Single-atom logic for heterocycle editing

Nature Synthesis, Journal Year: 2022, Volume and Issue: 1(5), P. 352 - 364

Published: April 11, 2022

Language: Английский

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Late-stage diversification of indole skeletons through nitrogen atom insertion

Science, Journal Year: 2022, Volume and Issue: 377(6610), P. 1104 - 1109

Published: Sept. 1, 2022

Compared with peripheral late-stage transformations mainly focusing on carbon-hydrogen functionalizations, reliable strategies to directly edit the core skeleton of pharmaceutical lead compounds still remain scarce despite recent flurry activity in this area. Herein, we report skeletal editing indoles through nitrogen atom insertion, accessing corresponding quinazoline or quinoxaline bioisosteres by trapping an electrophilic nitrene species generated from ammonium carbamate and hypervalent iodine. This reactivity relies strategic use a silyl group as labile protecting that can facilitate subsequent product release. The utility highly functional group-compatible methodology context several commercial drugs is demonstrated.

Language: Английский

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Scaffold hopping by net photochemical carbon deletion of azaarenes

Science, Journal Year: 2022, Volume and Issue: 376(6592), P. 527 - 532

Published: April 28, 2022

Discovery chemists routinely identify purpose-tailored molecules through an iterative structural optimization approach, but the preparation of each successive candidate in a compound series can rarely be conducted manner matching their thought process. This is because many necessary chemical transformations required to modify cores straightforward fashion are not applicable complex contexts. We report method that addresses one facet this problem by allowing hop directly between chemically distinct heteroaromatic scaffolds. Specifically, we show selective photolysis quinoline

Language: Английский

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Strain-Release Photocatalysis

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(38), P. 20716 - 20732

Published: Sept. 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.

Language: Английский

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Stereoselective Synthesis of Cyclobutanes by Contraction of Pyrrolidines

Journal of the American Chemical Society, Journal Year: 2021, Volume and Issue: 143(45), P. 18864 - 18870

Published: Nov. 8, 2021

Here we report a contractive synthesis of multisubstituted cyclobutanes containing multiple stereocenters from readily accessible pyrrolidines using iodonitrene chemistry. Mediated by nitrogen extrusion process, the stereospecific involves radical pathway. Unprecedented unsymmetrical spirocyclobutanes were prepared successfully, and concise, formal cytotoxic natural product piperarborenine B is reported.

Language: Английский

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Skeletal Editing: Interconversion of Arenes and Heteroarenes

Helvetica Chimica Acta, Journal Year: 2023, Volume and Issue: 106(3)

Published: Jan. 13, 2023

Abstract Skeletal editing involves making specific point‐changes to the core of a molecule through selective insertion, deletion or exchange atoms. It thus represents potentially powerful strategy for step‐economic modification complex substrates and is perfect complement methods such as C−H functionalization that target molecular periphery. Given their ubiquity in biologically active compounds, ability perform skeletal on – therefore interconvert between aromatic heterocycles especially valuable. This review summarizes both recent key historical examples applied interconversion rings; we anticipate it will serve highlight not only innovative enabling nature current methods, but also tremendous opportunities still exist field.

Language: Английский

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Unified Access to Pyrimidines and Quinazolines Enabled by N–N Cleaving Carbon Atom Insertion

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(42), P. 19258 - 19264

Published: Oct. 14, 2022

Given the ubiquity of heterocycles in biologically active molecules, transformations with capacity to modify such molecular skeletons modularity remain highly desirable. Ring expansions that enable interconversion privileged heterocyclic motifs are especially interesting this regard. As such, known mechanisms for ring expansion and contraction determine classes heterocycle amenable skeletal editing. Herein, we report a reaction selectively cleaves N–N bond pyrazole indazole cores afford pyrimidines quinazolines, respectively. This chlorodiazirine-mediated provides unified route related pair otherwise typically prepared by divergent approaches. Mechanistic experiments DFT calculations support pathway involving pyrazolium ylide fragmentation followed cyclization ring-opened diazahexatriene intermediate yield new diazine core. Beyond enabling access valuable heteroarenes from easily starting materials, demonstrate synthetic utility editing synthesis Rosuvastatin analog as well an aryl vector-adjusting direct scaffold hop.

Language: Английский

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Skeletal Editing of (Hetero)Arenes Using Carbenes

Chemistry - A European Journal, Journal Year: 2023, Volume and Issue: 29(42)

Published: May 26, 2023

Abstract (Hetero)arenes continue to prove their indispensability in pharmaceuticals, materials science, and synthetic chemistry. As such, the controllable modification of biologically significant (hetero)arenes towards diverse more‐potent complex molecular scaffolds through peripheral skeletal editing has been considered a challenging goal organic Despite many excellent reviews on ( i. e ., C−H functionalization) (hetero)arenes, editings via single atom insertion, deletion, or transmutations have received less attention review literature. In this review, we systematically summarize state‐of‐the‐art reactions using carbenes, with focus general mechanistic considerations applications natural product syntheses. The potential opportunities inherent challenges encountered while developing these strategies are also highlighted.

Language: Английский

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Cobalt-Catalyzed Nitrogen Atom Insertion in Arylcycloalkenes

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(49), P. 22433 - 22439

Published: Nov. 30, 2022

Developing strategies enabling the modification of underlying molecular frameworks facilitates access to underexplored chemical spaces. Skeletal editing is an emerging technology for late-stage diversification bioactive molecules. However, current state this knowledge remains undeveloped. This work describes a simple protocol that "inserts" nitrogen atom into arylcycloalkenes form corresponding N-heterocycles. The use inexpensive cobalt catalyst under aqueous and open-air conditions makes very practical. Examples compounds pharmaceutical interest complex fused ring further demonstrated potentially broad applicability methodology.

Language: Английский

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Skeletal editing of pyridines through atom-pair swap from CN to CC

Nature Chemistry, Journal Year: 2024, Volume and Issue: 16(5), P. 741 - 748

Published: Jan. 18, 2024

Abstract Skeletal editing is a straightforward synthetic strategy for precise substitution or rearrangement of atoms in core ring structures complex molecules; it enables quick diversification compounds that not possible by applying peripheral strategies. Previously reported skeletal common arenes mainly relies on carbene- nitrene-type insertion reactions rearrangements. Although powerful, efficient and applicable to late-stage heteroarene structure modification, these strategies cannot be used pyridines. Here we report the direct pyridines through atom-pair swap from CN CC generate benzenes naphthalenes modular fashion. Specifically, use sequential dearomatization, cycloaddition rearomatizing retrocycloaddition one-pot sequence transform parent into bearing diversified substituents at specific sites, as defined reaction components. Applications pyridine cores several drugs are demonstrated.

Language: Английский

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