Strain-Release Photocatalysis

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(38), P. 20716 - 20732

Published: Sept. 15, 2023

The concept of strain in organic compounds is as old modern chemistry and was initially introduced to justify the synthetic setbacks along synthesis small ring systems (pars construens strain). In last decades, chemists have developed an arsenal strain-release reactions destruens strain) which can generate─with significant driving force─rigid aliphatic that act three-dimensional alternatives (hetero)arenes. Photocatalysis added additional dimension processes by leveraging energy photons create chemical complexity under mild conditions. This perspective presents latest advancements photocatalysis─with emphases on mechanisms, catalytic cycles, current limitations─the unique architectures be produced, possible future directions.

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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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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Three-dimensional saturated C(sp3)-rich bioisosteres for benzene

Nature Reviews Chemistry, Journal Year: 2024, Volume and Issue: 8(8), P. 605 - 627

Published: July 9, 2024

Language: Английский

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Tunable molecular editing of indoles with fluoroalkyl carbenes

Nature Chemistry, Journal Year: 2024, Volume and Issue: 16(6), P. 988 - 997

Published: March 5, 2024

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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Switching between the [2π+2σ] and Hetero‐[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(29)

Published: May 11, 2024

Abstract The exploration of the complex chemical diversity bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over past two decades. Regiodivergent syntheses thiabicyclo[4.1.1]octanes (S‐BCOs) highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid‐catalyzed formal cycloaddition bicyclobutanes (BCBs) 3‐benzylideneindoline‐2‐thione derivatives have been established. first hetero‐(4+3) BCBs, catalyzed by Zn(OTf) 2 , was achieved with broad substrate scope under mild conditions. In contrast, less electrophilic BCB ester undergoes Sc(OTf) 3 ‐catalyzed [2π+2σ] reaction 1,1,2‐trisubstituted alkenes, yielding BCHs spirocyclic quaternary carbon center. Control experiments preliminary theoretical calculations suggest that diastereoselective product formation may involve concerted between zwitterionic intermediate E ‐1,1,2‐trisubstituted alkenes. Additionally, nucleophilic ring‐opening mechanism.

Language: Английский

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Dearomatization of Pyridines: Photochemical Skeletal Enlargement for the Synthesis of 1,2-Diazepines

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(4), P. 2845 - 2854

Published: Jan. 18, 2024

In this report, we developed a unified and standardized one-pot sequence that converts pyridine derivatives into 1,2-diazepines by inserting nitrogen atom. This skeletal transformation capitalizes on the in situ generation of 1-aminopyridinium ylides, which rearrange under UV light irradiation. A thorough evaluation key parameters (wavelength, reaction conditions, activating agent) allowed us to elaborate simple, mild, user-friendly protocol. The model was extrapolated more than 40 examples, including drug derivatives, affording unique 7-membered structures. Mechanistic evidence supports transient presence diazanorcaradiene species. Finally, pertinent transformations products, ring contraction reactions form pyrazoles, were conducted paved way broad application

Language: Английский

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Catalytic Asymmetric Construction of Chiral Polysubstituted 3-Azabicyclo[3.1.1]heptanes by Copper-Catalyzed Stereoselective Formal [4π+2σ] Cycloaddition

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(30), P. 21069 - 21077

Published: July 16, 2024

The direct construction of bioisosteric compounds enriched in C

Language: Английский

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