Skeletal Ring Contractions via I(I)/I(III) Catalysis: Stereoselective Synthesis of cis-α,α-Difluorocyclopropanes

ACS Catalysis, Journal Year: 2022, Volume and Issue: 12(23), P. 14507 - 14516

Published: Nov. 10, 2022

The clinical success of α,α-difluorocyclopropanes, combined with limitations in the existing synthesis portfolio, inspired development an operationally simple, organocatalysis-based strategy to access cis-configured derivatives high levels stereoselectivity (up >20:1 cis:trans). Leveraging I(I)/I(III)-catalysis platform presence inexpensive HF source, it has been possible exploit disubstituted bicyclobutanes (BCBs) as masked cyclobutene equivalents for this purpose. In situ generation strained alkene, enabled by Brønsted acid activation, facilitates unprecedented 4 → 3 fluorinative ring contraction, furnish cis-α,α-difluorinated cyclopropanes a highly stereoselective manner 88% yield). Mechanistic studies are disclosed together conformational analysis (X-ray crystallography and NMR) validate cis-α,α-difluorocyclopropanes isosteres 1,4-dicarbonyl moiety. Given importance unit biology foundational no π* interactions that manifest themselves conformation (e.g., collagen), is envisaged title motif will find application focused molecular design.

Language: Английский

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Integrating I(I)/I(III) catalysis in reaction cascade design enables the synthesis of gem-difluorinated tetralins from cyclobutanols

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 2, 2023

Partially saturated, fluorine-containing rings are ubiquitous across the drug discovery spectrum. This capitalises upon biological significance of native structure and physicochemical advantages conferred by fluorination. Motivated aryl tetralins in bioactive small molecules, a reaction cascade has been validated to generate novel gem-difluorinated isosteres from 1,3-diaryl cyclobutanols single operation. Under Brønsted acidity catalysis conditions, an acid-catalysed unmasking/fluorination sequence generates homoallylic fluoride situ. species serves as substrate for I(I)/I(III) cycle is processed, via phenonium ion rearrangement, (isolable) 1,3,3-trifluoride. A final C(sp3)-F bond activation event, enabled HFIP, forges difluorinated tetralin scaffold. The highly modular, enabling intermediates be intercepted: this provides expansive platform generation structural diversity.

Language: Английский

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Copper-Initiated Regiodivergent Chloropentafluorosulfanylation of 1,3-Enynes under Substrate Control

Organic Letters, Journal Year: 2024, Volume and Issue: 26(23), P. 5049 - 5054

Published: June 4, 2024

A copper-catalyzed regiodivergent chloropentafluorosulfanylation strategy for 1,3-enynes using SF

Language: Английский

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Catalytic stereoselective synthesis involving hypervalent iodine-based chiral auxiliaries

Organic & Biomolecular Chemistry, Journal Year: 2023, Volume and Issue: 21(20), P. 4163 - 4180

Published: Jan. 1, 2023

A number of organic transformations have been achieved using hypervalent iodine reagents under mild reaction conditions. The use these as chiral organocatalyst exhibited highly selective asymmetric reactions.

Language: Английский

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Imidazole-mediated Defluorosulfonylation of N-(Fluorosulfonyl)oxazolidinones Accessed by an Organoiodine(I/III)-catalyzed Oxyamination

Tetrahedron, Journal Year: 2025, Volume and Issue: unknown, P. 134611 - 134611

Published: March 1, 2025

Language: Английский

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Catalytic, Regioselective 1,4‐Fluorodifunctionalization of Dienes

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(1)

Published: Nov. 8, 2022

Abstract A catalysis‐based regioselective 1,4‐fluorofunctionalization of trifluoromethyl substituted 1,3‐dienes has been developed to access compact, highly functionalized products. The process allows E , Z ‐mixed dienes be processed a single ‐alkene isomer, and leverages an inexpensive operationally convenient I(I)/I(III) catalysis platform. first example catalytic 1,4‐difluorination is disclosed subsequently evolved enable 1,4‐hetero‐difunctionalization, which δ‐fluoro‐alcohol amine derivatives forged in operation. protocol compatible with variety nucleophiles including fluoride, nitriles, carboxylic acids, alcohols even water thereby allowing products, stereocenter bearing both C(sp 3 )−F )−CF groups, generated rapidly. Scalability (up mmol), facile post‐reaction modifications are demonstrated underscore the utility method expanding organofluorine chemical space.

Language: Английский

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Oxidative Reactions Mediated by Hypervalent Iodine Reagents

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Investigating Reactivity and Selectivity in a Palladium-Catalyzed Heteroleptic Ligand System for Electrophilic Arene Fluorination

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

Published: April 7, 2025

Methods to access fluorinated molecules are of significant interest the medicinal and agrochemical industries. We report a series high-valent PdIV complexes stabilized by two distinct ligand cores, which mediate electrophilic fluorination reactions with excellent yields good regioselectivity. Using high-throughput experimentation kinetic analysis, roles each were uncovered. Synthetic modulation catalyst alongside density functional theory transition state modeling provided evidence into turnover-limiting step while revealing key insights origin This workflow presents general strategy for exploring heteroleptic systems as well synthetic enhancements relevant both industrial academic settings.

Language: Английский

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Difluorination of α-(bromomethyl)styrenes via I(I)/I(III) catalysis: facile access to electrophilic linchpins for drug discovery

Chemical Science, Journal Year: 2021, Volume and Issue: 12(17), P. 6148 - 6152

Published: Jan. 1, 2021

Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective organocatalyst when combined with Selectfluor® and simple amine·HF complexes. Modulating Brønsted acidity enables simultaneous geminal vicinal difluorination occur, thereby providing platform generate multiply fluorinated scaffolds for further downstream derivatization. The method facilitates access tetrafluorinated API candidate the treatment amyotrophic lateral sclerosis. Preliminary validation enantioselective process is disclosed α-phenyl-β-difluoro-γ-bromo/chloro esters.

Language: Английский

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Second-Layer Chiral Environment-Induced Steric Hindrance Enables Catalyst Conformation Lockdown in Enantioselective Hypervalent Iodine Organocatalysis

ACS Catalysis, Journal Year: 2023, Volume and Issue: 13(12), P. 8273 - 8280

Published: June 6, 2023

A class of confined chiral hypervalent iodines have been designed and developed by incorporating two sterically demanding BINOL-derived units, which form the second-layer environment, into iodine-containing molecules to lock down conformation catalyst indirectly create a compact environment around active site. Good-to-excellent enantioselectivities achieved with these catalysts for α-oxysulfonylation ketones (up 97.5:2.5 er) oxidative cyclization 5-oxo-5-arylpentanoic acids γ-butyrolactones 98:2 er), thereby demonstrating utility this strategy design.

Language: Английский

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