Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing oxygen-containing organic compound
Patent
1988-07-13
1990-01-16
Lilling, Herbert J.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing oxygen-containing organic compound
435155, 435156, 435197, 435280, 4352521, 560116, 560117, 560119, 549336, C12P 4100, C12P 1702, C12P 742, C07C17700
Patent
active
048943363
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process for stereospecific acylate hydrolysis of racemic 3-acyloxy-bicyclo[3.3.0]octan-7-one-2-carboxylic acid esters to optically active 3-alcohols with the help of enzymes or microorganisms.
It is particularly suitable for the production of optically active (+)-bicyclo[3.3.0]octanol derivatives of formula (+)-I. ##STR1## in which R.sub.1 and R.sub.2 together mean an oxygen atom or a double-bond radical --O--X--O-- with X as straight-chain or branched-chain alkylene with 1-7 C atoms or R.sub.1 and R.sub.2 mean in each case the radical OR.sub.5 with R.sub.5 as straight-chain or branched-chain alkyl with 1-7 C atoms and R.sub.3 means the radical COOZ with Z as hydrogen atom, straight-chain or branched-chain alkyl with 1-7 C atoms, cycloalkyl with 3-6 C atoms, phenyl or aralkyl with 7-10 C atoms or R.sub.3 means the radical -(CH.sub.2)n-O-COR.sub.4 with n meaning 1-4 and R.sub.4 as straight-chain or branched-chain alkyl with 1-7 C atoms, cycloalkyl with 3-6 C atoms, phenyl or aralkyl with 7-10 C atoms.
It is characterized in that racemic 3alpha-acyloxy-cisbicyclo[3.3.0]octane derivatives of the formula (.+-.)-II ##STR2## in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have the above-indicated meanings, are enzymatically or microbiologically subjected to a stereospecific acylate hydrolysis and the resulting (+)-bicyclo[3.3.0]octanol derivative (+)-I is separated from the unsaponified bicyclo[3.3.0]octanol acylate of formula (-)-II or the unsaponified enantiomer (+)-II is separated from the saponified bicyclo[3.3.0]octanol derivative (-)-I and then subjected to a chemical acylate hydrolysis.
If X means a straight-chain or branched-chain alkylene radical with 1-7 C atoms, the following radicals are meant by it: --CH.sub.2)n with n=1-7 (methylene, ethylene, tri-, tetra-, penta-, hexa--and hepta--methylene, --C(CH.sub.3).sub.2 --, --CH(CH.sub.3)--, --CH((CH.sub.3)--CH.sub.2 --, --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(CM.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
Z, R.sub.4 and R.sub.5 as straight-chain or branched-chain alkyl radicals with 1=7 C 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.
Z or R.sub.4 as aralkyl radicals with 7-10 C atoms are to comprise the following radicals: ##STR3##
Z or R.sub.4 as cycloalkyl radicals with 3-6 C atoms comprise the following radicals: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
Optically active 6alpha-carbaprostacyclin and especially some compounds derived from it have, as stable analogs of the natural prostacyclin (PGI.sub.2), a high therapeutic benefit [R. C. Nickolson, M. H. Town, H. Vorbrueggen: Prostacyclin Analogs, Medical Research Reviews, Vol. 5, No. 1, pp. 1-53 (1985). The syntheses specified in this more recent survey are long and lead partially only to racemic carbacyclins. The syntheses, which lead to the carbacyclins in the absolute configuration corresponding to the natural PGI.sub.2, are especially costly. This is due to the fact that readily accessible, suitable initial materials are achiral and the optical activity must be introduced into the intermediate stages suitable for this purpose only in the course of the synthesis.
Several syntheses already start from optically active 7alpha-hydroxy-6beta-hydroxymethyl-2-oxa-bicyclo[3.3.0]octan-3-one derivatives. Thus the problem of the introduction of optical activity is inde desolved. But further multistage synthesis sequences must still be performed for the substitution of the 2-oxa function by a methylene group, to reach derivatives of 3alpha-hydroxy-2b
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Dahl Helmut
Petzoldt Karl
Skuballa Werner
Lilling Herbert J.
Schering Aktiengesellschaft
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