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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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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Radical Hydrocarboxylation of Unactivated Alkenes via Photocatalytic Formate Activation

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(20), С. 10991 - 10997

Опубликована: Май 15, 2023

Herein we disclose a strategy to promote the hydrocarboxylation of unactivated alkenes using photochemical activation formate salts. We illustrate that an alternative initiation mechanism circumvents limitations prior approaches and enables this challenging substrate class. Specifically, found accessing requisite thiyl radical initiator without exogenous chromophore eliminates major byproducts have plagued attempts exploit similar reactivity for alkene substrates. This redox-neutral method is technically simple execute effective across broad range Feedstock alkenes, such as ethylene, are hydrocarboxylated at ambient temperature pressure. A series cyclization experiments indicate how described in report can be diverted by more complex processes.

Язык: Английский

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Synthetic Advantages of Defluorinative C−F Bond Functionalization

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(49)

Опубликована: Авг. 22, 2023

Abstract Much progress has been made in the development of methods to both create compounds that contain C−F bonds and functionalize bonds. As such, are becoming common versatile synthetic functional handles. This review summarizes advantages defluorinative functionalization reactions for small molecule synthesis. The coverage is organized by type carbon framework fluorine attached mono‐ polyfluorinated motifs. main challenges, opportunities advances discussed each class organofluorine. Most text focuses on case studies illustrate how defluorofunctionalization can improve routes targets or properties enable unique mechanisms reactions. broader goal showcase incorporating exploiting design routes, improvement specific advent new methods.

Язык: Английский

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Light‐Driven Synthesis and Functionalization of Bicycloalkanes, Cubanes and Related Bioisosteres

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(14)

Опубликована: Янв. 5, 2024

Bicycloalkanes, cubanes and their structural analogues have emerged as bioisosteres of (hetero)arenes. To meet increasing demand, the chemical community has developed a plethora novel synthetic methods. In this review, we assess progress made in field light-driven construction functionalization such relevant molecules. We focused on diverse targets, well reaction processes giving access to: (i) [1.1.1]-bicyclopentanes (BCPs); (ii) [2.2.1]-bicyclohexanes (BCHs); (iii) [3.1.1]-bicycloheptanes (BCHeps); (iv) cubanes; other structurally related scaffolds. Finally, future perspectives dealing with identification manifolds to new functionalized bioisosteric units are discussed.

Язык: Английский

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Unexpected Cyclization Product Discovery from the Photoinduced Bioconjugation Chemistry between Tetrazole and Amine

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(3), С. 2122 - 2131

Опубликована: Янв. 8, 2024

Bioconjugation chemistry has emerged as a powerful tool for the modification of diverse biomolecules under mild conditions. Tetrazole, initially proposed bioorthogonal photoclick handle 1,3-dipolar cyclization with alkenes, was later demonstrated to possess broader photoreactivity carboxylic acids, serving versatile bioconjugation and photoaffinity labeling probe. In this study, we unexpectedly discovered validated between tetrazole primary amine afford new 1,2,4-triazole product. Given significance functionalized N-heterocycles in medicinal chemistry, successfully harnessed serendipitously reaction synthesize both pharmacologically relevant DNA-encoded chemical libraries (DELs) small molecule compounds bearing scaffolds. Furthermore, conditions stable linkage found broad application photoinduced scenarios, spanning from intramolecular peptide macrocyclization templated DNA cross-linking intermolecular proteins. Triazole products on lysine side chains were identified tetrazole-labeled proteins, refining comprehensive understanding photo-cross-linking profiles tetrazole-based probes. Altogether, tetrazole-amine expands current toolbox creates possibilities at interface biology.

Язык: Английский

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Photochemical Methods Applied to DNA Encoded Library (DEL) Synthesis

Accounts of Chemical Research, Год журнала: 2023, Номер 56(3), С. 385 - 401

Опубликована: Янв. 19, 2023

ConspectusDNA-encoded library technology (DELT) is a new screening modality that allows efficient, cost-effective, and rapid identification of small molecules with potential biological activity. This emerging technique represents an enormous advancement that, in combination other technologies such as high-throughput (HTS), fragment-based lead generation, structure-based drug design, has the to transform how discovery carried out. DELT hybrid which chemically synthesized compounds are linked unique genetic tags (or "barcodes") contain readable information. In this way, millions billions building blocks (BBs) attached on-DNA via split-and-pool synthesis can be evaluated against target single experiment. Polymerase chain reaction (PCR) amplification next-generation sequencing (NGS) analysis sequence oligonucleotides DNA tag used identify those ligands high affinity for target. innovative fusion chemical was conceived 1992 by Brenner Lerner (Proc. Natl. Acad. Sci. 1992, 89, 5381–5383) under accelerated development implementation synthetic techniques protocols compatible DNA. fact, compatibility key parameter increasing chances ligand, central focus been transformations transition robust synthesis. Because sole use amplifiable barcode, its structural integrity during process mandatory. As such, these sensitive, polyfunctional substrates typically requires aqueous solutions within defined pH temperature ranges, considered notable challenge DEL synthesis.Using low-energy visible light driving force promote attractive alternative classical methods, it important well-established tool forging bonds way radical intermediates. Recent advances field photocatalysis extraordinary, powerful research arena still continuous development. Several applications taking advantage mild conditions photoinduced have directed toward synthesis, allowing expansion space available evaluation on-DNA. There no doubts visible-light-driven reactions become one most approaches DELT, given easy they provide construct challenges achieve equal success protocols.Key characteristics photocatalytic include short times efficiency, translate into retention integrity. Account, we describe recent diversification prepared on-DNA, highlighting amenability employed preserving structure molecules. We demonstrate from our group applicability summary table containing all methods reported date demonstrating their aspects scope, applications, compatibilities. With information, practitioners provided compelling reasons developing/choosing applications.

Язык: Английский

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Evolution of chemistry and selection technology for DNA-encoded library

Acta Pharmaceutica Sinica B, Год журнала: 2023, Номер 14(2), С. 492 - 516

Опубликована: Окт. 11, 2023

DNA-encoded chemical library (DEL) links the power of amplifiable genetics and non-self-replicating phenotypes, generating a diverse world. In analogy with biological world, DEL world can evolve by using central dogma, wherein DNA replicates PCR reactions to amplify genetic codes, sequencing transcripts information, DNA-compatible synthesis translates into phenotypes. Importantly, is key expanding space. Besides, evolution-driven selection system pushes chemicals under selective pressure, i.e., desired strategies. this perspective, we summarized recent advances in synthetic toolbox panning strategies, which will shed light on drug discovery harnessing vitro evolution via DEL.

Язык: Английский

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Iodopentafluorosulfanylation of [1.1.1]propellane and further functionalizations

Science China Chemistry, Год журнала: 2023, Номер 66(10), С. 2871 - 2877

Опубликована: Авг. 24, 2023

Язык: Английский

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