Enzymatic synthesis of optically active hydroxamic acids and...

Details Enzymatic synthesis of optically active hydroxamic acids and... Enzymatic synthesis of optically active hydroxamic acids and...

1999-04-05

2001-08-28

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

06281003

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to the enzymatic synthesis of optically active hydroxamic acids and to their conversion to optically active primary amines by a Lossen rearrangement.
2. Background of the Prior Art
Hydroxamic acids are compounds of great pharmaceutical interest. Hydroxamic acid derivatives exist which have antibacterial and fungicidal properties (Duda et al., 1965; Hase et al., 1971). Alkylaminopropionohydroxamic acids exhibit hypotensive properties (Coutts et al., 1971). Hypocholesterolaemic actions have also been demonstrated for hydroxamic acids (Ludwig et al., 1967). p-Butoxyphenylacetohydroxamic acid possesses an anti-inflammatory action (Dell et al., 1971) and is used in human medicine. Some hydroxamic acids have been studied for their efficacy against malaria (Hynes, 1970; Hynes & Hack, 1972).
Enantiomerically pure hydroxamic acids, however, are of particular importance. Their pharmacological activity is higher than that of the racemates. Furthermore, via the Lossen rearrangement, they also open up a new route to chiral primary amines. This class of substances is pharmacologically of great importance as well. Thus chiral &bgr;-amino alcohols, for example, are used in large amounts as &bgr;-adrenoceptor antagonists, abbreviated to &bgr;-blockers.
However, the preparation of enantiomerically pure hydroxamic acids by the conventional methods of organic chemistry is expensive. It normally requires a racemate separation or the use of metal-organic catalysts, but the latter are generally unsuitable for the preparation of drugs. Such methods are described for example in DE-PS 2 400 531, EP-A-203 379 and EP-A-268 215.
SUMMARY OF THE INVENTION
The object of the invention is therefore to provide a novel method of preparing optically active hydroxamic acids which is not associated with the above-mentioned problems.
Surprisingly it has now been found that amides, carboxylic acid esters and carboxylic acids which have a centre of chirality on the &agr;-carbon atom can be enantioselectively converted to optically active hydroxamic acids by acyltransferases in the presence of hydroxylamine.
The invention therefore provides a method of preparing optically active hydroxamic acids of the general formula
wherein R
1
, R
2
and R
3
are different and are a cyclic or linear, aliphatic or aromatic, substituted or unsubstituted hydrocarbon radical which can optionally contain heteroatoms, said method being characterized in that a racemate of chiral amides, carboxylic acid esters or carboxylic acids of the general formula
wherein R
1
, R
2
and R
3
are as defined above and X is —NH
2
, —OR or —OH, R being any organic radical, is reacted with hydroxylamine, NH
2
OH, in the presence of an acyltransferase, and the optically active hydroxamic acid (I) formed is then separated from the unconverted enantiomer of general formula (II).


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