Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1997-11-21
2000-07-11
Lilling, Herbert J.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
435117, 435121, 435155, C12P 1716, C12P 1700, C12P 1710, C12P 702
Patent
active
060871377
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a process for preparing optically active compounds, e.g. 1-hydroxy-2-substituted indans, and to a process for converting these compounds into the corresponding amido and amino compounds. These optically active compounds are valuable intermediates for synthesis of biologically active pharmaceuticals and agrochemicals, for example inhibitors of enzymes involved in human immunodeficiency virus (HIV) infection such as L-735,524 of Merck and Co. Inc. and novel analogues thereof.
According to a first aspect of the present invention there is provided a process for conversion of a compound of the Formula (1): ##STR3## into a compound of the Formula (2): ##STR4## using a dioxygenase enzyme; wherein: b, c and d is a nitrogen atom and all of the others are selected from CH and CY;
The dioxygenase enzyme is preferably a naphthalene dioxygenase enzyme or, more preferably, a toluene dioxygenase enzyme. The dioxygenase enzyme may be in any form capable of converting a compound of Formula (1) into a compound of Formula (2), for example in the form of a cell-free extract, a synthetic form, disintegrated cells or, preferably, the dioxygenase enzyme is present in whole cells. The dioxygenase enzyme is present in whole cells in various strains of E. Coli (e.g. E. Coli pKS T11 clone, described in J. Chem. Soc. Chem. Commun. 1995, 119-120, which expresses the toluene dioxygenase gene from P. putida NCIMB 11767) and various Pseudomonas putida micro-organisms. It is preferred that a compound of Formula (1) is converted into a compound of Formula (2) in the presence of a Pseudomonas putida micro-organism, more preferably a mutant strain of Pseudomonas putida NCIMB 11680 (deposited Oct. 02, 1981) or NCIMB 11767 (deposited Dec. 13, 1982), especially Pseudomonas putida UV4, more especially Pseudomonas putida NCIMB 8859 (deposited February 1957, available from the NCIMB Catalogue of Strains). Preparation of mutant strains of Pseudomonas putida NCIMB 11680 and NCIMB 11767, including Pseudomonas putida UV4, are described in European Patent No. 253,485.
To avoid conversion of the compound Formula (2) to the corresponding compound having a double bond between the carbon atoms to which the OH and X groups are attached the process is preferably performed in the absence of a cis dihydrodiol dehydrogenase enzyme.
Pseudomonas putida UV4 and its use are described in a number of publications, e.g. Tetrahedron Letters, vol 32, No. 31, pp 3887-3890 (1991); J. Chem. Soc. Chem. Commun. pp 49-51 (1993); Tetrahedron: Asymmetry Vol. 4, No. 6, pp1307-1324 (1993); J. Chem. Soc., Chem. Commun, pp 974-976, (1993); J. Am. Chem. Soc 116, pp 1147-1148, (1994); and J. Chem. Soc., Chem. Commun., pp 117-118 (1995). However none of these publications describe the valuable process according to the present invention in which compounds of Formula (1) having a 2-substituent are converted to the compounds of Formula (2) having the stereochemistry shown above.
Each X and each Y independently is preferably alkyl, --OH, --OR, --OCOR, --SH, --SR, --F, --Cl, --Br, --I, --NH.sub.2, --NHR, --NRR.sup.1, --NHCOR, --NRCOR.sup.1, --CN, --COOR, --COOH, --COR, --CONH.sub.2, --CONHR, --CONRR.sup.1, --NO.sub.2, --N.sub.3, --PRR.sup.1, --P(O)RR.sup.1, --P(O)(OH).sub.2, --P(O)(OROH), --P(O)OROR.sup.1, --S(O)R, --SO.sub.2 R, --SO.sub.2 H or --SO.sub.3 H; more preferably alkyl, --OH, --OR, --OCOR, --SR, --F, --Cl, --Br, --I, --NH.sub.2, --NHR, --NRR.sup.1, --CN or --N.sub.3 ; wherein R and R.sup.1 are each independently alkyl, aryl or aralkyl.
Preferably a, b, c and d are all selected from CY and CH, more preferably they are all CH, i.e. the 6-membered ring they form part of is a benzene ring.
When Z is CH.sub.2, CHR, NH or S it is possible to form derivatives in minor amounts in which one of the H atoms in the Z group is replaced by --OH during the process. For example the compound of Formula ##STR5## 1S-hydroxy-2-ketoindan and 2R-hydroxy-1-ketoindan are formed as minor components.
When any one of R, R.sup.1, X, Y or Z is or contains an alkyl the alkyl is pref
REFERENCES:
Mitrochkine et al: Synthesis of Enantiomerically Pure (1S,2R)-Epoxy Indane and cis-(1R,2S)-2-Amino-1-indanol. Tetrahedron Asymmetry vol. 6, No. 1, pp 59-62, 1995 XP002014730, see the whole document.
Boyd et al: "Structures and Stereochemical Assignments of Some Novel Chiral Synthons Derived from the Biotransformation of 2,3-Dihydrobenzofuran and benzofuran by Pseudomonas putida", Tetrahedron Asymmetry vol. 4, No. 6, pp 11307-1324 1993, XP002014731 see the whole document.
Chemical Abstracts, vol. 122, No. 13, Mar. 27, 1995, abstract No. 155016, Resnick et al: "Regiospecific and stereoselective hydroxylation of 1-indanone and 2-indanone by naphthalene dioxygenase and toluene dioxygenase", XP002014734 see abstract & Appl. Environ.Microbiol.(1994),60(9),3323-8.
Chemical Abstracts, vol. 117, No. 23, Dec. 7, 1992, abstract No. 229878, Brand et al: "Stereospecific hydroxylation of indan by Escherichia coli containing the cloned toluene dioxygenae genes from Pseudomonas putida F1", XP002014735, see abstract & Appl Environ. Microbiol.(1992)58(10),3407-9 Coden: AEMIDF; ISSN:0099-2240.
Computer Caplus 1983:160361 Boyd et al J. Chem Soc. Perkin Trans. 1 (1982) (11) pp 2767-70, 1983.
J. Chem Soc., Chem.Commun. (1995), (2), 117-18 Coden:JCCCAT;ISSN: 0022-4936, 1995, XP002014732. Allen et al:"Enntioselective bacterial biotransformation routes to cis-diol metabolites of monosubstituted benzenes, napthalene and benzocycloalkenes of either absolute configuration" see the wole document.
J. Chem So., Chem Commun. (1989), (6), 339-40 Coden: JCCCAT;ISSN: 0022-4936, 1989, XP002014733, Boyd et al: "Stereospecific bensylic hydroxylation of bicyclic alkenes ny Pseudomonas putida: isolation of (+)-R-1-hydroxy-1,2-dihydronaphthalene, an arene hydrate of naphthalene from metabolism of 1,2-dihydronaphthalene" see the whole document.
Blacker Andrew John
Bowers Nigel
Boyd Derek Raymond
Dalton Howard
Lilling Herbert J.
Weber Jon P.
Zeneca Limited
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