A biocatalytic redox cascade approach for one-pot deracemization of carboxyl-substituted tetrahydroisoquinolines by stereoinversion

Ju, Shuyun; Qian, Mingxin; Li, Jing; Xu, Gang; Yang, Lirong; Wu, Jianping

doi:10.1039/c9gc02795e

Cited by 13 publications

(10 citation statements)

References 45 publications

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“…We reasoned that biocatalytic oxidation, using an amine oxidase (AmOx), of the THP in situ would generate the corresponding dihydropyridiniums (DHPs), generating an activated C=C bond conjugated to the C=N bond, which could then be reduced with these biocatalysts to generate a cascade to the desired 3-and 3,4-substituted piperidines. This cascade would complement previously reported amine oxidase AmOx-IRED deracemisation processes in which only amine oxidation and C=N bond reduction take place (24,25).…”

Section: Introductionsupporting

confidence: 82%

Synthesis of stereoenriched piperidines via chemo-enzymatic dearomatization of activated pyridines

Harawa

Thorpe

Marshall

et al. 2021

Preprint

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The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature has yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of the antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.

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Section: Introductionsupporting

confidence: 82%

Synthesis of stereoenriched piperidines via chemo-enzymatic dearomatization of activated pyridines

Harawa

Thorpe

Marshall

et al. 2021

Preprint

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“…Comparison of this newly identified Cg ADH with Lb ADH and Tb ADH was performed (Table ). Lb ADH and Tb ADH belong to Mg 2+ -dependent SDR and Zn 2+ -dependent medium-chain dehydrogenase/reductase (MDR), respectively. , However, Cg ADH was not dependent on any metal ions. The oxidative activity toward isopropanol and the reductive activity toward the acetone of Lb ADH were 0.43 and 3.56 U·mg –1 , respectively, with an oxidative/reductive ratio of ca.…”

Section: Resultsmentioning

confidence: 99%

“…However, few enzymes with self-sufficient NADPH regeneration capability have been identified. 20,21 To the best of our knowledge, LbADH from Lactobacillus brevis and TbADH from Thermoanaerobacter brockii were the two enzymes with selfsufficient NADPH regeneration. NADPH-dependent enzymes were evolutionarily distinct with the NADH-dependent enzymes and usually display a wider substrate spectrum.…”

Section: ■ Introductionmentioning

confidence: 99%

Novel Alcohol Dehydrogenase CgADH from Candida glabrata for Stereocomplementary Reduction of Bulky–Bulky Ketones Featuring Self-Sufficient NADPH Regeneration

Sun

Zhang

Yin

et al. 2022

ACS Sustainable Chem. Eng.

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Bioreduction of ketones with self-sufficient cofactor regeneration is green and sustainable for the synthesis of chiral secondary alcohols. In this study, a novel alcohol dehydrogenase CgADH was identified from Candida glabrata through genome hunting, exhibiting high oxidation and reduction activities. Conserved motif analysis revealed that CgADH belongs to the extended SDR subfamily. CgADH is NADP(H) dependent and displays the highest activity at pH 5.0 and 65 °C. Substrate spectrum analysis indicated that CgADH exhibited high specificity toward 2-propanol and 2,3butanediol. Rational engineering of CgADH was performed to modulate its stereoselectivity in the asymmetric reduction of bulky−bulky ketones. Two stereocomplementary mutants, C244A and V222G/C244N, were obtained with e.e. values of 99.6% (R) or 94.5% (S) toward (4-chlorophenyl)-pyridin-2-ylmethanone, respectively. Moreover, the catalytic efficiency (k cat /K M ) of C244A and V222G/C244N increased by 70-and 25-fold compared with the wild type (WT), respectively. C244A and V222G/ C244N also displayed significantly enhanced catalytic efficiency and stereoselectivity toward diaryl ketones with different substituents. Using isopropanol both as a co-substrate and as a co-solvent, a concise selfsufficient NADPH regeneration system was developed to demonstrate the advantage of CgADH. This study provides evidence of the application potential of the newly identified CgADH in the preparation of enantiopure diaryl alcohols with low byproducts and E factor.

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“…Cyclic cascades require recycling of some intermediates to the starting materials, for example in deracemization reactions. An excellent recent example of this is the deracemization of tetrahydroisoquinolines [34]. This one-pot enzymatic cascade improved on a previously described chemoenzymatic reaction [35].…”

Section: Uses and Categorisation Of Cascade Reactionsmentioning

confidence: 94%

Using enzyme cascades in biocatalysis: Highlight on transaminases and carboxylic acid reductases

Cutlan

Rose²,

Isupov³

et al. 2020

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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A biocatalytic redox cascade approach for one-pot deracemization of carboxyl-substituted tetrahydroisoquinolines by stereoinversion

Abstract: We describe a biocatalytic redox cascade reaction for one-pot enantioselective synthesis of (S)-carboxyl substituted tetrahydroisoquinolines.

Cited by 13 publications

References 45 publications

Synthesis of stereoenriched piperidines via chemo-enzymatic dearomatization of activated pyridines

Synthesis of stereoenriched piperidines via chemo-enzymatic dearomatization of activated pyridines

Novel Alcohol Dehydrogenase CgADH from Candida glabrata for Stereocomplementary Reduction of Bulky–Bulky Ketones Featuring Self-Sufficient NADPH Regeneration

Using enzyme cascades in biocatalysis: Highlight on transaminases and carboxylic acid reductases

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