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Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis

Efficient access to the morphinan scaffold remains a major challenge in both synthetic chemistry and biotechnology. Here, a biomimetic chemo-enzymatic strategy to synthesize the natural promorphinan intermediate (+)-salutaridine is demonstrated. By combining early-stage organic synthesis with enzyma...

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Autores principales: Cigan, Emmanuel, Pletz, Jakob, Berger, Sarah A., Hierzberger, Bettina, Grilec-Zlamal, Michael, Steiner, Alexander, Oroz-Guinea, Isabel, Kroutil, Wolfgang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10510765/
https://www.ncbi.nlm.nih.gov/pubmed/37736642
http://dx.doi.org/10.1039/d3sc02304d
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author Cigan, Emmanuel
Pletz, Jakob
Berger, Sarah A.
Hierzberger, Bettina
Grilec-Zlamal, Michael
Steiner, Alexander
Oroz-Guinea, Isabel
Kroutil, Wolfgang
author_facet Cigan, Emmanuel
Pletz, Jakob
Berger, Sarah A.
Hierzberger, Bettina
Grilec-Zlamal, Michael
Steiner, Alexander
Oroz-Guinea, Isabel
Kroutil, Wolfgang
author_sort Cigan, Emmanuel
collection PubMed
description Efficient access to the morphinan scaffold remains a major challenge in both synthetic chemistry and biotechnology. Here, a biomimetic chemo-enzymatic strategy to synthesize the natural promorphinan intermediate (+)-salutaridine is demonstrated. By combining early-stage organic synthesis with enzymatic asymmetric key step transformations, the prochiral natural intermediate 1,2-dehydroreticuline was prepared and subsequently stereoselectively reduced by the enzyme 1,2-dehydroreticuline reductase obtaining (R)-reticuline in high ee and yield (>99% ee, up to quant. conversion, 92% isol. yield). In the final step, membrane-bound salutaridine synthase was used to perform the selective ortho-para phenol coupling to give (+)-salutaridine. The synthetic route shows the potential of combining early-stage advanced organic chemistry to minimize protecting group techniques with late-stage multi-step biocatalysis to provide an unprecedented access to the medicinally important compound class of promorphinans.
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spelling pubmed-105107652023-09-21 Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis Cigan, Emmanuel Pletz, Jakob Berger, Sarah A. Hierzberger, Bettina Grilec-Zlamal, Michael Steiner, Alexander Oroz-Guinea, Isabel Kroutil, Wolfgang Chem Sci Chemistry Efficient access to the morphinan scaffold remains a major challenge in both synthetic chemistry and biotechnology. Here, a biomimetic chemo-enzymatic strategy to synthesize the natural promorphinan intermediate (+)-salutaridine is demonstrated. By combining early-stage organic synthesis with enzymatic asymmetric key step transformations, the prochiral natural intermediate 1,2-dehydroreticuline was prepared and subsequently stereoselectively reduced by the enzyme 1,2-dehydroreticuline reductase obtaining (R)-reticuline in high ee and yield (>99% ee, up to quant. conversion, 92% isol. yield). In the final step, membrane-bound salutaridine synthase was used to perform the selective ortho-para phenol coupling to give (+)-salutaridine. The synthetic route shows the potential of combining early-stage advanced organic chemistry to minimize protecting group techniques with late-stage multi-step biocatalysis to provide an unprecedented access to the medicinally important compound class of promorphinans. The Royal Society of Chemistry 2023-08-24 /pmc/articles/PMC10510765/ /pubmed/37736642 http://dx.doi.org/10.1039/d3sc02304d Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Cigan, Emmanuel
Pletz, Jakob
Berger, Sarah A.
Hierzberger, Bettina
Grilec-Zlamal, Michael
Steiner, Alexander
Oroz-Guinea, Isabel
Kroutil, Wolfgang
Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis
title Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis
title_full Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis
title_fullStr Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis
title_full_unstemmed Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis
title_short Concise synthesis of (R)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis
title_sort concise synthesis of (r)-reticuline and (+)-salutaridine by combining early-stage organic synthesis and late-stage biocatalysis
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10510765/
https://www.ncbi.nlm.nih.gov/pubmed/37736642
http://dx.doi.org/10.1039/d3sc02304d
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