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Amine Transaminases in Multi-Step One-Pot Reactions
KTH, School of Biotechnology (BIO), Industrial Biotechnology.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amine transaminases are enzymes that catalyze the mild and selective formation of primary amines, which are useful building blocks for biologically active compounds and natural products. In order to make the production of these kinds of compounds more efficient from both a practical and an environmental point of view, amine transaminases were incorporated into multi-step one-pot reactions. With this kind of methodology there is no need for isolation of intermediates, and thus unnecessary work-up steps can be omitted and formation of waste is prevented. Amine transaminases were successfully combined with other enzymes for multi-step synthesis of valuable products: With ketoreductases all four diastereomers of a 1,3-amino alcohol could be obtained, and the use of a lipase allowed for the synthesis of natural products in the form of capsaicinoids. Amine transaminases were also successfully combined with metal catalysts based on palladium or copper. This methodology allowed for the amination of alcohols and the synthesis of chiral amines such as the pharmaceutical compound Rivastigmine. These examples show that the use of amine transaminases in multi-step one-pot reactions is possible, and hopefully this concept can be further developed and applied to make industrial processes more sustainable and efficient in the future.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2017. , p. 58
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 2017:3
Keywords [en]
Biocatalysis, enzyme, amine transaminase, ω-transaminase, amination, primary amine, chiral amine, chemoenzymatic, green chemistry, synthesis, cascade
National Category
Biochemistry and Molecular Biology
Research subject
Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-199646ISBN: 978-91-7729-254-8 (print)OAI: oai:DiVA.org:kth-199646DiVA, id: diva2:1064519
Public defence
2017-02-17, Kollegiesalen, Brinellvägen 8, KTH, 10:00 (English)
Opponent
Supervisors
Note

QC 20170113

Available from: 2017-01-13 Created: 2017-01-12 Last updated: 2017-01-13Bibliographically approved
List of papers
1. Selective Access to All Four Diastereomers of a 1,3-Amino Alcohol by Combination of a Keto Reductase- and an Amine Transaminase-Catalysed Reaction
Open this publication in new window or tab >>Selective Access to All Four Diastereomers of a 1,3-Amino Alcohol by Combination of a Keto Reductase- and an Amine Transaminase-Catalysed Reaction
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2015 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 357, no 8, p. 1808-1814Article in journal (Refereed) Published
Abstract [en]

The biocatalytic synthesis of chiral amines has become a valuable addition to the chemists' tool-box. However, the efficient asymmetric synthesis of functionalised amines bearing more than one stereocentre, such as 1,3-amino alcohols, remains challenging. By employing a keto reductase (KRED) and two enantiocomplementary amine transaminases (ATA), we developed a biocatalytic route towards all four diastereomers of 4-amino-1-phenylpentane-2-ol as a representative molecule bearing the 1,3-amino alcohol functionality. Starting from a racemic hydroxy ketone, a kinetic resolution using an (S)-selective KRED provided optically active hydroxy ketone (86% ee) and the corresponding diketone. Further transamination of the hydroxy ketone was performed by either an (R)- or an (S)-selective ATA, yielding the (2R,4R)- and (2R,4S)-1,3-amino alcohol diastereomers. The remaining two diastereomers were accessible in two subsequent asymmetric steps: the diketone was reduced regio- and enantioselectively by the same KRED, which yielded the (S)-configured hydroxy ketone. Eventually, the subsequent transamination of the crude product with (R)- and (S)-selective ATAs yielded the remaining (2S,4R)and (2S,4S)-diastereomers, respectively.

Keywords
amine transaminase, amino alcohols, enzyme catalysis, keto reductase
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-172237 (URN)10.1002/adsc.201500214 (DOI)000355235700020 ()2-s2.0-84930202995 (Scopus ID)
Note

QC 20150825

Available from: 2015-08-25 Created: 2015-08-14 Last updated: 2017-12-04Bibliographically approved
2. Total Synthesis of Capsaicin Analogues from Lignin-Derived Compounds by Combined Heterogeneous Metal, Organocatalytic and Enzymatic Cascades in One Pot
Open this publication in new window or tab >>Total Synthesis of Capsaicin Analogues from Lignin-Derived Compounds by Combined Heterogeneous Metal, Organocatalytic and Enzymatic Cascades in One Pot
2014 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 356, no 9, p. 2113-2118Article in journal (Refereed) Published
Abstract [en]

The total synthesis of capsaicin analogues was performed in one pot, starting from compounds that can be derived from lignin. Heterogeneous palladium nanoparticles were used to oxidise alcohols to aldehydes, which were further converted to amines by an enzyme cascade system, including an amine transaminase. It was shown that the palladium catalyst and the enzyme cascade system could be successfully combined in the same pot for conversion of alcohols to amines without any purification of intermediates. The intermediate vanillyl-amine, prepared with the enzyme cascade system, could be further converted to capsaicin analogues without any purification using either fatty acids and a lipase, or Schotten-Baumann conditions, in the same pot. An aldol compound (a simple lignin model) could also be used as starting material for the synthesis of capsaicin analogues. Using l-alanine as organocatalyst, vanillin could be obtained by a retro-aldol reaction. This could be combined with the enzyme cascade system to convert the aldol compound to vanillylamine in a one-step one-pot reaction.

Keywords
aldol reaction, amine transferase, biocatalysis, capsaicin analogues, oxidation, palladium, renewable resources
National Category
Bioprocess Technology
Identifiers
urn:nbn:se:kth:diva-148291 (URN)10.1002/adsc.201301148 (DOI)000337609400023 ()2-s2.0-84902535619 (Scopus ID)
Funder
Swedish Research CouncilVinnova
Note

QC 20140807

Available from: 2014-08-07 Created: 2014-08-05 Last updated: 2017-12-05Bibliographically approved
3. Chemoenzymatic amination of alcohols by combining oxidation catalysts with transaminases in one pot
Open this publication in new window or tab >>Chemoenzymatic amination of alcohols by combining oxidation catalysts with transaminases in one pot
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Chemoenzymatic methods for the amination of alcohols have been developed. The reactions were performed in a one-pot two-step fashion, where the alcohol starting material was first oxidized to the corresponding carbonyl compound and then subsequently converted to the amine product with an enzymatic system based on an amine transaminase. The enzyme system was able to operate in a water/organic solvent two-phase system in the presence of either a heterogeneous palladium(0) catalyst or a homogeneous copper(I) catalyst. High conversions to the product amines were achieved for a range of substituted benzyl alcohols and similar compounds, but unfortunately the use of aliphatic alcohols resulted in lower conversions and secondary alcohols could not be converted to the corresponding amines with this methodology.

Keywords
Biocatalysis, enzyme, amine transaminase, ω-transaminase, green chemistry, palladium, copper, TEMPO
National Category
Organic Chemistry
Research subject
Biotechnology
Identifiers
urn:nbn:se:kth:diva-199644 (URN)
Note

QC 20170117

Available from: 2017-01-12 Created: 2017-01-12 Last updated: 2017-01-23Bibliographically approved
4. Integrated Heterogeneous Metal/Enzymatic Multiple Relay Catalysis for Eco-Friendly and Asymmetric Synthesis
Open this publication in new window or tab >>Integrated Heterogeneous Metal/Enzymatic Multiple Relay Catalysis for Eco-Friendly and Asymmetric Synthesis
Show others...
2016 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 6, p. 3932-3940Article in journal (Refereed) Published
Abstract [en]

Organic synthesis is in general performed using stepwise transformations where isolation and purification of key intermediates is often required prior to further reactions. Herein we disclose the concept of integrated heterogeneous metal/enzymatic multiple relay catalysis for eco-friendly and asymmetric synthesis of valuable molecules (e.g., amines and amides) in one-pot using a combination of heterogeneous metal and enzyme catalysts. Here reagents, catalysts, and different conditions can be introduced throughout the one-pot procedure involving multistep catalytic tandem operations. Several novel cocatalytic relay sequences (reductive amination/amidation, aerobic oxidation/reductive amination/amidation, reductive amination/kinetic resolution and reductive amination/dynamic kinetic resolution) were developed. They were next applied to the direct synthesis of various biologically and optically active amines or amides in one-pot from simple aldehydes, ketones, or alcohols, respectively.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
Keywords
heterogeneous metal, enzyme, reductive amination, relay catalysis, heterogeneous catalysis, tandem reactions, kinetic resolution, dynamic kinetic resolution
National Category
Organic Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kth:diva-187377 (URN)10.1021/acscatal.6b01031 (DOI)000377326700066 ()2-s2.0-84973911460 (Scopus ID)
Note

QC 20160623

Available from: 2016-05-22 Created: 2016-05-22 Last updated: 2017-11-30Bibliographically approved

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