A cascade reaction for the synthesis of d-fagomine precursor revisited: Kinetic insight and understanding of the system

The synthesis of aldol adduct (3S,4R)-6-[(benzyloxycarbonyl)amino]-5,6-dideoxyhex-2-ulose, a precursor of the interesting dietary supplement, iminosugar d-fagomine, was studied in a cascade reaction with three enzymes starting from Cbz-N-3-aminopropanol. This system was studied previously using a st...

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Autores: Sudar, Martina, Česnik, Morana, Clapés Saborit, Pere, Pohl, Martina, Vasić-Rački, Đurđa, Findrik Blažević, Zvjezdana
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/236913
Acceso en línea:http://hdl.handle.net/10261/236913
Access Level:acceso abierto
Palabra clave:Cascade reaction
d-fagomine precursor
Mathematical model
Reaction optimization
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spelling A cascade reaction for the synthesis of d-fagomine precursor revisited: Kinetic insight and understanding of the systemSudar, MartinaČesnik, MoranaClapés Saborit, PerePohl, MartinaVasić-Rački, ĐurđaFindrik Blažević, ZvjezdanaCascade reactiond-fagomine precursorMathematical modelReaction optimizationddc:540ddc:540The synthesis of aldol adduct (3S,4R)-6-[(benzyloxycarbonyl)amino]-5,6-dideoxyhex-2-ulose, a precursor of the interesting dietary supplement, iminosugar d-fagomine, was studied in a cascade reaction with three enzymes starting from Cbz-N-3-aminopropanol. This system was studied previously using a statistical optimization method which enabled a 79 % yield of the aldol adduct with a 10 % yield of the undesired amino acid by-product. Here, a kinetic model of the cascade, including enzyme operational stability decay rate and the undesired overoxidation of the intermediate product, was developed. The validated model was instrumental in the optimization of the cascade reaction in the batch reactor. Simulations were carried out to determine the variables with the most significant impact on substrate conversion and product yield. As a result, process conditions were found that provided the aldol adduct in 92 % yield with only 0.7 % yield of the amino acid in a one-pot one-step reaction. Additionally, compared to previous work, this improved process outcome was achieved at lower concentrations of two enzymes used in the reaction. With this study the advantages are demonstrated of a modelling approach in developing complex biocatalytical processes. Mathematical models enable better understanding of the interactions of variables in the investigated system, reduce cost, experimental efforts in the lab and time necessary to obtain results since the simulations are carried out in silico.The authors wish to acknowledge the support of the Croatian Ministry of Science Education and Sports and the Spanish National Research Council in the Frame of the ERA-IB Project (EIB. 10.012.MicroTechEnz, ERA-IB MICINN PIM2010EEI-00607), the Ministerio de Economía y Competitividad (MINECO) and the Fondo Europeo de Desarrollo Regional (FEDER) (grant no. RTI2018-094637-B-I00).Peer reviewedElsevierMinisterio de Economía y Competitividad (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202120212021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/236913reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#MICIU/ICTI2017-2020/RTI2018-094637-B-I00https://doi.org/10.1016/j.nbt.2021.02.004Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2369132026-05-22T06:33:51Z
dc.title.none.fl_str_mv A cascade reaction for the synthesis of d-fagomine precursor revisited: Kinetic insight and understanding of the system
title A cascade reaction for the synthesis of d-fagomine precursor revisited: Kinetic insight and understanding of the system
spellingShingle A cascade reaction for the synthesis of d-fagomine precursor revisited: Kinetic insight and understanding of the system
Sudar, Martina
Cascade reaction
d-fagomine precursor
Mathematical model
Reaction optimization
ddc:540
ddc:540
title_short A cascade reaction for the synthesis of d-fagomine precursor revisited: Kinetic insight and understanding of the system
title_full A cascade reaction for the synthesis of d-fagomine precursor revisited: Kinetic insight and understanding of the system
title_fullStr A cascade reaction for the synthesis of d-fagomine precursor revisited: Kinetic insight and understanding of the system
title_full_unstemmed A cascade reaction for the synthesis of d-fagomine precursor revisited: Kinetic insight and understanding of the system
title_sort A cascade reaction for the synthesis of d-fagomine precursor revisited: Kinetic insight and understanding of the system
dc.creator.none.fl_str_mv Sudar, Martina
Česnik, Morana
Clapés Saborit, Pere
Pohl, Martina
Vasić-Rački, Đurđa
Findrik Blažević, Zvjezdana
author Sudar, Martina
author_facet Sudar, Martina
Česnik, Morana
Clapés Saborit, Pere
Pohl, Martina
Vasić-Rački, Đurđa
Findrik Blažević, Zvjezdana
author_role author
author2 Česnik, Morana
Clapés Saborit, Pere
Pohl, Martina
Vasić-Rački, Đurđa
Findrik Blažević, Zvjezdana
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cascade reaction
d-fagomine precursor
Mathematical model
Reaction optimization
ddc:540
ddc:540
topic Cascade reaction
d-fagomine precursor
Mathematical model
Reaction optimization
ddc:540
ddc:540
description The synthesis of aldol adduct (3S,4R)-6-[(benzyloxycarbonyl)amino]-5,6-dideoxyhex-2-ulose, a precursor of the interesting dietary supplement, iminosugar d-fagomine, was studied in a cascade reaction with three enzymes starting from Cbz-N-3-aminopropanol. This system was studied previously using a statistical optimization method which enabled a 79 % yield of the aldol adduct with a 10 % yield of the undesired amino acid by-product. Here, a kinetic model of the cascade, including enzyme operational stability decay rate and the undesired overoxidation of the intermediate product, was developed. The validated model was instrumental in the optimization of the cascade reaction in the batch reactor. Simulations were carried out to determine the variables with the most significant impact on substrate conversion and product yield. As a result, process conditions were found that provided the aldol adduct in 92 % yield with only 0.7 % yield of the amino acid in a one-pot one-step reaction. Additionally, compared to previous work, this improved process outcome was achieved at lower concentrations of two enzymes used in the reaction. With this study the advantages are demonstrated of a modelling approach in developing complex biocatalytical processes. Mathematical models enable better understanding of the interactions of variables in the investigated system, reduce cost, experimental efforts in the lab and time necessary to obtain results since the simulations are carried out in silico.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/236913
url http://hdl.handle.net/10261/236913
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
MICIU/ICTI2017-2020/RTI2018-094637-B-I00
https://doi.org/10.1016/j.nbt.2021.02.004
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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