Applying statistical modeling strategies to sparse datasets in synthetic chemistry

Science Advances, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 1, 2025

The application of statistical modeling in organic chemistry is emerging as a standard practice for probing structure-activity relationships and predictive tool many optimization objectives. This review aimed tutorial those entering the area chemistry. We provide case studies to highlight considerations approaches that can be used successfully analyze datasets low data regimes, common situation encountered given experimental demands Statistical hinges on (what being modeled), descriptors (how are represented), algorithms modeled). Herein, we focus how various reaction outputs (e.g., yield, rate, selectivity, solubility, stability, turnover number) structures binned, heavily skewed, distributed) influence choice algorithm constructing chemically insightful models.

Language: Английский

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Unlocking Chiral Sulfinimidoyl Electrophiles: Asymmetric Synthesis of Sulfinamides Catalyzed by Anionic Stereogenic-at-Cobalt(III) Complexes

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Asymmetric catalysis involving a sulfoxide electrophile intermediate presents an efficient methodology for accessing stereogenic-at-sulfur compounds, such as sulfinate esters, sulfinamides, etc., which have garnered increasing attention in modern pharmaceutical sciences. However, the aza-analog of electrophiles, asymmetric issues about electrophilic sulfinimidoyl species remain largely unexplored and represent significant challenge sulfur stereochemistry. Herein, we exhibit anionic stereogenic-at-cobalt(III) complex-catalyzed synthesis chiral sulfinamides via iodide intermediates. Mechanistic investigations reveal that catalytic cycle is initiated by oxidative iodination, generating iodides. These active intermediates subsequently undergo enantiospecific nucleophilic substitution with water, affording diverse array enantioenriched sulfinamides. Notably, these promising antifungal activities against Sclerotinia sclerotiorum serve ideal platform molecules facilitating stereospecific transformation into various stereogenic aza-sulfur compounds.

Language: Английский

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Enantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(12), P. 8536 - 8546

Published: March 13, 2024

Methods to access chiral sulfur(VI) pharmacophores are of interest in medicinal and synthetic chemistry. We report the desymmetrization unprotected sulfonimidamides via asymmetric acylation with a cinchona-phosphinate catalyst. The desired products formed excellent yield enantioselectivity no observed bis-acylation. A data-science-driven approach substrate scope evaluation was coupled high throughput experimentation (HTE) facilitate statistical modeling order inform mechanistic studies. Reaction kinetics, catalyst structural studies, density functional theory (DFT) transition state analysis elucidated turnover-limiting step be collapse tetrahedral intermediate provided key insights into catalyst-substrate structure–activity relationships responsible for origin enantioselectivity. This study offers reliable method accessing enantioenriched propel their application as serves an example insight that can gleaned from integrating data science traditional physical organic techniques.

Language: Английский

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AI for organic and polymer synthesis

Science China Chemistry, Journal Year: 2024, Volume and Issue: 67(8), P. 2461 - 2496

Published: June 26, 2024

Language: Английский

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

ACS Central Science, Journal Year: 2024, Volume and Issue: unknown

Published: April 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.

Language: Английский

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Predictive catalysis: a valuable step towards machine learning

Trends in Chemistry, Journal Year: 2023, Volume and Issue: 5(12), P. 935 - 946

Published: Nov. 18, 2023

Language: Английский

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Ligand-Based Principal Component Analysis Followed by Ridge Regression: Application to an Asymmetric Negishi Reaction

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(7), P. 5027 - 5038

Published: March 20, 2024

In this study, we introduce an approach for predicting the enantioselectivity of P-chiral monophosphorus ligands from ligand-based descriptors that can be applied to catalytic systems with small experimental datasets without reliance on mechanistic knowledge. Principal component analysis (PCA) is used map out chemical space described by steric and electronic computed dihydrobenzooxaphosphole (BOP) dihydrobenzoazaphosphole (BAP) ligands. The PCA captures trends in experimentally measured four C–C bond-forming reactions identifies "hotspots" selective provide insight into optimal balance sterics electronics each reaction. Furthermore, are train a ridge regression model quantitatively predicts Pd-catalyzed Negishi cross-coupling coefficients fundamental understanding reveal π-stacking interaction one results unexpected selectivity inversion. Overall, integrated combines qualitative quantitative (ridge regression) predictions.

Language: Английский

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Enantioconvergent synthesis of axially chiral amides enabled by Pd-catalyzed dynamic kinetic asymmetric aminocarbonylation

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 23, 2024

Atropisomeric biaryls bearing carbonyl groups have attracted increasing attention due to their prevalence in diverse bioactive molecules and crucial role as efficient organo-catalysts or ligands asymmetric transformations. However, preparation often involves tedious multiple steps, the direct synthesis via carbonylation has scarcely been investigated. Herein, we report an palladium-catalyzed enantioconvergent aminocarbonylation of racemic heterobiaryl triflates with amines dynamic kinetic transformation (DyKAT). This protocol features a broad substrate scope excellent compatibility for rapid construction axially chiral amides good high yields enantioselectivities. Detailed mechanistic investigations discover that base can impede intramolecular hydrogen bond-assisted axis rotation products, thus allowing success achieve enantioselectivity. Moreover, achieved be directly utilized N,N,N-pincer copper-catalyzed enantioselective formation C(sp3)-N C(sp3)-P bonds. Axially containing not only exist various drug candidates but also serve authors transformation.

Language: Английский

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Synthesis of chiral sulfilimines by organocatalytic enantioselective sulfur alkylation of sulfenamides

Science Advances, Journal Year: 2024, Volume and Issue: 10(37)

Published: Sept. 13, 2024

Sulfilimines are versatile synthetic intermediates and important moieties in bioactive molecules. However, their applications drug discovery underexplored, efficient asymmetric methods highly desirable. Here, we report a transition metal–free pentanidium-catalyzed sulfur alkylation of sulfenamides with exclusive chemoselectivity over nitrogen high enantioselectivity. The reaction conditions were mild, wide range enantioenriched aryl alkyl sulfilimines obtained. utility practicability this robust protocol further demonstrated through gram-scale reactions late-stage functionalization drugs.

Language: Английский

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Decoupling strategy-enabled radical generality via an asymmetric SH2 path

Published: Feb. 12, 2024

Reaction generality is essential for evaluating the value and impact of a synthetic method. However, asymmetric catalysis, particularly that involving highly reactive species such as radicals, typically prioritizes enantioselectivity at expense generality. Selectivity reactivity often conflict because bond-forming step usually also stereodetermining. If these two steps were separated, reaction selectivity issues could then be addressed independently. Herein we report catalytic radical coupling with great by merging copper-catalyzed enantioselective S(IV) center formation copper-mediated enantiospecific SH2 coupling. This decoupling strategy has enabled successful over 30 different carbon-, nitrogen-, oxygen-based radicals having broad range N-acyl sulfenamides, leading to diverse S-chiral compounds exceptional enantioselectivity. Thus, it offers holistic approach accessing rich portfolio S(VI) chiral centers, which anticipated have transformative on synthesis benefit medicinal chemistry other related fields. Furthermore, this via processes promising potential enable comprehensive single-electron methodology forging centers heteroatoms phosphorous(III) silicon(IV), eventually carbon atoms.

Language: Английский

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