Bridged bicyclic compounds: Comprehending a novel compound class as potential anti-seizure agents.

OBJECTIVE: In the present study, we describe a novel class of small-molecule synthetic compounds that ameliorate seizure-like behavior, using an electroshock assay to examine seizure duration in Caenorhabditis elegans. We also examine the hypothesis that these compounds, which we have called resveramorphs (RVMs), act by an irreversible binding mechanism. METHODS: Our electroshock assay examines seizure duration in C. elegans and can be used as a drug-screening platform for the identification of novel anti-seizure agents. The use of C. elegans allows for a rapid and efficient method of drug screening that may take years in other higher-order model organisms. A novel wash method, paired with our electroshock assay, allows us to discern differences in biological activity when the C. elegans are incubated in different drug solutions, to establish whether these compounds can be "washed" off. RESULTS: One of the RVMs (RVM-3), reported here for the first time, was found to be potent at picomolar concentrations. Insights also provided information on the potential mechanisms of action of this compound. Covalent binding is thought to provide a strong irreversible bond because of a change in structure between two of the novel RVMs described in this work. This was also discerned through the novel wash method paired with our electroshock assay. SIGNIFICANCE: RVM-3 was evaluated using our assay and found to possess anti-seizure activity at picomolar concentrations. These insights also provide information on the potential mechanisms of action of these compounds, which may include covalent binding. This was also discerned through a novel wash method paired with our electroshock assay.

Crown Ether Nucleophilic Catalysts (CENCs): Agents for Enhanced Silicon Radiofluorination.

New bifunctional phase transfer agents were synthesized and investigated for their abilities to promote rapid fluorination at silicon. These agents, dubbed crown ether nucleophilic catalysts (CENCs), are 18-crown-6 derivatives containing a side-arm and a potentially nucleophilic hydroxyl group. These CENCs proved efficacious in the fluorination of hindered silicon substrates, with fluorination yields dependent on the length of linker connecting the metal chelating unit to the hydroxyl group. The efficacy of these CENCs was also demonstrated for rapid radiofluorination under mild conditions for eventual application in molecular imaging with positron emission tomography (PET). The hydrolysis-resistant aryl silicon fragment is promising as a convenient synthon for labeling potential PET radiotracers.

Allenyl esters as quenching agents for ruthenium olefin metathesis catalysts.

In the attempt to synthesize substituted allenyl esters through a metathesis coupling of unsubstituted allenyl esters and alkenes using a variety of ruthenium catalysts, it was discovered that allenyl esters themselves cleanly arrested the activity of the catalysts. Further studies suggests possible utility of allene esters as general quenching agents for metathesis reactions. To explore this idea, several representative olefin metathesis reactions, including ring closing, were successfully terminated by the addition of simple allenyl esters for more convenient purification.

A Teaching Experiment to Elucidate a Cation-π Effect in an Alkyne Cycloaddition Reaction and Illustrate Hypothesis Driven Design of Experiments.

An organic chemistry experiment is described that is based on recent research to elucidate a novel cation-π interaction between tetraalkammonium cations and propargyl hydrazines. This non-bonded interaction is a key component of the mechanism of ammonium-catalyzed intramolecular cycloaddition of nitrogen to the terminal carbon of a C-C triple bond of the propargyl substrate. In this teaching experiment, reactions and control experiments are employed to demonstrate the testing of two alternative mechanistic hypotheses. Specifically, cyclization reactions are performed with a soluble base (sodium phenoxide) with and without tetrabutylammonium bromide under homogeneous conditions. Students observe that the added ammonium salt accelerates the reaction. They are then encouraged to develop a testable hypothesis for the role of the ammonium salt in the cyclization mechanism: typical phase transfer or other. IR spectroscopy is then used to directly observe a dose dependent shift of the alkyne stretching mode due to a cation-π interaction. In this experiment, undergraduate "researchers" were able to practice the scientific method on a contemporary system and see how data are generated and interpreted to adjudicate between rival hypotheses in a way that emulates authentic and current research in a lab setting. This experimental design was tested on students enrolled in the introductory undergraduate Organic Chemistry Lab.

Annulation reactions of allenyl esters: an approach to bicyclic diones and medium-sized rings.

A flexible approach to construct sterically congested bicyclo-alkenedione frameworks is reported. Under the action of potassium carbonate, α-sulphonyl cycloalkanones are added to functionalized allenyl esters, leading to a lactone intermediate that is subsequently reduced to initiate an intramolecular aldol cyclization to [3.2.1], [3.3.1], and [4.3.1] bicycles. Oxidation then affords bicyclic diones in good three-step yields. Under exceptionally mild conditions, these bicycles are converted to highly functionalized medium-sized rings through a Grob-type fragmentation.

Enhanced Nucleophilic Fluorination and Radiofluorination of Organosilanes Appended with Potassium-Chelating Leaving Groups.

Here we aimed to explore the feasibility of enhancing the fluorination of organosilanes by appending potassium-chelating groups to the substrates. For this purpose, eight organosilanes were prepared in which a linear or cyclic leaving group, with putative potassium-chelating ability, was attached covalently to a congested silicon atom via an ether linkage to serve as a potential nucleophilic assisting leaving group (NALG). Organosilicon-NALGs with expected strong potassium-chelating capability enhanced reactions with potassium fluoride in acetonitrile to produce organofluorosilanes without any need to separately add phase transfer reagent. Similar rate enhancements were also observed with cyclotron-produced [18F]fluoride ion (t1/2 = 109.7 min, ß+ = 97%) in the presence of potassium carbonate in MeCN-0.5% H2O. This study found that metal-chelating NALG units can accelerate fluorination and radiofluorination reactions at sterically crowded silicon atoms.

Stereoretentive Copper (II) Catalyzed Ritter Reactions of Secondary Cycloalkanols.

A Ritter-like coupling reaction of cyclic alcohols and both aryl and alkyl nitriles to form amides catalyzed by copper (II) triflate is described. These reactions proceed in good yields under mild and often solvent-free conditions. With 2- and 3-substituted cycloalkanols, amide products are formed with near complete retention of configuration. This is likely due to fast nucleophilic capture of a non-planar carbocations (hyperconjomers) stabilized by ring hyperconjugation. A critical aspect of this novel catalytic cycle is the in situ activation of the alcohol substrates by thionyl chloride to form chlorosulfites.

Stereoretentive chlorination of cyclic alcohols catalyzed by titanium(IV) tetrachloride: evidence for a front side attack mechanism.

A mild chlorination reaction of alcohols was developed using the classical thionyl chloride reagent but with added catalytic titanium(IV) chloride. These reactions proceeded rapidly to afford chlorination products in excellent yields and with preference for retention of configuration. Stereoselectivities were high for a variety of chiral cyclic secondary substrates including sterically hindered systems. Chlorosulfites were first generated in situ and converted to alkyl chlorides by the action of titanium tetrachloride which is thought to chelate the chlorosulfite leaving group and deliver the halogen nucleophile from the front face. To better understand this novel reaction pathway, an ab initio study was undertaken at the DFT level of theory using two different computational approaches. This computational evidence suggests that while the reaction proceeds through a carbocation intermediate, this charged species likely retains pyramidal geometry existing as a conformational isomer stabilized through hyperconjugation (hyperconjomers). These carbocations are then essentially "frozen" in their original configurations at the time of nucleophilic capture.

Chiral Allenylcarbonyls - Underexploited Building Blocks for Complex Synthesis.

Chiral allenylcarbonyls such as allenoates remain underutilized in complex synthesis despite recent advances in synthesis methods to prepare them non-racemically. The field is now ripe for the employment of this class of allenes as building blocks to facilitate the construction of complex small-molecule compounds, such as bridged bicycles.

Diastereoselective additions of H-phosphinates to alkenyl ketones under phase-transfer conditions.

Additions of bulky H-phosphinates to ß,ß-disubstituted alkenyl ketones under the action of a phase transfer-catalyst led to a new class of carbon quaternary center-containing phosphinates with unprecedented control of the relative configuration of the adjacent carbon and phosphorous chiral centers with high diastereoselectivity in most cases.

A Direct and Stereoretentive Synthesis of Amides from Cyclic Alcohols.

Chlorosulfites prepared in situ using thionyl chloride react with nitrile complexes of titanium (IV) fluoride to give a one-pot conversion of alcohols into amides. For the first time, amides are obtained from cyclic alcohols with stereoretention. Critical to the design of these new Ti(IV) reactions has been the use of little explored Ti(IV) nitrile complexes which are thought to chelate chlorosulfites in the transition state to create a carbocation that is rapidly captured by the nitrile nucleophile via a front-side attack mechanism.

Anion-catalyzed addition of gamma-silylallenyl esters to aldehydes: a new entry into [3.2.1] bicyclic natural products.

A significant improvement in the generality and reactivity of MBH-type reactions is made possible by anion catalysis and a 1,3-Brook rearrangement. In this new reaction, both aliphatic and aromatic aldehydes are rapidly added to silylallenes, leading to gamma-carbinol allenoates at low temperatures. The utility of these reaction products is demonstrated by a fast-tracked synthesis of a [3.2.1] bisoxa bicycle that makes up the framework of many biologically active natural products, including vitisinol D, an antithrombotic agent.

Selective one-pot synthesis of allenyl and alkynyl esters from beta-ketoesters.

A convenient method is described for the dehydration of beta-ketoesters to generate conjugated and deconjugated alkynyl esters and conjugated allenyl esters. This sequential one-pot method involves the formation of a vinyl triflate monoanion intermediate that leads to the selective formation of alkynes or allenes depending on additives and conditions used. Product outcomes appear to be a function of unique mono- and dianion mechanisms which are described.

Nucleophile assisting leaving groups: a strategy for aliphatic 18F-fluorination.

A series of arylsulfonate nucleophile assisting leaving groups (NALGs) were prepared in which the metal chelating unit is attached to the aryl ring via an ether linker. These NALGs exhibited significant rate enhancements in halogenation reactions using metal halides. Studies with a NALG containing a macrocyclic ether unit suggest that rate enhancements of these nucleophilic halogenation reactions are facilitated by stabilization of charge in the transition state rather than through strong precomplexation with metal cation. In several cases, a primary substrate containing one of the new leaving groups rivaled or surpassed the reactivity of triflates when exposed to nucleophile but was otherwise highly stable and isolable. These and previously disclosed chelating leaving groups were used in (18)F-fluorination reactions using no-carrier-added [18F]fluoride ion (t(1/2) = 109.7 min, beta+ = 97%) in CH3CN. Under microwave irradiation and without the assistance of a cryptand, such as K2.2.2, primary substrates with select NALGs led to a substantial improvement (2-3-fold) in radiofluorination yields over traditional leaving groups.

Carbon-Carbon Bond Formation Facilitated by π-Complexed Organometallic Auxiliaries: An Overview.

Organometallic moieties attached to substrates via π-complexation play an important role as auxiliaries. As described in the present review, η-linked auxiliaries have been employed to overcome numerous synthesis obstacles that continue to present significant challenges for catalyzed reactions. This has been particularly true in carbon-carbon bond forming reactions involving highly unsaturated systems such as arenes, dienes and allenes, which are emphasized here.

Allenoate Prenucleophiles: A Triply Diastereoselective Approach to ß-Hydroxy Esters Containing All-Carbon α-Quaternary Centers.

Allenyl esters activated by titanium(IV) underwent additions to a wide range of aldehydes in high regio- and diastereoselectivities leading to products containing an all-carbon quaternary center bearing an α-vinyl group that was installed with high selectivity for the Z-geometry. An aldol product was also converted to an indanone offering a new route to this important compound class. Product triple diastereoselectivity has been rationalized using a concerted transition-state model.

Resveratrol-Inspired Bridged Bicyclic Compounds: A New Compound Class for the Protection of Synaptic Function from Acute Oxidative Stress.

While resveratrol protects organisms from the deleterious effects of oxidative stress, its multifarious mechanism of action limits its potential as a selective medicinal agent. To address this shortcoming, we have designed a molecular scaffold that we have termed a resveramorph. The structure of this compound class possesses much of the functional group characteristics of resveratrol but in a nonplanar molecular arrangement, and, in the present work, we probe the neuroprotective activities of two resveramorph analogues. These novel compounds were found to protect neurotransmission from hydrogen peroxide-induced oxidative stress. Our findings demonstrate that, at a subnanomolar level, one analogue, resveramorph 1, protects synaptic transmission from acute oxidative stress at the Drosophila neuromuscular junction. These results position resveramorphs as potential lead compounds in the development of new drugs for neurodegenerative diseases.

Diversification reactions of γ-silyl allenyl esters: selective conversion to all-carbon quaternary centers and γ-allene dicarbinols.

The unique reactivity of γ-silyl allenyl esters is described. Taking advantage of the silyl group as a fluoride acceptor, these allenoates readily underwent addition to a variety of electrophiles to selectively yield products with all-carbon quaternary centers or allenoate dicarbinols. These dicarbinols were subsequently converted to novel highly substituted 6-hydro-2-pyrones.

Alkyne Cycloadditions Mediated by Tetrabutylammonium Fluoride: A Unified and Diversifiable Route to Isoxazolines and Pyrazolines.

A versatile approach to isoxazolines and pyrazolines by the cyclization of alkyne substrates using tetrabutylammonium fluoride (TBAF) is described. The reported diheteroatom cycles were produced under mild reaction conditions and with broad product scope. Evidence is also provided for a vinyl anion intermediate produced under unusually mild conditions, which was trapped in situ as part of a tandem cyclization/aldehyde addition sequence. Finally, a deprotection/functionalization method is described, leading to a substituted pyrazoline in good diastereoselectivity.