Photocatalyzed [2σ + 2σ] and [2σ + 2π] Cycloadditions for the Synthesis of Bicyclo[3.1.1]heptanes and 5- or 6-Membered Carbocycles

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(46), P. 25411 - 25421

Published: Nov. 7, 2023

We report the use of photocatalysis for homolytic ring-opening carbonyl cyclopropanes. In contrast to previous studies, our approach does not require a metal cocatalyst or strong reductant. The cyclopropanes can be employed both [2σ + 2σ] and 2π] annulation with either alkenes/alkynes bicyclo[1.1.0]butanes, yielding cyclopent-anes/-enes bicyclo[3.1.1]heptanes (BCHs), respectively. BCHs are promising bioisosteres 1,2,4,5 tetra-substituted aromatic rings. Mechanistic including density functional theory computation trapping experiment DMPO, support 1,3-biradical generated from cyclopropane as key intermediate these transformations.

Language: Английский

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Intermolecular Formal Cycloaddition of Indoles with Bicyclo[1.1.0]butanes by Lewis Acid Catalysis

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(48)

Published: Aug. 16, 2023

Abstract Herein, we develop a new approach to directly access architecturally complex polycyclic indolines from readily available indoles and bicyclo[1.1.0]butanes (BCBs) through formal cycloaddition promoted by commercially Lewis acids. The reaction proceeded stepwise pathway involving nucleophilic addition of BCBs followed an intramolecular Mannich form rigid indoline‐fused structures, which resemble indole alkaloids. This tolerated wide range BCBs, thereby allowing the one‐step construction various indoline polycycles containing up four contiguous quaternary carbon centers.

Language: Английский

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Silver‐Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes**

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(48)

Published: Oct. 12, 2023

Bicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but difficult to access. Here a silver-catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N-unprotected indoles bicyclobutane precursors is described. The strain-release operates under mild conditions, tolerating wide range functional groups. It capable forming with up four contiguous quaternary carbon centers, achieving yields 99 %. In addition, scale-up experiment synthetic transformations cycloadducts further highlighted utility.

Language: Английский

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Photoredox-Enabled Dearomative [2π + 2σ] Cycloaddition of Phenols

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(4), P. 2789 - 2797

Published: Jan. 18, 2024

Dearomative photocycloaddition of monocyclic arenes is an appealing strategy for comprehending the concept "escape from flatland". This brings replacement readily available planar aromatic hydrocarbon units with a 3D fused bicyclic core sp3-enriched carbon units. Herein, we outline intermolecular approach dearomative phenols. In order to circumvent ground-state aromaticity and construct conformationally restrained building blocks, bicyclo[1.1.0]butanes were chosen as coupling partners. renders straightforward access bicyclo[2.1.1]hexane unit cyclic enone moiety, which further contributed synthetic linchpin postmodifications. Mechanistic experiment advocates plausible onset both reactants, depending on redox potential.

Language: Английский

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1,2-Disubstituted bicyclo[2.1.1]hexanes as saturated bioisosteres of ortho-substituted benzene

Chemical Science, Journal Year: 2023, Volume and Issue: 14(48), P. 14092 - 14099

Published: Jan. 1, 2023

1,2-Disubstituted bicyclo[2.1.1]hexanes have been synthesized, characterized, and biologically validated as saturated bioisosteres of the ortho -substituted benzene ring.

Language: Английский

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Eu(OTf)₃‐Catalyzed Formal Dipolar [4π+2σ] Cycloaddition of Bicyclo‐[1.1.0]butanes with Nitrones: Access to Polysubstituted 2‐Oxa‐3‐azabicyclo[3.1.1]heptanes

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(13)

Published: Jan. 30, 2024

Abstract Herein, we have synthesized multifunctionalized 2‐oxa‐3‐azabicyclo[3.1.1]heptanes, which are considered potential bioisosteres for meta ‐substituted arenes, through Eu(OTf) 3 ‐catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones. This methodology represents the initial instance fabricating bicyclo[3.1.1]heptanes adorned multiple heteroatoms. The protocol exhibits both mild reaction conditions and a good tolerance various functional groups. Computational density theory calculations support that mechanism likely involves nucleophilic addition nitrones to bicyclo[1.1.0]butanes, succeeded by an intramolecular cyclization. synthetic utility this novel has been demonstrated in concise synthesis analogue Rupatadine.

Language: Английский

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Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5 + 3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(29), P. 19621 - 19628

Published: May 13, 2024

For nearly 60 years, significant research efforts have been focused on developing strategies for the cycloaddition of bicyclobutanes (BCBs). However, higher-order and catalytic asymmetric BCBs long-standing formidable challenges. Here, we report Pd-catalyzed ligand-controlled, tunable cycloadditions divergent synthesis bridged bicyclic frameworks. The dppb ligand facilitates formal (5+3) vinyl oxiranes, yielding valuable eight-membered ethers with scaffolds in 100% regioselectivity. Cy-DPEphos promotes selective hetero-[2σ+2σ] to access pharmacologically important 2-oxabicyclo[3.1.1]heptane (O-BCHeps). Furthermore, corresponding O-BCHeps 94–99% ee has achieved using chiral (S)-DTBM-Segphos, representing first cross-dimerization two strained rings. obtained are promising bioisosteres ortho-substituted benzenes.

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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Silver‐Enabled Cycloaddition of Bicyclobutanes with Isocyanides for the Synthesis of Polysubstituted 3‐Azabicyclo[3.1.1]heptanes

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(21)

Published: March 5, 2024

Abstract Synthesis of bicyclic scaffolds has emerged as an important research topic in modern drug development because they can serve saturated bioisosters to enhance the physicochemical properties and metabolic profiles candidates. Here we report a remarkably simple silver‐enabled strategy access polysubstituted 3‐azabicyclo[3.1.1]heptanes single operation from readily accessible bicyclobutanes (BCBs) isocyanides. The process is proposed involve formal (3+3)/(3+2)/retro‐(3+2) cycloaddition sequence. This novel protocol allows for rapid generation molecular complexity starting materials, products be easily derivatized, further enriching BCB chemistry growing set valuable sp 3 ‐rich building blocks.

Language: Английский

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Double Strain-Release [2π+2σ]-Photocycloaddition

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(8), P. 5232 - 5241

Published: Feb. 13, 2024

In pursuit of potent pharmaceutical candidates and to further improve their chemical traits, small ring systems can serve as a potential starting point. Small units have the additional merit loaded strain at core, making them suitable reactants they capitalize on this intrinsic driving force. With introduction cyclobutenone strained precursor ketene, photocycloaddition with another unit, bicyclo[1.1.0]butane (BCB), enables reactivity both π-units in transient ketene. This double strain-release driven [2π+2σ]-photocycloaddition promotes synthesis diverse heterobicyclo[2.1.1]hexane units, pharmaceutically relevant bioisostere. The effective under catalyst-free conditions high functional group tolerance defines its synthetic utility. Experimental mechanistic studies density theory (DFT) calculations suggest that takes place via triplet mechanism.

Language: Английский

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