Photoredox-catalysed amidyl radical insertion to bicyclo[1.1.0]butanes DOI Creative Commons
Chetan C. Chintawar, Ranjini Laskar,

Debanjan Rana

et al.

Nature Catalysis, Journal Year: 2024, Volume and Issue: 7(11), P. 1232 - 1242

Published: Oct. 22, 2024

Abstract Replacing planar aromatic rings in drug molecules with C( sp 3 )-rich isosteric mimetics, such as bicyclo[ n .1.1]alkanes, can significantly alter their physicochemical and pharmacokinetic properties, often leading to higher clinical success rates. However, unlike a benzene ring, the structurally rigid mimetics of heteroaromatic are rare. Heterobicyclo[ .1.1]alkanes promising this regard, but lack modular synthetic methods has currently hindered exploration. We envisioned that strategic selective insertion different heteroatomic units bicyclo[1.1.0]butanes could offer highly platform access diverse heterobicyclo[ .1.1]alkanes. Herein we report photoredox-catalysed regioselective chemoselective amidyl radicals bicyclo[1.1.0]butanes, providing direct 2-oxa-4-azabicyclo[3.1.1]hept-3-enes. The exit vector analysis shows geometric resemblance these heterobicyclic motifs pyridine pyrimidine derivatives, suggesting potential medicinally important heterocycles. Additionally, various downstream transformations demonstrate utility versatile building blocks chemistry.

Language: Английский

Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5 + 3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes DOI
Jin‐Lan Zhou, Yuanjiu Xiao,

Linke He

et al.

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

Citations

46
Three-dimensional saturated C(sp3)-rich bioisosteres for benzene DOI
Jet Tsien, Chao Hu, Rohan R. Merchant

et al.

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

Published: July 9, 2024

Language: Английский

Citations

45
Silver‐Enabled Cycloaddition of Bicyclobutanes with Isocyanides for the Synthesis of Polysubstituted 3‐Azabicyclo[3.1.1]heptanes DOI
Yujie Liang, Ronewa Nematswerani, Constantin G. Daniliuc

et al.

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

Citations

43
Double Strain-Release [2π+2σ]-Photocycloaddition DOI
Subhabrata Dutta, Yilin Lu, Johannes E. Erchinger

et al.

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

Citations

42
Synthesis of Azabicyclo[3.1.1]heptenes Enabled by Catalyst-Controlled Annulations of Bicyclo[1.1.0]butanes with Vinyl Azides DOI

Zhongren Lin,

Haosong Ren,

Xinbo Lin

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(27), P. 18565 - 18575

Published: June 27, 2024

Bridged bicyclic scaffolds are emerging bioisosteres of planar aromatic rings under the concept "escape from flatland". However, adopting this into exploration pyridines remains elusive due to challenge incorporating a N atom such bridged structures. Herein, we report practical routes for divergent synthesis 2- and 3-azabicyclo[3.1.1]heptenes (aza-BCHepes) as potential readily accessible vinyl azides bicyclo[1.1.0]butanes (BCBs) via two distinct catalytic annulations. The reactivity tailored with BCBs is key achieving transformations. Ti

Language: Английский

Citations

41
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 DOI
Jijie Wang, Lei Tang, Yuanjiu Xiao

et al.

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

Citations

37
Catalytic Asymmetric Construction of Chiral Polysubstituted 3-Azabicyclo[3.1.1]heptanes by Copper-Catalyzed Stereoselective Formal [4π+2σ] Cycloaddition DOI

Xunhua Wang,

Rongkai Gao,

Xiaoxun Li

et al.

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

Citations

33
Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π + 2σ] Cycloaddition Reactions DOI Creative Commons
Jasper L. Tyler, Felix Schäfer, Huiling Shao

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(23), P. 16237 - 16247

Published: May 29, 2024

As the chemistry that surrounds field of strained hydrocarbons, such as bicyclo[1.1.0]butane, continues to expand, it becomes increasingly advantageous develop alternative reactivity modes harness their unique properties access new regions chemical space. Herein, we report use photoredox catalysis promote single-electron oxidation bicyclo[1.1.0]butanes. The synthetic utility resulting radical cations is highlighted by ability undergo highly regio- and diastereoselective [2π + 2σ] cycloaddition reactions. most notable feature this transformation breadth alkene classes can be employed, including nonactivated alkenes, which have so far been elusive for previous strategies. A rigorous mechanistic investigation, in conjunction with DFT computation, was undertaken order better understand physical nature bicyclo[1.1.0]butyl thus provides a platform from further studies into applications these intermediates built upon.

Language: Английский

Citations

32
Strain-release transformations of bicyclo[1.1.0]butanes and [1.1.1]propellanes DOI Creative Commons
Qianqian Hu, Jie Chen, Yang Yang

et al.

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

Citations

27
B(C6F5)3-Catalyzed Formal (n + 3) (n = 5 and 6) Cycloaddition of Bicyclo[1.1.0]butanes to Medium Bicyclo[n.1.1]alkanes DOI
Liang‐Liang Yang, Haiyang Wang, Ming Lang

et al.

Organic Letters, Journal Year: 2024, Volume and Issue: 26(19), P. 4104 - 4110

Published: May 3, 2024

Herein, a B(C6F5)3-catalyzed formal (n + 3) = 5 and 6) cycloaddition of bicyclo[1.1.0]butanes (BCBs) with imidazolidines/hexahydropyrimidines is described. The reaction provides modular, atom-economical, efficient strategy to two libraries synthetically challenging medium-bridged rings, 2,5-diazabicyclo[5.1.1]nonanes 2,6-diazabicyclo[6.1.1]decanes, in moderate excellent yields. This also features simple operation, mild conditions, broad substrate scope. A scale-up experiment various synthetic transformations products further highlight the utility.

Language: Английский

Citations

25