Interrogation of Enantioselectivity in the Photomediated Ring Contractions of Saturated Heterocycles

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

We recently reported a chiral phosphoric acid (CPA) catalyzed enantioselective photomediated ring contraction of piperidines and other saturated heterocycles. By extruding single heteroatom from ring, this transformation builds desirable C(sp3)–C(sp3) bonds in the contracted products; however, origins enantioselectivity remain poorly understood. In work, has been explored across an expanded structurally diverse substrate scope, revealing wide range enantioselectivities (0–99%) using two distinct CPA catalysts. Mechanistic investigations support rate-determining excitation that generates short-lived achiral intermediates are intercepted by enantiodetermining closure. The effects competitive uncatalyzed reactivity light-driven reversibility closure on have elucidated. Statistical models were built regressing scope against key structural features products for both resultant suggested factors influence response each catalyst enabled rational modification pharmaceutically relevant target molecule to improve enantioselectivity. Finally, density functional theory (DFT)-based transition state analysis identified noncovalent interactions with correlated unique selectivity-relevant uncovered through statistical modeling. Our findings not only offer comprehensive insight into system but should also aid future development related CPA-catalyzed reactions.

Language: Английский

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Selective nitrogen insertion into aryl alkanes

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

Published: July 17, 2024

Abstract Molecular structure-editing through nitrogen insertion offers more efficient and ingenious pathways for the synthesis of nitrogen-containing compounds, which could benefit development synthetic chemistry, pharmaceutical research, materials science. Substituted amines, especially alkyl heterocyclic are widely found in nature products drugs. Generally, accessing these compounds requires multiple steps, result low efficiency. In this work, a molecular editing strategy is used to realize using aryl alkanes as starting materials. Using derivatives O -tosylhydroxylamine source, method enables precise into C sp 2 -C 3 bond alkanes. Notably, further applications demonstrate that be prepare bioactive molecules with good efficiency modify skeleton Furthermore, plausible reaction mechanism involving transformation carbocation imine intermediates has been proposed based on results control experiments.

Language: Английский

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Recent Advances in Single-Electron Reduction-Induced Ring Opening of N-Acyl Cyclic Amines

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

Published: Jan. 16, 2025

Abstract Cyclic amines represent ubiquitous structural motifs in organic chemistry, prominently featured natural products and pharmaceuticals. The development of synthetic methodologies targeting cyclic has attracted considerable interest, given their significance medicinal chemistry. These transformations can be broadly categorized into two main types: (1) peripheral modification (2) skeletal remodeling. Recent advancements late-stage C–H functionalization have showcased the potential strategies. Conversely, remodeling, particularly through ring opening amines, emerged as a powerful approach to access structurally diverse amines. Ring initiated by C–N bond cleavage, predominantly relies on two-electron mechanisms. Strained readily undergo such transformations, while those with larger-membered ring, like pyrrolidines, present greater challenges. Oxidative von Braun-type approaches facilitated heterolytic offering broad applicability across various In contrast, reductive approaches, which enable homolytic provide unique radical-mediated transformations. This short review highlights recent progress single electron reduction induced ring-opening methodologies, focusing α-aminoketyl radical generation for selective amide cleavage. Advances aziridines, azetidines, other are discussed, along implications future prospects. 1 Introduction 2 Opening Aziridines 2.1 Hydrogenation Alkylation 2.2 Isomerization 2.3 Arylation 3 Azetidines 4 Pyrrolidines Other Amines 5 Conclusion Outlook

Language: Английский

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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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Cheminformatic Analysis of Core-Atom Transformations in Pharmaceutically Relevant Heteroaromatics

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

Heteroaromatics are the basis for many pharmaceuticals. The ability to modify these structures through selective core-atom transformations, or "skeletal edits", can dramatically expand landscape drug discovery and development. However, despite importance of modifications, quantitative impact such transformations on accessible chemical space remains undefined. Here, we report a cheminformatic platform analyze which skeletal edits would most increase access novel space. This study underscores significance emerging single multiple heteroaromatics in enhancing diversity, example, at late-stage campaign. Our findings provide framework prioritizing modifications heteroaromatic structural motifs, calling development new methods achieve types transformations.

Language: Английский

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New Efficient D‐π‐A and A‐π‐A Structured Type I Radical Photoinitiators for Additive Manufacturing Nanomaterials Preparation

Advanced Materials Technologies, Journal Year: 2025, Volume and Issue: unknown

Published: March 27, 2025

Abstract Here, a group of new type‐I radical photoinitiators, 1,1‐dimethoxy‐1‐phenylpropan‐2‐one, and its derivative are presented. Because the extended conjugation system, their absorption is strongly redshifted, activating them under visible light; best derivatives active even at 470 nm. Thanks to use aldol condensation for synthesis compounds, it possible obtain an entire library compounds photopolymerization processes. The developed photoinitiators found be effective in photoinitiating free‐radical polymerization acrylate metacrylate monomers. Owing excellent activities, presented can used 3D printing applications. research described here indicates that properties enable efficient preparation nanocomposites vat printing. This provides significant advancement development one‐component light.

Language: Английский

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Ring Contraction of Saturated Cyclic Amines and Rearrangement of Acyclic Amines Through Their Corresponding Hydroxylamines

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 23, 2024

Compared to modifications at the molecular periphery, skeletal adjustments present greater challenges. Within this context, rearrangement technology stands out for its significant advantages in rapidly achieving structural diversity. Yet, development of ring contraction saturated cyclic amines remains exceedingly rare. While most existing methods rely on specific substitution patterns achieve contraction, there is a persistent demand more general strategy substitution-free amines. To address issue, we report B(C

Language: Английский

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Homologation of Alkenyl Carbonyls via a Cyclopropanation/Light‐Mediated Selective C‐C Cleavage Strategy

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

We report herein our studies on the direct photoactivation of carbonyl cyclopropanes to give biradical intermediates, leading selective cleavage more substituted carbon-carbon bond. Depending substrate structure, extended alkenes were isolated or directly reacted in a photo-Nazarov process bicyclic products. Based these results, unified reductive ring-opening reaction was developed by using diphenyl disulfide as hydrogen atom transfer (HAT) reagent. By performing sequential cyclopropanation/selective ring opening reaction, we achieved CH

Language: Английский

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Ring Contraction of Saturated Cyclic Amines and Rearrangement of Acyclic Amines Through Their Corresponding Hydroxylamines

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(40)

Published: July 2, 2024

Abstract Compared to modifications at the molecular periphery, skeletal adjustments present greater challenges. Within this context, rearrangement technology stands out for its significant advantages in rapidly achieving structural diversity. Yet, development of ring contraction saturated cyclic amines remains exceedingly rare. While most existing methods rely on specific substitution patterns achieve contraction, there is a persistent demand more general strategy substitution‐free amines. To address issue, we report B(C 6 F 5 ) 3 ‐catalyzed hydroxylamines with hydrosilanes. This methodology, when combined N‐hydroxylation amines, enables regioselective and proves equally effective rapid reorganization acyclic amine skeletons. By this, direct scaffold hopping drug molecules strategic deletion carbon atoms are achieved mild manner. Based mechanistic experiments density functional theory calculations, possible mechanism process proposed.

Language: Английский

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Homologation of Alkenyl Carbonyls via a Cyclopropanation/Light‐Mediated Selective C‐C Cleavage Strategy

Angewandte Chemie, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

Abstract We report herein our studies on the direct photoactivation of carbonyl cyclopropanes to give biradical intermediates, leading selective cleavage more substituted carbon‐carbon bond. Depending substrate structure, extended alkenes were isolated or directly reacted in a photo‐Nazarov process bicyclic products. Based these results, unified reductive ring‐opening reaction was developed by using diphenyl disulfide as hydrogen atom transfer (HAT) reagent. By performing sequential cyclopropanation/selective ring opening reaction, we achieved CH 2 insertion into α,β bond both acyclic and cyclic unsaturated compounds. Our protocol provides further tool for modification carbon framework organic compounds, complementing recent progress “skeletal editing”.

Language: Английский

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