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

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(8), P. 1155 - 1163

Published: June 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.

Language: Английский

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Conquering the Synthesis and Functionalization of Bicyclo[1.1.1]pentanes

JACS Au, Journal Year: 2023, Volume and Issue: 3(6), P. 1539 - 1553

Published: May 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.

Language: 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, Journal Year: 2023, Volume and Issue: 145(9), P. 5363 - 5369

Published: Feb. 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.

Language: 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, Journal Year: 2023, Volume and Issue: 62(39)

Published: May 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.

Language: Английский

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General and Modular Route to (Halo)alkyl BCP-Heteroaryls Enabled by α-Aminoalkyl Radical-Mediated Halogen-Atom Transfer

ACS Catalysis, Journal Year: 2023, Volume and Issue: 14(2), P. 619 - 627

Published: Dec. 28, 2023

Synthesis of bicyclo[1.1.1]pentane (BCP) heteroaryls continues to be a part the most important tasks in organic synthesis because they are significant class bioisosteres with universal applications drug discovery. However, substrate scope current multicomponent reactions is limited tertiary alkyl radicals and prefunctionalized (het)arenes due their intrinsic mechanisms, resulting decrease application value. Herein, we report straightforward alternative for (halo)alkyl BCP-heteroaryls from [1.1.1]propellane enabled by α-aminoalkyl radical-mediated halogen-atom transfer (XAT). Carbon derived commonly available precursors such as primary, secondary, halides polyhalides perform additions onto give BCP radicals, which then engage C–H/C–C couplings different heteroarenes. A wide range easily constructed moderate-to-good yields. Late-stage functionalization performed on approved derivatives proceeds good efficiency produce corresponding BCP-heteroaryls. The control experiments density functional theory (DFT) calculations reveal radical nature reaction. This approach not only verifies (XAT) strategy but also provides practical efficient route multifunctionalized BCPs, significantly expands BCP-heteroaryl-type development.

Language: Английский

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Three-dimensional saturated C(sp3)-rich bioisosteres for benzene

Nature Reviews Chemistry, Journal Year: 2024, Volume and Issue: 8(8), P. 605 - 627

Published: July 9, 2024

Language: Английский

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Synthesis of 1-(Halo)alkyl-3-heteroaryl Bicyclo[1.1.1]pentanes Enabled by a Photocatalytic Minisci-type Multicomponent Reaction

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(8), P. 6247 - 6258

Published: April 10, 2024

Aryl-substituted bicyclo[1.1.1]pentane (BCP-aryl) derivatives represent the most important bioisosteres of biaryl scaffolds and widely exist in numerous complex pharmaceutical molecules. The current synthetic method limitations using only tertiary radical precursors, prefunctionalized heteroarenes, toxic transition metals, expensive photocatalysts make it urgent to develop a more simple practical protocol. To confront enrich Minisci-type chemistry, herein, we disclose photocatalytic multicomponent reaction for synthesis various (halo)alkyl BCP-aryls [1.1.1]propellane, alkyl halides, unfunctionalized heteroarenes as starting materials. Diverse kinds radicals (primary, secondary, carbons) derived from chlorides, bromides, fluoroalkyl iodides are very compatible this transformation. practicability is additionally boosted by product derivatizations late-stage functionalization pharmaceutically relevant mechanistic studies demonstrate that relay mechanism initiated consecutive photoinduced electron transfer (ConPET) process operation. We anticipate methodology would act useful tool biaryl-type drug derivatives, ultimately resulting great utility discovery program.

Language: Английский

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Strain-release transformations of bicyclo[1.1.0]butanes and [1.1.1]propellanes

Tetrahedron Chem, Journal Year: 2024, Volume and Issue: 9, P. 100070 - 100070

Published: Feb. 28, 2024

Bicyclo[1.1.0]butanes (BCBs) and [1.1.1]propellanes (tricyclo[1.1.1.01,3]pentanes, TCPs) are structurally unique compounds with different chemical properties. Strain-release driven reactions have emerged as an atom- step-economic strategy for the organic synthesis. Using this strategy, a variety of functional ring molecules been efficiently synthesized, including various cyclobutane molecules, bicyclo[2.1.1]hexanes, bicyclo[1.1.1]pentanes, others. More specifically, these strain release-driven include aspects nucleophilic addition, radical electrophilic or transition metal catalysis. This review will discuss recent developments in strain-release transformations bicyclo[1.1.0]butanes [1.1.1]propellanes.

Language: Английский

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Titanium catalyzed [2σ + 2π] cycloaddition of bicyclo[1.1.0]-butanes with 1,3-dienes for efficient synthesis of stilbene bioisosteres

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 23, 2024

Abstract Natural stilbenes have shown significant potential in the prevention and treatment of diseases due to their diverse pharmacological activities. Here we present a mild effective Ti-catalyzed intermolecular radical-relay [2σ + 2π] cycloaddition bicyclo[1.1.0]-butanes 1,3-dienes. This transformation enables synthesis bicyclo[2.1.1]hexane (BCH) scaffolds containing aryl vinyl groups with excellent regio- trans -selectivity broad functional group tolerance, thus offering rapid access structurally stilbene bioisosteres.

Language: Английский

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Enantioselective construction of stereogenic-at-sulfur(IV) centres via catalytic acyl transfer sulfinylation

Nature Chemistry, Journal Year: 2024, Volume and Issue: 16(8), P. 1301 - 1311

Published: May 8, 2024

Language: Английский

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