Showing papers by "Kendall N. Houk published in 1998"

An antibody exo Diels-Alderase inhibitor complex at 1.95 Angstrom resolution

Abstract: A highly specific Diels-Alder protein catalyst was made by manipulating the antibody repertoire of the immune system. The catalytic antibody 13G5 catalyzes a disfavored exo Diels-Alder transformation in a reaction for which there is no natural enzyme counterpart and that yields a single regioisomer in high enantiomeric excess. The crystal structure of the antibody Fab in complex with a ferrocenyl inhibitor containing the essential haptenic core that elicited 13G5 was determined at 1.95 angstrom resolution. Three key antibody residues appear to be responsible for the observed catalysis and product control. Tyrosine-L36 acts as a Lewis acid activating the dienophile for nucleophilic attack, and asparagine-L91 and aspartic acid-H50 form hydrogen bonds to the carboxylate side chain that substitutes for the carbamate diene substrate. This hydrogen-bonding scheme leads to rate acceleration and also pronounced stereoselectivity. Docking experiments with the four possible ortho transition states of the reaction explain the specific exo effect and suggest that the (3R,4R)-exo stereoisomer is the preferred product.

Theoretical Prediction and Experimental Tests of Conformational Switches in Transition States of Diels−Alder and 1,3-Dipolar Cycloadditions to Enol Ethers

Abstract: Transition structures for the cycloadditions of butadiene, acrolein, nitrosoethylene, and methylenenitrone to 1-butene, silyl vinyl ether, and methyl vinyl ether have been located using ab initio RHF theory with the 3-21G basis set and with density functional theory using the Becke3LYP functional and the 6-31G* basis set. The computational results show that there is a switch in the conformation of the enol ether from syn (COCC = 0°), which is favored by 2.3 kcal/mol in the reactant, to anti (COCC = 180°), which is favored by 1.2−6.6 kcal/mol in the various transition structures studied here. The results are consistent with the experimental stereoselectivities in reactions of chiral enol ethers observed by Denmark and Reissig. The preference of the anti conformation in the transition structures is due primarily to electrostatic effects and, to a lesser extent, steric effects. The preference is predicted to be influenced significantly by polar solvents. The magnitude of this preference was calculated theore...

Origins of Selectivity in Molecular and Supramolecular Entities: Solvent and Electrostatic Control of the Translational Isomerism in [2]Catenanes†

Abstract: The fundamental basis for the stabilization of molecular complexes of various dioxyarenes and/or dithiaarenes and a tetracationic cyclophane was established by empirical force field and ab initio quantum mechanical calculations. The more stable translational isomers of the related [2]catenanes do not necessarily correspond to the more stable complexes involving the individual components. The origin of this anomaly was investigated using the AMBER* force field. Each [2]catenane is composed of cyclobis(paraquat-p-phenylene)the tetracationic cyclophaneand one constitutionally unsymmetrical macrocyclic polyether, incorporating 1,4-dioxybenzene and a dioxyarene or a dithiaarene unit as its two π-electron rich recognition sites. The calculated and experimental isomer ratios at equilibrium for these [2]catenanes are in good agreement. In two instances, the calculated ratios invert as a result of changing the solvation model from H2O to CHCl3. There is a correlation between the experimental and theoretical observ...

A theoretical investigation of phosphonamidates and sulfonamides as protease transition state isosteres

Abstract: The conformations and electrostatic potentials of phosphonamides, phosphonamidates and sulfonamides have been compared to the tetrahedral intermediate for base-catalyzed amide hydrolysis. The wide ...

Studies of Diastereoselectivity in Conjugate Addition of Organoaluminum Reagents to (R)-[(p-Tolylsulfinyl)methyl]quinols and Derivatives

Abstract: (R)-4-Hydroxy-4-[(p-tolylsulfinyl)methyl]-2,5-cyclohexadienones 1−3, and 6 reacted with organoaluminum derivatives from the pro-R conjugated position in a highly π-facial diastereoselective manner directed by the C-4 OH. A similar facial diastereoselectivity arose from reactions with 3-alkyl-substituted analogues 4 and 5 and 5-alkyl-4-hydroxy-4-[(p-tolylsulfinyl)methyl]-2-cyclohexenones 10a,b. Semiempirical calculations (AM1 model) provide data on transition-state energies for additions in full agreement with the experimental results.

Experimental and computational studies of nucleophilic additions of metal hydrides and organometallics to hindered cyclohexanones

Abstract: The stereochemistries of nucleophilic additions of several hydride, methyl, and acetylenic Grignard and lithium reagents to hindered cyclohexanones were investigated experimentally. Acetylenic reagents attack hindered cyclohexanones from the axial direction, in contrast to the result with other reagents. Ab initio calculations and a modified MM2 transition-state force field were used to study the origins of stereoselectivity.

Stereoselectivities of nucleophilic additions to cycloheptanones. Experimental and theoretical studies and general purpose force field for the prediction of nucleophilic addition stereoselectivities

Abstract: The selectivities of nucleophilic additions of ethyl, vinyl, and ethynyllithium and Grignard reagents to a 2-(3‘-phenylpropyl)cycloheptanone were investigated experimentally. In all cases, cis-cycloheptanol was formed preferentially (40:1−6:1). Theoretical studies were performed on the stereoselectivities of nucleophilic additions of hydride and ethynyllithium reagents to cycloheptanones. An empirical force field for transition states of hydride and ethynyl reagents was used for transition-state geometries and conformational searches. Quantum mechanical calculations on HLi addition to cycloheptanones were compared to the corresponding cyclohexanone calculations. These results show that the formation of 2-alkyl-substituted cis-cycloheptanols is preferred for all nucleophiles studied as a result of torsional and steric effects in the transition states of these reactions.

Analysis of Substituent Effects on the Claisen Rearrangement with ab initio and Density Functional Theory.

Abstract: Transition structures for the Claisen rearrangements of 2- and (E)-6-substituted allyl vinyl ethers with CN, CH3, and NH2 groups were located with the Hartree−Fock method and the 6-31G* basis set. Energies were obtained using MP2 single points and B3LYP/6-31G* calculations. A Marcus theory type analysis was applied to separate the intrinsic and thermodynamic contributions to the activation energies. The calculations predict a decrease in the activation barrier for the 2-CN, 2-NH2, and 6-NH2 derivatives, while a large increase in the activation energy is predicted for the 6-CN derivative. The 2-CN and 6-NH2 groups decrease the barrier height due to intrinsic contributions, while the rest are controlled by thermodynamic factors. To estimate solvent effects on rates, SCRF calculations for benzene and acetonitrile were performed.