Investigating Substituent Interactions with Cationic Catalysts.

Rates of isothiourea catalyzed silylation and acylation reactions were measured for substrates with various electronic substituents at the aryl group. Through these measurements, the intermolecular interactions between cationic catalyst intermediates and different aryl groups were explored. These studies were performed to understand how changes in the catalyst structure affected electrostatic intermolecular interactions. Three different catalysts (N-methylimidazole and two isothioureas) were employed that varied in their ability to delocalize their cationic nature. The results show that more delocalization on the catalyst reduces the sensitivity to the electronics on the aryl group. Surprisingly, the isothiourea with a fused benzene ring provided additional points of interaction with groups that contained lone-pairs, significantly affecting the overall rate. This work helps explore the interactions that dominate in these types of catalytic systems, to aid in future organocatalysis development. Density functional theory (DFT) studies further confirmed isothiourea/aryl ring interaction with the alcohol substrate in the acylation process, which confirmed these hypotheses. Electron rich or lone-pair bearing functional groups stabilize the cationic catalyst core, thereby stabilizing the transition states and accelerating the reaction. It was also discovered that in one case, the formation of a stable substrate dimer was responsible for its lower reactivity.

Mechanistic investigations of alcohol silylation with isothiourea catalysts.

The mechanism of the asymmetric silylation of alcohols with isothiourea catalysts was studied by employing reaction progress kinetic analysis. These reactions were developed by the Wiskur group, and use triphenyl silyl chloride and chiral isothiourea catalysts to silylate the alcohols. While the order of most reaction components was as expected (catalyst, amine base, alcohol), the silyl chloride was determined to be a higher order. This suggested a multistep mechanism between the catalyst and silyl chloride, with the second equivalent of silyl chloride assisting in the formation of the reactive intermediate leading to the rate-determining step. Through the addition of additives and investigating changes in the silyl chloride, an understanding of the catalyst equilibrium emerged for this reaction and provided pathways for further reaction development.

Cycloaddition/Electrocyclic Ring Opening Sequence between Alkynyl Sulfides and Azodicarboxylates To Provide N,N-Dicarbamoyl 2-Iminothioimidates.

The α-oxidized thioimidates are useful bidentate ligands and are important motifs in pharmaceuticals, pesticides, and fungicides. Despite their broad utility, a direct route for their synthesis has been elusive. Herein, we describe a one-step synthesis of N,N-dicarbamoyl 2-iminothioimidates from easily accessible thioacetylenes and commercially available azodicarboxylates (20 examples, ≤99% yield). Additionally, the mechanism of the transformation was extensively explored by variable-temperature NMR, in situ IR, and quantum mechanical simulations. These experiments suggest that the reaction commences with a highly asynchronous [2 + 2] cycloaddition, which leads to a four-membered diazacyclobutene intermediate with a barrier consistent with the observed reaction rate. This intermediate was then isolated for subsequent kinetic measurements, which yielded an experimental barrier within 1 kcal/mol of the calculated barrier for a subsequent 4π electrocyclic ring opening leading to the observed iminothioimidate products. This method represents the first direct route to α-oxidized thioimidates from readily accessible starting materials.

Understanding Internal Chirality Induction of Triarylsilyl Ethers Formed from Enantiopure Alcohols.

Chirality transmission from point chirality to helical chirality was explored using triarylsilyl ethers. Circular dichroism (CD) spectroscopy was employed to show that the alcohol stereocenter of silylated, enantiopure secondary alcohols can transmit chirality to the aryl groups on the silicon resulting in a higher population of one helical conformation over another. Cotton effects characteristic of the aryl groups organized into one preferred conformation were observed for all of the compounds examined, which included both triphenyl- and trinaphthylsilyl groups. Alcohols with an R configuration typically induced a PMP helical twist, while an S configuration induced a MPM helical twist. Molecular modeling combined with solid-state structures also gave evidence signifying that point chirality adjacent to triphenylsilyl groups could bias the conformation of the phenyl groups. This work helps in our understanding of the origin of selectivity in our silylation-based kinetic resolutions and a role the phenyl groups play in that selectivity.

Diastereoselective and enantioselective silylation of 2-arylcyclohexanols.

The silylation-based kinetic resolution of trans 2-arylcyclohexanols was accomplished by employing a triaryl silyl chloride as the derivatizing reagent with a commercially available isothiourea catalyst. The methodology is selective for the trans diastereomer over the cis, which provides an opportunity to selectively derivatize one stereoisomer out of a mixture of four. By employing this technology, a facile, convenient method to form a highly enantiomerically enriched silylated alcohol was accomplished through a one-pot reduction-silylation sequence that started with a 2-aryl-substituted ketone.

Linear free-energy relationship and rate study on a silylation-based kinetic resolution: mechanistic insights.

The substituent effect of different p-substituted triphenylsilyl chlorides on silylation-based kinetic resolutions was explored. Electron-donating groups slow down the reaction rate and improve the selectivity, while electron-withdrawing groups increase the reaction rate and decrease the selectivity. Linear free-energy relationships were found correlating both selectivity factors and initial rates to the σ(para) Hammett parameters. A weak correlation of selectivity factors to Charton values was also observed when just alkyl substituents were employed but was nonexistent when substituents with more electronic effects were incorporated. The rate data suggest that a significant redistribution of charge occurs in the transition state, with an overall decrease in positive charge. The linear free-energy relationship derived from selectivity factors is best understood by the Hammond postulate. Early and late transition states describe the amount of substrate participation in the transition state and therefore the difference in energy between the diastereomeric transition states of the two enantiomers. This work highlights our efforts toward understanding the mechanism and origin of selectivity in our silylation-based kinetic resolution.

Silylation-based kinetic resolution of α-hydroxy lactones and lactams.

A silylation-based kinetic resolution has been developed for α-hydroxy lactones and lactams employing the chiral isothiourea catalyst (-)-benzotetramisole and triphenylsilyl chloride as the silyl source. The system is more selective for lactones than lactams, and selectivity factors up to 100 can be achieved utilizing commercially available reagents.

Obtaining enriched compounds via a tandem enantioselective reaction and kinetic resolution polishing sequence.

Herein we describe a tandem method of coupling an enantioselective reaction with a nonenzymatic kinetic resolution to prepare highly enantioenriched compounds. The procedure employs a moderately selective enantioselective reaction on a ketone or aldehyde to form an enriched alcohol followed by a kinetic resolution of the alcohol to generate ee's of >99% in yields greater than what is possible with a kinetic resolution. This method highlights an avenue to quickly acquire highly enriched compounds without developing and optimizing a new methodology.

Silylation-based kinetic resolution of monofunctional secondary alcohols.

The nucleophilic small molecule catalyst (-)-tetramisole was found to catalyze the kinetic resolution of monofunctional secondary alcohols via enantioselective silylation. Optimization of this new methodology allows for selectivity factors up to 25 utilizing commercially available reagents and mild reaction conditions.

Catalytic asymmetric synthesis of esters from ketenes.

By building on elementary principles of Brønsted acid-base chemistry, a nucleophile-catalyzed method for the asymmetric synthesis of esters from ketenes has been transformed into a much more versatile and effective Brønsted acid-catalyzed process. The product aryl esters can be converted into useful derivatives, such as enantioenriched alcohols and carboxylic acids.

Tuning the specificity of a synthetic receptor using a selected nucleic acid receptor.

Because of their relative simplicity, synthetic receptors often lack the selectivity observed for biopolymer receptors, such as aptamers. However, aptamer recognition of ligands is limited by the chemistries inherent in the four canonical nucleotides. Here, we report the design and selection of a ternary complex in which the specificity of a bis-boronic acid synthetic host (1) that binds to various carboxylic acids is tuned by a surrounding aptamer. Although, the synthetic receptor alone has higher selectivity for citrate over DL-tartrate, the formation of the aptamer:receptor complex reversed the organic host selectivity to preferentially bind tartrate. The RNA conformation changed upon the introduction of the synthetic host, consistent with an induced-fit mechanism for binding.

Thermodynamic analysis of receptors based on guanidinium/boronic acid groups for the complexation of carboxylates, alpha-hydroxycarboxylates, and diols: driving force for binding and cooperativity.

The thermodynamics of guanidinium and boronic acid interactions with carboxylates, alpha-hydroxycarboxylates, and diols were studied by determination of the binding constants of a variety of different guests to four different hosts (7-10). Each host contains a different combination of guanidinium groups and boronic acids. The guests included molecules with carboxylate and/or diol moieties, such as citrate, tartrate, and fructose, among others. The Gibbs free energies of binding were determined by UV/Vis absorption spectroscopy, by use of indicator displacement assays. The receptor based on three guanidinium groups (7) was selective for the tricarboxylate guest. The receptors that incorporated boronic acids (8-10) had higher affinities for guests that included alpha-hydroxycarboxylate and catechol moieties over guests containing only carboxylates or alkanediols. Isothermal titration calorimetry revealed the enthalpic and entropic contributions to the Gibbs free energies of binding. The binding of citrate and tartrate was investigated with hosts 7-10, for which all the binding events were exothermic, with positive entropy. Because of the selectivity of hosts 8-10, a simple boronic acid (14) was also investigated and determined to be selective for alpha-hydroxycarboxylates and catechols over amino acids and alkanediols. Further, the cooperativity of 8 and 9 in binding tartrate was also investigated, revealing little or no cooperativity with 8, but negative cooperativity with 9. A linear entropy/enthalpy compensation relationship for all the hosts 7-10, 14, and the carboxylate-/diol-containing guests was also obtained. This relationship indicates that increasing enthalpy of binding is offset by similar losses in entropy for molecular recognition involving guanidinium and boronic acid groups.

Using indicator-displacement assays in test strips and to follow reaction kinetics.

[structure: see text] An indicator-displacement assay was used to study the kinetics of reactions that produce tartrate. The same assay was also found to be useful in developing tartrate test strips, by coating filter paper with the same receptor and indicator.

Threshold detection using indicator-displacement assays: an application in the analysis of malate in Pinot Noir grapes.

The mathematics for modeling indicator-displacement assay isotherms is presented and contrasted to the classical host-guest binding isotherm. It is shown that the signal response can be tuned to occur closer to 1 equiv of guest relative to a standard binding algorithm. This delay in response leads to a better triggering protocol for threshold detection schemes. The determination of malate in Pinot Noir must was calculated using this new mathematical model, which demonstrates how a color change can be tuned to occur near a desired concentration of analyte.

Cross-couplings of alkyl electrophiles under "ligandless" conditions: Negishi reactions of organozirconium reagents.

This report establishes that simple, "ligandless" palladium complexes can catalyze the first zirconium-Negishi reactions of alkyl electrophiles. In view of the attractiveness of ligandless catalysts (cost, simplicity, and ease of purification), these observations add a significant and intriguing new dimension to the development of effective palladium-based processes for coupling alkyl electrophiles.