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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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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Strain-release transformations of bicyclo[1.1.0]butanes and [1.1.1]propellanes

Tetrahedron Chem, Journal Year: 2024, Volume and Issue: 9, P. 100070 - 100070

Published: Feb. 28, 2024

Bicyclo[1.1.0]butanes (BCBs) and [1.1.1]propellanes (tricyclo[1.1.1.01,3]pentanes, TCPs) are structurally unique compounds with different chemical properties. Strain-release driven reactions have emerged as an atom- step-economic strategy for the organic synthesis. Using this strategy, a variety of functional ring molecules been efficiently synthesized, including various cyclobutane molecules, bicyclo[2.1.1]hexanes, bicyclo[1.1.1]pentanes, others. More specifically, these strain release-driven include aspects nucleophilic addition, radical electrophilic or transition metal catalysis. This review will discuss recent developments in strain-release transformations bicyclo[1.1.0]butanes [1.1.1]propellanes.

Language: Английский

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Enantioselective formal (3 + 3) cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 12, 2024

Language: Английский

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Zinc‐Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(48)

Published: Sept. 2, 2024

Abstract The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp 3 )‐rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is scarcity of catalytic asymmetric cycloadditions BCBs to fulfill the need enantioenriched saturated bicycles in drug design development. In this study, an synthesis valuable azabicyclo[2.1.1]hexanes (aza‐BCHs) by enantioselective zinc‐catalyzed (3+2) with imines reported. proceeds effectively novel type BCB that incorporates 2‐acyl imidazole group diverse array alkynyl‐ aryl‐substituted imines. target aza‐BCHs, consist α‐chiral amine fragments two quaternary carbon centers, are efficiently synthesized up 94 % 96.5:3.5 er under mild conditions. Experimental computational studies reveal follows concerted nucleophilic ring‐opening mechanism This distinct from previous on Lewis acid‐catalyzed BCBs.

Language: Английский

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Facile Synthesis of Housanes by an Unexpected Strategy

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

Published: Feb. 17, 2025

Rigid bicyclic hydrocarbons have emerged as important building blocks in the drug discovery industry. Despite progress this general area, bicyclo[2.1.0]pentanes (housanes) are an understudied class of molecules. Herein we report unconventional synthesis borylated housanes. Our method features a broad scope and high diastereoselectivities versatile intermediates. The route involves strain-release diboration bicyclo[1.1.0]butane intramolecular deborylative alkylation. versatility bridgehead boronic ester was demonstrated several functionalizations. Lastly, mechanism reaction investigated, unusual stereospecific diastereoselective ring expansion uncovered.

Language: Английский

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syn-Selective Difunctionalization of Bicyclobutanes Enabled by Photoredox-Mediated C–S σ-Bond Scission

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(43), P. 23771 - 23780

Published: Oct. 18, 2023

Given the importance of cyclic frameworks in molecular scaffolds and drug discovery, it is intriguing to precisely forge manipulate ring systems synthetic chemistry. In this field, intermolecular synthesis densely substituted cyclobutanes with precise diastereocontrol under simple reaction conditions remains a challenge. Herein, photoredox strategy for difunctionalization bicyclo[1.1.0]butanes (BCBs) high regio- syn-selectivity disclosed. C-S σ-bond cleavage partially unsaturated sulfur-containing bifunctional reagents an overall strain-release-driven process enables thio-alkynylation, -alkenylation, -allylation BCBs mild demonstrates generality protocol. Mechanistic studies suggest that intermediacy distonic radical cations might be key efficient scission σ-bonds origin diastereoselectivity.

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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Photoredox-Catalyzed Alkylarylation of N-Aryl Bicyclobutyl Amides with α-Carbonyl Alkyl Bromides: Access to 3-Spirocyclobutyl Oxindoles

Organic Letters, Journal Year: 2024, Volume and Issue: 26(10), P. 2073 - 2078

Published: March 6, 2024

A visible-light-induced radical alkylarylation of N-aryl bicyclobutyl amides with α-carbonyl alkyl bromides for the synthesis functionalized 3-spirocyclobutyl oxindoles is described in which β-selective addition to forms a key intermediate followed by interception intrinsic arene functional group. This approach can be applicable wide range bromides, including primary, secondary, and tertiary α-bromoalkyl esters, ketones, nitriles, nitro compounds.

Language: Английский

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