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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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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Dearomative ring expansion of thiophenes by bicyclobutane insertion

Science, Год журнала: 2023, Номер 381(6653), С. 75 - 81

Опубликована: Июль 6, 2023

Skeletal ring enlargement is gaining renewed interest in synthetic chemistry and has recently focused on insertion of one or two atoms. Strategies for heterocyclic expansion through small-ring remain elusive, although they would lead to the efficient formation bicyclic products. Here, we report a photoinduced dearomative thiophenes by bicyclo[1.1.0]butanes produce eight-membered rings under mild conditions. The value, broad functional-group compatibility, excellent chemo- regioselectivity were demonstrated scope evaluation product derivatization. Experimental computational studies point toward photoredox-induced radical pathway.

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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Practical and Facile Access to Bicyclo[3.1.1]heptanes: Potent Bioisosteres of meta-Substituted Benzenes

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(48), С. 21848 - 21852

Опубликована: Ноя. 7, 2022

There is increasing interest in replacement of the planar aromatic rings drug candidates with three-dimensional caged scaffolds order to improve physical properties, but bioisosteres meta-substituted benzenes have remained elusive. We focused on bicyclo[3.1.1]heptane (BCH) scaffold as a novel bioisostere benzenes, anticipating that [3.1.1]propellane (2) would be versatile precursor diversely functionalized BCHs. Here, we describe practical preparative method for from newly developed 1,5-diiodobicyclo[3.1.1]heptane (1), well difunctionalization reactions 2 leading also report postfunctionalization these products.

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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Visible-light-induced direct perfluoroalkylation/heteroarylation of [1.1.1]propellane to diverse bicyclo[1.1.1]pentanes (BCPs) under metal and photocatalyst-free conditions

Green Chemistry, Год журнала: 2023, Номер 25(3), С. 986 - 992

Опубликована: Янв. 1, 2023

This study describes a green and novel multi-component reaction for direct perfluoroalkylation/heteroarylation of [1.1.1]propellane with heteroarenes perfluoroalkyl iodines to diverse bicyclo[1.1.1]pentanes (BCPs).

Язык: Английский

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A General and Modular Approach to BCP Alkylamines via Multicomponent Difunctionalization of [1.1.1]Propellane

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(9), С. 5363 - 5369

Опубликована: Фев. 21, 2023

Over the past decade, bicyclo[1.1.1]pentane (BCP) motifs have come to fore as valuable pharmaceutical bioisosteres of para-disubstituted benzenes. However, limited approaches and requisite multistep syntheses useful BCP building blocks are hampering early discovery research in medicinal chemistry. Herein we report development a modular strategy for divergent preparation functionalized alkylamines. In this process, general method introduce fluoroalkyl groups scaffolds using readily available easy-to-handle sulfinate salts was also developed. Moreover, can be extended S-centered radicals incorporation sulfones thioethers into core. Overall, multicomponent enables rapid construction BCP-type applications drug discovery.

Язык: Английский

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