Regiodivergent and Enantioselective Synthesis of Cyclic Sulfones via Ligand-Controlled Nickel-Catalyzed Hydroalkylation.

Cyclic sulfones have demonstrated important applications in drug discovery. However, the catalytic and enantioselective synthesis of chiral cyclic sulfones remains challenging. Herein, we develop nickel-catalyzed regiodivergent and enantioselective hydroalkylation of sulfolenes to streamline the synthesis of chiral alkyl cyclic sulfones. The method has broad scope and high functional group tolerance. The regioselectivity can be controlled by ligands only. A neutral PYROX ligand favors C3-alkylation whereas an anionic BOX ligand favors C2-alkylation. This control is kinetic in origin as the C2-bound Ni intermediates are always thermodynamically more stable. Reactivity study of a wide range of relevant Ni intermediates reveal a NiI/NiIII catalytic cycle with a NiII-H species as the resting state. The regio- and enantio-determining step is the insertion of this NiII-H species into 2-sulfolene. This work provides an efficient catalytic method for the synthesis of an important class of organic compounds and enhances the mechanistic understanding of Ni-catalyzed stereoselective hydroalkylation.

Development and Applications of Chimera Platforms for Tyrosine Phosphorylation.

Chimeric small molecules that induce post-translational modification (PTM) on a target protein by bringing it into proximity to a PTM-inducing enzyme are furnishing novel modalities to perturb protein function. Despite recent advances, such molecules are unavailable for a critical PTM, tyrosine phosphorylation. Furthermore, the contemporary design paradigm of chimeric molecules, formed by joining a noninhibitory binder of the PTM-inducing enzyme with the binder of the target protein, prohibits the recruitment of most PTM-inducing enzymes as their noninhibitory binders are unavailable. Here, we report two platforms to generate phosphorylation-inducing chimeric small molecules (PHICS) for tyrosine phosphorylation. We generate PHICS from both noninhibitory binders (scantily available, platform 1) and kinase inhibitors (abundantly available, platform 2) using cysteine-based group transfer chemistry. PHICS triggered phosphorylation on tyrosine residues in diverse sequence contexts and target proteins (e.g., membrane-associated, cytosolic) and displayed multiple bioactivities, including the initiation of a growth receptor signaling cascade and the death of drug-resistant cancer cells. These studies provide an approach to induce biologically relevant PTM and lay the foundation for pharmacologic PTM editing (i.e., induction or removal) of target proteins using abundantly available inhibitors of PTM-inducing or -erasing enzymes.

Copper-Catalyzed Benzylic Functionalization of Lignin-Derived Monomers.

Within the field of lignin biorefining, significant research effort has been dedicated to the advancement of catalytic methods for lignocellulose depolymerization. However, another key challenge in lignin valorization is the conversion of the obtained monomers into higher value-added products. To address this challenge, new catalytic methods that can fully embrace the inherent complexity of their target substrates are needed. Here, we describe copper-catalyzed reactions for benzylic functionalization of lignin-derived phenolics via intermediate formation of hexafluoroisopropoxy-masked para-quinone methides (p-QMs). By controlling the rates of copper catalyst turnover and p-QM release, we have developed copper-catalyzed allylation and alkynylation reactions of lignin-derived monomers to install various unsaturated fragments amenable to further synthetic applications.

Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification.

Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C-H activations, these arene functionalizations generally require directing groups to enable the C-H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C-H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C-H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C-H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C-H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations.

Proximity-inducing modalities: the past, present, and future.

Living systems use proximity to regulate biochemical processes. Inspired by this phenomenon, bifunctional modalities that induce proximity have been developed to redirect cellular processes. An emerging example of this class is molecules that induce ubiquitin-dependent proteasomal degradation of a protein of interest, and their initial development sparked a flurry of discovery for other bifunctional modalities. Recent advances in this area include modalities that can change protein phosphorylation, glycosylation, and acetylation states, modulate gene expression, and recruit components of the immune system. In this review, we highlight bifunctional modalities that perform functions other than degradation and have great potential to revolutionize disease treatment, while also serving as important tools in basic research to explore new aspects of biology.

Enantioselective palladaelectro-catalyzed C-H olefinations and allylations for N-C axial chirality.

Enantioselective palladaelectro-catalyzed C-H alkenylations and allylations were achieved with easily-accessible amino acids as transient directing groups. This strategy provided access to highly enantiomerically-enriched N-C axially chiral scaffolds under exceedingly mild conditions. The synthetic utility of our strategy was demonstrated by a variety of alkenes, while the versatility of our approach was reflected by atroposelective C-H allylations. Computational studies provided insights into a facile C-H activation by a seven-membered palladacycle.

Enantioselective Ruthenium-Catalyzed C-H Alkylations by a Chiral Carboxylic Acid with Attractive Dispersive Interactions.

Asymmetric ruthenium-catalyzed C-H alkylations were enabled by a chiral C2-symmetric carboxylic acid. The mild cooperative ruthenium(II) catalysis set the stage for the assembly of chiral tetrahydrocarbazoles and cyclohepta[b]indoles with high levels of enantioselectivity at room temperature. Mechanistic studies by experiment and computation identified a fast C-H ruthenation, along with a rate- and enantio-determining proto-demetalation. The asymmetric induction was governed by weak attractive secondary dispersion interactions as found in NCI analysis of the key transition states.

Cobaltaelectro-catalyzed C-H activation for resource-economical molecular syntheses.

The direct cleavage of otherwise inert C-H bonds has emerged as a sustainable approach for organic synthesis; in contrast to other approaches, these reactions result in the formation of fewer undesired by-products and do not require pre-functionalization steps. In recent years, oxidative C-H/N-H alkyne annulations and C-H oxygenations were realized by 3d metals. Unfortunately, most of these reactions require stoichiometric amounts of often toxic chemical oxidants. This protocol provides a general method for cobaltaelectro-catalyzed C-H activations of benzamides. Here, anodic oxidation obviates the need for a chemical oxidant and uses 10-20% of a more environmentally benign, inexpensive catalyst. We outline a detailed and precise description of the designed electrolytic cell for metallaelectrocatalysis, including readily available electrode materials and electrode holders. The custom-made device is further compared with the commercially available and standardized ElectraSyn 2.0 electrochemistry kit. As example applications of this approach, we describe cobaltaelectro-catalyzed C-H activation protocols for the direct C-H oxygenation of benzamides and resource-economical synthesis of isoquinolones. The cobaltaelectrocatalysis setup and reaction take about 17 h, while an additional 5 h have to be anticipated for workup and chromatographic purification. The methods described herein feature broad functional group tolerance, operational simplicity, low waste-product formation and an overall exceptional level of resource economy.

Enantioselective Pallada-Electrocatalyzed C-H Activation by Transient Directing Groups: Expedient Access to Helicenes.

Asymmetric pallada-electrocatalyzed C-H olefinations were achieved through the synergistic cooperation with transient directing groups. The electrochemical, atroposelective C-H activations were realized with high position-, diastereo-, and enantio-control under mild reaction conditions to obtain highly enantiomerically-enriched biaryls and fluorinated N-C axially chiral scaffolds. Our strategy provided expedient access to, among others, novel chiral BINOLs, dicarboxylic acids and helicenes of value to asymmetric catalysis. Mechanistic studies by experiments and computation provided key insights into the catalyst's mode of action.

Cobalt-Catalyzed Oxidative C-H Activation: Strategies and Concepts.

Inexpensive cobalt-catalyzed oxidative C-H functionalization has emerged as a powerful tool for the construction of C-C and C-Het bonds, which offers unique potential for transformative applications to modern organic synthesis. In the early stage, these transformations typically required stoichiometric and toxic transition metals as sacrificial oxidants; thus, the formation of metal-containing waste was inevitable. In contrast, naturally abundant molecular O2 has more recently been successfully employed as a green oxidant in cobalt catalysis, thus considerably improving the sustainability of such transformations. Recently, a significant momentum was gained by the use of electricity as a sustainable and environmentally benign redox reagent in cobalt-catalyzed C-H functionalization, thereby preventing the consumption of cost-intensive chemicals while at the same time addressing the considerable safety hazards related to the use of molecular oxygen in combination with flammable organic solvents. Considering the unparalleled potential of the aforementioned approaches for sustainable green synthesis, this Review summarizes the recent progress in cobalt-catalyzed oxidative C-H activation until early 2020.

Synthesis of quinones with highlighted biological applications: A critical update on the strategies towards bioactive compounds with emphasis on lapachones.

Naphthoquinones are of key importance in organic synthesis and medicinal chemistry. In the last few years, various synthetic routes have been developed to prepare bioactive compounds derived or based on lapachones. In this sense, this review is mainly focused on the synthetic aspects and strategies used for the design of these compounds on the basis of their biological activities for the development of drugs against the neglected diseases leishmaniases and Chagas disease and also cancer. Three strategies used to develop bioactive quinones are discussed and categorized: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Framed within these strategies for the development of naphthoquinoidal compounds against T. cruzi. Leishmania and cancer, reactions including copper-catalyzed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, C-H activation reactions, Ullmann couplings and heterocyclisations reported up to July 2019 will be discussed. The aim of derivatisation is the generation of novel molecules that can potentially inhibit cellular organelles/processes, generate reactive oxygen species and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against leishmaniases, Chagas disease and cancer.

Enantioselective C-H Activation with Earth-Abundant 3d Transition Metals.

Molecular syntheses largely rely on time- and labour-intensive prefunctionalization strategies. In contrast, C-H activation represents an increasingly powerful approach that avoids lengthy syntheses of prefunctionalized substrates, with great potential for drug discovery, the pharmaceutical industry, material sciences, and crop protection, among others. The enantioselective functionalization of omnipresent C-H bonds has emerged as a transformative tool for the step- and atom-economical generation of chiral molecular complexity. However, this rapidly growing research area remains dominated by noble transition metals, prominently featuring toxic palladium, iridium and rhodium catalysts. Indeed, despite significant achievements, the use of inexpensive and sustainable 3d metals in asymmetric C-H activations is still clearly in its infancy. Herein, we discuss the remarkable recent progress in enantioselective transformations via organometallic C-H activation by 3d base metals up to April 2019.

Enantioselective Cobalt(III)-Catalyzed C-H Activation Enabled by Chiral Carboxylic Acid Cooperation.

The enantioselective cobalt(III)-catalyzed C-H alkylation was achieved through the design of a novel chiral acid. The cobalt(III)-catalyzed enantioselective C-H activation was characterized by high position-, regio- and enantio-control under exceedingly mild reaction conditions. Thereby, the robust cooperative cobalt(III) catalysis proved tolerant of valuable electrophilic functional groups, including hydroxyl, bromo, and iodo substituents. Mechanistic studies revealed a considerable additive effect on kinetics and on a negative non-linear-effect.

Mild Cobalt(III)-Catalyzed Allylative C-F/C-H Functionalizations at Room Temperature.

Sustainable, cobalt-catalyst enabled, synthetically significant C-F/C-H functionalizations were achieved with an ample substrate scope at an ambient temperature of 25 °C, thereby delivering perfluoroallylated heteroarenes. Detailed experimental and computational mechanistic studies on the C-F/C-H functionalizations provided strong support for a facile C-F cleavage.

Palladium catalyzed selective distal C-H olefination of biaryl systems.

Palladium catalyzed selective distal C-H activation with nitrile based templates has been of significant research interest in recent times. In this report, we disclose the distal C-H olefination of biphenyl systems with high regio- and stereo-selectivity and useful synthetic yields. The utility of this method has been demonstrated through its wide olefin scope, its operation at the gram scale and the easy removal/recovery of the directing group.