Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1995-02-28
1996-12-03
Naff, David M.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
4352529, 4352554, 4352555, 4352561, 435280, C12P 1716, C12N 120, C12N 114
Patent
active
055807640
DESCRIPTION:
BRIEF SUMMARY
This invention relates to an asymmetric reduction process. The compound ##STR2## is a topically active carbonic anhydrase inhibitor which is proposed for treatment of glaucoma. The compound with a methyl substituent in the 6 position in which the orientation is trans with regard to the 4-substituent (the 4S,6S diastereoisomer) is of therapeutic interest, but it is difficult to produce in the absence of a preponderant amount of the cis isomer (the 4R,6S diastereoisomer).
We have devised a process for producing a compound of formula ##STR3## in which X is hydrogen or a group of formula --SONH.sub.2 which is a useful intermediate in the production of the desired trans (4S,6S) isomer III described above and derivatives thereof in an amount greater that that of the corresponding cis isomer from a compound of formula I ##STR4##
Background chemistry related to the synthesis of these materials is disclosed in Jones, et al, J. Org. Chem 1991 56 763-769, Shinkai, J. Heterocyclic Chem. (1992) 29 627-639 and U.S. Pat. Nos. 4,968,814 and 4,968,815, and, in a publication made subsequently to the priority of this patent application, by Blacklock et al J. Org Chem. 1993 58 1672-1679.
The reduction of compound (I) using reducing agents such as boranetetrahydrofuran complex results in the formation of the (4R,6S) diastereoisomer (IV) as the major product (>90%) with the desired (4S,6S) trans diastereoisomer (II) accounting for a minor proportion of the product. ##STR5##
Jones et al, J Org. Chem. (1991), 56, 763-769 have disclosed a method for the enantioselective reduction of a close analogue, compound (V), using bakers yeast (Saccharomyces cerevisiae). This reaction yields the (R)- and (S)-alcohols in the ratio 11:89. ##STR6##
However, when a range of bakers' and brewers' yeasts were tested in the reduction of compound (I) the undesired cis diastereoisomer was the major product (60 to 85%). Examination of a wider range of microorganisms (bacteria, yeasts and fungi) demonstrated that most produced predominantly the undesired cis diastereoisomer. Surprisingly, however, we have found that it is in fact possible to produce the trans isomer in preponderant yield by enzyme reduction and have identified a range of microorganisms including bacteria, fungi and yeasts which are able to reduce compound (I) to the desired trans alcohol (II).
This invention comprises a process in which a compound of formula ##STR7## in which X is hydrogen or a group of formula --SO.sub.2 NH.sub.2 is converted into a compound of formula ##STR8## by contacting it with an enzyme reduction system. Suitable systems comprise a suitable oxido reductase enzyme and the reduced form of a co-factor for the enzyme. The enzyme reduction system may be provided as whole or broken cells of suitable microorganisms.
By "selectively" is meant that more of the trans (4S,6S) isomer is produced than of the cis (4R,6S) isomer. Preferably at least 60% and more preferably at least 80% for example at least 90% of the product is the trans isomer.
The process is preferably carried out at a pH of at most 8 and more preferably at most 6. We have found that the stereospecificity of the process is improved by operation under acidic conditions and it is preferred that it be carried out at a pH of 2 to 5. Microorganisms containing the enzyme reduction systems are surprisingly resistant to such conditions.
Suitable oxido reductases may be found by a process of screening. Examples of suitable reductases are those from Lactobacillus plantarum NCIMB 40027, Pichia haplophila CBS 2008, Candida utilis NCYC 322, Lactobacillus buchneri NCIMB 8818, Aspergillus flavus oryzae IMI 51983 or especially that from Neurospora crassa IMI 19419.
In general, bakers' and brewers' yeasts give the undesired cis product.
The co-factor may be for example, NADH, NADPH, FADH, FMNH and/or PQQ or any cofactor which occurs with the aforesaid enzyme in a microorganism. Preferably means to reduce the co-factor continuously are also present.
Very suitably the enzyme and co-factor may be supplied as broken or prefera
REFERENCES:
patent: 4968815 (1990-11-01), Blacklock et al.
patent: 5039802 (1991-08-01), Blacklock et al.
patent: 5474919 (1995-12-01), Chartrain et al.
Jones, et al: "An asymmetric systhesis of MK-0417 Observationson oxazaborolidine-catalyzed reductions", Journal of Organic Chemistry, vol. 56, No. 2, Jan. 18, 1991, pp. 763-769.
Davies et al, J. Am. Chem Soc 101:5405-5410 (1979).
Jones J. B. Tetrahedron 42: 3351-3403 (1986).
Christen M. et al, J. Chem Soc., Chem Commun (1988) 264-266.
Holt Robert A.
Rigby Stuart R.
Naff David M.
Saucier S.
Zeneca Limited
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