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New racemic and enantiopure N-phosphorylated thioureas bearing 1-phenylethyl or tetrahydronaphthalenyl fragments were synthesized. According to NMR data assisted by DFT calculations, the preferred conformation is stabilized by an intramolecular hydrogen bond. This form in solution is in equilibrium with dimeric N–H···S hydrogen-bonded associates, the population depending on the concentration. In the crystalline phase the low-energy conformation with an intramolecular H-bond is realized only in the racemic tetrahydronaphthalenyl derivative. In most crystals various types of intermolecular hydrogen bonding are observed, accompanied by the formation of infinite linear chains or helical structures. Due to the conformational lability of compounds and competitive intermolecular H-bonding, multiple polymorphic modifications are formed. Therefore, crystallization of enantiopure 1-phenylethyl derivatives from various solvents results in concomitant polymorphs at room temperature. One of them undergoes reversible two-step phase transitions from the high-symmetry I41 space group (Z′ = 1, no disorder) via the P41 space group (Z′ = 6) to the monoclinic P21 space group (Z′ = 16) accompanied by drastic concerted conformational changes. Notably, the optimization of the crystal packing is observed upon phase transitions with a gradual reduction of the void space in the unit cell from 4.5% to 0.8%. This is a rare case of several high-Z′ polymorphs for one compound, with chirality playing an important role.

The reaction of (R)-1-(1-phenyl)ethyl-3-(O,O-diethylthiophosphoryl)thiourea with Cu(II) acetate is accompanied by copper reduction and leads to the formation of a chiral polynuclear Cu6L6 complex. In the crystalline phase the complex consists of six Cu(I) ions alternating with sulfur atoms in the central core, with all six ligands exhibiting similar 1,5-S,S-coordination modes. This structural multinuclear arrangement is preserved in solutions, while at the same time partial disproportionation is observed with the formation of complexes of lower dimensionality. Synchronous redox processes are observed for all six copper ions in the complex in the solid state. The mechanism of copper reduction with the ligand itself as a reducing agent is proposed.

The synthesis for a single enantiomer timolol maleate based on an initial Jacobsen hydrolytic kinetic resolution of racemic epichlorohydrin and on the stereochemistry of the subsequent chemical transformations has been proposed. The feature of this synthesis is that both products of the kinetic resolution, ( R )-epichlorohydrin ( R )- 4 and ( S )-3-chloropropane-1,2-diol ( S )- 5 , have been utilized in the synthesis of the target, ( S )-timolol. The mirror stereochemical results can be obtained with the use of ( R , R )-salen Co(III) catalyst instead of ( S , S )-salen Co(III).

Asymmetric dihydroxylation of mono nitrophenyl allyl ethers leads to the corresponding non-racemic 3-(nitrophenoxy)-propane-1,2-diols 1a – c . As this takes place, regardless of the reagent used (AD-mix-α or AD-mix-β), the configuration of the predominant enantiomer for the para - and meta -nitrosubstituted products is opposite to the configuration of the ortho -nitrophenyl derivative. A correlation between the melting points and vibrational spectra of the racemic and enantiopure diols 1a – c allowed us to establish that all of the chiral substances investigated formed stable racemic compounds in the solid phase.

Oxidation of accessible (R)-3-chloropropane-1,2-diol to (R)-3-chloro-2-hydroxypropanoic acid and subsequent reaction of the latter with ortho-substituted sodium phenoxide gave a number of enantiomerically pure 3-aryloxy-2-hydroxypropanoic acid which are intermediate products in the synthesis of nonracemic 4-aminochroman-3-ols.

A series of enantiopure and racemic p -alkylphenyl glycerol ethers 1a – k were synthesized. A new, sensitive, and pictorial method of comparison of the IR spectra of solid enantiopure and racemic samples was developed to obtain preliminary information on the crystallization types of these compounds. In order to detect the subtle differences in the organization of the chiral solid phase, a new easily implemented approach, based on a chromatographic measuring of the relative abundance of the enantiomers in a single solution in equilibrium with a solid sample of arbitrary (0 n -Pr) and one borderline case (Alk = n -Bu) are disclosed. Higher members of the series of 1 (starting with an n -Bu derivative) are turned into liquid crystals upon melting; no significant differences between racemic and non-racemic samples were found. Only enantiopure methyl-, n -butyl, n -pentyl, n -hexyl, and n -heptyl substituted 1 were able to form supramolecular gels in hydrocarbon solvents; all racemic ethers 1 did not show such ability.

Popular chiral drugs, guaifenesin, methocarbamol, and mephenesin were investigated by single-crystal X-ray analysis both for enantiopure and racemic samples. The absolute configurations for all substances were established through Flack parameter method. The conglomerate-forming nature for the compounds was confirmed by equivalence of crystal characteristics of enantiopure and racemic samples. The molecular structures and crystal packing details were evaluated and compared with one another for all three investigated substances.

The muscle relaxant methocarbamol 2 and tranquilizer mephenoxalone 3, as well as intermediate cyclic carbonate 4, have been prepared in enantiopure form by starting from enantiopure guaifenesin 1 easily available by an entrainment resolution procedure. Thermal investigations reveal that 2 is probably a conglomerate forming substance, 3 forms a stable racemic compound, and 4 occupies an intermediate position. The enantiomeric excess of a binary phase eutectic point for these substances comprises 0%, 85%, and 10%, respectively.

Regardless of the reagent used (AD-mix-α or AD-mix-β), the configuration of the predominant enantiomer formed in the Sharpless asymmetric dihydroxylation of p- and m-nitrophenyl allyl ethers is opposite to the configuration of the product derived from o-nitrophenyl allyl ether.

Nonracemic β-blockers, viz., (S)-propranolol and (S)-timolol, were prepared from (S)-glycidol in three steps consisting in the reaction with SOCl2 followed by the reaction of the resulting (4S)-4-chloromethyl-2-oxo-1,3,2-dioxathiolanes with the corresponding phenol and the final cleavage of (4R)-aryloxymethyl sulfites under the action of amines in DMF.

The reactions of 4-chloromethyl-1,3,2-dioxathiolane 2-oxides with PhONa in EtOH are accompanied by ring opening under the action of the ethoxide ion rather than leading to a rearrangement of the starting molecule as has been assumed previously. Under conditions precluding competition with other nucleophiles, the phenoxide anion smoothly replaces the chlorine atom in chloromethyl-substituted cyclic sulfites.

Reactions of 2,3-epoxyalcohols (glycidols) with thionyl chloride or sulfuryl chloride afford cyclic sulfites or sulfates, respectively. These reactions yield predominantly 4-chloroalkyl-1,3,2-dioxathiolane oxides. The configuration of the C(4) atom in the latter compounds exactly corresponds to that of the C(2) atom of the parent glycidol, whereas the configuration of the exocyclic atom is almost completely reversed with respect to that of the C(3) atom of the precursor.

The conglomerate-forming nature of 3-(2-hydroxyphenoxy)propane-1,2-diol was established by IR, DSC, and XRD methods; racemic diol could be resolved by a moderate efficiency preferential crystallization procedure.

2,3-Epoxy alcohols (glycidols) react with carboxylic acid dichlorides to form cyclic esters of 3-chloro-1,2-diols. The reaction proceeds with complete retention of the configuration of the C(2) atom of the initial glycidol and with predominant (but not complete) inversion of the configuration of the C(3) atom in the final heterocycle.

2,3-Epoxy alcohols (glycidols) react with carboxylic acid dichlorides to form cyclic esters of 3-chloro-1,2-diols. The reaction proceeds with complete retention of the configuration of the C(2) atom of the initial glycidol and with predominant (but not complete) inversion of the configuration of the C(3) atom in the final heterocycle.

The interaction of (S)-glycidol with SOCl2 or SO2Cl2 in stoichiometric amounts leads to the formation of cyclic (4S)-chloromethyl sulfite or sulfate derivatives with the same enantiomeric purity; based on this reaction, a new procedure for the synthesis of (S)-propranolol was developed.

Seven chiral arylglycerol ethers 2-R-C6H4-O-CH2CH(OH)CH2OH (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. Chirality, 2008. © 2008 Wiley-Liss, Inc.

The chiral drug methocarbamol, which is prone to spontaneous resolution, is an effective molecular hydrogelator as both an enantiomer and a racemate; the samples of methocarbamol having an intermediate enantiomeric composition generate clearly visible periodic structures (Liesegang rings) during the gelation process.

The reactions of 4-chloromethyl-1,3,2-dioxathiolane 2-oxides with PhONa in EtOH are accompanied by ring opening under the action of the ethoxide ion rather than leading to a rearrangement of the starting molecule as has been assumed previously. Under conditions precluding competition with other nucleophiles, the phenoxide anion smoothly replaces the chlorine atom in chloromethyl-substituted cyclic sulfites.

The interaction of (S)-glycidol with SOCl2 or SO2Cl2 in stoichiometric amounts leads to the formation of cyclic (4S)-chloromethyl sulfite or sulfate derivatives with the same enantiomeric purity; based on this reaction, a new procedure for the synthesis of (S)-propranolol was developed.