Ring Interconversion Research Articles

Skeletal Editing: Interconversion of Arenes and Heteroarenes

AbstractSkeletal editing involves making specific point‐changes to the core of a molecule through the selective insertion, deletion or exchange of atoms. It thus represents a potentially powerful strategy for the step‐economic modification of complex substrates and is a perfect complement to methods such as C−H functionalization that target the molecular periphery. Given their ubiquity in biologically active compounds, the ability to perform skeletal editing on – and therefore interconvert between – aromatic heterocycles is especially valuable. This review summarizes both recent and key historical examples of skeletal editing as applied to interconversion of aromatic rings; we anticipate that it will serve to highlight not only the innovative and enabling nature of current skeletal editing methods, but also the tremendous opportunities that still exist in the field.

Synthesis of penta- and hexa(3,4-thienylene): size-dependent structural properties of cyclic oligothiophenes.

Penta- and hexa(3,4-thienylene)s were synthesized as a potential precursor for thiophene-containing polyarenes, and the structures were determined via X-ray crystallography. The interconversion of thiophene rings is fast in penta(3,4-thienylene), and slow in hexa(3,4-thienylene) reflecting the activation energy for enantiomerization. Size-dependent bathochromic shifts were observed in UV-vis absorption spectra.

Molecular Mechanism Exploration of Potent Fluorinated PI3K Inhibitors with a Triazine Scaffold: Unveiling the Unusual Synergistic Effect of Pyridine-to-Pyrimidine Ring Interconversion and CF3 Defluorination.

The phosphatidylinostitol-3-kinase (PI3K)/AKT/mammalian target of rapamycin signaling pathway is a vital regulator of cell proliferation, growth, and survival, which is frequently overactivated in many human cancers. To this effect, PI3K, which is an important mediator of this pathway, has been pinpointed as a crucial target in cancer therapy and hence the importance of PI3K inhibitors. It was recently reported that defluorination and pyridine-to-pyrimidine ring interconversion increase the potency of specific small-molecule inhibitors of PI3K. Compound 4, an inhibitor with the difluorinated pyrimidine motif, was found to be eight times more potent against PI3K than compound 1, an inhibitor with the trifluorinated pyridine motif. This observation presents the need to rationally resolve the differential inhibitory mechanisms exhibited by both compounds. In this present work, we employed multiple computational approaches to investigate and distinguish the binding modes of 1 and 4 in addition to the effects they mediate on the secondary structure of PI3K. Likewise, we evaluated two other derivatives, compounds 2 with the difluorinated pyridine motif and 3 with the trifluorinated pyrimidine motif, to investigate the cooperativity effect between the defluorination of CF3 and pyridine-to-pyrimidine ring interconversion. Findings revealed that PI3K, upon interaction with 4, exhibited a series of structural changes that favored the binding of the inhibitor at the active-site region. Furthermore, a positive (synergistic) cooperativity effect was observed between CF3 defluorination and pyridine-to-pyrimidine ring interconversion. Moreover, there was a good correlation between the binding free energy estimated and the biological activity reported experimentally. Energy decomposition analysis revealed that the major contributing force to binding affinity variations between 1 and 4 is the electrostatic energy. Per-residue energy-based hierarchical clustering analysis further identified four hot-spot residues ASP841, TYR867, ASP964, and LYS833 and four warm-spot residues ASP836, SER806, ASP837, and LYS808, which essentially mediate the optimal and higher-affinity binding of compound 4 to PI3K relative to 1. This study therefore provides rational insights into the mechanisms by which 4 exhibited superior PI3K-inhibitory activities over 1, which is vital for future structure-based drug discovery efforts in PI3K targeting.

Dynamics in the plastic crystalline phase of cyanocyclohexane and isocyanocyclohexane probed by 1H field cycling NMR relaxometry.

Proton Field-Cycling (FC) nuclear magnetic resonance (NMR) relaxometry is applied over a wide frequency and temperature range to get insight into the dynamic processes occurring in the plastically crystalline phase of the two isomers cyanocyclohexane (CNCH) and isocyanocyclohexane. The spin-lattice relaxation rate, R1(ω), is measured in the 0.01-30MHz frequency range and transformed into the susceptibility representation χNMR ″ω=ωR1ω. Three relaxation processes are identified, namely, a main (α-) relaxation, a fast secondary (β-) relaxation, and a slow relaxation; they are very similar for the two isomers. Exploiting frequency-temperature superposition, master curves of χNMR ″ωτ are constructed and analyzed for different processes. The α-relaxation displays a pronounced non-Lorentzian susceptibility with a temperature independent width parameter, and the correlation times display a non-Arrhenius temperature dependence-features indicating cooperative dynamics of the overall reorientation of the molecules. The β-relaxation shows high similarity with secondary relaxations in structural glasses. The extracted correlation times well agree with those reported by other techniques. A direct comparison of FC NMR and dielectric master curves for CNCH yields pronounced difference regarding the non-Lorentzian spectral shape as well as the relative relaxation strength of α- and β-relaxation. The correlation times of the slow relaxation follow an Arrhenius temperature dependence with a comparatively high activation energy. As the α-process involves liquid-like isotropic molecular reorientation, the slow process has to be attributed to vacancy diffusion, which modulates intermolecular dipole-dipole interactions, possibly accompanied by chair-chair interconversion of the cyclohexane ring. However, the low frequency relaxation features characteristic of vacancy diffusion cannot be detected due to experimental limitations.

Conformational Mobility Study in Mono Quinone Derivative of Calix[4]arene by Low Temperature NMR Spectroscopy

: Calix[4]monoquinone (3) has been synthesized by oxidation of rigid cone conformation of tripropoxy calix[4]arene (2), and conformational characteristics of this molecule have been studied by means of dynamic nuclear magnetic resonance (DNMR) and HH- correlated nuclear magnetic resonance spectroscopy (HH-COSY NMR). On the basis of the data that have been obtained, free Gibbs energy of activation (ΔG#) for quinone ring interconversion process of 3 was determined 12.3±0.05 Kcal/mol by coalescence approximation method.

Conformational Analysis of (1,1′-Phenyl-1,1′-silacyclohex-1-yl)disiloxane. DFT and Low-Temperature 13C NMR Spectroscopy Study

The DFT and MP2 theoretical conformational analysis of the recently synthesized (1,1′-phenyl-1,1′-silacyclohex-1-yl)disiloxane has revealed the energetic preference of the Phax,Phax conformer. The Phax,Phax: Phax,Pheq: Pheq,Pheq conformers ratio has been estimated as of 46.6: 33.1: 20.3 from the M062X/6-311G(d,p) free energy simulation, suggesting the possibility of detecting individual conformers experimentally, e.g., by low-temperature 1H and 13C NMR spectroscopy. However, only the presence of several conformers has been detected by means of 1H NMR spectroscopy at 113 K; determination of the Δν (Hz) and ΔG# (kcal/mol) parameters for the 6-membered ring interconversion has been impossible due to the signals broadening at low temperature, signal temperature shifts, and extremely low barrier of ring inversion at Tc < 113 K.

NMR spectroscopic conformational analysis of 4-methylene-cyclohexyl pivalate-The effect of sp2 hybridization.

The conformational equilibrium of the axial/equatorial conformers of 4-methylene-cyclohexyl pivalate is studied by dynamic NMR spectroscopy in a methylene chloride/freon mixture. At 153K, the ring interconversion gets slow on the nuclear magnetic resonance timescale, the conformational equilibrium (-ΔG°) can be examined, and the barrier to ring interconversion (ΔG# ) can be determined. The structural influence of sp2 hybridization on both ΔG° and ΔG# of the cyclohexyl moiety can be quantified.

Structure and conformational analysis of 2-hydroxy-5-isobutyl-1,3,2-dioxaborinane

The structure of 2-hydroxy-5-isobutyl-1,3,2-dioxaborinane, one of the major autooxidation products of 5-isobutyl-2-isopropyl-1,3,2-dioxaborinane, has been studied by 1H, 13C, and 11B NMR spectroscopy together with X-ray analysis. Molecules of the title compounds adopt a sofa conformation with equatorial isobutyl substituent. The ring interconversion path, free conformational energy, and optimal conformation of the isobutyl group (corresponding to the X-ray diffraction data) were determined by DFT quantum chemical calculations at the PBE/3ξ level of theory.

Synthesis, spectroscopic, structural and conformational study of some tri-substituted ureas derived from N-methylpiperazine containing phenyl and N-heterocyclic substituents

A series of tri-substituted ureas containing an N-methylpiperazine moiety as well as phenyl and N-heterocyclic substituents were synthesized and studied by 1H, 13C NMR and IR spectroscopies. From 1H and 13C NMR data, in CDCl3 solution at room temperature, a fast inter-conversion of the piperazine ring with the N-CH3 group in equatorial position can be proposed. Amino–imino tautomerism is observed for both thiazole and benzothiazole derivatives. Moreover, with the exception of the imino form of the thiazole derivative, the aryl substituted N-carbamoyl group rotates freely. IR data show that the compounds adopt a planar trans conformation of the CONH moiety.

The employment of a hydrophilic tris(morpholino)phosphine ligand in diiron propane-1,3-dithiolate complexes for potentially water-soluble iron-only hydrogenase active-site mimics

A tris(morpholino)phosphine (TMP) ligand was introduced into the diiron dithiolate complexes in order to improve the hydro- and protophilicity of the iron-only hydrogenase active site models. Mono- and di-TMP substituted diiron complexes, (μ-pdt)[Fe(CO)3][Fe(CO)2(TMP)] (2, pdt = 1,3-propanedithiolato) and (μ-pdt) [Fe(CO)2(TMP)]2 (3), were synthesized and spectroscopically characterized. The coordination configuration of 3 was determined by single X-ray analysis. Temperature-dependent 1H and 31P NMR spectroscopy studies provided insight into the interconversion of the irondithiacyclohexane ring and the rotation of the [Fe(CO)2PR3] moieties for 2 and 3 in solution. The electrochemical properties of 2 and 3 were investigated in pure CH3CN and CH3CN–H2O mixtures in the absence and presence of acetic acid. Hydrogen production and the dependence of current on acid concentration indicated that complexes 2 and 3 exhibited electrocatalytic activities for proton reduction in both pure and H2O-containing CH3CN solutions. The current sensitivities, i.e., electrocatalytic activities, were demonstrated to be greater in CH3CN–H2O mixtures than in pure CH3CN. The most effective electrocatalytic activities of 2 and 3 were observed with 10% added water.

Conformational analysis of 2-methyl-1,3,2-oxaza- and 2-methyl-1,3,2-oxathiaborinane associates with water molecule

The structure and conformational behavior of 1: 1 molecular assotsiates of 2-methyl-1,3,2-oxazaand 2-methyl-1,3,2-oxathiaborinanes with water were studied ab initio in terms of HF/6-31G(d) and PBE/3z quantum-chemical approximations. The most stable complexes are formed via hydrogen bonding with the heteroatoms (oxygen and nitrogen or sulfur). Their conformational behavior implies equilibrium between sofa and half-chair conformers, and intermolecular hydrogen bond is retained in the course of ring interconversion. No associate with a dative O→B bond is formed.

New dithiazinanes and bis‐dithiazinanes‐bearing pendant ethylamines: Structure and reactivity

AbstractThe structure and reactivity of a series of new ethylaminedithiazinanes and bis‐diethylaminedithiazinanes synthesized from formaldehyde, NaSH, and N,N‐dimethyl‐ethylene‐diamine (1), N‐methyl‐ethylene‐diamine (2), and N‐ethyl‐ethylene‐diamine (3) are reported. Compound 1 afforded 2‐([1,3,5]‐dithiazinan‐5‐yl)‐ethylene‐N,N‐dimethyl‐amine (4). The reaction of 4 with dry CH2Cl2 gave N‐{2‐([1,3,5]dithiazinan‐5‐yl)‐ethylene}‐N‐chloromethyl‐N,N‐dimethyl‐ammonium chloride (5) in high yield, whereas in wet CH2Cl2 and DMSO provided a mixture of 5 with N‐{2‐([1,3,5]‐dithiazinan‐5‐yl)‐ethylene}‐N,N‐dimethyl‐ammonium hydrochloride (6).bis‐{2‐([1,3,5]‐Dithiazinan‐5‐yl)‐ethylene‐N‐alkyl‐amino}‐methylene‐disulfides (7) and (8) formed by two dithiazinanes linked through the chain (CH2)2NRCH2SSCH2NR(CH2)2‐ (7 R = methyl, 8 R = ethyl) reacted with CH2Cl2 giving after neutralization of the hydrolysis products the ethylaminedithiazinanes with different pendant N‐groups [(CH2)2NMeH2+(9); (CH2)2NEtH2+ (10); (CH2)2NMeH (11); (CH2)2NEtH (12); (CH2)2NMeHBH3 (13) (CH2)2NEtHBH3 (14). (CH2)2NMe2BH3 (15), and (CH2)2NEtMeBH3.(16)]. The x‐ray diffraction analyses of compounds 5, 6, 9, and 10 are reported. Variable temperature NMR experiments afforded the Δ G≠ of the ring interconversion of the six‐membered heterocycles 6, 9, and 10. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 22:59–71, 2011; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20657

ChemInform Abstract: Homo- and Heteroatomic Chalcogen Rings

Abstract This review describes recent progress in the chemistry of homo- and heterocyclic chalcogen species summarizing their preparation, structural characterization, bonding, and spectroscopic properties. Although it is possible to prepare stoichiometrically pure chalcogen rings, many reactions result in the formation of complicated mixtures. The crystal and molecular structures of many homocyclic rings are known. All heterocyclic rings, however, are disordered and therefore it has not been possible to determine accurate bond parameters for them. The identification of individual molecular species and the composition of mixtures of chalcogen ring molecules have been studied successfully with HPLC and Raman spectroscopy, as well as with 77 Se and 125 Te NMR spectroscopy. With development of computing techniques, it has been possible to perform MO calculations with increasing sophistication. They have yielded reliable predictions on ground state geometries and electronic structures of different chalcogen rings. The emphasis of research in recent years has shifted from purely structural studies towards understanding the facile interconversion reactions that take place between the different chalcogen rings. The experimental and theoretical evidence on the mechanism of these ring interconversion pathways are discussed.

Several transition states from 4C1 to skew conformations of β- d-glucopyranose

The interconversion pathways in the ring distortion of β- d-glucopyranose were investigated using density functional calculations. We examined the energies of several conformers of β- d-glucopyranose and tried to obtain the transition-state conformation and determine the pathway between a 4 C 1 chair and some distorted ring conformers. The results showed that two E 3/ 2 H 3 conformations and one E 3/ 4 H 3 conformation were transition states in such ring puckering. The transition state with the lowest energy conformation is the E 3/ 2 H 3 ring conformation with the side-chain conformation of r- ggG +. Intrinsic reaction coordinate calculations indicated that the E 3/ 2 H 3 conformation with the lowest conformational energy is a transition state of the ring interconversion path between the conformations of 4 C 1 and 2 S O/ B 3,O. The energy barrier of this interconversion was 6.13 kcal/mol. As far as we know, this is the first example of finding pathways for an interconversion of glucopyranose ring puckering at the level of a quantum chemical calculation.

Pyrimidine ortho-quinodimethanes. Part 2: Synthesis of new [60]fullerene adducts based on substituted pyrimidine derivatives and their 1H NMR dynamic study

The Diels–Alder reaction of various pyrimidine ortho-quinodimethanes generated in situ with C 60 gives access to a variety of new fullerodihydroquinazoline derivatives. This variety is increased since substituents on the pyrimidine ring can be easily modified before or after its reaction with C 60. Variable temperature 1H NMR spectra provided thermodynamic parameters related to the boat-to-boat interconversion of the cyclohexene ring fused to the fullerene moiety. The mass spectra of the prepared cycloadducts show that the retro-Diels–Alder process takes place easily with elimination of the corresponding diene molecule.

Identification and Structural Characterization of an Unusual RING-Like Sequence within an Extracellular Biomineralization Protein, AP7

The RING or Really Interesting New Gene represents a family of eukaryotic sequences that bind Zn (II) ions and participate in intracellular processes involving protein-protein interaction. Although found in over 400 different proteins, very little is known regarding the structure-function properties of these domains because of the aggregation problems associated with RING sequences. To augment this data set, we report an unusual 36 AA C-terminal sequence of an extracellular matrix mollusk shell protein, AP7, that exhibits partial homology to the RING family. This Cys, His-containing sequence, termed AP7C, binds Zn (II) and other multivalent ions, but does not utilize a tetracoordinate complexation scheme for binding such as that found in Zn (II) finger polypeptides. Moreover, unlike Zn (II) finger and RING domains, this 36 AA can fold into a relatively stable structure in the absence of Zn (II). This folded structure consists of three short helical segments (A, B, and C), with segments A and B separated by a 4 AA type I beta-turn region and segments B and C separated by a 7 AA loop-like region. Interestingly, the putative RING-like region, -RRPFHECALCYSI-, experiences slow conformational exchange between two structural states in solution, most likely in response to imido ring interconversion at P8 and P21. Poisson-Boltzmann solvation calculations reveal that the AP7C molecular surface possesses a cationic region near its N-terminus, which lies adjacent to the 30 AA mineral modification domain in the AP7 protein. Given that the AP7C sequence does not influence mineralization, it is probable that this cationic pseudo-RING region is utilized by the AP7 protein for other tasks such as protein-protein interaction within the mollusk shell matrix.

Synthesis of Ethyl 8‐Aryl‐8‐hydroxy‐3‐oxo‐8H[1,2,4]oxadiazolo‐[3,4‐c] [1,4]thiazine‐5‐carboxylates by Ring‐Expansion Rearrangement.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Aza‐Wittig Reaction, Carbodiimide‐Mediated Ring Closure, and Enol‐Induced Ring Interconversion: A Domino Process for the Synthesis of 4‐Methylene‐4H‐3,1‐benzoxazines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Phosphane and Phosphite Unsymmetrically Disubstituted Diiron Complexes Related to the Fe‐Only Hydrogenase Active Site

AbstractA series of unsymmetrically disubstituted diiron complexes [(μ‐pdt){Fe(CO)2L1}{Fe(CO)2L2}] [pdt = 1,3‐propanedithiolato; L1 = PMe3, L2 = PMe2Ph, 4; PPh3, 5; PCy3, 6; P(OEt)3, 7; L1 = PMe2Ph, L2 = PPh3, 8; P(OEt)3, 9; L1 = P(OEt)3, L2 = PPh3, 10; PCy3, 11] and [(μ‐edt){Fe(CO)2PMe3}{Fe(CO)2PPh3}] (edt = 1,2‐ethanedithiolato, 12) were prepared by means of stepwise CO displacements of [(μ‐pdt)Fe2(CO)6] and [(μ‐edt)Fe2(CO)6] by different tertiary phosphane and phosphite ligands. The interconversion of the irondithiacyclohexane ring and the rotation of the [Fe(CO)2PR3] subunit were studied using by variable‐temperature 31P{1H} NMR spectroscopy of 4, 6 and 12 in solution. The molecular structures of 4–6, 8–10 and 12 show that complexes 4–6, 8, 9 and 12 possess an apical/basal coordination mode and complex 10 has an apical/apical conformation. The X‐ray analyses indicate that the PMe2Ph ligand in the apical position of the starting complex [(μ‐pdt){Fe(CO)3}{FeCO2(PMe2Ph)}] rotates to the basal position on conversion to the products 8 and 9. Cyclic voltammograms of 4–11 were studied both under argon and CO. The influences of the phosphane and phosphite ligands on the redox properties of the unsymmetrically disubstituted diiron complexes are discussed. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2007)

Aza-Wittig Reaction, Carbodiimide-Mediated Ring Closure, and Enol-­Induced Ring Interconversion: A Domino Process for the Synthesis of 4-Methylene-4H-3,1-Benzoxazines

4-Methylene-4 H-3,1-benzoxazines have been prepared in excellent yields from the reaction of iminophosphorane derived of N-(2-acetylphenyl)-2-azidobenzamide with triphenylphosphine with isocyanates. This transformation involves an initial aza-Wittig reaction to give a carbodiimide, which undergoes ring closure across the enol form of the carboxamide group and eventually an unprecedent imino-benzoxazine-methylene-benzoxazine rearrangement. A slight variation allows the preparation of one analogue of the marine alkaloid rhopaladin D.