Dataset Information

Hydrofluoromethylation of alkenes with fluoroiodomethane and beyond.

ABSTRACT: A process for the direct hydrofluoromethylation of alkenes is reported for the first time. This straighforward silyl radical-mediated reaction utilises CH₂FI as a non-ozone depleting reagent, traditionally used in electrophilic, nucleophilic and carbene-type chemistry, but not as a CH₂F radical source. By circumventing the challenges associated with the high reduction potential of CH₂FI being closer to CH₃I than CF₃I, and harnessing instead the favourable bond dissociation energy of the C-I bond, we demonstrate that feedstock electron-deficient alkenes are converted into products resulting from net hydrofluoromethylation with the intervention of (Me₃Si)₃SiH under blue LED activation. This deceptively simple yet powerful methodology was extended to a range of (halo)methyl radical precursors including ICH₂I, ICH₂Br, ICH₂Cl, and CHBr₂F, as well as CH₃I itself; this latter reagent therefore enables direct hydromethylation. This versatile chemistry was applied to ¹⁸F-, ¹³C-, and D-labelled reagents as well as complex biologically relevant alkenes, providing facile access to more than fifty products for applications in medicinal chemistry and positron emission tomography.

SUBMITTER: Hell SM

PROVIDER: S-EPMC8457377 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Hydrofluoromethylation of alkenes with fluoroiodomethane and beyond.

Hell Sandrine M SM Meyer Claudio F CF Ortalli Sebastiano S Sap Jeroen B I JBI Chen Xuanxiao X Gouverneur Véronique V

Chemical science 20210811 36

A process for the direct hydrofluoromethylation of alkenes is reported for the first time. This straighforward silyl radical-mediated reaction utilises CH2FI as a non-ozone depleting reagent, traditionally used in electrophilic, nucleophilic and carbene-type chemistry, but not as a CH2F radical source. By circumventing the challenges associated with the high reduction potential of CH2FI being closer to CH3I than CF3I, and harnessing instead ...[more]

PMID: 34667580

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Project description:Enzymes catalyze organic transformations with exquisite levels of selectivity, including chemoselectivity, stereoselectivity, and substrate selectivity, but the types of reactions catalyzed by enzymes are more limited than those of chemical catalysts. Thus, the convergence of chemical catalysis and biocatalysis can enable enzymatic systems to catalyze abiological reactions with high selectivity. Recently, we disclosed artificial enzymes constructed from the apo form of heme proteins and iridium porphyrins that catalyze the insertion of carbenes into a C-H bond. We postulated that the same type of Ir(Me)-PIX enzymes could catalyze the cyclopropanation of a broad range of alkenes with control of multiple modes of selectivity. Here, we report the evolution of artificial enzymes that are highly active and highly stereoselective for the addition of carbenes to a wide range of alkenes. These enzymes catalyze the cyclopropanation of terminal and internal, activated and unactivated, electron-rich and electron-deficient, conjugated and nonconjugated alkenes. In particular, Ir(Me)-PIX enzymes derived from CYP119 catalyze highly enantio- and diastereoselective cyclopropanations of styrene with ±98% ee, >70:1 dr, >75% yield, and ∼10,000 turnovers (TON), as well as 1,2-disubstituted styrenes with up to 99% ee, 35:1 dr, and 54% yield. Moreover, Ir(Me)-PIX enzymes catalyze cyclopropanation of internal, unactivated alkenes with up to 99% stereoselectivity, 76% yield, and 1300 TON. They also catalyze cyclopropanation of natural products with diastereoselectivities that are complementary to those attained with standard transition metal catalysts. Finally, Ir(Me)-PIX P450 variants react with substrate selectivity that is reminiscent of natural enzymes; they react preferentially with less reactive internal alkenes in the presence of more reactive terminal alkenes. Together, the studies reveal the suitability of Ir-containing P450s to combine the broad reactivity and substrate scope of transition metal catalysts with the exquisite selectivity of enzymes, generating catalysts that enable reactions to occur with levels and modes of activity and selectivity previously unattainable with natural enzymes or transition metal complexes alone.

Dataset Information

Hydrofluoromethylation of alkenes with fluoroiodomethane and beyond.

Publications

Hydrofluoromethylation of alkenes with fluoroiodomethane and beyond.

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