NO850847L - Prostaglandin intermediates - Google Patents

Description

The present invention relates to prostaglandin intermediates and a method for their production. More particularly, the invention relates to compounds of formula I

wherein Z is >C=0 or >C^ forms together with the oxygen atom to which it is bound a hydrolysable ester group; R together with the oxygen atom to which it is bound forms a hydrolyzable ether group; and t denotes a trans configuration;

diastereoisomeric isomers thereof of which the ring substituents have the opposite steroconfiguration to that given above and mixtures thereof.

As used in this application, the term "lower alkyl" includes both straight and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl and propyl, preferably methyl. As used herein, the term "lower alkoxy" means groups having from 1 to 7 carbon atoms such as methoxy and ethoxy. As also used herein, the expression "lower alkanoic acids" means an alkanoic acid with from 1 to 7 carbon atoms such as formic acid and acetic acid.

As further used herein, the term "halogen" or "halo", unless otherwise stated, means all halogen atoms such as fluorine, chlorine, bromine and iodine.

As also used herein, the term "aryl" means mononuclear aromatic hydrocarbon groups such as phenyl which may be unsubstituted or substituted in one or more positions with a lower alkylenedioxy, a halogen, a nitro group,

a lower alkyl or a lower alkoxy substituted and polynuclear aryl groups such as naphthyl, anthryl, phenanthryl, azilyl, etc., which may be substituted with one or more of the previously mentioned groups. The preferred aryl groups

per are substituted and unsubstituted mononuclear aryl groups, especially phenyl. The term "aryl lower alkyl" means groups in which aryl and lower alkyl are defined as above, especially benzyl. The term "aryl lower alkanoic acid" means acids in which "aryl" and "lower alkanoic acid" are defined as above, especially benzoic acid.

As used herein, the term "hydrolyzable protecting group" refers to any protecting group that can be hydrolyzed to yield the group that it protects. Functional hydroxy groups can be protected through the formation of hydrolyzable esters, acetals, ketals or ethers. Exemplary groups useful for forming esters to protect organic acids are lower alkyl groups or halo lower alkyl groups etc. A suitable ether protecting group is e.g. the hydrolyzable lower alkyl ethers such as t-butyl, tetrahydropyranyl ethers. Other ether groups are aryl methyl ethers such as benzyl, benzhydryl, or trityl ethers or alpha-lower alkoxy lower alkyl ethers, e.g., methoxymethyl, methoxypropyl or allyl ethers, or tri(substituted)silyl ethers in which the substitution is lower alkyl and/or aryl such as trimethyl silyl ether or dimethyl tert-butyl silyl ethers and dimethyl phenyl ethers.

In the pictorial representations of the compounds in this application, a thickened pointed line (f) indicates a substituent that is in the beta orientation (which is in the molecular plane), a dashed line (=) indicates a substituent that is in the alpha orientation (below the molecular plane) and a wavy line h^*) indicates a substituent that is either in the alpha or beta orientation or mixtures of these isomers.

Another aspect of the present invention relates to a process for the preparation of a compound of formula I in which Z is>C=0, diastereomeric isomers thereof where the ring substituents have the opposite stereoconfiguration from that shown in formula I above and mixtures thereof, which method consists of reacting a compound of formula in which X is halogen and R and t are as above with a compound of formula

where R"*" is as above,

in an anhydrous, inert organic solvent medium containing as a catalyst a salt or complex of a transition metal and then treating the reaction product with a protonating agent.

In the process above, a compound of formula VI is reacted with a compound of formula III to form a compound of formula VII-A or VII-B

or mixtures thereof.

When the CH^ group has alpha orientation on the cyclopentene ring

in the compound of formula III, this reaction forms the compound of formula VII-A. When the CH^ group, on the other hand, has beta orientation on the cyclopentene ring in the compound of formula III, the reaction forms a compound of formula VII-B. If the compound of formula III is present as a mixture of alpha and beta methyl compounds, this reaction forms a mixture of the compounds of formula VII-A and VII-B. Accordingly, this reaction with the zirconium reagent of formula VI introduces the protected 3-hydroxy-4,4-dimethyl-1-octenyl side chain in a stereospecific manner depending on the stereoposition of the methyl group on the cyclopentenyl ring in the compound of formula III. Consequently, through this reaction the methyl group and the octenyl side chain on the cyclopentyl ring are introduced in a stereospecific

trans relationship to each other. Any conventional inert organic solvent can be used in carrying out this reaction whereby aromatic hydrocarbon solvents such as benzene and toluene and ether solvents such as tetrahydrofuran are particularly preferred. When carrying out this reaction, temperatures in the range -20°C to 50°C can be used, whereby temperatures from approx. -10°C to 25°C

is particularly preferred. The coupling reaction of the compound of formula VI with the compound of formula III is usually carried out in the presence of a salt or complex of a transition metal catalyst. Among the catalysts are salts or complexes of nickel, cobalt, iron, manganese and palladium. When carrying out this reaction, conventional salts or complexes of transition metals can be used. Generally, it is preferred to carry out this reaction using a complex or salt of nickel (I) as catalyst, which catalyst is generated in situ in this reaction using a nickel (II) salt or complex and a reducing agent. Conventional nickel (II) complexes or salts and reducing agents can be used to form the nickel (I) catalyst. Among the preferred nickel (II) complexes or salts for forming the nickel (I) catalyst is nickel (II) acetylacetonate. Among the preferred reducing agents is diisobutylaluminum hydride (DIBAL).

The compounds of formula VII-A and VII-B or mixtures thereof are converted to the corresponding compounds of formula I wherein Z is ^C=0 by treatment with a protonating agent. Any conventional protonating agent can be used when carrying out this reaction. Among the conventional protonating agents are included anhydrous or aqueous organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, etc. This protonation preferably takes place in an anhydrous medium. This reaction is carried out using a conventional inert organic solvent medium. Among the preferred inert organic solvents are ethers such as tetrahydrofuran, diethyl ether, dioxane, toluene, benzene, etc.. It 6

preferred protonating agent is hydrochloric acid in its anhydrous form, i.e., hydrogen chloride. When this reaction is carried out, temperature and pressure are not critical and this reaction can be carried out at room temperature.

Protonation of the compound of formula VII-A and/or VII-B produces the compound of formula I wherein Z is C=0 and/or the corresponding diastereomeric isomer with the ester group attached to the cyclopentyl moiety on the same side as the methyl substituent.

Therefore, this protonation introduces the ester group into the cyclopentene ring in a stereospecific manner. During the protonation with a hydrohalic acid, bis(cyclopentadienyl)-zirconium dihalide is formed as a by-product. This zirconium halide can be recovered from the reaction mixture and used to recover the zirconium reagent of formula X. Another aspect of this invention relates to a process for preparing a compound of formula

wherein R and t are as above, diastereomeric isomers thereof wherein the ring substituents have the opposite stereoconfiguration to that given above and mixtures thereof, which consist of treating a compound of formula I wherein Z is

>C=0, diastereomeric isomers thereof wherein the ring substituents have the opposite stereoconfiguration to that given above and mixtures thereof, with an aluminum or borohydride reducing agent in the presence of an agent to deactivate the aluminum hydride reducing agent.

Reduction of the compound of formula V with aluminum or borohydride reducing agents stereospecifically reduces the keto group to a hydroxy group such that the hydroxy group is alpha to the cyclopentane ring. On the other hand, when the keto group in the diastereomeric isomer of the compound of formula V is reduced, the hydroxy group will form beta to the cyclopentane structure. This reduction reaction is carried out using an aluminum or borohydride reducing agent. Among the preferred reducing agents are the alkyl aluminum hydrides and the alkali metal borohydride reducing agents. Any conventional dialkylaluminum hydride reducing agent can be used, with diisobutylaluminum hydride being particularly preferred. When carrying out this reaction with an aluminum hydride reducing agent, an organic compound is usually used which conventionally deactivates the aluminum hydride reducing agents. Any conventional organic agent for deactivating aluminum hydride reducing agents can be used in accordance with this invention. Among the preferred deactivating agents are the di- or tri(alkyl) substituted phenols such as 2,6-di-tert-butyl-4-methyl-phenol, 2,3,6-trimethylphenol, etc. Any conventional alkali metal borohydride can be used, whereby potassium tris(sec-butyl)borohydride and sodium borohydride are preferred. When carrying out this reaction, temperatures from -30 to 10°C are usually used. With an alkali metal aluminum hydride reducing agent, such as lithium aluminum hydride, it is usually preferred to use very low temperatures. When carrying out this reaction, any conventional inert organic solvent which is liquid at -30°C to 10°C can be used.

Among the preferred solvents are the aromatic hydrocarbon solvents such as toluene, benzene, etc.

In the reduction reaction, compounds of formula I are formed in which Z is and their diastereomeric isomers where

^ H

the ring substituents have the opposite stereoconfiguration, as transition intermediates which are converted under these reducing conditions to the lactones of formula V and their corresponding diastereomeric isomers. The connection with

lactonizes stereospecifically to the compound of formula V and the diastereomeric isomer of the compound of formula I lactonizes stereospecifically to the diastereomeric isomer of the compound of formula V. If one uses the compound of formula III in which the methyl group is alpha to the plane of the cyclopentene ring, the various reactions of this invention to form the compound of formula V stereospecifically. The compound of formula V can be directly converted into the "anti-secretory" agent of formula IV

as described in US Patent No. 4,227,019.

Accordingly, this synthesis provides a method for forming the compound of formula IV asymmetrically without the necessity of cleavage. On the other hand, mixtures of the compounds of formula I and their diastereoisomers are formed if the compound of formula III is a mixture of alpha and beta isomers. These mixtures can be separated into the individual compounds by conventional means such as chromatography.

The following examples are illustrative but not limiting of the invention according to the claims. In the examples, Jones Reagent was prepared by weighing 134 g of chromium trioxide into a 500 ml volumetric flask and adding approx. 200 ml of water. This mixture was stirred while 120 ml of aqueous sulfuric acid was slowly added. The resulting mixture was cooled to room temperature and water was added to form 500 ml of reagent. In all examples, all temperatures are in degrees Celsius.

Example 1

A 1-liter three-neck round-bottomed flask equipped with one mechanical stirrer, a 250 mL constant addition funnel, and gas inlet was flame-dried under an inert atmosphere. After cooling, 130 g (445 mmol) of dichlorobis(eta 2,4-cyclopentadien-1-yl)zirconium was added to the flask. 400 mL of dry, degassed toluene was transferred through a cannula onto the solid dichloride. A solution of the lithium aluminum hydride bis tetrahydrofuran complex in toluene (103 mL, 111 mmol) was transferred via a cannula to the feed funnel. The constant infusion took one hour and was carried out in the dark (foil-covered bottle). The resulting pale pink-white mixture was stirred for two hours before being filtered through a coarse frit under an inert atmosphere. The solid was purified with 3 x 100 mL of freshly distilled THF and was dried in the dark at 1 mm Hg overnight (15 hours) at 25°C to give 97 g (85%) of snow white chlorbis (eta^-2,4 -cyclopentadien-1-yl) zirconium hydride. Analysis of the percent overreduced dihydride, bis(eta 5-2,4-cyclopentadien-l-yl)dihydrozirconium, was made by adding 25 microliters of dry acetone to a mixture of 0.5 mL of benzene-d-6 and 20 mg of the product. After stirring for 90 min. the clear colorless solution was transferred to an NMR tube for analysis. The analysis of the above sample indicated 98.5% monohydride and 1.5% dihydride.

Example 2

4, 4-Dimethyl-1-octyn-3-one

To a 3 liter three-necked round-bottomed flask equipped with a mechanical stirrer, a thermometer and an addition funnel was added 100.0 g (0.649 mol) of 4,4-dimethyl-1-octyn-3-ol and 1150 ml of acetone p.a. The addition funnel was filled with 241 ml of freshly prepared Jones reagent. The flask was cooled with an ice-methanol bath to -5°C. Jones reagent was slowly added while keeping the temperature below 10°C. The addition lasted approx. 20 min. The reaction was stirred for an additional 10 min. before the mixture was poured into a 6 liter Erlenmeyer flask containing 2.2 liters of petroleum ether and 2.2 liters of ice water. The mixture was stirred for 5 min. and was then transferred to a separatory funnel. The organic layer was separated and the aqueous phase was extracted with 3 x 700 ml of petroleum ether. The combined organic phases were washed with 200 ml of water, 300 ml of saline and were dried over 300 cm 2 of sodium sulfate. The solvent was removed by water jet pressure using a rotary evaporator to give 98.5 g of the crude product. GLPC analysis showed 0.1% of the starting alcohol. Distillation at 17 mm Hg and 78°C gave four fractions.

Example 3

( R )- 4, 4- dimethyl- 1- octyn- 3-ol

To a flame-dried nitrogen-filled 5 liter three-necked round bottom flask, equipped with a reflux condenser, a static nitrogen inlet and a thermometer and a magnetic stirrer was added 245 mL (0.782 mol) of lithium aluminum hydride bis(diethyl ether) complex as a 3.2 M soln. -ning in toluene. A solution of 191 g (1.56 mol) of 3,5-dimethylphenol in 800 ml of diethyl ether (freshly opened jug, passed through basic alumina under a nitrogen atmosphere) was charged into the addition funnel and slowly added over a period of 2.5 hours to The lithium aluminum hydride solution (hydrogen evolution). The reaction was stirred at room temperature for 1.5 hours while 140 g (0.782 mol) of N-methyl-d-ephedrine was added via a solids funnel over a period of 2.5 hours (hydrogen evolution). The resulting solution was stirred at room temperature overnight. The next morning, the reaction was cooled to -17 to -22°C and a solution of

66.6 g (0.438 mol) of 4,4-dimethyl-1-octyn-3-one in 900 ml diethyl ether was added over a 105 minute period. The reaction was stirred for a further 15 min. to form the product. The reaction was then quenched by adding 30 ml of water which was added carefully (hydrogen evolution). After gas evolution ceased, the cooling bath was removed and 1.2 liters of 3 N hydrochloric acid was added. After stirring for 10 min. the organic phase was separated and washed with 800 ml of 3 N hydrochloric acid. The combined acid layers were extracted with 3 x 400 ml of ether and kept for amine recovery. The combined ether phases were washed with 2 x 500 ml of 10% sodium hydroxide solution and 6 x 500 ml of 15% sodium hydroxide. GC analysis showed only traces of residual phenol. The organic phase was washed with 500 ml of water, 500 ml of brine and was dried over 300 cm 3 of sodium sulfate. The ether was removed by water jet pressure using a rotary evaporator. Distillation at 40 mm Hg removed the toluene. The pressure was reduced to 9 mm Hg and 58.3 g (86%) of the product was collected at 78°C. GLPC analysis showed 96% purity. GLPC analysis of (-)-alpha-methoxy--alpha-trifluoromethylphenyl-acetate derivative of the product showed a diastereomeric purity of 98% of (R)-4,4-dimethyl--1-octyn-3-ol.

Example 4

rac-(R)-2-/(1-ethynyl-2,2-dimethylhexyl)oxy/- tetrahydro- 2H

- pyran

Into a dry, nitrogen-filled, 100 ml, two-necked, round-bottomed flask equipped with a magnetic stir bar, a static nitrogen inlet and a reflux condenser was added 539 g (6.39 mol) of freshly distilled dihydropyran, 363 g (2.36 mol) of (R)-4,4-dimethyl-octyn-1,3-ol, and 1.0 g (5.26 mmol) of p-toluenesulfonic acid monohydrate. The reaction was heated in a 105-115°C oil bath for 2 hours. After cooling to a suitable temperature, 46 g (0.33 mol) of potassium carbonate were added. The condenser was replaced with a distillation head and excess dihydropyran was removed at 50 mm Hg.

The product was distilled at 3 mm Hg and 90-105°C to

give 518 g (92%) of the product as a colorless liquid, /alpha/25D 105.4 (c = 1, MeOH).

Example 5

In an argon-purged, 250 mL, 3-necked, round-bottomed flask equipped with a stirrer, a gas inlet, a septum, and a powder addition funnel contained 16.3 g (62.4 mmol) of chlorobis-(eta^-2,4-cyclopentadiene -1-yl)zirconium hydride, was added, 15.9 g (66.8 mmol) of rac-(R<*>)-2-(1-ethynyl-2,2-dimethylhexyl)oxy/-tetrahydro-2 H-pyran and 55 ml of freshly distilled THF (from sodium benzophenone ketyl). The powdered hydride chloride was added to the solution of the acetylene side chain precursor at 20°C in small portions, allowing the solid to react (dissolve with) between additions. The addition required four hours. The solution was stirred for a further 2 hours at 20°C before the THF was removed under vacuum. An amount of 54 moles of THF was recovered.

(E,R)-chlorobis(eta<5->2,4-cyclopentadienyl-1-yl)/(3-tetrahydro-2H-pyran-2-yloxy)-4,4-dimethyl-1-octenyl/zirconium / the vinyl zirconium reagent/ was dissolved in 10 mL of THF for the coupling.

Example 6

A 12 liter, 3 neck, round bottom flask was charged with 474 g (3.04 mol) of (S)-(-)-citronellal in 2.37 L of methanol. The mixture was ozonized at -65°C for 4 1/2 hours and the solvent was removed in vacuo at 45°. The residue was dissolved in 3.79 L of 90% formic acid, a reflux condenser was attached to the dummy and 200 ml of 30% hydrogen peroxide was added to the solution. The mixture was heated to 55° to initiate the reaction, 500 ml of formic acid was added, followed by the dropwise addition of 1.7 L of 30% hydrogen peroxide. The degree of addition was such that it maintained a mild reflux. The mixture was stirred at room temperature overnight, diluted with 1.0 L of saturated brine, and extracted with ethyl acetate (3 x 1.0 L). The extract was dried (MgSO 4 ) and evaporated in vacuo to give 468.7

g of crude (S)-3-methyladipic acid, which was purified by dissolving in 1.5 l of acetonitrile followed by 268 g of morpholine. The mixture was stirred at room temperature overnight and the crystals were collected by filtration. The crystals were dissolved in 200 ml of 25% hydrochloric acid and the mixture was extracted with ethyl acetate (3x11). The extract was dried (MgSO4)

and evaporated to give (S)-(-)-3-methyladipic acid, m.p. 80-83°; /c^/<25>D= -5.95° (ethyl acetate, C = 0.97).

Example 7

A solution of 320 g (2.0 mol) of (S)-(-)-3-methyl-adipic acid in 1.5 L of methylene chloride was cooled to -20° and treated with 1.5 L of cold (-20° ) isobutylene followed by 20 ml of concentrated sulfuric acid. The mixture was held under 200 lb/in 2 pressure of nitrogen for 20 hours and then completely saturated with sodium bicarbonate. The organic phase was collected, dried (MgSC>4), and evaporated to give 443 g of (S)-(-)-3-methyl-hexanedioic acid bis (1,1-dimethylethyl)-ester, /<X/ D = -3.34°; Calculated for GcH„o<0.:>C, 66.14; H, 10.36. Found C, 65.98; H, 10.33.

Example 8

A flame-dried 5-liter, 3-neck, round-bottomed flask equipped with a mechanical stirrer, condenser, and argon inlet was charged with 84.0 g (2.15 mol) of sodium amide and 1.966 mL of toluene. The mixture was stirred at 90°C and treated dropwise with a solution of 4.11 g (1.51 mol) of (S)-3-methylhexanedioic acid bis(1,1-dimethylethyl) ester in 500 ml of anhydrous toluene. The mixture was stirred at reflux for 4 hours then at room temperature overnight, diluted with 200 ml of toluene, acidified with 242 ml of acetic acid, and then diluted with 500 ml of water. The organic layer was collected, washed with 500 ml of saturated brine, dried (MgSO 4 ) and evaporated to give 234 g of 2-(1,1-dimethylethoxy)carbonyl/-(S)-4-methylcyclopentanone, contaminated with approx. 10% of 2-/(1,1-dimethylethoxy)carbonyl/-(S)-3-methyl-cyclopentanone, b.p. 76-82° / 0.25mm; calculated for C11H18°3: C'66'64^H'9.15-Found: C, 66.66; H, 9.26.

Example 9

A 2-liter, 3-necked, round-bottomed flask equipped with a condenser and a mechanical stirrer was charged with 269 g (1.35 mol) of 2-carboethoxy-(S)-4-methylcyclopentanone followed by 145.3 g (1.425 mol ) of ethyl glyoxylate. The mixture was stirred at room temperature overnight to give crude alpha-hydroxy-(S)-4-methyl-1-(1,1-dimethylethoxy)carbonyl/-2-oxocyclopentane acetic acid ethyl ester as a viscous oil. A pure sample of which was obtained by chromatography over silica gel with 10% ethyl acetate in hexane as eluent. Calculated for C15<H>24°6<:><C>' 59'98'H'8'05-Found: C, 59.91; H,

7, 90.

Example 10

A solution of 406.5 g (1.347 M) of alpha-hydroxy-(S)-4-methyl-1-(1,1-dimethylethoxy)carbonyl/2-oxocyclopentane acetic acid ethyl ether in 627 g of trifluoroacetic acid was stirred at room temperature in 2 hours and concentrated in vacuo at 40°. The residue was extracted with 1 liter of ethyl acetate, and washed with 1.75 liters of saturated sodium bicarbonate. The aqueous phase was re-extracted with ethyl acetate (2 x 60 ml) and the combined extracts were dried (MgSO 4 ) and evaporated to give 261 g of alpha-hydroxy-(S)-4-methyl-2-oxocyclopentaneacetic acid ethyl ester, b.p. 95-97°/0.05 mmHg.

Example 11

A solution of alpha-hydroxy-(S)-4-methyl-2-oxo-cyclopentaneacetic acid ethyl ester obtained in Example 10 in 3.9 1 of cyclohexane was treated with 12.30 g of p-toluenesulfonic acid monohydrate. The mixture was stirred at reflux for 3 hours with azeotropic removal of water, cooled to room temperature and washed with 400 ml of saturated sodium bicarbonate. The organic phase was separated, washed with 200 ml of saturated brine, and dried (MgSO 4 ) and evaporated to give 185 g of crude (R)-4-methyl-2-oxo-cyclopentylidene acetic acid ethyl ester.

Example 12

A solution of 184 g (1.01 mol) of (R)-4-methyl-2-oxo-cyclopentylideneacetic acid ethyl ester in 1.84 L of toluene was treated with 17.3 g of 4-dimethylaminopyridine. The mixture was refluxed overnight, cooled to room temperature, and washed with 400 mL of 1N hydrochloric acid, followed by 200 mL of 10% sodium bicarbonate and 300 mL of saturated brine. The organic phase was dried (MgSO 4 ), and evaporated to give 192 g of crude product, which was purified by chromatography on 1.5 kg of silica gel with 10% ethyl acetate in hexane as eluent to give 92.8 g of pure (R) -3-methyl-5-oxo-1-cyclopentene-1-acetic acid ethyl ester, b.p. 80-90°/ 0.03mm; /<25>D = + 91.79° (CHCl 3 , C = 0.99).

Example 13

To a flame-dried, argon-purged, 250 mL three-necked round-bottom flask equipped with a 50 mL membrane-closed addition funnel, gas inlet, a magnetic stirrer, and an additional membrane was added 0.98 g (3.8 mmol) of freshly sublimed and dried nickel(II) acetylacetonate and 8 ml of freshly distilled THF. The mixture was stirred and the resulting solution was cooled to -6°C before 3.8 mL (3.8 mmol) of diisobutylaluminum hydride (DIBAH) in toluene was added over a period of 1 minute. A total of 10.3 g (54.3 mmol, 95% purity in the GC range) of deoxygenated (R)-3-methyl-5-oxo-l-cyclopentene-l-acetic acid ethyl ester /the enone/ was transferred via a cannula to the dropping funnel and 5 min. after DIBAH was added, the enone was added to the nickel(I) solution over a period of 5 min. The vinyl zirconium reagent in THF prepared as in Example 5 was transferred via a cannula to the addition funnel with the addition of 5 ml of THF to ensure full-. permanent transfer. The vinyl zirconium reagent was added over a 5 minute period. The flask was placed in a

bath with a constant temperature of 15°C and stirred for 17 hours.

GC analysis showed that the reaction had reached 97% conversion. The reaction was cooled to -15°C and quenched with 20.5 mL (78 mmol, 1.25 equivalents relative to zirconium) of anhydrous 3.8 N HCL in THF (The solution was freshly prepared by bubbling anhydrous HCL through cold THF and titrate with standardized sodium hydroxide solution). After 5 minutes, 75 mL of THF was added to the thick mixture to facilitate filtration. The mixture was filtered in an inert atmosphere through a medium frit covered with 10 g of anhydrous sodium bicarbonate in an inert atmosphere. The reaction vessel was washed with 2 x 75 ml of THF and filtered through the same substrate. The THF solution was concentrated using a rotary evaporator. The residue was mixed with 250 mL of hexane, vortexed vigorously, and decanted from the dense white solid. The solid was mixed with an additional 250 mL of hexane and filtered. After drying, the crude white bis(cyclopentadienyl)zirconium dichloride weighed 19 g (theory 18.2). The combined hexane portions were filtered to remove 50 mg of finely suspended solids and concentrated under reduced pressure to give a green viscous oil. Most of the olefin formed from protonolysis of excess vinyl zirconium reagent was removed at 80-110°C and .1 mm Hg. The crude product /1S-/lalpha,2beta(1E,3R<*>), 3alpha/-2-/3-/(tetrahydro-2H-pyran-2-yl)oxy/-4,4-dimethyl-1-octenyl/ -3-methyl-5-oxocyclopentaneacetic acid ethyl ester was found to have a purity of 86% in GC area percent. The weight was 23.8 g. (About 48 mmol (89%) based on GC purity). This crude product was used in the next step.

Example 14

A 1 liter, four-necked round bottom flask equipped with a mechanical stirrer, a 250 ml addition funnel, a gas inlet and a thermometer was flame dried in an inert atmosphere. After cooling, 47.0 g (211 mmol) of 2,6-i-tert-butyl-4-methylphenol (BHT) was added followed by 267 ml of toluene from a newly opened bottle. The mixture was stirred and the resulting solution was deoxygenated by bubbling argon through a gas bubbler fitted with a coarse frit for 20 min. 175 ml of diisotuyl aluminum hydride (DIBAL, 0.6 mmol/ml in toluene, 105 mmol) were transferred to the addition funnel by means of a needle. The BHT solution was cooled to -5°C and DIBAL was added at a rate such that the temperature was maintained between 5° and 0°C (30 min.). The resulting clear, colorless solution was stirred at -2°C for 2 hours. The crude /1S-(1α,-2beta(1E,3R<*>),3α-α//- 2-/ 3-/ (tetrahydro-2H-pyran-2-yl)-oxy/-4,4- Dimethyl-1-octenyl/-3-methyl-5-oxocyclopentane-acetic acid ethyl ether prepared in Example 13 (23.75 g) was dissolved in 25 ml of toluene and was deoxygenated as before and was transferred by cannula to the addition funnel using 5 mL of toluene. The DIBAL-BHT solution was cooled to -15°C and the contents of the addition funnel were added over a period of 30 min while keeping the temperature constant. The reaction was stirred for a further 2 h before 13 mL of a saturated sodium sulfate solution was added . The cooling bath was removed and the reaction was stirred for an additional 45 minutes. The mixture was filtered through a "Buchner" funnel fitted with "Whatman" No. 1 filter paper and was rinsed with 2 x 50 mL toluene. The yellow solution was dried with 50 g anhydrous sodium sulfate and the toluene were removed using a rotary evaporator at 10 mm Hg and 40-50° C. The residue was finally heated at 100-110° C at 5 mm Hg

for 20 min. The raw lactone weighed 70g. The HPLC analysis showed a 9 to 1 ratio of major diastereomers /3aR,6aS,4R,3 '-R,5R,E/-3,3a,4,5,6,6a-hexahydro-4-/4,4-dimethyl -3-(tetrahydro-2H-pyran-2-yl)oxy/-1-octenyl/-5-methyl 2H-cyclo-penta/b/furan-2-one to the diastereomer present in lower yield,

/3aS,6aR,4S,3'R,5S,E/-3,3a,4,5,6,6a-hexahydro-4-/4,4-dimethyl-3-/(tetrahydro-2H-pyran-2 -yl)oxy/-1-octenyl/-5-methyl 2H-cyclopenta/b/furan-2-one. BHT was separated by placing a 40% by weight solution in 1% ethyl acetate hexane on a 125 g silica gel column (70-230 mesh). The column was eluted with 600 ml of 1% ethyl acetate hexane and 1 liter of 50% ethyl acetate hexane. The BHT was in the 1% ethyl acetate eluate and the product was in the 50% ethyl acetate eluate. The lactonin-

the retained fraction was concentrated on the rotary evaporator at 100°C and 15 µm Hg to give 16.4 g of the above analyzed mixture of product diastereomers (99% purity by GC; 79% yield based on the starting cyclopentenone).

Example 15

To an argon-purged, 2 liter, three-necked round bottom flask equipped with a mechanical stirrer and a gas inlet was added 161 g (624.35 mmol) of chlorobis(eta<5->2,4-cyclopentadien-1-yl)zirconium hydride, 163 g (684 .53 mmol) of rac-(R)-2-(1-ethynyl-2,2-dimethylhexyl)oxy/-tetrahydro-2H-pyran and 208 ml of freshly distilled tetrahydrofuran (THF). After 15 min. the exothermic reaction began and gave a temperature rise to 30°C. The reaction was cooled to 23°C and then cooled every 15 min. for the next 2 hours until no further increase in temperature was observed. After 4 hours, the reaction became a red-orange solution containing (E,R)-chlorobis(eta<5->2,4-cyclopentaiden-1-yl)/(3-tetrahydro-2H-pyran-2-yloxy)-4, 4-dimethyl-1-octenyl/zirconium.

To a flame-dried argon-purged 3 liter four-necked round-bottomed flask equipped with a mechanical stirrer, a 1.0 liter dropping funnel, a "Claisen" setup equipped with a thermometer and an argon inlet and an intermediate piece equipped with a membrane was added 19 g, (73.96 mmol) freshly sublimed and dried Ni(II) acetylacetonate and 208 ml of freshly distilled THF. The mixture was stirred and the resulting solution was cooled to -15°C while 65 mL (71.5 mmol) of diisobutylaluminum hydride (DIBAL) in toluene was transferred by cannula to the dropping funnel. The DIBAL solution was added during approx. 5 min. The temperature had risen to 15°C after the addition was complete, but was quickly cooled to -10°C. A total of 87.2 g (99% pure,

478.6 mmol) of (R)-3-methyl-5-oxo-l-cyclopentenyl-l-acetic acid ethyl ether was transferred to the dropping funnel by means of a needle and 5 minutes after DIBAL was added, this cyclopentene was added over a five-minute period .

The solution containing (E,R)-chlorobis(eta 5-2,4-cyclopentadien-1-yl)-(3-tetrahydro-2H-pyran-2-yloxy)-4, 4-dimethyl-1- octenyl/zirconium /vinyl zirconium reagent/ was transferred by means of a needle to the addition funnel and 5 min. after the cyclopentene was added, the addition of the vinyl zirconium reagent began. The addition took 30 min. to keep the reaction temperature below 0°. After the addition, the reaction was kept at -6°C for 23 hours.

After 23 hours, the reaction mixture containing the zirconium enolate, /3R-/30, (1E , 3R* ), 4A/-chloro-bis( eta -2,4-cyclopentadien-1-yl/2-ethoxy-2- oxo-ethyl)-3-(tetrahydro--2H-pyran-2-yl)oxy/-4,4-dimethyl-1-octenyl/-4-methyl-1-cyclopentene-1-olatozirconium(-1) was cooled to -15°C before quenching with 180 mL (780.44 mmol) of 4.45 N HCl in THF (1.25 equivalents per zirconium). (The solution was freshly prepared by bubbling anhydrous hydrogen chloride through stirred, cold tetrahydrofuran and titrating with standardized sodium hydroxide solution). After 5 minutes, the viscous mixture was filtered through a layer of 35 g of sodium bicarbonate over a coarse-grained glass frit in an argon atmosphere. The reaction vessel was washed with 5 x 100 ml of THF and filtered through the layer of bicarbonate. The filtrate was

- stripped of solvent with a rotary evaporator at water jet pressure. The product residue was washed with 2 x 250 ml of hexane. At each wash, the mixture was vigorously stirred before the large mass of white crystalline material was allowed to settle. The hexane plants contained a fine suspension of dark solid which was decanted from the dense white solid. The first hexane wash portion was filtered to give 24.3 g of a green-gray black solid of bis(cyclopentadienyl)zirconium dichloride and the second filtration gave 20.15 g of this zirconium chloride as a dried green-gray solid. One

precipitate was formed in the filtered hexane. The hexane had to be filtered twice yielding 3.3 g and 9.2 g of this zirconium dichloride as a white solid before the hexane remained clear. This solid zirconium dichloride, yielded after two decantations weighed 132 g. The total weight of recovered zirconium dichloride solid was 189 g (theory

182.5 g). The hexanes were collected and stripped of solvent on the rotary evaporator to give the product /1S-/lalf a, 2beta ( 1E , 3R* ), 3 alfa a//-2-/3-/tetra ahydro-2H-pyran-2 -yl)oxy/-4,4dimethyl-1-octenyl/-3-methyl-5-oxo-cyclopentaneacetic acid ethyl ester as a green viscous oil. The olefin formed from the protonation of excess vinyl zirconium reagent was distilled from the product at 5 pm Hg and 80-110°C. The product was found to be 93% pure by GLPC (area percentage). The weight of the product (1S-/1alpha,2beta/1E,3R<*>), 3alpha//-2-/3-/(tetrahydro-2H-pyran-2-yl)oxy/-4,4-dimethyl-1-octenyl /-3-methyl-5-oxocyclopentaneacetic acid ester was 215 g (93% pure, 473 mmol) for a yield of 98%.

Example 16

A 5 liter three-necked round bottom flask equipped with a mechanical stirrer, a one liter dropping funnel equipped with a membrane and a "Claisen" apparatus containing a gas inlet and a thermometer were flame dried under argon. After cooling, 426 g (1.93 mol) of 2,6-di-tert-butyl-4-methyl-phenol (BHT) were added followed by 2.3 L of toluene. The mixture was stirred to dissolve the BHT and was deoxygenated by passing argon through a gas bubbler fitted with a coarse frit for 20 min. 898 ml diisobutylaluminum hydride (DIBAL, 1.1 mmol/ml in toluene 988 mmol) was transferred to the dropper using a needle. The BHT toluene solution was cooled to -5°C and DIBA1 was added over 30 min. at a rate such that the temperature was maintained between -5°C

and 0°C. The clear colorless solutions containing bis/2,6-di-tert-butyl-4-methylphenoxy/aluminum hydride were stirred at -2°C for 2 hours under Ar. 215 g (93% pure GLPC, 473 mmol) of /1S-/lalfa,2beta (1E,3R<*>), 3alpha//-2-/3-/(tetrahydro-2H-pyran-2-yl)oxy /-4,4-dimethyl-octenyl/-3

-methyl-5-oxo-cyclopentaneacetic acid ethyl ester was dissolved in 200 ml of toluene and deoxygenated for 20 min. as described above. This toluene solution was transferred via a cannula to the dropping funnel and added over thirty minutes. to the clear colorless solution cooled to -15°C. During the addition, the temperature was kept at -15°C +2°C<R>e<ak->

The reaction was stirred for 2 hours after the addition was complete. To the solution at -15°C was added 50 ml of a saturated aqueous ^£30^ solution. The temperature rose to 0°C and was then cooled to -8°C. A TLC indicated incomplete cyclization. The solution was removed from the cooling bath and another 50 ml of saturated SiO 2 solution was added and stirred until the temperature rose to 25°C, a TLC plate indicated complete cyclization with 2 major spots and 2 minor spots (THP diastereomers). After stirring for 30 min. at 25°C, the mixture was filtered through a "Buchner" funnel equipped with filter paper, and washed with 2 x 200 ml of toluene, dried with 50 g of anhydrous sodium sulfate and filtered. The toluene was evaporated using a rotary evaporator at 10 mm Hg and in a 40°C water bath and the remaining toluene was removed by heating to 100-110°C at 5 µm Hg for 20 min. The crude weight of the product /3aR,6aS,4R,3'R,5R,5/-3,3a,4,5,6,6a-hexa-hydro/-4-/4,4-dimethyl-3-/(tetrahydro -2H-pyran-2-yl)oxy/-1-octenyl/-5-methyl-2H-cyclopenta/b/furan-2-one was 613 g. The analysis of the crude product showed a ratio of diastereomers of 92 to 8. BHT was separated by placing a 40% by weight solution of the crude product containing as solvent 19% by volume EtOAc in 99% by volume/hexane on 1 kg of silica gel (70-230 mesh). The silica gel column was gradient eluted using hexane diluted with ethyl acetate in the sequence shown below:

The combined fractions with products were as shown below.<*>

BHT was present in fractions 1, 2 and 3. The combined fractions were evaporated on a rotary evaporator and the remaining solvent was evacuated in high vacuum at 5 pm Hg and 100°C. The yield of /3aR,6aS,4R,3 'R,5R,E/-3,3a,4,5,6,6a-hexahydro-4-(4,4-dimethyl-3-/(tetrahydro-2H-pyran -2-yl)oxy/-1-octenyl/-5-methyl-2H-cyclopenta/b/furan-2-one based on the starting cyclopentenone compound was 80%.

Claims (10)

1. Process for preparing a compound of formula I ;R^ taken together with the oxygen atom to which it is attached forms a hydrolyzable ester group; R taken together with the oxygen atom to which it is attached forms a hydrolysable ether group; and t denotes a trans configuration; diastereomeric isomers thereof where the ring substituents have the opposite stereoconfiguration to that given above and mixtures thereof, characterized by reacting a compound of formula VI wherein X is halogen and R and t are as above with a compound of formula III wherein R"'" is as above, in an anhydrous, inert organic solvent medium containing as a catalyst a salt or complex of a transition metal and then treating the reaction product with a protonating agent. 2. Method according to claim 1, characterized in that a complex or salt of nickel (I) is used as catalyst. 3. Method according to claim 1, characterized in that the reaction between the compound of formula III and the compound of formula IV is carried out at -20° to 50°C. 4. Method according to claim 1, characterized in that the protonating agent is water. 5. Method according to claim 1, characterized in that the protonating agent is an organic or inorganic acid. 6. Process for the preparation of a compound with wherein R and t are as in claim 1 and diastereomeric isomers thereof where the ring substituents have the opposite stereoconfiguration of that given above and mixtures thereof, characterized by treating a compound of formula I in claim 1 , wherein Z is C=0, diastereomeric isomers thereof wherein the ring substituents have the opposite stereoconfiguration to that given above and mixtures thereof with an aluminum or borohydride reducing agent in the presence of an agent for deactivating the aluminum hydride reducing agent. 7. A compound of formula I R" <*> " taken together with the oxygen atom to which it is attached forms a hydrolyzable ester group; R taken together with the oxygen atom to which it is attached forms a hydrolyzable ether group and t denotes the trans configuration; diastereomeric isomers thereof in which the ring substituents have the opposite stereoconfiguration to that given above and mixtures thereof. 8. A compound according to claim 9, wherein Z is CO, diastereomeric isomers thereof wherein the ring substituents have the opposite stereoconfiguration to that given above, and mixtures thereof. 9. A compound according to claim 9, wherein Z is diastereomeric isomers thereof wherein the ring substituents have the opposite stereoconfiguration to that given above and mixtures thereof. 10. A compound of formula VI wherein X is halogen and R is as in claim 1.