DD290662A5 - PROCESS FOR PREPARING (1S, 4R) -1-ACYLOXY-4-HYDROXY-CYCLOPENT-2-ENENE - Google Patents

Abstract

The invention relates to a process for preparing * the general formula * in which R 1 is hydrogen, alkyl or aryl. These compounds serve as starting material for the synthesis of optically active prostaglandins and prostaglandin derivatives as well as for the synthesis of cyclopentanoid natural products and their Abkoemmlinge. According to the invention * are prepared by enzyme-catalyzed esterification of * (II) with carboxylic acid derivatives of the general formula (III) in organic solvents, wherein the yield of * the general formula (I) according to the invention at temperatures below 0C under otherwise identical conditions is higher than in known methods for enzymatic esterification. The desired products are present in high enantiomeric excess. Formula (I) {production; stereoselective synthesis; enzyme-catalyzed esterification; * * Carboxylic acid derivative; organic solvents; optically active prostaglandins; lipase; Porcine pancreatic lipase; pancreatin; enantiomeric purity; Increase in yield}

Description

Object of the invention

The object of the invention is to provide the enantioselective synthesis of (1S, 4R) -1-acyloxy-4-hydroxycyclopent-2-enes of the general formula (I) from cis-1-dihydroxycyclopentene-1 in an economical process a significantly higher chemical yield than previously known method at a high enantiomeric excess of the product provides perform.

Explanation of the essence of the invention

The object of the invention is to provide a process for the preparation of (1S, 4R) -1-acyloxy-4-hydroxycyclopent-2-enes of the general formula (I)

(D

where R 'is hydrogen, alkyl or aryl, by enzyme-catalyzed esterification in organic solvents, in which the stereoselective enzymatic esterification of the cis-1,4-dihydroxy-cyclpent-2-ene to corresponding (1S, 4R) -1-acyloxy -hydroxycyclopent ^ -enen the general formula (I) proceeds in higher yields than in known methods. This object is achieved by the present invention, the meso compound cis-i ^ -Dihydroxycyclopent ^ -en of the formula (II)

(II)

(G.O. Schneck, O.E. Dunlap; Angew. Chemie 68,248 [1956]; C.Kaneko, A.Sugimote, 0.Tanaka; Synthesis 1974, 876) with carboxylic acid derivatives of the general formula (III)

R ¹ ~ C-0-R ² !

Ii: ^(lll >

in which R ^{1 is} hydrogen, alkyl or aryl and in which R ^{2 is} hydrogen, alkyl, alkenyl, aryl or acyl, in particular carboxylic acid esters with simultaneous addition of an organic base such as pyridine, triethylamine, 4-N, N-dimethylaminopyridine or imidazole, but also carboxylic acid anhydrides without addition of a base in an organic solvent having a water content between 0 and 20% by volume, preferably between 0 and 5% by volume, in particular a water-miscible organic solvent, such as tetrahydrofuran, but also diethyl ether or toluene in the presence of an animal lipase, of vegetable or microbial origin or of a lipase-containing preparation of animal, vegetable or microbial origin in free or immobilized form, preferably of crude porcine pancreatic lipase in the form of the preparation pancreatin, at temperatures between 0 and -100 ° C, preferably between 0 and -70 ° C is implemented. Surprisingly, in this process procedure (IS ^ RM-Acyloxy ^ -hydroxycyclopent ^ -ene of the general formula (I) with significantly higher yield than in previously known processes for the stereoselective esterification of cis ^, 1,4-dihydroxycyclopent-2-ene and with a obtained high enantiomeric excess.

Contrary to statements in the literature, according to which the polar b2W. water-immiscible solvents are more suitable for enzymatic reactions in an organic medium (Yu L. Khmelnitsky, A. Levashov, N. Klyachko, Enzyme Microb Technol 10, 1988, 1010 and the literature cited therein) proved to be suitable for the reaction under these conditions especially such water-miscible solvents as THF, but also requires diethyl ether and toluene as suitable.

For aqueous media, in the case of alcohol dehydrogenase, a temperature-dependent enantiomeric purity of the product of the enzymatic reaction has been described for certain substrates (E.Keinen, FVHafeli, KK Seih, R. Lamed, J. Am. Chem. Soc., 108 [1986] 162; VT Pham RS Phillips, LG Ljungdahl, J. Am. Chem. Soc., 111 [1989] 1985). In an aqueous

Liquid membrane system is for the esterase-catalyzed hydrolytic resolution of acetoxycyclopentenone at two

different temperatures also described a difference in the enantiomeric purity of the product (E. Meyer;

T.Scheper; Hitzmann; K. Schügerl, Blotechnol. Techn. 2 [1988] 127). The more astonishing and unexpected is that in the organic environment, at low temperatures, instead of a change in the Anantiomerenreinheit of the product is an increase in yield. A reference or patent for the use of enzymes in organic solvents at temperatures below ⁰ ° C.

for the purpose of increasing the yield of stereoselective enzymatic reaction was not found.

embodiments The invention will be explained in more detail with reference to exemplary embodiments without limiting them. example 1

Tine solution of 1 g OOmmol) cis-M-Dihydroxycyclopent ^ -en II, 5ml acetic anhydride in 25 ml of absolute tetrahydrofuran is added at -4 ⁰ C with 5g raw porcine pancreatic lipase in the form of the preparation pancreatin and until reaching a

Enantiomeric excess of 96% at a temperature of -4 ° C stirred. Thereafter, the suspension is filtered and the Filter residue washed with ethyl acetate. The filtrate is concentrated in vacuo. The residue is dissolved in aqueous Natriumhydr ^ encarbonatlösung taken from the by mohr or continuous extraction in ethyl acetate or

another suitable solvent is to extract the products. The ethyl acetate solution of the products is concentrated in vacuo. The residue is purified by flash chromatography or simple filtration through silica gel. This gives 750 mg (53%) of (IS ^ RM-acetoxy ^ -hydroxycyclopent ^ -en of formula I with R '= CH ₃ as colorless crystals of melting point 46 ^o Cbis48 ^o C.

Enantiomeric excess: e.e. 96% 736 mg (40%) of cis-1,4-diacetoxycyclopent-2-ene are also obtained. Example 2 A solution of 0.1 g (1 mmol) of cis-1,4-L ': hydroxycyclopent-2-ene II, 1 ml of trichloroethyl acetate and 0.1 ml of triethylamine in 2.5 ml Tetrahydrofuran (water content: 5%) at -4 ⁰ C with 0.5 g of crude porcine pancreatic lipase in the form of the preparation, pancreatin

added and stirred for 48 hours at a temperature of -4 ⁰ C Thereafter, the suspension is filtered and the filter residue with

Washed with ethyl acetate. The filtrate is concentrated in vacuo. The residue is purified by flash chromatography or simple filtration through silica gel. You get 78mg (55%)

dS / RM-acetoxy-hydroxycyclopentene-1 of the formula I.

Enantiomeric excess: e.e. 94% Example 3 A solution of 0.1 g (1 mmol) of cis-IADihydroxycyclopentene-II, 0.5 ml of acetic anhydride in 2.5 ml of absolute Tetrahydrofuran at -25 ⁰ C with 0.1 g of porcine pancreatic lipase (SERVA) was added and 72 hours at a temperature of

-25 ⁰ C left.

A workup analogous to Example 1 gives 85 mg (60%) of (1S, 4R) -1-acetoxy-4-hydroxycyclopent-2-ene of the formula I. Enantiomeric excess: e.e. 96% Example 4 A solution of 0.1 g (1 mmol) of cis-1,4-dihydroxycyclopent-2-ene II, 1.0 ml of trichloroethyl acetate and 100 ml of triethylamine in 2.5 ml Tetrahydrofuran (water content: 10%) at -25 ⁰ C with 0.5 g crude porcine pancreatic lipase in the form of the preparation Pancreatin added and allowed to stand for 96 hours at a temperature of -25 ⁰ C. A work-up analogous to Example 2 gives 87 mg (61%) of (IS / tRM-acetoxy) -hydroxycyclopent ^ -en of the formula I. Enantiomeric excess: e.e. 95% Example 5 A solution of 0.1 g (1 mmol) of cis-1,4-dihydroxycyclopent-2-ene II, 0.5 ml of acetic anhydride in 2.5 ml of absolute Tetrahydrofuran is added at -7O ⁰ C with 0.5 g crude porcine pancreatic lipase in the form of the preparation pancreatin and 6 days

at a temperature of -70 ⁰ C gehhänssen.

A work-up analogous to Example 1 gives 105 mg (74%) of (IS 1, 2-RM-acetoxy) -hydroxycyclopentene-1 of the formula I. Enantiomeric excess: e.e. 96%

Claims (9)

1. Process for the preparation of (1S, 4R) -1-acyloxy-4-hydroxycyclopent-2-enes of the general formula (I) (D in which R ^{1 is} hydrogen, alkyl or aryl, characterized in that cis-1,4-dihydroxycyclopent-2-enes of the formula (II) oh: (II) - OH ^! with carboxylic acid derivatives of the general formula (III), R ¹ -CO-R ² Il ^(III) in which R ^{1 is} hydrogen, alkyl or aryl and in which R ^{2 is} hydrogen, alkyl, alkenyl, aryl or acyl, in an organic solvent having a water content between 0 and 20% by volume in the presence of a lipase or a lipase-containing preparation at temperatures between 0 and -10ü ° C is implemented. 2. The method according to claim 1, characterized in that the reaction temperature is 0 to -70 ⁰ C. 3. The method according to claim 1 and 2, characterized in that the lipase is a lipase of animal, vegetable or microbial origin or as a lipase-containing preparation, a lipase-containing preparation of animal, vegetable ouo microwave origin is used. 4. Varfahren according to claim 3, characterized in that is used as lipase of animal origin crude porcine pancreatic lipase in the form of the preparation pancreatin. 5. The method according to claim 1 to 4, characterized in that an organic solvent having a water content between 0 and 5 vol .-%, in particular a water-miscible organic solvent, is used. 6. The method according to claim 1 to 5, characterized in that is used as the organic solvent tetrahydrofuran, diethyl ether or toluene. 7. The method according to claim 1 to 6, characterized in that a carboxylic acid ester is used with the addition of an organic base as the carboxylic acid derivative. 8. The method according to claim 7, characterized in that is used as the organic base is pyridine, triethylamine, 4-N, N-dimethylaminopyridine or imidazole. 9. The method according to claim 1 to 6, characterized in that a carboxylic anhydride is used without the addition of a base as the carboxylic acid derivative. Field of application of the invention The invention relates to a process for the preparation of (IS ^ Rl-i-acyloxy-'t-hydroxycyclopent ^ -enen of the general Formula (I) wherein R 'represents hydrogen, alkyl or aryl. The compound of general formula (I) is starting material for the synthesis of optically active prostaglandins and Prostaglandin derivatives used for the prevention and treatment of cardiovascular diseases, for gynecological indications, for the prevention and treatment of gastric and intestinal ulcers in human medicine and for birth and Ore synchronization in animal production are useful as well as for the synthesis of cyclopentanoid natural products and their Descendants. Characteristic of the known state of the art (1 S, 4R) -1 -Acyloxy ^ -hydroxycyrlopent ^ -ene of the general formula (I) were previously accessible by asymmetric enzyme-catalyzed hydrolysis of the meso compounds cis-1,4-Diacyloxycyclopent-2-ene by means of microorganisms or isolated Enzymes of various origins (PE ^ S 2552871; S.Takano, K.Tanigawa, K.Ogasawara; J. Chem. Soc. Chem. Commun. 1976 189; JP 78/005140; S.Miura, S.Kurozumi, T.Toru.T.Tanaka, M.Kobayashi, S.Matsubara, S.lshimoto; Tetrahedron 32, 1893 [1976]; DE-OS 3439b98; K. Laumen, M. Schneider; Tetrahedron Lett. 25, 5875 [1984]; Y.-F. Wang, C.-S.Chen, G.Grdaukas, C.J.Sih; J. Am. Chem. Soc. 106 [1984] 3695; K. Laumen, E.H. Reimerdes, M. Schneider; Tetrahedron Lett. 26,407 [1985]; DE-OS 3620646; DD-WP 273448). The enantiomeric excess in these reactions is between 4 to 9%. With Exception of the method proposed in DE-OS 3620646 are the optical purities at a maximum of 74%, d. H. to the significant loss of substance is connected. Certain enzymes, e.g. As the acetylcholinesterase of the shaking chamber or certain lipases, provide (1 R, 4S) -1-acyloxy-4- hydroxycyclopent-2-ene (D.R.Deardorff, A. J. Mathews, D.S. McMeekin, C. L. Craney, Tetrahedron Lett 27,1255 [19861; K. Laumen, M.P. Schnueider, J. Chem. Soc. Chem. Commun. 1986.1298; T. Sugai, K. Mori; Synthesis 198819), i. the optical Antipodes of (I). For the conversion of (IR) -SM-acyloxy-hydroxycyclopent-1-ene into (1S, 4R) -1-tetrahydropyranyloxy-4-hydroxycyclopent-2-ene, a compound which leads analogously to the compound of general formula (I) in the series of natural prostaglandins, then two more synthetic steps are required. All of these enantioselective hydrolyses run in the aqueous medium. This has the disadvantage of causing problems regarding Solubility of the substrate and in the isolation of the products can come. In 1987, the synthesis of (1 S, 4R) -1-acyloxy-hydroxycyclopent-1-enes of the general formula (I) by enzyme-catalyzed Transesterification of cis-i ^ -Dihydroxycyclopent ^ -en with carboxylic acid esters in the presence of a base at temperatures between O ⁰ C and 80 ° C described in organic solvents (Theil, F .; Ballschuh, S .; Schick, H .; Hafner, B .; Main, M .; palm, H.-J .; Black, S .; 1987, DD-WP 264707). This process gives the compounds of general formula (I) with a high Enantiomeric excess. However, the yield of at most 48%, which is given for the process at 0 to 8O ⁰ C, criticism. This is especially true when the high expenditure of energy and time just for the most common, d. H. which accounts for the photochemical synthesis step in the preparation of the cis-1,4-dihydroxycyclopent-2-ene.