Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Reexamination Certificate
1999-05-21
2002-04-09
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
Reexamination Certificate
active
06368850
ABSTRACT:
The invention relates to a novel process for the preparation of (1R,4S)- or (1S,4R)-1-amino-4-(hydroxymethyl)-2-cyclopentene of the formulae
and/or of (1S,4R)- or (1R4S)-amino alcohol derivatives of the general formulae
and to novel microorganisms which are able to utilize a cyclopentene derivative of the general formula
as sole nitrogen source, as sole carbon source or as sole carbon and nitrogen source.
The invention further relates to enzyme extracts and enzymes having N-acetylamino-alcohol hydrolase activity obtainable from these microorganisms.
BACKGROUND OF THE INVENTION
(1R,4S)-1-Amino-4-(hydroxymethyl)-2-cyclopentene of the formula I is an important intermediate for the preparation of carbocyclic nucleosides such as, for example, Carbovir® (Campbell et al., J. Org. Chem. 1995, 60, 4602-4616).
Processes for the preparation of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene are described by Campbell et al. (ibid) and by Park K. 11. & Rapoport H. (J. Org. Chem. 1994, 59, 394-399).
The precursor used in these processes is either D-glucono-&dgr;-lactone or D-serine, and about 15 synthesis stages are necessary to form (1R,4S)-N-tert-butoxycarbonyl-4-hydroxymethyl-2-cyclopentene, which is then deprotected to give (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene. These two processes are costly, elaborate and cannot be implemented industrially.
WO 93/17020 describes a process for the preparation of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene, wherein (1R,4S)-4-amino-2-cyclopentene-1-carboxylic acid is reduced with lithium aluminium hydride to the desired product.
The disadvantage of this process is, on the one hand, that the double bond of the cyclopentene ring is also reduced, the lithium aluminium hydride is difficult to handle, and, on the other hand, that it is too costly.
Taylor, S. J. et al. (Tetrahedron: Asymmetry Vol. 4, No. 6, 1993, 1117-1128) describe a process for the preparation of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene starting from (±)-2-azabicyclo[2.2.1]hept-5-en-3-one as precursor. In this case, the precursor is converted by means of microorganisms of the species
Pseudomonas solanacearum
or
Pseudomonas fluorescens
into (1R, 4S)-2-azabicyclo[2.2.1]hept-5-en-3-one, which is then converted with di-tert-butyl dicarbonate into (1R,4S)-N-tert-butoxycarbonyl-2-azabicyclo[2.2.1]hept-5-en-3-one, which is reduced with sodium borohydride and trifluoroacetic acid to the desired product. This process is much too costly.
In addition, Martinez et al. (J. Org. Chem. 1996, 61, 7963-7966) describe a 10-stage synthesis of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentene starting from diethyl dialkylmalonate. This process also has the disadvantage that it is elaborate and cannot be implemented industrially.
SUMMARY OF THE INVENTION
It was an object of the present invention to provide a simple process for the preparation of (1R,4S)-
1
-amino-4-(hydroxymethyl)-2-cyclopentene.
This object is achieved with the microorganisms of the invention according to claim
1
, and enzyme extracts therefrom, with the enzymes of the invention according to claim
4
and with the process of the invention according to claim
7
.
REFERENCES:
patent: WO9101318 (1991-02-01), None
patent: WO9101319 (1991-02-01), None
patent: WO9115447 (1991-10-01), None
patent: WO9317020 (1993-09-01), None
Martinez et al., 1996, “Highly efficient and enantioselective synthesis of carbocylic nucleoside analogs using selective early transition metal catalysis”,J. Org. Chem.61:7963-7966.
Campbell et al., 1995, Chirospecific synthesis of precursors of cyclopentane and cyclopentane carbocyclic nucleosides by [3+3]-coupling and transannular alkylation,J. Org. Chem. 60:4602-4616.
Park et al., 1994, “Enantioselective synthesis of (1R,4S)-1-amino-4-(hydroxymethyl)-2-cyclopentane, a precursor for carbocyclic nucleoside synthesis”,J. Org. Chem. 59:394-399.
Taylor, et al., 1993, Development of the biocatalytic resolution of 2-azabicyclo[2.2.1]hept-5-en-3-one as an entry to single enantiomer carbocyclic nucleosides,Tetrahedron: Asymmetry4: 1117-1128.
Norman et al., 1992, “Novel synthesis of (+/−)-cis-4-amino-2-cyclopentene-1-methanol, a key intermediate in the preparation of carbocyclic 2′,3′-didehydro-2′,3′-dideoxy nucleosides”,Synthetic Communications22, 3197-3204.
Bernegger-Egli Christine
Birch Olwen M.
Bossard Pierre
Brieden Walter
Brux Frank
Lonza AG
Saucier Sandra E.
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