Design of chiral organocatalysts for practical asymmetric synthesis of amino acid derivatives

A series of structurally rigid, chiral quaternary ammonium salts and several chiral sec-amine catalysts derived from commercially available (R)- or (S)-binaphthol have been designed as new C(2)-symmetric chiral phase-transfer catalysts and chiral bifunctional amino-catalysts. These chiral organocatalysts have been successfully applied to the highly practical asymmetric synthesis of various amino acid derivatives.     

Synthesis of a novel sterically hindered chiral cyclic phosphoric acid derived from l-tartaric acid and application to the asymmetric catalytic Biginelli reaction

A novel sterically hindered chiral cyclic phosphoric acid derived from l-tartaric acid was designed and synthesized based on highly regioselective cyclosulfitation of chiral 1,1,4,4-tetraphenylbutanetetraol. The asymmetric Biginelli reaction catalyzed by this newly synthesized chiral phosphoric acid was examined, and enantioselectivities up to 99% ee was obtained.     

Enantiomeric separation of chiral peptide nucleic acid monomers by capillary electrophoresis with charged cyclodextrins

Direct chiral separation of chiral peptide nucleic acid (PNA) monomers has been achieved for the first time by capillary electrophoresis (CE) with charged cyclodextrins as chiral selectors added to the electrophoretic buffer. Selectively modified 6-deoxy-6-N-histamino-beta-cyclodextrin and sulfobutyl ether-beta-CD were successfully used as chiral selectors for the enantiomeric separation of chiral monomers based on different aminoethylamino acids bearing thymine or adenine as nucleobases. Chiral separations were obtained at low selector concentrations (1-3 mM) with good enantioselectivity and resolution factors. Separations were optimized as a function of pH in order to exploit the effect of the electrostatic interactions between the oppositely charged selector and selectand. The method has been applied to the analysis of the enantiomeric excess of chiral monomers used for the solid phase synthesis of chiral PNA oligomers. CE chiral analysis showed that a very high enantiomeric purity was generally achieved in the synthesis of all monomers, except for histidine and aspartic acid based monomers in which ca. 10% of the "wrong" enantiomer was always present.     

Chiral supramolecular thiophene fluorophore consisting of thiophenecarboxylic acid derivatives

Solid-state chiral supramolecular thiophene fluorophore has been successfully prepared by using chiral (R)-1-(2-naphthyl)ethylamine and 5-bromothiophene-2-carboxylic acid. This chiral supramolecular thiophene fluorophore is formed by assembling chiral 2₁-helical columnar network structures composed of (R)-1-(2-naphthyl)ethylamine and 5-bromothiophene-2-carboxylic acid. This supramolecular organic fluorophore exhibits circularly polarized luminescence (CPL) even in the solid state.     

Direct enantiomeric TLC resolution of dl-penicillamine using (R)-mandelic acid and l-tartaric acid as chiral impregnating reagents and as chiral mobile phase additive

DL-Penicillamine has been resolved into its enantiomers by normal-phase TLC using L-tartaric acid as chiral impregnating reagent as well as chiral mobile phase additive, while (R)-mandelic acid has been found to be successful as a chiral impregnating reagent. The solvent system acetonitrile-methanol-water (5:1:1, v/v) was found to be successful when L-tartaric acid was used as impregnating agent while the solvent combination acetonitrile-methanol-(0.5% l-tartaric acid in water, pH 5)-glacial acetic acid (7:1:1.1:0.7, v/v) was successful as mobile phase as it contained L-tartaric acid as the chiral additive. (R)-mandelic acid was successful as chiral impregnating reagent with ethyl acetate-methanol-water (3:1:1, v/v), as the mobile phase. The effects of concentration of chiral selectors, temperature and pH were examined on enantiomeric resolution. The spots were detected with iodine vapors and the detection limits were found to be 0.12 microg for each enantiomer of penicillamine with L-tartaric acid, under both the conditions, and 0.11 microg with (R)-mandelic acid.     

Enantioseparation of amino acid derivatives on an immobilized network polymer derived from L-tartaric acid

Seven structurally related amino acid derivatives were successfully enantioseparated by HPLC with a commercially available column containing a chiral immobilized network polymer derived from L-tartaric acid. The experiments were carried out under normal-phase conditions. All the solutes could be baseline separated using n-hexane/2-propanol (95/5) as eluent at a flow rate of 1 ml/min at 25 degrees C, with reasonable retention time (<12 min). The effects of the polar alcohol modifier (type and content) in the mobile phase and the column temperature on the enantioseparation were studied. Apparent thermodynamic parameters were also calculated from the plots of ln alpha or ln k' versus 1/T. Some mechanistic aspects of chiral recognition were discussed with respect to the structures of the solutes. It was found that the enantioseparations are all enthalpy driven, and the N-acyl groups of the solutes have significant influence on the chiral recognition.     

Recognition of enantiomers with chiral molecular tweezers derived from (+)- or (−)-usnic acid

The synthesis of four stereoisomers of a chiral molecular tweezer using trans-1,2-diaminocyclohexane as spacer and two molecules of usnic acid as pincers is reported. The behavior of these chiral tweezers as chiral complexing agents was evaluated in NMR with various chiral esters containing an electron-poor aromatic ring to allow non-covalent aromatic–aromatic interactions.     

Local and global chirality at surfaces: succinic acid versus tartaric acid on Cu110

A detailed comparison of tartaric acid (HOOC-CHOH-CHOH-COOH) and succinic acid (HOOC-CH(2)-CH(2)-COOH) molecules on a Cu(110) surface is presented with a view to elucidate how the two-dimensional chirality exhibited by such robust, chemisorbed systems is affected when both OH groups of the former molecule are replaced with H groups, a stereochemical change that leaves the metal-bonding functionalities of the molecule untouched but destroys both chiral centers. It is found that this change does not significantly affect the thermodynamically preferred chemical forms that are adopted, namely the doubly deprotonated bicarboxylate at low coverages (theta 相似文献   

Regulation of the chiral twist and supramolecular chirality in co-assemblies of amphiphilic L-glutamic acid with bipyridines

A series of amphiphilic L-glutamic acid derivatives with various saturated alkyl chains has been designed and their co-assembly with 4,4'-bipyridine in aqueous media has been investigated. While the individual amphiphiles formed hydrogels with water and self-assembled into fine fiber networks, the addition of 4,4'-bipyridine caused significant changes in the co-assembled nanostructures such that twisted chiral ribbons were formed. In these supramolecular systems, either fine structural changes or adjustment of the stoichiometric ratio of the two components had crucial effects on the formation of the chiral twists. Based on detailed investigations by SEM and XRD analyses, FTIR, CD, and UV/Vis spectroscopies, and molecular simulation, it is considered that a delicate synergistic balance between π-π stacking, hydrophobic, and chiral interactions is responsible for the formation of the chiral twists. An interesting sandwich structure, in which an excess of 4,4'-bipyridine is inserted into the space of primary cages constructed from the amphiphile and 4,4'-bipyridine, is proposed. Remarkably, the handedness of these chiral twists is related not only to the chiral center of the glutamic unit, but also the chain length of the alkyl tails. This work provides a deeper understanding of the formation mechanism of chiral twists, and exemplifies a feasible shortcut to the rational design of chiral structures from basic molecular structures to supramolecular systems.     

Design and synthesis of novel chiral molecular tweezers based on deoxycholic acid

A novel type of chiral molecular tweezers has been designed and synthesized by using deoxycholic acid as backbone and ethanoyl and the chiral unsymmetrical urea unit as arms. Their structures were characterized by 1H NMR, IR, MS spectra and elemental analysis. These molecular tweezers showed good binding ability for neutral molecules and chiral molecules.     

Enantioselective synthesis of beta-aryl-gamma-amino acid derivatives via Cu-catalyzed asymmetric 1,4-reductions of gamma-phthalimido-substituted alpha,beta-unsaturated carboxylic acid esters

A series of chiral beta-aryl-substituted gamma-amino butyric acid derivatives were synthesized in good enantioselectivities via the Cu-catalyzed asymmetric conjugate reduction of gamma-phthalimido-alpha,beta-unsaturated carboxylic acid esters using Cu(OAc)2 x H2O as a catalyst precursor, (S)-BINAP as a ligand, PMHS as a hydride source, and t-BuOH as an additive. The methodology has been applied successfully to the enantioselective synthesis of a chiral pharmaceutical, (R)-baclofen.     

Chiral synthesis of functionalized tetrahydropyridines: gamma-aminobutyric acid uptake inhibitor analogues

[Chemical reaction: See text] A convenient preparation of functionalized chiral tetrahydropyridine-3-carboxylates from nitriles in 68-90% enantiomeric excess (ee) via allylboration, followed by a conjugate addition-elimination and ring-closing metathesis, has been developed. Thus, the treatment of the acetate derived from vinylalumination of formaldehyde by use of [alpha-(ethoxycarbonyl)vinyl]diisobutylaluminum with chiral beta-substituted and beta-unsubstituted homoallylic amines, prepared in >98% diastereomeric excess (de) and 68-90% ee via allylboration of the corresponding N-aluminoimines, furnished functionalized aminodienes, which underwent ring-closing metathesis to provide chiral C5-C6 disubstituted tetrahydropyridine-3-carboxylates. This methodology has been applied for the synthesis of a chiral C6-substituted tetrahydropyridine with known GABA-inhibiting properties at low concentrations.     

Comparison of monomeric and polymeric amino acid based surfactants for chiral separations

To better understand chiral recognition with polymeric amino acid based surfactants, the chromatographic performance of 18 monomeric and polymeric surfactants were compared for chiral analytes with various charge states and hydrophobicities. In this study, four amino acids (glycine, L-alanine, L-valine, and L-leucine) were chosen, and all possible combinations of the chiral single amino acid and dipeptide surfactants were synthesized. The results indicate that polymeric surfactants usually provide better chiral resolution for enantiomers of lorazepam, temazepam, 1,1'-bi-2-naphthol, and propranolol as compared to monomeric surfactants. In contrast, monomers perform better for chiral recognition of the 1,1'-bi-2-naphthyl-2,2'-diyl hydrogenphosphate enantiomers.     

Chiral recognition capabilities of melamine and cyanuric acid supramolecular structures

Currently, there are numerous papers that discuss local chiral domains in supramolecular structures of achiral molecules established using the STM method, and by using DFT calculations. However, there are no data regarding the obtainment of macroscopically chiral 2D-supramolecular structures from achiral molecules. In this study, melamine and cyanuric acid supramolecular structures were self-assembled on a graphitized carbon black surface, which had a surface structure that was identical to HOPG, and also on the surface of an inert solid support for chromatography. Chirality induction according to the Kondepudi effect was used. For the supramolecular structures, MD calculations showed the possibility of obtaining a chiral structure. To establish macroscopic chirality, we proposed the use of the difference in enantiomer adsorption on the modified adsorbents. For this, two indirect methods were used: static adsorption with a polarimetric control and gas chromatography. Both methods indicated the chiral recognition ability of the adsorbents used.     

Chiral acid selectivity displayed by PEDOT electropolymerised in the presence of chiral molecules

Chiral conducting polymers prepared by electropolymerising PEDOT in the presence of chiral anions such as hyaluronic acid and anionic collagen or in a chiral nematic phase (hydroxypropyl cellulose, HPC) show excellent chiral acid recognition. This paper demonstrates the enantioselective recognition and transfer of protonated mandelic acid and protons using chiral PEDOTs. Discrimination between (R)-(-)- and (S)-(+)-mandelic acid was observed using cyclic voltammetry and square-wave voltammetry.     

Synthesis of anti-Alzheimer (R)-arundic acid

The asymmetric synthesis of the anti-Alzheimer agent (R)-arundic acid has been performed via a diastereoselective photodeconjugation reaction as the key-step. The synthetic approach involves a readily available chiral auxiliary, diacetone-d-glucose, and allows access to either enantiomer as illustrated by the synthesis of (S)-arundic acid. Both enantiomers were obtained in 88% ee using the same chiral auxiliary.     

Design and synthesis of fused-ring chiral ionic liquids from amino acid derivatives

Six novel imidazolium salts, which contain a chiral moiety as well as a fused-ring system, have been designed, synthesized, and fully characterized. The synthesis of these ionic liquids is concise and practical due to the commercial availability of the starting materials. These imidazolium compounds were readily prepared from 1-methyl-2-imidazoliumcarboxaldehyde and chiral amino alcohols. Salts that contain the PF₆ anion were solids, but salts with the NTf₂ anion were liquids at room temperature. We envision that these new chiral imidazolium compounds can serve as effective reaction media as well as chiral catalysts for asymmetric reactions, which are presently being investigated in our lab.     

CE‐LIF chiral separation of aspartic acid and glutamic acid enantiomers using human serum albumin and sodium cholate as dual selectors

Sodium cholate (SC), β‐CD, hydroxypropyl (HP)‐β‐CD, HSA, and the dual mixtures of them were evaluated for the analysis of aspartic acid (Asp) and glutamic acid (Glu) enantiomers fluorescently tagged with 5‐(4,6‐dichloro‐s‐triazin‐2‐ylamino) fluorescein (DTAF) by CE with LIF detection. Among the investigated chiral selectors and the dual selector systems, the dual selector systems of HSA and SC resulted to be the most useful chiral selectors allowing relatively high chiral resolution. Several experimental parameters such as chiral reagent type and concentration, buffer concentration, and pH, type and concentration of organic modifier were studied in order to find the optimum conditions for the chiral resolution of the two derivatized amino acids in their enantiomers. The effect of different variables that affect derivatization (time, temperature, pH, and DTAF concentration) was studied. Under optimum conditions, the analytes were separated in a short 10.5 min analysis time, and the RSDs for migration time and peak area were less than 0.12 and 2.8%, respectively. The method was applied for the analysis of compound amino acids injection without interference from other amino acids in the sample matrices observed.     

Factors affecting the efficiency and stereoselectivity of α-amino acid synthesis by the Petasis reaction

The use of chiral secondary amines containing only one branched substituent has been shown to give optimal yields and stereoselectivities in the preparation of α-amino acids using the Petasis reaction. While the use of chiral primary amines generally gives products in low to moderate diastereoselectivity, chiral secondary amines generally give products in >95:5 diastereoselectivity. Additionally, the use of amines with two chiral (and by definition, branched) N-alkyl substituents results in significantly reduced yields with respect to to secondary amines with one or no branched N-alkyl substituents.     

Chiral separation of amino acid esters by micellar electrokinetic chromatography

Micellar electrokinetic chromatography (MEKC) was used for the chiral separation of uncharged analytes (C- and N-protected amino acids). Sodium dodecyl sulfate (SDS) was the micelle forming agent, and different cyclodextrin (CD) derivatives were added as chiral selectors. Suitable conditions for the enantioseparation were found by variation of the separation conditions. The influence of addition of organic solvents like acetonitrile or methanol, and other chiral additives (camphor-10-sulfonic acid, malic acid) was examined. The addition of an organic modifier resulted in different effects on micelle formation, and thereby on the separation. The used chiral additives did not improve the selectivity. Furthermore, dependence of the electroosmotic flow (EOF), and the capacity factors on the concentration of CDs was investigated. Increasing the CD concentration, both the EOF to a smaller extent as well as the capacity factors decrease. Nevertheless, the enantioseparation is improved with a CD-concentration up to 30 mM. Higher CD-concentrations reduce the separation of the analytes.