[18F]Difluorocarbene for positron emission tomography.

The advent of total-body positron emission tomography (PET) has vastly broadened the range of research and clinical applications of this powerful molecular imaging technology1. Such possibilities have accelerated progress in fluorine-18 (18F) radiochemistry with numerous methods available to 18F-label (hetero)arenes and alkanes2. However, access to 18F-difluoromethylated molecules in high molar activity is mostly an unsolved problem, despite the indispensability of the difluoromethyl group for pharmaceutical drug discovery3. Here we report a general solution by introducing carbene chemistry to the field of nuclear imaging with a [18F]difluorocarbene reagent capable of a myriad of 18F-difluoromethylation processes. In contrast to the tens of known difluorocarbene reagents, this 18F-reagent is carefully designed for facile accessibility, high molar activity and versatility. The issue of molar activity is solved using an assay examining the likelihood of isotopic dilution on variation of the electronics of the difluorocarbene precursor. Versatility is demonstrated with multiple [18F]difluorocarbene-based reactions including O-H, S-H and N-H insertions, and cross-couplings that harness the reactivity of ubiquitous functional groups such as (thio)phenols, N-heteroarenes and aryl boronic acids that are easy to install. The impact is illustrated with the labelling of highly complex and functionalized biologically relevant molecules and radiotracers.

Palladium-catalysed electrophilic aromatic C-H fluorination.

Aryl fluorides are widely used in the pharmaceutical and agrochemical industries, and recent advances have enabled their synthesis through the conversion of various functional groups. However, there is a lack of general methods for direct aromatic carbon-hydrogen (C-H) fluorination. Conventional methods require the use of either strong fluorinating reagents, which are often unselective and difficult to handle, such as elemental fluorine, or less reactive reagents that attack only the most activated arenes, which reduces the substrate scope. A method for the direct fluorination of aromatic C-H bonds could facilitate access to fluorinated derivatives of functional molecules that would otherwise be difficult to produce. For example, drug candidates with improved properties, such as increased metabolic stability or better blood-brain-barrier penetration, may become available. Here we describe an approach to catalysis and the resulting development of an undirected, palladium-catalysed method for aromatic C-H fluorination using mild electrophilic fluorinating reagents. The reaction involves a mode of catalysis that is unusual in aromatic C-H functionalization because no organometallic intermediate is formed; instead, a reactive transition-metal-fluoride electrophile is generated catalytically for the fluorination of arenes that do not otherwise react with mild fluorinating reagents. The scope and functional-group tolerance of this reaction could provide access to functional fluorinated molecules in pharmaceutical and agrochemical development that would otherwise not be readily accessible.

Organophotoredox Hydrodefluorination of Trifluoromethylarenes with Translational Applicability to Drug Discovery.

Molecular editing such as insertion, deletion, and single atom exchange in highly functionalized compounds is an aspirational goal for all chemists. Here, we disclose a photoredox protocol for the replacement of a single fluorine atom with hydrogen in electron-deficient trifluoromethylarenes including complex drug molecules. A robustness screening experiment shows that this reductive defluorination tolerates a range of functional groups and heterocycles commonly found in bioactive molecules. Preliminary studies allude to a catalytic cycle whereby the excited state of the organophotocatalyst is reductively quenched by the hydrogen atom donor, and returned in its original oxidation state by the trifluoromethylarene.

Direct Oxidation of Csp3 -H bonds using in Situ Generated Trifluoromethylated Dioxirane in Flow.

A fast, scalable, and safer Csp 3 -H oxidation of activated and un-activated aliphatic chains can be enabled by methyl(trifluoromethyl)dioxirane (TFDO). The continuous flow platform allows the in situ generation of TFDO gas and its rapid reactivity toward tertiary and benzylic Csp3 -H bonds. The process exhibits a broad scope and good functional group compatibility (28 examples, 8-99 %). The scalability of this methodology is demonstrated on 2.5 g scale oxidation of adamantane.

Divergent Late-Stage (Hetero)aryl C-H Amination by the Pyridinium Radical Cation.

(Hetero)arylamines constitute some of the most prevalent functional molecules, especially as pharmaceuticals. However, structurally complex aromatics currently cannot be converted into arylamines, so instead, each product isomer must be assembled through a multistep synthesis from simpler building blocks. Herein, we describe a late-stage aryl C-H amination reaction for the synthesis of complex primary arylamines that other reactions cannot access directly. We show and rationalize through a mechanistic analysis the reasons for the wide substrate scope and the constitutional diversity of the reaction, which gives access to molecules that would not have been readily available otherwise.

Aryl Sulfonium Salts for Site-Selective Late-Stage Trifluoromethylation.

Incorporation of the CF3 group into arenes has found increasing importance in drug discovery. Herein, we report the first photoredox-catalyzed cross-coupling of aryl thianthrenium salts with a copper-based trifluoromethyl reagent, which enables a site-selective late-stage trifluoromethylation of arenes. The reaction proceeds with broad functional group tolerance, even for complex small molecules on gram scale. The method was further extended to produce pentafluoroethylated derivatives.

Late-Stage 18 F-Difluoromethyl Labeling of N-Heteroaromatics with High Molar Activity for PET Imaging.

Despite a growing interest in CHF2 in medicinal chemistry, there is a lack of efficient methods for the insertion of CHF18 F into druglike compounds. Herein described is a photoredox flow reaction for 18 F-difluoromethylation of N-heteroaromatics that are widely used in medicinal chemistry. Following the two-step synthesis for a new 18 F-difluoromethylation reagent, the photoredox reaction is completed within two minutes and proceeds by C-H activation, circumventing the need for pre-functionalization of the substrate. The method is operationally simple and affords straightforward access to radiolabeled N-heteroaromatics with high molar activity suitable for biological in vivo studies and clinical application.

Selective Methylation of Arenes: A Radical C-H Functionalization/Cross-Coupling Sequence.

A selective, nonchelation-assisted methylation of arenes has been developed. The overall transformation, which combines a C-H functionalization reaction with a nickel-catalyzed cross-coupling, offers rapid access to methylated arenes with high para selectivity. The reaction is amenable to late-stage methylation of small-molecule pharmaceuticals.

Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands.

Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.

C-H Cyanation of 6-Ring N-Containing Heteroaromatics.

Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far-reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C-H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one-pot protocol is simple to perform, is applicable to a broad range of decorated 6-ring N-containing heterocycles, and has been shown to be suitable for late-stage functionalization of complex drug-like architectures.

A general copper-mediated nucleophilic 18F†fluorination of arenes.

Molecules labeled with fluorine-18 are used as radiotracers for positron emission tomography. An important challenge is the labeling of arenes not amenable to aromatic nucleophilic substitution (SNAr) with [(18)F]F(-). In the ideal case, the (18)F fluorination of these substrates would be performed through reaction of [(18)F]KF with shelf-stable readily available precursors using a broadly applicable method suitable for automation. Herein, we describe the realization of these requirements with the production of (18)F arenes from pinacol-derived aryl boronic esters (arylBPin) upon treatment with [(18)F]KF/K222 and [Cu(OTf)2(py)4] (OTf = trifluoromethanesulfonate, py = pyridine). This method tolerates electron-poor and electron-rich arenes and various functional groups, and allows access to 6-[(18)F]fluoro-L-DOPA, 6-[(18)F]fluoro-m-tyrosine, and the translocator protein (TSPO) PET ligand [(18)F]DAA1106.

Photoredox catalysis with aryl sulfonium salts enables site-selective late-stage fluorination.

Photoredox catalysis, especially in combination with transition metal catalysis, can produce redox states of transition metal catalysts to facilitate challenging bond formations that are not readily accessible in conventional redox catalysis. For arene functionalization, metallophotoredox catalysis has successfully made use of the same leaving groups as those valuable in conventional cross-coupling catalysis, such as bromide. Yet the redox potentials of common photoredox catalysts are not sufficient to reduce most aryl bromides, so synthetically useful aryl radicals are often not directly available. Therefore, the development of a distinct leaving group more appropriately matched in redox potential could enable new reactivity manifolds for metallophotoredox catalysis, especially if arylcopper(III) complexes are accessible, from which the most challenging bond-forming reactions can occur. Here we show the conceptual advantages of aryl thianthrenium salts for metallophotoredox catalysis, and their utility in site-selective late-stage aromatic fluorination.

Synthesis of 18F-difluoromethylarenes using aryl boronic acids, ethyl bromofluoroacetate and [18F]fluoride.

Herein, we report the radiosynthesis of 18F-difluoromethylarenes via the assembly of three components, a boron reagent, ethyl bromofluoroacetate, and cyclotron-produced non-carrier added [18F]fluoride. The two key steps are a copper-catalysed cross-coupling reaction, and a Mn-mediated 18F-fluorodecarboxylation.

Development of a Flow Photochemical Aerobic Oxidation of Benzylic C-H Bonds.

A continuous mesofluidic process has been developed for benzylic C-H oxidation with moderate to good yields using a photocatalyst (riboflavin tetraacetate, RFT) activated by a UV lamp and an iron additive [Fe(ClO4)2] via incorporation of singlet oxygen (1O2) for the direct formation of oxidized C═O or CH-OH compounds.

Synthesis of Electron-Deficient Heteroaromatic 1,3-Substituted Cyclobutyls via Zinc Insertion/Negishi Coupling Sequence under Batch and Automated Flow Conditions.

Synthesis of 1,3-substituted cyclobutyls enabled by zinc insertion into functionalized iodocyclobutyl derivatives followed by Negishi coupling with halo-heteroaromatics is reported. Two distinct sets of conditions were developed; the first involved a two-step batch protocol using activated Rieke zinc, and the second involved a multistep continuous flow process. Both methods showed complementarity and allowed for rapid access to these medicinally relevant motifs, the possibility of scaling up, and automation for library synthesis.

Direct sulfonylation of anilines mediated by visible light.

Sulfones feature prominently in biologically active molecules and are key functional groups for organic synthesis. We report a mild, photoredox-catalyzed reaction for sulfonylation of aniline derivatives with sulfinate salts, and demonstrate the utility of the method by the late-stage functionalization of drugs. Key features of the method are the straightforward generation of sulfonyl radicals from bench-stable sulfinate salts and the use of simple aniline derivatives as convenient readily available coupling partners.

Enhanced copper-mediated (18)F-fluorination of aryl boronic esters provides eight radiotracers for PET applications.

[(18)F]FMTEB, [(18)F]FPEB, [(18)F]flumazenil, [(18)F]DAA1106, [(18)F]MFBG, [(18)F]FDOPA, [(18)F]FMT and [(18)F]FDA are prepared from the corresponding arylboronic esters and [(18)F]KF/K222 in the presence of Cu(OTf)2py4. The method was successfully applied using three radiosynthetic platforms, and up to 26 GBq of non-carrier added starting activity of (18)F-fluoride.

Back-up strategies in drug discovery: what, how and when?

The management of back-up strategies in drug discovery and development is usually done on an ad hoc basis depending upon a series of external factors including overall portfolio status and resource and/or budget availability. These are however an essential component of risk management and merit a more structured and systematic conduct throughout the lifetime of a project. An approach based upon a thorough alignment of decision points and data availability as well as a tailor-made progression of various types of back-up program as a function of project categorization is suggested.

Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex.

An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.