Data Science-Enabled Palladium-Catalyzed Enantioselective Aryl-Carbonylation of Sulfonimidamides

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(38), С. 20959 - 20967

Опубликована: Сен. 1, 2023

New methods for the general asymmetric synthesis of sulfonimidamides are great interest due to their applications in medicinal chemistry, agrochemical discovery, and academic research. We report a palladium-catalyzed cross-coupling method enantioselective aryl-carbonylation sulfonimidamides. Using data science techniques, virtual library calculated bisphosphine ligand descriptors was used guide reaction optimization by effectively sampling catalyst chemical space. The optimized conditions identified using this approach provided desired product excellent yield enantioselectivity. As next step, science-driven strategy also explore diverse set aryl heteroaryl iodides, providing key information about scope limitations method. Furthermore, we tested range racemic compatibility coupling partner. developed offers efficient accessing enantioenriched sulfonimidamides, which should facilitate application industrial settings.

Язык: Английский

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At the Speed of Light: The Systematic Implementation of Photoredox Cross-Coupling Reactions for Medicinal Chemistry Research

The Journal of Organic Chemistry, Год журнала: 2024, Номер 89(22), С. 16070 - 16092

Опубликована: Март 5, 2024

The adoption of new and emerging techniques in organic synthesis is essential to promote innovation drug discovery. In this Perspective, we detail the strategy used for systematic deployment photoredox-mediated, metal-catalyzed cross-coupling reactions AbbVie's medicinal chemistry organization, focusing on topics such as assessment, evaluation, implementation, accessibility. comprehensive evaluation photoredox reaction setups published methods will be discussed, along with internal efforts build expertise high-throughput experimentation capabilities. We also highlight academic–industry collaborations field that have been leveraged develop synthetic strategies, discussing reactions. work described herein has culminated robust photocatalysis capabilities which are viewed key platforms research at AbbVie.

Язык: Английский

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Organocatalyzed Photoelectrochemistry for the Generation of Acyl and Phosphoryl Radicals through Hydrogen Atom-Transfer Process

The Journal of Organic Chemistry, Год журнала: 2024, Номер 89(11), С. 7531 - 7540

Опубликована: Май 18, 2024

An organocatalyzed photoelectrochemical method for the generation of acyl and phosphoryl radicals from formamides, aldehydes, phosphine oxides has been developed. This protocol utilizes 9,10-phenanthrenequinone (PQ) as both a molecular catalyst hydrogen atom-transfer (HAT) reagent, eliminating requirement external metal-based reagents, HAT oxidants. The generated can be applied to range radical-mediated transformation reactions, including C–H carbamoylation heteroarenes, intermolecular tandem radical cyclization CF3-substituted N-arylacrylamides, well intramolecular reactions. use in these transformations offers an efficient sustainable approach accessing structurally diverse carbonyl compounds.

Язык: Английский

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Enabling Deoxygenative C(sp²)-C(sp³) Cross-Coupling for Parallel Medicinal Chemistry

ACS Medicinal Chemistry Letters, Год журнала: 2023, Номер 14(6), С. 853 - 859

Опубликована: Май 22, 2023

Herein we report the development of an automated deoxygenative C(sp2)-C(sp3) coupling aryl bromide with alcohols to enable parallel medicinal chemistry. Alcohols are among most diverse and abundant building blocks, but their usage as alkyl precursors has been limited. Although metallaphotoredox is becoming a promising strategy form bond, reaction setup limits its widespread application in library synthesis. To achieve high throughput consistency, workflow involving solid-dosing liquid-handling robots developed. We have successfully demonstrated this high-throughput protocol robust consistent across three automation platforms. Furthermore, guided by cheminformatic analysis, examined comprehensive chemical space coverage established meaningful scope for chemistry applications. By accessing rich diversity alcohols, potential substantially increase impact cross-coupling drug discovery.

Язык: Английский

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C–H Aminoalkylation of 5-Membered Heterocycles: Influence of Descriptors, Data Set Size, and Data Quality on the Predictiveness of Machine Learning Models and Expansion of the Substrate Space Beyond 1,3-Azoles

The Journal of Organic Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 11, 2025

We report a general C-H aminoalkylation of 5-membered heterocycles through combined machine learning/experimental workflow. Our work describes previously unknown functionalization reactivity and creates predictive learning (ML) model iterative refinement over 6 rounds active learning. The initial established with 1,3-azoles predicts the reactivities N-aryl indazoles, 1,2,4-triazolopyrazines, 1,2,3-thiadiazoles, 1,3,4-oxadiazoles, while other substrate classes (e.g., pyrazoles 1,2,4-triazoles) are not predicted well. final includes additional heterocyclic scaffolds in training data, which results high accuracy across all tested cores. prediction performance is shown both within set via cross-validation (CV R2 = 0.81) when predicting unseen substrates diverse molecular weight structure (Test 0.95). concept feature engineering discussed, we benchmark mechanistically related DFT-based features that more time-intensive laborious comparison descriptors fingerprints. Importantly, this establishes novel for methods underdeveloped. Since such key motifs drug discovery development, expect to be significant use synthetic synthesis-oriented ML communities.

Язык: Английский

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Recent advancements in metal-free C–C bond formation via C–H bond functionalization

Organic & Biomolecular Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

This review delves into the peroxides or visible light induced metal-free C–H bond cleavage to accomplish C(sp/sp 2 /sp 3 )–H alkylation, alkenylation, arylation, carbonylation, carbamoylation, alkynylation and cyanation.

Язык: Английский

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High-Throughput Optimization of a High-Pressure Catalytic Reaction

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Фев. 20, 2025

High-throughput optimization of a hydroformylation reaction using CO2 instead CO was performed through Bayesian in combination with high-throughput screening system. and H2 pressure as well catalyst composition were efficiently optimized by transferring surrogate model, constructed optimization, for the comprehensive entire search space. This method successfully increased aldehyde yield 1.5 times compared to that reported literature small amounts Rh Ru catalysts combined ionic liquid chloride ions. The completed within 1-2 months AI, robotics, human expertise, demonstrating feasibility rapid development, even high-pressure reactions.

Язык: Английский

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Unveiling CO₂ reactivity with data-driven methods

Digital Discovery, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

We present a data-driven approach that integrates supervised learning, quantum chemistry, and uncertainty quantification to determine CO 2 reactivity, enabling advances in carbon capture the design of value-added chemicals.

Язык: Английский

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Predicting and Explaining Yields with Machine Learning for Carboxylated Azoles and Beyond

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Фев. 7, 2025

Carbon dioxide (CO2) can be transformed into valuable chemical building blocks, including C2-carboxylated 1,3-azoles, which have potential applications in pharmaceuticals, cosmetics, and pesticides. However, only a small fraction of the millions available 1,3-azoles are carboxylated at C2 position, highlighting significant opportunities for further research synthesis application these compounds. In this study, we utilized supervised machine learning approach to predict reaction yields data set amide-coupled 1,3-azoles. To facilitate molecular design, integrated an interpretable heat-mapping algorithm named PIXIE (Predictive Insights Xplainability Informed space Exploration). visualizes influence substructures on predicted by leveraging fingerprint bit importances, providing synthetic chemists with powerful tool rational design molecules. While heat mapping is established technique, its integration machine-learning model tailored represents advancement. This not enables targeted exploration underrepresented space, fostering discovery new bioactive compounds, but also demonstrates combining methods broader other domains.

Язык: Английский

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Diiminium Nucleophile Adducts Are Stable and Convenient Strong Lewis Acids**

Chemistry - A European Journal, Год журнала: 2023, Номер 29(58)

Опубликована: Июль 10, 2023

Strong Lewis acids are essential tools for manifold chemical procedures, but their scalable deployment is limited by costs and safety concerns. We report a scalable, convenient, inexpensive synthesis of stable diiminium-based reagents with acidic carbon centre. Coordination pyridine donors stabilises these centres; the 2,2'-bipyridine adduct shows chelation effect at carbon. Due to high fluoride, hydride, oxide affinities, diiminium adducts promising soft hard acids. They effectively produce acylpyridinium salts from carboxylates that can acylate amines give amides imides even electronically intractable coupling partners.

Язык: Английский

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