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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Selective [2σ + 2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(7), С. 4304 - 4310

Опубликована: Фев. 10, 2023

In contrast to the traditional and widely-used cycloaddition reactions involving at least a π bond component, [2σ + 2σ] radical between bicyclo[1.1.0]butanes (BCBs) cyclopropyl ketones has been developed provide modular, concise, atom-economical synthetic route substituted bicyclo[3.1.1]heptane (BCH) derivatives that are 3D bioisosteres of benzenes core skeleton number terpene natural products. The reaction was catalyzed by combination simple tetraalkoxydiboron(4) compound B2pin2 3-pentyl isonicotinate. broad substrate scope demonstrated synthesizing series new highly functionalized BCHs with up six substituents on 99% isolated yield. Computational mechanistic investigations supported pyridine-assisted boronyl catalytic cycle.

Язык: Английский

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Lewis Acid Catalyzed Formal (3+2)‐Cycloaddition of Bicyclo[1.1.0]butanes with Ketenes

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

Опубликована: Май 11, 2023

Design, synthesis and application of benzene bioisosteres have attracted a lot attention in the past 20 years. Recently, bicyclo[2.1.1]hexanes emerged as highly attractive for ortho- meta-substituted benzenes. Herein we report mild, scalable transition-metal-free protocol construction substituted bicyclo[2.1.1]hexan-2-ones through Lewis acid catalyzed (3+2)-cycloaddition bicyclo[1.1.0]-butane ketones with disubstituted ketenes. The reaction shows high functional group tolerance documented by successful preparation various 3-alkyl-3-aryl well 3,3-bisalkyl (26 examples, up to 89 % yield). Postfunctionalization exocyclic ketone moiety is also demonstrated.

Язык: Английский

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Diboron(4)‐Catalyzed Remote [3+2] Cycloaddition of Cyclopropanes via Dearomative/Rearomative Radical Transmission through Pyridine

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(52)

Опубликована: Ноя. 8, 2022

Abstract Ring structures such as pyridine, cyclopentane or their combinations are important motifs in bioactive molecules. In contrast to previous cycloaddition reactions that necessitated a directly bonded initiating functional group, this work demonstrated novel through‐(hetero)arene radical transmission concept for selective activation of remote bond. An efficient, metal‐free and atom‐economical [3+2] between 4‐pyridinyl cyclopropanes alkenes alkynes has been developed modular synthesis pyridine‐substituted cyclopentanes, cyclopentenes bicyclo[2.1.1]hexanes difficult access using known methods. This complexity‐building reaction was catalyzed by very simple inexpensive diboron(4) compound took place via dearomative/rearomative processes. The substrate scope broad more than 100 new compounds were prepared generally high yields. Mechanistic experiments density function theory (DFT) investigation supported relay catalytic cycle involving alkylidene dihydropyridine intermediates boronyl transfer.

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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General access to cubanes as benzene bioisosteres

Nature, Год журнала: 2023, Номер 618(7965), С. 513 - 518

Опубликована: Апрель 4, 2023

Язык: Английский

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Photocatalyzed [2σ + 2σ] and [2σ + 2π] Cycloadditions for the Synthesis of Bicyclo[3.1.1]heptanes and 5- or 6-Membered Carbocycles

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(46), С. 25411 - 25421

Опубликована: Ноя. 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.

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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