Biomedical subjects

K N Houk

Publications and source records attributed to K N Houk.

At least 91 records · Page 5Linked to original sources

PubMed2003

One-bond, two-bond, and three-bond mechanisms in thermal deazetizations of 2,3-diazabicyclo[2.2.2]oct-2-enes, trans-azomethane, and 2,3-diazabicyclo[2.2.1]hept-2-ene.

The thermal deazetizations of a series of substituted 2,3-diazabicyclo[2.2.2]oct-2-enes and some simpler model systems have been studied using the UB3LYP/6-31G(d) and CASPT2 methods, with a variety of active spaces. A fused cyclopropane exerts unique control on the mechanism and rate of deazetization. When the Walsh sigma-orbitals are appropriately aligned in an exo orientation, a pericyclic three-bond cleavage occurs. For an endo-fused cyclopropane, sequential one-bond cleavages occur to take advantage of orbital overlap with the Walsh orbitals. In systems lacking strongly directing substituents, concerted two-bond cleavage pathways to form diradical intermediates have a small enthalpic advantage (DeltaH(0K)++) over sequential one-bond cleavage pathways. However, the one-bond mechanism has an entropic advantage over the two-bond; consequently, at 400-500 K where decomposition occurs, one-bond and two-bond diradical cleavages both occur simultaneously. The thermal decompositions of trans-azomethane and 2,3-diazabicyclo[2.2.1]hept-2-ene are also studied, and the results are compared to extensive computational studies in the literature. Comparisons of UB3LYP, CASSCF, and CASPT2 surfaces for these reactions are made.

Journal Article↗

PubMed2003

Stereoselectivity of nitrile oxide cycloadditions to chiral allylic fluorides: experiment and theory.

The cycloadditions of nitrile oxides with new and previously studied allylic fluorides were examined. The 1,3-dipolar cycloaddition reactions were also investigated theoretically with density functional theory (B3LYP) based transition-state modelling. The predictions provided reasonable agreement with experiment, indicating that both steric and electronic effects have important influences on the stereoselectivities of these reactions.

Fluorides↗

PubMed2003

Intramolecular 1,3-dipolar ene reactions of nitrile oxides occur by stepwise 1,1-cycloaddition/retro-ene mechanisms.

Density functional theory studies of intramolecular ene-like (or the so-called 1,3-dipolar ene) reactions between nitrile oxides and alkenes (Ishikawa, T.; Urano, J.; Ikeda, S.; Kobayashi, Y.; Saito, S. Angew. Chem., Int. Ed. 2002, 41, 1586) show that this reaction is a three-step process involving a stepwise carbenoid addition of nitrile oxide to form a bicyclic nitroso compound, followed by a retro-ene reaction of the nitrosocyclopropane intermediate. The competitive reactions, either the intramolecular (3+2) reactions between nitrile oxides and alkenes or the intermolecular dimerizations of nitrile oxides to form furoxans, can overwhelm the intramolecular 1,3-dipolar ene reactions when the tether joining the nitrile oxide and alkene is elongated or some substituents such as trimethylsilyl are absent.

Journal Article↗

PubMed2003

Binding affinities of host-guest, protein-ligand, and protein-transition-state complexes.

The affinities of hosts-ranging from small synthetic cavitands to large proteins-for organic molecules are well documented. The average association constants for the binding of organic molecules by cyclodextrins, synthetic hosts, and albumins in water, as well as of catalytic antibodies or enzymes for substrates are 10(3.5+/-2.5) M(-1). Binding affinities are elevated to 10(8+/-2) M(-1) for the complexation of transition states and biological antigens by antibodies or inhibitors by enzymes, and to 10(16+/-4) M(-1) for transition states with enzymes. The origins of the distributions of association constants observed for the broad range of host-guest systems are explored in this Review, and typical approaches to compute and analyze host-guest binding in solution are discussed. In many classes of complexes a rough correlation is found between the binding affinity and the surface area that is buried upon complexation. Enzymes transcend this effect and achieve transition-state binding much greater than is expected from the surface areas.

Animals↗

PubMed2003

Unexpected syn hydride migration in the non-aldol aldol reaction.

[structure: see text] Non-aldol aldol rearrangement of the epoxy silyl ether 13b afforded the expected anti methyl ketone 14, while the diastereomeric epoxy silyl ether 13a afforded the syn methyl ketone 8b via an unprecedented syn hydride migration. Calculations suggest that this unusual reaction proceeds via the carbocation, which cannot easily rotate due to steric hindrance.

Aldehydes↗

PubMed2003

Oxidation of N-hydroxyguanidines by copper(II): model systems for elucidating the physiological chemistry of the nitric oxide biosynthetic intermediate N-hydroxyl-L-arginine.

The redox chemistry of models of N-hydroxy-L-arginine, the biosynthetic intermediate in the synthesis of NO by the family of nitric oxide synthase enzymes, has been explored experimentally and theoretically. The oxidation of N-hydroxyguanidine model compounds by Cu(II) was studied as a means of establishing possible metabolic fates and intermediates of this important functional group. These studies indicate than an iminoxyl intermediate is formed and may be an important biological species generated from N-hydroxyguanidines including N-hydroxy-L-arginine.

Arginine↗

PubMed2003

Strategies for the design of organic aziridination reagents and catalysts: transition structures for alkene aziridinations by NH transfer.

B3LYP/6-31G* transition structures for aziridination of various alkenes by substituted oxaziridines and diaziridinum salts were located. Oxaziridines substituted with electron-withdrawing groups have activation energies for nitrogen transfer similar to those calculated for epoxidation by various known organic oxidants. These transition states are relatively insensitive to alkene substituents, but highly electron deficient alkenes were calculated to have low activation energies. N-Trimethylsilyl-derived oxaziridines are predicted to be good targets for alkene aziridination reagents. Activation energies calculated for aziridination by diaziridinium salts are generally lower in energy. Aziridinations of electron-rich and highly electron deficient alkenes by diaziridinium salts are predicted to be rapid. N-Methyl, N-trifluoroacetyl, and N-trimethylsilyl derivatives showed reasonable activation energies for nitrogen transfer.

Aziridines↗

PubMed2003

A theoretical study on the mechanism of the cyclopolymerization of diallyl monomers.

The cyclization and intermolecular propagation steps of the cyclopolymerization mechanism are studied with density functional theory. In addition to standard cyclization and intermolecular propagation reactions of cyclopolymerization, competing reactions that lead to chain transfer and termination are also discussed. The mechanistic study of the cyclopolymerization reaction of two representative monomers, N,N-diallylamine (1) and N,N-dimethyl-N,N-diallylamonium (2), was carried out with B3LYP/6-31G computations. Monomer 1 has almost the same activation barriers for homopolymerization and cyclization. In monomer 2, cyclization is much more facile than homopolymerization, leading to the higher cyclopolymerization efficiency. In the case of 2, methyl substituents on nitrogen inhibit hydrogen abstraction, whereas in 1, hydrogen abstraction reactions from the neutral monomer yield stabilized products leading to chain transfer. Calculations show that facile competing reactions of monomer 1 lower the polymerization efficiency. Monomer 2 displays a stronger preference for cyclization relative to other processes.

Allyl Compounds↗

PubMed2003

A cornucopia of cycloadducts: theoretical predictions of the mechanisms and products of the reactions of cyclopentadiene with cycloheptatriene.

The potential cycloaddition reactions between cyclopentadiene and cycloheptatriene have been explored theoretically. B3LYP/6-31G was used to locate the transition states, intermediates, and products for concerted pathways and stepwise pathways passing through diradical intermediates. Interconversions of various cycloadducts through sigmatropic shifts were also explored. CASPT2/6-31G single point calculations were employed to obtain independent activation energy estimates. MM3 was also used to compute reaction energetics. Several bispericyclic cycloadditions in which two cycloadducts are linked by a sigmatropic shift have been identified. B3LYP predicts, in line with frontier molecular orbital predictions, that the [6+4] cycloaddition is the favored concerted pathway, but an alternative [4+2] pathway is very close in energy. By contrast, CASPT2 predicts that a [4+2] cycloaddition is the preferred pathway. B3LYP predicts that the lowest energy path to many of the cycloadducts will involve diradical intermediates, whereas CASPT2 predicts that each of the products of orbital symmetry allowed reactions will be reached most readily by closed shell processes-concerted cycloadditions and sigmatropic shift rearrangements of cycloadducts.

Journal Article↗

PubMed2003

Nitroxyl disulfides, novel intermediates in transnitrosation reactions.

A novel anionic RSN(O)SR species, the intermediate in transnitrosation reactions, was explored computationally with B3LYP and CBS-QB3 methods. The species resembles a nitroxyl coordinated to a highly distorted disulfide, and it differs significantly from intermediates in nucleophilic acyl substitution. Reactions of the following species were computed for comparison: MeS(-) + MeSNO; MeO(-) + MeONO; MeS(-) + MeSCHO; MeO(-) + MeOCHO. The last two have very different intermediates from the first two. Mass spectrometric experimental evidence is presented that is consistent with the formation of a nitroxyl disulfide in the gas phase. The calculated proton affinity and redox potentials of the intermediate are also reported.

Disulfides↗

PubMed2003

Dissociative and associative mechanisms of cope rearrangements of fluorinated 1,5-hexadienes and 2,2'-bis-methylenecyclopentanes.

The effects of fluorine substitution on the Cope rearrangements of 1,5-hexadiene and 2,2'-bis-methylenecyclopentane have been examined computationally using (U)B3LYP/6-31+G(d,p) and CASPT2/6-31G(d) methodology. The calculations indicate that fluorine substituents at the hexadiene termini generally stabilize the transition states relative to the ground states of the chair conformations and destabilize pathways that occur via boat conformations, in accord with the experimental observations of Dolbier. With meso-2,2'-bis(difluoromethylene)cyclopentane, this destabilization is sufficient to favor a relatively dissociative concerted transition state resembling weakly interacting allyl radicals over a normal aromatic concerted boat transition state. This preference is due partly to an increase in the activation enthalpy for the concerted rearrangement coupled with the more favorable entropy for dissociation. In octafluoro- and decafluorohexadienes, the situation is reversed, and reaction through a cyclohexane-1,4-diyl is favored. Even in the octafluoro system with no radical stabilizing substituents at C(2) and C(5), the preference of fluorine for sp(3) centers causes reaction via the cyclohexane-1,4-diyl. In establishing methodology for this study, the conformations of 1,2-difluoroethane and 1,1,2,2-tetrafluoroethane were also examined thoroughly by the B3LYP method using three basis sets.

Journal Article↗

PubMed2003

Structural basis for antibody catalysis of a cationic cyclization reaction.

Antibody 4C6 efficiently catalyzes a cationic cyclization reaction. Crystal structures of the antibody 4C6 Fab in complex with benzoic acid and in complex with its eliciting hapten were determined to 1.30A and 2.45A resolution, respectively. These crystal structures, together with computational analysis, have elucidated a possible mechanism for the monocyclization reaction. The hapten complex revealed a combining site pocket with high shape complementarity to the hapten. This active site cleft is dominated by aromatic residues that shield the highly reactive carbocation intermediates from solvent and stabilize the carbocation intermediates through cation-pi interactions. Modeling of an acyclic olefinic sulfonate ester substrate and the transition state (TS) structures shows that the chair-like transition state is favored, and trapping by water directly produces trans-2-(dimethylphenylsilyl)-cyclohexanol, whereas the less favored boat-like transition state leads to cyclohexene. The only significant change observed upon hapten binding is a side-chain rotation of Trp(L89), which reorients to form the base of the combining site. Intriguingly, a benzoic acid molecule was sequestered in the combining site of the unliganded antibody. The 4C6 active site was compared to that observed in a previously reported tandem cyclization antibody 19A4 hapten complex. These cationic cyclization antibodies exhibit convergent structural features with terpenoid cyclases that appear to be important for catalysis.

Antibodies, Catalytic↗

PubMed2003

Altering the allowed/forbidden gap in cyclobutene electrocyclic reactions: experimental and theoretical evaluations of the effect of planarity constraints.

The allowed conrotatory cyclobutene ring-opening has a distinctly nonplanar carbon skeleton. Classic experiments by Brauman and Archie, and by Freedman et al., placed the allowed/forbidden gap at greater than 15 kcal/mol. Wolfgang Roth proposed that a system forced to planarity might have a smaller preference for the conrotatory mode than unconstrained systems. Such systems have now been studied theoretically and experimentally, and results that confirm Roth's postulate are presented here. The experiments were performed in Bochum, and the calculations were carried out in Osaka and Los Angeles. As the cyclobutene ring-opening transition structure approaches planarity, the energy gap between allowed conrotatory and the forbidden disrotatory pathways decreases. For the ring-opening of a cyclobutene fused to norbornene, the energy gap between the forbidden and the allowed transition state is only 4.1 kcal/mol by CASSCF and 8.0 kcal/mol by CAS-MP2 as compared to 13.4 and 19.2 kcal/mol, respectively, for the parent cyclobutene. Experimental studies of 3,4-dimethylcyclobutenes fused to various ring systems are reported, and a trend is found toward a reduced allowed/forbidden gap as the planarity of the cyclobutene is enforced.

Journal Article↗

PubMed2003

Origins of inward torquoselectivity by silyl groups and other sigma-acceptors in electrocyclic reactions of cyclobutenes.

Recent reports of inward torquoselectivities in thermal electrocyclic ring-opening reactions of 3-silylcyclobutenes have revealed that saturated silyl substituents, just like the extensively studied pi-acceptors, can exert contrasteric effects. The origins of torquoselectivity for substituents lacking pi orbitals have been explained using B3LYP density functional calculations. Orbital interactions involving the substituent vacant orbitals and the occupied orbitals associated with the breaking bonds are found to control these contrasteric torquoselectivities, with minor contributions from electrostatic effects. Reaction energetics and transition states for electrocyclic ring-opening reactions of 3-silyl, fluorosilyl, difluorosilyl, trifluorosilyl, methylsilyl, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ammonio, phosphonio, formyl, and borohydrido cyclobutenes are reported to complement previous extensive studies of unsaturated substituents. Inward stereoselectivities are predicted for various silyl and phosphonium substituents, along with potent pi-acceptors studied earlier. Cope and Diels-Alder reactions involving silyl substituents are also computed.

Journal Article↗

PubMed2003

Mechanism of cis-enamide formation from N-(alpha-silyl)allyl amides: synthetic potential of stepwise dyotropic rearrangements.

A novel transformation of silyl amides to N-cis-propenyl amides was recently reported, the reaction of which is a formal 10-electron double sigmatropic, or dyotropic, rearrangement. Density functional calculations (B3LYP/6-311++G(3d,3p)//B3LYP/6-31G(d)) have been carried out to investigate the mechanism of this reaction. A two-step process involving sequential 1,4-silyl and 1,4-hydrogen shifts is predicted. The 1,3-dipolar azomethine ylide intermediate profits from charge stabilization by allylic resonance and phenyl conjugation. The consecutive thermal migration of two sigma-bonds (stepwise dyotropic rearrangement) is an example of a host of reactions with synthetic potential.

Allyl Compounds↗

PubMed2003

The mechanism and regioselectivity of the ene reactions of nitroso compounds: a theoretical study of reactivity, regioselectivity, and kinetic isotope effects establishes a stepwise path involving polarized diradical intermediates.

A theoretical study of the mechanisms of ene reactions of nitroso compounds has been completed, using UB3LYP, CASPT2, UCCSD(T) and UQCISD(T) methods. Stepwise paths through polarized diradical intermediates are always preferred. These intermediates have unusual properties, involving high rotational barriers about formally single bonds, which permit them to maintain stereochemical relationships. The diradicals may exchange the RNO moiety between the two ends of the alkene via an aziridine N-oxide. The aziridine N-oxide cannot be accessed directly from reactants and cannot lead directly to ene products. It is therefore an innocent by-stander in the way proposed by Singleton for the aziridinium imide in the ene reactions of triazolinediones. A detailed analysis of the electronic structure of the polarized diradicals is given. The kinetic isotope effects measured in a Stephenson isotope effect test have been reproduced. These kinetic isotope effects are consistent with a mechanism in which partitioning of the polarized diradical between cyclization to an aziridine N-oxide and H-abstraction to ene product takes place, and in which the formation of the polarized diradical is to some extent reversible. Finally, calculated regioselectivities reproduce those observed experimentally.

Journal Article↗

PubMed2003

Origins of opposite absolute stereoselectivities in proline-catalyzed direct Mannich and aldol reactions.

[structure: see text] The first computational studies to elucidate the stereoselectivity of the proline-catalyzed direct Mannich reaction have been performed using density functional theory (B3LYP/6-31G*). The transition states for the proline-catalyzed direct Mannich reaction of the proline enamine of acetone with the N-phenyl imine of acetaldehyde are reported here. The computed transition states provide a general model that explains the origin of the opposite stereoselectivities of proline-catalyzed Mannich and aldol reactions.

Acetaldehyde↗

PubMed2003

Theoretical elucidation of kinetic and thermodynamic control of radical addition regioselectivity.

The cyclizations of two structurally similar 2-oxo-5-hexenyl-type radicals have been investigated by ab initio and density functional (UB3LYP/6-31+G**//UHF/6-31G* and UB3LYP/6-31G*//UB3LYP/6-31G*) calculations. The origin of apparently contradictory reports of 6-endo and 5-exo cyclizations is determined. Kinetic control favors 6-endo cyclization, while thermodynamic control gives 5-exo cyclization, and the observation of different products from different research groups arises from the difference in experimental conditions used by the two groups. The outcome of a new cyclization reaction was predicted by using these theoretical techniques. Kinetic control is predicted to yield exclusively the products of 6-endo cyclization, while thermodynamic control would lead to an approximately equal mixture of one 6-endo and one 5-exo cyclized product. Experimental studies revealed that the reaction yields only the products of 6-endo cyclization through kinetic control.

Alkenes↗