Revisiting the Reactivity of the Dismissed Hydrogen Atom Transfer Catalyst Succinimide-N-oxyl.

Phthalimide-N-oxyl (PINO) and related radicals are promising catalysts for C-H functionalization reactions. To date, only a small number of N-oxyl derivatives have demonstrated improved activities over PINO. We postulate that the lack of success in identifying superior catalysts is associated not only with challenges in the design and synthesis of new structures, but also the way catalysts are evaluated and utilized. Catalyst evaluation typically relies on the use of chemical oxidants to generate N-oxyl radicals from their parent N-hydroxy compounds. Herein we provide an example where a potential-controlled electrochemical analysis reveals that succinimide-N-oxyl (SINO) compares favorably to PINO as a hydrogen atom transfer (HAT) catalyst-in contrast to previous claims based on other approaches. Our efforts to understand the basis for the greater reactivity of SINO relative to PINO have underscored that the HAT kinetics are significantly influenced by factors beyond changes in thermodynamics. This is perhaps best illustrated by the similar reactivity of tetrachloro-PINO and SINO despite the latter engaging in substantially more exergonic reactions. The key role of HAT transition state (TS) polarization prompted the design and initial characterization of a chlorinated SINO derivative, which we found to be the most reactive N-oxyl HAT catalyst reported to date.

Catalytic Olefin Transpositions Facilitated by Ruthenium N,N,N-Pincer Complexes.

In this report, we demonstrate olefin transposition/isomerization reactions catalyzed by a series of N,N,N-pincer (1,3-bis(2-pyridylimino)isoindoline) Ru-hydride complexes. The protocol proceeds at room temperature for most substrates, achieving excellent yields, regioselectivity, and diastereoselectivity in short reaction times. The air-stable Ru-chloride derivatives of these complexes exhibit comparable reactivity enabling benchtop setup and synthetic versatility. Furthermore, we demonstrate the potential for one-pot cascade sequences of the products derived from the transposition reactions.

Aryl Transfer Strategies Mediated by Photoinduced Electron Transfer.

Radical aryl migrations are powerful techniques to forge new bonds in aromatic compounds. The growing popularity of photoredox catalysis has led to an influx of novel strategies to initiate and control aryl migration starting from widely available radical precursors. This review encapsulates progress in radical aryl migration enabled by photochemical methods─particularly photoredox catalysis─since 2015. Special attention is paid to descriptions of scope, mechanism, and synthetic applications of each method.

Bicyclo[2.1.1]hexanes via Intramolecular Formal (3+2)-Cycloaddition.

We report a synthesis of bicyclo[2.1.1]hexanes via an intramolecular formal (3+2) cycloaddition of allylated cyclopropanes bearing a 4-nitrobenzimine substituent. Both activated and unactivated alkenes are tolerated in the transformation. The bicyclic imine products are prone to photo-induced ring opening, allowing for the epimerization of C5-stereogenic compounds.

Attenuating N-Oxyl Decomposition for Improved Hydrogen Atom Transfer Catalysts.

The design of N-oxyl hydrogen atom transfer catalysts has proven challenging to date. Previous efforts have focused on the functionalization of the archetype, phthalimide-N-oxyl. Driven in part by the limited options for modification of this structure, this strategy has provided only modest improvements in reactivity and/or solubility. Our previous mechanistic efforts suggested that while the electron-withdrawing carbonyls of the phthalimide are necessary to maximize the O-H bond dissociation enthalpy of the HAT product hydroxylamine and overall reaction thermodynamics, they undergo nucleophilic substitution leading to catalyst decomposition. In an attempt to minimize this vulnerability, we report the characterization of N-oxyl catalysts wherein the aryl ring in PINO is replaced with the combination of a substituted heteroatom and quaternary carbon. By rendering one carbonyl carbon less electrophilic and the other less sterically accessible, the corresponding N1-aryl-hydantoin-N3-oxyl radical showed significantly higher stability than PINO as well as a modest improvement in reactivity. This proof-of-principle in new scaffold design may accelerate future HAT catalyst discovery and development.

Exploring Cuneanes as Potential Benzene Isosteres and Energetic Materials: Scope and Mechanistic Investigations into Regioselective Rearrangements from Cubanes.

Cuneane is a strained hydrocarbon that can be accessed via metal-catalyzed isomerization of cubane. The carbon atoms of cuneane define a polyhedron of the C2v point group with six faces─two triangular, two quadrilateral, and two pentagonal. The rigidity, strain, and unique exit vectors of the cuneane skeleton make it a potential scaffold of interest for the synthesis of functional small molecules and materials. However, the limited previous synthetic efforts toward cuneanes have focused on monosubstituted or redundantly substituted systems such as permethylated, perfluorinated, and bis(hydroxymethylated) cuneanes. Such compounds, particularly rotationally symmetric redundantly substituted cuneanes, have limited potential as building blocks for the synthesis of complex molecules. Reliable, predictable, and selective syntheses of polysubstituted cuneanes bearing more complex substitution patterns would facilitate the study of this ring system in myriad applications. Herein, we report the regioselective, AgI-catalyzed isomerization of asymmetrically 1,4-disubstituted cubanes to cuneanes. In-depth DFT calculations provide a charge-controlled regioselectivity model, and direct dynamics simulations indicate that the nonclassical carbocation invoked is short-lived and dynamic effects augment the charge model.

Formal Cycloadditions Driven by the Homolytic Opening of Strained, Saturated Ring Systems.

The field of strain-driven, radical formal cycloadditions is experiencing a surge in activity motivated by a renaissance in free radical chemistry and growing demand for sp3 -rich ring systems. The former has been driven in large part by the rise of photoredox catalysis, and the latter by adoption of the "Escape from Flatland" concept in medicinal chemistry. In the years since these broader trends emerged, dozens of formal cycloadditions, including catalytic, asymmetric variants, have been developed that operate via radical mechanisms. While cyclopropanes have been studied most extensively, a variety of strained ring systems are amenable to the design of analogous reactions. Many of these processes generate lucrative, functionally decorated sp3 -rich ring systems that are difficult to access by other means. Herein, we summarize recent efforts in this area and analyze the state of the field.

Leveraging the Persistent Radical Effect in the Synthesis of trans-2,3-Diaryl Dihydrobenzofurans.

A simple method for accessing trans-2,3-diaryl dihydrobenzofurans is reported. This approach leverages the equilibrium between quinone methide dimers and their persistent radicals. This equilibrium is disrupted by phenols that yield comparatively transient phenoxyl radicals, leading to cross-coupling between the persistent and transient radicals. The resultant quinone methides with pendant phenols rapidly cyclize to form dihydrobenzofurans (DHBs). This putative biomimetic access to dihydrobenzofurans provides superb functional group tolerance and a unified approach for the synthesis of resveratrol-based natural products.

High-Throughput Optimization of Photochemical Reactions using Segmented-Flow Nanoelectrospray-Ionization Mass Spectrometry.

Within the realm of drug discovery, high-throughput experimentation techniques enable the rapid optimization of reactions and expedited generation of drug compound libraries for biological and pharmacokinetic evaluation. Herein we report the development of a segmented flow mass spectrometry-based platform to enable the rapid exploration of photoredox reactions for early-stage drug discovery. Specifically, microwell plate-based photochemical reaction screens were reformatted to segmented flow format to enable delivery to nanoelectrospray ionization-mass spectrometry analysis. This approach was demonstrated for the late-stage modification of complex drug scaffolds, as well as the subsequent structure-activity relationship evaluation of synthesized analogs. This technology is anticipated to expand the robust capabilities of photoredox catalysis in drug discovery by enabling high-throughput library diversification.

Development of an automated screen for Kv7.2 potassium channels and discovery of a new agonist chemotype.

To identify pore domain ligands on Kv7.2 potassium ion channels, we compared wild-type (WT) and W236L mutant Kv7.2 channels in a series of assays with previously validated and novel agonist chemotypes. Positive controls were retigabine, flupirtine, and RL-81; i.e. Kv7.2 channel activators that significantly shift voltage-dependent activation to more negative potentials (ΔV50) at 5 µM. We identified 6 new compounds that exhibited differential enhancing activity between WT and W236L mutant channels. Whole cell patch-clamp electrophysiology studies were conducted to identify Kv7.2. Kv7.2/3, Kv7.4, and Kv7.5 selectivity. Our results validate the SyncroPatch platform and establish new structure activity relationships (SAR). Specifically, in addition to selective Kv7.2, Kv7.2/3, Kv7.4. and Kv7.5 agonists, we identified a novel chemotype, ZK-21, a 4-aminotetrahydroquinoline that is distinct from any of the previously described Kv7 channel modifiers. Using flexible receptor docking, ZK-21 was predicted to be stabilized by W236 and bind perpendicular to retigabine, burying the benzyl carbamate group into a tunnel reaching the core of the pore domain.

Evolution towards green radical generation in total synthesis.

The use of radicals as intermediates in total synthesis has evolved since their initial use in the latter half of the twentieth century. Radical generation from metal hydride methodologies has shifted to "greener" techniques including catalytic metal-mediated systems, electrochemical and photoredox-mediated processes. This review will focus on these classical and contemporary methods for radical generation and their applications in recent total syntheses.

Photochemical Formal (4 + 2)-Cycloaddition of Imine-Substituted Bicyclo[1.1.1]pentanes and Alkenes.

Amines containing bridged bicyclic carbon skeletons are desirable building blocks for medicinal chemistry. Herein, we report the conversion of bicyclo[1.1.1]pentan-1-amines to a wide range of polysubstituted bicyclo[3.1.1]heptan-1-amines through a photochemical, formal (4 + 2)-cycloaddition of an intermediate imine diradical. To our knowledge, this is the first reported method to convert the bicyclo[1.1.1]pentane skeleton to the bicyclo[3.1.1]heptane skeleton. Hydrolysis of the imine products gives complex, sp3-rich primary amine building blocks.

Mechanism of Electrochemical Generation and Decomposition of Phthalimide-N-oxyl.

Phthalimide N-oxyl (PINO) is a potent hydrogen atom transfer (HAT) catalyst that can be generated electrochemically from N-hydroxyphthalimide (NHPI). However, catalyst decomposition has limited its application. This paper details mechanistic studies of the generation and decomposition of PINO under electrochemical conditions. Voltammetric data, observations from bulk electrolysis, and computational studies suggest two primary aspects. First, base-promoted formation of PINO from NHPI occurs via multiple-site concerted proton-electron transfer (MS-CPET). Second, PINO decomposition occurs by at least two second-order paths, one of which is greatly enhanced by base. Optimal catalytic efficiency in PINO-catalyzed oxidations occurs in the presence of bases whose corresponding conjugate acids have pKa's in the range of ∼11-15, which strikes a balance between promoting PINO formation and minimizing its decay.

Electro-reductive Fragmentation of Oxidized Lignin Models.

Lignin provides a potential sustainable source for production of electron-rich aromatic compounds. Recently, electrochemical lignin degradation via an oxidation/reduction sequence under mild conditions has garnered much attention within the lignin community, as electrochemistry simplifies redox reactions and offers an electron source/sink for synthesis without using stoichiometric oxidants or reductants. This paper describes a fundamental approach for the electrochemical fragmentation of the primary connection in native lignin, ß-O-4. Potential-controlled electrolysis enables selective reduction and provides fragmentation products and/or coupling products in isolated yields of 59-92%.

Synthesis of Vitisins A and D Enabled by a Persistent Radical Equilibrium.

The first total synthesis of the resveratrol tetramers vitisin A and vitisin D is reported. Electrochemical generation and selective dimerization of persistent radicals is followed by thermal isomerization of the symmetric C8b-C8c dimer to the C3c-C8b isomer, providing rapid entry into the vitisin core. Computational results suggest that this synthetic approach mimics Nature's strategy for constructing these complex molecules. Sequential acid-mediated rearrangements consistent with the proposed biogenesis of these compounds afford vitisin A and vitisin D. The rapid synthesis of these complex molecules will enable further study of their pharmacological potential.

Biosynthesis of an Anti-Addiction Agent from the Iboga Plant.

(-)-Ibogaine and (-)-voacangine are plant derived psychoactives that show promise as treatments for opioid addiction. However, these compounds are produced by hard to source plants, making these chemicals difficult for broad-scale use. Here we report the complete biosynthesis of (-)-voacangine, and de-esterified voacangine, which is converted to (-)-ibogaine by heating, enabling biocatalytic production of these compounds. Notably, (-)-ibogaine and (-)-voacangine are of the opposite enantiomeric configuration compared to the other major alkaloids found in this natural product class. Therefore, this discovery provides insight into enantioselective enzymatic formal Diels-Alder reactions.

Radicals in natural product synthesis.

Free radical intermediates have intrigued chemists since their discovery, and an ever-increasing appreciation for their unique reactivity has resulted in the widespread utilization of these species throughout the field of chemical synthesis. This is most evident from the recent surge in the application of intermolecular radical reactions that feature in complex molecule syntheses. This tutorial review will discuss the diverse methods utilized for radical generation and reactivity to form critical bonds in natural product total synthesis. In particular, stabilized (e.g. benzyl) and persistent (e.g. TEMPO) radicals will be the primary focus.

Exploiting Imine Photochemistry for Masked N-Centered Radical Reactivity.

This report details the development of a masked N-centered radical strategy that harvests the energy of light to drive the conversion of cyclopropylimines to 1-aminonorbornanes. This process employs the N-centered radical character of a photoexcited imine to facilitate the homolytic fragmentation of the cyclopropane ring and the subsequent radical cyclization sequence that forms two new C-C bonds en route to the norbornane core. Achieving bond-forming reactivity as a function of the N-centered radical character of an excited state Schiff base is unique, requiring only violet light in this instance. This methodology operates in continuous flow, enhancing the potential to translate beyond the academic sector. The operational simplicity of this photochemical process and the structural novelty of the (hetero)aryl-fused 1-aminonorbornane products are anticipated to provide a valuable addition to discovery efforts in pharmaceutical and agrochemical industries.

Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis.

The use of photochemical transformations is a powerful strategy that allows for the formation of a high degree of molecular complexity from relatively simple building blocks in a single step. A central feature of all light-promoted transformations is the involvement of electronically excited states, generated upon absorption of photons. This produces transient reactive intermediates and significantly alters the reactivity of a chemical compound. The input of energy provided by light thus offers a means to produce strained and unique target compounds that cannot be assembled using thermal protocols. This review aims at highlighting photochemical transformations as a tool for rapidly accessing structurally and stereochemically diverse scaffolds. Synthetic designs based on photochemical transformations have the potential to afford complex polycyclic carbon skeletons with impressive efficiency, which are of high value in total synthesis.