Process for producing optically active bicyclo[3.3.0]octanedione

Details Process for producing optically active bicyclo[3.3.0]octanedione Process for producing optically active bicyclo[3.3.0]octanedione

1988-07-13

1992-03-03

Robinson, Douglas W.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing oxygen-containing organic compound

435147, 435149, 435213, 435280, C12P 762, C12P 738, C12P 724, C12N 976

Patent

active

050932500

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

Optically active 6a-carbaprostacyclin and, in particular, several compounds derived therefrom possess, as stable analogs of the natural prostacyclin [PGI.sub.2 ], a high therapeutic utility [R. C. Nickolson, M. H. Town, H. Vorbruggen: "Prostacyclin-Analogs", Medicinal Research Reviews, 5, 1:1-53 (1985)]. The syntheses listed in this more recent overview are long and lead, in part, merely to racemic carbacyclins. The syntheses resulting in carbacyclins in the absolute configuration corresponding to natural PGI.sub.2 are especially expensive. This is due to the fact that readily accessible, suitable starting materials are achiral, and the optical activity must be introduced during the course of the synthesis into intermediate stages suitable for this purpose.
Several syntheses start with already optically active 7.alpha.-hydroxy-6.beta.-hydroxymethyl-2-oxabicyclo[3.3.0]-octan-3-one derivatives. Although this solves the problem of introducing optical activity, it is necessary to perform still further multistage synthesis sequences for the substitution of the 2-oxa function by a methylene group in order to obtain derivatives of 3.alpha.-hydroxy-2.beta.-hydroxymethylbicyclo[3.3.0]octan-7-one which are the ones suitable for the addition of the .alpha.- and .omega.-chains in each case typical for the carbacyclin analogs.
A more recent publication describes the use of cis-bicyclo[3.3.0]octane-3,7-dione derivatives for the synthesis of optically active carbacyclins. Kojima et al. describe a process in Chem. Pharm. Bull. 33:2688 (1985) which includes the separation of diastereomeric salts of racemic 7,7-ethylenedioxy-3.alpha.-hydroxy-cis-bicyclo[3.3.0]octane-2-carboxylic acid.
This method still requires seven reaction steps in order to obtain the starting material for carbacyclin analogs, starting with 3-oxoglutaric esters. Additionally, the procedure passes through an unstable .beta.-keto acid intermediate stage.
Furthermore, no synthesis route permitting simple production is known for the preparation of optically active carbacyclin analogs as described above.


SUMMARY OF THE INVENTION

It has now been found that the above-mentioned prochiral dicarboxylic acid esters of prostacyclin and carbacyclin intermediate stages can be saponified and decarboxylated enantioselectively to the monocarboxylic acid esters in very good yields by using enzymes, particularly .alpha.-chymotrypsin.
The invention is particularly suited for the enzymatic enantioselective monosaponification and decarboxylation of the prostacyclin and carbacyclin intermediates 1-4 set forth below. ##STR3##
Accordingly, the invention relates to a process for producing optically active bicyclo[3.3.0]octanedionecarboxylic acid esters of Formula I ##STR4## wherein R.sub.1 and R.sub.2 jointly represent an oxygen atom or the residue --O--X--O-- where X means a straight or branched-chain alkylene group of 1-7 carbon atoms, or R.sub.4 means a straight or branched-chain alkyl of 1-7 carbon atoms, and acid diester of Formula II ##STR5## wherein R.sub.1, R.sub.2 and R.sub.3 have the meanings set forth above, is enantioselectively saponified and decarboxylated with enzymes.
If X means a straight-chain or branched-chain alkylene residue of 1-7 carbon atoms, the following residues are meant: penta-, hexa- and heptamethylene), --C(CH.sub.3).sub.2 --CH.sub.2 --, --CH.sub.2 --CH(CH.sub.3)--, CH.sub.2 --C(CH.sub.3).sub.2, --CH.sub.2 --CH(CH.sub.3)--CH.sub.2 --, --CH.sub.2 --C(CH.sub.3).sub.2 --CH.sub.2 --, --CH--(C.sub.2 H.sub.5)--, --C(C.sub.2 H.sub.5).sub.2 --, --CH(C.sub.2 H.sub.5)--CH.sub.2 --, --C(C.sub.2 H.sub.5).sub.2 --CH.sub.2 --, --CH.sub.2 --CH(C.sub.2 H.sub.5)--, --CH.sub.2 --C(C.sub.2 H.sub.5).sub.2 --, --CH.sub.2 --CH(C.sub.2 H.sub.5)--CH.sub.2 --, --CH.sub.2 --C(C.sub.2 H.sub.5).sub.2 --CH.sub.2 -- etc. 1-10 and, respectively, 1-7 carbon atoms mean methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, octyl, nonyl, decyl.
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REFERENCES:
patent: 4800162 (1989-01-01), Matson

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