Daniel A. DiRocco

Late‐Stage Functionalization of Biologically Active Heterocycles Through Photoredox Catalysis

The direct CH functionalization of heterocycles has become an increasingly valuable tool in modern drug discovery. However, the introduction of small alkyl groups, such as methyl, by this method has not been realized in the context of complex molecule synthesis since existing methods rely on the use of strong oxidants and elevated temperatures to generate the requisite radical species. Herein, we report the use of stable organic peroxides activated by visible-light photoredox catalysis to achieve the direct methyl-, ethyl-, and cyclopropylation of a variety of biologically active heterocycles. The simple protocol, mild reaction conditions, and unique tolerability of this method make it an important tool for drug discovery.

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

A light approach to C-N bond formation The need to form C-N bonds arises frequently in drug discovery research. One versatile approach involves the attachment of the C and N fragments to a Pd catalyst. This approach needs a bulky ligand to “crowd” the fragments together off the metal center. Corcoran et al. present a complementary approach that uses Ni in place of Pd. Instead of the bulky ligand, they used a light-activated cocatalyst that strips an electron from the Ni to accelerate the bond formation. A screen involving elaborately substituted reagents confirmed the utility of this approach in cases that challenge the traditional Pd coupling. Science, this issue p. 279 Transient oxidation of nickel by a photoexcited cocatalyst accelerates C–N bond formation without the need for bulky ligands. 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.

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 earths 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.

A multifunctional catalyst that stereoselectively assembles prodrugs

Getting phosphorus into healthy shape ProTide therapeutics play a trick on the body, getting nucleoside analogs where they need to be by decorating them with unnatural phosphoramidates in place of ordinary phosphates. These compounds pose an unusual synthetic challenge because their configuration must be controlled at phosphorus; most methods have been refined to manipulate the geometry of carbon. DiRocco et al. report a metal-free, small-molecule catalyst that attains high selectivity for nucleoside phosphoramidation by activating both reaction partners. Kinetic studies with an early prototype revealed a double role for the catalyst that inspired the rational design of a more active and selective dimeric structure. Science, this issue p. 426 A doubly activating catalyst efficiently forms key phosphorus-based chiral centers inherent to ProTide therapeutics. 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.

The discovery of high affinity agonists of GPR109a with reduced serum shift and improved ADME properties

Amino-anthranilic acid derivatives have been identified as a new class of low serum shifted, high affinity full agonists of the human orphan G-protein-coupled receptor GPR109a with improved ADME properties.

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.

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.Direct coupling of aliphatic C–H nucleophiles to aryl electrophiles is described, through the combination of light-driven polyoxometalate hydrogen atom transfer and nickel catalysis.

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

A rapid screen for complex reactants Chemists engaged in reaction discovery tend to report outcomes involving a few, relatively simple reactants. It remains a major challenge to fine-tune reported conditions when the reactants become more structurally complex, as often happens in pharmaceutical research. Lin et al. developed a protocol for rapidly screening different catalytic conditions for C–N coupling across a wide range of complex substrates. The product detection scheme relies on mass spectrometry of nanomole-scale reaction mixtures without any need for intervening chromatography. Science, this issue p. eaar6236 Mass spectrometry is used to screen catalytic conditions for C–N coupling of a wide variety of complex reactants. INTRODUCTION The invention of new chemical reactions provides new bond construction strategies for improved access to diverse regions of structural space. However, a pervasive, long-standing bias toward reporting successful results means that the shortcomings of even mature reaction methods remain poorly defined, making practical syntheses of structurally diverse targets far from certain. Distinct tools and experimental approaches are required to expose and record the problematic structural elements that limit different synthetic methods. The experimental space required to systematically survey reaction failure is vast, and existing ultrahigh-throughput (uHT) reaction screening approaches are inadequate for exploring the diversity of conditions pertaining in modern synthetic methods. Additionally, analytical approaches must continuously improve to meet the throughput demands of this expansive reaction screening. RATIONALE We report a nanomole-scale screening protocol that can be used to execute heterogeneous reactions with heating and agitation, use of volatile solvents, and capacity for photoredox chemistry. These advances in miniaturized chemistry screening were combined with the use of matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry (MALDI-TOF MS), enabling analysis of 1536 reactions in ~10 min. Together, these advances create a platform that can enable systematic reaction evaluation and data capture to survey the dark space of chemical reactions. RESULTS Using the Buchwald-Hartwig C–N coupling reaction to exemplify this process, an uHT Glorius fragment additive poisons diagnostic approach was first applied to demonstrate that MALDI-MS could provide adequate data quality to monitor the formation of a single product under a wide variety of different synthetic conditions. Four catalytic methods—Ir/Ni and Ru/Ni dual-metal photoredox catalysis, as well as heterogeneous and high-temperature Cu and Pd catalysis—with extended nanomole chemistry requirements were evaluated for the synthesis of a single product in the presence of 383 structurally diverse simple and complex potential poisons. Using a normalizing internal standard that was closely related to the product and optimized operating parameters, MALDI-MS provided good correlation with existing ultra performance liquid chromatography (UPLC)–MS approaches (coefficient of determination R2 up to 0.85), allowing correct binning of “hits” and “misses” (defined as >50% product signal knockdown) up to 95% of the time. Next, the more challenging goal of exploring diverse whole-molecule C–N couplings was explored. In this case, it was not practical to have either product standards or closely related internal standards to enable analytical quantitation. A “simplest-partner test” was employed, in which 192 aryl bromides and 192 secondary amines were each coupled with a MS-active “simplest partner,” guaranteeing a somewhat normalized MS response for all products. The formation of 384 different products using the four aforementioned synthetic methods was monitored by MALDI-MS, with pass-fail binning of results correlating well with UPLC-MS in the identification of common structural elements (such as functional group counts, H-bond donors and acceptors, and polar surface area) that lead to reaction failure. CONCLUSION In the near future, each problematic structural element that is identified through systematic dark-space exploration can be promoted for in-depth examination to precisely define the specific parameters that determine reaction outcome at the atomic and quantum molecular level. Predictive machine learning models will use this focused data to enable synthetic practitioners to select the most appropriate reactions for use in a particular synthetic setting. In addition, functionality that persistently fails across synthetic methods can sharply define important challenges for the invention of improved chemical reactions. Extended nanomole chemistry and MALDI-TOF MS for systematic reaction profiling. Nanomole-scale chemistry tools that can execute a wide variety of synthetic protocols are combined with rapid MALDI-TOF MS analysis to enable broad reaction profiling to map the dark space of chemical reactivity. DMSO, dimethyl sulfoxide; DABCO, 1,4-diazabicyclo[2.2.2]octane. 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.