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

Synlett, Год журнала: 2024, Номер 35(08), С. 862 - 876

Опубликована: Янв. 15, 2024

Abstract The field of C–H functionalization chemistry has experienced rapid growth in the past twenty years, with increasingly powerful applications organic synthesis. Recognizing potential this emerging to impact drug discovery, a dedicated effort was established our laboratories more than ten years ago, goal facilitating application chemistries active medicinal-chemistry programs. Our approach centered around strategy late-stage (LSF) wherein is employed systematic and targeted manner generate high-value analogues from advanced leads. To successfully realize approach, we developed broadly useful LSF platforms workflows that increased success rates accelerated access new derivatives. strategy, when properly applied, enabled synthesis molecules designed address specific issues. Several case studies are presented, along descriptions group’s workflows. 1 Introduction 2 Building an Chemistry Toolbox 2.1 Borylation 2.2 Minisci Platforms 2.3 Automated Direct-Metalation Platform 3 Workflow 4 Application Case Studies 4.1 BTK Inhibitor Program 4.2 GPR40 Agonist 5 Conclusions

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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Are activation barriers of 50–70 kcal mol⁻¹ accessible for transformations in organic synthesis in solution?

Chemical Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

High-temperature organic chemistry represents a transformative approach for accessing reaction pathways previously deemed unattainable under conventional conditions.

Язык: Английский

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Nitrogen-Based Organofluorine Functional Molecules: Synthesis and Applications

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Апрель 22, 2025

Fluorine and nitrogen form a successful partnership in organic synthesis, medicinal chemistry, material sciences. Although fluorine-nitrogen chemistry has long rich history, this field received increasing interest made remarkable progress over the past two decades, driven by recent advancements transition metal organocatalysis photochemistry. This review, emphasizing contributions from 2015 to 2023, aims update state of art synthesis applications nitrogen-based organofluorine functional molecules chemistry. In dedicated sections, we first focus on fluorine-containing reagents organized according type groups attached nitrogen, including N-F, N-RF, N-SRF, N-ORF. review also covers nitrogen-linked building blocks, catalysts, pharmaceuticals, agrochemicals, underlining these components' broad applicability growing importance modern

Язык: Английский

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Regioselective, Lewis Acid-Catalyzed Ring-Openings of 2,3-Aziridyl Alcohols with Azoles

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

Опубликована: Апрель 25, 2025

Methods for regioselective ring-opening reactions of N-sulfonyl-protected aziridyl alcohols with azole nucleophiles have been developed. Several classes azoles, including indazole, substituted pyrazole, benzotriazole, and tetrazole, employed as reaction partners, giving rise to C3-selective opening >3:1 N-selectivity. BF3•OEt2 is the optimal catalyst most substrate combinations, although examples where diphenylborinic acid (Ph2BOH) provides higher yields, or proceed efficiently without a catalyst, are also described. Computational modeling BF3•OEt2-catalyzed consistent observed regiochemical outcome. The calculated transition state appears be stabilized by an unconventional OH···FB hydrogen-bonding interaction.

Язык: Английский

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