Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing oxygen-containing organic compound
Reexamination Certificate
2000-10-11
2002-08-13
Weber, Jon P. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing oxygen-containing organic compound
C435S155000, C435S170000, C435S041000
Reexamination Certificate
active
06432685
ABSTRACT:
The invention relates to a process for the oxidation of substituted trimethylcyclohexenyl compounds in the presence of microorganisms of the order Actinomycetales and to the use of microorganisms in oxidation reactions.
Compounds having a trimethylcyclohexenyl ring occur widely in nature. They are important intermediates in the terpenoid metabolism and occur, for example, during carotinoid biosynthesis. They can be isolated from a series of natural sources. For example, in addition to the carotinoids, a large number of fragrances and/or flavorings have a trimethylcyclohexenyl ring. They are also found in a large number of vegetable oils.
There have been a variety of attempts in the past at the biotechnological oxidation of compounds having a trimethylcyclohexenyl ring. Thus, Mikami et al. (Appl. Environ. Microbiol., Vol. 41, No. 3, 1981: 610-617) describes the microbial transformation of &bgr;-ionone and &bgr;-methylionone by the fungus
Aspergillus niger.
The main products of the reaction with &bgr;-ionone as starting material were identified as (R)-4-hydroxy-&bgr;-ionone and (S)-2-hydroxy-&bgr;-ionone, and also 2-oxo-, 4-oxo-, 3,4-dehydro-, 2,3-dehydro-4-oxo-, 3,4-dehydro-2-oxo-, (S)-2-acetoxy-, (R)-4-acetoxy-, 5,6-epoxy-&bgr;-ionone and 4-(2,3,6-trimethylphenyl)but-3-en-2-one. Analogous transformation products were identified with &bgr;-methylionone as starting material. A reaction with such a large number of secondary products is unsuitable for industrial purposes.
DE 32 43 091 describes the oxidation of &bgr;-ionone to (R)-4-hydroxy-&bgr;-ionone by the fungus
Gongronella butleri.
In this reaction, the principal secondary product formed is 2-hydroxy-&bgr;-ionone, which is hydroxylated in the 2-position and an undesired product.
A reaction which is an improvement on Mikami et al. is described by Yamazaki et al. (Appl. Environ. Microbiol., Vol. 54, No. 10, 1988: 2354-2360). Yamazaki uses the fungus
Aspergillus niger
JTS 191 as catalyst for the reaction. The main products described are a cis/trans isomer mixture (=cis-3-hydroxy-&agr;-ionone and trans-3-hydroxy-&agr;-ionone), together with 3-oxo-&agr;-ionone. Other secondary products which were identified are 2,3-dehydro-&agr;-ionone, 3,4-dehydro-&agr;-ionone and 1-(6,6-dimethyl-2-methylene-3-cyclohexenyl)buten-3-one. Again, this process cannot be exploited industrially due to the spectrum of main and secondary products, specifically due to the cis/trans isomer mixture. Nor does the process described in FR 2 661 190, in which the fungus Mucor is employed, lead to satisfactory results.
In 1995, a fed-batch biotransformation of &bgr;-ionone using
Aspergillus niger
was described by Larroche et (Appl. Microbiol. Biotechnol., 43, 1995: 222-227). This biotransformation not only yields 4-hydroxy-&bgr;-ionone, but also 2-hydroxy-&bgr;-ionone and 4-oxo-&bgr;-ionone, both of which are undesired.
Our own work with a variety of fungi as catalysts has demonstrated that the oxidation of compounds having a trimethylcyclohexenyl ring leads to a multiplicity of main and secondary products.
It is an object of the present invention to provide a process for the oxidation of compounds having trimethylcyclohexenyl rings which does not exhibit the above-mentioned disadvantages and which selectively leads to oxidation products.
We have found that this object is achieved by the process according to the invention for the oxidation of compounds of the structure I
to compounds of the structure II
the substituents in formulae I and II being as defined below:
R
1
=substituted or unsubstituted, branched or unbranched, saturated or unsaturated C
1
-C
8
-Alkyl-,
R
2
and R
3
independently of one another are hydrogen, oxo- or hydroxyl-, at least one radical R
2
or R
3
being other than hydrogen,
which comprises carrying out the oxidation of the compounds of the structure I in the presence of bacteria of the order Actinomycetales.
It is preferred to use the process according to the invention for oxidizing compounds of the structure Ia
to compounds of the structure IIa
in the presence of bacteria of the order Actinomycetales, the substitutent R
1
in formulae I and IIa being as defined above and R
2
being oxo- or hydroxyl-.
In the compounds of the formulae I, Ia, II and IIa, R
1
denotes substituted, or unsubstituted, branched or unbranched, saturated or unsaturated C
1
-C
8
-alkyl-.
Saturated alkyl radicals which may be mentioned are substituted or unsubstituted branched or unbranched C
1
-C
8
-alkyl chains, such as, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl-, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl or n-octyl.
Unsaturated alkyl radicals which may be [lacuna] are subsituted or unsubstituted, branched or unbranched C
2
-C
8
-alkenyl chains, such as, for example, ethenyl, propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylpropenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl or 7-octenyl,
Other unsaturated alkyl radicals which may be [lacuna] are substituted or unsubstituted, branched or unbranched C
2
-C
6
-alkynyl chains, such as, for example, ethynyl-, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl, 3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl, n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl, 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl.
Suitable substituents for the above-mentioned radicals of R
1
are, in principle, all conceivable consistuents, for example one or more substituents such as oxo, acyl-, CHR
4
OR
5
— (=acetal), halogen such as fluorine, chlorine or bromine, cyano, nitro, amino, hydroxyl, alkyl, cycloalkyl, aryl, alkoxy, benzyloxy, phenyl or benzyl, preferably oxo, hydroxyl-, acyl- or CHR
4
OR
5
— (=acetal), alkyl and cycloalkyl. R
4
and R
5
in the radicals independently of one another denote C
1
-C
4
-Alkyl- or C
3
Fischer Peter
Hauer Bernhard
Lutz-Wahl Sabine
Scherr Oliver
Schmid Rolf D.
BASF - Aktiengesellschaft
Keil & Weinkauf
Patten Patricia
Weber Jon P.
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