Conformation In Solid State Research Articles

The role of hydrogen bonding in conformational stabilization of 3,5,6- and 3,5-substituted (pyridin-2-yl)aminomethane-1,1-diphosphonic acids and related (pyrimidin-2-yl) derivative

The crystal structures of three new members of the (pyridin-2-yl)aminomethane-1,1-diphosphonic acid ( 1- a) family are determined by X-ray diffraction and discussed with respect to molecular geometry and solid state organization. The striking structural feature of (3,5-dibromo-6-methylpyridin-2-yl)aminomethane-1,1-diphosphonic acid ( 2) and (3-chloro-5-trifluoromethylpyridin-2-yl)aminomethane-1,1-diphosphonic acid ( 3) is that regardless of a multiple substitution on the pyridyl ring the key factor for their conformational stabilization is the intramolecular N–H⋯X (X = Cl, Br) hydrogen bond involving substituent at 3-ring position. In contrast, the solid state conformation of (pyrimidin-2-yl)aminomethane-1,1-diphosphonic acid ( 4) is stabilized through intermolecular, bifurcated N–H⋯O hydrogen bonds, which is similar to that observed previously in 4- and 5-substituted Z-zwitterionic derivatives of (pyridin-2-yl)aminomethane-1,1-diphosphonic acid. Moreover, the 31P NMR spectra of 4 suggest similar dynamic process in solution, attributable to the rotation around the C ring–N amino bond. However, the rotational barrier in 4 is markedly lower as compared to 4- and 5-substituted (pyridin-2-yl)aminomethane-1,1-diphosphonic acids. This is attributed to low basicity of the nitrogen atom of the 1,3-diazinyl ring, which results in loss of conformational stabilization provided by intermolecular N–H⋯O hydrogen bonds in solution at low pH.

ChemInform Abstract: Synthesis and Structure of 6-Amino-2,3,6-trideoxy-D-erythro-hexono-1,6-lactam and 6-Amino-3,6-dideoxy-D-xylo-hexono-1,6-lactam

Abstract Solid-state conformations of 6-amino-2,3,6-trideoxy- d - erythro -hexono-1,6-lactam ( 3a ) and 6-amino-3,6-dideoxy- d - xylo -hexono-1,6-lactam ( 7a ) were determined using X-ray diffraction. Conformations of the compounds 3a , 7a , and their per- O -acetyl derivatives 4,5-di- O -acetyl-6-amino-2,3,6-trideoxy- d - erythro -hexono-1,6-lactam ( 3b ) and 2,4,5-tri- O -acetyl-6-amino-3,6-dideoxy- d - xylo -hexono-1,6-lactam ( 7b ) in solutions were deduced from the analysis of NMR spectra using a modified Karplus equation and compared with the results of circular dichroism measurement of lactams 3a and 7a . Conformation 4 C 1,N was revealed for solid lactams 3a and 7a and for lactams 7a and 7b in solution, while lactams 3a and 3b in solution exist in the ∼1:1 equilibrium of the conformers 4 C 1,N and 1,N C 4 .

Synthesis, Crystal Structure and ab initio Studies of Cyclohexyl N-Phenylcarbamate

Cyclohexyl N-phenylcarbamate, C13H17NO2 (I), which is a useful target for biotransformations by fungi, has been synthesized and the structure has been solved by X-ray diffraction. The crystals are triclinic, space group P $$ \bar{1} $$ , with a = 5.2581 (2) A, b = 9.5080 (3) A, c = 12.6165 (4) A, α = 70.544 (2)°, β = 89.075 (2)°, γ = 80.447 (2)°, M r = 219.28, V = 585.96 (3) A3, Z = 2 and R = 0.065. In the title compound the phenyl ring makes a dihedral angle of 30.68(7)° with the carbamate group The molecules are linked into infinite chains via N–H···O hydrogen bonds along the a axis. These hydrogen-bonded chains are further linked by weaker C–H···π interactions. Quantum-mechanical ab initio calculations for the free molecule reproduce well the observed bond lengths and valency angles but show that the crystal packing might be responsible for the rotation of the phenyl ring out of the carbamate plane in the solid state conformation. In cyclohexyl N-phenylcarbamate the molecules are linked into infinite chains via N–H...O hydrogen bonds along the a axis. Ab initio calculations for the free molecule show that the crystal packing might be responsible for the rotation of the phenyl ring out of the carbamate plane in the solid state conformation.

Design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as potent orexin receptor antagonists

Orexins are neuropeptides that regulate wakefulness and arousal. Small molecule antagonists of orexin receptors may provide a novel therapy for the treatment of insomnia and other sleep disorders. In this Letter we describe the design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as orexin receptor antagonists. The design of these constrained analogs was guided by an understanding of the preferred solution and solid state conformation of the diazepane central ring.

New hybrids of clozapine and haloperidol and their isosteric analogues: synthesis, X-ray crystallography, conformational analysis and preliminary pharmacological evaluation

Schizophrenia is a debilitating mental disorder which affects approximately 1% of the world’s population. Clozapine is an atypical antipsychotic showing unmatched effectiveness in the control of treatment-resistant schizophrenia. Unlike typical antipsychotics, clozapine does not induce extrapyramidal side effects (EPS), tardive dyskinesia or elevate prolactin levels. However, clozapine can induce a potentially fatal blood disorder, agranulocytosis, in 1–2% of patients, severely limiting its clinical use. The model for antipsychotic activity under investigation is based on obtaining a clozapine-like profile with preferential dopamine D4 and serotonin 5-HT2A receptor affinity. Profiled herein are three unique members of a series of prospective antipsychotic agents. Compound (I) originated from the structural hybridization of the commercial therapeutics, clozapine and haloperidol, whilst compounds (II) and (III) possess an alternative tricyclic nucleus derived from JL13; a clozapine-like atypical antipsychotic developed by Liegeois et al. These compounds have been synthesized and characterized by means of elemental analysis, IR, 1H and 13C-NMR spectroscopy, MS and X-ray diffraction. Compound (I) crystallizes in space group P(−1) with a = 10.5032(1), b = 10.6261(2), c = 12.6214(3) A, α = 81.432(1)°, β = 83.292(1)°, γ = 61.604(1)°, Z = 2, V = 1223.62(4) A3, C28H29ClN4O, M r = 473.00, D c = 1.284 Mg/m3, μ = 0.185 mm−1, F(000) = 500, R = 0.0506 and wR = 0.1304. Compound (II) crystallizes in the monoclinic space group P21/c with a = 10.8212(2), b = 9.3592(2), c = 22.9494(5) A, β = 106.471(1)°, Z = 4, V = 2228.88(8) A3, C25H25ClN4O2, M r = 448.94, D c = 1.338 Mg/m3, μ = 0.202 mm−1, F(000) = 944, R = 0.0529 and wR = 0.1129. Compound (III) crystallizes in the monoclinic space group P21/c with a = 10.5174(2), b = 9.3112(2), c = 24.2949(5) A, β = 98.666(1)°, Z = 4, V = 2352.03(8) A3, C25H24Cl2N4O2, M r = 483.38, D c = 1.365 Mg/m3, μ = 0.306 mm−1, F(000) = 1008, R = 0.0478 and wR = 0.1067. The solid state conformations of (I), (II) and (III) exhibit the characteristic V-shaped buckled nature of the respective dibenzodiazepine and pyridobenzoxazepine nuclei with the central seven-membered heterocycle in a boat conformation. The molecules of (I) form a head-to-tail dimeric motif stabilized by hydrogen bonding. The results of a conformational analysis of compounds (I)–(III) investigating the effect of environment (in vacuo and aqueous solution) are presented. These analogues were tested for in vitro affinity for the dopamine D4 and serotonin 5-HT2A receptors and their comparative receptor binding profiles to clozapine and JL13 are reported.

Conformational properties of the residues connected by ester and methylated amide bonds: theoretical and solid state conformational studies

Peptides produced by bacteria and fungi often contain an ester bond in the main chain. Some of them have both an ester and methylated amide bond at the same residue. A broad spectrum of biological activities makes these depsipeptides potential drug precursors. To investigate the conformational properties of such modified residues, a systematic theoretical analysis was performed on N-acetyl-L-alanine N'-methylamide (Ac-Ala-NHMe) and the analogues with the ester bond on the C-terminus (Ac-Ala-OMe), N-terminus (Ac-[psi](COO)-Ala-NHMe) as well as the analogues methylated on the N-terminus (Ac-(Me)Ala-OMe) and C-terminus (Ac-[psi](COO)-Ala-NMe(2)). The phi, psi potential energy surfaces and the conformers localised were calculated at the B3LYP/6-311++G(d,p) level of theory both in vacuo and with inclusion of the solvent (chloroform, water) effect (SCRF method). The solid state conformations of the studied residues drawn from The Cambridge Structural Database have been also analysed. The residues with a C-terminal ester bond prefer the conformations beta, C5, and alpha(R), whereas those with N-terminal ester bond prefer the conformations beta, alpha(R), and the unique conformation alpha' (phi, psi = -146 degrees , -12 degrees ). The residues with N-terminal methylated amide and a C-terminal ester bond prefer the conformations beta, beta2, and interestingly, the conformation alpha(L). The residues with a C-terminal methylated amide and an N-terminal ester bond adopt primarily the conformation beta. The description of the selective structural modifications, such as those above, is a step towards understanding the structure-activity relationship of the depsipeptides, limited by the structural complexity of these compounds.

Synthesis, Structures, and Conformational Characteristics of Triptycene-Derived Calix[5]arenes

A series of novel calix[5]arenes 5 containing one 1,8-dimethoxytriptycene moiety were synthesized through an efficient fragment coupling strategy. The subsequent demethylation of 5 with BBr(3) in dry dichloromethane gave the calix[5]arenes 6. Debutylation of both 5a-b and 6a-b with AlCl(3) resulted in the same products 7a-7b. The structural studies revealed that all of the macrocyclic compounds have well-defined structures with fixed cone conformations in both solution and solid state. Moreover, it was also found that the triptycene-derived calix[5]arenes could encapsulate small neutral molecules in the solid state.

Helical conformations of hexapeptides containing N‐terminus diproline segments

The role of N-terminus diproline segments in facilitating helical folding in short peptides has been investigated in a set of model hexapeptides of the type Piv-Xxx-Yyy-Aib-Leu-Aib-Phe-OMe (Piv, pivaloyl). Nine sequences have been investigated with the following N-terminus dipeptide segments: (D)Pro-Ala (4) and Pro-PsiPro (5, Psi, pseudoproline), Ala-Ala (6), Ala-Pro (7), Pro-Ala (8), Aib-Ala (9), Ala-Aib (10). The analog sequences Piv-Pro-Pro-Ala-Leu-Aib-Phe-OMe (2) and Piv-Pro-Pro-Ala-Aib-Ala-Aib-OMe (3) have also been studied. Solid state conformations have been determined by X-ray crystallography for peptides 4, 6, and 8 and compared with the previously determined crystal structure of peptide 1 (Boc-Pro-Pro-Aib-Leu-Aib-Val-OMe); (Rai et al., JACS 2006, 128, 7916-7928). Peptides 1 and 6 adopt almost identical helical conformations with unfolding of the helix at the N-terminus Pro (1) residue. Peptide 4 reveals the anticipated (D)Pro-Ala type II' beta-turn, followed by a stretch of 3(10)-helix. Peptide 8 adopts a folded conformation stabilized by four successive 4-->1 intramolecular hydrogen bonds. Ala (2) adopts an alpha(L) conformation, resulting in a type II beta-turn conformation followed by a stretch of 3(10)-helix. Conformational properties in solution were probed using solvent perturbation of NH chemical shifts which permit delineation of hydrogen bonded NH groups and nuclear Overhauser effects (NOEs) between backbone protons, which are diagnostic of local residue conformations. The results suggest that, continuous helical conformations are indeed significantly populated for peptides 2 and 3. Comparison of the results for peptides 1 and 2, suggest that there is a significant influence of the residue that follows diproline segments in influencing backbone folding.

Crystal structure of the insect neuropeptide proctolin.

The crystal structure of the neuropeptide proctolin (Arg-Tyr-Leu-Pro-Thr) is reported revealing the solid-state conformation of its molecules and their association in the crystal.

The Discodermolide Hairpin Structure Flows from Conformationally Stable Modular Motifs

(+)-Discodermolide (DDM), a polyketide macrolide from marine sponge, is a potent microtubule assembly promoter. Reported solid-state, solution, and protein-bound DDM conformations reveal the unusual result that a common hairpin conformational motif exists in all three microenvironments. No other flexible microtubule binding agent exhibits such constancy of conformation. In the present study, we combine force-field conformational searches with NMR deconvolution in different solvents to compare DDM conformers with those observed in other environments. While several conformational families are perceived, the hairpin form dominates. The stability of this motif is dictated primarily by steric factors arising from repeated modular segments in DDM composed of the C(Me)-CHX-C(Me) fragment. Furthermore, docking protocols were utilized to probe the DDM binding mode in beta-tubulin. A previously suggested pose is substantiated (Pose-1), while an alternative (Pose-2) has been identified. SAR analysis for DDM analogues differentiates the two poses and suggests that Pose-2 is better able to accommodate the biodata.

A [2+3] fragment coupling approach to N,O-bridged calix[1]arene[4]pyridines and their complexation with C 60

Functionalized N,O-bridged calix[1]arene[4]pyridines, first examples of the odd-numbered heterocalixaromatics containing mixed heteroatom bridges and mixed aromatic units, have been synthesized from the Pd 2(dba) 3/dppp-catalyzed 2+3 macrocyclic fragment coupling reaction between readily available staring materials. These novel macrocyclic compounds, which adopted distorted 1,3-alternate conformation in solid state, were powerful host molecules able to form 1:1 complex with fullerene C 60 in solution, giving binding constant up to 49,494 M −1.

Triptycene-Derived N(H)-Bridged Azacalixarenes: Synthesis, Structure, and Encapsulation of Small Neutral Molecules in the Solid State

Four pairs of novel N(H)-bridged azacalixarenes derived from triptycene were synthesized by both one-pot and two-step fragment-coupling approaches. Due to the unique 3D rigid structure of triptycene, the macrocycles all adopted fixed conformations in both solution and solid state. X-ray crystallographic analyses also revealed that the cis isomers with boat conformations showed the capability of encapsulating methanol and acetone molecules inside.

Asymmetric Synthesis of All-Carbon Benzylic Quaternary Stereocenters via Conjugate Addition to Alkylidene and Indenylidene Meldrum’s Acids

A systematic study outlining the enantioselective 1,4-addition of dialkylzinc reagents to 5-(1-arylalkylidene) and indenylidene Meldrum's acids is presented. Variation of the aryl and alkyl groups present on the alkylidene was thoroughly explored. The 1,4-addition displayed compatibility with a wide range of heteroaromatics and functional groups, and the arene pattern of substitution affected enantioselection, with a para-substituted aryl group consistently leading to high enantioselectivities. The nature of the organozinc reagent on the efficiency and selectivity of the conjugate addition was also investigated. The solid-state conformation was determined for a number of alkylidene Meldrum's acids and correlated with the observed enantioselectivity in relation to the arene pattern of substitution.

5,10:13,14-Disecosteroids: novel modified steroids containing 10- and 9-membered rings

In this paper a synthetic pathway to the modified 5,10:13,14-bisfragmentation cholestane derivatives 8– 14 is described. The synthesis involves introduction of the 5α- and 14α-hydroxyl groups in the cholestane molecule and subsequent cleavage of the C(5)–C(10) bond in 5α,14α-dihydroxycholestan-3β-yl acetate ( 4) with the HgO/I 2 reagent and the C(13)–C(14) bond in the stereoisomeric 14α-hydroxy-5,10-secosteroids 5 and 6 with the Pb(OAc) 4/I 2 reagent. Complete and unambiguous 1H and 13C NMR resonance assignments of the obtained secosteroids, as well as the solution conformations of their 10- and 9-membered rings were determined by extensive analysis of 1D and 2D NMR spectral data. The structures and the solid-state conformations of 5,10-secosteroids 5– 7 were confirmed by X-ray analysis. All diseco-compounds have a novel 5,10:13,14-disecocholestane skeleton.

Critical Role of External Axial Ligands in Chirality Amplification of trans-Cyclohexane-1,2-diamine in Salen Complexes

A series of Mn(IV)(salen)(L)(2) complexes bearing different external axial ligands (L = Cl, NO(3), N(3), and OCH(2)CF(3)) from chiral salen ligands with trans-cyclohexane-1,2-diamine as a chiral scaffold are synthesized, to gain insight into conformational properties of metal salen complexes. X-ray crystal structures show that Mn(IV)(salen)(OCH(2)CF(3))(2) and Mn(IV)(salen)(N(3))(2) adopt a stepped conformation with one of two salicylidene rings pointing upward and the other pointing downward due to the bias from the trans-cyclohexane-1,2-diamine moiety, which is in clear contrast to a relatively planar solid-state conformation for Mn(IV)(salen)(Cl)(2). The CH(2)Cl(2) solution of Mn(IV)(salen)(L)(2) shows circular dichroism of increasing intensity in the order L = Cl < NO(3) << N(3) < OCH(2)CF(3), which indicates Mn(IV)(salen)(L)(2) adopts a solution conformation of an increasing chiral distortion in this order. Quantum-chemical calculations with a symmetry adapted cluster-configuration interaction method indicate that a stepped conformation exhibits more intense circular dichroism than a planar conformation. The present study clarifies an unexpected new finding that the external axial ligands (L) play a critical role in amplifying the chirality in trans-cyclohexane-1,2-diamine in Mn(IV)(salen)(L)(2) to facilitate the formation of a chirally distorted conformation, possibly a stepped conformation.

Free and bound state structures of 6- O-methyl homoerythromycins and epitope mapping of their interactions with ribosomes

The solution and solid state conformations of several 6- O-methyl homoerythromycins 1– 4 were studied using a combination of X-ray crystallography, NMR spectroscopy and molecular modelling calculations. In the solid state 1 was found to exist as the two independent molecules with similar structures termed 3- endo-folded-out. In solution a significant conformational flexibility was noticed especially in the C2 to C5 region. The compounds 1 and 2 unlike 14-membered macrolides adopted the 3- endo-folded-out conformation while 3 and 4 existed in the classical folded-out conformation. TrNOESY and STD experiments showed that 1 and 2 bound to the Escherichia coli ribosome while 3 and 4, lacking the cladinose sugar, did not exhibit binding activities, this being in accordance with biochemical data. The bound conformations were found to be very similar to the free ones, some small differences were observed and discussed. The STD experiments provided evidence on binding epitopes. The structural parts of 1 and 2 in close contact with ribosome were similar, however the degree of saturation transfer was higher for 2. The differences between tr-NOE data and STD enhancements in 1 and 2 arouse as a consequence of structural changes upon binding and a closer proximity of 2 to the ribosome surface. An understanding of the molecular mechanisms involved in the interaction of macrolides with ribosomes can help in developing strategies aiming at design of potential inhibitors.

Molecular Solids from Symmetrical Bis(piperazine-2,5-diones) with Open- and Closed-Monomer Conformations

The design, synthesis and solid state structures of a new class of xylylene-linked bis(1,4- piperazine-2,5-diones) are reported in an effort to extend the molecular framework of piperazine-2,5-diones. These compounds were derived from piperazine-2,5-dione as the core structure, synthesized via a new efficient route, and their crystal structures were determined. We examined the effects of side chain substitution on conformations of the linked bis-DKPs. Crystallization of 3,3'-[1,4-phenylenebis(methylene)]-bis[6-(hydroxymethyl)-1,4-dimethylpiperazine-2,5-dione] yielded molecular solids with an unusual network of "C"-shaped monomers held together by four intermolecular hydrogen bonds per asymmetric unit. Similarly, intermolecular interactions between the iodomethyl groups in 3,3'-[1,4-phenylenebis(methylene)]-bis[6-(iodomethyl)-1,4-dimethyl-piperazine-2,5-dione] result in the monomers adopting a "C"-shape in the solid state. Assembly of the monomers with side chains converted to methyl groups or tert-butyldimethylsilyl ethers, thereby lacking these stabilizing intermolecular interactions, results in an infinite array of "S"-shaped conformations. These results suggest that the interplay between the attractive intermolecular interactions and repulsive steric interactions of the substituents at the C6 and C6' positions of the diketopiperazine rings is important in determining the solid-state conformations of xylylene-linked bis(piperazine-2,5-diones).

Structural analysis of bis-amidines and bis-nitriles in solid-state by combining NMR spectroscopy and molecular modeling

The paper presents the analysis of the structures of four novel sulfonamide-based bis-amidines, and four novel interesting intermediates leading to them, named bis-nitriles, in solid-state based on 13C CP/MAS NMR spectroscopy and theoretical calculations of shielding constants at DFT level of theory. We have observed double 13C resonances in solid-state spectra as compared with solution spectra. The considerations of experimental chemical shifts followed by shielding computations allowed us to define essential geometric details regarding the most probable conformations in solid-state. All compounds have one independent molecule in the asymmetric unit, and a main reason of splittings of NMR signals in solid-state is different orientation of alkoxy fragments (methyl groups and linker) with reference to benzene rings.

2-[6,8-Dibromo-3-(4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazolin-2-yl]-6-methoxyphenol

The title compound, C21H24Br2N2O3, was synthesized by the condensation reaction of 3-methoxy­salicylaldehyde with 4-(2-amino-3,5-dibromo­benzyl­amino)cyclo­hexa­nol in a methanol solution. The dihedral angle between the two benzene rings is 76.4 (3)°. The cyclo­hexyl ring adopts a chair configuration. There is an intra­molecular O—H⋯N hydrogen bond which affects the solid state conformation of the mol­ecule. The crystal structure is stabilized by inter­molecular O—H⋯O hydrogen bonds, forming chains running along the b axis.

3-Oxoandrosta-4,6-dien-17β-yl 2-methyl-1H-imidazole-1-carboxylate and 3-oxo-5α-androst-17β-yl 2-methyl-1H-imidazole-1-carboxylate: C—H...π and π–π intermolecular interactions

The title compounds, C(24)H(30)N(2)O(3), (I), and C(24)H(34)N(2)O(3), (II), both contain an androstane backbone and a 2-methylimidazole-1-carboxylate moiety at the 17-position. Compound (I) contains two symmetry-independent molecules (denoted 1 and 2), while compound (II) contains just one molecule in the asymmetric unit. The C-C-O-C torsion angle that reflects the twisting of the 2-methylimidazole-1-carboxylate moiety from the mean steroid plane is 143.1 (2) degrees for molecule 1 of (I), 73.1 (3) degrees for molecule 2 of (I) and 86.63 (17) degrees for (II). The significance of this study lies in its observation of significant differences in both molecular conformation and supramolecular aggregation between the molecules of the title compounds. The solid-state conformations compared with those obtained theoretically from ab initio methods for the isolated molecules show large differences, especially in the orientation of the methylimidazole substituent.