Skeletal Editing of Isoindolines to Tetralins

Chemistry - A European Journal, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Abstract We present a skeletal editing strategy for transforming isoindolines into tetralins via cascade N‐atom removal deconstruction followed by Diels‐Alder reaction between in situ generated o‐ quinodimethanes and activated alkenes. This approach features broad substrate scope, excellent stereoselectivity, high yields, demonstrating its applicability to complex bioactive compounds natural products. Notably, case studies showcase the efficient construction of challenging spirocyclic bridged systems, underscoring method's versatility potential advancing applications synthetic chemistry.

Language: Английский

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N-Atom Deletion Involving Rearrangement of Sulfamoyl Azides or Triazanium Salts

Accounts of Chemical Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

ConspectusAmines are frequent structural components in natural products, pharmaceuticals, ligands, and catalysts, making their synthesis transformation essential to organic chemistry. While C-N bond formation has become a well-established reliable synthetic strategy, the selective cleavage of bonds remains relatively underexplored. This challenge arises from low heterolytic nucleofugality nitrogen, property that limits practical application cleavage. gap underscores significant area methodology need further development. In this context, N atom deletion─defined as removal nitrogen via cleavage, while preserving integrity remaining framework─has emerged promising approach for skeletal editing. Since Levin's landmark 2021 report, deletion gained attention its potential precisely modify molecular skeletons. Building on editing concepts advanced by Levin Sarpong, particularly strategies modifying cyclic frameworks, we recognized critical developing mild efficient methods enable manipulation systems.This Account summarizes our research since 2017, focusing two approaches with distinct mechanisms: rearrangement sulfamoyl azides conversion triazanium intermediates. Initially, explored optimized thermal derived secondary amines, discovering viable strategy deletion. 2024, introduced an O-diphenylphosphinyl hydroxylamine (DPPH)-promoted deletion, involving generation novel Both polar aliphatic amines into nonpolar scaffolds applicable both linear molecules systems varying sizes. The DPPH-based approach, particular, demonstrated exceptional effectiveness sterically hindered substrates reaction conditions no anhydrous or oxygen-free environments. mechanisms methods─both isodiazene radical intermediates─were elucidated through rigorous experimental investigation. Additionally, observed rapid hydro(deutero)deamination products when primary were exposed DPPH.Beyond role typical crucial approach. Though limitations, it transforms challenging task constructing C-C more manageable sequence: following removal. We have applied hydrocarbon cages, pharmaceuticals. hope work will stimulate interest encourage incorporation methodologies, thereby expanding utility across diverse areas

Language: Английский

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Nitrene-mediated Aminative N–N–N Coupling: Facile Access to Triazene 1-Oxides

Chemical Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

A nitrene-mediated aminative N–N–N coupling enables direct triazene 1-oxide synthesis via an aminonitrene–nitrosoarene pathway.

Language: Английский

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Late-Stage N-Atom Deletion of Multisubstituted 2-Azabicyclo[2.1.1]Hexanes

ACS Catalysis, Journal Year: 2025, Volume and Issue: unknown, P. 5825 - 5834

Published: March 25, 2025

Rigid three-dimensional scaffolds such as 2-azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) serve unique saturated isosteres of arenes, offering distinct substitution patterns due to their differing molecular exit vectors. This study introduces a skeletal editing strategy that efficiently transforms multisubstituted aza-BCHs into BCPs via an O-diphenylphosphinylhydroxylamine-promoted N-atom deletion process. method effectively addresses the challenge creating sterically hindered (2°)C–C(3°) bonds by removing nitrogen atom encased within bulky alkyl groups, reconstructing strained aza-BCH structure more BCP without generating undesired ring-opening diene byproducts. The used can be prepared from modified intermolecular [3 + 2] cycloaddition between bicyclo[1.1.0]butanes imines, making this practical. approach achieves remarkable efficiency, with yields up 99% scalability decagram quantities. resulting carboxylates further functionalized through decarboxylation, highlighting potential for programmed divergent synthesis BCPs. broad substrate scope high functional group tolerance protocol emphasize its versatility, it particularly valuable late-stage contained peptides, natural products, pharmaceuticals.

Language: Английский

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Switchable and Stereospecific C-Glycosylation Strategy via Formal Functional Group Deletion

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Carbohydrates constitute an important class of biologically relevant natural products. Among the synthetic glycomimetics, C-glycosides are particularly interesting due to their chemical and metabolic stability toward acidic enzymatic hydrolysis at anomeric position. The stereochemical outcomes traditional methodologies access rely heavily on substrate control. Herein, we report a novel strategy diverse with precise control position via formal functional group deletion, where both α- β-anomers furanoses pyranoses can be obtained as single stereoisomers. Additionally, broad scope heterocyclic this further illustrates its potential for empowering future application in biology research drug discovery.

Language: Английский

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Skeletal Editing of Mechanically Interlocked Molecules: Nitrogen Atom Deletion from Crown Ether-Dibenzylammonium Rotaxanes

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(43), P. 29496 - 29502

Published: Oct. 21, 2024

Removing the nitrogen atom from secondary amines while simultaneously linking remaining fragments is a powerful form of late-stage skeletal editing. Here, we report its use for deletion dibenzylammonium template used to assemble crown ether rotaxanes. The reaction uses an anomeric amide that activates generate carbon-carbon bond replaces amine nitrogen. Despite potential dethreading intermediate diradical pair, was successfully deleted series rotaxane axles as long macrocycle could access coconformations did not inhibit group. skeletally edited interlocked molecules were obtained directly parent ether-dibenzylammonium rotaxanes in modest yields (23-36%) and characterized by NMR spectroscopy, mass spectrometry, X-ray crystallography. One shows network weak CH···O hydrogen bonds between benzylic methylene groups axle solid state, place ether-ammonium binding motif parent, unedited, rotaxane.

Language: Английский

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Hydro- and deutero-deamination of primary amines using O-diphenylphosphinylhydroxylamine

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

Published: Nov. 24, 2024

Abstract While selective defunctionalizations are valuable in organic synthesis, hydrodeamination of primary amines poses challenges. Deuterodeamination, analogous to hydrodeamination, presents even greater difficulties due its frequently slower deuteration rate, interference by hydrogenation and constraints deuterated sources. This study introduces a reliable, robust, scalable hydro- deuterodeamination method capable handling various amines. Defined mild reaction conditions, rapid completion, simplified purification facilitated water-soluble byproducts, the leverages deuterium oxide as source employs commercialized O-diphenylphosphinylhydroxylamine for deamination. Applied diverse range biologically active molecules, it has consistently achieved high yields efficient incorporation. By synergizing with site-selective C–H functionalization aliphatic amines, our reveals synthetic strategies utilizing nitrogen atom traceless directing group, encompassing deaminative alkylation, 1,1-deuteroalkylation, 1,1-dialkylation, 1,1,1-deuterodialkylation, arylation, 1,3-deuteroarylation. Emphasizing this innovation, processes degree-controlled have been developed.

Language: Английский

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Accessing Sulfonamides via Formal SO2 Insertion into C–N Bonds

Published: Aug. 22, 2024

Functional group interconversions of abundant substructures that accommodate the often-complex molecular architectures seen in pharmaceuticals are particularly sought after by medicinal chemists as a means to enable both lead optimization and library diversification. Here, we report conceptually new strategy enables net SO 2 -insertion into C–N bond primary amines, enabling direct synthesis sulfonamides without pre-activation effectively inverting nitrogen’s properties (acidity, hydrogen bonding, etc.). The key realizing this overall transformation is implementation an anomeric amide dual-function reagent which serves cleave initial deliver nitrogen atom product incorporation. process tolerates wide array functionalities can be run automated fashion thus allowing libraries amines viable progenitors highly desirable sulfonamides. Mechanistic studies support isodiazene radical chain mechanism generates intermediate sulfinate reacts with forge S–N bond. As proof concept, our protocol was used conduct high-throughput diversification campaign, applied modification approved active pharmaceutical ingredients CO-to-SO “isosteric replacement” approach. Conceptually, successful translation originally developed for deletion insertion has important implications skeletal editing.

Language: Английский

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Synthesis of Substituted Tetralins via Nitrogen Deletion/Diels–Alder Cascade Reaction

The Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Skeletal editing is an important approach for the modification and diversification of biologically active molecules. The utilization nitrogen deletion strategies in skeletal has recently emerged as a new method compound modification. Here, we report unexpected isoindolines. Contrary to anticipated outcome cyclobutane formation via intramolecular radical couplings, isoindoline triggers Diels–Alder cycloaddition facilitated by situ ortho-xylylene yield tetraline. Inspired this reaction, developed strategy synthesizing substituted tetralins, employing isoindoline, reagent (anomeric amide), dienophiles. This methodology demonstrates pathway tetralin synthesis

Language: Английский

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Quinazolinone-to-Isoquinoline Metamorphosis by Ruthenium-Catalyzed [4+2] Annulation with Sulfoxonium Ylides

Organic Letters, Journal Year: 2024, Volume and Issue: 26(50), P. 10951 - 10957

Published: Dec. 10, 2024

Molecular editing of quinazolinones to isoquinolines by a novel ruthenium-catalyzed [4+2] annulation with sulfoxonium ylides has been developed. The method permits the precise and rapid assembly multisubstituted aminoisoquinolines, class heterocycles that play privileged role in organic synthesis pharmaceutical development. This new catalytic process exhibits programmability, including directed C–H acetylation, nucleophilic cyclization, alcoholysis. Remarkably, various 2-arylquinazolinones could be employed excellent yields broad functional group tolerance. heterocycle-to-heterocycle protocol is compatible green chemistry using an EtOH solvent releasing H2O dimethyl sulfoxide as byproducts.

Language: Английский

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