Antiperiplanar Conformation Research Articles

Intramolecular chiral relay at stereogenic nitrogen. Synthesis and application of a new chiral auxiliary derived from (1R,2S)-norephedrine and acetone.

(1R,2S)-Norephedrine has been employed in the synthesis of a novel 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-one via reductive alkylation with acetone, N-nitrosation, reduction, and cyclization. The oxadiazinone was treated with either propionyl chloride or 3-thiophenylpropionyl chloride to afford the corresponding N(3)-acylated oxadiazinones 9a and 9b, respectively. X-ray crystallographic analysis of the N(3)-thiophenylpropionyl oxadiazinone 9b revealed that the C(2)-urethane carbonyl and the N(3)-carbonyl are arranged in an anti-periplanar conformation. The oxadiazinones were subsequently applied in the titanium-mediated asymmetric aldol addition reaction by treatment with titanium tetrachloride, triethylamine, and a variety of aldehydes at 0 degrees C. The aldol adducts 10a-i and 11a,b were found to have diastereoselectivities ranging from 8:1 to >99:1 favoring the formation of the non-Evans syn configuration. The absolute stereochemistry of the adduct 10a was determined by acid hydrolysis. This process afforded the N(4)-isopropyloxadiazinone 8 and (2S,3S)-3-hydroxy-2-methyl-3-phenylpropanoic acid 14 in >/=95% enantiomeric excess.

(R*,S*)-Methyl 2-(2′-methylenecyclopropyl)hydroxyacetate

The relative configuration of the title mol­ecule, C7H10O3, has been determined. The asymmetric C atoms are of opposite chirality (R,S or S,R), as opposed to having the same chirality (R,R or S,S). The mol­ecule adopts an antiperiplanar conformation around the bond connecting the cyclo­propyl and carbonyl groups. In the crystal structure, mol­ecules form hydrogen-bonded chains.

UV Spectra and Structure of 2-Diethylamino-3-phenylpropenal: Enamine or Enal?

According to the data of UV, IR, 1H and 13NMR spectra and also quantum-chemical calculations (B3LYP/631G*), Z- and E-isomers of 2-diethylamino-3-phenylpropenal in inert environment exist as antiperiplanar conformers. The energy of electron transitions therein depends on the orientation both f the benzene ring and the unshared electron pair of the nitrogen with respect to the C = C bond. 2-Diethylamino-3-phenylpropenal is an enamine, but the extent of the pπ* interaction in its prevailing Z-isomer is small.

Conformational restraint in thermal rearrangements of a cyclobutane: 3,4-dicyanotricyclo[4.2.2.0(2,5)]decane.

There being no study of a cyclobutane so fused to another cyclic system that an antiperiplanar conformation of the related diradical be precluded, the system in the title has been synthesized and studied for its thermal behavior. In comparison to the thermal behavior of unconstrained 1,2-dicyanocyclobutane in stereomutation and fragmentation to acrylonitrile, the constrained system shows a approximately 10-fold higher ratio of stereomutation to fragmentation to the three cis-1,4-bis-beta-cyanovinylcyclohexanes. In these diolefins, a stereochemical correlation between the two olefinic fragmentation products is preserved. Revealed in the thermal rearrangement of isomer trans-1 is a surprising excess (78%) of cis-1-cis-beta-cyanovinyl-4-trans-beta-cyanovinylcyclohexane, cis,trans-2, the result of zero internal rotations within the diradical-in-caldera prior to fragmentation (retention of configuration). Similarly, to a comparably striking extent, anti,cis-1 gives trans,trans-2 as its major product (71%), again by zero internal rotations.

Meso-Tetrahydropyranylperoxides: molecular structures in solution, in the crystal, and by DFT calculations and their isomerization to the racemate.

The crystalline peroxide 3a is the main product (out of 10 theoretically possible) from the aerial peroxidation of all-cis-2,4,6-trimethyltetrahydropyran (2a). It has a similar structure both in solution and in the crystal as shown by nuclear Overhauser effects and X-ray analysis, respectively. Theoretical calculations at a density functional theory level (B3LYP/6-31G) provide insight into the stabilities of the different stereoisomers of this peroxide, accounting for the facile, acid-catalyzed isomerization from the meso form to the racemate. Peroxide 3b, which is the 2-tert-butyl analogue of 3a, out of 22 theoretically possible isomers, crystallizes in a similar meso form. As a result of crystal packing effects and the intrinsically (axial) chiral peroxy "chromophore" that deviates slightly from the antiperiplanar conformation, both enantiomorphic forms of 3b are encountered in the lattice.

2,2'-(1,2-Ethanediyldithio)bis(1,3-benzothiazole).

In the title compound, C(16)H(12)N(2)S(4), which is the result of the S-alkylation reaction of 2-mercaptobenzothiazole with ethylene dibromide, the planes of the two benzothiazole moieties form a dihedral angle of 3.84 (14) degrees. The bridging chain moiety, -SCH(2)CH(2)S-, adopts an antiperiplanar conformation. There are intermolecular S.S non-bonded contacts of 3.6471 (9) A, which stabilize the crystal packing.

Supramolecular stereoisomer – the conformational isomer of 1,1,6,6-tetraphenylhexa-2,4-diyne-1,6-diol in the different inclusion compounds

The host 1,1,6,6-tetraphenylhexa-2,4-diyne-1,6-diol (1) exhibits different conformational isomers in inclusion compounds with 1,3,3-trimethyl-2-oxabicyclo[2,2,2]octane (2) and trans-p-propenylanisole (3). The molar ratios of hosts and guests in an asymmetric unit of complexes (1)+(2) and (1)+(3) are 1∶2 and 2∶1, respectively. In the complex of (1)+(2), the host (1) is linked with (2) via hydrogen bonding and exhibits antiperiplanar conformation, whereas in the 2∶1 host–guest complex (1)+(3), hosts (1) are associated with each other by hydrogen bonding and the complex adopts a gauche conformation; guests contact with hosts by C–H⋯π weak hydrogen bonding. The structures of the two complexes and conformational isomers of the host have been determined by X-ray crystallographic analysis.

Quantum-Chemical Study of the Structure of Cyanophosphines and Their Oxides

The structure of cyanophosphines and their oxides was studied by ab initio (RHF/6-31G**) and semiempirical (PM3) methods. Both methods predict that MeOP(CN)2, (MeO)2PCN, and (MeO)2P(O)CN exist in noneclipsed antiperiplanar and synclinal conformations. The calculation results nicely agree with measured dipole moments and Kerr constants of these compounds. The phenyl and diphenyl derivatives PhP(CN)2, Ph2PCN, Ph(Et)PCN, and Ph2P(O)CN prefer forms in which the phenyl ring plane is eclipsing the phosphorus lone electron pair or the phosphoryl bond. The interactions of the phosphorus lone electron pair with the phenyl ring and with the cyano group are lacking in the title compounds.

The structure of O-phospho- l-threonine in different chemical environments

The crystal and molecular structures of the potassium ( I), ammonium ( II) and diammonium ( III) salts of O-phospho- l-threonine were determined by X-ray methods. The crystal structure of I contains two independent monoanions [denoted as (1) and (2)] and that of II four independent monoanions [denoted as (1), (2), (3) and (4)], while III contains one independent dianion in an asymmetric unit. The monoanions of O-phospho- l-threonine contain the ionized carboxyl group (more acidic) and singly protonated phosphate group which is double ionized in the dianion of III. The overall conformation of the threonine moiety in all anions is similar to that found in the zwitterions of phosphothreonine but differs from that in l-threonine. The carbon atom chains adopt antiperiplanar conformation in all anions of O-phospho- l-threonine. The anions differ slightly in the orientation of the terminal phosphate O atoms with regard to the threonine moiety. In all three crystals, the molecules are arranged in three-dimensional networks via N–H⋯O [and O–H⋯O in I and II] hydrogen bonds in which all N-bonded [and O-bonded in I and II] H atoms are involved. Additionally, the crystal structures are stabilized by C–H⋯O interactions of less than 3.5 Å.

2(S)-N-tert-Butoxycarbonylamino-N-methoxy-N-methylbutanamide

In the solid state the title compound, C11H22N2O4, is in an antiperiplanar conformation. The conformation of the compound shows no similarity with the synclinal conformation of the chelated intermediate formed during nucleophilic attack.

The Conformation of 2-Phenylpropionaldehyde and Alkyl 1-Phenylethyl Ketones as Evidenced by Ab Initio Calculations. Relevance of the CH/π and CH/O Interactions in Stereochemistry

Abstract Ab initio MO calculations were carried out for the conformation of 2-phenylpropionaldehyde 1 and related ketones CH3CH(C6H5)–CO–R (R = CH3 2, C2H5 3, i-C3H7 4, and t-C4H9 5) at the MP2/6-311G(d,p)//MP2/6-31G(d) level. The conformation whereby the alkyl group R is synclinal to the phenyl group (rotamer a, C6H5–C–CO–R torsion angle φ 64–93°) has been found to be the most stable. The second most favorable one has been shown to have R flanked by the benzylic methyl group and C6H5 (rotamer b: φ 282–297°). The difference in the enthalpy between a and b has been calculated to be 1.58, 2.16, 2.19, 2.08, and 4.89 kcal mol−1, respectively, for 1, 2, 3, 4, and 5. The C6H5/R antiperiplanar conformation (rotamer c) has been shown to be the least stable for 1 (φ 171°) and is not at an energy minimum for 2–5. In rotamers a and b, short interatomic distances have been shown between one of the alkyl hydrogens and the phenyl group. In rotamer a, a short distance has been calculated between one of the hydrogens of the benzylic methyl group and the carbonyl oxygen. The ab initio results are compatible with those obtained by NMR measurements. Contributions of the CH/π and CH/O interactions to the conformational equilibria have been invoked to accommodate the above results. Instability of rotamer c may be due to the unfavorable electrostatic interaction of the C=O dipole vs the quadrupole of the phenyl group. Conformational energies of methyl formate 6, N-methylformamide 7, and propionaldehyde 8 were also calculated to examine the effect of the CH/O interaction in carbonyl compounds. The results are consistent with the notion that the CH/O interaction is important in stabilizing the CH3/O eclipsed conformation.

Isolation and structural characterisation of two sterically crowded diphosphanes

Under specific conditions the reduction of the chlorophosphanes R(Me 2NCH 22-C 6H 4)PCl or RPCl 2 [R=(Me 3Si) 2CH] with LiAlH 4 gives the diphosphanes {R(Me 2NCH 22-C 6H 4)P} 2 ( 2) and RPHPHR ( 3), respectively, in moderate to good yields. Compound 2 may be obtained in higher yield from the reaction of {R(Me 2NCH 22-C 6H 4)P}Li with PbI 2. Compounds 2 and 3 have been characterised by multi-element NMR spectroscopy and the meso-diastereomers of both compounds have been characterised by X-ray crystallography. In the solid state both meso- 2 and meso- 3 adopt an antiperiplanar conformation.

Molecular Structure of Complexes with Bifurcated Hydrogen Bond: I. N-(4-Methyl-2-nitrophenyl)acetamide

According to the results of HF/6-31G* and B3LYP/6-31G* nonempirical calculations, N-(4-methyl- 2-nitrophenyl)acetamide in the synperiplanar and antiperiplanar conformations gives stable complexes with protophilic solvents, which are stabilized by bifurcated (three-center) hydrogen bond. The complexes are characterized by (1) opposite variations of the interatomic distances and angles corresponding to intra- and intermolecular components of the bifurcated hydrogen bond, (2) extension of the intramolecular component and a more pronounced shortening of the intermolecular component with increase in the strength of the three-center H-complex, and (3) nonlinear and nonmonotonic relation between the NH stretching vibration frequency and the energy of complex formation.

Solvatochromism of Heteroaromatic Compounds: XI. 1-Ethyl-2-formylbenzimidazole

Two regression dependences of the energy of the intramolecular charge-transfer transition in 1-ethyl-2-formylbenzimidazole on the polarity and polarizability of the medium have been established; one relates to the syn-periplanar conformer and the other, to the anti-periplanar conformer. The different solvatochromism of the two molecular forms is associated with the different sensitivity of low-energy electronic transitions of these conformers to nonspecific solvation.

Chemical Shifts and Spin−Spin Coupling Constants in Me α-d-Xylopyranoside: A DFT Approach

Chemical shieldings and coupling constants in a monosaccharide Me α- d-xylopyranoside were computed by density functional theory (DFT) method. The differences between the experimental and computed chemical shifts, for both DFT and MM3 geometries, showed that the method used reliably computes these NMR parameters. The agreement with experimental values was also obtained for proton−proton and proton−carbon coupling constants across one or more bonds. Furthermore, the effect of conformation upon both NMR shielding tensors (the values and orientation of its principal components) and couplings has also been investigated. The change of conformation around the C1−O1 linkage resulted in variations of mainly anomeric proton and carbon chemical shieldings as well as both the ring and O1 oxygens. The observed variations were found similar to those in Me β-d-xylopyranoside [Hricovíni, M.; Malkina, O. L.; Bízik, F; Turi Nagy, L.; Malkin, V. G. J. Phys. Chem. 1997, 101, 9756]. Similarly, the magnitudes of 1JC-H and 3JC-H varied upon the dihedral angle φ [H1−C1−O1−CMe]. 1JC1-H1 couplings, based on DFT geometry, changed between 151.7 and 165.6 Hz with the smallest values found for φ within −60° to 60°. 3JH1-C1-O1-CMe varied between 0 and 11.2 Hz (DFT geometry) and showed the dependence comparable with the previous one for β anomer with one exception: the magnitude of 3JC-H for antiperiplanar conformation is about 3 Hz larger for the α anomer. Such differences could be important for the determination of glycosidic linkage conformation of carbohydrates and may suggest that this type of dependence should be parametrized separately for α- and β-linked carbohydrates.

Pentopyranosyl oligonucleotide systems. Part 11: systems with shortened backbones: ( d)-β-ribopyranosyl-(4′→3′)- and ( l)-α-lyxopyranosyl-(4′→3′)-oligonucleotides

The ( l)-α-lyxopyranosyl-(4′→3′)-oligonucleotide system—a member of a pentopyranosyl oligonucleotide family containing a shortened backbone—is capable of cooperative base-pairing and of cross-pairing with DNA and RNA. In contrast, corresponding ( d)-β-ribopyransoyl-(4′→3′)-oligonucleotides do not show base-pairing under similar conditions. We conclude that oligonucleotide systems can violate the ‘six-bonds-per-backbone-unit’ rule by having five bonds instead, if their vicinally bound phosphodiester bridges can assume an antiperiplanar conformation. An additional structural feature that seems relevant to the cross-pairing capability of the ( l)-α-lyxopyranosyl-(4′→3′)-oligonucleotide system is its (small) backbone/basepair axes inclination. An inclination which is similar to that in B-DNA seems to be a prerequisite for an oligonucleotide system's capability to cross-pair with DNA.

Investigations of new lead structures for the design of selective estrogen receptor modulators.

Heterocyclic derivatives of (R,S)/(S,R)-1-(2-chloro-4-hydroxyphenyl)-2-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (L1) were synthesized and tested for estrogen receptor binding. The selection of the heterocycles was based on theoretical consideration. (2R,3S)/(2S,3R)-2-(2-Chloro-4-hydroxyphenyl)-3-(2,6-dichloro-4-hydroxyphenyl)piperazine 2, (4R,5S)/(4S,5R)-4-(2-chloro-4-hydroxyphenyl)-5-(2,6-dichloro-4-hydroxyphenyl)-2-imidazoline 3, and 4-(2-chloro-4-hydroxyphenyl)-5-(2,6-dichloro-4-hydroxyphenyl)imidazole 4 possess a spatial structure with neighboring aromatic rings as is realized in hormonally active [1,2-diphenylethylenediamine]platinum(II) complexes. The 1,2-diphenylethane pharmacophor, however, cannot adapt an antiperiplanar conformation to interact with the estrogen receptor (ER) comparable to synthetic (e.g., diethylstilbestrol (DES)) or steroidal (e.g., estradiol (E2)) estrogens. Due to the different spatial structures, the heterocycles cause only a marginal displacement of E2 from its binding site (relative binding affinity (RBA) < 0.1%). Nevertheless, unequivocally ER mediated gene activation was verified on the MCF-7-2a cell line. Imidazoline 3 as the most active compound reached the maximum effect of E2 (100% activation) in a concentration of 5 x 10(-7) M, while piperazine 2 and imidazole 4 activate luciferase expression only in a small but significant amount of 20% and 27%, respectively. We therefore assigned these heterocyclic compounds to a second class of hormones (type-II-estrogens), which are attached at the ER at different amino acids than DES or E2 (type-I-estrogens).

Solvatochromism of Heteroaromatic Compounds: VIII. 2-(Tricyanovinyl)-5-phenylpyrrole

Rotational isomerism of 2-(tricyanovinyl)-5-phenylpyrrole and formation of complexes with a three-centered (bifurcational) hydrogen bond were studied by UV spectroscopy and quantum-chemical calculations. In the gas phase and in weakly and moderately protophilic media these compounds have mainly the syn-periplanar form stabilized by the intramolecular hydrogen bond involving the orthogonal π system of the nitrile group and the NH hydrogen atom. No intermolecular H complex is formed in such solvents. In tetrahydrofuran, cyclohexanone, pyridine, and some other media a complex conformational equilibrium is observed. Interaction with aliphatic alcohols, amides, dimethyl sulfoxide, and triethylamine results in stabilization of the H complex of the anti-periplanar conformer.

A density functional theory study of the conformational properties of 1,2-ethanediamine: protonation and solvent effects

The structures and the conformational energies of nonprotonated, monoprotonated and diprotonated 1,2-ethanediamine have been investigated through density functional theory. The relative performance of local and gradient-corrected functionals is discussed. The existence of hydrogen-bond formation has been determined with electron localisation function calculations. Proton affinities for nonprotonated and monoprotonated 1,2-ethanediamine have been calculated and are in agreement with experimental data. The influence of solvation has been accounted for through the self-consistent isodensity polarisable continuum model. The results for the nonprotonated conformers show that solvation stabilises those conformers which have the lone pair in an antiperiplanar conformation. Solvation of the monoprotonated conformer stabilises significantly the “anti” conformation, which is unstable in the gas phase. For the di-protonated species, solvation stabilises slightly the gauche conformer, which is unstable in the gas phase.

Correlated ab initio molecular orbital (MP3, MP4) and density functional (PW91, MPW91) studies on the conformations of 1,2-diphenylethane

Density functional (PW91, MPW91) and high level correlated ab initio molecular orbital (MP4SDQ) calculations were carried out to determine the molecular geometries and the relative energies of the conformations of 1,2-diphenylethane. The computed data are indicative of a small difference in the energies of the two main conformations: the synclinal (gauche Ph/Ph) and the antiperiplanar (anti Ph/Ph) ones. The DFT methods with the large basis set (6-311++G) gave small energy preference (about 0.3kJmol−1) of the antiperiplanar conformation, while the corrections for the electron correlation energies at the MP4SDQ level produced about 1.0kJmol−1 lower energy for the synclinal conformation. It is proposed that entropy effects play an important role for the observed prevalence of the antiperiplanar conformation. The results are discussed in relation to their potential utilization as computed observables in molecular mechanics parameterization of the 1,2-diphenylethane skeleton.