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 (Piers's 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.

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.

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 (E(0)) 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 E(0) 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.

Isotope effects and the nature of selectivity in rhodium-catalyzed cyclopropanations.

The mechanism of the dirhodium tetracarboxylate catalyzed cyclopropanation of alkenes with both unsubstituted diazoacetates and vinyl- and phenyldiazoacetates was studied by a combination of (13)C kinetic isotope effects and density functional theory calculations. The cyclopropanation of styrene with methyl phenyldiazoacetate catalyzed by Rh(2)(octanoate)(4) exhibits a substantial (13)C isotope effect (1.024) at the terminal olefinic carbon and a smaller isotope effect (1.003-1.004) at the internal olefinic carbon. This is consistent with a highly asynchronous cyclopropanation process. Very similar isotope effects were observed in a bisrhodium tetrakis[(S)-N-(dodecylbenzenesulfonyl)prolinate] (Rh(2)(S-DOSP)(4) catalyzed reaction, suggesting that the chiral catalyst engages in a very similar cyclopropanation transition-state geometry. Cyclopropanation with ethyl diazoacetate was concluded to involve an earlier transition state, based on a smaller terminal olefinic isotope effect (1.012-1.015). Density functional theory calculations (B3LYP) predict a reaction pathway involving complexation of the diazoesters to rhodium, loss of N(2) to afford a rhodium carbenoid, and an asynchronous but concerted cyclopropanation transition state. The isotope effects predicted for reaction of a phenyl-substituted rhodium carbenoid with styrene match within the error of the experimental values, supporting the accuracy of the theoretical calculations and the rhodium carbenoid mechanism. The accuracy of the calculations is additionally supported by excellent predictions of reaction barriers, stereoselectivity, and reactivity trends. The nature of alkene selectivity and diastereoselectivity effects in these reactions is discussed, and a new model for enantioselectivity in Rh(2)(S-DOSP)(4)-catalyzed cyclopropanations is presented.

Effect of HD-23, a potent long acting cocaine-analog, on cocaine self-administration in rats.

RATIONALE: "Agonist" therapy for drug addiction proposes that a long acting analog, with similar properties to the abused substance might serve as a useful therapeutic agent. HD-23 is a very long acting tropane analog that displays a neurochemical profile similar to cocaine. OBJECTIVE: To determine, using self-administration procedures and three different schedules of reinforcement, the effect of HD-23 on rate of cocaine intake (fixed ratio), the effect of HD-23 on the motivation to respond (progressive ratio) and the time course of HD-23 pretreatment (discrete trials). METHODS: Male Sprague-Dawley rats were implanted with chronically indwelling intravenous cannulae and trained to self-administer cocaine (1.5 mg/kg per infusion) on a fixed ratio schedule. After a stable baseline was established, separate groups of rats ( n=6-8) were given access to various doses of cocaine (0.37, 0.75, 1.5 or 3.0 mg/kg per injection) on a fixed ratio schedule during daily 3-h sessions, or to various doses of cocaine (0.18, 0.37, 0.75, 1.5 mg/kg per injection) on a progressive ratio schedule during daily 5-h sessions. A separate group of rats ( n=10) was tested using a discrete trials procedure; animals were given the opportunity to self-administer cocaine (1.5 mg/kg per injection) during 10-min trials which were initiated every 20 min throughout the day/night cycle. RESULTS: On the FR schedule, pretreatment with HD-23 (1.0 mg/kg) decreased the rate of cocaine intake. HD-23 shifted the dose-response curve on the PR schedule to the left. On the discrete trials schedule, animals displayed a circadian pattern of drug intake; pretreatment with HD-23 significantly increased cocaine intake for about 8 h during the light phase when the probability of responding would otherwise have been very low. Animals pretreated with HD-23 displayed a high probability of cocaine self-administration for about 14 h. CONCLUSIONS: The results are consistent with the idea that an acute pretreatment with the long-acting agonist, HD-23, augmented rather than diminished the motivation to self-administer cocaine.

Diastereoselective Manipulations of Bicyclo[m.1.0]alkane Derivatives. 4. Reactions of Nucleophiles with Bicyclo[m.1.0]alk-3-en-2-ones.

Enantiomerically enriched bicyclo[m.1.0]alk-3-en-2-ones possessing 8-, 12-, and 15-membered rings were prepared and subjected to additions of nucleophiles. 1,2-Additions of n-butyllithium were highly diastereoselective for all cyclopropyl enones examined. Reactions of (Z)-bicyclo[6.1.0]non-3-en-2-one and (E)-bicyclo[13.1.0]hexadec-3-en-2-one with dimethyloxosulfonium methylide were highly diastereoselective, while reaction of (E)-bicyclo[10.1.0]tridec-3-en-2-one with this reagent was not diastereoselective. In contrast, 1,4-additions of lithium diorganocuprates were highly diastereoselective for the 8- and 12-membered enones but were not diastereoselective for the 15-membered enone. All reactions were chemically efficient. The diastereoselectivities observed for 1,2-additions, which are thought to involve early transition states, can be rationalized by consideration of the low-energy conformations of each cyclopropyl enone. The diastereoselectivities observed for 1,4-additions, which may involve late transition states, do not correlate simply with the lowest energy conformations of these enones.

Development of Molecular Mechanics Torsion Parameters for alpha,beta-Cyclopropyl Ketones and Conformational Analysis of Bicyclo[m.1.0]alkan-2-ones.

Conformations of cyclopropyl methyl ketone have been studied using ab initio methods in an effort to quantify the effects of conjugative overlap between the cyclopropane ring and an adjacent ketone carbonyl. Results were comparable with previous experimental and theoretical studies. Cyclopropyl methyl ketone exhibits a global energy minimum in the s-cis conformer and a local energy minimum near the s-trans conformer. The potential energy curve obtained was used to derive torsion parameters which were employed in molecular mechanics studies of the conformations of the set of bicyclo[m.1.0]alkan-2-ones having larger ring sizes from five- to 16-membered. Similar conformations for the cyclopropyl ketone substructure are observed for all the medium and large ring systems examined. Possible synthetic ramifications of local conformational anchoring by this functional group array are discussed.

Diastereoselective Manipulations of Bicyclo[m.1.0]alkane Derivatives. 2. Nucleophilic Additions to the Carbonyl Carbons of Bicyclo[m.1.0]alkan-2-ones(1).

Enantiomerically enriched bicyclo[m.1.0]alkan-2-ones having larger ring sizes between five and 16 members were prepared and subjected to additions of nucleophiles to the carbonyl carbon. Such additions were efficient and highly diastereoselective for all nucleophiles for bicycles with ring sizes greater than seven. Diastereoselectivity for these additions is rationalized by assuming early transition states and exposure of the same carbonyl face to the ring exterior in the vast majority of populated conformers for each bicyclic ketone.