Overcoming Product Inhibition in a Nucleophilic Aromatic Substitution Reaction.

The development of a nucleophilic aromatic substitution (SNAr) reaction for the synthesis of belzutifan and related analogues is disclosed. This classical transformation suffered from reaction stalling, despite prolonged reaction times. Through experimental and mechanistic studies, product inhibition was revealed and rationalized. Herein, we describe our efforts to overcome this synthetic challenge and demonstrate the importance of the judicious choice of the solvent to achieve reactivity.

Engineering Hydroxylase Activity, Selectivity, and Stability for a Scalable Concise Synthesis of a Key Intermediate to Belzutifan.

Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising for a range of selective oxidations, practical use of enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering and practical application of a non-heme iron and α-ketoglutarate-dependent dioxygenase for the direct stereo- and regio-selective hydroxylation of a non-native fluoroindanone en route to the oncology treatment belzutifan, replacing a five-step chemical synthesis with a direct enantioselective hydroxylation. Mechanistic studies indicated that formation of the desired product was limited by enzyme stability and product overoxidation, with these properties subsequently improved by directed evolution, yielding a biocatalyst capable of >15,000 total turnovers. Highlighting the industrial utility of this biocatalyst, the high-yielding, green, and efficient oxidation was demonstrated at kilogram scale for the synthesis of belzutifan.

Nickel-Catalyzed Sulfonylation of Aryl Bromides Enabled by Potassium Metabisulfite as a Uniquely Effective SO2 Surrogate.

The development and mechanistic investigation of a nickel-catalyzed sulfonylation of aryl bromides is disclosed. The reaction proceeds in good yields for a variety of substrates and utilizes an inexpensive, stench-free, inorganic sulfur salt (K2 S2 O5 ) as a uniquely effective SO2 surrogate. The active oxidative addition complex was synthesized, isolated, and fully characterized by a combination of NMR spectroscopy and X-ray crystallography analysis. The use of the isolated oxidative addition complex in both stoichiometric and catalytic reactions revealed that SO2 insertion occurs via dissolved SO2 , likely released upon thermal decomposition of K2 S2 O5 . Key to the success of the reaction is the role of K2 S2 O5 as a reservoir of SO2 that is slowly released, thus preventing catalyst poisoning.

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

The merger of decatungstate and copper catalysis to enable aliphatic C(sp3)-H trifluoromethylation.

The introduction of a trifluoromethyl (CF3) group can dramatically improve a compound's biological properties. Despite the well-established importance of trifluoromethylated compounds, general methods for the trifluoromethylation of alkyl C-H bonds remain elusive. Here we report the development of a dual-catalytic C(sp3)-H trifluoromethylation through the merger of light-driven, decatungstate-catalysed hydrogen atom transfer and copper catalysis. This metallaphotoredox methodology enables the direct conversion of both strong aliphatic and benzylic C-H bonds into the corresponding C(sp3)-CF3 products in a single step using a bench-stable, commercially available trifluoromethylation reagent. The reaction requires only a single equivalent of substrate and proceeds with excellent selectivity for positions distal to unprotected amines. To demonstrate the utility of this new methodology for late-stage functionalization, we have directly derivatized a broad range of approved drugs and natural products to generate valuable trifluoromethylated analogues. Preliminary mechanistic experiments reveal that a 'Cu-CF3' species is formed during this process and the critical C(sp3)-CF3 bond-forming step involves the copper catalyst.

Synthesis of Sterically Hindered Primary Amines by Concurrent Tandem Photoredox Catalysis.

Primary amines are an important structural motif in active pharmaceutical ingredients (APIs) and intermediates thereof, as well as members of ligand libraries for either biological or catalytic applications. Many chemical methodologies exist for amine synthesis, but the direct synthesis of primary amines with a fully substituted α carbon center is an underdeveloped area. We report a method which utilizes photoredox catalysis to couple readily available O-benzoyl oximes with cyanoarenes to synthesize primary amines with fully substituted α-carbons. We also demonstrate that this method enables the synthesis of amines with α-trifluoromethyl functionality. Based on experimental and computational results, we propose a mechanism where the photocatalyst engages in concurrent tandem catalysis by reacting with the oxime as a triplet sensitizer in the first catalytic cycle and a reductant toward the cyanoarene in the second catalytic cycle to achieve the synthesis of hindered primary amines via heterocoupling of radicals from readily available oximes.

Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer.

Accessing hindered amines, particularly primary amines α to a fully substituted carbon center, is synthetically challenging. We report an electrochemical method to access such hindered amines starting from benchtop-stable iminium salts and cyanoheteroarenes. A wide variety of substituted heterocycles (pyridine, pyrimidine, pyrazine, purine, azaindole) can be utilized in the cross-coupling reaction, including those substituted with a halide, trifluoromethyl, ester, amide, or ether group, a heterocycle, or an unprotected alcohol or alkyne. Mechanistic insight based on DFT data, as well as cyclic voltammetry and NMR spectroscopy, suggests that a proton-coupled electron-transfer mechanism is operational as part of a hetero-biradical cross-coupling of α-amino radicals and radicals derived from cyanoheteroarenes.

Direct arylation of strong aliphatic C-H bonds.

Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp3-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners1,2. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks3-5, the direct functionalization of carbon-hydrogen (C-H) bonds-the most abundant moiety in organic molecules-represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp3)-heteroatom bonds from strong C-H bonds has been reported6,7. Additionally, valuable technologies have been developed for the formation of carbon-carbon bonds from the corresponding C(sp3)-H bonds via substrate-directed transition-metal C-H insertion8, undirected C-H insertion by captodative rhodium carbenoid complexes9, or hydrogen atom transfer from weak, hydridic C-H bonds by electrophilic open-shell species10-14. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp3)-H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp3) arylation of a diverse set of aliphatic, C-H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C-H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp3)-C(sp2) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods.

Mapping the dark space of chemical reactions with extended nanomole synthesis and MALDI-TOF MS.

Understanding the practical limitations of chemical reactions is critically important for efficiently planning the synthesis of compounds in pharmaceutical, agrochemical, and specialty chemical research and development. However, literature reports of the scope of new reactions are often cursory and biased toward successful results, severely limiting the ability to predict reaction outcomes for untested substrates. We herein illustrate strategies for carrying out large-scale surveys of chemical reactivity by using a material-sparing nanomole-scale automated synthesis platform with greatly expanded synthetic scope combined with ultrahigh-throughput matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS).

Facile Quantum Yield Determination via NMR Actinometry.

A simplified approach to quantum yield ([Formula: see text]) measurement using in situ LED NMR spectroscopy has been developed. The utility and performance of NMR actinometry has been demonstrated for the well-known chemical actinometers potassium ferrioxalate and o-nitrobenzaldehyde. A novel NMR-friendly actinometer, 2,4-dinitrobenzaldehyde, has been introduced for both 365 and 440 nm wavelengths. The method has been utilized successfully to measure the quantum yield of several recently published photochemical reactions.

Selective Hydrogen Atom Abstraction through Induced Bond Polarization: Direct α-Arylation of Alcohols through Photoredox, HAT, and Nickel Catalysis.

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 Evolution of Chemical High-Throughput Experimentation To Address Challenging Problems in Pharmaceutical Synthesis.

The structural complexity of pharmaceuticals presents a significant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made to apply them to complex drug intermediates. The use of high-throughput experimentation (HTE) techniques offers a means to overcome this fundamental challenge by facilitating the rational exploration of large arrays of catalysts and reaction conditions in a time- and material-efficient manner. Initial forays into the use of HTE in our laboratories for solving chemistry problems centered around screening of chiral precious-metal catalysts for homogeneous asymmetric hydrogenation. The success of these early efforts in developing efficient catalytic steps for late-stage development programs motivated the desire to increase the scope of this approach to encompass other high-value catalytic chemistries. Doing so, however, required significant advances in reactor and workflow design and automation to enable the effective assembly and agitation of arrays of heterogeneous reaction mixtures and retention of volatile solvents under a wide range of temperatures. Associated innovations in high-throughput analytical chemistry techniques greatly increased the efficiency and reliability of these methods. These evolved HTE techniques have been utilized extensively to develop highly innovative catalysis solutions to the most challenging problems in large-scale pharmaceutical synthesis. Starting with Pd- and Cu-catalyzed cross-coupling chemistry, subsequent efforts expanded to other valuable modern synthetic transformations such as chiral phase-transfer catalysis, photoredox catalysis, and C-H functionalization. As our experience and confidence in HTE techniques matured, we envisioned their application beyond problems in process chemistry to address the needs of medicinal chemists. Here the problem of reaction generality is felt most acutely, and HTE approaches should prove broadly enabling. However, the quantities of both time and starting materials available for chemistry troubleshooting in this space generally are severely limited. Adapting to these needs led us to invest in smaller predefined arrays of transformation-specific screening "kits" and push the boundaries of miniaturization in chemistry screening, culminating in the development of "nanoscale" reaction screening carried out in 1536-well plates. Grappling with the problem of generality also inspired the exploration of cheminformatics-driven HTE approaches such as the Chemistry Informer Libraries. These next-generation HTE methods promise to empower chemists to run orders of magnitude more experiments and enable "big data" informatics approaches to reaction design and troubleshooting. With these advances, HTE is poised to revolutionize how chemists across both industry and academia discover new synthetic methods, develop them into tools of broad utility, and apply them to problems of practical significance.

Oxyfunctionalization of the Remote C-H Bonds of Aliphatic Amines by Decatungstate Photocatalysis.

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 H2 O2 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.

Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir.

A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,ß-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.

A multifunctional catalyst that stereoselectively assembles prodrugs.

The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.

Acridinium-Based Photocatalysts: A Sustainable Option in Photoredox Catalysis.

The emergence of visible light photoredox catalysis has enabled the productive use of lower energy radiation, leading to highly selective reaction platforms. Polypyridyl complexes of iridium and ruthenium have served as popular photocatalysts in recent years due to their long excited state lifetimes and useful redox windows, leading to the development of diverse photoredox-catalyzed transformations. The low abundances of Ir and Ru in the earth's crust and, hence, cost make these catalysts nonsustainable and have limited their application in industrial-scale manufacturing. Herein, we report a series of novel acridinium salts as alternatives to iridium photoredox catalysts and show their comparability to the ubiquitous [Ir(dF-CF3-ppy)2(dtbpy)](PF6).

Photoredox-Catalyzed Hydroxymethylation of Heteroaromatic Bases.

We report the development of a method for room-temperature C-H hydroxymethylation of heteroarenes. A key enabling advance in this work was achieved by implementing visible light photoredox catalysis that proved to be applicable to many classes of heteroarenes and tolerant of diverse functional groups found in druglike molecules.

Aryl amination using ligand-free Ni(II) salts and photoredox catalysis.

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.

Discovery and mechanistic study of a photocatalytic indoline dehydrogenation for the synthesis of elbasvir.

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.