Timothy M. Gregg

On the Mechanism and Selectivity of the Combined C−H Activation/Cope Rearrangement

The combined C-H activation/Cope rearrangement (CHCR) is an effective C-H functionalization process that has been used for the asymmetric synthesis of natural products and pharmaceutical building blocks. Up until now, a detailed understanding of this process was lacking. Herein, we describe a combination of theoretical and experimental studies that have resulted in a coherent description of the likely mechanism of the reaction. Density functional studies on the reactions of rhodium vinylcarbenoids at allylic C-H sites demonstrate that the CHCR proceeds through a concerted, but highly asynchronous, hydride-transfer/C-C bond-forming event. Even though most of the previously known examples of this process are highly diastereoselective, the calculations demonstrate that other transition-states and stereochemical outcomes might be possible by appropriate modifications of the reagents, and this was confirmed experimentally. The calculations also indicate that there is a potential energy surface bifurcation between CHCR and the competing direct C-H insertion.

Design and control of acetylcholine receptor conformational change

Allosteric proteins use energy derived from ligand binding to promote a global change in conformation. The “gating” equilibrium constant of acetylcholine receptor-channels (AChRs) is influenced by ligands, mutations, and membrane voltage. We engineered AChRs to have specific values of this constant by combining these perturbations, and then calculated the corresponding values for a reference condition. AChRs were designed to have specific rate and equilibrium constants simply by adding multiple, energetically independent mutations with known effects on gating. Mutations and depolarization (to remove channel block) changed the diliganded gating equilibrium constant only by changing the unliganded gating equilibrium constant (E0) and did not alter the energy from ligand binding. All of the tested perturbations were approximately energetically independent. We conclude that naturally occurring mutations mainly adjust E0 and cause human disease because they generate AChRs that have physiologically inappropriate values of this constant. The results suggest that the energy associated with a structural change of a side chain in the gating isomerization is dissipated locally and is mainly independent of rigid body or normal mode motions of the protein. Gating rate and equilibrium constants are estimated for seven different AChR agonists using a stepwise engineering approach.

Rhodium-Mediated Enantioselective Cyclopropanation of Allenes

Reaction of monosubstituted allenes with aryldiazoacetate esters under dirhodium tetracarboxylate catalysis led to alkylidene cyclopropane products in 80-90% ee. Monosubstituted alkyl- and arylallene substrates gave 60-75% yield under standard conditions, while yields for 1,1-disubstituted allenes were significantly lower. Cyclopropanation of 1-methyl-1-(trimethylsilyl)allene proceeded in higher yield than other 1,1-disubstituted substrates, suggesting rate enhancement mediated by a significant beta-silicon effect.

Guide to Enantioselective Dirhodium(II)-Catalyzed Cyclopropanation with Aryldiazoacetates.

Catalytic enantioselective methods for the generation of cyclopropanes has been of longstanding pharmaceutical interest. Chiral dirhodium(II) catalysts prove to be an effective means for the generation of diverse cyclopropane libraries. Rh2(R-DOSP)4 is generaally the most effective catalyst for asymmetric intermolecular cyclopropanation of methyl aryldiazoacetates with styrene. Rh2(S-PTAD)4 provides high levels of enantioinduction with ortho-substituted aryldiazoacetates. The less-established Rh2(R-BNP)4 plays a complementary role to Rh2(R-DOSP)4 and Rh2(S-PTAD)4 in catalyzing highly enantioselective cyclopropanation of 3- methoxy-substituted aryldiazoacetates. Substitution on the styrene has only moderate influence on the asymmetric induction of the cyclopropanation.

Inhibitory Effect of Ethylene in Ene–Yne Metathesis: The Case for Ruthenacyclobutane Resting States

Reaction kinetics and mechanistic studies for ethylene-internal alkyne metathesis promoted by the phosphine-free initiator Ru1 (Pierss catalyst) is described. The kinetic order of reactants and catalyst was determined. The effect of ethylene was studied at different solution concentrations using ethylene gas mixtures applied at constant pressure. Unlike earlier studies with the second-generation Grubbs complex, ethylene was found to show an inverse first-order rate dependence. Under catalytic conditions, a ruthenacyclobutane intermediate was observed by proton NMR spectroscopy at low temperature. Combined with the kinetic study, these data suggest a catalytic cycle involving a reactive L(n)Ru═CH2 species in equilibrium with ethylene to form a ruthenacyclobutane, a catalyst resting state. Rates were determined for a variety of internal alkynes of varying substitution. Also, at low ethylene pressures, preparative syntheses of several 2,3-disubstituted 1,3-butadienes were achieved. Using the kinetic method, several phosphine-free inhibitors were examined for their ability to promote ethylene-alkyne metathesis and to guide selection of the optimal catalyst.

Energy for Wild-Type Acetylcholine Receptor Channel Gating from Different Choline Derivatives

Agonists, including the neurotransmitter acetylcholine (ACh), bind at two sites in the neuromuscular ACh receptor channel (AChR) to promote a reversible, global change in protein conformation that regulates the flow of ions across the muscle cell membrane. In the synaptic cleft, ACh is hydrolyzed to acetate and choline. Replacement of the transmitters ester acetyl group with a hydroxyl (ACh→choline) results in a + 1.8 kcal/mol reduction in the energy for gating generated by each agonist molecule from a low- to high-affinity change of the transmitter binding site (ΔG(B)). To understand the distinct actions of structurally related agonist molecules, we measured ΔG(B) for 10 related choline derivatives. Replacing the hydroxyl group of choline with different substituents, such as hydrogen, chloride, methyl, or amine, increased the energy for gating (i.e., it made ΔG(B) more negative relative to choline). Extending the ethyl hydroxide tail of choline to propyl and butyl hydroxide also increased this energy. Our findings reveal the amount of energy that is available for the AChR conformational change provided by different, structurally related agonists. We speculate that a hydrogen bond between the choline hydroxyl and the backbone carbonyl of αW149 positions this agonists quaternary ammonium group so as to reduce the cation-π interaction between this moiety and the aromatic groups at the binding site.