Enantioselective synthesis of 2-substituted bicyclo[1.1.1]pentanes via sequential asymmetric imine addition of bicyclo[1.1.0]butanes and skeletal editing

Nature Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Language: Английский

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Triftosylhydrazone in Single-Atom Skeletal Editing

Accounts of Chemical Research, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

ConspectusIn the past decade, single-atom skeletal editing, which involves precise insertion, deletion, or exchange of single atoms in core skeleton a molecule, has emerged as promising synthetic strategy for rapid construction diversification complex molecules without laborious de novo processes. Among them, carbene-initiated editing is particularly appealing due to ready availability and diverse reactivities carbene species. The initial endeavors modify heteroarenes through carbon-atom insertion could date back 1881, when Ciamician Denstedt described conversion pyrroles pyridines by trapping haloform-derived free carbene. Despite its potential value, general applicability this one-carbon seen limited progress poor yields harsh reaction conditions. Significant advances via were achieved only 3 years Levin, Ball, Xu, Song, Glorius, others. hallmark these approaches facile halocyclopropanation followed regioselective ring opening facilitated expulsion halide ion. Consequently, specially designed α-halocarbene precursors, such haloform derivatives, α-halodiazoacetates, chlorodiazirines, α-chlorodiazo oxime esters, can be employed achieve Ciamician–Denstedt-type editing. This not limits types functional groups installed on expansion products but also prevents their widespread adoption, especially late-stage contexts. enduring quest develop environmentally friendly versatile superior group compatibility, application diversifications investigation mechanistic insights into carbon reactions remain fundamental objective.In our over 5 years, we have developed o-trifluoromethylbenzenesulfonylhydrazones (named Triftosylhydrazones) operationally safe easily decomposable diazo surrogates explored various challenging catalytic transfer reactions. Recently, put great efforts expanding scope unlocking triftosylhydrazones precursors Since 2018, realized range acyclic 1,3-dicarbonyls with silver carbenes access 1,4-dicarbonyls, proceeding cyclopropanation/ring-opening process. Inspired results, recently demonstrated series transition-metal-catalyzed highly selective medicinally interesting like pyrroles, indoles, 1,2-diazoles carbenic insertion. We then strained three-membered nitrogen- oxygen-containing heterocycles single-carbon atoms. In Account, present an overview achievements heterocycles, organized based three situ-generated key intermediates, cyclopropane, N-ylide, O-ylide from focus scopes, features, applications. hope that Account will provide valuable contribute development new methodologies both chemistry fields.

Language: Английский

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Molecular Ring Remodeling through C–C Bond Cleavage

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

Published: Feb. 27, 2025

ConspectusStable and inert C-C bonds form the fundamental framework of organic compounds. Consequently, direct transformations involving bond cleavage present an innovative approach for rapid modification remodeling molecular skeletons. In recent years, concept skeletal editing has garnered widespread attention been significantly developed, providing new opportunities late-stage bioactive molecules, high-value transformation bulk chemicals, a revolution in traditional fragment coupling strategies chemical synthesis. Notable advancements this field have focused on cyclic including ring expansion, contraction, ring-opening reactions, thereby enriching synthetic toolbox available to chemists. However, selective remains formidable challenge, especially complex due high dissociation energy difficulty achieving precise selectivity control. Over past few our group made efforts address these challenges. We demonstrated potential molecule reactions as efficient strategy synthesis molecules.Herein, we two major thematic achieved by group, utilizing cascade activation entropy-driven reconstruction via cleavage. These are characterized mild conditions, accessibility catalysts reagents, exceptional functional compatibility, emerging novel approaches through atom-incorporation mainly nitrogenation, oxygenation, halogenation synthesize pharmaceuticals, natural products, material molecules. (1) Ring expansion reactions: developed that enable insertion C-, N-, O-containing units into rings. methodologies offer practical routes synthesizing amides, amines, lactones, nitrogen-containing heterocycles. (2) Ring-opening enables construction distally difunctionalized frameworks. By transition metal catalysis radical-mediated process, successfully both single C═C double within Furthermore, tackled highly challenging arene (ARO) reaction, enabling stereoselective conjugated systems unsaturation liberation aromatic systems. Mechanistic studies DFT calculations provided critical insights processes. also identified key intermediates involved cleavage, benzyl azide, O-acetyl hydroxylamine, β-azido peroxyl radical, copper bisnitrene, 2-nitrene indazole. findings deepened understanding mechanisms strategy, which further promoted discovery related acyclic substrates.

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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Atom-swapping skeletal editing of benzo[c]oxepines for the construction of 2-benzodiazepines via a continuous manufacturing one-pot synthesis

Chinese Chemical Letters, Journal Year: 2025, Volume and Issue: unknown, P. 111200 - 111200

Published: April 1, 2025

Language: Английский

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C-to-N atom swapping and skeletal editing in indoles and benzofurans

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: May 21, 2025

Abstract Skeletal editing comprises the structural reorganization of compounds. Such can be achieved through atom swapping, insertion, deletion or compound’s backbone structure 1,2 . Conducted at a late stage in drug development campaigns, skeletal enables diversification an existing pharmacophore, enhancing efficiency development. Instead constructing heteroarene classically from basic building blocks, variants are readily accessible directly starting lead compound approved pharmacophore. Here we present C to N swapping indoles C2 position give indazoles oxidative cleavage indole core and subsequent ring closure. Reactions proceed ring-opened oximes as intermediates. These deconstructed intermediates also diverted into benzimidazoles resulting overall with concomitant reorganization. The same diverting strategies equally well applicable benzofurans leading either benzisoxazoles benzoxazoles. classes obtained these methods—indazoles 3,4 , 5 6,7 benzoxazoles 8 —are biologically relevant moieties found substructures natural products pharmaceuticals. procedures introduced substantially enlarge methods portfolio emerging field editing.

Language: Английский

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Skeletal Editing via Transition‐Metal‐Catalyzed Nitrene Insertion

The Chemical Record, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 28, 2024

Abstract Metal‐nitrenes are valuable reactive intermediates for synthesis and widely used to construct biologically relevant scaffolds, complexes functionalized molecules. The ring expansion of cyclic molecules via single‐nitrogen‐atom insertion nitrene or metal‐nitrenoid has emerged as a promising modern strategy driving advantageous nitrogen‐rich compound synthesis. In recent years, the catalytic single nitrogen atom into carbocycles, leading N‐heterocycles, become an important focus synthetic approaches with applications in medicinal chemistry, materials science, industry. Catalytic insertions have been increasing prominence organic due their capability high‐value added nitrogen‐containing heterocycles from simple feedstocks. this review, we will discuss rapidly growing field skeletal editing using transition metal catalysis access heterocycles, on across wide spectrum carbocycles.

Language: Английский

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Photoredox/Iron Dual-Catalysis-Enabled [4 + 2] Cyclization of Acyl Nitrene with Alkynes

Organic Letters, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 13, 2024

In this work, the annulation of acyl nitrene with alkynes is reported under photoredox/iron dual-catalysis for synthesis a series isoquninalin-2-ones. The reaction featured high regioselectivity and good generality. particular, resulting isoquinalin-2-ones could be structurally elaborated into several biologically interesting scaffolds. Mechanism investigation suggests that was ascribed to formal [4 + 2] cyclization. It believed represents an initial example preparing isoquinolin-1-ones from ferric peroxyl-catalyzed insertion.

Language: Английский

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Nitrogenation of Alkynes with Nitrones to Prepare Functionalized [1,4]Oxazinones through Csp–Csp² Bond Cleavage

Organic Letters, Journal Year: 2024, Volume and Issue: 26(44), P. 9541 - 9546

Published: Oct. 25, 2024

Herein, we report a novel strategy of hypervalent iodine(III) compound-mediated selective Csp–Csp2 bond cleavage alkynes and C═N/N–O nitrones recombination C–C/C–O/C–N multiple bonds to access various functionalized [1,4]oxazinones bearing vicinal carbon stereocenter in good yields high diastereoselectivity. Mechanistic studies revealed that the reaction undergoes domino [4 + 3] cycloaddition, 1,3-rearrangement N–O bond, intramolecular cyclization, dearomatization, rearomatization over four steps single flask. The present method features functional group tolerance, broad substrate scope, C–C/C═N/N–O recombination.

Language: Английский

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