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

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(18), С. 7988 - 7994

Опубликована: Апрель 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.

Язык: Английский

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Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane

Nature, Год журнала: 2022, Номер 611(7937), С. 721 - 726

Опубликована: Сен. 15, 2022

Язык: Английский

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Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]heptanes

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(51), С. 23685 - 23690

Опубликована: Дек. 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.

Язык: Английский

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Synthesis of Polysubstituted 2-Oxabicyclo[2.1.1]hexanes via Visible-Light-Induced Energy Transfer

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(44), С. 20207 - 20213

Опубликована: Окт. 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.

Язык: Английский

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Catalytic Formal [2π+2σ] Cycloaddition of Aldehydes with Bicyclobutanes: Expedient Access to Polysubstituted 2‐Oxabicyclo[2.1.1]hexanes

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(34)

Опубликована: Июнь 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.

Язык: Английский

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

Nature Chemistry, Год журнала: 2023, Номер 15(8), С. 1155 - 1163

Опубликована: Июнь 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.

Язык: Английский

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Conquering the Synthesis and Functionalization of Bicyclo[1.1.1]pentanes

JACS Au, Год журнала: 2023, Номер 3(6), С. 1539 - 1553

Опубликована: Май 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.

Язык: 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, Год журнала: 2023, Номер 62(48)

Опубликована: Окт. 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.

Язык: Английский

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

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(39)

Опубликована: Май 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.

Язык: Английский

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Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space

Chemical Science, Год журнала: 2023, Номер 14(36), С. 9885 - 9891

Опубликована: Янв. 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.

Язык: Английский

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