Computational Approach to the Receptor-Bound Conformation of Cyclosporin A

The conversion of the conformation of cyclosporin A (CsA) observed in CHCl₃ to the receptor-bound state is investigated by two molecular-mechanics methods, template forcing and dynamic forcing. The conformations of CsA in CHCl₃ and complexed with LiCl in THF as determined by NMR are used as starting structures. The transition starting from the CsA/CHCl₃-derived conformation is hindered by steric interactions of two side chains (MeBmt¹ and Val⁵). While starting with the CsA/LiCl-derived conformation, the conversion is facile. It is illustrated that these calculations, which are of artificial character, using only the starting and final structures of the observed conformational transition during the receptor-binding event, allow an insight into the interactions between the substrates and receptor in terms of an induced fit.     

Conformational Analysis of Didemnins. A multidisciplinary approach by means of X-Ray,NMR, molecular-dynamics,and molecular-mechanics techniques

We present the application of several homo- and heteronuclear 1D- and 2D-NMR techniques to assign the ¹H-NMR chemical shifts of the dominant conformation of didemnin B ( 2 ; three different conformations in (D₆)DMSO solution in the ratio 8:1:1) and its conformational analysis, as well as the solution conformation of didemnin A ( 1 ). The conformations were refined by restrained molecular-dynamics calculations using the GROMOS program and by MOMO, a novel personal-computer-based interactive molecular-graphics and molecular-mechanics package, using experimental distances (via a H…H pseudo potential function) as restraints. The solution structures of 1 and 2 obtained by GROMOS and MOMO calculations were compared with each other and related to the recently solved crystal structure of 2 . Focusing on the main conformer, the two kinds of the distance-restrained conformational calculations for 2 yielded a ‘solution structure’ close to the crystal structure. Almost all of the 40 restrained H…H distances coincided (within the estimated standard deviations) with those observed in the crystal structure. One more hydrogen bond was detected in solution involving the lactoyl OH group (disordered in the crystal structure) and the dimethyltyrosine (Me₂Tyr⁵) carbonyl O-atom. The macrocyclic ring system in the modeled solution structure of 1 exhibited a topology close to those of the solution and crystal structures of 2 . The main difference between 1 and 2 could be traced back to a significant change in the Ψ angle of the N-methyl-D-leucine (MeLeu⁷) residue. In 1 , the N-methyl moiety of MeLeu⁷ points inward within the macrocyclic ring toward the 1st and Hip region. We also tested the suitability of structures obtained from NMR data as ‘search fragments’ in the ‘Patterson search approach’ of crystal-structure analysis. It proved possible to resolve the crystal structure of 2 a posteriori with the Patterson search program PATSEE, in this way.     

Carbon-13 nuclear magnetic resonance spectra and conformations of cis,cis-1,5-cyclooctadiene monoepoxide and cis,syn,cis-1,5-cyclooctadiene diepoxide

The natural-abundance ¹³C NMR spectra of cis,cis-1,5-cyclooctadiene monoepoxide and cis,syn,cis-1,5-cyclooctadiene diepoxide have been investigated over the temperature range of – 10 to – 180°C. Whereas the spectra of the former showed no dynamic NMR effect, two different conformations in the ratio of 3:1 were observed at low temperatures for the latter. The free-energy barrier (ΔG^≠) for conversion of the major conformation to the minor conformation is calculated to be 5.9°0.2 kcal mol^?1 from a line-shape analysis of spectra obtained at intermediate temperatures. It is shown that cis,syn,cis-1,5-cyclooctadiene diepoxide exists in solution in chair (major) and in twist-boat (minor) conformations of slightly different energies. Interconversion paths between these conformations are discussed. The monoepoxide is suggested to have a twist-boat conformation that is rapidly pseudorotating via a boat conformation even at – 180°C.     

Cyclic Heptapeptides Axinastatin 2, 3, and 4: Conformational analysis and evaluation of the biological potential

The conformational analysis of naturally occurring cytostatic cyclic heptapeptides axinastatin 2, 3, and 4 was carried out by two-dimensional NMR spectroscopy in combination with distance-geometry (DG) and molecular-dynamics (MD) calculations in explicit solvents. The synthesized secondary metabolites were examined in (D₆)DMSO. Axinastatin 2 was also investigated in CD₃OH. In all structures, Pro² is in the i + 1 position of a βI turn and Pro⁶ occupies the i + 2 position of a βVIa turn about the cis amide bond between residue 5 and Pro^6. In all peptides, a bifurcated H-bond occurs between residue 4 CO and the amide protons of residue 1 and 7. For axinastatin 2 and 3, an Asn I_g turn was found about Asn¹ and Pro^2. We compared these structures with conformations of cyclic heptapeptides obtained by X-ray and NMR studies. A β-bulge motif with two β turns and one bifurcated H-bond is found as the dominating backbone conformation of cyclic all-L-heptapeptides. Axinastatin 2, 3, and 4 can be characterized by six trans and one cis amide bond resulting in a β/βVI(a)-turn motif, a conformation found for many cyclic heptapeptides. Detailed biological tests of the synthetic compounds in different human cancer cell lines indicates these axinastatins to be inactive or of low activity.     

IR and NMR spectra,intramolecular hydrogen bonding and conformations of para-tert-butyl-aminothiacalix[4]arene in solid state and chloroform solution

It is demonstrated that dissolution of aminothiacalix[4]arene in chloroform results in transformation of 1,3-alternate conformation, adopted in single-crystal and bulk polycrystalline solids, to the pinched-cone form. This conformer is stabilised by the intramolecular hydrogen bonds of two distal amino-groups acting as H-donors with another two amino moieties that appear as H-acceptors. The H-bonds cause quite small (ca. 10–20 cm^?1) red shift of the IR bands of the NH₂ stretching vibrations, which suggests rather weak NH?N hydrogen bonding. This latter is sufficient to stabilize the pinched-cone conformation in the chloroform solution, but the energy gap between the pinched-cone and other conformations is small, and solid-state intermolecular forces easily overcome it, leading to realisation of the 1,3-alternate conformer. The comparison of the DFT computed and experimental vibrational and NMR spectra demonstrates good quality of present quantum-chemical computations, allows complete interpretation of the spectra and reveals simple IR and NMR spectroscopic markers of the conformers of aminothiacalix[4]arenes.     

Conformation of α,α,α′-Trisubstituted Cyclododecanone

Ten α,α,α′-trisubstituted cyclododecanones were synthesized and characterized by elemental analyses, infrared, 1^H NMR and 13^C NMR spectra, and X-ray diffraction. NMR data could not give conformational information clearly, but some of their ring skeleton conformations of cyclododecanone moiety were showed to remain the unchanged [3333]-2-one conformation with little distortion, while the others were changed to the [3324]-2-one conformation in their crystal structures. These are consistent with the results of molecular mechanics calculation with Sybyl 6.9 software and Tripos force field, and semi-empirical quantum calculation with AM 1 method in Gaussian 98 software. Two geminal substituting groups are located at α-corner carbon atom, and the third group is at α-side-exo carbon atom in both conformations. Both [3333]-2-one and [3324]-2-one conformations are present in a dynamic equilibrium in the solution, but only one preferred conformation exists in the crystal solid.     

Conformational analysis of cis‐3, 5‐dioxa‐bicyclo[5.4.0]undecane and its 4‐substituted derivatives by DNMR,molecular modeling,and GIAO/DFT methods

Temperature‐dependent ¹H and ¹³C‐NMR spectra of the title compounds are presented. Coalescence effects are discussed and assigned to dynamic process—the interconversion of bicyclic system. The free energies of activation covered the range 39–52 kJ/mol. The dioxepane ring adopts twist‐chair (TC) conformation. GIAO/DFT calculation of isotropic shieldings for the set of low‐energy conformations showed that only one conformer is present at 298 K in solution that matched well with experimental data. Copyright © 2010 John Wiley & Sons, Ltd.     

The use of MM/QM calculations of 13C and 15N chemical shifts in the conformational analysis of alkyl substituted anilines

The calculation of the ¹³C and ¹⁵N NMR chemical shifts by a combined molecular mechanics (Pcmodel 9.1/MMFF94) and ab initio (GIAO (B3LYP/DFT, 6-31 + G(d)) procedure is used to investigate the conformations of a variety of alkyl substituted anilines. The ¹³C shifts are obtained from the GIAO isotropic shielding (Ciso) with separate references for sp³ and sp² carbons (δc = δref − Ciso). The ¹⁵N shifts are obtained similarly from the GIAO isotropic shielding (Niso) with reference to the ¹⁵N chemical shift of aniline. Comparison of the observed and calculated shifts provides information on the molecular conformations. Aniline and the 2,6-dialkylanilines exist with a rapidly inverting symmetric pyramidal nitrogen atom. The 2-alkylanilines have similar conformations with the NH₂ group tilted away from the 2-alkyl substituent. The N,N-dialkylanilines show more varied conformations. N,N-dimethylaniline has a similar structure to aniline, but N-ethyl, N-methylaniline, N,N-diethylaniline, and N,N-diisopropylaniline are conformationally mobile with two rapidly interconverting conformers. In contrast, the anilines substituted at C₂ and the nitrogen atom exist as one conformer where the steric interaction between the C₂ substituent and the N substituent determines the conformation. In 2-methyl-N-methylaniline, the nitrogen atom is pyramidal as usual with the N-methyl opposite to the 2-methyl, but in 2-methyl-N,N-dimethyl aniline, the NMe₂ group is now almost orthogonal to the phenyl plane. This is also the case with 2-methyl-N,N-diethylaniline and 2,6-diisopropyl-N,N-dimethylaniline. The comparison of the observed and calculated ¹⁵N chemical shifts confirms the above findings, in particular the pyramidal conformation of aniline and the above observations with respect to the conformations of the N,N-dialkylanilines.     

Conformational equilibrium in 8-methyl-cis-2-thiahydrindane and 8-methyl-cis-2-oxahydrindane by 13C NMR spectroscopy

The preferred conformation of 8-methyl-cis-thiahydrindane has been both estimated by ¹³C NMR chemical shifts and determined by low temperature ¹³C NMR spectroscopy to be the conformer with the methyl group equatorial with respect to the cyclohexane ring. This result is in disagreement with the interpretation of the temperature dependence of the CD spectra of (+) and (?) 8-methyl-cis-2-thiahydrindane, whereby the conformation with the methyl group axial with respect to the cyclohexane ring was claimed to be the preferred conformation. The preferred conformation of the related oxygen heterocycle, 8-methyl-cis-2-oxahydrindane, has been estimated by ¹³C NMR chemical shifts to be the conformer with the methyl group axial with respect to the cyclohexane ring. Possible reasons for these observations are discussed.     

Boat form contributions in crowded piperidines: Theoretical and experimental study

The preferred conformations of N-nitroso-t(3)-alkyl-r(2),c(6)-bis(2′-furyl)-piperidin-4-ones 1–3 [alkyl = CH₃, C₂H₅ and CH(CH₃)₂] and N-nitroso-t(3),t(5)-dimethyl-r(2),c(6)-bis(2′-furyl)piperidin-4-one 4 in solutions were assigned by means of ¹H and ¹³C NMR studies. The results derived from NMR spectra indicate the presence of an equilibrium mixture of boat conformation B ₁ and alternate chair conformation CA for the E isomers of 1–3 and Z isomers of 2–3. For the Z isomer of 1 boat form B ₂ is predicted to be the major conformer. The N-nitroso-3,5-dimethyl derivative 4 exists in the boat form B ₁ only. Conformational analysis performed through semiempirical molecular orbital calculations also supports the conformations for 3–4. The presence of one conformer in the equilibrium can be predicted to a reasonable accuracy by theoretical studies in 1–2. The effects due to N-nitrosation on ¹H and ¹³C chemical shifts are also interpreted in terms of these conformations. The conformation of isopropyl group at C(3) was also predicted by spectral and theoretical studies.     

Synthesis,spectral properties and conformational preferences of macrocyclic compounds containing 2,5-dithio-1,3,4-thiadiazole subunits

The syntheses of macrocyles 1–6, containing 2,5 - dithio - 1,3,4 - thiadiazole subunits connected by 1,2-, 1,3- and 1,4-bis(methylene)benzenes, as well as of the appropriate open-chain model compounds 7–12 are described. Structure proofs were afforded by their mass and ¹H NMR spectra. Different decompostion processes upon electron-impact are ascertained for compounds 1–12, depending on the position of the bridges and ortho substitution; therefore, the mass spectra can provide a sensitive diagnostic tool for structure elucidation of positional isomers. The NMR spectral data of macroycyles 1–6, coupled with those of the corresponding open-chain derivatives 7–12, indicate that the preferred conformations are determined primarily by the size and shape of their ring systems. Furthermore, variable-temperature NMR studies on intraannularly methyl substituted macrocyles 3 and 6 provide evidence that the 20-membered mesityl derivative 3 adopt the saddle-shape conformation (IV) (the energy barrier for the restricted rotation of methylene bridges if found to be ΔG^≠= 13.8 kcal/mole at + 5°), while the duryl groups in the 22-membered macrocycle 6 are free rotating even at ?60°.     

Conformations of the Nine‐Membered Ring in the B‐Nor‐5,10‐secosteroids. X‐Ray and NMR Analysis

The conformations of (Z)‐ and (E)‐5‐oxo‐B‐nor‐5,10‐secocholest‐1(10)‐en‐3β‐yl acetates ( 2 and 3 , resp.) were examined by a combination of X‐ray crystallographic analysis and NMR spectroscopy, with emphasis on the geometry of the cyclononenone moiety. The ¹H‐ and ¹³C‐NMR spectra showed that the unsaturated nine‐membered ring of (E)‐isomer 3 in C₆D₆ and (D₆)acetone solution exists in a sole conformation of type B ₁ , which is similar to its solid‐state conformation. The (Z)‐isomer 2 in C₆D₆, CDCl₃, and (D₆)acetone solution, however, exists in two conformational forms of different families, with different orientation of the carbonyl group, the predominant form (85%) corresponding to the conformation of type A ₁ and the minor (15%) to the conformation A ₂ present also in the crystalline state. In this solid‐state conformations of the nine‐membered ring of both compounds, the 19‐Me and 5‐oxo groups are ‘β’‐oriented. The NMR analysis suggests that the nine‐membered ring of 4 has a conformation of type C ₁ in CDCl₃ solution.     

SYNTHESIS AND CONFORMATIONAL ANALYSIS OF 16H-DINAPHTHO AND 12 H-DIBENZO [D,G][1,3,2]DIOXASILOCINE

Abstract

The conformation of the heterocyclic eight-membered ring in 16H-dinaphtho and 12H-dibenzo [d,g][1,3,2]dioxasilocine was investigated in solution by ¹H NMR spectroscopy. The barrier to ring inversion in the 16H-dinaphtho compound 3a was found to be 8.6±0.2 Kcal/mol and for the 12 H-dibenzo compound 4a, 8±0.2 Kcal/mol. Molecular mechanics calculations show three energy minima conformations for both compounds, boat chair(BC), twist boat(TB) and twist boat boat(TBB). Twist boat form is estimated to be the global minimum for the dibenzo compounds while TBB is the global conformation of the dinaphtho compounds. The result of molecular mechanics calculations are supported by analysis of the ¹H-NMR spectra.     

β‐Turn Analogues in Model αβ‐Hybrid Peptides: Structural Characterization of Peptides Containing β2,2Ac6c and β3,3Ac6c Residues

The effect of gem‐dialkyl substituents on the backbone conformations of β‐amino acid residues in peptides has been investigated by using four model peptides: Boc‐Xxx‐β^2,2Ac₆c(1‐aminomethylcyclohexanecarboxylic acid)‐NHMe (Xxx=Leu ( 1 ), Phe ( 2 ); Boc=tert‐butyloxycarbonyl) and Boc‐Xxx‐β^3,3Ac₆c(1‐aminocyclohexaneacetic acid)‐NHMe (Xxx=Leu ( 3 ), Phe ( 4 )). Tetrasubstituted carbon atoms restrict the ranges of stereochemically allowed conformations about flanking single bonds. The crystal structure of Boc‐Leu‐β^2,2Ac₆c‐NHMe ( 1 ) established a C₁₁ hydrogen‐bonded turn in the αβ‐hybrid sequence. The observed torsion angles (α(?≈?60°, ψ≈?30°), β(?≈?90°, θ≈60°, ψ≈?90°)) corresponded to a C₁₁ helical turn, which was a backbone‐expanded analogue of the type III β turn in αα sequences. The crystal structure of the peptide Boc‐Phe‐β^3,3Ac₆c‐NHMe ( 4 ) established a C₁₁ hydrogen‐bonded turn with distinctly different backbone torsion angles (α(?≈?60°, ψ≈120°), β(?≈60°, θ≈60°, ψ≈?60°)), which corresponded to a backbone‐expanded analogue of the type II β turn observed in αα sequences. In peptide 4 , the two molecules in the asymmetric unit adopted backbone torsion angles of opposite signs. In one of the molecules, the Phe residue adopted an unfavorable backbone conformation, with the energetic penalty being offset by a favorable aromatic interaction between proximal molecules in the crystal. NMR spectroscopy studies provided evidence for the maintenance of folded structures in solution in these αβ‐hybrid sequences.     

A conformational study of aromatic imide compounds. Part 2. Compounds containing diphenyl sulfide,diphenyl sulfone,and diphenylmethane moieties

An attempt was made to estimate the dihedral angles, φ, ψ, ω₁, and ω₂, of bis(4-hydroxyphthalimide)s (BHPI) and bis(phenylphthalimide)s (BPI) having diphenyl sulfide, diphenyl sulfone, or diphenylmethane linkages at the center of molecules using solid–state ¹³C CP/MAS NMR and ab initio nuclear shielding calculations. The TOSS and TOSS & DD pulse sequences were performed in the NMR measurements to obtain exact chemical shifts of each carbon. Total energies were calculated using the B3LYP/6-31G(d) level of theory, and shielding constants were calculated using the RHF/6-31G(d) level of theory for diphenyl sulfide, diphenyl sulfone, diphenylmethane with varying angles of φ, ψ from 0 to 180° at intervals of 10°. It was clarified that the –S– and –SO₂– linkages lead asymmetrical conformations with different ω₁ and ω₂ or with different φ and ψ for BHPIs and BPIs. In contrast, the compounds having –CH₂– linkages have symmetrical conformations. The dihedral angle of imide ring and phenylene ring (ω) are in the range of 40–90°, and the dihedral angles (φ,ψ) distribute in the stable regions of the energy surfaces ranging from 40 to 90°.     

Sequencing of cyclosporins by fast atom bombardment and linked-scan mass spectrometry

The mass spectrometric sequence determination of amino acid residues in cyclosporins using fast atom bombardment, collisionally activated dissociations in the first field-free region and linked B/E scan is described. The general fragmentation scheme was derived from the spectra of cyclosporins A, B, C, D, F, G, L and [DH-MeBmt¹]CS. The main fragmentation pathways start by primary splitting between amino acids 2–3, 1–11 and 5–6. The corresponding N-terminal b-type ions are common fragment types in the mass spectra. The 1–11 splitting can be enhanced by the introduction of a lactone group into the peptide ring by conversion of cyclosporins into isocyclosporins. The fragmentation scheme was used for amino acid sequence determination in four new natural cyclosporins, [MeLeu¹]CS, [Leu⁴]CS, [Ile⁴]CS and [Leu⁵]CS.     

5‐Ethynyl‐2′‐deoxycytidine: a DNA building block with a `clickable' side chain

The title compound [systematic name: 4‐amino‐1‐(2‐deoxy‐β‐d ‐erythro‐pentofuranosyl)‐5‐ethynylpyrimidin‐2(1H)‐one], C₁₁H₁₃N₃O₄, shows two conformations in the crystalline state. The N‐glycosylic bonds of both conformers adopt similar conformations, with χ = −149.2 (1)° for conformer (I‐1) and −151.4 (1)° for conformer (I‐2), both in the anti range. The sugar residue of (I‐1) shows a C2′‐endo envelope conformation (²E, S‐type), with P = 164.7 (1)° and τ_m = 36.9 (1)°, while (I‐2) shows a major C3′‐exo sugar pucker (C3′‐exo‐C2′‐endo, ₃T², S‐type), with P = 189.2 (1)° and τ_m = 33.3 (1)°. Both conformers participate in the formation of a layered three‐dimensional crystal structure with a chain‐like arrangement of the conformers. The ethynyl groups do not participate in hydrogen bonding, but are arranged in proximal positions.     

The structure of angustifoline,an alkaloid ofLupinus angustifolius,in solution

Summary The¹H and¹³C NMR spectra of the lupin alkaloidangustifoline 1 in four solvents (cyclohexane-d₁₂, CDCl₃, CD₃CN, and C₆D₆) were assigned using 2D H,H and H,C COSY and 2D J-resolved spectra. The torsional HCCH angles calculated from the vicinalJ _HH coupling constants are essentially in agreement with those expected for the deformed all-chair conformation withendo oriented N(12)-H bond, reported earlier for1 in the solid state. Some arguments seem to point, however, to a small contribution of other conformations: with ring A deformed in another direction, deformed all-chair withexo oriented N(12)-H bond and/or a conformation with ring C in the boat form.Lupin Alkaloids, part 7     

Infrared spectra and configuration of N,N'-diaryl-thioureas

The conformation of the —NH—CS—NH— grouping in a series of N,N'-diarylthioureas some of which possess a marked anti-viral activity is studied using IR spectral data. The results indicate that in organic solvents (CCl₄, CHCl₃, C₂C1₄, CH₂C1₂) the compounds studied participate in an equilibrium between several isomeric forms arising from the possibility of a cis or trans structure of the —CS—NH— groups. The increased solvent polarity favours the cis conformation.     

The conformation and dynamic behaviour of tetrathiacalix[4]arenes functionalized by hydrazide and hydrazone groups

The ¹H, ¹³C and ¹⁵N NMR data, conformation and dynamic behaviour of the new tetrathiacalix[4]arenes functionalized by hydrazide and hydrazone groups are reported and compared with the result of earlier investigations of 4-tert-butylphenoxyacetylhydrazones. The unusual fact of formation of N,N′-diacetylhydrazine bridge and factors leading to its formation in the cone conformer of calixarene has been discussed. The barriers of rotation of hydrazone fragments of tetrathiacalix[4]arenes were determined by NMR-measurements at various temperatures. The structure of 1,3-alternate conformer of 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetrakis[hydrazinocarbonylmethyl]-2,8,14,20-tetrathiacalix[4]arene in solution is compared with crystal structure obtained by the X-ray analysis.