Bicyclobutanes: from curiosities to versatile reagents and covalent warheads

Chemical Science, Год журнала: 2022, Номер 13(40), С. 11721 - 11737

Опубликована: Янв. 1, 2022

A flurry of reports for preparing, functionalizing, and using bicyclo[1.1.0]butanes (BCBs) have positioned them to be powerful synthons with numerous applications. This review discusses the recent developments regarding this strained carbocycle.

Язык: Английский

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Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis

Communications Chemistry, Год журнала: 2023, Номер 6(1)

Опубликована: Янв. 12, 2023

Abstract Bicyclobutanes are among the most highly strained isolable organic compounds and their associated low activation barriers to reactivity make them intriguing building-blocks in chemistry. In recent years, numerous creative synthetic strategies exploiting heightened have been presented these discoveries often gone hand-in-hand with development of more practical routes for synthesis. Their proclivity as strain-release reagents through weak central C–C bond has harnessed a variety addition, rearrangement insertion reactions, providing rapid access rich tapestry complex molecular scaffolds. This review will provide an overview different options available bicyclobutane synthesis, main classes that can be prepared from bicyclobutanes, modes used.

Язык: Английский

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Strain-Release Photocatalysis

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(38), С. 20716 - 20732

Опубликована: Сен. 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.

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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A Practical and Scalable Approach to Fluoro‐Substituted Bicyclo[1.1.1]pentanes

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(29)

Опубликована: Май 31, 2022

After more than 20 years of trials, a practical scalable approach to fluoro-substituted bicyclo[1.1.1]pentanes (F-BCPs) has been developed. The physicochemical properties the F-BCPs have studied, and core was incorporated into structure anti-inflammatory drug Flurbiprofen in place fluorophenyl ring.

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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