Production of optically active 1,2-dihydroxyindance derivatives

Details Production of optically active 1,2-dihydroxyindance derivatives Production of optically active 1,2-dihydroxyindance derivatives

1997-04-04

1998-09-22

Saucier, Sandra E.

Chemistry: molecular biology and microbiology

Process of utilizing an enzyme or micro-organism to destroy...

Resolution of optical isomers or purification of organic...

435877, C12P 4100

Patent

active

058112944

DESCRIPTION:

BRIEF SUMMARY
This application is the national phase of international application PCT/GB95/02051 filed Aug. 31, 1995 which designated the U.S.
This invention relates to a process for the resolution of racemic diols, particularly to a process for the resolution of racemic cis-diols and especially to a process for the resolution of racemic aromatic, alicylic and heterocyclic cis-diols particularly dihydroxydihydroindenes and more particularly vicinal cis dihydroxydihydroindenes.
Resolved dihydroxydihydroindenes are valuable intermediates for the synthesis of biologically active compounds such as pharmaceuticals and agrochemicals.
It has now been found that resolved diols, particularly dihydroxydihydroindenes, more particularly vicinal cis dihydroxydihydroindenes may be conveniently prepared in high enantiomeric excess (e.e.) in good overall yield via biotransformations using appropriate microorganisms.
According to the present invention there is provided a process for resolution of a mixture of dihydroxydihydroindene enantiomers comprising treating the mixture of enantiomers with a Pseudomonas putida species microorganism.
The mixture of dihydroxydihydroindene enantiomers preferably comprises compounds of the general Formula (1): ##STR1## in which R and R.sup.4 each independently is --H, halogen, --N.sub.3,--OH, --CN, alkyl, alkenyl, aryl, --CX.sub.3, --OR.sup.1, --SR.sup.1, --NR.sup.1 R.sup.2, --PR.sup.1 R.sup.2, --COR.sup.1, --CO.sub.2 R.sup.1, in which X is halogen, and R.sup.1 and R.sup.2 each independently is alkyl, aryl, alkenyl or aralkyl.
Each of the alkyl, alkenyl, aryl and aralkyl groups represented by R, R.sup.1, R.sup.2 and R.sup.4 may be optionally substituted by substituents selected from --NO.sub.2, --CN, --F, --Cl, --Br, --I, --C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, --CF.sub.3, --OH, --OR.sup.3 in which R.sup.3 is alkyl, aryl, alkenyl or aralkyl.
Where one of R, R.sup.1, R.sup.2, R.sup.3 or R.sup.4 is alkyl it is preferably C.sub.1-10 -alkyl, more preferably C.sub.1-6 -alkyl and especially C.sub.14 -alkyl.
Where one of R, R.sup.1, R.sup.2, R.sup.3 or R.sup.4 is alkenyl it is preferably C.sub.2-10 -alkenyl, more preferably C.sub.2-6 -alkenyl. Where one of R, R.sup.1, R.sup.2, R.sup.3 or R.sup.4 is aryl it is preferably phenyl.
Where one of R.sup.1, R.sup.2 or R.sup.3 is aralkyl it is preferably C.sub.1-6 -alkylphenyl more preferably benzyl.
R and R.sup.4 each independently is preferably --H, --F, --Cl, --Br, --I, --N.sub.3, --OH, --CN, alkyl, alkenyl, aryl, --CX.sub.3, --OR.sup.1, --SR.sup.1 or --COR.sup.1 in which X is halogen and R.sup.1 is alkyl, aryl, alkenyl or aralkyl, more preferably --H, --F, --Cl, --Br, --I, --N.sub.3, --OH, --CN, C.sub.1-6 -alkyl, C.sub.2-6 -alkenyl, phenyl, --CF.sub.3, --CCI.sub.3, --OC.sub.1-6 -alkyl, --SC.sub.1-6 -alkyl or --COC.sub.1-6 -alkyl; and especially --H, --F, --Cl, --Br, --I, --N.sub.3, --OH, --CN, --CH.sub.3, --C.sub.2 H.sub.5, --OCH.sub.3, --SCH.sub.3 or --COCH.sub.3. ##STR2## in which R and R.sup.4 are as hereinbefore defined.
Especially preferred compounds of Formulae (1) and (2) are those in which R is as hereinbefore defined and R.sup.4 is --H, alkyl or alkoxy.
Where R is a substituent other than --H the carbon atom to which R is attached is a chiral centre. The present process provides a means of resolving dihydroxydihydroindenes which have three chiral centres at the 1-, 2- and 3- positions of the 5 membered ring and accordingly forms a further feature of the present invention.
Where one of R, R.sup.4 or X is halogen it is preferably --F, --Cl, --Br or --I, more preferably --F, --Cl or --Br.
The process is preferably performed in an aqueous medium, more preferably in a buffered aqueous medium. Suitable buffers may be inorganic or organic and are preferably those which control the pH of the medium in the range 4 to 9, more preferably in the range 6 to 8, and especially at a pH of 7. The buffer is preferably inorganic, more preferably an alkali metal phosphate, especially potassium phosphate. A particularly suitable aqueous medium is 0.1 M potassium phosphate.
A c

REFERENCES:
Jones JB, "Enzymes in Organic Synthesis", Tetrahedon 42 : 3351-3403 (1986).
Boyd et al: Stereospecific Benzylic Hydroxylation of Bicyclic Alkenes by Pseudomonas putida;: Isolation of (+)-R-1-Hydroxy-1,2-dihydronaphthalene, an Arene Hydrate of Naphthalene from Metabolism of 1,2-Dihydronaphthalene, Journal of the Chemical Society, Chemical Communications, No. 6, 1989, pp. 339-340.
Wackett et al: "Benzylic monooxygenation catalyzed by Toluene monooxygenase from Psudomonas putida", Biochemistry, vol. 27, No. 4, Feb. 23, 1988 pp. 1360-1367.
Boyd et al: "Stereodirecting substituent effects during enzyme-catlysed sunthesis of cis-dihydrodiol metabolites, og 1,4-Disubstituted benzene substrates", Journal of the Chemical Sociey, Chemical Communications,No. 11, Jun. 7, 1993, pp. 974-976.
Allen et al: "Enantioselective bacterial biotransformation routes to cis-diol metabolities of monosubstituted benzenes, naphthalene and bensocycloalkenes of either absolute configuration", Journal of the Chemical Society, Chemical Communictions, No. 2, Jan. 21, 1995, pp. 117-119.

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