Imine Reductase-Catalyzed Synthesis of a Key Intermediate of Avacopan: Enzymatic Oxidative Kinetic Resolution with Ex Situ Recovery and Dynamic Kinetic Reduction Strategies toward 2,3-Disubstituted Piperidine

Organic Process Research & Development, Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

Язык: Английский

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Synthesis of Chiral 3-Piperidin-2-ones and 3-Piperidines via Ni-Catalyzed Reductive Coupling

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Май 13, 2025

Herein, an approach to a wide range of chiral 3-substituted δ-lactams from reductive coupling Csp2-hybridized organohalides and 3-chloro-δ-lactams was described, the products are versatile precursors for accessing enantioenriched piperidines. The utility reaction highlighted by economic synthesis Preclamol Niraparib. Notably, modified Bilm ligands were found be key factor reactivity enantioselectivity.

Язык: Английский

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Recent Progresses in the Catalytic Stereoselective Dearomatization of Pyridines

Molecules, Год журнала: 2023, Номер 28(17), С. 6186 - 6186

Опубликована: Авг. 22, 2023

1,2- and 1,4-dihydropyridines N-substituted 2-pyridones are very important structural motifs due to their synthetic versatility vast presence in a variety of alkaloids bioactive molecules. In this article, we gather summarize the catalytic stereoselective synthesis partially hydrogenated pyridines pyridones via dearomative reactions pyridine derivatives up mid-2023. The material is fundamentally organized according type reactivity (electrophilic/nucleophilic) nucleus. further sub-divided taking into account nucleophilic species when dealing with electrophilic considering manifold behaving as nucleophiles at nitrogen site. latter more recent approach allows for an unconventional entry chiral 2- 4-pyridones non-racemic form.

Язык: Английский

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Biocatalysis in Drug Design: Engineered Reductive Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple Stereocenters

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(40), С. 22041 - 22046

Опубликована: Окт. 2, 2023

Novel building blocks are in constant demand during the search for innovative bioactive small molecule therapeutics by enabling construction of structure-activity-property-toxicology relationships. Complex chiral molecules containing multiple stereocenters an important component compound library expansion but can be difficult to access traditional organic synthesis. Herein, we report a biocatalytic process specific diastereomer amine block used drug discovery. A reductive aminase (RedAm) was engineered following structure-guided mutagenesis strategy produce desired isomer. The RedAm (IR-09 W204R) able generate (S,S,S)-isomer 3 45% conversion and 95% ee from racemic ketone 2. Subsequent palladium-catalyzed deallylation yielded target primary 4 73% yield. This biocatalyst at preparative scale represents potential starting point further engineering development.

Язык: Английский

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Application of Imine Reductase in Bioactive Chiral Amine Synthesis

Organic Process Research & Development, Год журнала: 2024, Номер 28(8), С. 3035 - 3054

Опубликована: Июль 11, 2024

Язык: Английский

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Modular Construction of Chiral Aminopiperidine via Palladium-Catalyzed Hydroamination of 1,2-Dihydropyridine

Organic Letters, Год журнала: 2025, Номер unknown

Опубликована: Фев. 12, 2025

In this study, we describe a generally straightforward methodology for the catalytic synthesis of chiral aminopiperidine from pyridine and azoles. The key step was palladium-catalyzed regioselective N–H insertion into double bond 1,2-dihydropyridine. This hydroamination exhibits wide substrate scope functional group compatibility. Mechanistic study revealed that C═C followed cis addition. utility protocol demonstrated by diverse functionalization enamine bond.

Язык: Английский

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Deconstruction of Desacetamidocolchicine’s B Ring Reveals a Class 3 Atropisomeric AC Ring with Tubulin Binding Properties

The Journal of Organic Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Май 27, 2025

Colchicine is one of the oldest known microtubule-targeting agents and also represents a classic example axial chirality atropisomerism in medicine. This because colchicine's axially chiral methoxytropone-trimethoxybenzene (called AC ring) directly responsible for tubulin binding thermodynamically set into requisite aR form by point acetamido group on its B ring. Indeed, desacetamidocolchicine (DAAC), colchicine analogue without group, racemizes within minutes. Herein, we describe synthesis as well physical biological characterization series ring-containing molecules that represent B-ring further deconstructed variants DAAC. These studies revealed novel with an ring highly stable to epimerization based not thermodynamic stabilization but rather high rotational barrier energy. Profiling dihedral angles were carried out computationally experimentally using vibrational circular dichroism, demonstrating ground state new differ significantly from those colchicine. However, despite this difference, molecule retained antiproliferative, tubulin-binding, polymerization inhibitory activity.

Язык: Английский

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Engineered Biocatalysts for Enantioselective Reductive Aminations of Cyclic Secondary Amines

ChemCatChem, Год журнала: 2023, Номер 15(11)

Опубликована: Март 22, 2023

Abstract Reductive aminases (RedAms) have recently emerged as promising biocatalysts for the synthesis of chiral secondary amines by coupling primary with aldehydes/ketones. However, access to tertiary remains more problematic, particularly when ketones amines. Here we show that scope these enzymes can be extended allow selective reductive aminations cyclic amines, such piperidines and morpholines, both aldehydes ketones. These biotransformations provide important motifs found in active pharmaceutical ingredients other bioactive molecules. RedAm‐361, discovered from a metagenomic library, was engineered via directed evolution efficient carbonyl partners, including dynamic kinetic resolutions α‐functionalized enantioselective amination RedAms now serve valuable scaffolds engineering industrial produce key intermediates.

Язык: Английский

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Palladium‐Catalyzed Arylation of Endocyclic 1‐Azaallyl Anions: Concise Synthesis of Unprotected Enantioenriched cis‐2,3‐Diarylpiperidines

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(36)

Опубликована: Июль 18, 2023

Unprotected cis-2,3-diarylpiperidines are synthesized through an unprecedented palladium-catalyzed cross-coupling reaction between aryl halides and elusive endocyclic 1-azaallyl anions. These intermediates generated in situ by the deprotonation of 2-aryl-1-piperideines, precursors that readily prepared two operations from simple piperidines. An asymmetric version this with (2R, 3R)-iPr-BI-DIME as ligand provides products moderate to good yields enantioselectivities. This study significantly expands synthetic utility

Язык: Английский

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A General Strategy for N-(Hetero)arylpiperidine Synthesis Using Zincke Imine Intermediates

Journal of the American Chemical Society, Год журнала: 2023, Номер 146(1), С. 936 - 945

Опубликована: Дек. 28, 2023

Methods to synthesize diverse collections of substituted piperidines are valuable due the prevalence this heterocycle in pharmaceutical compounds. Here, we present a general strategy access N-(hetero)arylpiperidines using pyridine ring-opening and ring-closing approach via Zincke imine intermediates. This process generates pyridinium salts from wide variety pyridines (heteroaryl)anilines; hydrogenation reactions nucleophilic additions then N-(hetero)arylpiperidine derivatives. We successfully applied high-throughput experimentation (HTE) pharmaceutically relevant (heteroaryl)anilines as inputs developed one-pot anilines nucleophiles salt-forming processes. is viable for generating piperidine libraries applications such convergent coupling complex fragments.

Язык: Английский

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