An imine reductase that captures reactive intermediates in the biosynthesis of the indolocarbazole reductasporine

Journal of Biological Chemistry, Год журнала: 2024, Номер 300(2), С. 105642 - 105642

Опубликована: Янв. 8, 2024

Imine reductases (IREDs) and reductive aminases (RedAms) have been used in the synthesis of chiral amine products for drug manufacturing; however, little is known about their biological contexts. Here we employ structural studies site-directed mutagenesis to interrogate mechanism IRED RedE from biosynthetic pathway indolocarbazole natural product reductasporine. Co-crystal structures with substrate-mimic arcyriaflavin A reveal an extended active site cleft capable binding two molecules. Site-directed a conserved aspartate primary reveals new role this residue anchoring substrate above NADPH cofactor. Variants targeting secondary greatly reduce catalytic efficiency, while accumulating oxidized side-products. As intermediates are susceptible spontaneous oxidation, propose acts protect against autooxidation, drives catalysis through precise orientation desolvation effects. The structure its can be starting point as scaffold engineering IREDs RedAms intercept large substrates relevant industrial applications.

Язык: Английский

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Rhodium-Catalyzed Asymmetric Functionalization of Quinoxalinium Salts

Organic Letters, Год журнала: 2023, Номер 25(50), С. 8987 - 8991

Опубликована: Дек. 7, 2023

We report a rhodium-catalyzed asymmetric addition of aryl and alkenyl boronic acids to quinoxalinium salts that generates dihydroquinoxalines with high enantioselectivity. Functionalization the reaction products, dihydroquinoxaline, allows preparation tetrahydroquinoxalines various substitution patterns.

Язык: Английский

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A General Strategy for N–(Hetero)aryl Piperidine Synthesis Using Zincke Imine Intermediates

Опубликована: Окт. 11, 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, ring-closing approach via Zincke imine intermediates. This process generates pyridinium salts from wide variety pyridines and (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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Harnessing Biocatalytic Cascades to Access Pharmaceutically Relevant Piperidines

Synfacts, Год журнала: 2023, Номер 19(03), С. 0310 - 0310

Опубликована: Фев. 13, 2023

Key words biocatalysis - piperidines amine oxidase ene-imine reductase

Язык: Английский

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A Chemo-Enzymatic Dearomatization Cascade Approach to Enantioenriched Piperidines from Pyridines

Synfacts, Год журнала: 2023, Номер 19(03), С. 0293 - 0293

Опубликована: Фев. 13, 2023

Key words amine oxidase - ene-imine reductase chemo-enzymatic dearomatization piperidine synthesis

Язык: Английский

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