Synthesis of 2‐Azanorbornanes via Strain‐Release Formal Cycloadditions Initiated by Energy Transfer DOI Creative Commons

Yu‐Che Chang,

Christophe Salomé, Thomas C. Fessard

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(51)

Published: Nov. 14, 2023

Rigid bicycles are becoming more popular in the pharmaceutical industry because they allow for expansion to new and unique chemical spaces. This work describes a strategy construct 2-azanorbornanes, which can act as rigid piperidine/pyrrolidine scaffolds with well-defined exit vectors. To achieve synthesis of strain-release reagent, azahousane, is introduced along its photosensitized formal cycloaddition alkenes. Furthermore, reactivity between housane an imine disclosed. Both strategies lead various substituted 2-azanorbornanes good selectivities.

Language: Английский

Strain-Release Photocatalysis DOI
Peter Bellotti, Frank Glorius

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

Citations

131
Photocatalyzed [2σ + 2σ] and [2σ + 2π] Cycloadditions for the Synthesis of Bicyclo[3.1.1]heptanes and 5- or 6-Membered Carbocycles DOI
Tin V. T. Nguyen, André Bossonnet, Matthew D. Wodrich

et al.

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

Citations

93
Silver‐Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes** DOI
Lei Tang, Yuanjiu Xiao, Feng Wu

et al.

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

Citations

75
Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space DOI Creative Commons

Marius Reinhold,

Justin Steinebach,

Christopher Golz

et al.

Chemical Science, Journal Year: 2023, Volume and Issue: 14(36), P. 9885 - 9891

Published: Jan. 1, 2023

Crossed [2 + 2] cycloaddition yields bicyclo[2.1.1]hexanes with 11 different substitution patterns. ortho -, meta - and polysubstituted benzene bioisosteres, structures substituent patterns that go beyond aromatic chemical space can be prepared.

Language: Английский

Citations

47
1,2-Disubstituted bicyclo[2.1.1]hexanes as saturated bioisosteres of ortho-substituted benzene DOI Creative Commons

Aleksandr Denisenko,

Pavel Garbuz,

Yelyzaveta Makovetska

et al.

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

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

39
Light‐Driven Synthesis and Functionalization of Bicycloalkanes, Cubanes and Related Bioisosteres DOI Creative Commons
Sara Cuadros, Julien Paut, Elsa Anselmi

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(14)

Published: Jan. 5, 2024

Bicycloalkanes, cubanes and their structural analogues have emerged as bioisosteres of (hetero)arenes. To meet increasing demand, the chemical community has developed a plethora novel synthetic methods. In this review, we assess progress made in field light-driven construction functionalization such relevant molecules. We focused on diverse targets, well reaction processes giving access to: (i) [1.1.1]-bicyclopentanes (BCPs); (ii) [2.2.1]-bicyclohexanes (BCHs); (iii) [3.1.1]-bicycloheptanes (BCHeps); (iv) cubanes; other structurally related scaffolds. Finally, future perspectives dealing with identification manifolds to new functionalized bioisosteric units are discussed.

Language: Английский

Citations

28
Titanium catalyzed [2σ + 2π] cycloaddition of bicyclo[1.1.0]-butanes with 1,3-dienes for efficient synthesis of stilbene bioisosteres DOI Creative Commons
Yonghong Liu, Zhixian Wu, Jing‐Ran Shan

et al.

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

Published: May 23, 2024

Abstract Natural stilbenes have shown significant potential in the prevention and treatment of diseases due to their diverse pharmacological activities. Here we present a mild effective Ti-catalyzed intermolecular radical-relay [2σ + 2π] cycloaddition bicyclo[1.1.0]-butanes 1,3-dienes. This transformation enables synthesis bicyclo[2.1.1]hexane (BCH) scaffolds containing aryl vinyl groups with excellent regio- trans -selectivity broad functional group tolerance, thus offering rapid access structurally stilbene bioisosteres.

Language: Английский

Citations

21
Zinc‐Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes DOI Open Access
Feng Wu, Wen‐Biao Wu, Yuanjiu Xiao

et al.

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

Citations

20
Spiro-C(sp 3 )-atom transfer: Creating rigid three-dimensional structures with Ph 2 SCN 2 DOI
Qiu Sun,

Jan-Niklas Belting,

Julian Hauda

et al.

Science, Journal Year: 2025, Volume and Issue: 387(6736), P. 885 - 892

Published: Feb. 20, 2025

The introduction of a single C-atom into organic substrates typically results in the formation flat molecules containing unsaturated C(sp)-centers. Adding C(sp3)-atom surrounded by four σ-C-C bonds, which opens up three-dimensional space, is an unresolved problem synthetic chemistry. We report synthesis and application diazosulfur ylide Ph2S=C=N2 reagent that combines reactivity both sulfur ylides diazo compounds to create carbon spiro-centers general fashion sequential or single-step installation C(sp3)-atom. New C-C C-X (where X O N) bonds can be created around C(sp3)-atom, ultimately extended σ-bonds one step without resorting transition metal catalysis. Ph2SCN2 also used access highly strained frameworks (oxa)spiro[2.2]pentanes as well tricyclic spiro-compounds.

Language: Английский

Citations

3