A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N- or O-arylation step leading to indolines, dihydrobenzofurans, and six-membered analogues. The general applicability and functional group tolerance of this method were exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran.
View Article and Find Full Text PDFActa Crystallogr B Struct Sci Cryst Eng Mater
February 2016
Analysis of neutron and high-resolution X-ray diffraction data on form (III) of carbamazepine at 100 K using the atoms in molecules (AIM) topological approach afforded excellent agreement between the experimental results and theoretical densities from the optimized gas-phase structure and from multipole modelling of static theoretical structure factors. The charge density analysis provides experimental confirmation of the partially localized π-bonding suggested by the conventional structural formula, but the evidence for any significant C-N π bonding is not strong. Hirshfeld atom refinement (HAR) gives H atom positional and anisotropic displacement parameters that agree very well with the neutron parameters.
View Article and Find Full Text PDFLow-frequency collective vibrational modes in proteins have been proposed as being responsible for efficiently directing biochemical reactions and biological energy transport. However, evidence of the existence of delocalized vibrational modes is scarce and proof of their involvement in biological function absent. Here we apply extremely sensitive femtosecond optical Kerr-effect spectroscopy to study the depolarized Raman spectra of lysozyme and its complex with the inhibitor triacetylchitotriose in solution.
View Article and Find Full Text PDF5,6-Disubstituted phenanthridinium cations have a range of redox, fluorescence and biological properties. Some properties rely on phenanthridiniums intercalating into DNA, but the use of these cations as exomarkers for the reactive oxygen species (ROS), superoxide, and as inhibitors of acetylcholine esterase (AChE) do not require intercalation. A versatile modular synthesis of 5,6-disubstituted phenanthridiniums that introduces diversity by Suzuki–Miyaura coupling, imine formation and microwave-assisted cyclisation is presented.
View Article and Find Full Text PDFHigh resolution X-ray diffraction data on forms I-IV of sulfathiazole and neutron diffraction data on forms II-IV have been collected at 100 K and analyzed using the Atoms in Molecules topological approach. The molecular thermal motion as judged by the anisotropic displacement parameters (adp's) is very similar in all four forms. The adp of the thiazole sulfur atom had the greatest amplitude perpendicular to the five-membered ring, and analysis of the temperature dependence of the adps indicates that this is due to genuine thermal motion rather than a concealed disorder.
View Article and Find Full Text PDFThe enantioselective total syntheses of 10 cladiellin natural products have been completed, starting from the known allylic alcohol (+)-14, which can be prepared in large quantities. The bridged tricyclic core of the cladiellins has been constructed via three ring-forming reactions: (i) an intramolecular reductive cyclization between an aldehyde and an unsaturated ester, mediated by samarium(II) iodide, to form a tetrahydropyranol; (ii) reaction of a metal carbenoid, generated from a diazo ketone, with an ether to produce an ylide-like intermediate that rearranges to produce E- or Z-oxabicyclo[6.2.
View Article and Find Full Text PDFA base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6-substituted-4-oxo-L-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation.
View Article and Find Full Text PDFA one-pot tandem process involving an Overman rearrangement, ring closing enyne metathesis and a hydrogen bonding directed Diels-Alder reaction has been developed for the efficient diastereoselective synthesis of functionalised amino substituted tetralin and indene ring systems.
View Article and Find Full Text PDFA new synthetic approach has been developed for the preparation of 7-deoxypancratistatin analogues bearing a syn-(4aS,10bS)-phenanthridone ring junction. A one-pot tandem process involving a substrate-directed Overman rearrangement and ring closing metathesis reaction was developed for the stereoselective synthesis of a carbocyclic allylic trichloroacetamide. Conversion to a 6-bromopiperonyl amide, followed by a Heck reaction generated a homoallylic alcohol and completed the syn-(4aS,10bS)-phenanthridone carbon skeleton.
View Article and Find Full Text PDFIn a recent publication in this journal, an experimental charge density analysis on the triruthenium cluster Ru(3)(CO)(12) showed unusual C...
View Article and Find Full Text PDFThe preference of β-fluoroimines to adopt a gauche conformation has been studied by single-crystal X-ray diffraction analysis and DFT methods. Empirical and theoretical evidence for a preferential gauche arrangement around the NCCF torsion angle (φ) is presented ((E)-2-fluoro-N-(4-nitrobenzylidene)ethanamine: φ(NCCF) =70.0°).
View Article and Find Full Text PDFThe charge density in the tri-iron methoxymethylidyne cluster Fe(3)(μ-H)(μ-COMe)(CO)(10) (1) has been studied experimentally at 100 K and by DFT calculations on the isolated molecule using the Quantum Theory of Atoms in Molecules (QTAIM). The COMe ligand acts as a nearly symmetric bridge toward two of the Fe atoms (Fe-C = 1.8554(4), 1.
View Article and Find Full Text PDFThe charge density in (+/-)-8'-benzhydrylideneamino-1,1'-binaphthyl-2-ol (1) has been studied experimentally using Mo Kalpha X-ray diffraction at 100 K, and by theory using density-functional thoery (DFT) calculations at the B3LYP/6-311++G** level. The nature of the weak intramolecular peri-C..
View Article and Find Full Text PDFThe gauche effect that is induced upon reversible formation of an iminium ion (see structure: green F, blue N) provides a powerful method for the preorganization of transient intermediates that are central to secondary amine catalyzed processes. This phenomenon has been exploited in the design of a novel organocatalyst and is showcased in the stereoselective epoxidation of alpha,beta-unsaturated aldehydes.
View Article and Find Full Text PDFCombined quantum-mechanics/molecular-mechanics (QM/MM) approaches have become the method of choice for modeling reactions in biomolecular systems. Quantum-mechanical (QM) methods are required for describing chemical reactions and other electronic processes, such as charge transfer or electronic excitation. However, QM methods are restricted to systems of up to a few hundred atoms.
View Article and Find Full Text PDFWe present a microiterative adiabatic scheme for quantum mechanical/molecular mechanical (QM/MM) energy minimization that fully optimizes the MM part in each QM macroiteration. This scheme is applicable not only to mechanical embedding but also to electrostatic and polarized embedding. The electrostatic QM/MM interactions in the microiterations are calculated from electrostatic potential charges fitted on the fly to the QM density.
View Article and Find Full Text PDFCombined quantum-mechanics/molecular-mechanics (QM/MM) methods are making rapid progress both methodologically and with respect to their range of application. Mechanistic studies on enzymes, including contributions towards the understanding of enzyme catalysis, continue to be a major target. They are joined by calculations of pK(a) values, redox properties, ground- and excited-state spectroscopic parameters, and excited-state dynamics.
View Article and Find Full Text PDFThe effects of the solvent and finite temperature (entropy) on the Wittig reaction are studied by using density functional theory in combination with molecular dynamics and a continuum solvation model. Standard gas-phase zero-temperature calculations are found to give similar results to previous studies. Gas-phase dynamics simulations allow the free energy profile of the reaction to be calculated through thermodynamic integration.
View Article and Find Full Text PDFWe used the free-energy perturbation (FEP) method in quantum mechanics/molecular mechanics (QM/MM) calculations to compute the free-energy profile of the hydroxylation reaction in the enzyme p-hydroxybenzoate hydroxylase (PHBH). k statistics were employed to analyze the FEP sampling including estimation of the sampling error. Various approximations of the free-energy perturbation method were tested.
View Article and Find Full Text PDFJ Am Chem Soc
October 2005
The C-F bond-forming step in the fluorinase, the only native fluorination enzyme characterized to date, has been studied. The enzyme catalyzes the reaction between S-adenosyl-L-methionine (SAM) and fluoride ions to form 5'-fluoro-5'-deoxyadenosine (5'-FDA) and L-methionine. To obtain an insight into the mechanism of this unusual enzymatic reaction and to elucidate the role of the enzyme in catalysis, we have explored the conformational energetics of SAM and the intrinsic reactivity patterns of SAM and fluoride with DFT (BP86) and continuum solvent methods, before investigating the full enzymatic system with combined DFT/CHARMM calculations.
View Article and Find Full Text PDFWe investigate the OH transfer step of the hydroxylation reaction of p-hydroxybenzoate in the enzyme p-hydroxybenzoate hydroxylase (PHBH) using QM/MM molecular dynamics methods. The QM region (49 atoms) is treated at the AM1 level, while the MM part (ca. 23 000 atoms) is described by the GROMOS force field.
View Article and Find Full Text PDFA computational study of a series of N(1)- and/or C(6)-alkyl-5,6-dihydrothymine diastereomers at theory levels up to MP4(SDTQ)/6-31G//HF/6-31G and MP2/6-311G//HF/6-31G has demonstrated the respective importance of the substituents at positions 1, 5, and 6 on the energetically favored conformation of each isomer. Results obtained both in the gas and condensed phase indicate that unsubstitution of the N(1)-position favors a half-chair conformation with the C(5) -and C(6)-substituents in the equatorial position. On the other hand, in the case of the (6S)-1,6-dimethyl-5,6-dihydrothymine, the C(6)-substituent adopts the axial position to minimize its van der Waals interactions with the N(1)-substituent.
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