Formal Cycloadditions Driven by the Homolytic Opening of Strained, Saturated Ring Systems DOI Creative Commons
Alexander S. Harmata, Bec J. Roldan, Corey R. J. Stephenson

et al.

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(4)

Published: Oct. 14, 2022

Abstract The field of strain‐driven, radical formal cycloadditions is experiencing a surge in activity motivated by renaissance free chemistry and growing demand for sp 3 ‐rich ring systems. former has been driven large part the rise photoredox catalysis, latter adoption “Escape from Flatland” concept medicinal chemistry. In years since these broader trends emerged, dozens cycloadditions, including catalytic, asymmetric variants, have developed that operate via mechanisms. While cyclopropanes studied most extensively, variety strained systems are amenable to design analogous reactions. Many processes generate lucrative, functionally decorated difficult access other means. Herein, we summarize recent efforts this area analyze state field.

Language: Английский

Strain-Release [2π + 2σ] Cycloadditions for the Synthesis of Bicyclo[2.1.1]hexanes Initiated by Energy Transfer DOI
Renyu Guo,

Yu‐Che Chang,

Loïc Herter

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(18), P. 7988 - 7994

Published: April 27, 2022

Saturated bicycles are becoming ever more important in the design and development of new pharmaceuticals. Here a strategy for synthesis bicyclo[2.1.1]hexanes is described. These significant because they have defined exit vectors, yet many substitution patterns underexplored as building blocks. The process involves sensitization bicyclo[1.1.0]butane followed by cycloaddition with an alkene. scope mechanistic details method discussed.

Language: Английский

Citations

192
Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane DOI
Nils Frank, Jeremy Nugent,

Bethany R. Shire

et al.

Nature, Journal Year: 2022, Volume and Issue: 611(7937), P. 721 - 726

Published: Sept. 15, 2022

Language: Английский

Citations

143
Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes DOI
Yongxiang Zheng, Weichen Huang,

Roshan K. Dhungana

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(51), P. 23685 - 23690

Published: Dec. 16, 2022

The development of synthetic strategies for the preparation bioisosteric compounds is a demanding undertaking in medicinal chemistry. Numerous have been developed synthesis bicyclo[1.1.1]pentanes (BCPs), bridge-substituted BCPs, and bicyclo[2.1.1]hexanes. However, progress on bicyclo[3.1.1]heptanes, which serve as meta-substituted arene bioisosteres, has not previously explored. Herein, we disclose first photoinduced [3σ + 2σ] cycloaddition trisubstituted bicyclo[3.1.1]heptanes using bicyclo[1.1.0]butanes cyclopropylamines. This transformation only uses mild operationally simple conditions but also provides unique bioisosteres. applicability this method showcased by derivatization reactions.

Language: Английский

Citations

135
Synthesis of Polysubstituted 2-Oxabicyclo[2.1.1]hexanes via Visible-Light-Induced Energy Transfer DOI
Yujie Liang,

Roman Kleinmans,

Constantin G. Daniliuc

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(44), P. 20207 - 20213

Published: Oct. 27, 2022

Synthesis of bicyclic scaffolds has attracted growing interest because they are high importance in modern pharmaceutical development. Here we report a strategy to access polysubstituted 2-oxabicyclo[2.1.1]hexanes single operation from readily accessible benzoylformate esters and bicyclo[1.1.0]butanes via visible-light-induced triplet energy transfer catalysis. The process is proposed involve formal [2π + 2σ] photocycloaddition/backbone C-H abstraction/aryl group migration sequence. A diverse range (hetero)aryl groups successfully underwent the backbone (C2) position provide previously inaccessible molecules, ester product can serve as handle for downstream manipulation, thus offering opportunities rapidly build up molecular complexity new sp3-rich chemical space.

Language: Английский

Citations

123
Catalytic Formal [2π+2σ] Cycloaddition of Aldehydes with Bicyclobutanes: Expedient Access to Polysubstituted 2‐Oxabicyclo[2.1.1]hexanes DOI
Yujie Liang, Fritz Paulus, Constantin G. Daniliuc

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(34)

Published: June 12, 2023

Synthesis of bicyclic scaffolds has attracted tremendous attention because they are playing an important role as saturated bioisosteres benzenoids in modern drug discovery. Here, we report a BF3 -catalyzed [2π+2σ] cycloaddition aldehydes with bicyclo[1.1.0]butanes (BCBs) to access polysubstituted 2-oxabicyclo[2.1.1]hexanes. A new kind BCB containing acyl pyrazole group was invented, which not only significantly facilitates the reactions, but can also serve handle for diverse downstream transformations. Furthermore, aryl and vinyl epoxides be utilized substrates undergo BCBs after situ rearrangement aldehydes. We anticipate that our results will promote challenging sp3 -rich frameworks exploration BCB-based chemistry.

Language: Английский

Citations

105
2-Oxabicyclo[2.1.1]hexanes as saturated bioisosteres of the ortho-substituted phenyl ring DOI Creative Commons

Aleksandr Denisenko,

Pavel Garbuz,

Nataliya M. Voloshchuk

et al.

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(8), P. 1155 - 1163

Published: June 5, 2023

Abstract The ortho -substituted phenyl ring is a basic structural element in chemistry. It found more than three hundred drugs and agrochemicals. During the past decade, scientists have tried to replace bioactive compounds with saturated bioisosteres obtain novel patentable structures. However, most of research this area has been devoted replacement para ring. Here we developed improved physicochemical properties: 2-oxabicyclo[2.1.1]hexanes. Crystallographic analysis revealed that these structures indeed similar geometric properties. Replacement marketed agrochemicals fluxapyroxad (BASF) boscalid 2-oxabicyclo[2.1.1]hexanes dramatically their water solubility, reduced lipophilicity importantly retained bioactivity. This work suggests an opportunity for chemists medicinal chemistry agrochemistry.

Language: Английский

Citations

92
Conquering the Synthesis and Functionalization of Bicyclo[1.1.1]pentanes DOI Creative Commons

Bethany R. Shire,

Edward A. Anderson

JACS Au, Journal Year: 2023, Volume and Issue: 3(6), P. 1539 - 1553

Published: May 16, 2023

Bicyclo[1.1.1]pentanes (BCPs) have become established as attractive bioisosteres for para-substituted benzene rings in drug design. Conferring various beneficial properties compared with their aromatic "parents," BCPs featuring a wide array of bridgehead substituents can now be accessed by an equivalent variety methods. In this perspective, we discuss the evolution field and focus on most enabling general methods synthesis, considering both scope limitation. Recent breakthroughs synthesis bridge-substituted are described, well methodologies postsynthesis functionalization. We further explore new challenges directions field, such emergence other rigid small ring hydrocarbons heterocycles possessing unique substituent exit vectors.

Language: Английский

Citations

80
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
General Synthesis of 3‐Azabicyclo[3.1.1]heptanes and Evaluation of Their Properties as Saturated Isosteres** DOI Creative Commons

Dmitry Dibchak,

Mariya Snisarenko,

Artem Mishuk

et al.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(39)

Published: May 26, 2023

Abstract A general approach to 3‐azabicyclo[3.1.1]heptanes by reduction of spirocyclic oxetanyl nitriles was developed. The mechanism, scope, and scalability this transformation were studied. core incorporated into the structure antihistamine drug Rupatidine instead pyridine ring, which led a dramatic improvement in physicochemical properties.

Language: Английский

Citations

48
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

46