Shane W. Krska

Developing Pharmaceutically Relevant Pd-Catalyzed C–N Coupling Reactivity Models Leveraging High-Throughput Experimentation

Seung Kyun Ha, Dipannita Kalyani, Michael S. West, Jessica A. Xu et autres

This manuscript presents machine learning models for Pd-catalyzed C–N couplings constructed using a large, pharmaceutically relevant, structurally diverse dataset (4204 unique products) generated de novo using high-throughput experimentation. The dataset generation was enabled by the discovery of novel nanomole scale compatible automation …

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Rapid Affinity and Microsomal Stability Ranking of Crude Mixture Libraries of Histone Deacetylase Inhibitors

Sriram Tyagarajan, Christine L. Andrews, Douglas C. Beshore, Alexei V. Buevich et autres

The science of drug discovery involves multiparameter optimization of molecular structures through iterative design-make-test cycles. For medicinal chemistry library synthesis, traditional workflows involve the isolation of each individual compound, gravimetric quantitation, and preparation of a standard concentration solution for biological assays. In …

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Radical chlorination of non-resonant heterobenzylic C‒H bonds and high-throughput diversification of heterocycles

Dung L. Golden, Kaitlyn M Flynn, Santeri Aikonen, Christopher M Hanneman et autres

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Development of High-Throughput Experimentation Approaches for Rapid Radiochemical Exploration

Eric Webb, Kevin Cheng, Wade P. Winton, Brandon Klein et autres

Positron emission tomography is a widely used imaging platform for studying physiological processes. Despite the proliferation of modern synthetic methodologies for radiolabeling, the optimization of these reactions still primarily relies on inefficient one-factor-at-a-time approaches. High-throughput experimentation (HTE) has proven to be a …

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Parallel purification of microscale libraries via automated solid phase extraction

Michael Wleklinski, P Carpenter, Kevin D. Dykstra, Anthony E. Donofrio et autres

High-throughput experimentation (HTE) has become more widely utilized in drug discovery for rapid reaction optimization and generation of large synthetic compound arrays. While this has accelerated medicinal chemistry design, make, test (DMT) iterations, the bottleneck of purification persists, consuming time and resources. …

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Harnessing the Power of C–H Functionalization Chemistry to Accelerate Drug Discovery

Shane W. Krska, Bing Li, Sriram Tyagarajan, Kevin D. Dykstra et autres

Abstract The field of C–H functionalization chemistry has experienced rapid growth in the past twenty years, with increasingly powerful applications in organic synthesis. Recognizing the potential of this emerging field to impact drug discovery, a dedicated effort was established in our laboratories …

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Copper-Catalyzed Benzylic C–H Cross-Coupling Enabled by Redox Buffers: Expanding Synthetic Access to Three-Dimensional Chemical Space

Si-Jie Chen, Shane W. Krska, Shannon S. Stahl

Conspectus Cross-coupling methods are the most widely used synthetic methods in medicinal chemistry. Existing reactions are dominated by methods such as amide coupling and arylation reactions that form bonds to sp 2 -hybridized carbon atoms and contribute to the formation of “flat” …

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Cu Oxamate-Promoted Cross-Coupling of α-Branched Amines and Complex Aryl Halides: Investigating Ligand Function through Data Science

Adrian D. Matthews, Ellyn Peters, John S. Debenham, Qi Gao et autres

Synthesis of α-branched aryl amines is a continuing challenge in synthetic and medicinal chemistry. Although transition-metal-promoted C–N cross-coupling is a desirable approach to the synthesis of α-branched aryl amines, there are limited examples of methods that demonstrate broad generality and applicability using …

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Development of Approaches for High-Throughput Experimentation in Radiochemistry

Eric Webb, Kevin Cheng, Stefan Verhoog, Dipannita Kalyani et autres

Polar Heterobenzylic C(sp3)–H Chlorination Pathway Enabling Efficient Diversification of Aromatic Nitrogen Heterocycles

Soham Maity, Marco A. Lopez, Desiree M. Bates, Shishi Lin et autres

-H) functionalization and cross-coupling. The existing methods, however, are often ineffective with heterobenzylic C-H bonds in alkyl-substituted pyridines and related aromatic heterocycles that are prominently featured in pharmaceuticals and agrochemicals. Here, we report new synthetic methods that leverage polar, rather than radical, …

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A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C–H oxidation of carbocyclic N -heterocycles

Rachel K. Chambers, J. D. III WEAVER, Jinho Kim, Jason L. Hoar et autres

An emerging trend in small-molecule pharmaceuticals, generally composed of nitrogen heterocycles ( N -heterocycles), is the incorporation of aliphatic fragments. Derivatization of the aliphatic fragments to improve drug properties or identify metabolites often requires lengthy de novo syntheses. Cytochrome P450 (CYP450) enzymes …

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Accessing three-dimensional molecular diversity through benzylic C–H cross-coupling

Si-Jie Chen, Cyndi Qixin He, May Kong, Jun Wang et autres

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