Biomedical subjects
Publications and source records attributed to Elemér Fogassy.
N-formylphenylalanine was subjected to optical resolution using a chiral agent such as phenylethylamine enantiomer, (R)-phenylglycine methyl ester, (S)-N-benzyl-2-aminobutanol, alone or in a mixture with each other or in a mixture with benzylamine.
Racemic 1-phenylethylamine was optically resolved by its own derivative formed with glutaric acid namely (+)-(R)-N-(1-phenylethyl)glutaramic acid. The amide acid resolving agent was synthesized from (+)-(R)-1-phenylethylamine by N-derivatization. The glutaric acid derivative was the next in a homologous series of dicarboxilic acid derivatized resolving agents of racemic 1-phenylethylamine. Resolution results obtained with the oxalic, malonic, and succinic acid derivatives were previously discussed(1). Each of the above derivative resolving agents could be successfully applied as resolving agents of 1-phenylethylamine. The efficiency of the present optical resolution using (+)-(R)-N-(1-phenylethyl)glutaramic acid resolving agent was remarkably inferior to the results obtained by its shorter chained homologues(1). Use of achiral additives, like urea, thiourea, N-methylurea, and N,N'-dimethylurea caused large increase in the efficiency of the resolution by (+)-(R)-N-(1-phenylethyl)glutaramic acid resolving agent. Precipitated salts obtained in the resolutions performed in the presence of the additives were investigated by thermoanalysis, X-ray powder diffraction, and optical microscopy. Based on the analytical data, the improvement of the resolution results was attributed to the influence of the additives on the crystal nucleation processes of the diasteromeric salts.
Despite the large number of elaborate enantioselective syntheses for the preparation of a single enantiomer to achieve industrial and scientific goals, the separation and purification of enantiomers (components of racemic compounds) is also necessary. Hence, we present the most often used thought-provoking modern methods based on momentous recognitions (e.g. spontaneous resolution, induced crystallization, resolution by formation of diastereomers, resolution by formation of non-covalent diastereomers, resolution by diastereomeric salt formation, resolution by diastereomeric complex formation, "half equivalent" methods of resolution, separation by crystallization, separation by distillation, separation by supercritical fluid extraction, resolution with mixtures of resolving agents, resolution with a derivative of the target compound, enantioselective chromatography, resolution by formation of covalent diastereomers, resolution by substrate selective reaction, kinetic resolution without enzymes, kinetic resolution by enzyme catalysis, hydrolytic and redox enzymes, kinetic and thermodynamic control, resolutions combined with 2nd order asymmetric transformations, enrichment of partially resolved mixtures, role of the solvent and methods of optimization in the separation of diastereoisomers, non-linear effects and selected examples of resolution on an industrial scale).
A general method was found for the resolution of the racemic 1-phenyl-1-propanol (1) and 1-phenyl-2-propanol (2) with various resolving agents. Monoesters of the alcohols were prepared, which were then reacted with different chiral bases. Successful optical resolutions were achieved only with the maleic acid monoesters (3 and 6). Alcohol 1 has been resolved to >99% enantiomeric excess by diastereoisomeric salt formation via its maleic acid monoester (3) using cinchonidine (9) as resolving agent. Alcohol 2 has been obtained in 98% enantiomeric excess by diastereoisomeric salt formation via its the maleic acid monoester (6) using (+)-dehydroabietylamine (11) as resolving agent.
Substituted racemic 1-phenylethylamine derivatives were reacted in molten phase with chiral N-substituted 1-phenylethylamine dicarboxylic acid derivatives (4-9), and their mixtures (e.g., 4+6, 7+8, etc.) in different ratios, and the crystalline quasi-racemic diastereomers so formed were separated. Nonlinear behavior of the mixtures of resolving agents having related structure and considerable positive and negative chiral-chiral interactions were observed.
Structures of chiral and achiral alcohol-O,O'-dibenzoyl-(2R,3R)-tartaric acid (DBTA) complexes were investigated by single-crystal X-ray diffraction (seven new crystal structures were determined). The complexes contain DBTA and chiral alcohol in 1:1, DBTA and achiral alcohol in 1:2 host-guest stoichiometry. The hydrogen bonding structures of chiral alcohol-DBTA and achiral alcohol-DBTA complexes are different, but within a subclass they are isostructural ones.
The very first application of supercritical fluid extraction (SFE) on enantioseparation of alcohols is discussed. Resolution of three chiral alcohols (trans-2-chloro-cyclohexanol, trans-2-bromo-cyclohexanol, and trans-2-iodo-cyclohexanol) were performed by partial complexation with (-)-O,O'-dibenzoyl-(2R,3R)-tartaric acid monohydrate (DBTA). DBTA formed diastereomeric complexes with all S,S-enantiomers stable enough to extract the unreacted alcohols with supercritical carbon dioxide. Resolution efficiency increased with the size of halogen substituents, and by the proper selection of molar ratio, pure (-)-R,R-trans-2-iodo-cyclohexanol (ee > 99%, yield: 39%) or (+)-S,S-trans-2-iodo-cyclohexanol (ee = 98%, yield: 8%) were prepared in one process step. Achieved resolution efficiency values were much higher in all resolution procedures than in any other known enantioseparation of these racemic compounds. The developed method offers an environmentally friendly, efficient alternative of currently applied resolution processes, also on a preparative scale.
During an optical resolution it is the resolving agent that has the strongest influence on the outcome of the process. Applying a mixture of resolving agents can result either in antagonism or in synergy. We found that using mixtures of tartaric acid and its derivatives chiral selectivity is at least the same, but in several cases markedly better (synergistic effect), than the sum of the effect of the individual resolving agents. Thus, the "Dutch method," reported for the crystallization method, also works for distillation. A calculation method is applied for measuring the synergistic effect. Interestingly, an individually inactive resolving agent can be a useful contributor to the mixture of the resolving agents.
Extraction of 25 different binary mixtures of racemic acids [2-(4-isobutylphenyl)propionic acid, cis- and trans-chrysanthemic, and -permetric acid] and various chiral bases with supercritical carbon dioxide permitted the conclusion that molecular chiral differentiation in a supercritical fluid is more efficient than in conventional solvents. In the majority of cases, however, complete separation could not be achieved. In five cases, remarkable partial resolutions were realized (30-75% ee) and resolution was possible on a preparative scale. The pair cis-chrysanthemic acid and (S)-(+)-2-(benzylamino)-1-butanol was studied in detail. Pressure, temperature, time, as well as the molar ratio of base and acid had a marked influence on the quantity and quality of the products. Increasing pressure or decreasing temperature resulted in higher ee values. (-)-cis-Chrysanthemic acid in 99% ee was obtained from the raffinate in a single extraction step. Multiple extractions produced the (+)-cis-acid in 90% ee.