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.     

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.     

Synthesis of macrocycles and their application as chiral solvating agents in the enantiomeric recognition of carboxylic acids and α-amino acid derivatives

The chiral macrocycles 1 and 2 with multiple binding sites have been synthesized from D-phenylalanine as chiral solvating agents (CSAs) for the enantiomeric discrimination and determination of the enantiomeric excess of carboxylic acids and a-amino acids derivatives by the ¹H NMR spectroscopy. The results show that chiral macrocycles 1 and 2 are effective CSAs towards the carboxylic acids and a-amino acids derivatives.     

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.     

Silicon-mediated enantioselective synthesis of structurally diverseα-amino acid derivatives

The catalytic asymmetric synthesis of novel and chiral amino acid derivatives with unconventional chemo-, diastereo-, and enantio-selectivity remains a paramount challenge. Herein we reported a novel protocol for the use of highly enantioselective copper-catalyzed cycloaddition of α,β-unsaturated acylsilanes as a springboard reaction for the facile synthesis of structurally diversified pyrrolidines and complicated α-amino esters by desilylation. The newly developed process could provide a wide range of synthetically useful acylsilane-substituted pyrrolidines(ASiP) in high yields and excellent diastereo-and enantioselectivities with Cu/(R)-XylBINAP complex as the catalyst. And the downstream desilylation transformation enables to expand the potntial applications of 1,3-dipolar cycloaddition in the construction of structurally unique amino acid derivatives, in which an unprecedented and concerted fluoride anion-promoted C–X(X=H, Si, N, C) bond cleavage occurred to the enantioselective construction of aldehyde-substituted pyrrolidines, linear cinnamaldehyde or alkene-substituted amino esters in high ee values.     

Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide

A Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide is described. Asymmetric allylic substitution using acyclic β-keto esters with a nitrogen functional group at the α-carbon as prochiral nucleophiles proceeded in the presence of 5 mol % of Pd catalyst, 10 mol % of chiral diaminophosphine oxide 1j, BSA, and appropriate additives, affording the corresponding quaternary α-amino acid derivatives in excellent yield and in up to 92% ee.     

Highly enantioselective γ-amination of α,β-unsaturated acyl chlorides with azodicarboxylates: efficient synthesis of chiral γ-amino acid derivatives

The cinchona alkaloid-catalyzed γ-amination of α,β-unsaturated acyl chlorides with azodicarboxylates to give the corresponding dihydropyridazinones in good yields with high enantioselectivities has been developed. Reductive ring opening of the dihydropyridazinones afforded series of cyclic and acyclic γ-amino acid derivatives in good yields with high enantiopurity.     

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.     

Asymmetric syntheses of α-methyl γ-amino acid derivatives

This project was undertaken to demonstrate the potential of asymmetric hydrogenations mediated by the chiral, carbene-oxazoline analogue of Crabtree's catalyst "cat" in asymmetric hydrogenations of allylic amine derivatives of amino acids. Peripheral features of the substrates (protecting groups, functional groups related by redox processes, and alkene geometries) were varied to optimize the stereochemical vectors exerted by the substrate and align them with the catalyst vector. N-Acetyl-protected, O-TBDPS-protected allylic substrates 9a-e emerged as the best for this reaction; syn-products were formed from the E-alkenes, while the Z-isomers gave anti-target materials, both with high diastereoselectivities. This study featured asymmetric catalysis to elaborate optically active substrates into more stereochemically complex chirons; we suggest that the approach used, optimization of stereocontrol by varying peripheral aspects of the substrate, tends to be easier than de novo catalyst design for each substrate type. In other words, optimization of the substrate vector is likely to be more facile than enhancement of the catalyst vector via ligand modifications.     

Synthesis of arylglycine and mandelic acid derivatives through carboxylations of α-amido and α-acetoxy stannanes with carbon dioxide

Incorporation reactions of carbon dioxide (CO(2)) with N-Boc-α-amido and α-acetoxy stannanes were developed using CsF as a mild tin activator. Monoprotected α-amido stannanes could be used, and the corresponding arylglycine derivatives were obtained in moderate-to-high yields under 1 MPa (10 atm) of CO(2) pressure. α-Acetoxy stannanes also underwent carboxylation to afford mandelic acid derivatives in excellent yields under ambient CO(2) pressure. Both transformations enabled the synthesis of α-tertiary and α-quaternary carboxylic acid derivatives. In addition, the chirality of (S)-N-tert-butylsulfonyl-α-amido stannanes was transferred with up to 90% inversion of configuration at 100 °C.     

Resolution and use in α-amino acid synthesis of imidazolidinone glycine derivatives

The imidazolidinones (rac.-1 and rac.-2) obtained from pivalaldehyde and glycine amides are resolved efficiently by crystallization of diastereoisomeric ammonium salts with chiral acids (mandelates and a gulonate respectively). The free bases are acylated under Schotten-Baumann conditions to give enantiomerically pure 1-Bz., 1-BOC-, 1-2- or 1-formyl -2-t-butyl-3-methyl- or -3-benzyl-4-imidazolidinones. Diastereoselective alkylation of the 3-methyl derivatives (BMI) with a variety of electrophiles (LDA/THF -70 to + 25°) gives trans- disubstituted imidazolidinones exclusively (3–22). Some of these are hydrolysed by a procedure employing excess acidic ion exchange resin to give enantiomerically pure (R)- or (S)- amino acids. The procedure is compared with other methods of generating chiral glycine enolates.     

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.     

Synthesis of chiral β-amino acid derivatives by asymmetric hydrosilylation with an imidazole derived organocatalyst

The organocatalysed asymmetric hydrosilylation of a number of N-aryl and alkyl β-substituted enamino esters proceeds in generally good yield and enantioselectivity. Crucial to obtaining high yield and selectivity was the addition of benzoic acid as an additive and under these conditions, both N-alkyl and N-aryl substituents were well tolerated. β-Aryl and alkyl substituents were evaluated and a model proposed to account for the experimental observations based upon enamine tautomerisation and conformational preferences of the reactive ketimine intermediate.     

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.     

Intramolecular rearrangement of α-amino acid amide derivatives of 2-aminobenzothiazoles

We have found that α-amino acid amide derivatives of 2-aminobenzothiazoles undergo a time-dependent, thermal rearrangement in which the amine group attacks the 2-position carbon of the thiazole ring to form a 5,5-spiro ring system. This is followed by sulfur leaving and air oxidation to the corresponding symmetrical disulfide. The isolated yields of such products are quite high (>70%) if there is conformational bias to further promote the intramolecular reaction such as for the 2-aminobenzothiazole amides derived from proline or 4-aminopiperidine-4-carboxylic acid. This rearrangement has not been described previously for α-amino acid amide derivatives of 2-aminobenzothiazoles. However, a related reaction involving 2-semicarbazido benzothiazoles has been recently reported.     

Molecular recognition of α-amino acid esters with arylporphyrin zinc complexes

The recognition ability of 10 arylporphyrin zinc complexes with respect to glycine, -alanine, and leucine methyl esters in toluene at 20°C was studied by spectrophotometric titration. The formation of amino acid-porphyrin associates, depending on the substitution pattern in the macroring, was examined by ¹H NMR spectroscopy. The zinc complex with diarylporphyrin having hydroxy groups in the para positions of the benzene rings was found to be the best recognizing agent with respect to glycine methyl ester, while leucine methyl ester was recognized best by the complex with hydroxy groups in the ortho positions of the benzene rings.Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 9, 2004, pp. 1557–1562.Original Russian Text Copyright © 2004 by G. Mamardashvili, Storonkina, N. Mamardashvili.This revised version was published online in April 2005 with a corrected cover date.