Anodic Cyclizations, Densely Functionalized Synthetic Building Blocks, and the Importance of Recent Mechanistic Observations.

Anodic cyclization reactions can provide a versatile method for converting newly obtained chiral lactols to densely functionalized cyclic building blocks. The method works by first converting the lactol into an electron-rich olefin and then oxidatively generating a radical cation that is trapped by a nucleophile. Historically, such reactions have benefited from the use of less polar radical cations when the trapping nucleophile is a heteroatom and more polar radical cations when the reaction forms C-C bonds. This forced one to optimize underperforming reactions by resynthesizing the substrate. Here, we show that by taking advantage of methods that serve to drive a reversible initial cyclization reaction toward the product, this dichotomy and need to manipulate the substrate can be avoided. Two such methods were utilized: a faster second oxidation step and a mediated electrolysis. Both led to successful cyclizations using a polar radical cation and heteroatom nucleophiles.

Concluding remarks: A summary of the Faraday Discussion on electrosynthesis.

A summary of the Faraday Discussion presented in this issue and a perspective on that discussion is presented. The work highlights the specific science contributions made and the key conclusions associated with those findings so that readers can identify papers that they would like to explore in more detail.

A Building Block Approach for the Total Synthesis of YM-385781.

YM-254890 and FR900359 are potent and selective inhibitors of the Gq/11-signaling pathway. As such, they have been attractive targets for both synthesis and biological studies. Yet in spite of this effort, a versatile synthetic approach to the molecules that allows for the rapid construction of a variety of non-natural and labelled analogs and an increase in the amount of those analogs available remains elusive. We report here a convergent building block approach to the molecules that can solve this challenge.

Lessons from an Array: Using an Electrode Surface to Control the Selectivity of a Solution-Phase Chemical Reaction.

Electrochemistry offers a variety of novel means by which selectivity can be introduced into synthetic organic transformations. In the work reported, it is shown how methods used to confine chemical reactions to specific sites on a microelectrode array can also be used to confine a preparative reaction to the surface of an electrode inserted into a bulk reaction solution. In so doing, the surface of a modified electrode can be used to introduce new selectivity into a preparative reaction that is not observed in the absence of either the modified electrode surface or the effort to confine the reaction to that surface. The observed selectivity can be optimized in the same way that confinement is optimized on an array and is dependent on the nature of the functionalized surface.

Microelectrode arrays, electrosynthesis, and the optimization of signaling on an inert, stable surface.

Microelectrode arrays are powerful tools for monitoring binding interactions between small molecules and biological targets. In most cases, molecules to be studied using such devices are attached directly to the electrodes in the array. Strategies are in place for calibrating signaling studies utilizing the modified electrodes so that they can be quantified relative to a positive control. In this way, the relative binding constants for multiple ligands for a receptor can potentially be determined in the same experiment. However, there are applications of microelectrode arrays that require stable, tunable, and chemically inert surfaces on the electrodes. The use of those surfaces dictate the use of indirect detection methods that are dependent on the nature of the stable surface used and the amount of the binding partner that is placed on the surface. If one wants to do a quantitative study of binding events that involve molecules on such a stable surface, then once again a method for calibrating the signal from a positive control is needed. Fortunately, the electrodes in an array are excellent handles for conducting synthetic reactions on the surface of an array, and those reactions can be used to tune the surface above the electrodes and calibrate the signal from a positive control. Here, we describe how available Cu-based electrosynthetic reactions can be used to calibrate electrochemical signals on a polymer-coated electrode array and delineate the factors to be considered when choosing a polymer surface for such a study.

From Molecules to Molecular Surfaces. Exploiting the Interplay Between Organic Synthesis and Electrochemistry.

For many years, we have been looking at electrochemistry as a tool for exploring, developing, and implementing new synthetic methods for the construction of organic molecules. Those efforts examined electrochemical methods and mechanisms and then exploited them for synthetic gain. Chief among the tools utilized was the fact that in a constant current electrolysis the working potential at the electrodes automatically adjusted to the oxidation (anode) or reduction (cathode) potential of the substrates in solution. This allowed for a systematic examination of the radical cation intermediates that are involved in a host of oxidative cyclization reactions. The result has been a series of structure-activity studies that have led to far greater insight into the behavior of radical cation intermediates and in turn an expansion in our capabilities of using those intermediates to trigger interesting synthetic reactions. With that said, the relationship between synthetic organic chemistry and electrochemistry is not a "one-way" interaction. For example, we have been using modern synthetic methodology to construct complex addressable molecular surfaces on electroanalytical devices that in turn can be used to probe biological interactions between small molecules and biological receptors in "real-time". Synthetic chemistry can then be used to recover the molecules that give rise to positive signals so that they can be characterized. The result is an analytical method that both gives accurate data on the interactions and provides a unique level of quality control with respect to the molecules giving rise to that data. Synthetic organic chemistry is essential to this task because it is our ability to synthesize the surfaces that defines the nature of the biological problems that can be studied. But the relationship between the fields does not end there. Recently, we have begun to show that work to expand the scope of microelectrode arrays as bioanalytical devices is teaching us important lessons for preparative synthetic chemistry. These lessons come in two forms. First, the arrays have taught us about the on-site generation of chemical reagents, a lesson that is being used to expand the use of paired electrochemical strategies for synthesis. Second, the arrays have taught us that reagents can be generated and then confined to the surface of the electrode used for that generation. This has led to a new approach to taking advantage of molecular recognition events that occur on the surface of an electrode for controlling the selectivity of a preparative reaction. In short, the confinement strategy developed for the arrays is used to ensure that the chemistry in a preparative electrolysis happens at the electrode surface and not in the bulk solution. This Account details the interplay between synthetic chemistry and electrochemistry in our group through the years and highlights the opportunities that interplay has provided and will continue to provide in the future.

Anodic Olefin Coupling Reactions: Elucidating Radical Cation Mechanisms and the Interplay between Cyclization and Second Oxidation Steps.

Anodic olefin coupling reactions generate new bonds and ring skeletons through a net two electron process that reverses the polarity of a known, electron-rich functional group. While much of the early work on the mechanism of these reactions focused on the initial oxidation and cyclization steps of the process, the second oxidation step also plays a central role in determining the success of the reaction. Evidence supporting this observation is presented, along with evidence that optimization of this second oxidation step is not enough to pull a poor cyclization to the desired product. Successful cyclization reactions require optimization of both processes.

Capitalizing on Mediated Electrolyses for the Construction of Complex, Addressable Molecular Surfaces.

Synthetic organic chemists are beginning to exploit electrochemical methods in increasingly creative ways. This is leading to a surge in productivity that is only now starting to take advantage of the full-potential of electrochemistry for accessing new structures in novel, more efficient ways. In this perspective, we provide insight into the potential of electrochemistry as a synthetic tool gained through studies of both direct anodic oxidation reactions and more recent indirect methods, and highlight how the development of new electrochemical methods can expand the nature of synthetic problems our community can tackle.

Organic Electrochemistry: Expanding the Scope of Paired Reactions.

Paired electrochemical reactions allow the optimization of both atom and energy economy of oxidation and reduction reactions. While many paired electrochemical reactions take advantage of perfectly matched reactions at the anode and cathode, this matching of substrates is not necessary. In constant current electrolysis, the potential at both electrodes adjusts to the substrates in solution. In principle, any oxidation reaction can be paired with any reduction reaction. Various oxidation reactions conducted on the anodic side of the electrolysis were paired with the generation and use of hydrogen gas at the cathode, showing the generality of the anodic process in a paired electrolysis and how the auxiliary reaction required for the oxidation could be used to generate a substrate for a non-electrolysis reaction. This is combined with variations on the cathodic side of the electrolysis to complete the picture and illustrate how oxidation and reduction reactions can be combined.

Using Physical Organic Chemistry To Shape the Course of Electrochemical Reactions.

While organic electrochemistry can look quite different to a chemist not familiar with the technique, the reactions are at their core organic reactions. As such, they are developed and optimized using the same physical organic chemistry principles employed during the development of any other organic reaction. Certainly, the electron transfer that triggers the reactions can require a consideration of new "wrinkles" to those principles, but those considerations are typically minimal relative to the more traditional approaches needed to manipulate the pathways available to the reactive intermediates formed downstream of that electron transfer. In this review, three very different synthetic challenges-the generation and trapping of radical cations, the development of site-selective reactions on microelectrode arrays, and the optimization of current in a paired electrolysis-are used to illustrate this point.

Anti-hypertensive mechanisms of cyclic depsipeptide inhibitor ligands for Gq/11 class G proteins.

Augmented vasoconstriction is a hallmark of hypertension and is mediated partly by hyper-stimulation of G protein couple receptors (GPCRs) and downstream signaling components. Although GPCR blockade is a key component of current anti-hypertensive strategies, whether hypertension is better managed by directly targeting G proteins has not been thoroughly investigated. Here, we tested whether inhibiting Gq/11 proteins in vivo and ex vivo using natural cyclic depsipeptide, FR900359 (FR) from the ornamental plant, Ardisia crenata, and YM-254890 (YM) from Chromobacterium sp. QS3666, or it's synthetic analog, WU-07047 (WU), was sufficient to reverse hypertension in mice. All three inhibitors blocked G protein-dependent vasoconstriction, but to our surprise YM and WU and not FR inhibited K+-induced Ca2+ transients and vasoconstriction of intact vessels. However, each inhibitor blocked whole-cell L-type Ca2+ channel current in vascular smooth muscle cells. Subcutaneous injection of FR or YM (0.3 mg/kg, s.c.) in normotensive and hypertensive mice elicited bradycardia and marked blood pressure decrease, which was more severe and long lasting after the injection of FR relative to YM (FRt1/2 ≅ 12 h vs. YMt1/2 ≅ 4 h). In deoxycorticosterone acetate (DOCA)-salt hypertension mice, chronic injection of FR (0.3 mg/kg, s.c., daily for seven days) reversed hypertension (vehicle SBP: 149 ± 5 vs. FR SBP: 117 ± 7 mmHg), without any effect on heart rate. Our results together support the hypothesis that increased LTCC and Gq/11 activity is involved in the pathogenesis of hypertension, and that dual targeting of both proteins can reverse hypertension and associated cardiovascular disorders.

Paired Electrochemical Reactions and the On-Site Generation of a Chemical Reagent.

While the majority of reported paired electrochemical reactions involve carefully matched cathodic and anodic reactions, the precise matching of half reactions in an electrolysis cell is not generally necessary. During a constant current electrolysis almost any oxidation and reduction reaction can be paired, and in the presented work we capitalize on this observation by examining the coupling of anodic oxidation reactions with the production of hydrogen gas for use as a reagent in remote, Pd-catalyzed hydrogenation and hydrogenolysis reactions. To this end, an alcohol oxidation, an oxidative condensation, intramolecular anodic olefin coupling reactions, an amide oxidation, and a mediated oxidation were all shown to be compatible with the generation and use of hydrogen gas at the cathode. This pairing of an electrolysis reaction with the production of a chemical reagent or substrate has the potential to greatly expand the use of more energy efficient paired electrochemical reactions.

Organic Electrochemistry and a Role Reversal: Using Synthesis To Optimize Electrochemical Methods.

Diblock copolymers are excellent coatings for microelectrode arrays because they provide a stable surface that can support both synthetic and analytical electrochemistry. However, the surfaces that are optimal for synthetic studies are not the same as the surfaces that are optimal for analytical studies. Hence, no one surface provides an ideal platform for both building and analyzing a molecular library. Fortunately, the synthetic chemistry available on a microelectrode array allows a surface that is ideal for synthesis can be converted into one that is ideal for signaling studies; a scenario that allows for the use of an optimized synthetic and analytical surface on a single microelectrode array.

Anodic Cyclization Reactions and the Mechanistic Strategies That Enable Optimization.

Oxidation reactions are powerful tools for synthesis because they allow us to reverse the polarity of electron-rich functional groups, generate highly reactive intermediates, and increase the functionality of molecules. For this reason, oxidation reactions have been and continue to be the subject of intense study. Central to these efforts is the development of mechanism-based strategies that allow us to think about the reactive intermediates that are frequently central to the success of the reactions and the mechanistic pathways that those intermediates trigger. For example, consider oxidative cyclization reactions that are triggered by the removal of an electron from an electron-rich olefin and lead to cyclic products that are functionalized for further elaboration. For these reactions to be successful, the radical cation intermediate must first be generated using conditions that limit its polymerization and then channeled down a productive desired pathway. Following the cyclization, a second oxidation step is necessary for product formation, after which the resulting cation must be quenched in a controlled fashion to avoid undesired elimination reactions. Problems can arise at any one or all of these steps, a fact that frequently complicates reaction optimization and can discourage the development of new transformations. Fortunately, anodic electrochemistry offers an outstanding opportunity to systematically probe the mechanism of oxidative cyclization reactions. The use of electrochemical methods allows for the generation of radical cations under neutral conditions in an environment that helps prevent polymerization of the intermediate. Once the intermediates have been generated, a series of "telltale indicators" can be used to diagnose which step in an oxidative cyclization is problematic for less successful transformation. A set of potential solutions to address each type of problem encountered has been developed. For example, problems with the initial cyclization reaction leading to either polymerization of the radical cation, elimination of a proton from or solvent trapping of that intermediate, or solvent trapping of the radical cation can be identified in the proton NMR spectrum of the crude reaction material. Such an NMR spectrum shows retention of the trapping group. The problems can be addressed by tuning the radical cation, altering the trapping group, or channeling the reactive intermediate down a radical pathway. Specific examples each are shown in this Account. Problems with the second oxidation step can be identified by poor current efficiency or general decomposition in spite of cyclic voltammetry evidence for a rapid cyclization. Solutions involve improving the oxidation conditions for the radical after cyclization by either the addition of a properly placed electron-donating group in the substrate or an increase in the concentration of electrolyte in the reaction (a change that stabilizes the cation generated from the second oxidation step). Problems with the final cation typically lead to overoxidation. Solutions to this problem require an approach that either slows down elimination side reactions or changes the reaction conditions so that the cation can be quickly trapped in an irreversible fashion. Again, this Account highlights these strategies along with the specific experimental protocols utilized.

Insights into the Mechanism of Anodic N-N Bond Formation by Dehydrogenative Coupling.

The electrochemical synthesis of pyrazolidine-3,5-diones and benzoxazoles by N-N bond formation and C,O linkage, respectively, represents an easy access to medicinally relevant structures. Electrochemistry as a key technology ensures a safe and sustainable approach. We gained insights in the mechanism of these reactions by combining cyclovoltammetric and synthetic studies. The electron-transfer behavior of anilides and dianilides was studied and led to the following conclusion: The N-N bond formation involves a diradical as intermediate, whereas the benzoxazole formation is based on a cationic mechanism. Besides these studies, we developed a synthetic route to mixed dianilides as starting materials for the N-N coupling. The compatibility with valuable functionalities like triflates and mesylates for follow-up reactions as well as the comparison of different electrochemical set-ups also enhanced the applicability of this method.

Paired Electrolysis in the Simultaneous Production of Synthetic Intermediates and Substrates.

In electrochemical processes, an oxidation half-reaction is always paired with a reduction half-reaction. Although systems for reactions such as the reduction of CO2 can be coupled to water oxidation to produce O2 at the anode, large-scale O2 production is of limited value. One may replace a low-value half-reaction with a compatible half-reaction that can produce a valuable chemical compound and operate at a lower potential. In doing so, both the anodic and cathodic half-reactions yield desirable products with a decreased energy demand. Here we demonstrate a paired electrolysis in the case of the oxidative condensation of syringaldehyde and o-phenylenediamine to give 2-(3,5-dimethoxy-4-hydroxyphenyl)benzimidazole coupled with the reduction of CO2 to CO mediated by molecular electrocatalysts. We also present general principles for evaluating current-voltage characteristics and power demands in paired electrolyzers.

Chemoselectivity and the Chan-Lam Coupling Reaction: Adding Amino Acids to Polymer-Coated Microelectrode Arrays.

The placement of a peptide onto a microelectrode array is frequently complicated by the presence of multiple nucleophiles in the peptide. In the work reported here, we have found that the Chan-Lam coupling reactions used to site-selectively place thiol, alcohol, and amine nucleophiles onto diblock-copolymer-coated surfaces are chemoselective for the placement of thiol and alcohol nucleophiles on the arrays. This means that cysteine- and serine-containing peptides can be placed onto an array without any need to protect the N terminus of the peptide. Furthermore, it was found that placement of thiol groups onto an array with the Chan-Lam reaction using optimized reaction times leads to complete coverage of the electrodes. The extent of this coverage can be controlled by varying the reaction time in a manner that allows for the construction of arrays with a gradient of peptide concentrations.

Introduction to Microelectrode Arrays, the Site-Selective Functionalization of Electrode Surfaces, and the Real-Time Detection of Binding Events.

Microelectrode arrays have great potential as analytical tools because currents can be independently measured at each electrode in the array. In principle, these currents can be monitored in order to follow in real time the binding events that occur between the members of a molecular library and a biological target. To capitalize on this potential, the surface of the array must be selectively functionalized so that each unique member of the molecular library is associated with a unique individually addressable electrode or set of electrodes in the array. To this end, this instructional review summarizes methods for coating the arrays with porous polymers that allow for the attachment of molecules to the surface of the array, selectively conducting reactions at individual electrodes in the array, characterizing molecules that are placed on the arrays, and running the analytical experiments needed to monitor in real time binding events between molecules on the array and a biological target.

Photoredox catalysts: synthesis of the bipyrazine ligand.

The bipyrazine ligand is often employed in photoredox catalysts in order to increase the excited state oxidation potential of the catalyst. However, literature syntheses of the ligand are cumbersome and typically lead to low yields. This hampers use of the desired catalysts. We report here an efficient copper based synthesis of the bipyrazine ligand that affords the product in 65-76% yield on a multigram scale.