Alexander A. Bredikhin

Three different types of chirality-driven crystallization within the series of uniformly substituted phenyl glycerol ethers.

Seven chiral arylglycerol ethers 2-R-C(6)H(4)-O-CH(2)CH(OH)CH(2)OH (R = H, Me, Et, Allyl, n-Pr, i-Pr, tert-Bu) were synthesized in racemic and scalemic form. The IR spectra, melting points, and enthalpies of fusion for racemic and scalemic samples of every species were measured, the entropies of enantiomers mixing in the liquid state and Gibbs free energies of a racemic compound formation were derived and binary phase diagrams were reconstructed for the whole family. Solid racemic compounds stabilities were ranked for the four substances. Spontaneous resolution was established for the registered chiral drug mephenesin and its ethyl analogue. Metastable anomalous conglomerate, forming crystals having three independent R* and one independent S* molecules in the unit cell, is formed during solution crystallization of tert-butyl derivative; metastable phase transforms slowly into traditional racemic conglomerate.

Chiral drug timolol maleate as a continuous solid solution: Thermochemical and single crystal X-ray evidence

Thermochemical properties of binary mixtures of the popular chiral drug timolol maleate (TM) were investigated by differential scanning calorimetry. It was found that there are no eutectic points on the melting phase diagram, and the enantiomeric components form a continual set of solid solutions over a wide concentration range. The crystal structure of heterochiral racemic TM is essentially isostructural with that of the homochiral (S)-TM, having close cell parameters but containing a crystallographic inversion centre. The crystal structure of the homochiral TM contains two symmetry independent molecules in the unit cell. These molecules have different conformations but are approximate mirror images of each other in the crystal lattice. Within the homochiral crystals only one site of two changes its nature in the heterochiral crystals. The solid solution of TM could be treated as the solid solution of a regular racemic compound and a pure enantiomer.

Cyclic Sulfites, Key Intermediates in Synthesis of 1-Alkylamino-3-aryloxy-2-propanols from Glycidol

By treating glycidol with phenols a number of 3-aryloxypropanedioles were obtained. The latter with thionyl chloride afforded 4-aryloxymethyl-1,3,2-dioxathiolane 2-oxides. These compounds were also obtained from 4-chloromethyl-1,3,2-dioxathiolane 2-oxides by substitution aryloxy group for chlorine. The cyclic sulfides synthesized are universal intermediates in the synthesis of chiral aryloxypropanolamines among which are known β-adrenoblockaders, cardiovascular drugs. From (S)-glycidol were synthesized (S)-alprenolol, (S)-propanolol, and (S)-thymolol.

Crystal structure and phase behavior of the tolyl glycerol ethers. From the conglomerate former to the chirality-driven nanogelator

According to differential scanning calorimetry data ortho-, meta-, and para-tolyl glycerol ethers 1–3 form thermodynamically most stable crystal phases during solution crystallization. For all members of the series the crystal phases formed during melt crystallization have different thermodynamic characteristics from those of the stable ones. Binary melting diagrams were constructed for the stable solid phases; on this basis it was found that 1 is prone to spontaneous resolution, and 2 and 3 form stable solid racemic compounds, the Gibbs energy of formation for which are found to be −2.70 and −2.43 kJ mol−1. Solution grown single crystals of 1–3 were investigated by an X-ray diffraction method. The principal supramolecular crystal formative motifs were revealed: 1D columns for 1 and scal-2, 2D bilayers having developed a 2D system of intermolecular hydrogen bonds (IMHB) for rac-2 and rac-3, and 2D bilayer having 1D spiral IMHB organization for scal-3. The possible reasons preventing the solid racemic compound formation in the case of 1, and the spontaneous resolution manifestation in the cases of 2 and 3 are disclosed. It was demonstrated that, from the whole family of tolyl glycerol ethers, only scal-3 samples are capable of supramolecular gels formation. This property is connected with the peculiarities of the scalemic 3 crystal packing.

Crystal structure of chiral ortho-alkyl phenyl ethers of glycerol: true racemic compound, normal, false and anomalous conglomerates within the single five-membered family

For a family of chiral terminal ortho-alkylphenyl glycerol ethers [alkyl = Me (1), Et (2), n-Pr (3), i-Pr (4), t-Bu (5)] nine different crystalline modifications have been obtained and investigated by X-ray analysis. All possible types for chiral compound crystallization, including a very rare type of false conglomerate (polymorph of rac-4.1) and extremely rare case of anomalous conglomerate (metastable form of rac-5) have been found within this set. Three tested substances crystallize as normal conglomerates, while two are capable of forming normal racemic compounds. Centrosymmetrical dimers of enantiomers, which are typical for most racemates, are absent in all the investigated crystals. The samples of the enantiopure compound 2 and 3 form stable supramolecular gels in hydrocarbon solvents. Some assumptions have been made linking the features of the molecular and crystal structures in the investigated series.

Jacobsen-type enantioselective hydrolysis of aryl glycidyl ethers. 31P NMR analysis of the enantiomeric composition of oxiranes

The enantioselective partial hydrolysis of a number of racemic aryl glycidyl ethers in the presence of chiral Co(salen)-catalyst was studied. The enantiomeric composition of the isolated (R)-aryl glycidyl ethers was analyzed by 31P NMR using optically active substituted 2-chloro-1,3,2-dioxaphospholanes. A synthesis of β-adrenoblocking agents (S)-toliprolol and (S)-moprolol based on the simultaneously obtained (S)-3-aryloxypropane-1,2-diols was proposed.

Solubility and Some Crystallization Properties of Conglomerate Forming Chiral Drug Guaifenesin in Water

The solubility of 3-(2-methoxyphenoxy)-propane-1,2-diol, the well-known chiral drug guaifenesin 1, in water has been investigated by means of polythermal and isothermal approaches. It was found that the solubilities of racemic and enantiomeric diols rac- and (R)-1 depend strongly on temperature. The ternary phase diagram of the guaifenesin enantiomers in water in the temperature range between 10°C and 40°C was constructed. Clear evidence was obtained that rac-1 crystallizes as a stable conglomerate. The Meyerhoffer coefficient for the guaifenesin-water system is more than two and strongly depends on temperature. Neither crystalline hydrates nor polymorphs were detected within the range of conditions covered. Metastable zone width data with regard to primary nucleation were also collected for rac-1 and (R)-1. On the basis of the knowledge acquired, the resolution of racemic guaifenesin by preferential crystallization from solution could be realized successfully.

Oxidation of prochiral sulfides with chiral dioxirane

Dioxirane generated in situ by reaction of chiral 1,2:4,5-di-O-isopropylidene-D-erythro-hexo-2,4-diulo-2,6-pyranose with Oxone oxidizes prochiral sulfides to the corresponding sulfoxides with an enantiomeric excess of 2 to 25%.

Crystallization of chiral compounds. 2. Propranolol: free base and hydrochloride

The data from IR spectroscopy, differential scanning calorimetry, and X-ray diffraction analysis are compared for crystalline specimens of homochiral and racemic propranolol and its hydrochloride. The stabilities of the racemates were quantitatively characterized and the factors responsible for the order of their stability are revealed.

On the use of seven-membered phosphorous heterocycles based on 2,2′-dihydroxy-1,1′-binaphthalene and 1,4∶3,6-dianhydro-d-mannitol in the31P NMR analysis of the enantiomeric composition of chiral alcohols

Some aspects of phosphorylation of 2,2′-dihydroxy-1,1′-binaphthalene (BINOL) and 1,4∶3,6-dianhydro-d-mannitol (isomannide) were investigated. The possibility of using the corresponding cyclic chloro- and amidophosphites for the analysis of enantiomeric compositions of chiral primary and secondary alcohols by31P NMR was examined.