An ab initio theoretical study of the stereoisomers of tetrahydrocannabinols

An extensive theoretical study of the stereoisomers of tetrahydrocannabinols has been performed at the ab initio HF/6-31G^* and B3LYP/6-31G^* levels. Effects of solvation were calculated with the Onsager model (with full geometry optimization), SCRF with Tomasi's PCM, and isodensity polarization continuum models. Single-point MP2//HF/6-31G^* calculations were carried out. Frequency calculations for all the isomers at the HF/6-31G^* level and for two natural isomers ¹-THC-RR and ⁶-THC-RR at the B3LYP/6-31G^* level were performed. Our results support the findings of the previous AM1 studies that the orientation of the carbocyclic ring and its C1 substituent with respect to the phenyl group hydroxyl oxygen play the major role in the activity. The calculated values of the LUMO energy (lowest unoccupied molecular orbital) and the hardness of the stereoisomers show that for the trans isomers it is easier to remove one electron from its HOMO (highest occupied molecular orbital) to the LUMO and easier to accept an electron from the receptor binding site than for the cis isomers. Combining geometric features (the orientation of the carbocyclic ring and its C1 substituent with respect to the phenyl group hydroxyl oxygen) with electronic features (LUMO and hardness), we explain the activity differences among the stereoisomers.     

Synthesis and infrared spectra of stereoisomers of some 2-substituted <Emphasis Type="Italic">p</Emphasis>-(vinyl)phenylcyclopropanes

The IR spectra of the synthesized cis-and trans-stereoisomers of 2-ethoxycarbonyl-(I), 2-carboxy-(II), and 2-hydroxymethyl p-(vinyl)phenylcyclopropane (III) are analyzed. On the basis of the data obtained, the geometric structure of the isolated stereoisomers has been established.     

Synthesis of enantiomeric 9-(2′,3′,4′-trihydroxybutyl)adenine derivatives from l-ascorbic and d-isoascorbic acids

l-Ascorbic and d-isoascorbic acids were employed in syntheses of 9-(2′,3′,4′-trihydroxybutyl)adenines protected at 3′ and 4′ oxygens (all four enantiomers) and at 2′ oxygen (2′S,3′R and 2′S,3′S enantiomers).     

Stereoselective separation of (1S, 4S)‐sertraline from medicinal reaction mixtures by countercurrent chromatography with hydroxypropyl‐β‐cyclodextrin as stereoselective selector

Four stereoisomeric components were produced during the synthesis of the antidepressant drug (1S, 4S)‐sertraline hydrochloride due to the two chiral carbon centers in its chemical structure, including (1S, 4S), (1R, 4R), (1S, 4R), and (1R, 4S)‐isomer. Stereoselective separation of the target isomer (1S, 4S)‐sertraline from the medicinal reaction mixtures by countercurrent chromatography using hydroxypropyl‐β‐cyclodextrin as the stereoselective selector was investigated. A biphasic solvent system composed of n‐hexane/0.20 mol/L phosphate buffer solution with pH 7.6 containing 0.10 mol/L of hydroxypropyl‐β‐cyclodextrin (1:1, v/v) was selected for separation of cis‐sertraline and trans‐sertraline using reverse phase elution mode and (1S, 4S)‐sertraline was separated with (1R, 4R)‐sertraline using recycling elution mode. A fabricated in‐house analytical countercurrent chromatographic apparatus was used for optimization of the separation conditions. Stationary phase retention and peak resolution were investigated for separation of cis‐sertraline and trans‐sertraline by the analytical apparatus.     

Reaction of mercury salts with dimethyl tricyclo [4.2.2.02,5]deca-3,7-diene-cis-endo-9,10-dicarboxylate in acetic acid

The reaction of dimethyl tricyclo[4.2.2.0^2,5]deca-3,7-diene-cis-endo-9,10-dicarboxylate with mercury salts Hg(OCOR)₂ (R=CCl₃, CF₃, CH₂Cl) in acetic acid yields a mixture of solvoadducts and products of addition of the anionic moiety of the reagent having thetrans-configuration. In the case of Hg(OCOCCl₃)₂,cis-solvoadduct was detected along with thetrans-isomer. The amount of the addition products is determined by the nature of the mercury salt and increases in the order Hg(OCOCH₂Cl)₂<Hg(OCOCCl₃)₂=Hg(OCOCF₃)₂. The reaction is assumed to involve contact and solvent-separated ion pairs. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2173–2176, November, 1999.     

A highly efficient way to recycle inactive stereoisomers of Bedaquiline into two previous intermediates via base-catalyzed C_(sp3)–C_(sp3) bond cleavage

Bedaquiline is a new medicine for pulmonary multi-drug resistant tuberculosis(MDR-TB), which is a pure enantiomer with two chiral centers. The current industrial preparation process requires the separation of active Bedaquiline from a mixture of four isomers. Obviously, direct dispose of the other three undesired stereoisomers will cause significant waste and increase the unnecessary cost of production. Here, we developed an efficient, facile and scalable process for recycling the inactive stereoisomers of Bedaquiline. All these inactive stereoisomers could be recycled by their conversion to two important intermediates in the Bedaquiline synthesis via a base-catalyzed Csp3–Csp3 bond cleavage of a benzyl alcohol intermediate. And the precise conditions and mechanism of the base-catalyzed cleavage reaction were discussed.     

Intramolecular hydrogen bonding and structure of stereoisomeric 20(22)-hydroxy-22(23)-isoxazolinyl steroids

We have used IR spectroscopy and the quantum chemical AM1 method to study stereoisomeric 22(23)-isoxazolinyl steroids with a hydroxyl group at C₂₀ or C₂₂, in order to establish the spectral features that will allow us to identify their stereoisomers. We have carried out a conformational analysis of isoxazolinyl steroid stereoisomers, and we have calculated the populations of their stable conformers. We have assigned the bands in the IR spectra of the stereoisomers in the region of the stretching vibrations of OH groups, and have analyzed the possibility of intramolecular hydrogen bond formation between the OH groups and proton-acceptor centers of the isoxazoline ring. __________ Translated from Zhurnal Prikladnoi Spektroskopii, Vol. 73, No. 2, pp. 145–151, March–April, 2006.     

Molecular Modeling in Chromatoscopy as a New Tool in the Structure Elucidation of Novel Isomers by GC/MS

The importance of gas–solid chromatography on graphitized thermal carbon black (GTCB) as a source of additional data for the positive structural elucidation of novel isomers by gas chromatography–mass spectrometry is discussed. The retention parameters of isomers being investigated were calculated by Kiselev's method (chromatoscopy) to predict the order of their separation on a column packed with GTCB. To extend the possibilities of this method and to improve the accuracy of a prediction of retention parameters, the molecular mechanics was used for the optimization of hypothetical molecular models of isomers required for these calculations. As a test mixture 11 isomers of perhydroanthracene and perhydrophenanthrene were consedered. The predicted elution order from the column packed with GTCB of these isomers, calculated on the basis of molecular models optimized by molecular mechanics appeared to be close to the experiment, whereas the result obtained by a conventional approach appeared to fail. Molecular modeling in chromatoscopy was used for the structural elucidation of novel isomers of perhydroxanthene (PHX) and perhydro-4-thia-s-indacene (PHTI), which were found by GC–MS in reaction mixtures. The evidence for this assignment-based on the obtained GC and MS data, is discussed.