Copper-Catalyzed Enantioselective [4π + 2σ] Cycloaddition of Bicyclobutanes with Nitrones

Journal of the American Chemical Society, Год журнала: 2024, Номер unknown

Опубликована: Сен. 25, 2024

The selective construction of bridged bicyclic scaffolds has garnered increasing attention because their extensive use as saturated bioisosteres arene in pharmaceutical industry. However, sharp contrast to racemic counterparts, assembling chiral structures an enantioselective and regioselective manner remains challenging. Herein, we describe our protocol for constructing 2-oxa-3-azabicyclo[3.1.1]heptanes (BCHeps) by [4π + 2σ] cycloadditions bicyclo[1.1.0]butanes (BCBs) nitrones taking advantage a copper(II) complex Lewis acid catalyst. This method features mild conditions, good functional group tolerance, high yield (up 99%), excellent enantioselectivity 99% ee). Density theory (DFT) calculation elucidates the origin reaction's mechanism BCB activation Cu(II) complex.

Язык: Английский

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Facile access to bicyclo[2.1.1]hexanes by Lewis acid-catalyzed formal cycloaddition between silyl enol ethers and bicyclo[1.1.0]butanes

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 20, 2024

Abstract Saturated three-dimensional carbocycles have gained increasing prominence in synthetic and medicinal chemistry. In particular, bicyclo[2.1.1]hexanes (BCHs) been identified as the molecular replacement for benzenes. Here, we present facile access to a variety of BCHs via stepwise two-electron formal (3 + 2) cycloaddition between silyl enol ethers bicyclo[1.1.0]butanes (BCBs) under Lewis acid catalysis. The reaction features wide functional group tolerance ethers, allowing efficient construction two vicinal quaternary carbon centers silyl-protected tertiary alcohol unit streamlined fashion. Interestingly, with conjugated dienol can provide bicyclo[4.1.1]octanes (BCOs) equipped that facilitate further transformation. utilities this methodology are demonstrated by late-stage modification natural products, transformations units on bicyclo[2.1.1]hexane frameworks, derivatization bicyclo[4.1.1]octanes, delivering functionalized bicycles traditionally inaccessible.

Язык: Английский

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Enantioselective Synthesis of Tetrahydro-1H-1,3-methanocarbazoles by Formal (3 + 3)-Cycloaddition Using Bicyclo[1.1.0]butanes

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

Asymmetric synthesis presents many challenges, with the selective formation of chiral bridged polyheterocycles being a notable example. Cycloadditions using bicyclo[1.1.0]butanes (BCB) offer promising solution along those lines, yet, despite significant advances in that emerging area, asymmetric control has remained limited thus far. Here, we describe an organocatalytic, enantioselective formal (3 + 3)-cycloaddition BCBs 1H-indol-3-yl((hetero)aryl)methanol derivatives. This approach enables rapid and efficient tetrahydro-1H-1,3-methanocarbazole derivatives (34 examples) from readily available starting materials, very good stereochemical (up to 98:2 er). Successful scale-up experiments product modification demonstrated potential this methodology. Control DFT calculations provide insights into mechanistic pathway.

Язык: Английский

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Silver-mediated formal [4π + 2σ] cycloaddition reactions of bicyclobutanes with nitrile imines: access to 2,3-diazobicyclo[3.1.1]heptenes

Chemical Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

We disclose a method for silver-enabled formal [4π + 2 σ ] cycloaddition reactions between bicyclobutanes and nitrile imines (generated from hydrazonyl chlorides) to furnish diverse array of 2,3-diazo-BCHepes.

Язык: Английский

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Divergent Enantioselective Access to Diverse Chiral Compounds from Bicyclo[1.1.0]butanes and α,β-Unsaturated Ketones under Catalyst Control

Journal of the American Chemical Society, Год журнала: 2024, Номер unknown

Опубликована: Сен. 30, 2024

Achieving structural and stereogenic diversity from the same starting materials remains a fundamental challenge in organic synthesis, requiring precise control over selectivity. Here, we report divergent catalytic methods that selectively yield either cycloaddition or addition/elimination products bicyclo[1.1.0]butanes α,β-unsaturated ketones. By employing chiral Lewis acid Brønsted catalysts, achieved excellent regio-, diastereo-, enantioselectivity across all three distinct transformations, affording diverse array of synthetically valuable bicyclo[2.1.1]hexanes cyclobutenes. The outcomes are controlled by differential activation substrates specific catalyst with reaction conditions dictating pathway This strategy demonstrates power catalysis creating molecular complexity diversity, offering tool for synthesis enantioenriched building blocks.

Язык: Английский

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Photocatalytic Oxidative Activation of Bicyclo[1.1.0]butanes for Formal [2σ+2π] Cycloadditions

ACS Catalysis, Год журнала: 2024, Номер 14(18), С. 13987 - 13998

Опубликована: Сен. 6, 2024

Язык: Английский

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Ring Expansion toward Fused Diazabicyclo[3.1.1]heptanes through Lewis Acid Catalyzed Highly Selective C−C/C−N Bond Cross‐Exchange Reaction between Bicyclobutanes and Diaziridines

Angewandte Chemie International Edition, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 13, 2024

Abstract The synthesis of bicyclic scaffolds has garnered considerable interest in drug discovery because their ability to mimic benzene bioisosteres. Herein, we introduce a new approach that utilizes Lewis acid (Sc(OTf) 3 )‐catalyzed σ‐bond cross‐exchange reaction between the C−C bond bicyclobutanes and C−N diaziridines produce multifunctionalized medicinally interesting azabicyclo[3.1.1]heptane derivatives. proceeds well with different broad range aryl‐ as alkenyl‐, but also alkyl‐substituted (up 98 % yield). Conducting scale‐up experiment exploring synthetic transformations cycloadducts emphasized practical application synthesis. Furthermore, zinc‐based chiral catalytic system was developed for enantioselective version this 96 ee ).

Язык: Английский

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Palladium-catalyzed enantioselective [2σ + 2π] cycloadditions of vinyl-carbonyl-bicyclo[1.1.0]butanes with arylidenemalononitriles

Chinese Chemical Letters, Год журнала: 2025, Номер unknown, С. 111072 - 111072

Опубликована: Март 1, 2025

Язык: Английский

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Recent Progress in Accessing Multi-functionalized Caged Hydrocarbons: En Route to Highly Functionalized Saturated (Bio)isosteres of Benzene Rings

Synthesis, Год журнала: 2024, Номер unknown

Опубликована: Июль 4, 2024

Abstract Recently, many saturated bioisosteres of the benzene ring have been developed, and their applications in drug development evaluated. Most these are caged hydrocarbons, which rigid skeletons three-dimensional spaces. Recent efforts to synthesize hydrocarbons enabled access multi-functionalized congeners that expected be (bio)isosteres benzenes. This short review summarizes recently reported methods for obtaining (typically more than disubstituted) hydrocarbons. 1 Introduction 2 Proposed Structures Caged Hydrocarbons as Saturated (Bio)isosteres Benzene Ring: A Brief Summary 3 Access Multi-functionalized Hydrocarbons: De Novo Synthetic Approaches 3.1 Bicyclo[1.1.1]pentanes (BCPs) 3.2 Bicyclo[2.1.1]hexanes (BCHs) 3.3 Bicyclo[3.1.1]heptanes (BCHeps) 3.4 Others 4 C–H Functionalization 5 Conclusion

Язык: Английский

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In(OTf)₃-Catalyzed (3 + 3) Dipolar Cyclization of Bicyclo[1.1.0]butanes with N-Nucleophilic 1,3-Dipoles: Access to 2,3-Diazabicyclo[3.1.1]heptanes, 2,3-Diazabicyclo[3.1.1]heptenes, and Enantiopure 2-Azabicyclo[3.1.1]heptanes

ACS Catalysis, Год журнала: 2024, Номер unknown, С. 17837 - 17849

Опубликована: Ноя. 18, 2024

The investigation into the synthesis of azabicyclo[3.1.1]heptanes (azaBCHeps) as bioisosteres to flat aza-aromatics has garnered increasing attention, while it encounters significant challenges. Herein, we have demonstrated In(OTf)3-catalyzed (3 + 3) dipolar cyclization bicyclo[1.1.0]butanes (BCBs) with hydrazones and π-allyl-iridium 1,3-dipoles, engendering a diverse array azaBCHeps. BCBs furnished densely substituted 2,3-diazabicyclo[3.1.1]heptanes 2,3-diazabicyclo[3.1.1]heptenes under nitrogen oxygen atmospheres, respectively. A combination experimental computational investigations lends robust support for proton-transfer-interposed sequential mechanism. More importantly, by integrating In(OTf)3/iridium relay catalysis, enantiopure 2-azabicyclo[3.1.1]heptanes were constructed through aza-π-allyl-iridium in situ generated from N-allyl carbonates. Both methodologies exhibit mild reaction conditions good tolerance various functional groups. Moreover, copious derivatization products highlights utility newly synthesized heterobicyclic motifs versatile building blocks synthetic chemistry.

Язык: Английский

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