Synthesis of novel chiral lipophilic pyridyl-containing β-amino alcohol ligands and enantioselective hydrolysis of α-amino acid esters by chiral metallomicelles

Seven novel chiral lipophilic pyridyl-containing β-amino alcohol ligands have been synthesized by coupling of 6-alkoxymethyl-2-chloromethylpyridine 3 with the corresponding chiral β-amino alcohols or l-cysteine. Their metal ion complexes have been investigated as catalysts for the enantioselective hydrolysis of N-protected α-amino acid esters in aqueous comicellar solution. The results indicate that the hydrophobic interactions between substrate and metallocatalyst, the rigidity of the ligand, the hydroxyl group of the ligand acting as a nucleophile for the transacylation process, and the micellar microenvironment are important factors for the activity and enantioselectivity. Large rate accelerations (up to three orders of magnitude) and moderate enantioselectivities (up to 7.81 (k_R/k_S)) employing 4a–Cu²⁺ have been observed.     

Hydroxymethylated cyclic α-amino acid dipeptides by ruthenium ring closing metathesis

Stereoselective syntheses of cyclic α-amino-β-hydroxymethylcyclohexene-α-carboxylic acids are described. The acids were isolated as dipeptides. RCM reactions were effected by Ru(II)-catalysis on hydroxymethylated dienes. The diene substrates were available in stereochemically pure form by stepwise alkylations of (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with 4-bromo-1-butene and vinyloxirane.     

Synthesis of chiral cyclic β-amino ketones by Ru-catalyzed asymmetric hydrogenation

Synthesis of chiral cyclic β-amino ketones has been first reported via Ru-catalyzed asymmetric hydrogenation. High enantioselectivities were achieved by using (S)-C₃-TunePhos chiral ligand (up to 94% ee).     

Enantioselective hydrolysis of long chain α-amino acid esters by chiral sulfur-containing macrocyclic metallomicelles

A novel chiral lipophilic sulfur-containing macrocyclic ligand 5 with bis-pendant alcohols in the proximity of the coordination center has been synthesized. Its metal ion complexes have been investigated as catalysts for the enantioselective hydrolysis of long chain α-amino acid esters in aqueous comicellar solution with Brij35. Large rate accelerations (up to 220 times) and moderate enantioselectivities (up to 4.85 (k_S/k_R)) employing the macrocyclic 5-Cu²⁺ have been observed, whereas the acyclic 3-Cu²⁺ exhibits less reactivity and stereoselectivity. Taking the analogous ligand 4, lacking the hydroxy groups leads to a dramatic rate decrease, and an inversion of enantioselectivity is observed. The pKa value of the hydroxyl bound to Cu²⁺ is determined to be pKa=7.2 under our micellar reaction conditions.     

Synthesis of cyclic α-amino ketones

Summary A simple method is described for synthesizing cyclic -amino ketones by intramolecular cyclization of azlactones under the action of aluminum chloride.     

Visual chiral recognition of mandelic acid and α-amino acid derivatives by enantioselective gel formation and precipitation

Novel chiral receptors based on l-phenylalanine and l-valine have been synthesized and their chiral recognition properties toward mandelic acid and N-tosyl α-amino acids are studied. The phenylalanine-based receptor undergoes enantioselective gel formation with R-mandelic acid and N-tosyl-d-valine, whereas the valine-linked receptor in their presence results in the formation of precipitates.     

Conformational studies on peptides containing α,α-disubstituted α-amino acids: chiral cyclic α,α-disubstituted α-amino acid as an α-helical inducer

Four types of α,α-disubstituted amino acids {i.e., α-aminoisobutyric acid (Aib), 1-aminocyclopentanecarboxylic acid (Ac(5)c), (3S,4S)-1-amino-(3,4-dimethoxy)cyclopentanecarboxylic acid [(S,S)-Ac(5)c(dOM)] and its enantiomer (R,R)-Ac(5)c(dOM)} were introduced into l-leucine-based hexapeptides and nonapeptides. The dominant conformations of eight peptides: Cbz-(L-Leu-L-Leu-dAA)(2)-OMe [dAA = 1: Aib; 2: Ac(5)c; 3: (S,S)-Ac(5)c(dOM); 4: (R,R)-Ac(5)c(dOM)] and Boc-(L-Leu-L-Leu-dAA)(3)-OMe [dAA = 5: Aib; 6: Ac(5)c; 7: (S,S)-Ac(5)c(dOM); 8: (R,R)-Ac(5)c(dOM)], were investigated by IR, CD spectra and X-ray crystallographic analysis. The CD spectra revealed that Aib hexapeptide 1 and Ac(5)c hexapeptide 2 formed right-handed (P) 3(10)-helices, while Ac(5)c(dOM) hexapeptides 3 and 4 formed a mixture of (P) 3(10)- and α-helices. The Aib nonapeptide 5 formed a (P) 3(10)-helix, the Ac(5)c nonapeptide 6 formed a mixture of (P) 3(10)- and α-helices, and the Ac(5)c(dOM) nonapeptides 7 and 8 formed (P) α-helices. X-Ray crystallographic analysis revealed that the Aib hexapeptide 1 formed a (P) 3(10)-helix, while (S,S)-Ac(5)c(dOM) hexapeptide 3 formed a (P) α-helix. In addition, the Ac(5)c nonapeptide 6 and (R,R)-Ac(5)c(dOM) nonapeptide 8 formed (P) α-helices. The Aib and achiral Ac(5)c residues have the propensity to form 3(10)-helices in short peptides, whereas the chiral Ac(5)c(dOM) residues have a penchant for forming α-helices.     

Enhancement of α-helix mimicry by an α/β-peptide foldamer via incorporation of a dense ionic side-chain array

We report a new method for preorganization of α/β-peptide helices, based on the use of a dense array of acidic and basic side chains. Previously we have used cyclically constrained β residues to promote α/β-peptide helicity; here we show that an engineered ion pair array can be comparably effective, as indicated by mimicry of the CHR domain of HIV protein gp41. The new design is effective in biochemical and cell-based infectivity assays; however, the resulting α/β-peptide is susceptible to proteolysis. This susceptibility was addressed via introduction of a few cyclic β residues near the cleavage site, to produce the most stable, effective α/β-peptide gp41 CHR analogue identified. Crystal structures of an α- and α/β-peptide (each involved in a gp41-mimetic helix bundle) that contain the dense acid/base residue array manifest disorder in the ionic side chains, but there is little side-chain disorder in analogous α- and α/β-peptide structures with a sparser ionic side-chain array. These observations suggest that dense arrays of complementary acidic and basic residues can provide conformational stabilization via Coulombic attractions that do not require entropically costly ordering of side chains.     

Preparation of chiral α-diazophosphonic acid derivatives

The chiral α-diazophosphonic acid derivatives 3, 6 and 8 were prepared from (−)-ephedrine and (S,S)-N,N′-dimethyl-1,2-diaminocyclohexane; preliminary experiments suggest that the chiral auxiliary exerts little influence in the dirhodium(II) acetate catalysed OH and NH insertion reactions.     

Membrane transport of dicarboxylic and α-hydroxy carboxylic acids induced by α-amino phosphonates

New -amino phosphonates containing different alkyl and aryl substituents at the -carbon atom were synthesized in high yields by the Kabachnik—Fields and Pudovik reactions. These compounds were studied as carriers of several -hydroxy carboxylic and dicarboxylic acids through liquid impregnated membranes. These -amino phosphonates studied are capable of molecular recognition of oxalic acid among structurally similar -hydroxy carboxylic and dicarboxylic acids. The efficiency and selectivity of mass transfer of oxalic acid increase with an increase in the lipophilicity of the -amino phosphonate.     

Synthesis of the unusual α-amino acid component of some novel histone deacetylase inhibiting cyclic peptides

A flexible protocol for the synthesis of three lipophilic α-amino acid components of some novel cyclic peptides having important histone deacetylase inhibiting properties has been developed from a common source, which featured a cross-metathesis reaction between two unhindered terminal olefins as the key step.     

Stimuli-responsive polypeptide materials prepared by ring-opening polymerization of α-amino acid N-carboxyanhydrides

Design and synthesis of biodegradable stimuli-responsive polypeptides are important areas considering their promising applications in biomedical fields. This article summarizes the most recent progresses in the development of stimuli-responsive polypeptide materials prepared via ring-opening polymerization of α-amino acid N-carboxyanhydrides. We discuss the design, synthesis and structure-property correlation of emerging materials including thermo-responsive, redox-responsive, photo-responsive and biomolecule responsive polypeptides. Considering the unique structural features of amino acids, we try to emphasize that the thermo-responsive properties not only depend on the amino acid structure but also rely on the secondary structures of polypeptides. © 2013 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2013     

The asymmetric synthesis of chiral cyclic α-hydroxy phosphonates and quaternary cyclic α-hydroxy phosphonates

A highly practical, catalytic enantioselective cyclic phosphite addition to aldehydes and ketones was developed. The reaction rate of the asymmetric hydrophosphonylation was significantly enhanced by the addition of silver carbonate. Particularly, significant improvement has been achieved on the asymmetric hydrophosphonylation of unactivated ketones, giving quaternary α-hydroxy phosphonates with excellent enantioselectivity (up to 99% ee).     

Gd(III)[15-metallacrown-5] recognition of chiral α-amino acid analogues

Chiral Ln(III)[15-metallacrown-5] complexes with phenyl side chains have been shown to encapsulate aromatic carboxylates reversibly in their hydrophobic cavities. Given the importance of selective guest binding for applications of supramolecular containers in synthesis, separations, and materials design, the affinity of Gd(III)[15-metallacrown(Cu(II), L-pheHA)-5] hosts for a series of chiral carboxylate guests with varying substitutions on the α-carbon (phenylalanine, N-acetyl-phenylalanine, phenyllactate, mandelate, methoxyphenylacetate) has been investigated. Differential binding of S- and R-phenylalanine was revealed by X-ray crystallography, as the S-enantiomer exclusively forms associative hydrogen bonds with oxygen atoms in the metallacrown ring. Selective guest binding in solution was assessed with isothermal titration calorimetry, which measures the sequential guest binding in the hydrophobic cavity first and the hydrophilic face of the host, and a cyclic voltammetry assay, which quantifies guest binding strength in the hydrophobic cavity of the host exclusively. In solution, the Gd(III)[15-metallacrown(Cu(II), L-pheHA)-5] hydrophobic cavity exhibits modest chiral selectivity for enantiomers of phenylalanine (K(S)/K(R) = 2.4) and mandelate (K(S)/K(R) = 1.22). Weak binding constants of ～100 M(-1) were measured for neutral and -1 charged carboxylates with hydrophilic functional groups (ammonium, N-acetyl, methyl ether). Weaker binding relative to the unsubstituted guests is attributed to unfavorable interactions between the hydrophilic functionalities of the guest and the hydrophobic cavity of the host. In contrast, binding constants greater than 2000 M(-1) were measured for α-hydroxy analogues phenyllactate and mandelate. The significantly increased affinity likely arises from the guests being bound as a -2 anion upon metal-assisted deprotonation in the Gd(III)[15-metallacrown(Cu(II), l-pheHA)-5] cavity. It is established that guest binding affinity in the hydrophobic cavity of the host follows the general trend of neutral zwitterion < monoanion < dianion, with hydrophilic functional groups decreasing the binding affinity. These results have broad implications for the development of metallacrowns as supramolecular catalysts or in chiral separations.     

Synthesis of novel fullerene α-amino acid conjugates

Aspartic acid and glutamic acid with protectedα-amino andα-carboxyl groups had been used to react with the activated hydroxyl group of N-substituted 3,4-fullero pyrrolidine.The products were deprotected,affording two monofullereneα-amino acids,monofullerene aspartic acid(mFas)and monofullerene glutamic acid(mFgu).Then a bifullerene glutamic acid conjugate (bFguC)was synthesized by reaction of mFgu containing protected amino group with N-substituted 3,4-fullero pyrrolidine.     

Stereoselective alkylation of chiral glycine enolate synthons. The enantioselective synthesis of α-amino acid derivatives.

The highly stereoselective alkylation (% de=99.6 to 97.6) of a new chiral glycine enolate synthon derived from D-2-phenylglycinol is described. Deprotection of the alkylation adducts in a one-pot three-step procedure provides the ethyl ester hydrochloride salts of the corresponding α-amino acids with no attending racemization.     

Relationship between the helical structure and optical activity of some chiral cyclic esters

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Enantioselective synthesis of α-amino acids in chiral reverse micelles

Through alkylation of ethyl 2-phthalimidoacetate in chiral reverse micelles formed from chiral surfactants, followed by hydrazinolysis and hydrolysis of the resulting products, optically active α-amino acids were synthesized. The highest enantioselectivity was 59.5%. Meanwhile, we have found that the asymmetric induction depends on the reaction temperature, the alkyl chain length of surfactant and the strucure of the surfactants.     

Highly diastereoselective synthesis of quaternary α-trifluoromethyl α-amino acids by addition of benzylzinc reagents to chiral imines of trifluoropyruvate

An effective and facile method for highly diastereoselective synthesis of quaternary α-trifluoromethyl α-amino acids was developed in good yields with high diastereoselectivity (dr >20:1) via MgCl₂-accelerated addition of benzylzinc reagents (Knochel type organozinc reagents) to (R)-phenylglycinol methyl ether based imines of trifluoropyruvate.     

Synthesis of α-sulfanyl-β-amino acid derivatives by using nanocrystalline magnesium oxide

The Mannich-type reaction between alkyl, aryl and heterocyclic aldimines and sulfonium salts for the synthesis of α-sulfanyl-β-amino acid derivatives by using nanocrystalline magnesium oxide (NAP-MgO) is described. These products are obtained in moderate to high yields with moderate diastereoselectivities. The configuration of ethyl-3-{[(4-methylphenyl)sulfonyl]amino}-2-(methylsulfanyl)-3-(4-nitrophenyl)propanoate (major isomer) has been confirmed by X-ray diffraction technique to be anti, and consistent with the assignment based on ¹H NMR spectroscopy. These α-sulfanyl-β-amino acid derivatives are important building blocks for pharmaceuticals with potent biological activity.