Deconstructive Synthesis of Bridged and Fused Rings via Transition-Metal-Catalyzed “Cut-and-Sew” Reactions of Benzocyclobutenones and Cyclobutanones

Accounts of Chemical Research, Journal Year: 2022, Volume and Issue: 55(16), P. 2341 - 2354

Published: July 28, 2022

ConspectusBridged and fused rings are commonly found in biologically important molecules. Current tactics to construct these ring systems primarily based on stepwise formation (i.e., making one first followed by another) cycloaddition reactions (e.g., Diels–Alder reaction). To seek a complementary perhaps more unified ring-forming approach, deconstructive strategy C–C bond activation of cyclic ketones has been conceived. The named "cut-and-sew" reaction uses with tethered unsaturated moiety as substrates, which involves oxidative addition transition metal into the ketone intramolecular insertion unit. This proved successful access diverse scaffolds that nontrivial otherwise.This Account offers concise summary our laboratory's systematic efforts developing metal-catalyzed cut-and-sew for synthesis bridged over past 10 years. In particular, we will focus using readily available benzocyclobutenones cyclobutanones. date, scope greatly expanded. First, moieties can serve suitable coupling partners, such alkenyl, alkynyl, allenyl, carbonyl, iminyl groups. Second, variety modes have uncovered. this account, (4 + 2), 2 – 1), 1) cycloadditions lead range or be summarized. Third, enantioselective transformations realized efficiently chiral scaffolds, enabled two strategies: enantio-determining migratory desymmetrization Fourth, synthetic applications demonstrated streamlined total syntheses number complex natural products. Compared conventional logics, allows development new bond-disconnecting strategies. Thus, (−)-cycloclavine, (−)-thebainone A, penicibilaenes, proposed cycloinumakiol discussed detail.In narrative chemistry, also aims provide core guiding foundations inspirations toward broader through cleavage. It is anticipated classes compounds could substrates beyond cyclobutanones, coupled. envisaged innovative utilization organic revealed near future.

Language: Английский

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C(sp²)–H cyclobutylation of hydroxyarenes enabled by silver-π-acid catalysis: diastereocontrolled synthesis of 1,3-difunctionalized cyclobutanes

Chemical Science, Journal Year: 2023, Volume and Issue: 14(36), P. 9696 - 9703

Published: Jan. 1, 2023

Ring-opening of bicyclo[1.1.0]butanes (BCBs) is emerging as a powerful strategy for 1,3-difunctionalized cyclobutane synthesis. However, reported radical strain-release reactions are typically plagued with diastereoselectivity issues. Herein, an atom-economic protocol the highly chemo- and diastereoselective polar ring-opening BCBs hydroxyarenes catalyzed by π-acid catalyst AgBF4 has been developed. The use readily available starting materials, low loading, high selectivity (up to >98 : 2 d.r.), broad substrate scope, ease scale-up, versatile functionalizations products make this approach very attractive synthesis 1,1,3-trisubstituted cyclobutanes. Moreover, control experiments theoretical calculations were performed illustrate reaction mechanism selectivity.

Language: Английский

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Enantioselective Synthesis of Chiral Cyclobutenes Enabled by Brønsted Acid-Catalyzed Isomerization of BCBs

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(39), P. 21152 - 21158

Published: Sept. 21, 2023

Chiral cyclobutene units are commonly found in natural products and biologically active molecules. Transition-metal-catalysis has been extensively used asymmetric synthesis of such structures, while organocatalytic approaches remain elusive. In this study, bicyclo[1.1.0]butanes involved enantioselective transformation for the first time to offer a highly efficient route toward cyclobutenes with good regio- enantiocontrol. The utilization N-triflyl phosphoramide as chiral Brønsted acid promoter enables isomerization process proceed under mild conditions low catalyst loading well functional group compatibility. resulting could serve platform molecules downstream manipulations excellent reservation stereochemical integrity, demonstrating synthetic practicality developed method. Control experiments have also performed verify formation key carbocation intermediate at benzylic position.

Language: Английский

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Cobalt-Catalyzed Diastereo- and Enantioselective Carbon–Carbon Bond Forming Reactions of Cyclobutenes

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(6), P. 3588 - 3598

Published: Feb. 3, 2023

Catalytic enantioselective functionalization of cyclobutenes constitutes a general and modular strategy for construction enantioenriched complex cyclobutanes bearing multiple stereogenic centers, as chiral four-membered rings are common motifs in biologically active molecules versatile intermediates organic synthesis. However, synthesis through such remained significantly limited. Herein, we report series unprecedented cobalt-catalyzed carbon-carbon bond forming reactions that initiated carbometalation. The protocols feature diastereo- introduction allyl, alkynyl, functionalized alkyl groups. Mechanistic studies indicated an unusual 1,3-cobalt migration subsequent β-carbon elimination cascade process occurred the allyl addition. These new discoveries established elementary cobalt catalysis extension diversity nucleophiles transformations cyclobutenes.

Language: Английский

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Photochemical α-selective radical ring-opening reactions of 1,3-disubstituted acyl bicyclobutanes with alkyl halides: modular access to functionalized cyclobutenes

Chemical Science, Journal Year: 2023, Volume and Issue: 14(45), P. 13060 - 13066

Published: Jan. 1, 2023

Although ring-opening reactions of bicyclobutanes bearing electron-withdrawing groups, typically with β-selectivity, have evolved as a powerful platform for synthesis cyclobutanes, their application in the cyclobutenes remains underdeveloped. Here, novel visible light induced α-selective radical reaction 1,3-disubstituted acyl alkyl precursors functionalized is described. In particular, primary, secondary, and tertiary halides are all suitable substrates this photocatalytic transformation, providing ready access to single all-carbon quaternary center, or two contiguous centers under mild conditions.

Language: Английский

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Asymmetric Transfer Hydrogenation of Cyclobutenediones

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(7), P. 4942 - 4957

Published: Feb. 7, 2024

Four-membered carbocycles are fundamental substructures in bioactive molecules and approved drugs serve as irreplaceable building blocks organic synthesis. However, developing efficient protocols furnishing diversified four-membered ring compounds a highly regio-, diastereo-, enantioselective fashion remains challenging but very desirable. Here, we report the unprecedented asymmetric transfer hydrogenation of cyclobutenediones. The reaction can selectively afford three types products high yields with stereoselectivities, functionalized enable series further transformations to form more compounds. Asymmetric synthesis di-, tri-, tetrasubstituted has also been achieved. Systematic mechanistic studies theoretical calculations have revealed origin regioselectivity, key transition state models, sequence double triple processes. work provides new choice for catalytic cyclobutanes related structures demonstrates robustness accurate selectivity control substrates.

Language: Английский

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Diversified Synthesis of Chiral Fluorinated Cyclobutane Derivatives Enabled by Regio‐ and Enantioselective Hydroboration

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(23)

Published: April 2, 2024

The diversified synthesis of chiral fluorinated cyclobutane derivatives has remained a difficult task in synthetic chemistry. Herein, we present an approach for asymmetric hydroboration and formal hydrodefluorination gem-difluorinated cyclobutenes through rhodium catalysis, providing α-boryl cyclobutanes monofluorinated with excellent regio- enantioselectivity, respectively. key to the success two transformations relies on efficient, mild highly selective rhodium-catalyzed HBPin (pinacolborane), which subsequent addition base, catalytic amount palladium some cases, results formation products four-membered ring retained. obtained are versatile building blocks that provide platform enantioenriched great diversity.

Language: Английский

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Palladium-Catalyzed Divergent Enantioselective Functionalization of Cyclobutenes

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(18), P. 12691 - 12701

Published: April 27, 2024

Aliphatic strained rings have been increasingly applied in medicinal chemistry due to their beneficial physicochemical and pharmacokinetic properties. However, the divergent synthesis of enantioenriched cyclobutane derivatives with various structural patterns continues be a significant challenge. Here, we disclose palladium-catalyzed enantioselective desymmetrization cyclobutenes, resulting series hydroarylation 1,2- 1,3-diarylation products via interceptions common Heck intermediate. Mechanistic investigations provide valuable insights into understanding catalytic mode palladium catalysts observed variations deuterium-responsive behavior during reactions. Furthermore, synthetic utility is demonstrated syntheses deuterated drug candidate belaperidone skeletons pseudosymmetrical truxinic acid-type derivatives.

Language: Английский

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Palladium-catalyzed selective alkoxycarbonylation of different alcohols toward the direct synthesis of cyclobutanecarboxylates

Journal of Catalysis, Journal Year: 2025, Volume and Issue: unknown, P. 115956 - 115956

Published: Jan. 1, 2025

Language: Английский

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Site‐ and Stereoselective C(sp³)−H Borylation of Strained (Hetero)Cycloalkanols Enabled by Iridium Catalysis

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(8)

Published: Dec. 30, 2022

Transition metal-catalyzed site- and stereoselective C-H activation of strained (hetero)cycloalkanes remains a formidable challenge. We herein report carbamate-directed iridium-catalyzed asymmetric β-C(sp3 )-H borylation cyclopropanol derivatives. A variety densely functionalized cyclopropanols were obtained in good enantioselectivities via desymmetrization kinetic resolution. In addition, site-selective C(sp3 methine groups furnished α-borylated (hetero)cycloalkanols moderate to yields. The synthetic utility the method was further shown gram-scale synthesis diverse downstream transformations borylated products.

Language: Английский

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