Standardizing Substrate Selection: A Strategy toward Unbiased Evaluation of Reaction Generality

ACS Central Science, Год журнала: 2024, Номер unknown

Опубликована: Апрель 8, 2024

With over 10,000 new reaction protocols arising every year, only a handful of these procedures transition from academia to application. A major reason for this gap stems the lack comprehensive knowledge about reaction's scope, i.e., which substrates protocol can or cannot be applied. Even though chemists invest substantial effort assess scope protocols, resulting tables involve significant biases, reducing their expressiveness. Herein we report standardized substrate selection strategy designed mitigate biases and evaluate applicability, as well limits, any chemical reaction. Unsupervised learning is utilized map space industrially relevant molecules. Subsequently, potential candidates are projected onto universal map, enabling structurally diverse set with optimal relevance coverage. By testing our methodology on different reactions, were able demonstrate its effectiveness in finding general reactivity trends by using few highly representative examples. The developed empowers showcase unbiased applicability novel methodologies, facilitating practical applications. We hope that work will trigger interdisciplinary discussions synthetic chemistry, leading improved data quality.

Язык: Английский

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Development of High-Throughput Experimentation Approaches for Rapid Radiochemical Exploration

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(15), С. 10581 - 10590

Опубликована: Апрель 5, 2024

Positron emission tomography is a widely used imaging platform for studying physiological processes. Despite the proliferation of modern synthetic methodologies radiolabeling, optimization these reactions still primarily relies on inefficient one-factor-at-a-time approaches. High-throughput experimentation (HTE) has proven to be powerful approach optimizing in many areas chemical synthesis. However, date, HTE rarely been applied radiochemistry. This largely because short lifetime common radioisotopes, which presents major challenges efficient parallel reaction setup and analysis using standard equipment workflows. Herein, we demonstrate an effective workflow apply it copper-mediated radiofluorination pharmaceutically relevant boronate ester substrates. The utilizes commercial allows rapid reactions, exploring space aryl boronates radiofluorinations, constructing large radiochemistry data sets.

Язык: Английский

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Hydrogen-Bonding Ability of Noyori–Ikariya Catalysts Enables Stereoselective Access to CF₃-Substituted syn-1,2-Diols via Dynamic Kinetic Resolution

ACS Catalysis, Год журнала: 2023, Номер 13(9), С. 6242 - 6248

Опубликована: Апрель 21, 2023

Stereopure CF3-substituted syn-1,2-diols were prepared via the reductive dynamic kinetic resolution of corresponding racemic α-hydroxyketones in HCO2H/Et3N. (Het)aryl, benzyl, vinyl, and alkyl ketones are tolerated, delivering products with ≥95% ee ≥87:13 syn/anti. This methodology offers rapid access to stereopure bioactive molecules. Furthermore, DFT calculations for three types Noyori-Ikariya ruthenium catalysts performed show their general ability directing stereoselectivity hydrogen bond acceptor SO2 region CH/π interactions.

Язык: Английский

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Ring Expansion Strategies for the Synthesis of Medium Sized Ring and Macrocyclic Sulfonamides

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(13)

Опубликована: Янв. 30, 2023

Two new ring expansion strategies are reported for the synthesis of medium sized and macrocyclic sulfonamides. Both methods can be performed without using classical protecting groups, with key step initiated by nitro reduction amine conjugate addition respectively. Each method used to make diversely functionalised cyclic sulfonamides in good excellent yields, a range sizes. The size dependency synthetic reactions is agreement outcomes modelled Density Functional Theory calculations.

Язык: Английский

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Accessing Diverse Azole Carboxylic Acid Building Blocks via Mild C–H Carboxylation: Parallel, One-Pot Amide Couplings and Machine-Learning-Guided Substrate Scope Design

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(50), С. 23115 - 23126

Опубликована: Дек. 9, 2022

This manuscript describes a mild, functional group tolerant, and metal-free C-H carboxylation that enables direct access to azole-2-carboxylic acids, followed by amide coupling in one pot. demonstrates significant expansion of the accessible chemical space azole-2-amides, compared previously known methodologies. Key described reactivity is use silyl triflate reagents, which serve as reaction mediators deprotonation stabilizers (otherwise unstable) azole carboxylic acid intermediates. A diverse substrate scope designed via machine-learning-guided analysis broad utility sequence. Density theory calculations provide detailed insights into role triflates mechanism. Transferrable applications protocol are successfully established: (i) low pressure (CO2 balloon) option for synthesizing acids without need high-pressure equipment; (ii) 13CO2 synthesis labeled compounds; (iii) isocyanates alternative electrophiles amidation; (iv) developed chemistry 24 × 12 parallel workflow with 90% library success rate. Fundamentally, reported expands heterocycle functionalization from late-stage toward its synthesis. It provides general densely functionalized building blocks their one-pot diversification.

Язык: Английский

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Reaction development: a student's checklist

Chemical Society Reviews, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

So you've discovered a reaction. This review discusses the key areas involved in developing new reactions and provides handy checklist guide to help maximise potential of your novel transformation.

Язык: Английский

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Development of a Thioetherification of Heteroarene Electrophiles with Broad Scope via a Proton Transfer Dual Ionization Mechanism

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Фев. 13, 2025

Sulfur-derived functional groups represent prevalent motifs in highly sought-after small molecules, such as active pharmaceutical ingredients (APIs). Thioethers are one example, being commonly encountered APIs, prodrugs, and valuable synthetic "linchpins" to access an array of sulfur-derived groups. While nucleophilic aromatic substitution (SNAr) has traditionally been used synthesize aryl thioethers, modern approaches leverage transition metals catalyze thermal or photochemical cross-coupling. studying thioetherification reactions, we uncovered a remarkably mild condition that does not require light, metals, exogenous bases. An thiols halogenated heterocycles were coupled produce >70 diverse products. Reaction progress kinetic analysis (RPKA) computational studies support unique mechanism termed proton transfer dual ionization (PTDI) SNAr. Finally, predictive statistical model was constructed aided by high-throughput experimentation (HTE) understand when the PTDI processes successful, resulting completion ten target-oriented syntheses. This transformation complements thioether synthesis motivates additional research evaluating general activation mode between reaction partners.

Язык: Английский

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Probability Guided Chemical Reaction Scopes

Опубликована: Янв. 1, 2025

Язык: Английский

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Revealing the Relationship between Publication Bias and Chemical Reactivity with Contrastive Learning

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Март 2, 2025

A synthetic method's substrate tolerance and generality are often showcased in a "substrate scope" table. However, selection exhibits frequently discussed publication bias: unsuccessful experiments or low-yielding results rarely reported. In this work, we explore more deeply the relationship between such bias chemical reactivity beyond simple analysis of yield distributions using novel neural network training strategy, scope contrastive learning. By treating reported substrates as positive samples nonreported negative samples, our learning strategy teaches model to group molecules within numerical embedding space, based on historical trends published tables. Training 20,798 aryl halides CAS Content CollectionTM, spanning thousands publications from 2010 2015, demonstrate that learned embeddings exhibit correlation with physical organic descriptors through both intuitive visualizations quantitative regression analyses. Additionally, these applicable various reaction modeling tasks like prediction regioselectivity prediction, underscoring potential use data pretraining task. This work not only presents chemistry-specific machine learn literature new way but also represents unique approach uncover reflected by publications.

Язык: Английский

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Relative Generality and Risk: Quantitative Measures for Broad Catalyst Success

ACS Catalysis, Год журнала: 2024, Номер 14(22), С. 16849 - 16860

Опубликована: Окт. 31, 2024

The performance of chiral catalysts is typically evaluated against empirical reaction outputs like yield and selectivity with traditional analyses limited to a single model system. Expansion the space permits be assessed for generality, this provides another useful metric measuring effectiveness catalyst. catalyst generality algorithm will assign quantitative values structures, but such broad assessments are applied assumption that reactions under evaluation more or less same by disregarding any inherent challenges associated particular class. To address limitation, we introduce two metrics: relative risk. These designed correct variations in difficulty enable nuanced specific demands each reaction. We show number challenging examples these metrics allow researchers distinguish between genuinely exhibiting superior those appearing favorable due application toward demanding reactions. This represents significant advancement quantifying success demonstrated applications retrospective early insights into emerging classes.

Язык: Английский

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