Stereochemistry and mechanism of the hydrogenation of substituted cyclopentenes

1,2- and 2,3-disubstituted cyclopentenes were hydrogenated with several transition metal catalysts. The hydrogenation of 1,2-disubstituted cyclopentenes gave preferably the cis products with Raney Ni, whereas 2,3-disubstituted cyclopentenes gave preferably the trans isomers. The trans products were favoured in the hydrogenation of 1,2- and 2,3-dialkylcyclopentenes with Pt or Pd catalysts. A detailed product analysis of the hydrogenation of 1,2-dialkylcyclopentenes indicates that the double bond migration occurred to form 2,3-dialkylcyclopentenes in advance of the hydrogenation. In contrast, 1-methyl-2-phenylcyclopentene gave predominantly the cis product irrespective of the kind of catalyst. These results suggest the formation of a π-benzylic species during the course of the reaction. The mechanism is discussed in terms of the modified Horiuti-Polanyi mechanism.     

Stereochemistry of heterocycles

Some 2,5-dialkyl-2-methyl-1,3-dioxanes and 5-alkyl-2-methyl-2-phenyl-1,3-dioxanes have been synthesized. All the compounds studied consist of epimeric mixtures of geometric isomers the equilibrium in the course of the formation of which is shifted in the direction of the isomers with the diequatorial position of the largest substituents. The predominant conformation of the molecules of both isomers is the chair conformation. The cis isomers of the substances investigated consist of mixtures of conformers.For Communication XIX, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1240–1245, September, 1973.     

Simple Methods for Determining Relative Stereochemistry of Kainoid Amino Acids by (1)H NMR Chemical Shifts

The kainoid amino acids are biologically important compounds because they show remarkable neuroexcitatory and excitotoxic activities. For exhibiting potent activity, the stereochemical relationship of the substituents on the pyrrolidine ring is crucial. We found simple methods for determining the relative stereochemistry of these compounds on the basis of the (1)H NMR chemical shifts of H-2 and H-4 in D(2)O solution. The signals of H-2 appear at fields higher than 4.2 ppm when the compounds have 2,3-trans stereochemistry whereas, in the 2,3-cis compounds, they appear lower than 4.2 ppm, irrespective of the C-4 substituent. This criterion holds when the solution is in the range of pD 3-8. Moreover, when an epimeric pair at C-2 is available and the spectra are recorded at the same or nearly equal pD, the H-2 chemical shift of the 2,3-trans isomer is higher than that of the corresponding 2,3-cis isomer. Similarly, the relative stereochemistry between C-3 and C-4 can be determined from the chemical shift of H-4. The signals of H-4 of the 3,4-cis isomers appear at lower fields than those of the corresponding 3,4-trans isomers in each pair of C-4 epimers when the spectra are recorded at the same or nearly equal pD. This holds for the compounds bearing an unsaturated substituent at C-4. All these phenomena can be rationalized by the anisotropic effect of the pi-electron system in the C-2 and C-4 substituents.     

Saturated nitrogen-containing heterocycles. 13. Perhydroacridines. Synthesis and stereochemistry

The configurations of the perhydroacridines formed in the catalytic hydroamination of threo-methylenedicyclohexanone and the product of its cyclization — 2-hydroxy-2,3-tetramethylenebicyclo[3.3.1]nonan-9-one — were established by means of the ¹³C NMR spectra and alternative synthesis. It is shown that isomers with cis-anti-cis and cis-syn-cis configurations are formed as a result of the reactions. The results of x-ray diffraction analysis are presented for cis-syn-cis-N-(2-hydroxyethy1)perhydroacridine.See [1] for Communication 12.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1645–1650, December, 1987.     

Stereochemistry of heterocycles

Methods were developed for the synthesis of 2-ethoxy-1,4-butanediol and 2-ethoxy-1,4-pentanediol. The latter was a mixture of diastereomers. These diols were used to synthesize 5-ethoxy-1,3-dioxepan and 2,2,4-trimethyl-6-ethoxy-1,3-dioxepan. Gas-liquid chromatography was used to demonstrate that 2,2,4-trimethyl-6-ethoxy-1,3-dioxepan is a mixture of cis and trans isomers; the ratio of these isomers is similar to the ratio of diastereomers in the starting 2-ethoxy-1,4-pentanediol. The configurations of the indicated isomers were evaluated by conformational analysis.See [1] for communication XIII.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 3–6, January, 1972.     

Stereochemistry of the aza-Michael reaction with natural alantolactones

Hydrogenated 3-aminomethylnaphtho[2,3-b]furan-2-ones were synthesized by the reaction of natural alantolactones with pharmacophoric amines. Determination of the newly formed asymmetric center configuration by two-dimensional NMR data is presented. The structure of the obtained compounds was proved by X-ray structural analysis.     

Synthesis of esters of stereoisomeric 4,5-dimethylhepta-2,4-dien-6-ynoic acids

Summary We determined the ratio of the geometric isomers of 2,3-dimethyl-2-penten-4-yn-1-al, formed in the oxidation of 2,3-dimethyl-2-penten-4-yn-1-ol and of the corresponding bromide, and we also synthesized some esters of the isomeric 3,4-dimethylhepta-2,4-dien-6-ynoic acids.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 546–548, March, 1965     

Cyclopentanones—VIII : Stereochemistry of the lithium-liquid ammonia reduction of 2,3-dialkyl-4-hydroxy-2-cyclopentenones

2,3-Dialkyl-1,4-cyclopentanediols are obtained by lithium-liquidammonia-alcohol reduction of 2,3-dialkyl-4-hydroxy-2-cyclopentenones. The configuration of the diastereoisomers formed was proved by ¹H-NMR spectroscopy and by chemical evidence. In the most abundant isomer the alkyl groups are trans and each is in trans position to the vicinal hydroxyl function. In another diastereoisomer formed in substantial amount the alkyl groups have a cis orientation and are trans to the vicinal hydroxyl function. The ¹H-NMR parameters found are more useful generally for configurational assignments to synthetic and modified prostaglandins.     

Stereochemistry of heterocycles

2-Methyl-and 2,5-dialkyl-5-phenoxy-1,3-dioxanes were synthesized and separated into their geometrical isomers by precision rectification. The configuration and conformations of these isomers were determined by PMR spectroscopy. It is shown that the low-boiling trans isomers exist primarily in the chair conformation with an equatorial phenoxy group, whereas the high-boiling cis isomers exist primarily in the chair conformation with an axial phenoxy group.     

Stereochemistry of cyclic compounds—I : Synthesis and configurational assignment of diastereomeric 2,4-dioxaspiro[5.5]undec-8-enes

Several 2,4 - dioxaspiro[5.5]undec - 8 - enes have been prepared from the Diels-Alder adducts of butadiene and 2,3-dimethylbutadiene with acrolein. Contrary to literature reports on some 3-substituted derivatives, which were assumed to be pure compounds, it is shown that these spiro compounds are generally obtained as 1:1 mixtures of two diastereomers. The isomers have been separated in the case of the 3-methyl and 3-ethyl derivatives by fractional distillation. On the basis of ¹H NMR spectroscopy, the nature of the isomerism is shown to be of cis, trans type and an unambiguous cofigurational assignment of the isomers has been achieved. Although the diastereomers are of similar topography, they have distinctly different olfactory properties.     

Stereochemistry of chromium complexes with monosubstituted allenes

Previously unknown arenechromium dicarbonyl complexes with different allenes including functionally substituted ones were synthesized. The formed compounds represent a mixture of all three possible isomers and exhibit stereochemical nonrigidity. The isomerization process and stereochemical peculiarities of the complexes synthesized were studied using the ¹H NMR method.     

Stereochemistry of heterocycles

The conformations of stereoisomeric 2,5-dialkyl-1,3-dioxanes were studied by means of dipole moments (DM), and it was shown that the low-boiling isomers have a chair conformation or a somewhat distorted symmetrical boat conformation, while the high-boiling isomers have a chair conformation with diequatorial orientation of the substituents. The DM measurements lead to values for the ketals which are closest to those calculated for the chair conformation.See [1] for communication V.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 593–596, May, 1971.The authors sincerely thank Academician D. A. Arbuzov for his unflagging interest and involvement in this investigation.     

Stereochemistry of the thermal isomerizations of (2S,3R-methoxymethyl-2,3-dideuterio-1-(dideuteriomethylene)cyclopropane

The (2S,3R) isomer of 2-methoxymethyl-2,3-dideuterio-1-(dideuteriomethylene)cyclopropane has been synthesized and heated at 198.8°: from the experimentally observed mol fractions of the eight isomers of 2,3,α,α,- and 2,3,3,α - tetradeuterio - 2 - methoxymethyl - 1 - methylenecyclopropane in the pyrolysis product mixture have been derived rate constants for seven distinct modes of isomerization. One-center thermal epimerizations at C(2) and C(3) and the C(2)C(3) two-center epimerization are of kinetic importance. Only two of four observable stereochemical modes for carbon [1,3] shifts are seen: there is inversion of stereochemistry at the migrating C atom, while the C(3)H trans to C(2)-CH₂OCH₃ in starting material becomes syn 4 : 1 C(α)-H in the [1,3] shift product. Stereomutation at C(2) does not occur along the reaction coordinate for [1,3] carbon shifts.     

The Thermodynamic Parameters of Sorption and Selectivity of Chiral Nematic Liquid Crystals of Terephthalidene-bis-2-methylbutyl para-Aminobenzoate

The thermodynamic characteristics of sorption of n-alkanes, arenes, aldehydes, monoatomic alcohols, and isomeric forms of butanediol-2,3 by chiral nematic liquid crystals, terephthalidene-bis-2-methylbutyl para-aminobenzoate, were studied over the temperature range of the existence of the meso- and isotropic phases. The contributions of dipole—dipole and specific interactions to the enthalpy of sorption were estimated. Sorbate—liquid crystal systems were characterized by positive deviations from ideality caused by the enthalpy factor. The mesophase of the liquid crystal studied was found to possess selectivity with respect to the optical isomers of butanediol-2,3 (α_R/S = 1.03 over the temperature range 140–150°C). It was shown that diol–liquid crystal molecular H-complexes formed played an important role in the mechanism of chiral recognition of butanediol-2,3 optical isomers under gas-liquid chromatography conditions.     

Stereochemistry of heterometallic platinum clusters

Heterometallic platinum complexes cover a huge field, as shown by a recent survey covering the crystallographic and structural data of almost 1500 examples. About 5% of those complexes exists as isomers and are summarized in this review; except one cis-trans example, the remainder are distortion isomers. These are discussed in terms of the coordination about the platinum atom, and correlations are drawn between donor atom, bond lengths and interbond angles, with attention to trans effect and metal-metal bonds. Distortion isomers, differing only by degree of distortion in Pt–L and Pt–M distances and L–M–L bond angles, spread over a wide range of oxidation states of platinum: zero, +1, +2 (most common) and +4. The mean Pt–Pt bond distance elongate with increase in oxidation state of platinum: 2.705 Å (Pt(0)–Pt(0)) < 2.720 Å (Pt(I)–Pt(I)) < 2.773 Å (Pt(II)–Pt(II)). The shortest mean Pt–M bond distances are: Pt(0)–Ga = 2.37 Å; Pt(I) = Au 2.697 Å, Pt(II)–Fe = 2.625 Å and Pt(IV)–Sn, 2.580 Å.     

Addition of Vindoline to p-Benzoquinone: Regiochemistry,Stereochemistry and Symmetry Considerations

Vindoline and catharanthine are the major alkaloids of Catharanthus roseus and are extracted in large quantities to prepare the pharmaceutically important Vinca type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine makes it an attractive substrate for developing new chemistry and adding value to the plant. In this context, we have reacted vindoline with a selection of electrophiles among which benzoquinone. Conditions were developed to optimize the synthesis of a mono-adduct, of five bis-adducts, and of tri-adducts and tetra-adducts, several of these adducts being mixtures of conformational isomers. Copper(II) was added to the reactions to promote reoxidation of the intermediate hydroquinones and simplify the reaction products. The structures were solved by spectroscopic means and by symmetry considerations. Among the bis-isomers, the 2,3-diadduct consists of three unseparable species, two major ones with an axis of symmetry, thus giving a single set of signals and existing as two different species with indistinguishable NMR spectra. The third and minor isomer has no symmetry and therefore exhibits nonequivalence in the signals of the two vindoline moieties. These isomers are designated as syn (minor) and anti (major) and there exists a high energy barrier between them making their interconversion difficult. DFT calculations on simplified model compounds demonstrate that the syn-anti interconversion is not possible at room temperature on the NMR chemical shift time scale. These molecules are not rigid and calculations showed a back-and-forth conrotatory motion of the two vindolines. This “windshield wiper” effect is responsible for the observation of exchange correlations in the NOESY spectra. The same phenomenon is observed with the higher molecular weight adducts, which are also mixtures of rotational isomers. The same lack of rotations between syn and anti isomers is responsible for the formation of four tri-adducts and of seven tetra-adducts. On a biological standpoint, the mono adduct displayed anti-inflammatory properties at the 5 μM level while the di-adducts and tri-adducts showed moderate cytotoxicity against Au565, and HeLa cancer cell lines.     

Chlorination reactions of ephedrines revisited. Stereochemistry and functional groups effect on the reaction mechanisms

The stereochemistry of the chlorination reactions with SOCl₂ of free ephedrine and pseudoephedrine and their hydrochlorides, oxamides and sulfonamides was analyzed. Chlorination of free and hydrochloride erythro isomers occurs with 100% inversion of configuration at C-1 (S_N2 mechanism). Chlorination of oxamides and sulfonamides of erythro isomers occurs with retention of the configuration at C-1, (S_Ni mechanism). Chlorination reactions in all threo isomers and derivatives hydrochlorides, oxamides or sulfonamides gave the same ratio of erythro (40%) and threo isomers (60%) (S_N1 mechanism). Treatment of the isomeric mixture of the chlorodeoxyephedrine and chlorodeoxypseudoephedrine hydrochloride in DMSO with HCl changes the isomeric ratio, increasing the erythro isomer content (65%). Using the erythro ethanolamines it is possible to arrive stereoselectively at the erythro chloroamines if the compound is previously tosylated or converted to the amide, or to the threo chloroamines if the compound is directly chlorinated with SOCl₂.     

Synthesis of 1-(3-halotetrahydro-2-furyl) derivatives of uracil, 5-substituted uracils,and cytosine

The cis and trans isomers of 1-(3-halotetrahydro-2-furyl) derivatives of uracil, 5-substituted uracils, and cytosine were obtained by alkylation of 2,4-bis(trimethylsilyl) derivatives of uracil, 5-substituted uracils, and cytosine with 2,3-dihalotetrahydrofurans. 2,3-Anhydro compounds are also formed in the alkylation of 5-halouracil derivatives. The physicochemical properties of the compounds obtained and the antineoplastic activities of the 5-fluorouracil derivatives were studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 94–99, January, 1987.     

Stereochemistry of nitrogen heterocycles. 68. Stereochemistry of 2,5-dimethyl-4-piperidone, 2,5-dimethyl-4-piperidol,and their N-benzoyl derivatives

The isomers of 1-benzoyl-2,5-dimethyl-4-piperidone were obtained and equilibrated (89.8% cis 10.2% trans isomer, preferred conformations 2a, 5e, and 2a, 5a). The position of the equilibrium between the isomers of 2,5-dimethyl-4-piperidone was determined by two independent methods (89.5% trans 10.5% cis isomer). The differences in the free energies of the isomers, the conformational energy of the -CH₃ group, and the energy of syn-axial 1,3-interaction between the CH and the unshared electron pair were calculated; the decrease in the conformational energy of the -methyl group in the series of piperidine (1.6), 4-piperidone (1.47), and N-acyl-4-piperidone (1.28 kcal/mole) was explained by the successive weakening of the repulsive interaction between the -CH₃ group and the n-pair of the nitrogen as a result of the flattening of the ring and of the conjugation between the free electron pair of the nitrogen and the electrons of the acyl carbonyl group. The last previously unknown fourth isomer of 2,5-dimethyl-4-piperidol, which exists in the 2e,4a,5a conformation, was obtained by the reduction of cis-1-benzoyl-2,5-dimethyl-4-piperidone followed by debenzoylation. In contrast to the secondary amine, its N-benzoyl- and N-benzyl-substituted derivatives exist in the alternative 2a,4e,5e conformation. The configurations and conformations of the isomers were determined by means of the IR and NMR spectra.For Communication 67, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 953–961, July, 1989.     

Stereochemistry of Molecular Figures-of-Eight

A trans isomer of a figure-of-eight (Fo8) compound was prepared from an electron-withdrawing cyclobis(paraquat-p-phenylene) derivative carrying trans-disposed azide functions between its two phenylene rings. Copper(I)-catalyzed azide-alkyne cycloadditions with a bispropargyl derivative of a polyether chain, interrupted in its midriff by an electron-donating 1,5-dioxynaphthalene unit acting as the template to organize the reactants prior to the onset of two click reactions, afforded the Fo8 compound with C(i) symmetry. Exactly the same chemistry is performed on the cis-bisazide of the tetracationic cyclophane to give a Fo8 compound with C(2) symmetry. Both of these Fo8 compounds exist as major and very minor conformational isomers in solution. The major conformation in the trans series, which has been characterized by X-ray crystallography, adopts a geometry which maximizes its C?H???O interactions, while maintaining its π???π stacking and C?H???π interactions. Ab initio calculations at the M06L level support the conformational assignments to the major and minor isomers in the trans series. Dynamic (1) H?NMR spectroscopy, supported by 2D (1) H?NMR experiments, indicates that the major and minor isomers in both the cis and trans series equilibrate in solution on the (1) H?NMR timescale rapidly above and slowly below room temperature.