DD290663A5 - 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 R1 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, the esterification of * (II) with carboxylic anhydrides of the general formula (III) in organic solvents is produced by enzyme-catalyzed, although the reaction rate of the esterification is higher than otherwise known methods for enzymatic esterification under otherwise identical conditions despite the omission of a basic additional catalyst. The desired products are present in high enantiomeric excess. Formula (I) {production; stereoselective synthesis; enzyme-catalyzed esterification; * * Carboxylic anhydride; organic solvents; optically active prostaglandins; lipase; Porcine pancreatic lipase; pancreatin; enantiomeric purity}

Description

Field of application of the invention The invention relates to a process for the preparation of (1 S ^ RM-Acyloxy ^ -hydroxycyclopent ^ -enen of the general Formula (I) in which R ^{1 is} 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, 4 RJ-i-Acyloxy ^ -hydroxycyclopent ^ -enes 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 (DE-AS 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 3439598; K. Laumen, M. Schneider; Tetrahedron Lett. 25, 5875 [1984]; Y.-F. Wang, C-S.Chen, G.Girdaukas,

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 and 95%. With Exception of the method proposed in DE-OS 3620646, the optical purities are at most 74%, d. h., to Obtaining a product with an enantiomeric excess> 95% must be followed by a cleaning, which inevitably with

considerable. Substance loss is associated.

Certain enzymes, e.g. As the acetylcholinesterase of the shaker or certain lipases, provide (1 R, 4 S) -1 -Acyloxy-4-

hydroxycyclopent-2-ene (D.R. Deardorff, A.J. Matthews, D.S. McMeekin, CL Craney, Tetrahedron Lett 27,1255 (1986):

K. Laumen, M.P. Schneider, J. Chem. Soc. Chem. Commun. 1986.1298; T. Sugai, K. Mori; Synthesis 1988, 19), d. H. H ^ optical Antipodes of! '). For the conversion of (1R, 4S) -1-acyloxy-4-hydroxycyclopent-2-ene into (1S, 4R) -1-tetrahydropyranyloxy-4-hydroxycyclopent-2-one

en, a compound which leads analogously to the compound of the 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 (1S, 4R) -1-acyloxo-4-hydroxycyclopent-2-enes of the general formula (I) was accomplished by enzyme-catalyzed transesterification of cis-1-dihydroxycyclopentenes with carboxylic acid esters in the presence of an inorganic base Solids, (Theil, F., Ballschuh, S., Schick, H., Hafner, B., Haupt, M .; Palm, H.-J., Schwarz, S .;

1987, DD-WP 264707). This process gives the compounds of the general formula (I) in a satisfactory chemical yield and with a high enantiomeric excess.

Transesterification is by nature an equilibrium process. This forces you to use a considerable surplus Acylating agent. In such an equilibrium process, the rate of product formation decreases with that in the course of the reaction Increasing the product concentration constantly increasing rate of the reverse reaction. The use of activated esters accelerates this transesterification, but causes much higher costs for the Starting substance. In addition, the use of the base appears as a second catalyst, which is described as essential for the transesterification,

criticism.

Therefore, an acylating agent was sought which avoids the disadvantages mentioned. Carboxylic acid anhydrides are basic chemicals and are commonly used in the art. a. for the unselective chemical acylation of Hydroxy groups used in organic solvents. Porcine pancreatic lipase is preferred as the lipase preparation because of its low cost (T. Sugai, K. Mori; Synthesis 1988, 19; K. Laumen, M.P. Schneider; J. Chem. Soc. Chem. Commun. 1986, 129) is used for the acylation with carboxylic acid anhydrides

because of too little activity or too little enantioselectivity described as unsuitable (Bianchi, D., Cesti, P., Battistel, E.,

1988, J. Org. Chem. 53, 5531).

With regard to the solvent, it is stated in the literature that the less polar or water-immiscible solvents are more suitable for enzymatic reactions in the organic medium (Yu L. Khmelnitsky, A. Levashov, N. Klyac ^h "'> Enzymes Microb Technol The use of carboxylic anhydrides as acylating agents for esterase-catalyzed acylations in organic solvents also describes the water-immiscible solvents as the more favorable ones (T. Suzuki, K. Ohta, F. Kikumoto, EP 0269453).

Object of the invention

The aim of the invention is the enantioselective synthesis of (1 S, 4 RM-acyloxy) -hydroxycyclopentylenes of the general formula (I) from cis-1,4-dihydroxycyclopent-2-enes in an economical process comprising a satisfactory chemical yield and high enantiomeric excess guaranteed? jszuführen.

Explanation of the essence of the invention

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

(I)

in which R ¹ denotes hydrogen, alkyl or aryl,

by enzyme-catalyzed esterification in organic solvents with an economical acylating agent of non-esteric character and without the use of a base as a catalytic additive in which the enzymatic esterification of the cis-'M-dihydroxycyclopent ^ -ene to corresponding (1 S ^ RM-Acyloxy ^ - hydroxycyclopentene-Z-enes of the general formula (I) proceeds under otherwise analogous conditions faster than in known processes.This object is achieved by according to the invention the meso-compound cis-IADihydroxycyclopsnt ^ -en of the formula (II)

(II)

(G.O. Schenck, D.E. Dunlap; Angeww.Chemie68,248 [1956]; C.Kaneko, A.Sugimoto, S.Tanaka; Synthesis 1974,876) with carboxylic acid anhydrides of the general formula (III)

O ^(lll>

R ² -c '

in which R ¹ and R ^{2 are} identical or different hydrogen, alkyl or aryl, preferably with aliphatic carboxylic anhydrides with R ¹ and R ² It. General formol (III) is hydrogen or C ₁ to C ₅ , in an organic solvent with a Water content between C and 20 vol .-%, preferably between 0 and 5 vol .-%, in particular a water-miscible organic solvent such as tetrahydrofuran or 1,4-dicxane, but also diethyl ether or toluene in

Presence of a lipase of animal, vegetable or microwell origin or a lipase-containing animal preparation,

vegetable or microwave origin in free or immobilized form, preferably of crude porcine pancreatic

Lipase in the form of the preparation pancreatin, at temperatures between 0 and 8O ⁰ C, preferably between 5 and 35 ° C, implemented Surprisingly, in this process procedure (1 S, 4P1-1-acyloxy ^ -hydroxycyclopent ^ -ene of the general Formula (I) with a high Enantlomerenüberschuß and obtained in a satisfactory chemical yield. Contrary to statements in the literature, according to which the polar or water-immiscible solvents for enzymatic Reactions in organic environment are more suitable (Yu.L. Khmelnitsky, A. Levashov, N. KIyachko, Enzyme Microb'Technol.

10,1988,710 and cited in the literature), especially those water-miscible proved for the implementation

Solvents such as THF and dioxane, also requires diethyl ether and toluene as suitable. The great enantioselectivity of porcine pancreatic lipase in the purified as well as in the raw state in the form of the preparation Pancreatin, which is used for acylation with carboxylic acid anhydrides because of too low activity or too low enantioselectivity

Bianchi, P. Cesti, E. Battistel, 1988, J. Org. Chem., 53, 5531) was particularly surprising.

A further advantage is that the base described as essential for the transesterification (Theil, F., et al., DD-WP 264707)

is not used according to the invention and that the reaction rate of the reaction of cis-1,4-dihydroxycyclopent-2-enes of the formula (II) to (1 S, 4 R) -1 acyloxy-4-hydroxycyclopent-2-enes of the general formula (I) In the invention

Procedure without base addition under otherwise analogous conditions is even higher than in the method according to (Theil, F.,

ot al., DD-WP 264707) with base addition.

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

A solution of 1 g (10 mmol) of cis-1,4-dihydroxycyclopent-2-ene II, 5 ml of acetic anhydride in 25 ml of absolute tetrahydrofuran is added at 20X with 5 g of crude porcine pancreatic lipase in the form of the preparation pancreatin and until reaching an enantiomeric excess of 96% stirred at diner temperature of 20 ° C. Thereafter, the suspension is filtered and the filter residue washed with ethyl acetate. The filtrate is concentrated in vacuo. The residue is taken up in aqueous sodium bicarbonate solution from which the products are extracted by multiple or continuous extraction in ethyl acetate or other suitable solvent. 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 620 mg (44%) (1 S ^ RM-acetoxy ^ -hydroxycyclopent ^ -en of the formula I with R 'is CH ₃ as colorless crystals of melting point 46 ⁰ C to 48 ⁰ C.

 Enantiomeric excess: e.e. 96%

In addition, 850 mg (46%) of cis-1 ADiacetoxycyclopent ^ -en are obtained, which can be re-esterified after deacetylation.

Bet game 2

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 in 2OX with 0.1 g of porcine pancreatic lipase (SERVA) and Stirred at a temperature of 2O ⁰ C for 8 hours. A work-up analogous to Example 1 gives 54 mg (38%) of (1S) -H-acetoxy-hydroxycyclopentene-1 of the formula I. Enantiomeric excess: ee 94%

Example 3 A solution of 60 mg (0.6 mmol) of cis-1,4-dihydroxycyclopent-2-ene II, 0.3 ml of acetic anhydride in 1.5 ml of tetrahydrofuran

(Water content: 5%) at 20X with 100mg Pseudomonas sp. Lipase is added and stirred for 24 hours at a temperature of 20X.

A work-up analogous to Example 1 yields 26 mg (30%) of (1S, 4R) -1-acetoxy-4-hydroxycyclopent-2-ene of the formula I. Enantiomeric user: e.e. 30% Example 4 A solution of 0.1 g (1 mmol) of cis-1,4-dihydroxycyclopent-2-ene II, 0.5 ml of t-acetic anhydride in 2.5 ml of absolute dioxane

at 20 ° C with 400mg crude porcine pancreatic lipase in the form of the preparation pancreatin and 10 hours at a

Temperature of 20 ⁰ C stirred. A work-up analogous to Example 1 gives 58 mg (41%) of (1S, 4R) -1-acetoxv-4-hydroxycyclopent-2-ene of the formula I. Enantiomeric excess: e.e. 83% Example 5 A solution of 60 mg (0.6 mmol) of cis-1,4-dihydroxycyclopent-2-ene II, 0.3 ml of acetic anhydride in 1.5 ml of diethyl ether

(Water content: 10%) is added at 20X with 200mg crude porcine pancreatic lipase in the form of the preparation pancreatin and stirred for 10 hours at a temperature of 2O ⁰ C.

A workup analogous to Example 1 gives 33 mg (39%) of (1 S ^ RM-acetoxy-hydroxycyclopentene-1 of the formula I. Enantiomeric excess: e.e. 37% Examples A solution of 60 mg (0.6 mmol) of cis-M-dihydroxycyclopentene-II, 0.3 ml of acetic anhydride in 1.5 ml of tetrahydrofuran

at 7 ° C with 200mg crude porcine pancreatic lipase in the form of the preparation pancreatin and 30 hours in a

Temperature of 7 ° C stirred. A work-up analogous to Example 1 gives 38 mg (44%) of (1S, 4R) -1-acetoxy-4-hydroxycyclopent-2-ene of the formula I. Enantiomeric excess: e.e. 94% Example 7 A solution of 60 mg (0.6 mmol) of cis-1-dihydroxycyclopentene-II, 0.3 ml of acetic anhydride in 1.5 ml of absolute Tetrahydrofuran is mixed at 35 ⁰ C with 200mg crude porcine pancreatic lipase in the form of the preparation pancreatin and

Stirred for 18 hours at a temperature of 35 "C.

A work-up analogous to Example 1 gives 31 mg (36%) of (1 S ^ Rl-i-acetoxy ^ -hydroxycyclopent ^ -en of the formula I. Enantiomeric excess: e.e. 64%

Claims (8)

1. Process for the preparation of (1S) -NH-acyloxy-hydroxycyclopent-1-enes of the general formula (I) OH (I) in which R ^{1 is} hydrogen, alkyl or aryl, characterized in that cis-1,4-dihydroxycyclopent-2-enes of the formula (II) OH OH with carboxylic anhydrides of the general formula in which R ¹ and R ^{2 are} identical or different hydrogen, alkyl or aryl, is reacted in an organic solvent having a water content between 0 and 20 vol .-% in the presence of a lipase or a lipase-containing preparation at temperatures between 0 and 8O ⁰ C. 2. The method according to claim 1, characterized in that as the carboxylic anhydride, an aliphatic carboxylic acid anhydride with R ¹ and R ² It. General formula (III) is equal to hydrogen or equal to C ₁ to C ₆ is used. 3. Process according to Claims 1 and 2, characterized in that no base is added. 4. Process according to Claims 1 to 3, characterized in that a lipase of animal, vegetable or microwave origin or lipase-containing preparation of a lipase-containing preparation of animal, vegetable or microwave origin is used as the lipase. 5. The method according to claim 4, characterized in that is used as lipase of animal origin crude porcine pancreatic lipase in the form of the proteoate pancreatin. 6. Process according to Claims 1 to 5, characterized in that an organic solvent having a water content of between 0 and 5% by volume, in particular a water-miscible organic solvent, is used as the organic solvent. 7. The method according to claim 1 to 6, characterized in that is used as the organic solvent, in particular tetrahydrofuran or 1,4-dioxane, but also diethyl ether or toluene. 8. The method according to claim 1 to 7, characterized in that the reaction takes place at a temperature between 5 and 35 ^C C.