Chiral Lewis acid catalysis in a visible light-triggered cycloaddition/rearrangement cascade

Stegbauer, Simone; Jandl, Christian; Bach, Thorsten

doi:10.1039/d2sc03159k

“…The Supporting Information is available free of charge on the Wiley VCH GmbH Publications website: Experimental protocols, nuclear magnetic resonance spectra, HPLC traces and X‐ray crystallographic data. Additional references are cited within the Supporting Information [30–59] …”

Section: Supporting Informationmentioning

confidence: 99%

Catalytic Ring Expanding Difluorination: An Enantioselective Platform to Access β,β‐Difluorinated Carbocycles

Ruyet,

Roblick,

Häfliger

et al. 2024

Angewandte Chemie

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Cyclic β,β‐difluoro‐carbonyl compounds have a venerable history as drug discovery leads, but limitations in the synthesis arsenal continue to impede chemical space exploration. This challenge is particularly acute in the arena of fluorinated medium rings where installing the difluoromethylene unit subtly alters the ring conformation by expanding the internal angle (∠C‐CF2‐C > ∠C‐CH2‐C): this provides a handle to modulate physicochemistry (e.g. pKa). To reconcile this disparity, a highly modular ring expansion has been devised that leverages simple α,β‐unsaturated esters and amides, and processes them to one‐carbon homologated rings with concomitant geminal difluorination (6 to 10 membered rings, up to 95% yield). This process is a rare example of the formal difluorination of an internal alkene and is enabled by sequential I(III)‐enabled O‐activation. Validation of enantioselective catalysis in the generation of unprecedented medium ring scaffolds is reported (up to 93:7 e.r.) together with X‐ray structural analyses and product derivatization.

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“…The Supporting Information is available free of charge on the Wiley VCH GmbH Publications website: Experimental protocols, nuclear magnetic resonance spectra, HPLC traces and X‐ray crystallographic data. Additional references are cited within the Supporting Information [30–59] …”

Section: Supporting Informationmentioning

confidence: 99%

Catalytic Ring Expanding Difluorination: An Enantioselective Platform to Access β,β‐Difluorinated Carbocycles

Ruyet,

Roblick,

Häfliger

et al. 2024

Angew Chem Int Ed

0

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Cyclic β,β‐difluoro‐carbonyl compounds have a venerable history as drug discovery leads, but limitations in the synthesis arsenal continue to impede chemical space exploration. This challenge is particularly acute in the arena of fluorinated medium rings where installing the difluoromethylene unit subtly alters the ring conformation by expanding the internal angle (∠C‐CF2‐C > ∠C‐CH2‐C): this provides a handle to modulate physicochemistry (e.g. pKa). To reconcile this disparity, a highly modular ring expansion has been devised that leverages simple α,β‐unsaturated esters and amides, and processes them to one‐carbon homologated rings with concomitant geminal difluorination (6 to 10 membered rings, up to 95% yield). This process is a rare example of the formal difluorination of an internal alkene and is enabled by sequential I(III)‐enabled O‐activation. Validation of enantioselective catalysis in the generation of unprecedented medium ring scaffolds is reported (up to 93:7 e.r.) together with X‐ray structural analyses and product derivatization.

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“…Considering that the activation of the enone with Lewis acid can promote a photocycloaddition reaction more efficiently, [29,30,31] we evaluated the photoreactivity of 1 in the presence of BF 3 • OEt 2 using CH 2 Cl 2 as a solvent. Under these conditions and after 2 h of irradiation with violet LEDs, the photocycloaddition product 3 was not detected.…”

Section: Photo-reactivity Of αβ-Unsaturated Carbonyl Group From Solid...mentioning

confidence: 99%

Expanding Diterpene Complexity and Diversity via Photoinduced Ring Distortions

Luz Tibaldi‐Bollati,

Nicotra,

Oksdath‐Mansilla

et al. 2023

ChemPlusChem

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Natural products and their semi‐synthetic derivatives undoubtedly constitute an important source of therapeutic agents. Their importance lies in their own origin and evolution, since they have great chemical diversity, biochemical specificity, and pharmacological properties. Currently, there is a renewed interest in the development of methodologies capable of efficiently modifying the chemical structure of these bioactive platforms. In this work, the photoderivatization of the diterpene solidagenone was performed using a complexity‐to‐diversity‐oriented approach. By exploring [2+2]‐photocycloaddition, photoinduced‐hydrogen abstraction, and photoxygenation reactions, a set of solidagenone derivatives was obtained, showing different ring fusions, side chain rearrangements, and modifications of the original furan ring's substitution pattern. The derivatives obtained were characterised by NMR methodologies. To evaluate the structural diversity of the labdane‐derived compounds, their physicochemical properties, structural similarity, and chemical space were analysed. These results suggest that photochemical reactions are a useful tool for performing ring distortion transformations, generating derivatives of natural compounds with wide diversity, structural complexity, and with potential biological properties.

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Chiral Lewis acid catalysis in a visible light-triggered cycloaddition/rearrangement cascade

Abstract: Cascade (domino) reactions facilitate the formation of complex molecules from simple starting materials in a single operation. It was found that 1-naphthaldehyde derivatives can be converted to enantioenriched (82-96% ee)...

Cited by 9 publications

References 79 publications

Catalytic Ring Expanding Difluorination: An Enantioselective Platform to Access β,β‐Difluorinated Carbocycles

Catalytic Ring Expanding Difluorination: An Enantioselective Platform to Access β,β‐Difluorinated Carbocycles

Catalytic Ring Expanding Difluorination: An Enantioselective Platform to Access β,β‐Difluorinated Carbocycles

Expanding Diterpene Complexity and Diversity via Photoinduced Ring Distortions

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