Organic chemistry has largely been conducted in an ad hoc manner by academic laboratories that are funded by grants directed towards the investigation of specific goals or hypotheses. Although modern ...synthetic methods can provide access to molecules of considerable complexity, predicting the outcome of a single chemical reaction remains a major challenge. Improvements in the prediction of 'above-the-arrow' reaction conditions are needed to enable intelligent decision making to select an optimal synthetic sequence that is guided by metrics including efficiency, quality and yield. Methods for the communication and the sharing of data will need to evolve from traditional tools to machine-readable formats and open collaborative frameworks. This will accelerate innovation and require the creation of a chemistry commons with standardized data handling, curation and metrics.
Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. ...Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp³ carbon-hydrogen bonds in a single step, using isotopically labeled water (D₂O or T₂O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T₂O from T₂, providing access to high-specific-activity T₂O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies.
Over the past two decades, there have been major developments in transition metal–catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product ...isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon–nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event.
Methods to incorporate deuterium and tritium atoms into organic molecules are valuable for medicinal chemistry. The prevalence of pyridines and diazines in pharmaceuticals means that new ways to ...label these heterocycles will present opportunities in drug design and facilitate absorption, distribution, metabolism, and excretion (ADME) studies. A broadly applicable protocol is presented wherein pyridines, diazines, and pharmaceuticals are converted into heterocyclic phosphonium salts and then isotopically labeled. The isotopes are incorporated in high yields and, in general, with exclusive regioselectivity.
At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation ...platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic "toolkit" cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry–based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction.
Positron emission tomography (PET) radioligands (radioactively labelled tracer compounds) are extremely useful for in vivo characterization of central nervous system drug candidates, ...neurodegenerative diseases and numerous oncology targets
. Both tritium and carbon-11 radioisotopologues are generally necessary for in vitro and in vivo characterization of radioligands
, yet there exist few radiolabelling protocols for the synthesis of either, inhibiting the development of PET radioligands. The synthesis of such radioligands also needs to be very rapid owing to the short half-life of carbon-11. Here we report a versatile and rapid metallaphotoredox-catalysed method for late-stage installation of both tritium and carbon-11 into the desired compounds via methylation of pharmaceutical precursors bearing aryl and alkyl bromides. Methyl groups are among the most prevalent structural elements found in bioactive molecules, and so this synthetic approach simplifies the discovery of radioligands. To demonstrate the breadth of applicability of this technique, we perform rapid synthesis of 20 tritiated and 10 carbon-11-labelled complex pharmaceuticals and PET radioligands, including a one-step radiosynthesis of the clinically used compounds
CUCB-J and
CPHNO. We further outline the direct utility of this protocol for preclinical PET imaging and its translation to automated radiosynthesis for routine radiotracer production in human clinical imaging. We also demonstrate this protocol for the installation of other diverse and pharmaceutically useful isotopes, including carbon-14, carbon-13 and deuterium.
Aliphatic amines, oxygenated at remote positions within the molecule, represent an important class of synthetic building blocks to which there are currently no direct means of access. Reported herein ...is an efficient and scalable solution that relies upon decatungstate photocatalysis under acidic conditions using either H2O2 or O2 as the terminal oxidant. By using these reaction conditions a series of simple and unbiased aliphatic amine starting materials can be oxidized to value‐added ketone products. Lastly, NMR spectroscopy using in situ LED‐irradiated samples was utilized to monitor the kinetics of the reaction, thus enabling direct translation of the reaction into flow.
Going with the floW: Decatungstate anion, a UV absorbing photocatalyst, was utilized in the conversion of unprotected aliphatic amines, into products containing a ketone functionality at a remote position, by using either H2O2 or O2 as the terminal oxidant. NMR studies employing LED‐irradiated samples aided in the identification of a key reaction intermediate, and ultimately allowed the transformation to be translated into flow.
The combination of nickel metallaphotoredox catalysis, hydrogen atom transfer catalysis, and a Lewis acid activation mode, has led to the development of an arylation method for the selective ...functionalization of alcohol α‐hydroxy C−H bonds. This approach employs zinc‐mediated alcohol deprotonation to activate α‐hydroxy C−H bonds while simultaneously suppressing C−O bond formation by inhibiting the formation of nickel alkoxide species. The use of Zn‐based Lewis acids also deactivates other hydridic bonds such as α‐amino and α‐oxy C−H bonds. This approach facilitates rapid access to benzylic alcohols, an important motif in drug discovery. A 3‐step synthesis of the drug Prozac exemplifies the utility of this new method.
The power of three: A triple catalysis method was developed for C−C bond formation at the α‐carbon of alcohols using aryl halide electrophiles. This method provides generic access to a broad range of benzylic and heteroaryl benzylic motifs. A new strategy for the selective functionalization of alcohols by leveraging a Lewis acid additive was utilized to enable selective hydrogen atom transfer at the α‐carbon and suppress competing C−O coupling.
Elbasvir is a potent NS5A antagonist for the treatment of chronic hepatitis C. A seemingly trivial indoline oxidation en route to the target compound was complicated by epimerization of a stereogenic ...hemiaminal center under most standard oxidation conditions. To address this issue, a novel visible light photoredox process for indoline oxidation was developed involving an iridium photosensitizer and environmentally-benign perester oxidant. The reaction was discovered through a high-throughput experimentation campaign and the optimized process was demonstrated on 100 g scale in flow to afford a key intermediate towards the target compound. A battery of kinetic, electrochemical, and spectroscopic studies of this process indicates a radical chain mechanism of dehydrogenation involving selective HAT from the substrate by an alkoxy radicals. Notably, isotope effects were used to validate the chain mechanism when quantum yield data proved ambiguous.
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