Hydrogen atom transfer methodology for the synthesis of C-22, C-23, and C-25 stereoisomers of cephalostatin north 1 side chain from spirostan sapogenins

A simple synthesis of all eight C-22, C-23, and C-25 diastereoisomers of the cephalostatin north 1 side chain has been accomplished from (25R)-5α-spirostan-3β-ol (tigogenin). The synthesis involves selective hydroxylations at C-23 and C-25 and reductive opening of the 1,6-dioxaspiro[4.5]decane spirostan system to give a conveniently protected 5α-furostan-3β,23,25,26-tetrol. The construction of the required 1,6-dioxaspiro[4.4]nonane system entailed an intramolecular hydrogen abstraction reaction promoted by the C-25 alkoxyl radical as the key step. Acid-catalyzed isomerization of the spiroketal unit suggested that 22R isomers are the thermodynamic products while the 22S isomers are the result of kinetic control. The acid-catalyzed equilibrium between 1,6-dioxaspiro[4.4]nonane and 1,6-dioxaspiro[4.5]decane systems was also studied. In the 1,6-dioxaspiro[4.4]nonane units, the observed ³J_23,24 coupling constants suggest that the five-membered puckered ring-F undergoes substantial conformational changes on going from 22S to 22R isomers.     

Hybrid density functional theory with a specific reaction parameter: hydrogen abstraction reaction of trifluoromethane by the hydroxyl radical

Potential energy surfaces are developed and tested for the OH + CHF₃ → H₂O + CF₃ reaction. The objective is to obtain surfaces that give calculated rate constants comparable to the experimental ones. The potential energy surfaces are constructed using hybrid and hybrid meta density functional theory methods (mPW1PW91, B1B95, and mPW1B95) with specific reaction parameters in conjunction with the 6–31+ G(d,p) basis set. The rate constants are calculated over the temperature range 200–1,500 K using variational transition state theory with multidimensional tunneling contributions. The hybrid density functional theory methods with specific-reaction-parameter Hartree-Fock exchange contributions (32.8–34.8% for mPW1PW91, 34.2–36.0% for B1B95, and 37.8–39.7% for mPW1B95, respectively) provide accurate rate constants over an extended temperature range. The classical barrier height for the hydrogen abstraction reaction is determined to be 6.5–6.9 kcal/mol on these potential energy surfaces, and the best estimate value is 6.77 kcal/mol. Electronic Supplementary Material  Supplementary material is available for this article at and is accessible for authorized users.     

Theoretical Elucidation on Different Lipid-Oxidation Potentials of Aminoxyl Antioxidants

To elucidate the different lipid-oxidation potentials of aminoxyl antioxidants, a kind of combined density functional theory (DFT) method was employed to calculate C-H bond dissociation enthalpies (BDEs) of a model linoleic acid (LH) and O-H BDEs of hydrogenated aminoxyls. The higher the O-H BDE is, the more potent the amlnoxyl to abstract the H-atom from LH and the stronger the LH-oxidation potential. Accordingly,the prooxidant activity differences of amlnoxyls were elucidated by the different O--H BDEs of hydrogenated amlnoxyls, which were further clarified in terms of distinct electronic effects of the substituents.     

Direct ab initio dynamics calculations on the rate constants for the hydrogen-abstraction reaction of C2H5F with O (3P)

The hydrogen-abstraction reaction C₂H₅F+O → C₂H₄F+OH has been studied by a dual-level direct dynamics method. For the reaction, three reaction channels, one for α-abstraction and two for β-abstraction, have been identified. The potential-energy surface information is obtained at the MP2(full)/6-311G(d,p) and PMP2(full)/6-311G(3df,3pd) (single-point) levels. By canonical variational transition-state theory, rate constants for each reaction channel are calculated with a small-curvature tunneling correction. The total rate constant is calculated from the sum of the individual rate constants and the temperature dependence of the branching ratios is obtained over a wide range of temperatures from 300 to 5,000 K. The agreement of the rate constants with experiment is good in the experimental temperature range from 1,000 to 1,250 K. The calculated results indicate that at low temperatures α-abstraction is most likely to be the major reaction channel, while β-abstraction channels will significantly contribute to the whole reaction rate as the temperature increases. Received: 23 January 2002 / Accepted: 23 June 2002 / Published online: 20 September 2002     

The exchange reaction of hydrogen atoms in the system sterically hindered hydroxylamine-nitroxyl radical

The rate constants of the direct and reverse exchange reactions of the hydrogen atom in the system sterically-hindered nitroxyl radical-hydroxylamine of the quinoline, imidazoline, pyrrolidine, and piperidine series as well as diarylhydroxylamine were determined. A scale of the reductive abilities of the hydrolamines was established. A low value of the isotope effect is typical of the reactions of hydrogen exchange in the systems hydroxylamine-nitroxyl radical. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1324–1328, July, 1998.     

Geometric parameters of transition states of radical abstraction reactions with C...H...C reaction center

An algorithm of calculations of interatomic distances in the transition states (TS) of reactions of hydrogen abstraction by alkyl, allyl, and benzyl radicals from C—H bonds of organic molecules using the enthalpies of the corresponding reactions is proposed. The geometric parameters of the TS of the reactions involving carbon-centered radicals with the C...H...C reaction center, calculated using experimental data, are compared with other characteristics of the reactions and reactants. The r(C...H...C) distance in the TS of the reactions of alkyl radicals with alkanes remains unchanged as the enthalpies of reactions vary, being a characteristic parameter of a given class of reactions. -Bonds adjacent to the reaction center are responsible for an increase in the parameter r(C...H...C) in the TS.     

Ab initio study on the structures of fluorinated formates and hydrogen abstraction reaction with OH radical

The conformational potential energy surfaces for mono- and difluoromethyl formate have been determined by using a modified G2(MP2) level of calculations. The structures and vibrational frequencies for the conformers of mono- and difluoromethyl formate have been reported. The hydrogen abstraction reaction channels between these two formates and OH radicals have been studied at the same level of theory. Using the standard transition state theory and taking into account the effect of tunneling across the reaction barrier, we have estimated the rate constant for hydrogen abstraction by OH radical. The effect of successive fluorine substitution for methyl hydrogen on the conformational stability and on the hydrogen abstraction rate has been analyzed.     

Electrostatic Perturbations in the Substrate-Binding Pocket of Taurine/α-Ketoglutarate Dioxygenase Determine its Selectivity

Taurine/α-ketoglutarate dioxygenase is an important enzyme that takes part in the cysteine catabolism process in the human body and selectively hydroxylates taurine at the C¹-position. Recent computational studies showed that in the gas-phase the C²−H bond of taurine is substantially weaker than the C¹−H bond, yet no evidence exists of 2-hydroxytaurine products. To this end, a detailed computational study on the selectivity patterns in TauD was performed. The calculations show that the second-coordination sphere and the protonation states of residues play a major role in guiding the enzyme to the right selectivity. Specifically, a single proton on an active site histidine residue can change the regioselectivity of the reaction through its electrostatic perturbations in the active site and effectively changes the C¹−H and C²−H bond strengths of taurine. This is further emphasized by many polar and hydrogen bonding interactions of the protein cage in TauD with the substrate and the oxidant that weaken the pro-R C¹−H bond and triggers a chemoselective reaction process. The large cluster models reproduce the experimental free energy of activation excellently.     

Effect of solvent on reactions of Cp2Zr{(μ-H)2BHR}2 and Cp2ZrH{(μ-H)2BHR} (R = CH3, Ph) with B(C6F5)3

The effect that a solvent has on reactions of Cp₂Zr{(μ-H)₂BHR}₂ and Cp₂ZrH{(μ-H)₂BHR} (R = CH₃, Ph) with B(C₆F₅)₃ has been studied. From the reaction in benzene the metathesis product Cp₂Zr{(μ-H)₂B(C₆F₅)₂}₂, 2, was isolated. In the case of diethyl ether, different hydride abstraction products, including [Cp₂Zr(OEt₂){(μ-H)₂BHPh}][HB(C₆F₅)₃], 3, [Cp₂Zr(OEt₂){(μ-H)₂BHCH₃}][HB(C₆F₅)₃], 4, [Cp₂Zr(OEt₂){(μ-H)₂BH₂}][HB(C₆F₅)₃], 5, and [Cp₂Zr(OEt)(OEt₂)][HB(C₆F₅)₃], 6, were isolated depending on the starting zirconocene complex. The diethyl ether molecules of 3-6 are weakly coordinated to Zr and displaced in THF solution. Isolation of 3 and 4 is attributed to their fast precipitation from the reaction mixture, which prevented further reactions from occurring. In addition to the hydride abstraction, a hydride metathesis was also involved in the formation of 5. Time-elapsed ¹¹B NMR studies indicate that 3 and 4 are the intermediates on the pathway to 5 and 6. The molecular structures of 2-6 were determined by single-crystal X-ray diffraction.