Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing nitrogen-containing organic compound
Patent
1997-12-23
1999-12-14
Saucier, Sandra E.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing nitrogen-containing organic compound
435280, C12P 1300
Patent
active
060016159
DESCRIPTION:
BRIEF SUMMARY
THIS INVENTION relates to the reduction of ketone groups.
It is known from Brower et al. Tetrahedron letters 1992, pages 2279-2282 to synthesise a compound of formula ##STR4## by diastereoselective reduction of a compound of formula ##STR5## using the method of Chen et al, Tetrahedron Letters 1987 28 155 and Chem Lett 1987 1923 followed by protection as the acetonide. A cross Claisen approach to compound (1) was also reported. These routes involved the use of temperatures of -90.degree. C., which renders them expensive and inconvenient.
BRIEF DESCRIPTION OF THE DRAWING
The drawing is a graph showing the concentrations of compounds I and II at times up to about 50 hours during the reaction of Example 13.
Compound (1) may be used as an intermediate in the synthesis of CI-981, an inhibitor of HMG CoA reductase which reduces total plasma and low density lipoprotein cholesterol in man. Its key structural feature may also be derived from a compound of formula ##STR6##
In the above formula R is an alkyl group, preferably having 1 to 6 carbon atoms and is more preferably a t-butyl group.
We have found that compound (III) may be produced by reduction of compound (II) with moderate to high selectivity and at convenient temperatures using a ketone reductase commonly found among species of the genera Beauveria, Pichia, Candida, Kluyveromyces, and Torulaspora but that in each genus exceptions may occur or possibly the enzyme will be accompanied by one of opposite stereospecificity.
The invention therefore comprises producing a compound of formula (III) by selectively reducing a compound of formula (II) ##STR7## using a reductase possessing the properties of those produced by a microorganism selected from Beauveria preferably Beauveria bassiana, Pichia preferably Pichia pastoris, haplophila or membranefaciens, Candida preferably Candida humicola, solani, diddenssiae or friedrichii, Kluyveromyces preferably Kluyveromyces drosophilarum, or Torulaspora preferably Torulaspora hansenii and preferably Pichia angusta.
The invention also comprises producing a compound of formula (III) by selectively reducing a compound of formula (II) using whole cells of or extracts from the said microorganisms preferably Beauveria bassiana, Pichia pastoris, Pichia haplophila, Pichia membranefaciens, Candida humicola, Candida solani, Candida diddensiae, Candida friedrichii, Kluyveromyces drosophilarum, Torulaspora hansenii or preferably Pichia angusta.
The invention is preferably carried out using whole cells of the organism as this avoids the need to separate the desired enzyme and provides co-factors necessary for the reaction.
Any of the above species may be used but in order to obtain high conversions and high selectivity it is preferred to use the enzyme or whole cells of Pichia haplophila, or more preferably Pichia angusta.
In general a co-factor, normally AND(P)H (nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate) and a system for re-generating the co-factor, for example glucose and glucose dehydrogenase, are used with the enzyme to drive the reaction. As suitable co-factors and reduction mechanisms are present in the whole cells it is preferred to use the whole cells in a nutrient medium which preferably contains a suitable carbon source, which may include one or more of the following: a sugar, e.g. maltose, sucrose or preferably glucose, a polyol e.g. glycerol or sorbitol, citric acid, or a lower alcohol, for example methanol or ethanol.
If whole cells are intended to grow during the reaction nitrogen and phosphorus sources and trace elements should be present in the medium. These may be those normally used in culturing the organism.
The process may be carried out by adding a compound of formula II to a culture of the growing organism in a medium capable of supporting growth or to a suspension of the live cells in a medium which preferably contains a carbon source but which lacks one or more nutrients necessary for growth. Dead cells may also be used providing the necessary enzymes and co-factors are
REFERENCES:
patent: 5026642 (1991-06-01), Radunz et al.
patent: 5155251 (1992-10-01), Butler et al.
patent: 5324662 (1994-06-01), Patel et al.
Chemical Abstracts, vol. 120, No. 5, Jan. 31, 1994, abstract No. 52720, Patel, R et al: "Enantioselective microbial reduction of 3,5-dioxo-6-(benzyloxy)hexanoic acid, ethyl ester" XP002016585, see abstract & Enzyme Microb, Techno. (1993), 15(12), 1014-21 CODEN:EMTED2; 0141-0229, 1993.
Zelinski et al: "Purification and characterization of a novel carbonyl reductase isolated from Rodococcus erythropolis", Journal of Biotechnology, 33(3), 283-91.
Tetrahedron(1994), 51(3), 687-94 ; Nakamura et al:"Mechanistic study for sterochemical control of microbial reduction of alpha-keto esters in an organic solvent".
Saucier Sandra E.
Zeneca Limited
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