peptidization in an aqueous-organic solvent (i.e., in the absence of D2O) following the circadian rhythm, whereas two exogenous ones (i.e., L-Met and L-Hyp) do not. The third endogenous species (L-Ala) first undergoes two initials oscillations which are damped (not periodic) and the oscillatory changes are on a scale of ca. 10 h (as estimated with use of the Fourier transform approach) and after that, the system reaches a steady state.

Catalytic Asymmetric Access to Noncanonical Chiral α-Amino Acids from Cyclic Iminoglyoxylates and Enamides.

Here we describe an enantioselective Mannich reaction of cyclic iminoglyoxylates with enamides by virtue of chiral phosphoric acid catalysis in a one-pot manner. The wide substrate scope, mild reaction conditions, and constantly excellent enantioselectivities (>95% ee in most cases) render this protocol highly practical for the rapid construction of valuable noncanonical chiral α-amino-acid building blocks.

Nickel-Catalyzed Asymmetric Hydrogenation of 2-Amidoacrylates.

Earth-abundant nickel, coordinated with a suitable chiral bisphosphine ligand, was found to be an efficient catalyst for the asymmetric hydrogenation of 2-amidoacrylates, affording the chiral α-amino acid esters in quantitative yields and excellent enantioselectivity (up to 96 % ee). The active catalyst component was studied by NMR and HRMS, which helped us to realize high catalytic efficiency on a gram scale with a low catalyst loading (S/C=2000). The hydrogenated products could be simply converted into chiral α-amino acids, β-amino alcohols, and their bioactive derivatives. Furthermore, the catalytic mechanism was investigated using deuterium-labeling experiments and computational calculations.

A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives via a bicyclic imidazole-catalyzed direct enantioselective C-acylation.

Cα-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient synthesis of chiral Cα-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords the corresponding Cα-tetrasubstituted α-amino acid derivatives with excellent enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic chemistry.

Self-Replication of Chiral α-Amino Acids in Strecker-Type Synthesis via Asymmetric Induction and Amplification of Their Own Chiral Intermediate α-Aminonitriles

Abstract Self-replication is one of the essential characteristics of life, therefore, chemical reaction, in which biologically related chiral enantioenriched compounds can promote their own production, is an attractive challenge in broad scientific fields. Here, we found asymmetric Strecker-type synthesis, in which chiral l- and d-α-amino acids enantioselectively induced the formation and amplification of their own chiral intermediates l- and d-α-aminonitriles in solid state, respectively. Thus, after the hydrolysis of aminonitriles, enantioenriched amino acids with the same structure and the same absolute configuration as that of the original compounds could be replicatively produced with improvement of enantiomeric excess. Following our first report on the replication of α-(p-tolyl)glycine, here we found that the enantiomer of α-(1-naphthyl)glycine and α-(o-tolyl)glycine can also replicatively multiply in the Strecker-type synthesis via the amplification of the corresponding aminonitriles. From the viewpoint of the absolute asymmetric Strecker-type amino acid synthesis, spontaneous formation, amplification and multiplication, i.e., enantioselective reactive crystallization of α-aminonitriles will be discussed.

Access to Benzazepinones by Pd-Catalyzed Remote C–H Carbonylation of γ-Arylpropylamine Derivatives

A general method for the construction of seven-membered rings through Pd-catalyzed C(sp2)-H carbonylation at the remote ε-position of γ-arylpropylamine derivatives, including chiral α-amino acids, has been developed using Mo(CO)6 as the CO source, furnishing richly functionalized benzo[ c]azepin-1-one derivatives. The readily removable N-SO2Py protecting/directing group provides high levels of chemo-, regio- and diastereoselectivity. Furthermore, this method is amenable to the postsynthetic modification of complex molecules such as small peptides.

Aldehyde Carboxylation: A Concise DFT Mechanistic Study and a Hypothetical Role of CO2 in the Origin of Life

Carbon dioxide is arguably one of the most stable carbon-based molecules, yet enzymatic carbon fixation processes enabled the sustainable life cycle on Earth. Chemical reactions involving CO2-functionalization often suffer from low efficiency with highly reactive substrates. We recently reported mild carboxylation of aldehydes to furnish α-keto acids – a building block for chiral α-amino acids via reductive amination. Here, we discuss potential reaction mechanisms of aldehyde carboxylation reactions based on two promoters: NHCs and KCN in the carboxylation reaction. New DFT mechanistic studies suggested a lower reaction barrier for a CO2-functionalization step, implying a potential role of CO2 in prebiotic evolution of organic molecules in the primordial soup.1 Introduction: Aldehydes, Benzoins, Carboxylic Acids2 CO2-Activation: NHC, Cyanide, Lewis Acid and Water3 A Breslow Intermediate: Benzoin Reaction vs. Carboxylation with CO2 4 Carboxylation in the Primordial Soup5 Conclusion

Catalytic asymmetric propargyl- and allylboration of hydrazonoesters: a metal-free approach to sterically encumbered chiral α-amino acid derivatives.

A new asymmetric catalytic propargyl- and allylboration of hydrazonoesters is reported. The reactions utilize allenyl- and allylboronic acids in the presence of the inexpensive parent BINOL catalyst. The reactions can be performed under mild conditions (0 °C) without any metal catalyst or other additives affording sterically encumbered chiral α-amino acids. This is the first metal-free method for the asymmetric propargyl- and allylboration of hydrazonoesters.

A class of α-amino acids-derived multifunctional amidophosphane precatalysts: application to the highly enantio- and diastereoselective silver(I)-catalyzed 1,3-dipolar cycloaddition reaction

A class of multifunctional amidophosphanes derived from chiral α-amino acids have been developed with two amide bonds, a tertiary amine and a phosphine. In combination with Ag(I) salts, these amidophosphanes have been demonstrated as highly efficient multifunctional catalysts in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides as well as the three-component reaction of the α-iminoesters in situ generated. Under optimal conditions, highly functionalized endo-8 pyrrolidines were obtained with good to excellent yields (up to 99% yield) and enantioselectivities (up to 98% ee).

Amide-Phosphonium Salt as Bifunctional Phase Transfer Catalyst for Asymmetric 1,6-Addition of Malonate Esters to para-Quinone Methides.

Asymmetric 1,6-addition of malonates to para-quinone methides has been developed by using amide-phosphonium salts derived from easily available chiral α-amino acids as bifunctional phase transfer catalysts. Stabilized para-quinone methides with various substituents on the phenyl ring were reacted with diphenyl malonates to give functionalized diaryl methines in excellent yields and high to excellent ee's. Furthermore, to show the utility of this methodology, a gram scale synthesis of an 1,6-addition adduct and its further elaboration into the key intermediate for synthesis of GPR40 agonists were also described.

Visible-light photoredox synthesis of unnatural chiral α-amino acids.

Unnatural chiral α-amino acids are widely used in fields of organic chemistry, biochemistry and medicinal chemistry, and their synthesis has attracted extensive attention. Although the asymmetric synthesis provides some efficient protocols, noble and elaborate catalysts, ligands and additives are usually required which leads to high cost. Distinctly, it is attractive to make unnatural chiral α-amino acids from readily available natural α-amino acids through keeping of the existing chiral α-carbon. However, it is a great challenge to construct them under mild conditions. In this paper, 83 unnatural chiral α-amino acids were prepared at room temperature under visible-light assistance. The protocol uses two readily available genetically coded proteinogenic amino acids, L-aspartic acid and glutamic acid derivatives as the chiral sources and radical precursors, olefins, alkynyl and alkenyl sulfones, and 2-isocyanobiphenyl as the radical acceptors, and various unnatural chiral α-amino acids were prepared in good to excellent yields. The simple protocol, mild conditions, fast reactions, and high efficiency make the method an important strategy for synthesis of diverse unnatural chiral α-amino acids.

Formamide Synthesis through Borinic Acid Catalysed Transamidation under Mild Conditions.

A highly efficient and mild transamidation of amides with amines co-catalysed by borinic acid and acetic acid has been reported. A wide range of functionalised formamides was synthesized in excellent yields, including important chiral α-amino acid derivatives, with minor racemisation being observed. Experiments suggested that the reaction rely on a cooperative catalysis involving an enhanced boron-derived Lewis acidity rather than an improved Brønsted acidity of acetic acid.

Chiral α-Amino Acids by Palladium-Catalyzed Allylic Alkylation

Key words palladium - asymmetric catalysis - alkylation - amino acids - vicinal stereocenters

Synthesis and Application of Perfluoroalkylated Chiral α-Amino Acids

Synthesis and Application of Perfluoroalkylated Chiral α-Amino Acids

Hydrogen-Bond Directed Regioselective Pd-Catalyzed Asymmetric Allylic Alkylation: The Construction of Chiral α-Amino Acids with Vicinal Tertiary and Quaternary Stereocenters.

A Pd-catalyzed asymmetric allylic alkylation of azlactones with 4-arylvinyl-1,3-dioxolan-2-ones was developed, providing "branched" chiral α-amino acids with vicinal tertiary and quaternary stereocenters, in high yields and with excellent selectivities. Mechanistic studies revealed that the formation of a hydrogen bond between the Pd-allylic complex and azlactone isomer is responsible for the excellent regioselectivities. This asymmetric alkylation can be carried out on a gram scale without a loss of catalytic efficiency, and the resulting product can be further transformed to a chiral azetidine in two simple steps.

Nonenzymatic, Enantioconvergent Dynamic Kinetic Resolution (DKR) of Racemic 2-(1H-Pyrrol-1-yl)alkanoic Acids as α-Amino Acid Equivalents

Abstract We report an effective dynamic kinetic resolution (DKR) system of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which consists of a rapid racemization step via an activating substrate and an enantio-discriminating step via catalytic esterification. The combination of pivalic anhydride as an activating agent, bis(α-naphthyl)methanol as an achiral alcohol, (R)-BTM as a chiral acyl-transfer catalyst, and Hünig’s base converted racemic 2-(1H-pyrrol-1-yl)alkanoic acids to the corresponding chiral carboxylates, which can be transformed into chiral α-amino acid derivatives with maintained high enantiopurity.

Algorithm to design inhibitors using stereochemically mixed l,d polypeptides: Validation against HIV protease

Polypeptides have potential to be designed as drugs or inhibitors against the desired targets. In polypeptides, every chiral α-amino acid has enantiomeric structural possibility to become l or d amino acids and can be used as design monomer. Among the various possibilities, use of stereochemistry as a design tool has potential to determine both functional specificity and metabolic stability of the designed polypeptides. The polypeptides with mixed l,d amino acids are a class of peptidomimitics, an attractive drug like molecules and also less susceptible to proteolytic activities. Therefore in this study, a three step algorithm is proposed to design the polypeptides against desired drug targets. For this, all possible configurational isomers of mixed l,d polyleucine (Ac-Leu8-NHMe) structure were randomly modeled with simulated annealing molecular dynamics and the resultant library of discrete folds were scored against HIV protease as a model target. The best scored folds of mixed l,d structures were inverse optimized for sequences in situ and the resultant sequences as inhibitors were validated for conformational integrity using molecular dynamics. This study presents and validates an algorithm to design polypeptides of mixed l,d structures as drugs/inhibitors by inverse fitting them as molecular ligands against desired target.

Chiral Bis(imidazolidine)-Derived NCN Pincer Rh Complex for Catalytic Asymmetric Mannich Reaction of Malononitrile with N-Boc Imines.

Chiral bis(imidazolidine)-derived NCN-rhodium complexes ([PhBidine-RhX2 ] and [tBu-PhBidine-RhX2 ]) were prepared by a CH insertion method, and the structures were unequivocally determined by X-ray crystallographic analysis. The [tBu-PhBidine-Rh(OAc)2 ] complex smoothly catalyzed an asymmetric Mannich reaction of malononitrile with N-Boc imines to give products in up to 94 % ee, which are useful for the synthesis of chiral α-amino acids.