Photo-oxygenation of Styrenic Estrogens: Product characterization and kinetics of the dye-sensitized photo-oxygenation of 9,11-didehydroestrone derivatives

The dye-sensitized photo-oxygenation of 3-hydroxyestra-1,3,5(10), 9(11)-tetraen-17-one ( 8 ) gives a complex mixture from which only the 1,4-endo-peroxide 10 can be isolated in low yield. In contrast, the 3-methoxy derivative 9 yields the C-seco-aldehyde 11 as a major product, suggesting that 1,2-dioxetane is a primary photo-oxygenation intermediate. As the electron-donating character of the substituent at C(3) decreases in the sequence 12 (R = PhCO), 13 (R = Ac), and 14 (R = Ts), the rate constant in substrate disappearance becomes drastically smaller as compared with 8 and 9 , and no photoproducts are detected. The results are rationalized by means of electronic and conformational factors.     

Conformational Behavior of Rigid and Dancing (1,3)(1,4)Cyclophanes

Annelation or substitution of the (1,4)-bridged ring of [2₂](1,3)(1,4)cyclophane 4 , such as in 8 and 9 , respectively, result in two different conformational ground states in each case. Each conformational ground state involves a different destabilizing factor arising from one form of non-bonding interaction. Only the conformers 8b and 9b were isolated experimentally. Their corresponding precursors 11 and 23 were also found to be conformationally rigid. Only the conformers 11a and 23a were isolated indicating an abrupt change in conformational preference going from the dithia[3₂]cyclophanes to the respective [2₂]cyclophanes. The selectively methylated [2₂]cyclophanes 27 , 31 and 32 were, however, found to be conformationally mobile. There is an increase of about 10–15 kJ mol^?1 in conformational energy barrier going from 4 to 27 or 31 . This is consistent with the fact that the presence of the methyl substituents increases the relative conformational ground-state energy more than it would affect the transition-state energy. The conformational barrier of 32 was unexpectedly found to be similar to those of 27 and 31 . This could be explained by a decrease in the transition-state energy due to an inward bending of the (1,4)-bridged ring accompanied by a decrease in conformational ground-state energy due to an outward bending of the methyl groups in 32 .     

Catalytic itinerary in 1,3-1,4-β-glucanase unraveled by QM/MM metadynamics. Charge is not yet fully developed at the oxocarbenium ion-like transition state

Retaining glycoside hydrolases (GHs), key enzymes in the metabolism of polysaccharides and glycoconjugates and common biocatalysts used in chemoenzymatic oligosaccharide synthesis, operate via a double-displacement mechanism with the formation of a glycosyl-enzyme intermediate. However, the degree of oxocarbenium ion character of the reaction transition state and the precise conformational itinerary of the substrate during the reaction, pivotal in the design of efficient inhibitors, remain elusive for many GHs. By means of QM/MM metadynamics, we unravel the catalytic itinerary of 1,3-1,4-β-glucanase, one of the most active GHs, belonging to family 16. We show that, in the Michaelis complex, the enzyme environment restricts the conformational motion of the substrate to stabilize a (1,4)B/(1)S(3) conformation of the saccharide ring at the -1 subsite, confirming that this distortion preactivates the substrate for catalysis. The metadynamics simulation of the enzymatic reaction captures the complete conformational itinerary of the substrate during the glycosylation reaction ((1,4)B/(1)S(3) -(4)E/(4)H(3) - (4)C(1)) and shows that the transition state is not the point of maximum charge development at the anomeric carbon. The overall catalytic mechanism is of dissociative type, and proton transfer to the glycosidic oxygen is a late event, clarifying previous kinetic studies of this enzyme.     

Diastereomer-differentiating photochemistry of beta-arylbutyrophenones: Yang cyclization versus type II elimination

The diastereomers of ketones 2 and 3 are shown to exhibit distinct photochemical reactivities due to conformational preferences; while the anti isomers of 2 and 3 undergo efficient Yang cyclization in 75-90% yields with a remarkable diastereoselectivity (> 90%), the syn isomers predominantly undergo Norrish Type II elimination. The differences in the product profiles of the diastereomers are consistent with a mechanistic picture involving the formation of precursor diastereomeric triplet 1,4-biradicals in which the substituents at alpha and beta-positions stabilize the cisoid (cyclization) or transoid (elimination) geometry. The fact that such a diastereomeric relationship does indeed ensue at the triplet-excited-state itself is demonstrated via the nanosecond laser-flash photolysis of model ketones 1. The diastereomeric discrimination in the product profiles observed for ketones 2 and 3 as well as in the triplet lifetimes observed for ketones 1 can both be mechanistically traced back to different conformational preferences of the ground-state diastereomeric ketones and the intermediary 1,4-biradicals. Additionally, it emerges from the present study that the syn and anti diastereomers of ketones 2 and 3 represent two extremes of a broad range of widely examined butyrophenones, which lead to varying degrees of Yang photocyclization depending on the alkyl substitution pattern.     

Conformational analysis of sulfur-containing 6-deoxy-l-hexose derivatives by molecular modeling and NMR spectroscopy. A theoretical study and experimental evidence of intramolecular nonbonded interactions between sulfur and oxygen

6-Deoxy-l-mannose diphenyldithioacetal (1) unexpectedly gave the rearranged products phenyl 3,4-di-O-acetyl-2-S-phenyl-1,2-dithio-6-deoxy-beta-l-glucopyranoside (9) and 3,4-di-O-acetyl-2,5-anhydro-6-deoxy-l-glucose diphenyldithioacetal (10) upon treatment with acetyl chloride, while 6-deoxy-l-mannose ethylenedithioacetal (3) yielded (4aR,6S,7S,8R,8aS)-7,8-diacetyloxy-6-methylhexahydro-4aH-[1,4]dithiino[2,3b]pyran (11), whose structure was further confirmed by X-ray diffraction, and 3,4-di-O-acetyl-2,5-anhydro-l-rhamnose ethylenedithioacetal (12). The geometry of the four rearranged products as well as that of 1-thio-6-deoxy-l-mannopyranosides 5 and 7 and their acetyl derivatives 6 and 8 was studied by density functional theory (B3LYP/6-31G) molecular models, in combination with a Karplus-type analysis of the NMR vicinal coupling constants, revealing that the six-membered ring of pyranosides 5-9 and 11 exists in a slightly distorted chair conformation (6-13% distortion) and that the conformational behavior of the 2,5-anhydro-6-deoxy-l-glucose dithioacetals 10 and 12 is strongly influenced by the presence of stabilizing intramolecular nonbonded sulfur-oxygen 1,4- and 1,5-interactions. Compounds 9-12 were formed by a molecular rearrangement via sulfonium ion intermediates followed by stereoselective intramolecular cyclizations as formulated by the quantum chemical calculations performed in the present study.     

Nuclear magnetic resonance of psychotherapeutic agents. IV—conformational analysis of 2,3-dihydro-1H-1,4-benzodiazepines

The lanthanide shift reagent (LSR)/¹H NMR study of some 7-chloro-5-phenyl-2,3-dihydro-1 H-1, 4-benzodiazepines shows that these compounds exist in CDCI₃ solution as two pseudo-boat conformers, rapidly interconverting at room temperature. Computer simulated lanthanide induced shifts (LIS) are consistent with LSR complexation by the imine nitrogen atom. The lanthanide shifts the conformational equilibrium towards conformer (a), with a pseudoequatorial 1-substituent: this effect may be the result of the greater basicity of 4-N when the 1-N lone pair is pseudoaxially directed, thus permitting an extended electron delocalization from 1- to 4-N through the fused benzene ring. The detection of H-9/1-Me through space spin-spin coupling in medazepam (7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine) supports the observed higher availability of conformer (a) to LSR. A LIS computer calculation to predict the population ratio results in reasonable agreement with the conformational changes based on the response of ³J(HH) to lanthanide addition. The electronic and steric effects which determine the greater stability of conformer (a) may be effective in the drug-receptor interaction.     

Synthesis of nucleoside analogs of 1,4-oxathiane, 1,4-dithiane,and 1,4-dioxane

The two regioisomers 6-chloro-9-(1, 4-oxathian-3-yl)-9H-purine ( 5 ) and 6-chloro-9-(1,4-oxathian-2-yl)-9H-purine ( 6 ) were obtained when 3-acetoxy-1,4-oxathiane ( 3 ) was subjected to the acid-catalyzed fusion procedure; compound 3 was prepared by a Pummerer reaction with 1,4-oxathiane 4-oxide ( 2 ). The nucleoside analog 6 could he converted into the adenine derivative 7 and 9-(1,4-oxathian-2-yl)-9H-purine-6(1H)thione ( 8 ). The following nucleoside analogs have also been synthesized: 6-chloro-9-(1,4-dithian-2-yl)-9H-purine ( 13 ), 9-(1,4-dithian-2-yl)adenine ( 14 ), 9-(1,4-dithian-2-yl)-9H-purine-6(1H)thione ( 15 ), and 6-chloro-9-(1,4-dioxan-2-yl)-9H-purine ( 18 ).     

NMR stereotopic induced shifts in epimeric mixtures

The proton NMR spectra of epimeric mixtures of menthone ( 1 ), carvomenthone ( 2 ), carquejone ( 3 ), 2,5-dimethyl-1,4-cyclohexanedione ( 4 ) and piqueridione ( 5 ) were studied using the chemical shift reagent Eu(DPM)₃. The results allow quantifications of the epimers and some conformational assignments to be made.     

Restricted motion of guests confined in carceplexes and capsules

Guest orientation within carceplexes and capsules was determined qualitatively from NMR data, and the molecular mobility of guests was determined via coalescence of (1)H NMR signals. Both are highly dependent on guest size and shape, as is interconversion of twistomers. Incarceration of 1,4-thioxane results in a large (1.8 kcal/mol) constraint on thioxane's conformational mobility (chair-to-chair interconversion). Similar conformational constraints (1.6 kcal/mol) were determined for 1,4-dioxane both when incarcerated in carceplex 1b and when encapsulated reversibly in capsule 3b. Encapsulation-induced conformational constraints of this magnitude are unprecedented, and are particularly striking for the noncovalently linked capsules.     

Cu(I) complexes containing a multidentate and conformationally flexible dibenzylidene acetone ligand (dbathiophos): application in catalytic alkene cyclopropanation

The synthesis and characterisation of a multidentate conformationally flexible ligand based on the dibenzylidene acetone core structure, dbathiophos (1), is described. Ligand 1 has a high affinity for cationic and neutral Cu(I) species. Three unique Cu(I) complexes (4-6) are reported showing that the ligand backbone of dbathiophos is hemilabile, and able to adopt different 1,4-dien-3-one conformational geometries around Cu(I). Complexes 4 and 6 both effectively catalyse the cyclopropanation of styrene with ethyl diazoacetate at low catalyst loadings (1 mol% Cu).     

A computational study of conformational interconversions in 1,4-dithiacyclohexane (1,4-dithiane)

Ab initio molecular orbital theory with the 6-31G(d), 6-31G(d,p), 6-31+G(d), 6-31+G(d,p), 6-31+G(2d,p), 6-311G(d), 6-311G(d,p), and 6-311+G(2d,p) basis sets and density functional theory (BLYP, B3LYP, B3P86, B3PW91) have been used to locate transition states involved in the conformational interconversions of 1,4-dithiacyclohexane (1,4-dithiane) and to calculate the geometry optimized structures, relative energies, enthalpies, entropies, and free energies of the chair and twist conformers. In the chair and 1,4-twist conformers the C-Hax and C-Heq bond lengths are equal at each carbon, which suggest an absence of stereoelectronic hyperconjugative interactions involving carbon-hydrogen bonds. The 1,4-boat transition state structure was 9.53 to 10.5 kcal/mol higher in energy than the chair conformer and 4.75 to 5.82 kcal/mol higher in energy than the 1,4-twist conformer. Intrinsic reaction coordinate (IRC) calculations showed that the 1,4-boat transition state structure was the energy maximum in the interconversion of the enantiomers of the 1,4-twist conformer. The energy difference between the chair conformer and the 1,4-twist conformer was 4.85 kcal/mol and the chair-1,4-twist free energy difference (deltaG degrees (c-t)) was 4.93 kcal/mol at 298.15 K. Intrinsic reaction coordinate (IRC) calculations connected the transition state between the chair conformer and the 1,4-twist conformer. This transition state is 11.7 kcal/mol higher in energy than the chair conformer. The effects of basis sets on the 1,4-dithiane calculations and the relative energies of saturated and unsaturated six-membered dithianes and dioxanes are also discussed.     

重氮萘酮在环醚中热解反应研究

三种带有不同取代基的重氮萘酮(la～1c)在THF和二氧六环中加热分解给出不同的产物。1-重氮-4-萘酮(1a)的热解产物主要是重氮萘酮热解后产生的烯酮卡宾(2a)与环醚开环后形成的聚合物;3-甲基-1-重氮-4-萘酮(1b)的热解产物比较复杂,除冠醚类产物之外,还有烯酮卡宾对四氢呋喃和二氧六环的C-H键的插入反应产物、螺环化合物、2-甲基萘酚以及难以分离的聚合物;3-硝基-1-重氮-4-萘酮(1c)的热解产物主要是聚合物,此外还有少量C－H键的插入反应产物和2-硝基萘酚。对重氮萘酮热解反应的机理作了讨论。     

Synthese von Plectranthonen,diterpenoiden Phenanthren-1,4-chinonen

Synthesis of Plectranthons, Diterpenoid Phenanthrene-1,4-diones The following phenanthrene-1,4-diones have been synthesized by using the photocyclization of the corresponding highly substituted stilbenes as the key step: 3-hydroxy-5,7,8-trimethyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 1 ), (RS)-, (R)-, and (S)-2-[3-hydroxy-5,7,8-trimethyl-1,4-dioxophenanthren-2-yl]-1-methylethyl acetate ( 2 , 31 , and 32 , resp.), 3-hydroxy-7,8-dimethyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 3 ), 3-hydroxy-7,8,10-tri-methyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 4 ), 5,7,8-trimethyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 17 ), and 3-hydroxy-2-methylphenanthrene-1,4-dione ( 42 ). The quinones 1 and 3 proved to be identical with the recently isolated plectranthons A and C. Compounds 2 , 31 , and 32 exhibited the same UV/VIS, IR, ¹H-NMR and mass spectra as natural plectranthon B , but had different melting points. This might be due either to crystal modifications or to diastereoisomerism caused by the helical structure of the phenanthrene-1,4-dione skeleton. The spectral data of synthetic 4 were not compatible with those of natural plectranthon D for which structure 4 had been proposed based mainly on ¹H-NMR arguments concerning the chemical shifts of H? C(9) and H? C(10) in 1–3. Extensive ¹H-NMR investigations have now revealed that the currently stated assignments of the H? C(9)/ H? C(10) AB system have to be reversed for highly substituted phenanthrene-1,4-diones: in the model compounds 2-methylphenanthrene-1,4-dione (41) and 2, H? C(10) resonates al lower field as expected (peri-position), whereas in the highly substituted congeners 1 , 2 , 3 , 31 , and 32 , H? C(9) is shifted paramagnetically, a fact which had lead to the erroneous assignment of structure 4 for natural plectranthon D .     

Competitive reactions of interstrand and intrastrand DNA-Pt adducts: A dinuclear-platinum complex preferentially forms a 1,4-interstrand cross-link rather than a 1,2 intrastrand cross-link on binding to a GG 14-mer duplex

A study of the kinetics and mechanism of the reaction between the dinuclear Pt complex [(trans-PtCl(NH(3))(2))(2)(mu-NH(2)(CH(2))(6)NH(2))](2+) (1) and the 14-mer duplex 5'-d(ATACATG(7)G(8)TACATA)-3'.5'-d(TATG(25)TACCATG(18)TAT)-3' is reported. [(1)H,(15)N]-HSQC NMR was used to follow the reaction at 298 K, pH 5.4. The product is primarily the 5'-5' 1,4-interstrand cross-link between G(8) and G(18) bases and exists in two conformational forms. No evidence for the possible 1,2-intrastrand G(7)G(8) adduct was seen, confirming the preferential formation of interstrand cross-links by these dinuclear complexes. An initial electrostatic association of (15)N-1 with the duplex is indicated by changes in its (1)H/(15)N chemical shifts, followed by aquation of 1 to form the monoaqua monochloro species 2, with a rate constant of 4.00+/-0.03x10(-5) s(-1). Monofunctional binding to the duplex occurs primarily at G(8), the 3' base of the nucleophilic GG grouping, with a rate constant of 1.5+/-0.7 M(-1) s(-1). Changes in the (1)H/(15)N shifts indicate there is an electrostatic interaction between the unbound (PtN(3)Cl) group of the monofunctional adduct and the duplex. No peaks for a transient aquated monofunctional species are seen and closure of 3 to form the 1,4-G(8)G(18) interstrand cross-link (5) was treated as direct, with a rate constant of 4.47+/-0.06x10(-5) s(-1). The G(8)G(18) cross-link was confirmed from analysis of the NOESY NMR spectrum of the final product. Structural perturbations for the 1,4-interstrand cross-link extend over approximately four base-pairs and are similar to those found for a 1,4-interstrand cross-link with a shorter 8-mer -GTAC- sequence. A major distortion was evident for the 5'T (T(17)) adjacent to the platinated G(18), consistent with the findings from the use of chemical probes to investigate the conformation of 1,4-interstrand cross-links.     

N-aminopyrroledione-hydrazonoketene-pyrazolium oxide-pyrazolone rearrangements and pyrazolone tautomerism

Flash vacuum thermolysis (FVT) of 1-(dimethylamino)pyrrole-2,3-diones 5 causes extrusion of CO with formation of transient hydrazonoketenes 7. The transient ketenes 7 are observable in the form of weak bands at 2130 (7a) or 2115 cm-1 (7b) in the Ar matrix IR spectra resulting from either FVT or photolysis of either 5 or 1,1-dimethylpyrazolium-5-oxides 8, and these absorptions are in excellent agreement with B3LYP/6-31G* frequency calculations. Under FVT conditions the ketenes 7 cyclize to pyrazolium oxides 8, which undergo 1,4-migration of a methyl group to yield 1,4-dimethyl-3-phenylpyrazole-5(4H)-one 9a and 1,4,4-trimethyl-3- phenylpyrazole-5(4H)-one 9b. All three tautomers of 9a have been characterized, viz. the CH form 9a (most stable form in the gas phase, the solid state and solvents of low polarity), the OH form 9a' (metastable solid at room temperature) and the NH form 9a" (stable in aprotic dipolar solvents). The isomeric 1,4-dimethyl-5-phenylpyrazole-3(2H)- one 12 tautomerizes to the 3-hydroxypyrazole 12'. The crystal structure of the hydrochloride 14 of 9a'/9a" is reported, representing the first structurally characterised example of a protonated 5-hydroxypyrazole.     

Hybrid-DFT Study and NBO Analysis of the Stereoelectronic Interaction Effects (Associated with the Anomeric Effects) on the Conformational Properties of 2,3,5,6-Tetrahalo-1,4-dioxanes and Their Analogs Containing S and Se Atoms

NBO analysis and hybrid density functional theory–based method (B3LYP/6-311+G**) was used to study the anomeric effects (AE), dipole–dipole interactions, and steric repulsion effects on the conformational properties of 2,3,5,6-tetrahalo-1,4-dioxane [halo = F (1), Cl (2), Br (3)], 2,3,5,6-tetrahalo-1,4-dithiane [halo = F (4), Cl (5), Br (6)], and 2,3,5,6-etrahalo-1,4-diselenane [halo = F (7), Cl (8), Br (9)]. B3LYP/6-311+G** results revealed a strong axial preference in compounds 1–3. Gibbs free energy difference (G _eq–G _ax) values (e.g., ΔG _eq-ax) between the axial and equatorial conformations of compound 1 to compound 3 are 8.19, 3.86, and 3.13 kcal mol^?1, respectively, as calculated by the B3LYP/6-311+G** level of theory. On the other hand, the NBO analysis of donor–acceptor (bond–antibond) interactions revealed that the AE for compounds 1–3 are ?12.26, ?16.46, and ?18.11 kcal mol^?1, respectively. Contrary to the increase of the AE values from compound 1 to compound 3, the increase of the steric repulsions (e.g., 1,3-syn-axial repulsions) could fairly explain the decrease of the axial conformation stability in compounds 1–3 compared to their equatorial conformations. Further, the correlations between the AE, structural parameters, and conformational behavior of compounds 4–9 have been investigated.     

Ionothermal syntheses, crystal structures and properties of three-dimensional rare earth metal-organic frameworks with 1,4-naphthalenedicarboxylic acid

Twelve isostructural rare earth metal-organic frameworks, namely, [Hmim][RE(2)Cl(1,4-NDC)(3)] (RE = La (1), Ce (2), Pr (3), Nd (4), Sm (5), Eu (6), Gd (7), Tb (8), Dy (9), Ho (10), Er (11), Y (12), Hmim = 1-hexyl-3-methylimidazolium, 1,4-NDCH(2) = 1,4-naphthalenedicarboxylic acid), have been ionothermally synthesized and structurally characterized. The structures feature three-dimensionally anionic frameworks of [RE(2)Cl(1,4-NDC)(3)](n)(n-) with channels in which the Hmim(+) cations are located. The current results are the first ionothermal synthesis of rare earth metal-organic frameworks based on 1,4-NDCH(2) which possess a previously unknown (4,7)-connected 3-nodal network with the Schl?fli symbol of (3(2)·4(2)·5(2))(3(2)·4(9)·5(2)·6(8))(2)(4(3)·6(3))(2). Luminescent and magnetic properties of some of the title compounds have been studied. Thermogravimetric analyses indicated that all these compounds were thermally stable up to ca. 250 °C.     

Entropy-controlled selectivity in the vinylation of a cyclic chiral nitrone. An efficient route to enantiopure polyhydroxylated pyrrolidines

A short synthesis of 1,4-dideoxy-1,4-imino-L-arabinitol (LAB1) (4) and of 1,4-dideoxy-1,4-imino-D-galactitol (5), two azasugars active as enzymatic inhibitors, is reported. The key reaction is the addition of vinylmagnesium chloride to (3S,4S)-3,4-bis(benzyloxy)-3,4-dihydro-2H-pyrrole 1-oxide (3), a nitrone easily available from L-tartaric acid. Unexpectedly, the reaction affords the corresponding (2S,3S,4S)-1-hydroxy-2-ethenyl-3,4-bis(benzyloxy)pyrrolidine (9) in very good yield and in 93/7 diastereomeric ratio (dr) independently of the reaction temperature, thus representing a unique case of entropy-controlled reaction in a 100 K interval (from +20 degrees C to -80 degrees C). The trans intermediate 9 is converted in two steps (reduction, N-protection) into the common intermediate (2S,3S,4S)-1-(benzyloxycarbonyl)-3,4-bis(benzyloxy)-2-ethenylpyrrolidine (11). Double bond oxidation followed by reductive debenzylation opens a route to the target pyrrolidine azasugars 4 and 5.     

Synthesis and conformational analysis of a cyclic peptide obtained via i to i+4 intramolecular side-chain to side-chain azide-alkyne 1,3-dipolar cycloaddition

Intramolecular side-chain to side-chain cyclization is an established approach to achieve stabilization of specific conformations and a recognized strategy to improve resistance toward proteolytic degradation. To this end, cyclizations, which are bioisosteric to the lactam-type side-chain to side-chain modification and do not require orthogonal protection schemes, are of great interest. Herein, we report the employment of Cu(I)-catalyzed 1,3-dipolar cycloaddition of side chains modified with azido and alkynyl functions and explore alternative synthetic routes to efficiently generate 1,4-disubstituted [1,2,3]triazolyl-containing cyclopeptides. The solid-phase assembly of the linear precursor including epsilon-azido norleucine and the propargylglycine (Pra) in positions i and i+4, respectively, was accomplished by either subjecting the resin-bound peptide to selective on-resin diazo transformation of a Lys into the Nle(epsilon-N3) or the incorporation of Fmoc-Nle(epsilon-N3)-OH during the stepwise build-up of the resin-bound peptide 1b. Solution-phase Cu(I)-catalyzed 1,3-dipolar cycloaddition converts the linear precursor Ac-Lys-Gly-Nle(epsilon-N3)-Ser-Ile-Gln-Pra-Leu-Arg-NH2 (2) into the 1,4-disubstituted [1,2,3]triazolyl-containing cyclopeptide [Ac-Lys-Gly-Xaa(&(1))-Ser-Ile-Gln-Yaa(&(2))-Leu-Arg-NH2][(&(1)(CH2)4-1,4-[1,2,3]triazolyl-CH2&(2))] (3). The conformational preferences of the model cyclopeptide 3 (III), which is derived from the sequence of a highly helical and potent i to i+4 side-chain to side-chain lactam-containing antagonist of parathyroid hormone-related peptide (PTHrP), are compared to the corresponding lactam analogue Ac[Lys(13)(&(1)),Asp(17)(&(2))]hPTHrP(11-19)NH2 (II). CD and NMR studies of 3 and II in water/hexafluoroacetone (HFA) (50:50, v/v) revealed a high prevalence of turn-helical structures involving in particular the cyclic regions of the molecule. Despite a slight difference of the backbone arrangement, the side-chains of Ser, Gln, and Ile located at the i+1 to i+3 of the ring-forming sequences share the same spatial orientation. Both cyclopeptides differ regarding the location of the turn-helical segment, which in II involves noncyclized residues while in 3 it overlaps with residues involved in the cyclic structure. Therefore, the synthetic accessibility and conformational similarity of i to i+4 side-chain to side-chain cyclopeptide containing the 1,4-disubstituted [1,2,3]triazolyl moiety to the lactam-type one may result in similar bioactivities.     

Synthesis and structural characterization of new stiff rod oligomeric domains by X-ray crystallography and NMR

The monomers N,N'-dibenzylbenzene-1,4-diamine (1), N,N'-dibenzylnaphthalene-1,5-diamine (2), and N,N'-dibenzylanthracene-1,9-diamine (3) were reacted with phosgene in the presence of a base to produce the corresponding N,N'-dibenzyl-1,4-bis(chlorocarbonylamino)benzene (4), N,N'-dibenzyl-1,5-bis(chlorocarbonylamino)naphthalene (5), and N,N'-dibenzyl-9,10-bis(chlorocarbonylamino)anthracene (6). These monomers were used to create zigzag type stacks, in a stepwise fashion, of trimers and 9-mers of either 1,4-diureidobenzenes ((Phe)K(3) and (Phe)K(9)) or 1,5-diureidonaphthalenes ((Nap)K(3) and (Nap)K(9)). A byproduct in the formation of (Phe)K(9) was a cyclic hexamer (Phe)K(6). NMR gave evidence of the structure in solution while X-ray crystallographic information was obtained for 5, 6, (Nap)K(3), and the cyclic (Phe)K(6).