Exo Form Research Articles

New Experimental Conditions for Diels-Alder and Friedel-Crafts Alquilation Reactions with Thiophene: A New Selenocyanate with Potent Activity against Cancer.

The reactivity of thiophene in Diels-Alder reactions is investigated with different maleimide derivatives. In this paper, we have synthesized for the first time the Diels–Alder adducts of thiophene at room temperature and atmospheric pressure. Maleimido–thiophene adducts were promoted by AlCl3. The effects of solvent, time, temperature and the use of different Lewis acids were studied, showing dramatic effects for solvent and Lewis acid. Furthermore, the catalysis with AlCl3 is highly stereoselective, preferably providing the exo form of the adduct. Additionally, we also discovered the ability of AlCl3 to catalyze the arylation of maleimides to yield 3-aryl succinimides in a straightforward manner following a Friedel–Crafts-type addition. The inclusion of a selenocyanate group contributes to the cytotoxic activity of the adduct. This derivatization (from compound 7 to compound 15) results in an average GI50 value of 1.98 µM in the DTP (NCI-60) cell panel, resulting in being especially active in renal cancer cells.

Additive and Emergent Catalytic Properties of Dimeric Unnatural Amino Acid Derivatives: Aldol and Conjugate Additions.

Different densely substituted L‐ and D‐proline esters were prepared by asymmetric (3+2) cycloaddition reactions catalyzed by conveniently selected EhuPhos chiral ligands. The γ‐nitro‐2‐alkoxycarbonyl pyrrolidines thus obtained in either their endo or exo forms were functionalized and coupled to yield the corresponding γ‐dipeptides. The catalytic properties of these latter dimers were examined using aldol and conjugate additions as case studies. When aldol reactions were analyzed, an additive behavior in terms of stereocontrol was observed on going from the monomers to the dimers. In contrast, in the case of the conjugate additions between ketones and nitroalkenes, the monomers did not catalyze this reaction, whereas the different γ‐dipeptides promoted the formation of the corresponding Michael adducts. Therefore, in this latter case emergent catalytic properties were observed for these novel γ‐dipeptides based on unnatural proline derivatives. Under certain conditions stoichiometric amounts of ketone, acid and nitroalkene), formation of N‐acyloxy‐2‐oxooctahydro‐1H‐indoles was observed.

Tuning the thermoreversible temperature domain of PTMC-based networks with thermosensitive links concentration.

In this work, thermoreversible poly(trimethylene carbonate) (PTMC) based networks with different crosslinking densities were obtained by Diels-Alder (DA) reaction between furan-functionalized PTMC precursors and a bismaleimide. Furan-grafted PTMC with various functionalities determined by 1H-NMR analyses were prepared from telechelic PTMC oligomer, glycerol, 4,4'-methylenebis(cyclohexyl isocyanate) (H12MDI) and furfuryl alcohol. The formation of network structures by DA reaction between furan and maleimide groups were proved by Fourier-transform infrared spectroscopy (FT-IR). Although both exo and endo DA adduct forms exist, the thermally more stable exo form dominates. The thermoreversibility of networks was evidenced by FT-IR, solubility, differential scanning calorimetry (DSC) and rheology experiments at different temperatures. By increasing furan functionality or node concentration, denser and stiffer networks could be formed with higher Young's modulus and true stress at break in tensile tests, as well as higher crossover temperature, which indicates a nominal transition from elastic behavior to viscous state. The disruption of networks was found to occur in high temperature ranges from 130 to 160 °C, depending on their crosslinking density.

Selective Syntheses and Properties of Anionic Surfactants Derived from Isosorbide

AbstractTwo series of anionic surfactants (endo‐5‐O‐alkyl isosorbide‐2‐O‐propyl sulfonic acid sodium salt and exo‐2‐O‐alkyl isosorbide‐5‐O‐propyl sulfonic acid sodium salt) with straight alkyl chains (hexyl, octyl, decyl, and dodecyl) were synthesized from isosorbide derived from biomass, through steps of allylation, alkylation, and sulfonation. The selectivity and efficiency of the reactions were optimized by adjusting the solvent, catalyst, reactant molar ratio, and temperature. The product 2‐O‐allyl isosorbide was obtained with a yield of 81% and selectivity of 23:1 (endo:exo), and 2‐O‐alkyl isosorbide was obtained with a yield of 72% and selectivity of 24:1 (exo:endo). The synthesized anionic surfactants were characterized using the critical micelle concentration (CMC), surface activity, emulsion stability, foaming height, and the Turbiscan Stability Index. The CMC decreased with increasing alkyl chain length. The properties of endo form and exo form were compared.

Ultraviolet Photodissociation Spectroscopy of the Cold K⁺·Calix[4]arene Complex in the Gas Phase.

The cooling of ionic species in the gas phase greatly simplifies the UV spectrum, which is of special importance when studying the electronic and geometric structures of large systems, such as biorelated molecules and host-guest complexes. Many efforts have been devoted to achieving ion cooling with a cold, quadrupole Paul ion trap (QIT), but one problem was the insufficient cooling of ions (up to ∼30 K) in the QIT. In this study, we construct a mass spectrometer for the ultraviolet photodissociation (UVPD) spectroscopy of gas-phase cold ions. The instrument consists of an electrospray ion source, a QIT cooled with a He cryostat, and a time-of-flight mass spectrometer. With great care given to the cooling condition, we can achieve ∼10 K for the vibrational temperature of ions in the QIT, which is estimated from UVPD spectra of the benzo-18-crown-6 (B18C6) complex with a potassium ion, K(+)·B18C6. Using this setup, we measure a UVPD spectrum of cold calix[4]arene (C4A) complex with potassium ion, K(+)·C4A. The spectrum shows a very weak band and a strong one at 36018 and 36156 cm(-1), respectively, accompanied by many sharp vibronic bands in the 36000-36600 cm(-1) region. In the geometry optimization of the K(+)·C4A complex, we obtain three stable isomers: one endo and two exo forms. On the basis of the total energy and UV spectral patterns predicted by density functional theory calculations, we attribute the structure of the K(+)·C4A complex to the endo isomer (C2 symmetry), in which the K(+) ion is located inside the cup of C4A. The vibronic bands of K(+)·C4A at 36 018 and 36 156 cm(-1) are assigned to the S1(A)-S0(A) and S2(B)-S0(A) transitions of the endo isomer, respectively.

Determination of Unsaturation Level, Halogen Content, and Main Forms of Isoprene Units in Halogenated Butyl Rubbers by 1H NMR Spectroscopy

We have used 1 H NMR spectroscopy to study commercial samples of chloro-substituted and bromo-substituted butyl rubbers. We propose calculation formulas for quantitative determination of the main forms in halobutyl rubber (1,4-isoprene, exo form) and its characteristics: unsaturation level, halogen content in the isoprene units. We show that it is possible to determine the main structural characteristics of bromobutyl rubber in the presence of filler.

Isolation and characterization of conformational isomers ofN,N′-bis(3,5-dichlorosalicylidene)-2,2′-ethylenedianiline: crystal structure, photoluminescence, and density functional theory calculation

We have isolated two isomeric solids 1 and 2 of N,N′-bis(3,5-dichlorosalicylidene)-2,2′-ethylenedianiline and characterized by IR, UV/Vis, X-ray powder diffraction, thermogravimetric analysis/differential thermal analysis, and X-ray crystallography. Although the solids are same formulas, each shows different colors and crystal structures. Orange solid (1) shows endo conformation while yellow solid (2) exhibits exo form depending on packing modes. UV/Vis spectra of 1 and 2 appear very similar patterns in the solid state; however, the bands of 1 are slightly red-shifted compared with those of 2. 1 displays a strong fluorescent emission band at ~582 nm while 2 shows an intense fluorescent signal at ~563 nm. The charge density populations of 1 and 2 have been studied by computational simulations using density functional theory at pbe1pbe/6-311G** level. The calculated highest occupied molecular orbital and lowest unoccupied molecular orbital energies of 1 and 2 confirm that charge transfer occurs within the organic molecules. The energy difference of HOMO-LUMO in 1 is smaller slightly than that of 2 about 0.05 eV (~17 nm). Copyright © 2014 John Wiley & Sons, Ltd.

Synthesis, Crystal Structures, and Skeletal Inversion of Dithienodiphosphorines

ABSTRACTtrans‐ and cis_endo‐Diphenyl[c]dithienodiphosphorines 1a and 1b were successfully synthesized as phosphorus atoms are trivalent. Two stereoisomers, trans form 1a and cis_endo form 1b, were isolated by preparative gel permeation chromatography (GPC) and their butterfly structures were shown by X‐ray crystallographic analyses of the single crystals from hexane/CHCl3 and CH3CN/CHCl3, respectively. The VT‐31P{1H} NMR spectra in CD2Cl2 showed that the signal due to cis_endo form 1b appeared at δP −45.0 with 9.5 Hz of half‐width at −90°C, which is almost same as that at room temperature, while broadening of the signal due to trans form 1a was observed and finally the signal appeared at δP −33.7 with 55.5 Hz of half‐width at −90°C. The results indicated that the skeletal inversion of a tricyclic system in solution is a fast process on the NMR timescale. On the other hand, X‐ray crystallographic analysis showed that trans‐dimesityl[c]dithienodiphosphorine 2a has a planar structure, which is considered as the corresponding transition state of the skeletal inversion of trans form 1a. The 31P signal due to 2a in CD2Cl2 did not change at all even at −90°C, which was in a different manner from 1a at the same temperature, showing that its planar structure is also kept in solution because of the release of the steric repulsion between bulky mesityl groups and fused thiophene rings in the butterfly structure. The density functional theory calculations suggested the low‐energy barriers of the skeletal inversion of trans–trans and cis_endo–cis_exo forms, which were estimated to be 3.79 and 3.31 kcal/mol by searching for transition state using the synchronous transit‐guided quasi‐Newton (STQN) methods.

Determination of the relative configuration of tropinone and granatanone aldols by using TBDMS ethers

The relative configurations of tert-butyldimethylsilyl (TBDMS) ethers of all four diastereomers of the aldols of tropinone (8-methyl-8-azabicyclo[3.2.1]octan-3-one), as well as of granatanone (9-methyl-9-azabicyclo[3.3.1]nonan-3-one), were determined from NMR data, and from the observed interconversion of the diastereomers (exo,anti to endo,syn and exo,syn to endo,anti). The exo forms invert to endo isomers in the presence of silica gel. The relative configuration of a new isomer of tropinone aldol accessible synthetically through the direct solventless reaction of tropinone and benzaldehyde in the presence of water was determined as exo,syn by comparison of NMR data of the aldol isomers, in particular vicinal coupling constants and shifts corresponding to the side-chain CH group, with data of related TBDMS derivatives and confirmed by single-crystal X-ray diffraction.

Formation of exo–exo, exo–endo and tweezer conformation induced by axial ligand in a Zn(II) bisporphyrin: Synthesis, structure and properties

A detailed structural and spectroscopic investigation of axial ligand coordination on Zinc(II)pyrrole-bridged bisporphyrin (Zn2DEP), have been reported here. Our findings demonstrate that the DEP ligand system provides a Pacman pocket with very high vertical and horizontal flexibility that leads to the formation of exo–endo, exo–exo and tweezer complexes of ZnII(bisporphyrinato) depending upon the size and type of axial ligands used and all the complexes are isolated in solid and structurally characterized. While addition of excess 1-Me imidazole to Zn2DEP produces complex in which the axial ligand binds in the exo–endo fashion, addition of 3-Cl pyridine binds in exo–exo fashion. Here, six-membered aromatic ring occupy more space than that of five-membered ring and thus 3-Cl pyridine binds in an exo–exo fashion rather than exo–endo fashion which require even larger vertical flexibility of two porphyrin rings. However, addition of 1,2-diaminobenzene and pyrazine to Zn2DEP produce only tweezer complexes. The Zn···Zn non-bonding distances are 7.69 and 7.08Å in the exo–endo and exo–exo form, respectively. In the tweezer complexes, however, the values of said distances are 5.61 and 7.11Å with ODAB and pyrazine ligand, respectively. The Zn–Np distances are relatively shorter while Zn–Nax(L) distances are longer in tweezer complexes compared to exo–endo/exo–exo forms. Also, the displacements of Zn from the mean porphyrin planes are much less in tweezers. 1H NMR of the complexes in solution show large upfield shift of the axial ligand protons while protons of porphyrin subunits are shifted downfield.

ChemInform Abstract: Conformational Analysis. Part 17. An NMR and Theoretical Investigation of the Conformation of Bicyclo(5.2.1)decane-2,6-dione

The conformation of bicyclo[5.2.1]decane-2,6-dione in solution has been investigated by molecular modelling and the lanthanide-induced shift (LlS) technique. Of the five possible conformers two were eliminated due to their large calculated steric energy and a third ‘twist’ conformer due to the observed symmetry in the 13C NMR and the 1H NMR spectra. The remaining exo and endo conformers were calculated as having an energy difference of 1.5 kcal mol–1. However, MNDO calculated the endo form as the more stable in contrast to MM2 and COSMIC which gave the reverse order. The LIS investigation was in agreement with a lanthanide monodentate complex bound to the exo form only confirming the MM2 and COSMIC calculations.

ChemInform Abstract: Synthesis of a Novel Pyrazolo[1,5-c]pyrimidine C-Nucleoside and Conformational Analysis by NMR Spectroscopy.

Abstract Isopropylidenation of [4-methoxycarbonyl-5-(β-D-ribofuranosyl)-1H-pyrazol-3-yl]acetamide (1a) followed by the acidic cleavage of the sugar acetonide afforded 3-methoxycarbonyl-7, 7-dimethyl-2-(β-D-ribofuranosyl)-4H, 7H-pyrazolo[1,5-c] pyrimidine-5(6H)-one (2b), the structure of which was established unequivocally by X-ray structure analysis of the monocrystals. Compounds 1a and 2b have 75% and 70% preference for the N-type puckering between C3′-endo and C3′-endo-C4′-exo forms, and a great preference of 69% and 74% for γ+ rotamers in solution, respectively.

De(side chain) model of epothilone: bioconformer interconversions DFT study

Using ab initio methods, we have studied conformations of the de(sidechain)de(dioxy)difluoroepothilone model to quantify the effect of stability change between the exo and endo conformers of the epoxy ring. The DFT minimization of the macrolactone ring reveals four low energy conformers, although MP2 predicted five stable structures. The model tested with DFT hybride functional (B3LYP/6-31+G(d,p)) exhibits the global minimum for one of the exo forms (C), experimentally observed in the solid state, but unexpectedly with the MP2 electron correlation method for the virtual endo form (W). Using the QST3 technique, several pathways were found for the conversion of the low energy conformers to the other low energy exo representatives, as well as within the endo analog subset. The potential energy relationships obtained for several exo forms suggest a high conformational mobility between three, experimentally observed, conformers. The high rotational barrier, however, excludes direct equilibrium with experimental EC-derived endo form S. The highest calculated transition state for the conversion of the most stable exo M interligand to the endo S form is approximately a 28 kcal/mol above the energy of the former. The two-step interconversion of the exo H conformer to the endo S requires at least 28 kcal/mol. Surprisingly, we found that the transition state energy of the H form to the virtual endo W has the acceptable value of about 9 kcal/mol and the next energy barrier for free interconversion of endo W to endo S is 13 kcal/mol.

Unusual radical 6-endo cyclization to carbocyclic-ENA and elucidation of its solution conformation by 600 MHz NMR and ab initio calculations

In our previous paper (J. Am. Chem. Soc., 2007, 129, 8362), we reported the synthesis of 7-Me-Carba-LNA and 8-Me-Carba-ENA thymidine through 5-hexenyl or 6-heptenyl radical cyclization. Both 5-hexenyl and 6-heptenyl radical cyclized exclusively in the exo form, giving unwanted exocyclic C7-methyl group. In the present study, we showed that the regioselectivity of the 5-hexenyl radical cyclization could be favorably tuned by introduction of a hydroxyl group to the olefinic double bond, yielding about 9% of the 6-endo cyclization product. Possible pathways to give 6-endo cyclization product 9 compared to the intermediates responsible to give the 5-exo cyclization product 5 has been discussed. Based on this unique 6-endo cyclization strategy, a carbocyclic ENA modified thymidine (carba-ENA) has been successfully synthesized, which also enabled us to perform its full solution conformation analysis by using NMR (1H at 600 MHz) observables for the first time.

Bifunctional binding of cisplatin to DNA: why does cisplatin form 1,2-intrastrand cross-links with ag but not with GA?

The bifunctional binding of the anticancer drug cisplatin to two adjacent nucleobases in DNA is modeled using density functional theory. Previous experimental studies revealed that cisplatin binding to adjacent guanine and adenine is sensitive to nucleobase sequence. Whereas AG 1,2-intrastrand cross-links are commonly observed, the analogous GA adducts are not known. This study focuses on understanding this directional preference by constructing a full reaction profile using quantum chemical simulation methods. Monofunctional and bifunctional cisplatin adducts were generated, and the transition states that connect them were located for the dinucleotides d(pApG) and d(pGpA), assuming that initial platination takes place at the guanine site. Our computer simulations reveal a significant kinetic preference for formation of the AG over the GA adduct. The activation free energies of approximately 23 kcal/mol for AG and approximately 32 kcal/mol for GA suggest that bifunctional closure is approximately 6 orders of magnitude faster for AG than for GA. A strong hydrogen bond between one of the ammine ligands of cisplatin and the 5' phosphate group of the DNA backbone is responsible for the stabilization of the transition state that affords the AG adduct. This interaction is absent in the transition state that leads to the GA adduct because the right-handed helix of the DNA backbone places the phosphate out of reach for the ammine ligand. We found only an insignificant thermodynamic difference between AG and GA adducts and conclude that the preference of AG over GA binding is largely under kinetic control. The puckering of the deoxyribose ring plays an important role in determining the energetics of the bifunctional platination products. Whereas the 3'-nucleoside remains in the native C2'-endo/C3'-exo form of B-DNA, the deoxyribose of the 5'-nucleoside always adopts the C2'-exo/C3'-endo puckering in our simulations. A detailed analysis of the energies and structures of the bifunctional adducts revealed that the observed sugar puckering patterns are necessary for platinum to bind in a relaxed coordination geometry.

Syntheses and crystal structures of group 6 metal complexes containing allyl and cyanotrihydroborate groups

Compounds M(η 3-C 3H 5)(CO) 2(NCCH 3) 2(NCBH 3) and [N(CH 3) 4] 2[M(η 3-C 3H 5)(CO) 2(NCBH 3) 3] (M = Mo, W) were prepared and structurally characterized. In the solid state, the allyl group orients its open face to the two carbonyl groups producing an endo form in the above compounds. In solution, an exo form coexists with an endo form in compound Mo(η 3-C 3H 5)(CO) 2(NCCH 3) 2(NCBH 3). The cyanotrihydroborate ligand bonds to the metal through a nitrogen atom. Both of the IR and the 11B NMR spectroscopic data suggest the negative charge of the cyanotrihydroborate ligand on the complex is almost localized on the BH 3 and this negative charge only has small effect on the metal–nitrogen interaction.

Dual enantioselective Diels–Alder process in the cyclization of chiral acrylamide with dienes

AbstractDiels–Alder cycloadditions of chiral acrylamides with cyclopentadiene or 2, 3‐dimethyl butadiene proceed with high diastereofacial selectivity. Either endo‐R or endo‐S products have been obtained depending upon the structures of acrylamides and Lewis acids used. The endo form was exclusively obtained over the exo form. The dependence of the mechanism of formation of opposite configurations of endo‐R or endo‐S products on the Lewis acids is discussed. Copyright © 2004 John Wiley & Sons, Ltd.

Reaction of [M(η3-allyl)(η2-amidinato)(CO)2(pyridine)] complexes (M = Mo, W) with bidentate ligands: nitrogen donor vs. phosphorus donor

The reactivity of amidinato complexes of molybdenum and tungsten bearing pyridine as a labile ligand, [M(eta(3)-allyl)(eta(2)-amidinato)(CO)(2)(pyridine)](M = Mo; 1-Mo, M = W; 1-W), toward bidentate ligands such as 1,10-phenanthroline (phen) and 1,2-bis(diphenylphosphino)ethane (dppe) was investigated. The reaction of 1 with phen at ambient temperature resulted in the formation of monodentate amidinato complexes, [M(eta(3)-allyl)(eta(1)-amidinato)(CO)(2)(eta(2)-phen)](M = Mo; 2-Mo, M = W; 2-W), which has pseudo-octahedral geometry with the amidinato ligand coordinated to the metal in an eta(1)-fashion. The phen ligand was located coplanar with two CO ligands and the eta(1)-amidinato ligand was positioned trans to the eta(3)-allyl ligand. In solution, both complexes 2-Mo and 2-W showed fluxionality, and complex 2-Mo afforded allylamidine (3) on heating in solution. In the reaction of 1 with dppe at ambient temperature, the simple substitution reaction took place to give dppe-bridged binuclear complexes [{M(eta(3)-allyl)(eta(2)-amidinato)(CO)(2)}(2)(mu-dppe)](M = Mo; 5-Mo, M = W; 5-W), whereas mononuclear monocarbonyl complexes [M(eta(3)-allyl)(eta(2)-amidinato)(CO)(eta(2)-dppe)](M = Mo; 6-Mo, M = W; 6-W) were obtained under acetonitrile- or toluene-refluxing conditions. Mononuclear complex 6 was also obtained by the reaction of binuclear complex 5 with 0.5 equivalents of dppe under refluxing in acetonitrile or in toluene. The X-ray analyses and variable-temperature (31)P NMR spectroscopy of complex 6 indicated the existence of the rotational isomers of the eta(3)-allyl ligand, i.e., endo and exo forms, with respect to the carbonyl ligand. The different reactivity of complex 1 toward phen and dppe seems to have come from the difference in the pi-acceptability of each bidentate ligand.

Ramachandran backbone potential energy surfaces of aspartic acid and aspartate residues: implications on allosteric sites in receptor–ligand complexations

Ramachandran backbone potential energy surfaces (PES) were generated for N-acetyl- l-aspartic acid- N′-methylamide and N-acetyl- l-aspartate- N′-methylamide. Relatively few minima were observed from the Ramachandran PES of the aspartate ion while many existed for both endo and exo forms of the aspartic acid residue. By comparing the relative stabilization energies as well as the vertical and adiabetic proton affinities of the two forms the aspartic acid residue, it was previously determined that aspartic acid may rather change its backbone conformation before deprotonation into the aspartate ion. Taken together, many stable conformers may exist for both endo and exo forms of aspartic acid but when deprotonated they lead to the same aspartate ion which has remarkably few conformations. This feature may have significant biological implications, and a receptor–ligand complexation model is proposed where aspartate and aspartic acid could represent, respectively, resting and active states of a putative binding site in a hypothetical protein. More importantly, however, the aspartyl residues may represent important allosteric sites for regulatory ions, directly modulating the specificity of ligand docking in a receptor protein and affecting downstream biological mechanisms.

Mono- and binuclear bipyridyl derivatives of the Mo(η 3-C 3H 5)(CO) 2 fragment: structural studies and fluxionality in solution

New mono- and binuclear complexes of the Mo(η 3-C 3H 5)(CO) 2 fragment, containing bipyridyl ligands (2,2′-bpy, 4,4′-Me 2-2,2′-bpy) as chelates, and mono- (4-CNpy, 4-Mepy, NCMe, Br) or bidentate nitrogen ligands (4,4′-bpy, bipyridylethylene, pyrazine) as terminal or bridging ligands, respectively, were prepared. The binuclear complex [{Mo(η 3-C 3H 5)(CO) 2(2,2′-bpy)} 2(μ-4,4′-bpy)][PF 6] 2 ( 2) was shown by X-ray diffraction to assemble in the crystal forming large channels with a rectangular section. A longer bridge, such as bipyridylethylene, led to a different structure ( 3). 4-CNpy behaved as monodentate ligand ( 4), coordinating through the pyridine nitrogen as a terminal ligand. NMR spectroscopy studies showed that the complexes exhibited a fluxional behavior in solution, the endo and exo forms of the more symmetrical equatorial isomers being usually present and interconverting in solution. The solid state structures of the complexes revealed a preference for the more symmetrical equatorial isomer, with the two chelate ligands in trans positions in the binuclear species. The rings tended to become parallel in the organized crystal.