Conformational mobility of the six-membered ring in 5-oxo-1,3-cyclohexadiene and its derivatives

Molecular mechanics and MNDO calculations showed that the six-membered ring in the molecule of 5-oxo-1,3-cyclohexadiene possesses high conformational mobility. The transition from a planar equilibrium conformation to a distorted sofa conformation in which the C(sp²)-C(=O)-C(sp³)-C(sp²) torsion angle is equal to ±30° increases the energy of the molecule by less than 1 kcal mol^–1. The influence of steric (R = Me, Et, Prⁱ, Bu^t) and electronic (R = NH₂, NO₂) effects of substituents R on the equilibrium conformation and mobility of the carbocycle has been analyzed. Both types of substituents at unsaturated C atoms do not change the equlibrium conformation or flexibility of the six-membered ring. Substituents at saturated C atoms cause the transition of the carbocycle to the distorted sofa conformation and significantly restrict its mobility. The electronic structures of 5-oxo-1,3-cyclohexadiene and its amino and nitro derivatives have been analyzed.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 849–854, May, 1995.     

Molecular structure and conformational analysis of chirai (−)-3-(4-bromobenzylidene)-1-isopropyl-2-methoxy-4-methylcyclohexene

(–)-3-(4-Bromobenzylidene)-1-isopropyl-2-methoxy-4-methylcyclohexene, capable of inducing spiral supramolecular ordering when introduced to nematic and some smectic mesophases, has been studied by an X-ray structural analysis. The crystals are orthorhombic; at 20 °Ca = 6.055(1),b = 13.282(3),c=20.734(4) Å,V=1668(1) ų,d _calc = 1.380 g cm^–3, space groupP2 ₁2₁2₁ Z=4. The cyclohexene ring has a conformation intermediate between a sofa and a half-chair. The methyl and methoxyl groups are in asyn orientation with respect to the mean plane of the cycle. The angle between the plane of the aryl substituent and the exocyclic double bond is 33°. The observed distortions of bond angles at unsaturated carbon atoms are typical of derivatives of benzylidenecyclohexene. Molecular mechanics calculations demonstrated that the conformation observed in the crystalline state is not the most favorable, and this conformation is stabilized through intermolecular interactions upon stacking in crystals. It was shown that the relative orientation of the methyl and methoxyl groups as well as the orientation of the aryl substituent substantially affect the conformation of the cyclohexene ring.Deceased.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2437–2442, December, 1995.     

Effect of benzannelation on the conformational flexibility of the rings in oxo, imino, and methylene derivatives of cyclohexa-1,4-diene

The effect of benzannelation on the equilibrium conformation and flexibility of the dihydrocycle in cyclohexa-1,4-dienone,para-quinone, and their imino and methylene analogs was studied by the semiempirical quantum-chemical AM1 method. The equilibrium conformations of the carbonyl derivatives are planar. In the imino- and methylene-substituted analogs, the dihydrocycle adopts a boat conformation due to repulsions between substituted analogs, the dihydrocycle adopts a boat conformation due to repulsions between the hydrogen atoms at the exocyclic double bond and in theperi positions of the benzene rings. Annelation of cyclohexa-2,5-dien-1-one andpara-quinone with benzene rings at the C=C double bonds causes an increase in the conformational flexibility of the partially hydrogenated ring owing to an increase in the bending strain in the first compound and a decrease in the conjugation between the carbonyl groups and the remaining part of the molecule in the second compound. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 388–390, March, 1998.     

Molecular and crystal structures of stereoisomeric2R,3R,6S-2-(1′S-hydroxy-1′-biphenylyl)- and2R,3R,6S-2-(1′R-hydroxy-1′-biphenylyl)methyl-3-methyl-6-isopropylcyclohexanones

It was established by X-ray diffraction analysis that 2-(1′-hydroxy-1′-biphenylyl)methyl-3-methyl-6-isopropylcyclohexanone, one of the minor products of the directed aldol reaction of (−)-menthone bromomagnesium enolate with 4-phenylbenzaldehyde, has the2R,3R,6S, 1′R configuration. The characteristic features of the spatial structure of this β-hydroxyketone were compared with those of the major stereoisomeric product of the above-mentioned reaction. The latter has the2R,3R,6S,1′S configuration. In the crystals, both stereoisomers have the cyclohexanone ring in a chair-like conformation with the three substituents in equatorial positions and are characterized by the presence of the annelated (cis-fused) pseudoring with an −OH…O=C< intramolecular hydrogen bond. The structures of the stereoisomers differ in the orientation of the aryl group and the hydrogen atom at the C(1′) chiral center with respect to the cyclohexanone ring. The results of X-ray diffraction analysis were compared with the data of molecular mechanics calculation for the energetically most favorable conformations of the isolated molecules of β-hydroxyketones under study. Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 11, pp. 2251–2257, November, 1998.     

3-Ferrocenyl-3-(1-naphthyl)cyclopropene. Synthesis, structure, and chemical transformations

Crystalline 3-ferrocenyl-3-(1-naphthyl)cyclopropene was prepared by dehydrobromination ofZ- andE-2-bromo-1-ferrocenyl-1-(1-naphthyl)-cyclopropanes by Bu^tOK in DMSO. The resulting compound and the startingZ-monobromocyclopropane were characterized by X-ray diffraction analysis. The obtained cyclopropene reacts with 1,3-diphenylisobenzofuran to give a [4+2]-cycloadduct. The small ring opens upon treatment with HBF₄ etherate to afford isomericZ- andE-prop-1-enes and 1-ferrocenyl-3H-benzo[e]indene. Thermolysis of this cyclopropene results in the formation of 1-ferrocenyl-9bH-benzo[e]indene. In all cases, opening of the small ring is accompanied by exclusive alkylation of the naphthalene moiety. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 499–506, March, 1998.     

Conformational analysis of 2-oxo-1,2,3,4,-tetrahydropyridine and its alkyl- and phenyl-substituted derivatives

The molecular geometries and inversion barriers of the rings in 2-oxo-1,2,3,4-tetrahydropyridine and its alkyl-substituted (Me, Et, Prⁱ, or Bu^t) and phenyl-substituted derivatives were calculated by the molecular mechanics method. The introduction of substituents has no substantial effect on the equilibrium conformation of the heterocycle (a distorted sofa). For 4-alkyl- and 3-alkyl-substituted derivatives (except for 4-Me and 4-Et derivatives), an axial orientation of the alkyl group is more favorable. The phenyl substituents have equatorial and axial orientations at postions 4 and 3, respectively. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1584–1586, September, 1997.     

Synthesis, structural and crystallographic study of some carbamates derived from 9-methyl-9-azabicyclo[3.3.1]nonan-3α-ol

A series of benzimidazole, thiazole and benzothiazole carbamates derived from 9-methyl-9-azabicyclo[3.3.1]nonan-3α-ol was synthesized and studied by ¹H, ¹³C, 2D NMR and IR spectroscopy. To assist in the interpretation of the spectroscopic data, the crystal structure of 3 (9-methyl-9-azabicyclo[3.3.1]nonan-3α-yl 2-amino-1H-benzimidazole-1-carboxilate) was determined by X-ray diffraction. It has been found that 1-carbamates and 2-carbamates can be obtained in the case of the benzimidazole derivatives. The benzimidazole-1-carbamates are obtained in higher yields (41, 38%) than the benzimidazole-2-carbamates (3, 9%). The compounds studied displayed in CDCl₃ solution a preferred chair–boat conformation with the substituted ring in a distorted boat form and the N–CH₃ substituent in an axial position with respect to the chair piperidine ring. This conformation is similar to that determined by X-Ray diffraction for compound 3.     

Substituentenabhängigkeit der Ringinversion des Ungesättigten Siebenringes bei Benzocycloheptenderivaten. Konformative Beweglichkeit flexibler Ringsysteme—XIV: Untersuchungen mit Hilfe der Protonenresonanzspektroskopie

NMR spectroscopy has been used to investigate the ring inversions of the unsaturated seven membered ring system in a total of 20 benzocycloheptene derivatives with 1, 2 and 3 pairs of geminal substituents. For all compounds the inversion of the ring at ? 80°C is ‘frozen’ and at this temperature only one conformation is present in detectable quantity, presumably that of the chair form. The free activation enthalpies ΔG^≠ for the chair inversions lie between 9·9 and 13·7 kcal/mole. For disubstituted and tetrasubstituted benzocycloheptenes the ΔG^≠ values vary according to the positions of the ligands: for disubstituted derivatives ΔG^≠ is largest for the 5-position and smallest for the 3-position. For the tetrasubstituted derivatives the inversion of the ring—compared to that in the comparable dimethyl derivatives—is made more difficult when the ligands are in the 3,6- or 3,7- positions, but is facilitated when in the 3,5- or 4,6- positions. The effect observed in the 3,5- and 4,6- substituted rings is due to transanular repulsion of synaxial substituents, which leads to a flattening of the ring. Such a repulsion does not occur when the ligands are in the 3,6- positions. On the other hand, when the ligands are in 3,7- positions the transanular repulsion leads to a stronger puckering of the chair; the inversion could be hindered by this. For benzocycloheptene the activation energies for the inversions between chair, boat and twist (S, W, T) conformations were determined from model calculations. The best route for the inversion of the chair is the version way S → W via the transitional conformation V₄₅ and V₅₆. The calculated activation energy for this (14·6 kcal/mole) agrees well with the experimentally determined value (13 ± 1·5 kcal/mole). For the pseudorotation W → T a slightly lower calculated value of 11·1 kcal/mole was found.     

The stereochemistry of 1,6,7,12b-Tetrahydro-2H,4H-[1,2] oxazino[3′,4′:1,2]-pyrido[3,4-b]indole and of 1,2,3,6,7,12b-Hexahydro-3-methyl-4H-pyrimido[3′,4′:1,2]pyrido[3,4-6] indole

From an analysis of nmr spectral data, 1,6,7,12b-tetrahydro-2H,4H-[1,3 ]oxazino[3′, 4′ :1,2]-pyrido[ 3,4-b ]indole is shown to exist in solution at room temperature almost entirely in the cis-fused ring conformation with the nitrogen lone pair bisecting the C4 methylene group whereas under the same conditions 1,2,3,6,7,12b-hexahydro-3-methyl-4H-pyrimido[3′,4′:1,2] pyrido-[3,4-b ]indole exists as an approximately 50:50 equilibrium mixture of the cis and trans-fused ring conformations.     

Semisynthesis and absolute configuration of a novel rearranged 19,20‐δ‐lactone (9βH)‐pimarane diterpene

Annonalide (3β,20‐epoxy‐3α,16‐dihydroxy‐15‐oxo‐7‐pimaren‐19,6β‐olide, C₂₀H₂₆O₆, 1 ) is the major (9βH)‐pimarane diterpene isolated from tubers of Cassimirella ampla, and it exhibits cytotoxic properties upon interaction with ctDNA. We have prepared new derivatives of 1 by modification of the (9βH)‐pimarane backbone and report here the semisynthesis and absolute configuration of a novel rearranged 19,20‐δ‐lactone (9βH)‐pimarane. Our approach was the reduction of the carbonyl groups of 1 with sodium borohydride, at positions C15 (no stereoselectivity) and C3 (stereoselective reduction), followed by rearrangement of the 6,19‐γ‐lactone ring into the six‐membered 19,20‐δ‐lactone ring in 4a (3β,6β,16‐trihydroxy‐7‐pimaren‐19,20β‐olide monohydrate, C₂₀H₃₀O₆·H₂O). The absolute structure of the new compound, 4a , was determined unambiguously with a Flack parameter x of −0.01 (11), supporting the stereochemistry assignment of 1 redetermined here. Besides the changes in the pattern of covalent bonds caused by reduction and lactone rearrangement, the conformation of one of the three fused cyclohexane rings is profoundly different in 4a , adopting a chair conformation instead of the boat shape found in 1 . Furthermore, the intramolecular hydrogen bond present in 1 is lost in new compound 4a , due to hydrogen bonding between the 3‐OH group and the solvent water molecule.     

Synthesis,structural, conformational and pharmacological study of new fentanyl derivatives of the camphidine system

A series of N-phenethyl-8-β-amidocamphidines 4a-f (3-phenethyl-8-β-(N-arylamido)-3-azabicyclo-[3.2.1]octane) has been designed, synthesized and stereochemically characterized as semirigid analogous of the 4-anilidopiperidine analgesics in an attempt to study the influence of certain stereochemical factors on analgesia in this class of compounds. In deuteriochloroform and deuteriobenzene solution, compounds 4a-f display the same preferred conformation. The cyclopentane and piperidine rings adopt an envelope and distorted chair conformation respectively flattened at N-3, with the N and C-8 substituents in equatorial and axial positions with respect to the piperidine ring. In vivo pharmacological testing demonstrated that compounds 4a-f were inactive in the analgesic test, with the exception of compound 4f which showed an ED₅₀ of 250 mg/kg p.o.     

Calixrotanes: Calixarenes Incorporating Spiro-Linked Cyclopropyl Groups

Macrocyclic compounds (calix[4]- and calix[6]arene derivatives) with aryl rings interconnected by spirocyclopropyl groups have been synthesized and structurally characterized. The compounds were prepared by the reaction of dichlorocarbene with calixarenes possessing exocyclic double bonds at the bridges, followed by reductive perdechlorination of the spirocyclopropyl groups. In all systems, pairs of geminal rings connected to the quaternary spiro carbon atoms are oriented anti, and the methylene groups of the cyclopropyl rings are located in isoclinal positions. Calix[6]rotane adopts in the crystal and in solution a 1,3,5-alternate conformation. The presence of the spirocyclopropyl groups increases the rigidity of the macrocyclic ring.     

Synthesis of Tricyclic (λ5)-Phosphoranes; unusual N-demethylation/N-alkylation reactions during the oxidative addition of hexafluoroacetone and tetrachloro-ortho-benzoquinone to benzodiaza-λ3-phosphorinones. Single crystal X-ray diffraction studies of various products

The reaction of methylisatoic acid anhydride 1 with benzylamines led to the N-benzyl-N′-methylanthranilamide derivatives 2 – 4 . Their reaction with phosphorus trichloride furnished the 2-chloro-1-halobenzyl/benzyl-3-methyl-4(1 H)-1,3,2-benzodiazaphosphorin-4-ones 5 – 7 which, upon reaction with bis-(2-chloroethyl)ammonium chloride/triethylamine, were converted into the P-bis-(2-chloroethyl)amino-1-halobenzyl/benzyl-3-methyl-4(1 H)-1,3,2-benzodiazaphosphorin-4-ones 8 – 10 and 12 . With 2-chloroethylammonium chloride/triethyl-amine the P? NHCH₂CH₂Cl-substituted compound 11 was obtained from the P^IIICl-species 6 . The reaction of 8 – 10 and 12 with hexafluoroacetone (HFA) took an unusual course: apart from the oxidative addition of HFA and formation of the perfluoropinacolyl ring system, one of the two CH₂CH₂Cl groups was found to alkylate the CH₃N atom with formation of a five-membered (diazaphospholane) ring in the tricyclic phosphoranes 13 – 16 . The reaction of 11 with HFA also produced a spirophosphorane 17 which involved a λ⁵-oxazaphosphetidine ring system. In the reaction of 8, 10 and 12 with tetrachloro-o-benzoquinone, an oxidative addition reaction with concomitant N-alkylation and formation of the tricyclic phosphoranes 18 – 20 was found to take place. Single crystal X-ray structure determinations are described for the phosphoranes 13, 14 and 16 , and for the precursor compound 9 . The following features are common to the isostructural compounds 13 and 16 and the diethyl ether hemisolvate of 14 : the (λ⁵)-spiro phosphorus atom lies out of the plane of the other atoms of the rings to which it is common, and the dioxaphospholane rings display a twist conformation. In the λ³P-compound 9 the phosphorus atom also lies out of the plane of the other ring atoms.     

Synthesis and Conformational Analysis of 2′-Deoxy-2′-(3-methoxybenzamido)adenosine,a rational-designed inhibitor of trypanosomal glyceraldehyde phosphate dehydrogenase (GAPDH)

A series of 2′-benzamido-2′-deoxyadenosine analogues were synthesized in an effort to find new lead structures for the treatment of sleeping sickness. The 2′-deoxy-2′-(3-methoxybenzamido)adenosine ( 1h ) was proved to be a selective inhibitor of the parasite glyceraldehyde 3-phosphate dehydrogenase which confirms the modeling studies. The solution-state conformation of 2′-(thiophene-2-carboxamido) analogue 1d demonstrates a 2′-endo conformation, an orientation of the thiophene ring under the ribose moiety, and the base part occupying a ‘syn’/‘anti’ equilibrium.     

Cyclization of 3-Ethoxycarbonylmethyl-, 3-Cyanomethyl-, and 3-Acetylmethyl-1-amino-2-methylbenzimidazolium Salts Effected by Acetic Anhydride in the Presence of a Base

3-Ethoxycarbonylmethyl- and 3-cyanomethyl-1-amino-2-methylbenzimidazolium chlorides cyclized at treatment with acetic anhydride in the presence of potassium carbonate to afford a mixture of derivatives of pyrazolo[1,5-a]benzimidazole and 4-aminopyrrolo[1,2-a]benzimidazole. Therewith in the first case prevails the process of pyrazole ring fusion, and in the latter pyrrole ring is fused. 3-Aroyl(thenoyl)methyl-1-amino-2-methylbenzimidazolium bromides under the same conditions are converted into 1-aroyl(thenoyl)-2-methyl- and 2-4-acetamido-3-acetylpyrrolo[1,2-a]benzimidazoles.     

The conformation of erythronolide,the 14-membered aglycone ring of the erythromycin antibiotics

The solution conformation of erythronolide B and derivatives has been deduced from NMR and CD spectral data. The conformation is basically a “diamond lattice” type in which the ring atoms occupy cyclohexane-like positions but slightly modified to incorporate the lactone and ketone groups and to relieve an unfavorable syn-periplanar interaction. Variable temperature experiments revealed that erythronolide B and derivatives do not undergo facile ring inversion or pseudorotation and suggested the presence of a single stable conformation. Several features of the proposed conformation were demonstrated by the NMR and CD spectra of suitable derivatives. These features included the syn-periplanar relationship between the 3- and 5-OH groups, the axial orientation of the 11-OH group, and the proximity of the 6-OH group to the 9-ketone.     

Conformational Studies of Marine Polyhalogenated α-Chamigrenes Using Temperature-dependent NMR spectra inverted-chair and twist-boat cyclohexane moieties in the presence of an axial halogen atom at C(8)

α-Chamigren-3-one (+) -8 bearing an axial CI-atom at C(8) exists as a largely dominant conformer with Me—C(5) at the envelope-shaped enone ring pointing away from CI_ax?C(8) at the cyclohexane ring (= B) in the ‘normal’ chair conformation, as shown by ¹H-NMR. In contrast, the α-chamigren-3-ols (+) -9 and (+) -10 , obtained from hydride reduction of (+) -8 , show a temperature-dependent equilibrium of conformers where the major conformers have ring B in the inverted-chair (and twist-boat for (+) -9 ) conformation to avoid repulsions between Me?C(5) and CI_ax–C(8) (Scheme 1). This is in agreement with the conformation of the epoxidation product (+) -12 of (+) -9 where Me–C(5) is pushed away from CI_ax–C(8) in a ring-B chair similar to that of (+) -8 (Scheme 2). Introduction of a pseudoequatorial Br-atom at C(2) of (+) -8 , as in enone (+) -15 (Scheme 3), does not affect the conformation; but a pseudoaxial Br? C(2) experiences repulsive interactions with H_eq–C(7), as shown by the ¹H-NMR data of the isomeric enone (+) -16 where the ‘normal’-chair conformer Cβ -16 is in an equilibrium with the inverted chair conformer ICβ -16 (Scheme 3). These results and the accompanying paper allow a unifying view on the conformational behavior of marine polyhalogenated α-chamigrenes. This view is supported by the acid-induced isomerization of α-chamigrene (+) -9 (inverted chair) to β-chamigrene (+) -17 (‘normal’ chair; Scheme 4), the driving force being the lesser space requirement of CH₂?C(5) than of Me–C(5). This explains why β-chamigrenes are so common in nature.     

Conformational Behaviour of Substituted 2-Methoxy-2-Oxo-1,2-Oxaphospholan-3-Ols

Abstract

Conformational behaviour of about 30 2-methoxy-2-oxo-1,2- oxaphospho l an-3-0 1 s containing various substituents was examined by ¹H and ¹³C NMR. Vicinal coupling constants J(HCCH), J(HCCP), J(HCOP), J(CCOP) and J(CCCP) were employed in this study. Conformation of the 1,2-oxaphospholane ring is governed almost exclusively by substituents at C-3, C-4 and C-5, as we l l as by their orientation. The configuration of the P atom has little or no influence on conformation of the ring in diastsreomeric pairs. Strong preference of phenyl, methyl and substituted methyl groups to occupy the equatorial or pseudoequatoria l positions was observed for all but one compounds studied. In the cis-fused bicyclic syst ems conformat ionally rigid 6-membered rings forced the 1,2-oxaphospholane rings to adopt an enve l ope-l ike (E₄) conformation. No influence of the p=o……HO-C-3 hydrogen bond on conformation of the 1,2-oxaphospholane ring was found. Preferred conformations for (2R, 3R, 4R)-3-(hydroxymethyI)-2-methoxy-2-oxo-1,2-oxaphospho lane-3,4-diol and its triacetate are shown below.     

Synthesis,structural and conformational study of N-β(or γ)-acyloxyalkylnortropinones

A series of N-β(γ)-acyloxyalkylnortropinones have been synthesized and studied by ¹H and ¹³C nmr spectroscopy, and the crystal structure of N-[γ-(p-chlorophenylcarbonyloxy)propyl]nortropinone 4 has been determined by X-ray diffraction. The compounds studied display in deuteriochloroform solution the same preferred conformation. The pyrrolidine and piperidone rings adopt a flattened N-8 envelope and distorted chair conformation, puckered at N-8 and flattened at C-3 respectively, with the N-substituent in axial position with respect to the piperidone ring. These results are in close agreement with that found for compound 4 in the crystalline state.     

Molecular and electronic structures and conformational analysis of derivatives of 9-nitroanthracene, anionic σ-complexes

Potassium 10-methoxy-9-nitroanthracenide was studied by X-ray diffraction analysis. The central ring of the anthracene fragment adopts an asymmetrically flattened boat conformation. The bond lengths in the C(Ar)−C(NO₂)−C(Ar) fragment are indicative of the presence of conjugation between the π-systems of the benzene rings and the nitro group owing to a substantial contribution of theaci form to the structure of the nitro group. Quantum-chemical calculations of anionic σ-complexes of 9-nitroanthracene derivatives were performed. In all cases, the central ring adopts two conformations with the pseudoaxial and pseudoequatorial orientations of the substituents at the saturated C(10) atom, respectively. The relative stability of the conformers and the factors determining the stability were considered. The minima on the potential energy surface have a flattened shape in spite of relatively high barriers to the conformational transition (2–4 kcal mol⁻¹). The deviation of the C(Ar)−C(Ar)−C(sp³)−C(Ar) torsion angle from the equilibrium value by ±20° causes an increase in the energy of the anion by less than 1 kcal mol⁻¹. The effect of the substituents on the charge distribution was considered. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 438–443, March, 1998.