WO2008028526A1 - Procédé de fabrication d'1-arylalcools optiquement actifs par utilisation de l'halogénoperoxydase de l'agrocybe aegerita - Google Patents

Procédé de fabrication d'1-arylalcools optiquement actifs par utilisation de l'halogénoperoxydase de l'agrocybe aegerita Download PDF

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Publication number
WO2008028526A1
WO2008028526A1 PCT/EP2007/005230 EP2007005230W WO2008028526A1 WO 2008028526 A1 WO2008028526 A1 WO 2008028526A1 EP 2007005230 W EP2007005230 W EP 2007005230W WO 2008028526 A1 WO2008028526 A1 WO 2008028526A1
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WIPO (PCT)
Prior art keywords
reaction
enzymes
peroxidase
alkylaromatics
aap
Prior art date
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PCT/EP2007/005230
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German (de)
English (en)
Inventor
Thomas Gedig
Daniel Decker
Katrin Scheibner
Martin Hofrichter
Renè ULLRICH
Martin Kluge
Original Assignee
Clariant Specialty Fine Chemicals (Deutschland) Gmbh
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Application filed by Clariant Specialty Fine Chemicals (Deutschland) Gmbh filed Critical Clariant Specialty Fine Chemicals (Deutschland) Gmbh
Publication of WO2008028526A1 publication Critical patent/WO2008028526A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic

Definitions

  • the invention relates to a process for the enzymatic hydroxylation of alkylaromatics, to the corresponding aromatically substituted chiral alkanols.
  • biocatalysts are the cytochrome P450-dependent monooxygenases, which are found in almost all organisms. You are u.a. involved in the detoxification of toxic compounds in the human liver or in the synthesis of secondary metabolites (e.g., steroids used as membrane constituents, vitamins, hormones, bile acids or cardiac active).
  • secondary metabolites e.g., steroids used as membrane constituents, vitamins, hormones, bile acids or cardiac active
  • Whole cell catalysis uses whole organisms (bacteria, yeasts, molds) instead of isolated hydroxylating enzymes. In this way it is possible, in the sense of biotransformations to a series of substrates hydroxylate. Examples are the nicotinic acid hydroxylation by Achromobacter xylosooxidans, the hydroxylation of biphenyl derivatives by E. coli or the steroid transformation with the aid of molds of the genus Rhizopus (Liese et al., 2000, Industrial Biotransformations, Wiley-VCH, Weinheim). Disadvantages of catalysis with whole cells exist in the time and cost intensive
  • the object of the present invention is to carry out a process for the preparation of chiral alcohols from the corresponding precursors with the least possible procedural and equipment expense while simultaneously using inexpensive cosubstrates.
  • the reaction of the starting compounds should take place in the shortest possible incubation times without increased requirements for sterile or semisterile reaction conditions.
  • the reaction products are to be isolated with the least possible effort and a complex separation of enantiomers should be eliminated.
  • the present process solves this problem and relates to a process for the enzymatic, stereoselective hydroxylation of alkylaromatics to chiral aromatic-substituted alkanols by reacting alkylaromatics with an agrocyte aegerita peroxidase (AaP) in the presence of at least one oxidation agent in a one-step reaction process.
  • AaP agrocyte aegerita peroxidase
  • the starting compounds are in this case reacted with the enzyme designated Agrocybe- aegerita peroxidase (AaP), which has a particularly high peroxygenase activity, and at least one oxidizing agent, wherein the stereoselective oxygenation of certain C-H bonds takes place.
  • AaP Agrocybe- aegerita peroxidase
  • the oxidizing agent according to the invention preferably H 2 O 2
  • organic peroxides or hydroperoxides such as tert-butyl hydroperoxide, air or oxygen used.
  • expensive electron donors, such as NAD (P) H can at dispensed with the present process (concentration of the oxidizing agent: from 0.01 to 10 mmol / L, preferably 0.1 to 2 mmol / LH 2 O 2 ).
  • the reaction mixture can additionally accelerate the reaction of the starting compound with the AaP enzyme H 2 O 2 -generating enzymes, in particular oxidases such as glucose oxidase or aryl alcohol oxidase and their substrates, eg. As glucose or benzyl alcohol may be added.
  • H 2 O 2 -generating enzymes in particular oxidases such as glucose oxidase or aryl alcohol oxidase and their substrates, eg. As glucose or benzyl alcohol may be added.
  • Oxidizing agent e.g., peroxides
  • Oxidizing agent especially in buffered aqueous solutions, oxidizes aliphatic side chains of aromatic compounds (e.g., ethylbenzene) to the corresponding chiral 1-phenylalkanols, thereby achieving high enantiomeric purity (> 95% ee).
  • the enzyme used is a special haloperoxidase with peroxygenase function. It is produced by basidiomycetes of the families Bolbitiaceae (e.g., Agrocybe spp.) And Coprinaceae (e.g., Coprinus spp.) And is characterized by particular catalytic properties that clearly distinguish it from previously described peroxidases and cytochrome P450 enzymes. Enzyme production takes place in liquid culture, preferably in bioreactors and nitrogen-rich media (R. Ullrich, 2005, dissertation, IHI Zittau, M. Kluge, 2006, diploma thesis, IHI Zittau).
  • the reactions catalyzed by the enzyme termed Agrocybe aegerita peroxidase (AaP) do not require highly concentrated aggressive and environmentally hazardous reagents, and product recovery can dispense with chemical and time-consuming purification steps to separate the racemic mixtures.
  • the enzyme is used in a concentration of 0.02 U / mL to 10 U / mL AaP, in particular 0.09 to 8 U / mL AaP. This makes the reaction process shown particularly environmentally friendly.
  • Another advantage over purely chemical syntheses is the process control due to the AaP-catalyzed reaction according to the invention at room temperature and normal atmospheric pressure.
  • the process is carried out in aqueous, buffered solutions.
  • buffers based on organic acids preferably citric acid, and phosphates, preferably potassium hydrogen phosphates, may be added to the reaction mixture (buffer concentration 5 mmol / L to 500 mmol / L, preferably 20-100 mmol / L).
  • phosphates preferably potassium hydrogen phosphates
  • organic solvents may be added to the reaction mixture.
  • Solvents which can be used according to the invention are, for example, protic solvents, for example ethers (inter alia diisopropyl ether), methanol, acetone, acetonitrile, DMF (N, N-dimethylformamide) or DMSO (dimethyl sulfoxide).
  • the reaction is carried out in a range of 5 to 60 0 C, preferably at 20 to 30 0 C.
  • the reaction times are usually in the range of 1 to 90 minutes, in particular in the range of 5 to 30 minutes.
  • the achieved ee values are in the range of 80 to 99.9%, preferably greater than 95% ee; the yields are between 30 and 90%.
  • the advantages of the AaP-catalyzed reactions to catalysis with conventional cytochrome P450 enzymes (monooxygenases) are: i) the high enantiomeric purity of the reaction products, ii) the use of inexpensive peroxides instead of expensive electron donors [NAD (P) H], iii) in the independence of the hydroxylating enzyme of
  • AaP over conventional peroxidases (including chloroperoxidase, horseradish peroxidase, lignin peroxidase) are: i) a broader substrate spectrum, ii) a more pronounced peroxygenase activity, iii) an overall higher stability.
  • Fig. 1 General scheme
  • Fig. 2 Schematic diagram according to the embodiment

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention concerne un procédé d'hydroxylation enzymatique stéréosélective d'alkyles aromatiques en alcanols substitués par des aromatiques par réaction des alkyles aromatiques avec une peroxydade d'agrocybe aegerita (AaP) en présence d'au moins un oxydant dans un procédé réactionnel à une étape. La réaction selon l'invention est fortement stéréosélective, ce qui permet d'obtenir des unités d'énantiomère avec un ee de plus de 95 %. Le procédé peut être utilisé dans divers domaines de la chimie de synthèse, p. ex. pour la fabrication de médicaments et leurs intermédiaires, ainsi que d'arômes.
PCT/EP2007/005230 2006-09-05 2007-06-14 Procédé de fabrication d'1-arylalcools optiquement actifs par utilisation de l'halogénoperoxydase de l'agrocybe aegerita WO2008028526A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006041493A DE102006041493A1 (de) 2006-09-05 2006-09-05 Verfahren zur stereoselektiven Hydroxylierung von Alkylaromaten
DE102006041493.4 2006-09-05

Publications (1)

Publication Number Publication Date
WO2008028526A1 true WO2008028526A1 (fr) 2008-03-13

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PCT/EP2007/005230 WO2008028526A1 (fr) 2006-09-05 2007-06-14 Procédé de fabrication d'1-arylalcools optiquement actifs par utilisation de l'halogénoperoxydase de l'agrocybe aegerita

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DE (1) DE102006041493A1 (fr)
WO (1) WO2008028526A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011120938A3 (fr) * 2010-03-28 2011-11-24 Novozymes A/S Hydroxylation enzymatique d'hydrocarbure aliphatique

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113999879B (zh) * 2022-01-04 2022-04-08 中国科学院天津工业生物技术研究所 一种过氧化酶催化氧化芳香烃及其衍生物的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006034702A1 (fr) * 2004-09-28 2006-04-06 Jenabios Gmbh Procede d'hydroxylation enzymatique d'hydrocarbures non actives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006034702A1 (fr) * 2004-09-28 2006-04-06 Jenabios Gmbh Procede d'hydroxylation enzymatique d'hydrocarbures non actives

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CABA [online] CHEMICAL ABSTRACTS SERVICE; 2001, DANG, J. ET AL.: "Study on isoenzyme in Agrocybe chaxingu at different growth stages", XP002450062, Database accession no. 2002:138095 *
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM); September 2007 (2007-09-01), DAU, H.A. ET AL.: "The Coprophilous Mushroom Coprinus radians Secretes a Haloperoxidase That Catalyzes Aromatic Peroxygenation", XP002450157, Database accession no. 2007505300 *
ULLRICH, R. ET AL.: "Novel Haloperoxidase from the Agaric Basidiomycete Agrocybe aegerita Oxidizes Aryl Alcohols and Aldehydes", APPLIED AND ENVIRONMENTAL MICROBIOLOGY, vol. 70, no. 8, August 2004 (2004-08-01), pages 4575 - 4581, XP002364075 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011120938A3 (fr) * 2010-03-28 2011-11-24 Novozymes A/S Hydroxylation enzymatique d'hydrocarbure aliphatique
US9222109B2 (en) 2010-03-28 2015-12-29 Novozymes A/S Enzymatic hydroxylation of aliphatic hydrocarbon
US9534238B2 (en) 2010-03-28 2017-01-03 Novozymes A/S Enzymatic hydroxylation of aliphatic hydrocarbon
US9909147B2 (en) 2010-03-28 2018-03-06 Novozymes A/S Enzymatic hydroxylation of aliphatic hydrocarbon
US10174342B2 (en) 2010-03-28 2019-01-08 Novozymes A/S Enzymatic hydroxylation of aliphatic hydrocarbon

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