DE2405374A1 - OPTICALLY ACTIVE BORANA - Google Patents

Description

DR. ING. VAN DERWERTH DR. FRANZ LEDIlRER

21 HAMBURG 9O 8 MÖNCHEN

WILSTORFER STR. 32 · TEL. (Ct 111 77 Oa 61 O / Π CO 7 A LUCILE-GRAHN-STR. 22 · TEt. Ίθβ Μ! «7 29

Munich, Jan. 25, 1974 RAN 4303/4

F.HOI ¹ HvIAIOT-LA ROCHE & CO. Corporation

Basel, Switzerland

The invention relates to cyclic compounds which are used in the synthesis of optically active prostaglandin E ^ ot Find.

Optically active prostaglandin "_{2> χ} has been isolated from natural sources. These compounds, like 15-epi-? Rostaglandin Fp ^ compounds, are known agents for inducing labor in pregnant women and are agents for therapeutic termination pregnancy.

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In the past, racemic prostaglandin ^ p r </ from Fried, Journal of American Chemical Society, 94; (1972) pp. 4-34-2, 4-34-3 and by Corey, Tetrahedron Letters, 307 (197O) p. 311. Although racemic prostaglandin is also useful in inducing labor in pregnant women and in completing pregnancy, the racemic form of this compound is not as active as the optically active forms. Various procedures for synthesizing the optically active forms of prostaglandin F ₀ using cleavage techniques have been proposed. However, these procedures have been inefficient and cumbersome Would avoid cleavage work.

According to the invention, optically active prostaglandin can be obtained with the following general formula:

wherein R ¹ = -CH ₀ -CH ₀ -CH ₀ -CH ₀ -CH-, is dd cL d. 2 ⁷

as well as its optically active antipode with the following general formula:

OH

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_ X -

wherein the radical R ^{1 has} the meaning given above,

and optically active 15-epi-prostaglandin the general formula:

OH

OH

• II

in which the radical R ^{1 has} the meaning given above, as does its optically active antipode with the following general formula:

OH

OH

HA

wherein the radical R ^{1 has} the meaning given above,

asymmetric from cyclopentadiene without cumbersome cleavage procedures can be synthesized via optically active intermediate compounds of the formulas:

HO-CH ₀ -CH ₅

d I C-

III

AO 9 8 3 3/1048

IV

where -OR is one protected by an ether protection group Hydroxy group, which can be converted to the hydroxy group by hydrolysis, is,

or their optically active antipodes. According to this process, either the optical isomer of formula I or II or their optical antipodes, i.e. the compound of formula I-A or H-A directly from cyclopentadiene depending on synthesized under the reaction conditions used without the need for cleavage.

The term "lower alkyl" used in the specification includes both straight-chain and branched-chain alkyl radicals with 1 to 7 carbon atoms such as methyl, ethyl and propyl, preferably methyl. The one used in the description The term "lower alkoxy" embraces lower alkoxy radicals having 1 to 7 carbon atoms such as methoxy and ethoxy. Of the The term "lower alkanoic acids" also used in the specification includes alkanoic acids having 2 to 7 carbon atoms such as propionic acid and acetic acid. The term "halogen" also used in the specification includes unless otherwise specified indicated is fluorine, chlorine, bromine and iodine. The term "alkali metal" includes sodium, potassium, lithium, etc.

In the structural formula representation of the connections. in the description means a thickened, tapered one Line (T) a substituent which is in the beta orientation (above the plane of the cyclopentane unit), a

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dashed line () represents a substituent that appears in the

alpha orientation (below the plane of the cyclopentane unit), and a wavy line ( ^{r <} ^ ^v - ^) a substituent that is in either the alpha or beta orientation. It should be noted that the pictorial representations of the structural formulas represent the absolute configuration unless otherwise specified. In many cases, only one of the optically active antipodes is depicted for the sake of simplicity. It should be noted that the other, optically active, antipode has the same structural formula except that the dashed lines are thick tapered lines and that thick tapered lines are dashed lines.

The term "aryl" also used in the description means single ring aromatic hydrocarbon radicals such as phenyl, tolyl, etc. which are unsubstituted or attached to one or more positions with an aryl, lower alkylenedioxy, halogen, nitro, lower alkyl or lower Alkoxy substituents can be substituted, as well as four Aryl radicals such as naphthyl, anthryl, phenanthryl, azulyl radicals, etc., which are unsubstituted or with a or more of the aforementioned radicals can be substituted. The preferred aryl radicals are the substituted ones and unsubstituted, single-ring aryl or diaryl radicals, in particular phenyl or diphenyl. The term "aryl-lower alkyl" includes radicals in which the aryl radical and the lower alkyl radical have the meaning given above, especially the benzyl radical. The term "aryl-lower alkanoic acid" includes acids in which "aryl" and "lower alkanoic acid" have the meaning given above, in particular Haenylacetic acid. The term "aroyl" denotes Aroyl radicals in which the aryl radical is the above

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Has meaning. The preferred aroyl substituents are the benzoyl or phenylbenzoyl radical.

As used further in the specification, the term "carboxy protected with a hydrolysis convertible herein." The remainder "includes any conventional, organic acid-protecting group which can be removed by hydrolysis. The preferred, Organic acid protecting groups are the esters. Any common ester that hydrolyzes to form the acid can be used as a protecting group. Examples of esters useful for this purpose are lower alkyl esters such as ethyl, aryl esters, especially phenyl esters and the aryl-lower alkyl esters, especially benzyl esters or phenylbenzyl esters.

As used in the description, the term "hydroxy protected by an ester or ether radical included in the hydroxy radical can be converted by hydrolysis "refers to any ester or ether residue which can be converted to form the Hydroxyrestes can be hydrolyzed. Examples of ester radicals which are advantageous for this purpose are those in which the acyl moiety of a lower alkanoic acid, an aryl lower alkanoic acid, an aryl carboxylic acid, a lower alkanedicarboxylic acid or a carbamic acid such as an arylcarbamic acid, this being phenylcarbamic acid or p-phenylphenylcarbamic acid includes, descends. The acid derivatives that are used to form such ester residues can include the acid anhydrides and the acid halides, especially the chlorides or bromides, the lower alkanoic anhydrides, e.g. acetic anhydride and caproic anhydride, the aryl lower alkanoic anhydrides, e.g. benzoic anhydrides, lower alkanedicarboxylic anhydrides, e.g. succinic anhydride and chloroformates, e.g. Trichloräthylchlorforraiat, are preferred. In the production of an aryl carbamic acid ester, the free hydroxyl radical is reacted with an aryl isocyanate under conditions

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which are customary for the production of acid esters. One advantageous ether protecting groups are e.g. lower alkyl ethers such as methyl, ethyl or t-butyl ethers, tetrahydropyranyl ethers or 4-methoxy-5,6-dihydro-2H-pyranyl ether. Other protective groups are aryl methyl ethers such as benzyl, benzhydryl or trityl ethers or alpha-lower-alkoxy-lower-alkyl ethers, e.g. methoxymethyl, or allyl ethers or tri- (lower-alkyl) -silyl ethers such as trimethylsilyl ethers.

In the first stage of the process according to the invention Alkali metal and thallium (I) salts of cyclopentadiene with a compound of the following general formula:

XCH ₂ -C-OR ₁

where -COR _x . represents an ester protection group, which by

ti ¹ ο

Hydrolysis is convertible to the carboxy radical, and Z = halogen

to form a compound of the following formula

CH ₂ COR ₁

0 VI

wherein R _{1 has} the meaning given above, reacted.

The compound of formula V is with the alkali metal or thallium (I) salts of cyclopentadiene in an inert, organic Solvent implemented. Preferred inert organic solvents for carrying out this reaction are

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Ether solvents such as tetrahydrofuran, diethyl ether, glyme, diglyme, triglyme, tetraglyme, etc. When carrying out this reaction, any temperature from -10O ⁰ C to room temperature can be used. In general, the use of a temperature of -90 ⁰ C to -20 ⁰ C is preferred.

In the next stage of the process according to the invention, the compound of the formula VI is converted into the optically active one Isomers of the following formula converted:

VII

wherein R _{x has} the meaning given above, by first reacting the compound of the formula VI with an optically active, organic borohydride to form an optically active isomer of the following general formula

Il

CH-C-OR

VIII-A

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wherein R _n - is an optically active organic moiety; R _{1 has} the meaning given above, χ is an integer from 1 to 2, y is an integer from 0 to 1 with the proviso that the sum of χ and y = 2;

or an optically active isomer of the following general formula:

I!

VIII-B

where x, y, R. and R, - have the meaning given above, to manufacture.

By treatment with an alkali metal hydroperoxide or an organic peracid, the compound of the formula VIII-A can be converted into the compound of the formula VII, while the compound of the formula VIII-B into the optical active isomers of the formula:

CH ₂ -C-OR ₁

HO

VII-A

wherein R _{1 has} the meaning given above, can be converted.

Any conventional optically active organic borohydride can be used to convert the compound of Formula VI into a compound of the formula VIII-A or a compound of the formula VIII-B. Among the preferred

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organic borohydrides include those with. an optically active, organic unit (Rc), which is an optically active Is hydrocarbon radical, are disubstituted. These disubstituted Organo-hydroboranes are, as described in US Pat. No. 3,078,313, by hydroboration of a formed optically active, olefinic hydrocarbon. To the optically active, olefinic hydrocarbons, which Hydroborated in accordance with this invention include those optically active hydrocarbons disclosed in U.S. Patent 3,078,313. Among the preferred, visually active, olefinic hydrocarbons ranging from 6 to Containing carbon atoms and which can be used in the formation of the di- or tri-organo-boron hydrides include:

oc -Patschools, Cedren, Idmonen, Carvomenthen, 3-Menthene, Camphene, Teripinolen, ß-Pinene, T-Fenchen, T-Terpinene, Δ -Caren, A ^ -Caren and A -'- Androsten.

Particularly preferred among the organic borohydrides is (+) - di-3-pinanyl-borane or its optical isomer.

When the compound of formula VI is reacted with (+) - di-3-pinanyl-borane, the compound of the following formula becomes:

VIII-D

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wherein R>, has the meaning given above, is formed. On the other hand, when the compound of formula VI with (-) - di ~ 3-pinanyl-borane is implemented, becomes a compound of the following formula

VIII-E

wherein R ,, has the meaning given above.

The compound of the formula VIII-A or the formula VIII-B is formed by first treating the compound of the formula VI with a optiscli active organoborohydride is implemented «Whether the Compound of Formula VIIE-A. or of the formula VIII-B, depends on the choice of the optically active antipodes of the optically active borohydride, which with the compound of formula VI is implemented. This reaction is carried out in an inert, organic solvent. Any, usual, inert organic solvents can be used to carry out this. Reaction can be used. Among the preferred, inert, organic Solvents for use in this reaction include ethereal solvents such as those previously mentioned. The pre-

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A preferred ether solvent for use in this reaction is tetrahydrofuran. This reaction is carried out at a temperature from -10O ⁰ C to JQ ⁰ Q. In general, it is preferred to use a temperature of -90 to -20 ⁰ G ⁰ C. The compound of the formula VII-A or its optically active antipode, the compound of the formula VIII-B, is converted into the compound of the formula VII or its optically active antipode, ie the compound of the formula VII-A by using the compound of the formula VIII -A or the formula VIII-B is reacted with an alkali metal hydroperoxide or an organic peracid. This reaction is carried out in an inert, organic solvent or in the reaction medium in which the compound of the formula VIII-A or VIII-B was formed. Any conventional inert organic solvent can be used. The preferred inert organic solvents are ether solvents such as those already mentioned above, with tetrahydrofuran being preferred. Temperatures from -10 ⁰ C to +20 ⁰ C can be used, with temperatures from -5 ° C to +5 ⁰ C are preferred.

If an organic peracid is used, it can be used any customary organic peracid can be used. Organic peracids include lower alkane peracids such as Peracetic acid and peraryl carboxylic acids such as perbenzoic acid or

meta-chloroperbenzoic acid. Alternatively, an alkali metal hydroperoxide can be added to the reaction medium. Optionally, the alkali metal hydroperoxide in the reaction medium can be prepared by adding hydrogen peroxide and an alkali metal hydroxide to the reaction medium in which the compound of formula VIII-A or VIII-B has been formed. It then may be allowed that this reaction medium assumes a temperature of -10 ⁰ C to 20 ⁰ C, to form the compound of formula VII or a compound of formula VII-A.

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In accordance with the invention, the optically active antipode of Formula VII is passed through the process to form either the compound of Formula I or the compound of Formula II while maintaining the optical configuration. Therefore, if the compound of the formula I or the compound of the formula II is desired, the reaction sequence is carried out using the compound of the formula VII. If, on the other hand, the compound of the formula VII-A is passed through the various reaction stages of the process according to the invention, either the compound of the formula IA or of the formula HA can be prepared. This is because the compound of formula VIII-A is carried through the entire reaction sequence according to the invention while maintaining its optical configuration. Therefore, the method of the invention provides a method for producing prostaglandin ^ o / xL ° & ^βτ Ί5-QPi-P ^ OStaglandin Fp ^ in any of its optically active forms without the need for optical cleavage.

The optical configuration of the compound of the formula VII or its optically active antipode can be modified by lactonization in a compound of the following formula:

0.

IX

or their optically active antipodes via an intermediate compound of the following formula:

OHpCOH

HO

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or converted to their optically active antipodes. The optical configuration of the compound of formula VII or its optically active antipode can lead to a compound of the above formula IX via an intermediate of the following Formula:

XI

wherein R ^, has the meaning given above and -OHg a means removable group, or their optically active antipodes are converted.

In converting the compound of the formula VII or its optically active antipode to a compound of the formula IX or its optically active antipode via the intermediate of the formula X or its optically active antipodes becomes the Compound of the formula VII or its optically active antipode first for the preparation of a compound of the formula X or hydrolyzed their optically active antipode. Any conventional method of ester hydrolysis can convert the compound of the Formula VII or its optically active antipode can be used in the compound of the formula X or its optically active antipode. This hydrolysis is generally accomplished by treatment with an inert organic base such as an alkali metal hydroxide carried out. In carrying out this reaction, an aqueous medium is preferably used. This reaction will using any of the conditions customary for basic hydrolysis. When running this For the reaction, the temperature and pressure are not critical, and the reaction can be carried out at room temperature.

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The compound of the formula X or its optically active antipode is converted into the compound of the formula IX or its optically active antipode by lactonization by treatment with an acid halide of an organic sulfonic acid in the presence of an organic amine base. Any conventional halide of an organic sulfonic acid can be used. The preferred organic sulfonic acids include the lower alkyl sulfonic acids such as methyl sulfonic acid, aryl sulfonic acids and aralkyl sulfonic acids. Preferred aryl and aralkyl sulfonic acids which are advantageously used in this invention include those in which the aryl radical is phenyl or phenyl substituted with either a nitro, lower alkyl, or halogen substituent. These arylsulfonic acids and aralkylsulfonic acids include benzenesulfonic acid, toluenesulfonic acid, p-nitrobenzenesulfonic acid, chlorobenzenesulfonic acid and benzylsulfonic acid. The organic amine base serves as the solvent for this reaction. Any conventional organic amine base such as the lower alkyl amines and heterocyclic amines can be used in this reaction. The preferred organic amine bases include triethylamine, trimethylamine and pyridine. In carrying out this reaction, the temperature and pressure are not critical, and the reaction can be carried out at room temperature and atmospheric pressure. On the other hand, increased or decreased temperatures can also be used. In general, it is preferred to carry out this reaction at a temperature of -10 ° C to 40 ⁰ C. Although the hydroxy and carboxymethyl groups lie on opposite sides of the plane of the cyclopentyl ring unit of the compound of formula X or its optically active antipode, the lactonization in this procedure causes the formation of the lactone ring on the same side of the cyclopentyl ring unit as the carboxymethyl substituent. Therefore, this procedure causes the inversion by lactonization.

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The compound of the formula VII or its optically active antipode can be converted into the compound of the formula IX or its optically active antipode via an intermediate of the formula XI or its optically active antipode. The compound of the formula VII or its optically active antipode is converted into the compound of the formula XI or its optically active antipode by converting the free hydroxyl radical into a splitting group. Any conventional method of forming a leaving group can be used. The preferred cleavable groups which form RgO include the cleavable groups formed from organic sulfonic acids, such as organic sulfonyl radicals. Preferred organic sulfonyl radicals include lower alkyl sulfonyl, aryl sulfonyl and aryl alkyl sulfonyl. The preferred lower alkylsulfonyl is methylsulfonyl. The preferred arylsulfonyl and aralkylsulfonyl radicals are those in which the aryl substituent is phenyl or phenyl substituted with a lower alkyl, halogen or nitro substituent. These arylsulfonyl or aralkylsulfonyl radicals include toluene sulfonyl, benzenesulfonyl, p-nitrobenzenesulfonyl, p-chlorobenzenesulfonyl and benzylsulfonyl. According to a preferred embodiment, the releasing group is produced by reacting the compound of the formula VII or its optically active antipode with a reactive derivative of an organic sulfonic acid such as an organic sulfonic acid halide or an organic sulfonic acid anhydride in the presence of an organic amine base. Any of the conventional organic amine bases recited above can be used in carrying out this reaction. Generally, this reaction is carried out at a temperature of about -10 ° C to 4-0 ⁰ C.

The compound of the formula XI or its optically active antipode is converted into the compound of the formula IX or its optically active Antipodes by treating the compound of formula XI or its optically active antipodes with aqueous alkali metal hydroxide

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converted. All the usual conditions in ester hydrolysis can be used to carry out this reaction. In general, it is preferred to carry out this reaction by treating the compound of Formula XI or its optically active antipode with an alkali metal base such as sodium hydroxide in an aqueous medium. In general, for the sake of simplicity, it is preferred to use from 0.1 to 1.5 molar equivalents of base per molar equivalent of the compound of formula XI or its optically active antipode. However, a molar excess of the base can also be used to carry out this reaction. An inert, organic solvent can optionally be present in the reaction medium. Any conventional inert organic solvent can be present in the reaction medium. The preferred solvents include the ether solvents such as tetrahydrofuran, diethyl ether, dioxane, etc. In addition to the lactonization, this basic hydrolysis causes the inversion of the steric configuration. This can be seen from the fact that although the leaving group and the carboxymethyl group are on opposite sides of the plane formed by the cyclopentyl ring moiety in the compound of formula XI or its optically active antipode, treatment with the base will result in the formation of the lactone ring the same side of the plane of the cyclopentyl moiety as the carboxymethyl substituent. In carrying out this lactonization, temperature and pressure are not critical, and the reaction can be carried out at room temperature and atmospheric pressure. However, higher or lower temperatures can be used, that is, temperatures from -10 ⁰ C to 60 ° C.

If there is excess base in the lactonization described above the compound of formula XI or its optically active antipode is applied, the yield of the compound of the formula IX c that of its optically active antipode by the formation of an alkali metal salt of a compound of the following formula:

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CH ₉ GOOH

HO (XIII

or their optically active antipode reduced as a by-product.

The alkali metal salt of a compound of the formula XIlI or its Optically active antipodes can be converted into a compound of the formula IX or its optically active antipodes by neutralizing the Reaction medium by adding an acid such as a strong inorganic or organic acid, e.g. sulfuric acid or a hydrohalic acid to a pH of 4 to 7 being transformed. Preferred acids include aqueous hydrochloric acid and aqueous sulfuric acid. The usage an acid to neutralize the reaction mixture increases the yield of the compound of the formula IX or its optically active Antipodes made by this way of working.

The compound of the formula IX or its optically active antipode can be converted into a compound of the formula III or its optically active antipodes via the intermediate of the following formula:

CH ₂ CH ₂ OH

HO ( XII

or its optically active antipodes are converted

The compound of the formula IX or its optically active antipode is converted into the compound of the formula XII or its optically active Antipodes by treating the compound of formula IX or its optically active antipode with an aluminum hydride reducing agent converted. When using an aluminum hydride reducing agent, any conventional aluminum hydride reducing agent can be used be used. The applicable AIu-

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Minium hydrides include lithium aluminum hydride, sodium aluminum hydride, diisobutyl aluminum hydride, diisopropyl aluminum hydride, and sodium bis (2-methoxyethoxy) aluminum hydride. This reduction is carried out in the medium of an inert organic solvent. Any conventional inert organic solvent can be employed in carrying out this reaction. The preferred, inert, organic solvents include tetrahydrofuran, dioxane, diethyl ether, hexane, toluene, benzene and xylene. This reaction can be carried out at room temperature, ie 25 C, and atmospheric pressure. On the other hand, reduced or increased temperatures are preferred, ie from -3O ⁰ G to about 80 ⁰ C, with temperatures from 10 ⁰ C to 4-0 ⁰ C being particularly preferred.

The compound of the formula XII or its optically active antipode is converted into the compound of the formula III or its optically active antipode by treating the compound of the formula XII or its optically active antipode with an organic peracid. Any conventional organic peracid can be used in this reaction. Conventional, organic peracids include peracetic acid, perbenzoic acid, meta-chloroperbenzoic acid and mono-perphthalic acid. This reaction is usually carried out in an inert, organic solvent. Any conventional inert organic solvent can be used. The preferred, inert, organic solvents include aliphatic hydrocarbons, aromatic hydrocarbons and halogenated hydrocarbons such as hexane, benzene, methylene chloride and chloroform or lower alkanoic acids such as acetic acid. Generally, this reaction is carried out at a temperature of about -20 ⁰ C to 30 ⁰ C.

The compound of the formula XII or its optically active antipode can be converted into the compound of the formula III or their optically active antipodes are esterified. By esterifying the compound of the formula XII or its optical active antipodes with one equivalent of an esterifying agent

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is only the hydroxyl radical on the hydroxyethylene radical esterified. This esterification can be carried out by conventional means such as treatment with an active A derivative of an organic acid such as a lower alkanoic acid chloride or anhydride. The compound of the formula XII or its optically active antipode, the hydroxy radical of which is the hydroxyethylene substituent is esterified and whose free hydroxy unit is bound to the cyclopentene ring, can be incorporated into the compound of Formula III or its optically active antipodes by treatment with an organic peracid, as described above, " being transformed. The compound of the formula III or its optically active antipode, the hydroxy radical of which is the hydroxyethylene group is esterified, can be hydrolyzed to the free hydroxyethylene group by conventional, basic hydrolysis, as previously described will. The use of the esterified hydroxyethylene group in the compound of the formula XII or its optically active Antipodes provides a compound of the formula III or its optically active antipodes.

By epoxidizing the compound of the formula XII or its optically active antipode with an organic peracid the epoxy ring exclusively on the same side of the plane of the cyclopentane unit as both the hydroxymethylene substituent as well as the hydroxy substituent.

In accordance with another embodiment of the invention, this process provides a new and improved process for the preparation of the compound of Formula III as a racemate. This racemate of the formula III is a known intermediate in the production of racemic prostaglandin, mp ₀ ^, see Fried, Journal of American Chemical Society, ^ i (1972) pp. 434-3. In this procedure, the compound of the formula VI is first converted into a racemate of the formula VII by preparing a borane complex of the compound of the formula VII which has the following formula:

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where IL has the meaning given above and the boron the cyclopentene unit on the opposite side of the plane as the methylene carboxyester is bonded

This complex is made by reacting the compound of the formula YI prepared with borane under the same conditions used to form the compound of Formula VIII-A or Formula VIII-B from the compound of the formula VI were given »This borane complex is converted into the racemate of the formula VII by treatment with an alkali metal hydroperoxide or an organic peracid converted in the same manner as described in connection with the formation of the optically active compounds of Formula VII became. The racemate of the formula VII can be converted into the racemic lactone of the formula IX via the racemic form of the intermediate of the formula X or via the racemic form of the intermediate of the formula XI by the procedure described above being transformed. This racemic lactone can be converted into the racemic form of the compound of the formula III via the racemic Form of the intermediate of the formula XII can be converted according to the procedure described above.

The compound of the formula IX or its optically active antipode can be converted into the compound of the formula IV or its optically active Antipodes are converted via the following intermediates;

XIV

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XV

or their optically active antipodes.

The compound of the formula IZ or its optically active antipode is converted into the compound of the formula XIV or its optically active antipodes by treating the compound of the formula IX. with an organic peracid, preferably peracetic acid, converted. The same conditions used in connection with the conversion of a compound of Formula XII into a compound of the formula III were given, can be used to convert the compound of formula IX or its optically active antipode into the compound of formula XI? or their optically active antipodes can be applied. During this transformation, the epoxy bridge becomes on the same side of the cyclopentane ring as the lactone ring educated.

The compound of formula XIV or its optically active antipode is converted to the compound of formula XV or its optically active antipode by treating the compound of formula XIV with diisobutylaluminum hydride. This reaction is carried out at a temperature of -9O ° C to -5o ⁰ G where temperatures are preferably from -8 ° C to -60 5 G. Any conventional inert organic solvent can be used in carrying out this reaction. Preferred inert organic solvents include hydrocarbon solvents such as the aromatic and aliphatic hydrocarbons. Among the preferred solvents are toluene, benzene, xylene, etc.

The compound of the formula XV or its optically active antipode is converted into the compound of the formula IV or its optically active antipodes by conventional etherification procedures

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wandelto According to the method according to the invention, it was surprisingly found that the ether group in the compound of the formula = times IV or their optically active antipode if the connection of the formula ZV or its optically active antipode are etherified to the plane of the HoXsktile in the opposite direction from your Epoxjsubstituentea is bound «If therefore the epoxy group is in the alpha orientation, the ether group is located in the beta-cfeientierung. On the other hand, if the epoxy group is in the beta orientation, the Ither group is located in the alpha orientation «, in case one therefore has the connection of the formula XV etherified, the compound of the formula is obtained On the other hand, if one has the optical antipode of the compound of formula XV, the following formula?

> XV-A

etherified, one obtains the optical antipode of a connection of formula IV with the following formula:

RO

IV-A

wherein R has the meaning given above.

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As already described, the ether group can be formed by any conventional method of etherification of a hydroxyl radical. The preferred ethers are the lower alkyl ethers. Preferred methods of forming the ethers include treating the compound of Formula XV or its optically active antipode with a lower alkanol in the presence of an acid catalyst. Any conventional acid catalyst can be used in carrying out this reaction. Preferred acid catalysts include acidic cation exchange resins such as polystyrene sulfonic acid resin, inorganic acids such as sulfuric acid, Lewis acids such as boron trifluoride, aluminum trichloride, etc., and organic acids such as p-toluenesulfonic acid. In general, the lower alkanol can serve as the solvent medium. In carrying out this reaction temperatures are employed from -40 ⁰ to 10 ° G 0th The preferred catalyst for use in this reaction is boron trifluoride.

The compound of the formula IV or its optically active antipode can be converted into the compound of the formula I or I-A as well as the Compound of formula II or H-A can be converted via the following intermediates:

XVI

where R ₂ and R, are lower alkyl radicals and R has the meaning given above:

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OR

OH

XVII

^ CHO

wherein R has the meaning given above;

XVIII

OH

fl

wherein R and R ^{1 have} the meanings given above;

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XIX

wherein R and R ^{1 have} the meanings given above;

XX

wherein R and R ^{1 have} the meanings given above;

OH

XXI

wherein R ^{1 has} the meaning given above and

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XXII

wherein R ^{1 has} the meaning given above.

When a compound of formulas I-A or H-A is made is to be, the optically active antipode of the compound of formula IV becomes over the optically active antipode of the compounds of the formulas XVI »XVII, XVIII, XIX, XX, XXI and XXII converted into the compound of the formulas I-A or H-A.

The compound of the formula IV or its optically active antipode is converted into the compound of the formula XVI or its optically active Antipodes by reacting the compounds of the formula IV or their optically active antipodes with a compound of the following formula:

GH-GH = GH-SR SR ₂

XXV

wherein Y is an alkali metal or MgX ¹ ; X ¹ signifies chlorine> bromine or iodine and R ₂ and R ^ have the meaning given above, converted.

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The compound of the formula IV or its optically active antipode is reacted with the compound of the formula XXV using conditions which are customary in Grignard reactions in order to produce a compound of the formula XVI or its optically active antipodes. This reaction is carried out in an inert, organic solvent medium. Preferred solvents include diethyl ether and tetrahydrofuran. In carrying out this reaction, the temperature and pressure are not critical, and this reaction can be carried out at room temperature and atmospheric pressure. In general, it is preferred to carry out this reaction at a temperature of -9O ⁰ G G ⁰ to -5o.

The compound of the formula XVI or its optically active antipode is converted into the compound of the formula XVII or its optically active antipode by treating the compound of the formula XVI or its optically active antipode with a mercury (II) salt such as mercury (II) chloride Presence of a base such as calcium carbonate and water. This reaction can take place in the presence of an inert, organic solvent such as acetonitrile. In carrying out this reaction, the temperature and pressure are not critical, and this reaction can be carried out at room temperature. If necessary, temperatures as high as 60 ^° C. or temperatures as low as 10 G can be used.

The compound of the formula XVIII or its optically active antipode is by treatment of the compound of the formula XVII or of their optically active antipode made with a compound of the following formula:

Y-CH ₂ -GH ₂ -GH ₂ -GH ₂ -GH ₃ XXV-A

wherein I has the meaning given above.

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This reaction is carried out under the same conditions as used in connection with the reaction of the compound of formula IV with a compound of formula XXV to form a compound of formula XVI became. The compound of the formula XVIII or its optically active antipode can be converted into its two isomers, i.e. the compound of the formula XIX or their optically active antipodes and the compound of the formula XX or their optically active antipodes using any conventional method of separation, such as chromatography, be separated.

Di.e compound of the formula XVIII or its optically active antipode contains approximately equal parts by weight of one Mixture of the compound of the formula XIX and XX or their optically active antipodes. If, on the other hand, manufacture the compound of the formula XIX or its optically active antipode is desired in higher yields than them are obtained by the procedure described above, the compound of the formula XVII or its optically more active Antipode in the compound of formula XIX via the following Intermediate products converted:

9833/1

CHO ΧΧΙΙΪ;

OH XXIV

XXVI

409833/1048

and XXVII

OH

XXVIII

wherein R and R ^{1 have} the meanings given above and -OR.ρ denotes a hydroxy radical or a hydroxy radical protected by ester groups which can be converted into the hydroxy radical by hydrolysis, and their optically active antipodes.

The free hydroxy radical in the compound of the formula XVII or its optically active antipode can optionally to be protected. Any conventional method of esterifying a hydroxyl group can be used. to the preferred esters include aroyl esters such as the benzoyl and p ~ phenylbenzoyl esters and the aryl carbamate esters such as the

409833/1048

Phenyl carbamate or p-phenyl phenyl carbamate esters. The connection of the formula XXIII or its optically active antipode is converted into the compound of the formula. XXIV or their optically active Antipodes converted by reaction with a compound of Formula XXV-A in the same manner as previously described.

The compound of formula XXIV or its optically active antipode can be converted to the compound of formula XXVI by oxidation with manganese dioxide, dichloro-5,6-dicyanobenzoquinone or a chromate oxidizing agent such as chromium trioxide. If chromium trioxide is used, the free hydroxy group should be protected by an ester. If, on the other hand, manganese dioxide or 2,3-dichloro-5-6-dicyanobenzoquinone is used, the radical ORxip ^ ⁿ ^ er compound of the formula XXIV or its optically active antipode can be the hydroxy radical, or it can be an ester group. The compound of the formula XXVI or its optically active antipode is reduced to form the compound of the formula XXVII or its optically active antipode. This reduction is under. Use of an alkali metal-tri-lower-alkylborohydride oil as a reducing agent carried out. It has been found that in the reaction of the compound of the formula XXVI or its optically active antipode with an alkali metal tri-alkylborohydride reduction agent, the compound of the formula XXVII or its optically active antipode only with a small amount of the compound of the formula XXVIII or its optically active antipodes is produced. Therefore, if it is desired to prepare the compound of the formulas I or IA instead of the compound of the formulas II or HA, it is preferred to use the intermediates of the formulas XXIV, XXVI and XXVII or their optically active antipodes in the conversion of the compound of the formula XVII or its optically active antipode to the compound of the formula XIX or its optically active antipode.

409833/1048

The reduction of the compound of formula XXVI or its optically active antipode with an alkali metal tri-lower-alkylborohydride reducing agent is carried out using the conditions which are customary for the reduction with an alkali metal trialkylborohydride reducing agent, with the exception that temperatures of -11O ⁰ G to -5O ⁰ G can be used. The mixture prepared in this way predominantly contains the compound of the formula XXVII or its optically active antipode and a smaller amount of the compound of the formula XXVIII or its optically active antipode. These compounds can be separated by any conventional method of separation such as chromatography. Any conventional chromatographic technique can be used to carry out this separation. The compounds of the formulas XXVII or XXVIII in which -OR ^ o represents an ester protecting group, or their optically active antipodes can each be converted into the compound of the formulas XIX or XX or their optically active antipodes by ester hydrolysis. Any conventional method of ester hydrolysis, such as treatment with an alkali metal hydroxide in an aqueous medium, can be used to carry out this conversion.

The compound of the formula XIX is converted to the compound of the formula I via the intermediate of the compound of the formula XXII. On the other hand, if the optical antipode of the compound of Formula XIX is treated in the same manner, the compound becomes of formula I-A formed via the optical antipode of the compound of formula XXII. On the other hand, the connection of the formula XX converted into the compound of the formula II via the intermediate of the formula XXI. If the optical antit> ode the compound of the formula XX is used, the compound of the formula H-A is above the optical antipode of the intermediate the compound of formula XXI prepared.

409833/1048

The compound of the formula XIX is obtained by means of ether hydrolysis or its optically active antipode is converted into the compound of the formula XXII or its optically active antipode and the compound of the formula XX or its optically active antipode into the compound of the formula XXI or its optically active antipodes. Any conventional method of ether hydrolysis can be used to carry out this reaction will. The preferred methods of ether hydrolysis include the treatment of the compounds of the formulas XIX or XX or their optically active antipodes with a strong, inorganic acid such as hydrochloric acid or sulfuric acid in an aqueous medium.

The compound of the formula XXII or its optically active antipode is converted into the compound of the formula I and the compound of Formula XXI is converted into the compound of Formula II by reaction with an alkali metal salt of the compound of the following formula:

R ₁₀ -P = CH-CH ₂ -CH ₂ -CH ₂ -COOh XXV-B

where Rviqj R ^ and R ^, aryl or lower alkyl radicals, converted.

This reaction is carried out under conditions which are common for a Wittig synthesis. All usually at Conditions used in the Wittig synthesis can be used in carrying out this reaction.

According to a further embodiment of the invention, the Compound of the formula III or its optically active antipode into the compound of the formulas I or II or their optically active tive antipodes converted via the following intermediate products:

409833/1048

XXX

where R

■ 15

OR,

Is OR or OR

and -OR has the meaning given above;

XXXI

wherein R ^{1 has} the meaning given above; and Ry _{1 is} C = 'OH, <- ^ OH, or OH;

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XXXII

wherein R ¹ and

have the meanings given above;

OH

XXXIII

wherein R ¹ and

have the meanings given above

and -OR. ' represents an ether protection group, which in the Hydroxy radical is convertible by hydrolysis

409833/1048

XXXIV

wherein R ,. ¹ and R ^{1 have} the meanings given above;

XXXV

R ¹

OH

wherein R ,. ¹ and R 'have the meanings given above; or their optically active antipodes.

In converting the compound of the formula III or its optically active antipode into the compound of the formula XXX or its optically active antipodes, the compound of the formula III is reacted with a compound of the following formula:

409833/1048

20 2 - Lz-OrL-Un ₀ -On ₀ -LrJi ₀ -OxI ₀ -On _x juulv-o

wherein R. ^ has the meaning given above and R ₂ Q is a lower alkyl radical.

This reaction is carried out using conditions which are customary for carrying out G-rignard reactions. In carrying out this reaction temperatures of from 5O ° C to 7O ⁰ C preferred. In addition, preferred inert organic solvents are aromatic hydrocarbons such as benzene and toluene.

If a compound of the formula I or HA is to be prepared, the radical R _x ^ ₅ in the compound of the formula

XXXV-C OR. If a compound of the formulas I-A or

II is to be prepared, the radical R ^ <- in the compound of the formula XXXV-C P ^ "OR. On the other hand, if a compound of the formulas XXX, XXXI, XXXII and XXXIII is to be prepared as a mixture of isomers, a compound of the formula XXXV-C is used, in which the remainder is.

The compound of the formula XXX or its optically active antipode is / the compound of the formula XXI or its optically active antipode is converted by ether hydrolysis. Any conventional method of ether hydrolysis can be used for this conversion. The preferred hydrolysis methods, the treatment is part of the compound of formula XXX or of their optically active antipodes with a strong acid such as sulfuric acid, trifluoroacetic acid or hydrochloric acid at a temperature of -10 ⁰ C to +10 ⁰ C. The compound of formula XXXI or its optically active Antipode can be converted into the compound of formula XXXII or

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their optically active antipodes can be converted by reduction with an alkali metal aluminum hydride. Any conventional technique for reducing a triple bond to a double bond with an alkali metal aluminum hydride reducing agent can be used in carrying out this reaction. In general, it is preferred, at a temperature of about 40 ° C to 8Q ⁰ C in the presence of an ether solvent, zB.Tetrahydrofuran to carry out this reaction. The compound of the formula XXXII or its optically active antipode is converted into the compound of the formula XXXIII or its optically active antipode by etherification with one equivalent of an etherifying agent. Any conventional method of etherification can be used to convert the free terminal hydroxy group to an ether protecting group. In the compound of the formula XXXII or its optically active antipode, the terminal alkyl hydroxy group is far more reactive than the other hydroxy radicals. Thus, the compound of Formula XXXII or its optically active antipode can be selectively etherified by conventional procedures to form the compound of Formula XXXIII or its optically active antipode. Conventional etherification procedures that can be used include reacting the compound of Formula XXXII or its optically active antipode with a lower alkyl halide or an aralkyl halide such as benzyl halide or triphenylmethyl halide in the presence of an organic amine base such as pyridine.

If the radical R ₁₆ = ^ r ^ OE in the compound of the formula XXXIII or its optically active antipode, this compound can be converted into two epimeric, isomeric forms, ie the compound of the formula XXXIV or its optically active antipodes and the compound of FormulaXXXV or their optically active antipodes. Any conventional method of

409833/1 048

Separation can be used. The preferred methods of separation include chromatography.

If, on the other hand, the radical ILg = '^^' OH in the compound of the formula XXXIII or its optically active antipode, and one wishes to obtain a mixture which predominantly contains the isomer in which ILg = OH, the compound of the formula XXXIII, in which R ^ g = ^/ ^^ 0H, or its optically active antipode is first oxidized to a compound of the following formula:. .

OR. '

XXXVI

wherein R * and R ^{1 have} the meanings given above, or their optically active antipodes.

This oxidation is done with manganese dioxide or 2,3-chloro-5j6-dicyanobenzoquinone carried out as an oxidizing agent. Any conditions that apply when using these oxidizing agents common can be used in carrying out this reaction. The compound of the formula XXXVI or its optically active antipode is then reduced to produce a mixture which is predominantly the compound of the formula XXXIV or their optically active antipodes and a smaller amount of the compound of the formula XXXV or contains their optically active antipode. This mixture can be broken down into the individual isomers by conventional means, e.g.

409833/1048

by chromatography. The reduction by which the compound of formula XXXVI or its optically active antipode is converted into a mixture mainly containing the compound of formula XXXIV or its optically active antipode is carried out using alkali metal tri-lower alkyl borohydride. Any of the conventional when using these reducing agents and conditions may be employed in carrying out this reaction, with the exception that this reaction is carried out at a temperature of -110 to ⁰ O ⁰ -5o C '.

If the radical R ^ g in the compound of formula XXXII or

their optically active antipode - «^ OH or OH, can

this compound is converted into a compound of the following formula will:

XXXVII

where ~ ORop represents an ester protecting group which can be converted into the hydroxy radical by hydrolysis | and R / ig ¹ =

or - ^ 0 ^R 22 - ^ "k» ^{un <} ^ · ^R '^ - ^{e ot) en} has the meaning given;

or their optically active antipodes, via an intermediate the formula:

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where H ¹ ,
sit.

XXXVIII

and R ~ o cLie beDie meanings given above Compound of the formula XXXVIII or its optically active one Antipode is made by treating the compound of Formula XXXII or its optically active antipode with an esterifying agent educated. Any compound which esterifies an alcohol can be used for this purpose. Preferred means for this purpose include reactive ones Iferivate an organic acid such as a lower alkanoic acid anhydride or halide. Any of the for that Esterification of alcohols usual conditions can be used in this reaction. The compound of the formula XXXVII or its optically active antipode is by hydrolysis of the compound of the formula XXXVIII or its optically active antipodes formed with an alkali metal hydroxide in an aqueous medium. During execution this hydrolysis should only be 1 mol of alkali metal hydroxide per mol of the compound of the formula XXXVIII or its optical active enantiomers are present to the hydrolysis of the ester groups bonded directly to the cyclopentane ring and the to avoid a secondary carbon atom of the side chain attached ester group.

On the other hand, the compound of the formulas XXXIV and XXXV or their optically active antipodes can be incorporated into a compound of formulas XXXVII via an intermediate of the following Formula:

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OR

XL

wherein R ¹ , R ¹ ^, R _x . ¹ and R ^ p have the meanings given above, or their optically active antipodes are converted.

The compound of the formulas XXXIV and XXXV or their optically active antipodes are converted into the compound of the formula XL or their optically active antipodes converted by esterification in the manner already described. The compound of the formula XL or its optically active antipode is converted into the compound of the formula XXXVII or its optically active antipode Ether hydrolysis converted. Any conventional method of ether hydrolysis, e.g. treatment with a strong inorganic acid, can be applied.

The compound of the formula XXXVII or its optically active antipode is converted into the compound of the formulas I or II or their optically active antipodes are converted via the following intermediate products:

409833/1048

wherein R ¹ have;

and the meanings given above

wherein R ¹ , R ^{1 have} ^ g and R ^ o ;

or their optically active antipodes.

16

^0The given meanings

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The compound of the formula XXXVII or its optically active antipode is converted into the compound of the formula L or its optically active antipode by oxidation of the free hydroxyl group into an aldehyde group. Many of the conventional oxidizing agents used to convert alcohols to aldehydes can be used in carrying out this reaction. Preferred oxidizing agents for use in this stage of the process include chromate oxidizing agents such as chromium trioxide in pyridine and dimethyl sulfide in halogenated hydrocarbon solvents in the presence of a halogen or F-halosuccinimide followed by the addition of an organic base such as triethylamine. Any of the usual conditions for these oxidizing agents can be used in carrying out this reaction.

The compound of the formula L or its optically active antipode is converted into the compound of the formula LI or its optically active antipodes by reacting the compound of the formula L or its optically active antipode by means of a Wittig reaction with an alkali metal salt of the compound of the following formula:

• I ¹¹ l

R ₁₀ -P = CH (OH ₂ ) ^ - COH. XXV-B

wherein R ^ ₀ , R ^ ₁ and R ^ -, have the meanings given above, converted.

The compound of the formula XXV-B is used with a compound of the formula L or its optically active antipode for the preparation a compound of the formula LI or its optically active antipode using .any of the usual conditions for

409833/1048

Implementation of Wittig reactions. The connection of the formula LI or its optically active antipode can be converted into the compound of the formulas I or II or their optically active Antipodes can be converted by basic hydrolysis. Any conventional method of basic hydrolysis can be used to carry out this reaction. Basic hydrolysis is one of the preferred methods the reaction of the compound of the formula LI or its optically active antipode with an alkali metal base in an aqueous one Medium at a temperature of 10 ° C to 50 ° C.

The invention is illustrated in more detail by means of the following specific examples, without restricting it. The ether used in the examples was diethyl ether. The term "concentrated sulfuric acid" refers to a mixture containing 4 wt -.% Water and 96 wt .- ^ contains sulfuric acid. The term "concentrated hydrochloric acid" refers to an aqueous solution containing 38 weight percent hydrogen chloride.

example Λ

A solution of cyclopentadienyl sodium was made from 20.5 g (0.90 g at = gram atom) I sodium metal and 39.6 g (0.60 mol) cyclopentadiene at -10 ° C in 300 ml of tetrahydrofuran. The solution was filtered through glass wool and added dropwise to a solution of 91.8 g (0.60 mol) of methyl bromoacetate and 150 ml of tetrahydrofuran, which was kept at -78 ° C., were added. The cold mixture was stirred at -78 ° C. for 16 hours to produce methyl 2,4-cyclopentadiene-1-acetate.

During this time, (+) - di-3-pinanylborane was prepared by adding 600 ml (0.60 mol) of 1 M borane in tetrahydrofuran to 180.4 g (1.33 mol) of (-) - alpha-pinene at O ⁰ C. was added and the mixture was ^{stirred at 0 °} C. for 16 hours. The suspension was ^{cooled to -78 0} C, and the cold solution of

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Methyl S ^ -cyclopentadiene-i-acetate was added. The mixture was stirred at -78 ° C. for 6 hours and at ⁰ ° C. for 16 hours to give 2 (S) -Methoxycarbonylmethyl-3-cyclopenten-1R-yl-bis - {(1S, 2R, 3R, 5R) -2, 6, δ-trimethylbicyclo / J. 1.1_7heptan-3-yl} -b'orane.

A solution of 60 ml of 3N aqueous sodium hydroxide was added to the reaction mixture at 0 ° C., followed by the dropwise addition of 60 ml of 30% by weight hydrogen peroxide in water at ⁰ ° C. A total of 3 grams of sodium bisulfite was added to the stirred mixture, followed by 5 ^{seconds of} sodium chloride. The mixture was extracted with 3 × 250 ml of diethyl ether. The ether layers were combined and washed with 100 ml of water and 100 ml of saturated saline solution. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness to give 201.6 g of an oil. The distillation at 68 to 73 ° C (0.09 mm) yielded 25 * 8 g of a product mixture.

These 25 and 8 g of product mixture were dissolved in 600 ml of diethyl ether and washed with 3 × 250 ml of 1 M aqueous silver nitrate solution. The ether layer was discarded. The aqueous layers were combined and saturated with excess sodium chloride. The solution was then extracted with 3 × 250 ml of diethyl ether. The ether layers were washed with 100 ml of water and 100 ml of saturated saline solution. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness. The distillation at 65 to 66 ^° C. (0.03 mm Hg) yielded methyl 2R-hydroxy-4-cyclopentene-1R acetate, K. = 80 to 81 ^° C. (0.1 mmHg).

409833/1048

Example 2

A solution of cyclopentadienylsodium prepared from 20.5 g (0.90 g at) sodium metal and 39.6 g (0.60 mol) Cycbpentadien at -10 ⁰ C in 250 ml -tetrahydrofuran. The solution was filtered through glass wool and added dropwise to a solution of 91 »8 g (0.60 mol) of methyl bromoacetate and 200 ml of tetrahydrofuran which was maintained at -78 ⁰ C, was added '.. The cold mixture was stirred for 16 hours at -78 ⁰ C to form methyl-2,4-cyclopentadiene-i-acetate.

(-) - During this time, di-3-pinanylboran g by addition of 800 ml (0.80 mol) of 1 M borane in tetrahydrofuran to 239.8 (1,76MoI) (+) - alpha-pinene at 0 ⁰ C and stirring the mixture for 16 hours at 0 C. The suspension was cooled to -78 ° C and the cold solution of methyl 2,4-cyclopentadiene-1-acetate was added. The mixture was heated at -78 ° C. for 6 hours and at ⁰ ° C. for 16 hours with formation of 2R-methoxycarbonyl-methyl-J-cyclopenten-IS-yl-bis - {(1R, 2S, 3S, 5S) -2.6 , 6-trimethylbicyclo / 3.1.1_7heptan-3-yl} -borane stirred.

A solution of 60 ml of 3N aqueous sodium hydroxide was added added to the reaction mixture at 0 ° C., followed by the dropwise addition of 60 ml of 30% by weight aqueous Hydrogen peroxide at 0 C. A total of 5 g of sodium bisulfite and then 10 g of sodium chloride were added added to the mixture. The mixture was 3 x 250 ml Diethyl ether extracted. The ether layers were combined with one another and washed with 100 ml of water and 100 ml of saturated saline solution washed. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness, leaving 300 g a mixture of products.

409833/1048

The product mixture was dissolved in 500 ml of diethyl ether and washed with 3 × 250 ml of 1 M aqueous silver nitrate solution. The ether layer was discarded. The aqueous layers were combined and saturated with excess sodium chloride. The solution was then extracted with 3 × 250 ml of diethyl ether. The ether layers were washed with 100 ml of water and 100 ml of saturated saline solution. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness. The distillation at 75 to 76 ^° C. (0.05 mmHg) yielded methyl 2S-hydroxy-4-cyclopentene-1S acetate; K. = 80-81 ⁰ G (0.1 mmHg).

Example 3

A mixture of 2.30 grams (0.0348 moles) of 85 weight percent potassium hydroxide in water, 15 ml of water, 15 ml of methanol and 2.72 g (0.0174 moles) methyl 2R-hydroxy-4-cyclopentene-1R-acetate 16 hours at room temperature to form a solution which contained sodium 2R-hydroxy-4-cyclopentene-1R acetate, touched.

The solution was diluted with 30 ml v / water and with 3 x 100 ml Diethyl ether extracted. The combined ether extracts were washed with 50 ml of water and discarded. The united with each other Layers of water were made with a 1: 1 YoI excess of concentrated hydrogen chloride slurry acid-ice acidified and extracted with 3 x 50 ml diethyl ether. The combined ether layers were mixed with 50 ml of water washed and discarded.

The combined water layers were evaporated to dryness and the solid residue was washed with 3 x 150 ml of warm methylene chloride rubbed in. The methylene chloride solution was filtered and evaporated to dryness giving an oil which crystallized on standing.

409833/1048

An analytical sample was obtained by two recrystallizations from diethyl ether-hexane, fine needles with F. = 56 to 57 ⁰ O of 2R-hydroxy-4-cyclopentene-IR-acetic acid being obtained.

Example 4-

A mixture of 4.60 grams (0.0696 moles) of 85 weight percent potassium hydroxide in water, 50 ml of water, 25 ml of methanol and 5 »4-4-S (0.0348 mole) methyl 2S-hydroxy-4-cyclopentene-1S-acetate for 16 hours at room temperature to form a solution, which contained sodium 2S-hydroxy-4-cyclopentene-1S-acetate , touched.

The solution was diluted with 5 ° ml of water and with 3 x 100 ml Diethyl ether extracted. The combined ether extracts were washed with 50 ml of water and discarded. The combined water layers were washed with an excess of a slurry acidified by 1: 1 parts by volume of concentrated hydrochloric acid-ice and extracted with 3 x 100 ml of diethyl ether. The combined ether layers were with 2 × 50 ml Water washed and discarded.

The combined water layers were evaporated to dryness and the solid residue was washed with 3 x 150 ml of warm methylene chloride rubbed in. The methylene chloride solution was filtered and evaporated to dryness to give an oil which was Standing crystallized.

An analytical sample was obtained by two recrystallizations from ether-hexane, using fine needles of 2S-hydroxy-4- cyclopenten-1S-acetic acid with a temperature of 56 to 57 ° C was obtained.

409833/1048

Example 5

To a solution of 0.313 g (0.0020 mol) of methyl 2R-hydro: xy-4rcyelopenten-1R-acetate in 3 ml of pyridine at ⁰ ° G was added dropwise 0.252 g (0.0022 mol) of methanesulfonyl chloride. The mixture was ^{stirred at 0} ° C. for one hour and poured onto crushed ice. The mixture was diluted with 50 ml of saturated saline solution and extracted with 3 × 50 ml of diethyl ether. The combined ether layers were washed with 50 ml of 10% strength by weight sulfuric acid in water, 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated saline solution. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness at room temperature to give oily methyl-ZR-methylsulionyloxy - ^ - cyclopentene-IR acetate.

Example 6

To a solution of 0.625 g (0.0040 mol) of methyl 2S-hydroxy-4-cyclopentene-1S-acetate in 4 ml of pyridine at ⁰ ° O was added dropwise 0.504 x g (0.0044 mol) of methanesulfonyl chloride. The mixture was ^{stirred at 0} ° C. for 1 hour and poured onto crushed ice. The mixture was diluted with 50 ml of saturated saline solution and extracted with 3 × 50 ml of diethyl ether. The combined ether layers were washed with 50 ml of 10% strength by weight sulfuric acid in water, 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated saline solution. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness at room temperature to give oily methyl 2S-methylsulfonyloxy-4-cyclopentene-1S-acetate.

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Example 7

To a solution of 0.314 g (0.00134 mol) methyl-2R-methylsulfonyloxy-4-cyclopentene-IR-acetate, 14 ml of tetrahydrofuran and 4 ml of water at 0 ⁰ C was added dropwise 3 ml (0.0060 mol) of 2 N aqueous Sodium hydroxide added.

The two-phase ^{solution was stirred vigorously at 0} ° C. for one hour and at room temperature for 18 hours to form a solution which contained sodium 2S-hydroxy-4-cyclopentene-1R acetate.

This solution was diluted with 50 ml of water and extracted with 3 × 50 ml of diethyl ether. The ether extracts were combined with one another, washed with 25 ml of water and discarded. The water layers were combined with one another, cooled to 0 C and acidified with excess 6 N aqueous sulfuric acid. The acidic solution was saturated with sodium chloride and extracted with 3 × 50 ml of methylene chloride. The methylene chloride layers were combined and washed with 50 ml of saturated aqueous sodium bicarbonate solution. The solution was then dried over anhydrous magnesium sulfate and evaporated to dryness, 2S-hydroxy-4-cyclopentene-1R-acetic acid lactone being obtained as a white solid with a melting point of 45 to 46 ^° C.

Example 8

3 ml (0.0060 mol) of 2N sodium hydroxide solution were added dropwise to a solution of 0.308 g (0.00132 mol) of methyl 2S-methylsulfonyloxy-4-cyclopentene-IS acetate, 14 ml of tetrahydrofuran and 4 ml of water at ^{0 ° C.} added. The two-phase ^{solution was stirred vigorously at 0 °} C. for 1 hour and at room temperature for 18 hours to form a solution which contained sodium 2R-hydroxy-4-cyclopentene-1S acetate.

409833/1048

The mixture was diluted with 50 ml of water and extracted with 3 × 50 ml of diethyl ether. The ether extracts were combined with one another, washed with 25 ml of water and discarded. The water layers were combined with one another, ^{cooled to 0} ° C. and acidified with excess 6 N aqueous sulfuric acid. The acidic solution was saturated with sodium chloride and extracted with 3 × 50 ml of methylene chloride. The methylene chloride layers were combined and washed with 50 ml of saturated aqueous sodium bicarbonate solution. The solution was then evaporated dried over anhydrous magnesium sulfate and evaporated to dryness to give 2R-hydroxy-4-cyclopenten-1S-essigsäurelacton as a white solid was get to know said e-with mp = 45-46 ^0C.

Example 9

A mixture of 1.0 ml of a peracetic acid solution containing 40 wt .- ^ peracetic acid, 5 wt .- $ of hydrogen peroxide, 39 wt .- ^ acetic acid, 15 wt .- ^ water and 1 wt -.% Of sulfuric acid, of 3 * 0 ml of acetic acid and 0.40 g of anhydrous sodium acetate were ^{stirred at 0} ° C. for 10 minutes. A solution of 0.310 g (0.0025 mol) of 2S-hydroxy-4-cyclopentene-1R-acetic acid lactone in 1 ml of acetic acid was added dropwise. The mixture was ^{stirred at 0} ° C. for one hour and at room temperature for 16 hours.

The mixture was poured into 50 ml of water and with 3 x 5 ° ml Extracted methylene chloride. The combined methylene chloride layers were washed with 50 ml of saturated, aqueous sodium sulfite solution and 50 ml of saturated aqueous sodium bicarbonate solution washed. The aqueous washing liquids were each back-extracted with 25 ml portions of methylene chloride. the combined methylene chloride layers were dried over anhydrous magnesium sulfate and evaporated to dryness, whereby 0.342 g of a colorless oil were obtained.

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The oil was triturated with 1 ml of cold diethyl ether to induce crystallization of the oil. The ethereal solution was pipetted off from the crystals and evaporated to dryness, whereby 0.070 g of an oil was obtained, which was discarded became.

The recrystallization of the solid from ethyl acetate-heptane at ⁰ ° G gave a first amount of 1aR, 2.2aS, 5 »5aS, 5bS-hexahydro-4H-oxireno / ^, 4_7cyclopenta / T, 2-b_7furan-4-one. An analytical sample was prepared by a further recrystallization from ethyl acetate-heptane to give the furan l · -one was obtained as fine colorless needles with mp = 76-77 ⁰ C

Example 10

A mixture of 1.0 ml of the peracetic acid solution used in Example 9, 3 »0 ml acetic acid and 0.40 g anhydrous sodium acetate was ^{stirred at 0} ° G for 10 minutes. A solution of 0.310 g (0.0025 mol) of 2R-hydroxy-4-cyclopentene-1S-acetic acid lactone in 1 ml of acetic acid was added dropwise. The mixture was ^{stirred at 0} ° C. for one hour and at room temperature for 16 hours.

The mixture was poured into 50 ml of water and 3 x 50 ml Extracted methyl en chloride. The combined methylene chloride layers were with 50 ml of saturated, aqueous sodium sulfite solution and 50 ml of saturated aqueous sodium bicarbonate solution washed. The aqueous washing liquids were each back-extracted with 25 ml portions of methylene chloride. The combined methylene chloride layers were dried over anhydrous magnesium sulfate and evaporated to dryness, 0.350 g of a colorless oil were obtained.

The oil was triturated with 1 ml of ether at 0 C in order to crystallize bring about. The ethereal solution was from the crystals

409833/1048

pipetted off and evaporated to dryness, leaving 0.050 g of an oil which was discarded.

The recrystallization of the solid from ethyl acetate-heptane at ⁰ ° G gave a first amount of 1aS, 2.2aR, 5 »5aR, 5bR-hexahydro-4H-oxireno / 3,4_7cyclopenta / T, 2-b_7furan-4-one.

An analytical sample was obtained by a further crystallization from ethyl acetate-heptane, whereby fine, colorless Needles of the product with a F. = 76 to 77 ° C resulted.

Example 11

A mixture of 0.076 g (0.0020 mol) of lithium aluminum hydride, 15 ml of diethyl ether and 0.248 g (0.0020 mol) of 2S-hydroxy-4-cyclopentene-IR-acetic acid lactone was stirred at 0 G for one hour. To the solution at ⁰ ° C was added dropwise 0.15 ml of water and then 0.12 ml of an aqueous solution containing 10 wt -% containing sodium hydroxide, was added and the mixture was stirred for 0.5 hours at ⁰ G O.. The solution was then stirred with 0.10 g of anhydrous magnesium sulfate for 0.5 hour, diluted with 10 ml of methylene chloride and filtered. The solid residue was triturated with 2 × 10 ml of methylene chloride and filtered. The combined piltrate was evaporated to dryness, 0.265 g of a colorless, viscous oil being obtained.

The oil was purified by column chromatography on 5 g of silica gel (silica gel 0.05-0.20 mm). A total of 0.016 g impurity was eluted with 10 volume ethyl acetate in 90 volume benzene. The fractions of 25 vol .- # ethyl acetate-benzene gave oily 2R- (2-hydroxyethyl) -3-cyclopenten-1S-ol with K. = 83 to 84 ⁰ G (0.1 mmHg).

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Example 12

A mixture of 0.076 g (0.0020 mol) of lithium aluminum hydride, 15 ml of diethyl ether and 0.245 g (0.0020 mol) of 2R-hydroxy-4-cyclopentene-IS-acetic acid lactone was stirred at 0 C for one hour. To the solution at 0 G was added 0.15 ml dropwise Water and then 0.12 ml of 10% strength by weight aqueous sodium hydroxide solution was added and the mixture was stirred at 0 0 for 0.5 hours. The solution was then added with 0.10 g Stirred anhydrous magnesium sulfate for 0.5 hours, diluted with 10 ml of methylene chloride and filtered. The firm one The residue was triturated with 2 × 10 ml of methylene chloride and filtered. The combined IT filtrate became dry evaporated to give 0.270 g of a colorless, viscous oil.

The oil was purified by column chromatography on 5 L silica gel (silica gel, 0.05-0.20 mm). A total of 0.016 g of impurity was eluted with 10 vol .- # ethyl acetate and 90 vol .- # benzene. The fractions of 25 vol .- # ethyl acetate-benzene gave 2S- (2-hydroxyethyl) -3-cyclopentene-1R-ol with K. = 83 to 84- ⁰ C (0.1 mmHg).

Example 13

0.115 S (0.0010 mol) of methanesulfonyl chloride in 1 ml of pyridine were added dropwise to a solution of 0.14-2 g (0.0010 mol) of 2R-hydroxy-4-cyclopentene-1R-acetic acid and 1 ml of pyridine at ^{0 ° C.} was added and the mixture was stirred at 0 C for 1 hour and at room temperature for 18 hours to form a solution containing 2R-methylsulfonyloxy-4-cyclopentene-1R-acetic acid.

A total of 0.5 g of ice was added and the equipment was stirred for four hours at room temperature. That Mixture was poured into 50 nil saline and added 3 x 50 ml

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Extracted methylene chloride. The methylene chloride layers were washed with 50 ml of 10% strength by weight aqueous sulfuric acid solution and 50 ml of saturated aqueous sodium bicarbonate solution. The methylene chloride solution was dried over anhydrous magnesium sulfate and evaporated to dryness to give 0.082 g of a yellow solid. Recrystallization from ether-hexane at ⁰ ° C. gave 2S-hydroxy-4-cyclopentene-IR-acetic acid lactone with i ¹ . = 44 to 45 ° 0. An analytical sample of 2S-hydroxy-4-cyclopentene-1R-acetic acid lactone with F. = 45 to 46 ⁰ C was by a further recrystallization from ether. Hexane obtained at O ⁰ G.

Example 14

To a solution of 0.142 g (0.0010 mol) of 2S-hydroxy-4-cyclopentene-1S-acetic acid and 1 ml of pyridine at ⁰ G was added dropwise 0.115 g (0.0010 mol) of methanesulfonyl chloride in 1 ml of pyridine and the mixture was stirred for one hour at 0 G and for 18 hours at room temperature to form a solution which contained 2S-methylsulfonyloxy-4-cyclopentene-1S-acetic acid.

A total of 0.5 g of ice was added and the mixture was stirred at room temperature for 4 hours. The mixture was poured into 50 ml of brine and extracted with 3 x 50 ml of methylene chloride. The methylene chloride layers were washed with 50 ml of 10% strength by weight aqueous sulfuric acid and 50 ml of saturated aqueous sodium bicarbonate solution. The methylene chloride solution was dried over anhydrous magnesium sulfate and evaporated to dryness to give 0.078 g of a semi-solid. Two recrystallizations from ether-hexane at ^{0 0} G gave 2R-hydroxy-4-cyclopentene-1S-acetic acid lactone with m.s. = 45 to 46 ⁰ G.

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Example 15

A mixture of 0.192 g (0.00150 mol) of 2R- (2-hydroxyethyl) -3-eyclopenten-1S-ol, 5 ml of methylene chloride, and 0.40 g of sodium bicarbonate was ^{cooled to 0} ° G, and 0.335 g was obtained
(0.00165 mol) of m-chloroperbenzoic acid (purity of 85% by weight) in 3 nil of methylene chloride was added dropwise. The mixture was ^{stirred at 0 0} G for 0.5 hours and at room temperature for hours in the dark.

The mixture was diluted with 50 ml of ether and this solution was washed with 3 x 50 ml of water. The water layers were combined and concentrated to dryness, whereby
0.224 g of a colorless oil were obtained.

The oil was purified by column chromatography on 15 g of silica gel (silica gel, 0.05-0.20 mm). A total of 0,013 S to "impurities was eluted with chloroform. The fractions of 2 vol .- # Ghloroform methanol yielded oily 2S ~ hydroxy-4R, 5S-epoxycyclopentane-1S-ethanol with K. = 140 G ⁰
(0.1 mmllg).

Example 16

A mixture of 0.192 g (0.00150 mol) of 2S- (2-hydroxyethyl) -3-cyclopenten-1R-ol, 5 ml of methylene chloride and 0.40 g of sodium bicarbonate was ^{cooled to 0} ° C. and 0.335 g was obtained
(0.00165 mol) m-chloroperbenzoic acid (purity of 85 wt .- #) in 3 ml of methylene chloride was added dropwise. The mixture was ^{stirred at 0} G for 0.5 hours and at room temperature for 18 hours in the dark.

The mixture was diluted with 50 ml of ether and this solution was washed with 3 x 50 ml of water. The layers of water were combined with one another and evaporated to dryness, 0.218 g of a colorless oil being obtained.

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The oil was purified by column chromatography on 15 g of silica gel (silica gel; 0.05-0.20 mm). A total of 0.020 g of impurities was eluted with chloroform. Fractions of 2 vol .- # methanol-chloroform gave an oily 2R-hydroxy-4S, 5R-epoxycyclopentane-1R with ethanol K. = 140 ⁰ C (0.1 mmHg).

Example 17

To a solution of 0.070 g (0.00050 mol) of 1aR, 2.2aS, 5.5aS, -5bS-hexahydro-4H-oxireno / 3 \ 4_7cyclopenta / T, 2-b_7furan-4-one in 5 toluene at -78 ⁰ C were added 0.60 ml (0.00088 mole) of 1.4 to 7 M diisobutylaluminum hydride in toluene and the reaction mixture was stirred for 3 hours at -78 ⁰ C. The reaction mixture was quenched by adding 0.5 ml of methanol and diluted with 5 ml of saturated aqueous sodium sulfate solution and extracted with 3 × 30 ml of methylene chloride. The methylene chloride extracts were dried over anhydrous sodium sulfate and evaporated to dryness to give crystalline 1aR, 2aS, 4,5) 5aS, 5bS-hexahydro-4-hydroxy-2H-oxireno / 3,4_7cyclopenta / T, 2-b_7furan. An analytical sample was obtained by recrystallization from ether-hexane at 0 C, with fine, colorless needles of furan with a temperature of ^{65 to 66 0 C.}

Example 18

To a solution of 0.070 g (0.00050 mol) 1aS, 2.2aR, 5.5aR, 5bR-hexahydro-4H-oxireno / 3,4_7cyclopenta / T, 2-b_7furan-4-one in 5 ml toluene at -78 ⁰ C were added 0.60 ml (0.00088 mol) of 1.47 M diisobutylaluminum hydride in toluene, and the reaction mixture was stirred at -78 ° C for 3 hours. The reaction mixture was quenched by adding 0.5 ml of methanol and diluted with 5 ml of saturated aqueous sodium sulfate solution and extracted with 3 × 30 ml of methylene chloride. The methylene chloride extracts were dried over anhydrous sodium sulfate and dried to dryness

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evaporated to give crystalline 1aS, 2aR, 4-, 5,5aR, 5bR-hexahydro-4-hydroxy-2H-oxireno / 3,4_7cyclopenta / T, 2-b_7furan. An analytical sample was obtained by recrystallization from ether-hexane at 0 ⁰ G, wherein, fine colorless needles of the furan with mp = 65-66 ⁰ C were obtained.

Example 19

A solution of 0.109 g (0.000765 mol) 1aR, 2aS, 4-, 5.5aS, 5bS-hexahydro-4-hydroxy-2H-oxireno / J, 4_7 cyclopenta / ~ 1j2-b_7. furan in 2 ml of methanol was cooled to -25 ° C. and 0.010 g of boron trifluoride etherate in 0.5 ml of methanol was added dropwise. The mixture was stirred at -25 ° C. and 1 hour at ^{0 ° C. for 1.5 hours.} The reaction was stopped by adding 0.10 g of solid sodium bicarbonate and stirring for 10 minutes. The mixture was diluted with 25 ml of methylene chloride, dried over anhydrous magnesium sulfate and evaporated to dryness to give a colorless oil.

The distillation at 50 to 52 ⁰ G (0.1 mmHg) gave 1aR, 2aS, 4-, 5 »5aS, 5bS-hexahydro-4R-methoxy-2H-oxireno / ~ 3,4_7cyclopenta / ~ 1,2-b_7f urane .

Example 20

A solution of 0.113 g (0.000795 mol) 1aS, 2aR, 4,5,5aR, 5bR-hexahydro-4-hydroxy-2H-oxireno / ~ 3,4-_7cyclopenta / ~ 1 »2-b_7 for urane in 2 ml Methanol was cooled to -25 ° C. and 0.010 g of boron trifluoride etherate in 0.5 ml of methanol was added dropwise. The mixture was stirred at -25 G for 1.5 hours and at ^{0 0} G for 1 hour. The reaction mixture was quenched by adding 0.10 g of solid sodium bicarbonate and stirring for 10 minutes.

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The mixture was diluted with 25 ml of methylene chloride over dried anhydrous magnesium sulfate and evaporated to dryness to give a colorless oil.

The distillation at 50 to 52 ⁰ O (0.1 mmHg) gave 1aS, 2aR, 4.5> 5aR, 5bR-hexahydro-4S-methoxy-2H-oxireno / 3,4_7cyclopenta / T, 2-b_ / furan.

Example 21

A mixture of 9.35 ml (0.0140 mol) 1.5 M butyllithium in hexane, 1.16 g (0.0070 mol) 1,3-bis (methylthio) -2-methoxypropane, 1> 41 g ( 0.0140 mol) of diisopropylamine and 15 ml of tetrahydrofuran was stirred for 16 hours at -78 ° G 1 hour and at -10 ⁰ G to a dark red solution of 1,3-bis (methylthio) -allyllithium manufacture. This solution was again cooled to -78 ⁰ G, and a solution of 0.994 g (0.00636 mol) 1aR, 2aS, 4.5 »5aS, 5BS-hexahydro-4R-methoxy-2H-oxireno / 3,4_7cyclopenta / T, 2-b_7furan in 5 ml of tetrahydrofuran was added dropwise. The mixture was stirred for 5 hours at -78 ⁰ G, and the reaction was stopped by addition of 2 ml methanol.

The mixture was dissolved in 50 ml of saturated aqueous ammonium chloride solution poured in, and this solution was mixed with 4 × 50 ml of methylene chloride extracted. The methylene chloride layers were washed with 50 ml of water, dried over anhydrous magnesium sulfate and evaporated to dryness, a mixture of approx. 1: 1 parts by weight of 4R- (1,3-bismethylthio-2-propen-1-yl) -3,3aR, 4,5,6, 6aS-hexahydro-5R-hydroxy-2R-met'hoxy-2H-cyclopenta / b_7furan and of 5S- (1,3-bismethylthio-2-propen-1-yl) -3,3aR, 4,5,6,6aS-hexahydro-4S-hydroxy-2R-methoxy-2H-cyclopenta / b_7furan was obtained.

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Example 22

Following the procedure of Example 21, 1aS, 2aR, 4,5i5aR, 5bR-hexahydro-4S-methoxy-2H-oxireno / 3 \ 4j / ^r cyclopenta / T, 2-b_7-furan in a mixture of approx. 1: 1 Parts by weight of 4S- (1,3 ~ bismethylthio-2-propen-1-yl) -3aS, 4.5> 6.6aR-hexahydro-5S-hydroxy-2S-methoxy-2H-cyclopenta / b_7furan and of 5R- (1,3-bismethylthio-2-propen-1 -yl) -3 »3aS, 4.5» 6, öaR-hexaliydro ^ R-hydroxy-2S-methoxy-2H-cyclopenta / b_7furan.

Example 23

An approximately 1: 1 mixture of 1.78 g (0.00613 moles) of 4R- (1,3-bismethylthio-2-propene-1 -yl) -3, 3aR, 4-, 5,6,6aS-hexahydro-5R-hydroxy-2R-methoxy-2H-cyclopenta / b_7furan and 5S- (1, 3-bismethylthio-2-propen-1-yl) -3, 3aR, 4,5 »6, eaS-hexahydro- ^ S-hydroxy ^ R-methoxy-2H-cyclopenta / b_7furan, 5 »0 g (0.0184 mol) mercury (II) chloride, 1.84 g (0.0184 mole) calcium carbonate, 80 ml acetonitrile and 20 ml of water were mixed together at 50 to 55 ° G for 4 hours stirred and cooled. The mixture was filtered through diatomaceous earth, poured into 50 ™ l of saline solution and washed 3 x 5 ° ^ l Extracted methylene chloride. The methylene chloride layers were washed with 50 ml of brine, over anhydrous magnesium sulfate dried and evaporated to dryness, 1.28 g of a product mixture being obtained.

The mixture was purified by column chromatography on 45 g of silica gel (Silica gel; 0.05-0.20 mm).

The later fractions eluted with diethyl ether gave (3, 3aR, 4,5,6, oaS-hexahydro ^ R-hydroxy ^ R-methoxy ^ H-cyclopenta / b_7furan-4R-yl) -E-acrolein.

Example 24

The mixture prepared in Example 22 was made according to the procedure of Example 23 treated, wherein (3,3aS, 4.5 »6,6aR-hexahydro-58-hydroxy-2S-methoxy-2H-cyclopenta / b_7furan-4S-yl) -E-acrolein was produced.

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Example 25

To a solution of 0.54 g (0.00254 mol) (3,3aR, 4,5,6,6aS-hexahydro-5R-hydroxy-2R-methoxy-2H-cyclopenta / b_7furan-4R-yl) -E- acrolein in 12 ml of tetrahydrofuran at -25 ° G 6.0 ml (0.0066 mol) of 1.1 M n-pentyl were added in pentane, and the mixture was at -25 ⁰ C for 1 hour and at ⁰ G 1 hour touched. The mixture was poured into 50 ml of saturated aqueous ammonium chloride solution and extracted with 3 × 50 ml of methylene chloride. The methylene chloride extracts were washed with 50 ml of brine, dried over anhydrous magnesium sulfate and evaporated to dryness to give 0.70 g of an approximately 1: 1 weight mixture of products.

The mixture was purified by column chromatography on 30 g of silica gel (Silica gel; 0.05-0.20 mm). The early diethyl ether fractions yielded 1- (3,3aR, 4,5i6,6aS-hexahydro-5R-hydroxy-2R-methoxy-2H-cyclopenta / b-7furan-4R-yl) -1E-octene-3R-0I.

The later diethyl ether fractions yielded 1- (3? 3aR, 4.5 »6, 6aS-Hexahydro ~ 5R-hydroxy-2R-methoxy-2H-cyclopenta / b_7furan-4R-yl) -1E-octen-3S-ol.

Example 26

The compound (3> 3aS, 4.5 _? 6.5aR-hexahydro-5S-hydroxy-2S-methoxy-2H-cyclopenta / b_7furan-4S-yl) -E-acrolein was treated according to the procedure of Example 25 and after The procedure of Example 25 separated, with 1- (3 »3aS, 4.5> 6.6aR-hexahydro-5S-hydroxy-2S-methoxy-2H-cyclopenta / b-7furan-4S-yl) -1E-octene-3S-0I and 1- (3,3aS, 4,5,6,6aR-hexahydro-5S-hydroxy-2S-methoxy-2H-cyclopenta / b-7furan-4S-yl) -1E-octen-3R-ol were obtained.

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Example27

To a solution of 0.27 g (0.00095 mole) of 1- (3,3aR, 4,5,6,6aS-hexahydro-5R-hydroxy-2R-methoxy-2H-cyclopenta / b_7furan- ^z} -R- yl) -1E-octen-3S-ol, 4 x ml of acetonitrile and 1 ml of water were added dropwise to 1 ml of 0.1 N aqueous hydrochloric acid, and the mixture was stirred at room temperature for 2 hours. The solution was poured into 50 ml of brine and extracted with 3 x 50 ml of methylene chloride. The methylene chloride extracts were washed with 50 ml of brine, dried over anhydrous magnesium sulfate and evaporated to dryness, giving 1- (2,5R-dihydroxy-3,3aR, 4,5,6,6aS-hexahydro-2H-cyclopenta / b_7furan-4R- yl) -1E-octen-3S-ol was obtained.

Example 28

1 ~ (3,3aS, 4,5,6,6aR-hexahydro-5S-hydroxy-2S-methoxy-2H-cyclopenta / b-7furan-4S-yl) -1E-octen-3R-ol is after the procedure of Example 27 in 1- (2,5S-dihydroxy-3,3aS, 4, 5 »6, 6aR-hexahydro-2H-cyclopenta / b_7furan-4S-yl) -1E-octen-3R-ol converted.

Example 29

A mixture of 0.25 g (0.000925 moles) 1- (2,5R-dihydroxy-3,3aR, 4,5,6,6aS-hexahydro-2H-cyclopenta / b-7furan-4R-yl) -1E-octene -3S-ol, 2.05 g (0.00463 mole) of (4-carboxybutyl) triphenylphosphonium bromide, 30 ml of dimethyl sulfoxide and 0.108 g (0.00450 mole) of sodium hydride was stirred for 4 hours at 45 to 50 ⁰ g and cooled.

The mixture was dissolved in 100 ml of saturated aqueous ammonium chloride solution poured in, and the solution was with 4 χ 50 ml Extracted methylene chloride. The methylene chloride layers were washed with 50 ml of brine, over anhydrous magnesium sulfate dried and evaporated to dryness under high vacuum to give 0.36 g of a product mixture. The mixture

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was dissolved in 100 ml of methylene chloride, and the solution was washed with 2 × 25 ml of ice-cold, saturated, aqueous sodium bicarbonate solution. The aqueous layers were combined with one another, ^{cooled to 0} ° C. and carefully acidified with excess, aqueous 2 N sulfuric acid. The solution was saturated with excess sodium chloride and extracted with 4 × 50 ml of methylene chloride. The methylene chloride layers were washed with 50 ml of brine, dried over anhydrous magnesium sulfate, and evaporated to dryness to give oily naturally occurring (+) - prostaglandin ^ oqC) / T ^ Z / ~ + 22.4 ° (tetrahydrofuran) .

Example 50

1- (2,5S-dihydroxy-5,3aS, 4,5,6,6aR-hexahydro-2H-cyclopenta / b_7-furan-4S-yl) -1E-octen-3R-ol was carried out following the procedure of Example 29 in the optically active antipodes of prostaglandin

Pp converted, Γ & 7 ²⁵ = -23.0 ° (tetrahydrofuran).

Example 51

Following the procedure of Examples 27 and 29, the compound was obtained 1- (3,3aR, 4.5> 6.6aS-hexahydro-5R-hydroxy-2R-methoxy-2H-cyclopenta / b-7furan-4R-yl) -1E-octen-3R-ol in 15-epi-prostaglandin IV, ^ via the intermediate 1- (2,5R-dihydroxy-3,3aR, 4-, 5,6,6aS-hexahydro-2H-cyclopenta / b_7furan-'l · R-yl) -1E-octen-3R-ol converted. The oily 15-epi-prostaglandin F2 ^ shows one

optical rotation of / j ^ J = + 11.2 ° (tetrahydrofuran).

Example 32

Following the procedure of Examples 27 and 29, the compound 1- (3,3aS, 4 ·, 5,6,6aR-hexahydro-5S-hydroxy-2S-methoxy-2H-cyclopenta / b_7furan-4S-yl) -1E- octene-3S-ol in the optically active Antipodes of 15-epi-prostaglandin food over the intermediate

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product 1- (2,5S-dihydroxy-3,3aS, 4,5,6,6aR-hexahydro-2H-cyclopenta / b_7furan-4S-yl) -1E-octen-3S-ol. The oily, optically active antipode of 15-epi-prostaglandin F ₀ ^ shows an optical rotation of fo C / ^ = -10.9 (tetrahydrofuran).

Example 55

To a solution of 1.44 g (0.0100 mol) of 2S-hydroxy-4R, 5S-epoxy-cyclopentane-IS-ethanol in 50 ml of toluene were slowly added 22.23 g (0.100 mol) of 5S-tert.-Butyloχy- 1-octynyldinethylalane in 200 ml of toluene was added, and the mixture was stirred at 60 to 65 ° C. for 2 hours and cooled. The mixture was poured into 200 ml of saturated aqueous ammonium chloride solution at 0 g. The mixture was extracted with 3 x 200 ml of methylene chloride. The combined methylene chloride extracts were washed with 200 ml of brine and dried over anhydrous magnesium sulfate. The solution was concentrated to dryness, 4R- (2-hydroxyethyl) -5S- (3S-tert-butyloxy-1-octynyl) -cyclopentane-1R, 3S-diol was obtained, / ÖCJ = -41 (chloroform). ' ^D

Example 54

Following the procedure of Example 33, 2R-hydroxy-4S, 5R-epoxy cyclopentane-1R-ethanol in 4S- (2-hydroxyethyl) -5R- (3R-tert. butyloxy-1-octynyl) -cyclopentane-1S, 3R-diol by reaction with

3R-tert-butyloxy-1-octynyldimethylalane converted, / βέ + 41 ° (chloroform). · ^D

Example 55

A solution of 2.20 g (0.00675 mol) of 4R- (2-hydroxyethyl) -5S- (3S-tert-butyloxy-1-octynyl) -cyclopentane-1R, 3S-diol in 10 ml of trifluoroacetic acid was stirred at −10 ° C. for 4 hours. The cold one Solution was added dropwise to a stirred solution of

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50 ml ice-cold, aqueous 2 N sodium hydroxide solution added, and the mixture was stirred for 5 minutes.

The solution was evaporated to dryness in vacuo. The residue was washed twice with 100 ml portions of boiling Tetrahydrofuran triturated. The tetrahydrofuran solutions were filtered off from the solids and evaporated to dryness, whereby a colorless solid was obtained. Recrystallization from ethyl acetate gave 4R- (2-hydroxyethyl) -5S- (3S-hydroxy-1-octynyl) -cyclopentane-1R, 3S-diol, F. =

93 to 94- ° C, fe 7 ²⁵ = + 16 ° (GH ^ OH).

D °

Example 36

Following the procedure of Example 35, 4S- (2-hydroxyethyl) -5R- (3R-tert-butyloxy-1-octynyl) -cyclopentanes, 3R-diol in 4S- (2-hydroxyethyl) -5R- (3R-hydroxy -1-octynyl) -cyclopentane-1S, 3R-diol converted, m.p. 93 b, is 94- ° G, / S_7 ²⁵ = -16 ° (GH ^ OH).

D.

Example 37

1.80 g (0.00666 mol) of 4R- (2-hydroxyethyl) -5S- (3S-hydroxy-1-octynyl) - were added to a solution of 1.25 S (0.0330 mol) of lithium aluminum hydride in 50 ml of tetrahydrofuran cyclopentane-1R, 3S-diol in 50 ml of tetrahydrofuran was added, and the mixture was heated to reflux (65 ° C.) for 6 hours and cooled. 100 ml of ether were added to the solution and the solution was cooled to ^{0 ° G.} A total of 2.5 ml of water and then 2.0 ml of 10% by weight aqueous sodium hydroxide solution were added dropwise, and the mixture was stirred for 2 hours. The mixture was filtered and the solids were triturated with 3 x 50 ml methylene chloride. The ether and methylene chloride layers were combined and dried over anhydrous magnesium sulfate. The solution was evaporated to dryness, 4-R- (2-hydroxyethyl) -5R- (3S-hydroxy-1E-octenyl) -cycloOentane-1R, 3S-diol was obtained, / pcj ² ^ = + 25 ° (GH ₃ OH).

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Example 38

Following the procedure of Example 37, 4S- (2-hydroxyethyl) -5R- (3R-hydroxy-1-octynyl) -cyclopentane-1S, 3R- <iiol in 4S- (2-hydroxyethyl) -5S- (3R-hydroxy -1E-octenyl) -cyclopentane-1S _i 3R-diol converted, / öi 7 ²⁵ = -25 ° (CH, OH).
D ^

Example 39

To a solution of 1.76 g (0.00647 mol) of 4R- (2-hydroxyethyl) -5R- (3S-hydroxy-1E-octenyl) -cyclopentane-1R, 3S-diol in 15 ml of pyridine at ⁰ ° C. 1.81 g (0.00650 mol) of triphenylmethyl chloride in 10 ml of pyridine were added, and the mixture was ^{stirred at 0} ° C. for 2 hours and at room temperature for 16 hours.

The mixture was poured into 50 ml of saturated saline solution and the solution was extracted with 3 x 50 ml of methylene chloride. The methylene chloride layers were washed with 2 × 5 ° ml of 10% strength by weight aqueous sulfuric acid, 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated saline solution. The solution was then dried over anhydrous magnesium sulfate and evaporated to dryness to give 5R- (3S-hydroxy-1E-octenyl) -4R- (2-trityloxyethyl) -cyclopentane-1R, 3S-diol, m.p. 107-110 ° C, / &> _ 7 ²⁵ = -20 ° (CHCl ₅ ,).

D ^

Example 40

Following the procedure of Example 39, 4-S- (2-hydroxyethyl) -5S- (3R-hydroxy-1E-octenyl) -cyclopentane-1S, 3R-diol in 5S- (3R-hydroxy-1E-octenyl) -4S- (2-trityloxyethyl) -cyclopentane-1S, 3R-diol

converted, F. = 107 to 11O ⁰ C / 5 <7 ²⁵ = + 20 ° (CHCl.).

D ^

Example 41

To a mixture of 2.80 g (0.00545 mol) of 5R- (3S-hydroxy-1E-octenyl) -4R- (2-trityloxyethyl) -cyclopentane-1R, 3S-diol and 20 ml of pyridine at ⁰ ° C. were added dropwise 2.29 g (0.02180 mol) of vinegar

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acid anhydride (97 # purity) in 5 ml pyridine added, and the mixture was stirred at OC for 2 hours and at room temperature for 16 hours.

The mixture was poured into 50 ml of water and washed 3 x Extracted methylene chloride. The methylene chloride layers were saturated with 2 × 50 ml of 10% strength by weight aqueous sulfuric acid, 50 ml aqueous sodium bicarbonate solution and 50 ml of saturated Washed with saline. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness, whereby 5R- (3S-acetoxy-1E-octenyl) -4R- (2-trityloxyethyl) cyclopentane

1R, 3S-diol diacetate was obtained, / J ^ J ² ^ = + 12 ° (CHCl _x ).

D °

Example 42

Following the procedure of Example 41, 5S- (3R-hydroxy-1E-octenyl) -4S- (2-trityloxyethyl) -cyclopentane-1S, 3R-diol in 5S- (3R-acetoxy-1E-octenyl) -4S- (2-trityloxyethyl) -cyclo-

pentane-1S, 3R-diol diacetate converted, / cj £ _7 ² ^ = -12 ° (CHCl _x ).

D °

Example 4; 5

A mixture of 3.12 g (0.00487 mol) of 5R- (3S-acetoxy-1E-octenyl) -4R- (2-trityloxyethyl) -cyclopentane-1R, 3S-diol diacetate, 45 ml of acetic acid and 5 ml of water was added Stirred at room temperature for 24 hours. The mixture was poured into 100 ml of water and extracted with 3 × 75 ml of ethyl acetate. The ethyl acetate solution was washed with 2 × 100 ml of ice-cold, aqueous 10% by weight sodium hydroxide solution, 50 ml of water and 50 ml of saturated saline solution. The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with 4 50 ml petroleum ether (F. = 30 to 60 ⁰ C), and the petroleum ether solution was evaporated to dryness, whereby 5R- (3S-acetoxy-1E-octenyl) -4R- (2-hydroxyethyl) - cyclopentane-1R, 3S-diol diacetate was obtained, β <J = + 1 ° (CHCl _x ).

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Example 44

Following the procedure of Example 43, 5S- (3R-acetoxy-1E-octenyl) -4S- (2-trityloxyethyl) -cyclopentane-1S, 3R-diol diacetate in 5S- (3R-acetoxy-1E-octenyl) -4S - (2-hydroxyethyl) cyclopentane-1S, 3R-diol diacetate converted, £ ÖC / = -1 ° (CHCl ₃ ). ^D.

Example 45

To a vigorously stirred solution of 11.70 g (0.04520 mol) of dipyridine chromium (VI) oxide in 250 ml of methylene chloride were added 1.80 g (0.00452 mol) 5R- (3S-acetoxy-1E-octenyl) -4R- (2-hydroxyethyl) -cyclopentane-1R, 3S-diol diacetate in 10 ml of methylene chloride added, and the mixture was 20 minutes at room temperature touched.

The orange-brown solution was decanted from the solid precipitate and eluted through a column containing 50 g of silica gel (silica gel; 0.05-0.20 mm) with methylene chloride. The appropriate fractions from the column chromatography were combined and concentrated to dryness, 2R- (3S-acetoxy-1E-octenyl) -3R, 5S-diacetoxy-1R-cyclopentane acetaldehyde being ^{obtained, / p07 2} ^ = + 13 ° (CHCl,) .

D.
Example 4-6

Following the procedure of Example 4-5, 5S- (3R-acetoxy-1E-octenyl) -4-S- (2-hydroxyethyl) -cyclopentane-1S, 3R-diol diacetate converted to 2S- (3R-acetoxy-1E-octenyl) -3S, 5R-diacetoxy-1S-cyclopentane acetaldehyde, / öc7 = -13 ° (CHCl ^).

D ^

Example 4-7

A mixture of 1.30 g (0.00328 mol) of 2R- (3S-acetoxy-1E-octenyl) 3R, 5S-diacetoxy-1R-cyclopentane acetaldehyde, 7.27 g (0.0164-0 mol) (4-carboxybutyl) triphenylphosphonium bromide, 75 al dimethyl

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sulfoxide and 0.384 g (0.01600 mol) of sodium hydride was added to Stirred at room temperature for 24 hours.

The mixture was dissolved in 200 ml of saturated aqueous ammonium chloride solution poured. The solution was extracted with 4 × 100 ml of pentane. The pentane layers were washed with 2 × 100 ml of water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was dissolved in 250 ml of 1: 1 parts by volume of diethyl ether-pentane dissolved, and this solution was with 2 χ 50 ml washed ice-cold, saturated, aqueous sodium bicarbonate solution. The aqueous layers were combined with one another, cooled to 0 C and carefully washed with excess aqueous Acidified 2 N sulfuric acid. The solution was saturated with excess sodium chloride and with 3 x 100 ml of methylene chloride extracted. The methylene chloride layers were with 2 χ 5 ° ml Washed brine, dried over anhydrous magnesium sulfate and concentrated to dryness, whereby 7- / ~ 2R- (3S-acetoxy-1E-octenyl) -3R »5S-diacetoxy-1R-cyclopentyl_7-5Z-heptenoic acid was obtained.

Example 48

Following the procedure of Example 47, 2S- (3R-acetoxy-1E-octenyl) -3S, 5R-diacetoxy-1S-cyclopentane acetaldehyde in 7 - / "2S .- (3R-acetoxy-1E-octenyl) -3S, 5R-diacetoxy-1S-cyclopentyl_7-5Z-heptenoic acid converted.

Example 49

A mixture of 0.481 g (0.0010 mol) 7- / ~ 2R- (3S-acetoxy-1E-octenyl) -3R, 5S-diacetoxy-1R-cyclopentyl_7-5Z-heptenoic acid _? 0.660 g (0.0100 mol) potassium hydroxide (85 % pure) and 50 ml water was stirred for 18 hours at room temperature.

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The mixture was ^{cooled to 0} ° C. and acidified with excess, aqueous 2 N sulfuric acid. The solution was saturated with excess sodium chloride and extracted with 4 × 50 nil ethyl acetate. The ethyl acetate solution was washed with 2 × 5 ° ml of saturated saline solution, dried over anhydrous magnesium sulfate and evaporated to dryness, leaving naturally occurring (+) - prostaglandin

was obtained; / 3t7 ² ^ = + 23.2 ° (tetrahydrofuran).

According to the procedure given above, 7- / 2S- (3R-acetoxy-1E-octenyl) -3S, 5R-diacetoxy-1S-cyclopentyl7-52; -heptenic acid in the optically active antipodes of prostaglandin Pgoc ^around S ^ewan ~

deIt; / * _ 7 ²⁵ = -23.0 ° (tetrahydrofuran). D.

Example 50

To a solution of 3.60 g (0.0250 mol) of 2S-hydroxy-4R, 5S-epoxycyclopentane-IS-ethanol in 50 ml of toluene, 55.58 g (0.250 mol) of 3-tert.-butyloxy-1- octinyldimethylalan added in 450 ml of toluene, and the mixture was stirred for 2 hours at 50 to 65 ⁰ C and cooled.

The mixture was slowly poured into 500 ml of saturated aqueous ammonium chloride solution at 0 C, and the mixture was stirred for 0.5 hours. The mixture was 4 × 250 ml Extracted methylene chloride. The combined methylene chloride extracts were washed with 2 × 250 ml of brine and over dried anhydrous magnesium sulfate. The solution was evaporated to dryness, an approx. 1: 1 weight mixture of 4R- (2-hydroxyethyl) -5S- (3S-tert-butyloxy-1-octynyl) -cyclopentane-1R, 3S-diol and 4R- (2-hydroxyethyl) -5S- (3R-tert-butyloxy-1 -oetynyl) -cyclopentane-1R, 3S-diol was obtained.

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Example 51

A solution of 5.20 g (0.0159 mol) of an approx. 1: 1 mixture by weight of 4R- (2-hydroxyethyl) -5S- (3S-tert-butyloxy-1-octynyl) -cyclopentane-1R, 3S- diol and 4R- (2-hydroxyethyl) -5S- (3R-tert-butyloxy-1-octynyl) -cyclopentane-1R, 3S-diol in 25 ml of trifluoroacetic acid, the mixture was stirred at -10 ° C. for 4 hours. the cold solution was added dropwise to a stirred solution of 100 ml of ice-cold 2N aqueous sodium hydroxide solution was added and this mixture was stirred for 10 minutes.

The solution was saturated with excess sodium chloride and extracted with 4 × 100 ml of methylene chloride. The methylene chloride layers were washed with 2 × 100 ml of saturated saline solution and dried over anhydrous magnesium sulfate. Evaporation of the solution to dryness gave an approx. 1: 1 mixture by weight of 4R- (2-hydroxyethyl) -5S- (3S-hydroxy-1-octynyl) -cyclopentane-1R, 3S-diol and 4R- (2-hydroxyethyl) -5S- (3R-hydroxy-1-octynyl) -cyclopentane-1R, 3S-diol.

Example 52

To a stirred solution of 2.88 g (0.0760 mol) of lithium aluminum hydride in 150 ml of tetrahydrofuran at ^{0 0} O were added 4.10 g (0.0152 mol) of an approx. 1: 1 mixture by weight of 4R- (2-hydroxyethyl) -5S- (3S-hydroxy-1-octynyl) -cyclopentane-1R, 3S-diol and 4R- (2-hydroxyethyl) -5S- (3R-hydroxy-1-octynyl) -cyclopentane-IR ^ S-diol in 100 ml of tetrahydrofuran were added, the mixture was heated to reflux temperature, 65 ° C., and cooled for 6 hours. 250 ml of diethyl ether were added to this solution, and the solution was cooled to ^{0 ° G.} A total of 5> 75 ml of water was added dropwise, this was followed by the addition of 4.60 ml of 10% strength by weight aqueous sodium hydroxide solution, and the mixture was stirred for 2 hours. The mixture was filtered and the solids were triturated with 3 x 100 ml methylene chloride. The ether

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and methylene chloride layers were combined and dried over anhydrous magnesium sulfate. The solution was evaporated to dryness, a mixture of about 1: 1 parts by weight of 4R- (2-hydroxyethyl) -5R- (3S-hydroxy-1E-octenyl) -cyclopentane-1R, 3S-diol and 4R- (2-hydroxyethyl) -5R- (3R-hydroxy-1E-octenyl) -cyclopentane-1R, 3S-diol was obtained.

Example 55

To a solution of 3 * 82 g (0.014-0 mol) of a mixture of approx. 1: 1 parts by weight of 4R- (2-hydroxyethyl) -5R- (3S-hydroxy-1E-octenyl) -cyclopentane-1R, 3S- diol and 4R- (2-hydroxyethyl) -5R- (3R-hydroxy-1E-octenyl) -cyclopentane-1R, 3S-diol in 40 ml of pyridine at ⁰ ° C. were 4.03 g (0.0145 mol) of triphenylmethyl chloride in 20 ml of pyridine were added, and the mixture was ^{stirred at 0} ° C. for 2 hours and at room temperature for 18 hours.

The mixture was poured into 200 ml of saturated saline solution and the solution was extracted with 4 × 100 ml of methylene chloride. The methylene chloride layers were with 2 × 100 ml of 10 wt .- ^ iger aqueous sulfuric acid, 100 ml of saturated aqueous sodium bicarbonate solution and 100 ml of saturated saline solution. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness, a mixture of about 1: 1 parts by weight of 5R- (3S-hydroxy-1E-octenyl) -4R- (2-trityloxyethyl) -cyclopentane-1R, 3S-diol and 5R- (3R-hydroxy-1E-octenyl) -4R- (2-trityloxyethyl) -cyclopentane-1R, 3S-diol was obtained.

Example 54

A mixture of 5 »15 g (0.0100 mol) of a mixture of approx. 1: 1 parts by weight of 5R- (3S-hydroxy-1E-octenyl) -4R- (2-trityloxyethyl) -cyclopentane-1R, 3S-diol and 5R- (3R-Hydroxy-1E-octenyl) -4R- (2-trityloxyethyl) -cyclopentane-1R, 3S-diol, 8.69 g (0.100 mol) of activated manganese dioxide and 250 ml of methylene chloride became violent at room temperature for 18 hours touched.

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The solution was filtered through diatomaceous earth and the solids were triturated with 3 x 50 ml of methylene chloride and filtered. The combined methylene chloride layers were dried over anhydrous magnesium sulfate and dried to dryness evaporated, where 5R- (3-Oxo-1E-octenyl) -4-R- (2-trityloxyethyl> cyclopentane-1R, 3S-diol was obtained.

Example 5 ^

A mixture of 0.256 g (0.00050 mole) of 5R- (3-oxo-1E-octenyl) -4R- (2-trityloxyäthyl) cyclopentane-1R, 3S-diol in 25 ml of tetrahydrofuran was cooled to -78 ⁰ G, and a solution of 0.760 g (0.0040 mol) of lithium tri-sec-butylborohydride in 10 ml of tetrahydrofuran was added dropwise. The mixture was stirred at -78 ° for 24 hours and quenched by adding 5 ml of methanol. The mixture was warmed to 0 C and poured into 100 ml of saturated aqueous ammonium chloride solution. This solution was extracted with 4 × 50 ml of methylene chloride. The methylene chloride layers were washed with 2 × 50 ml of brine, dried over anhydrous magnesium sulfate and evaporated to dryness, a mixture of 3 ^: 1 parts by weight of 5R- (3S-hydroxy-1E-octenyl) -4R- (2-trityloxyethyl) cyclopentane -1R, 3S, diol and 5R- (3R-Hydroxy-1E-octenyl) -4R- (2-trityloxyethyl) -cyclopentane-1R, 3S-diol.

Samples of 5R- (3S-Hydroxy-1E ~ octenyl) -4R- (2-trityloxyethyl) -cyclopentane-1R, 3S-diol and 5R- (3R-hydroxy-1E-octenyl) -4R- (2-trityloxyethyl) -cyclopentane-1R, 3S-diol were using high pressure liquid-liquid chromatography using " a 2 mm χ 60 cm column with silica gel (silica gel) and 9: 1 parts by volume of chloroform-methanol as the solvent system or separated by column chromatography on 0.05-0.20 mm silica gel (silica gel).

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Example 56

A solution of 0.105 g (0.000495 mol) of (3, JaR, 4,5,6,6aS-hexahydro-5R-hydroxy-2R-methoxy-2H-cyclopenta / S_7furan-4R-yl) -E-acrolein in 2 ml of pyridine was ^{cooled to 0} ° C. and a solution of 0.118 g (0.00054-5 mol) of 4-biphenylcarbonyl chloride in 1 ml of pyridine was added dropwise. The mixture was stirred at 0 ° C. for 6 hours and poured into 50 ml of ice water.

The mixture was extracted with 3 × 50 ml of methylene chloride. The methylene chloride layers were with 50 ml of 10 wt .- ^ iger aqueous sulfuric acid and 50 ml of saturated, aqueous Washed sodium bicarbonate solution over anhydrous magnesium sulfate dried and evaporated to dryness, with / ~ 3,3aR, 4,5,6,6aS-hexahydro-2R-methoxy-5R- (p-phenylbenzoyloxy) -2H-cyclopenta / b_7furan-4R-yl7-E-acrolein was obtained.

Example 57

To a solution of 0.155 g (0.000394 mol) of / 3,3aR, 4,5,6,6aS-hexahydro-2R-methoxy-5R- (p-phenylbenzoyloxy) -2H-cyclopenta / b_7-furan-4R- yl_7-E-acrolein in 5 ml of tetrahydrofuran at -25 ° C were 0.37 ml (0.000406 mol) of 1.1M n-pentyllithium in Pentane was added and the mixture was stirred at -25 ° C for 4 hours. The cold mixture was added to 50 ml of saturated, aqueous ammonium chloride solution added and with 3 x 50 ml Extracted methylene chloride. The methylene chloride extracts were washed with 50 ml of brine, over anhydrous magnesium sulfate dried and evaporated to dryness, a mixture of approx. 1: 1 parts by weight of 1/3 »3aR, 4,5,6,6aS-hexahydro-2R-methoxy-5R- (p-phenylbenzoyloxy) -2H-cyclopenta / b_7furan-4R-yl_7-1E-octen-3R-ol and 1- / 3,3aR, 4,5,6,6aS-hexahydro-2R-methoxy-5R- (p-phenylbenzoyloxy) -2H-cyclopenta / b-7furan-4R-yl-7-1E-octen-3S-ol was obtained.

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Example 58

A mixture of 0.180 g (0.000388 moles) of a mixture of approx. 1: 1 parts by weight of 1- / 3.3aR, 4.5 »6.6aS-hexahydro-2R-methoxy-5R- (p-phenylbenzoyloxy) -2H-cyclopenta / b_7furan-4R-yl_7-1E-octen- 3R-ol and 1- / 3,3aR, 4,5,6,6aS-hexahydro-2R-methoxy-5R- (p-phenylbenzoyloxy) -2H-cyclopenta / b_7furan-4R-yl_7-1E-octen-3S-ol, 0.338 g (0.00388 moles) of activated magnesium dioxide and 15 ml of methylene chloride were added at room temperature Vigorously stirred for 24 hours.

The solution was diluted with 85 ml of methylene chloride and filtered through diatomaceous earth.

The solids were triturated with 2 × 25 ml of methylene chloride and filtered. The combined methylene chloride layers were dried over anhydrous magnesium sulfate and evaporated to dryness giving 3 _i 3aR, 4.5> 6.6aS-hexahydro-2R-methoxy-4R- (3-oxo-1E-octenyl) -5R- (p-phenylbenzoyloxy ) -2H-cyclopenta / b_7-furan was obtained.

Example 59

A mixture of 0.116 g (0.000251 moles) of 3,3aR, 4,5,6,6aS-hexahydro-2R-methoxy-4R- (3-oxo-1E-octenyl) -5R- (p-phenylbenzoyloxy) - 2H-cyclopenta / b_7furan in 15 ml of tetrahydrofuran was cooled to -78 ° C. and a solution of 0.286 g (0.00150 mol) of lithium tri-sec-butylborohydride in 5 ml of tetrahydrofuran was added dropwise. The mixture was stirred for 24 hours at -78 ⁰ C and quenched by addition of 3 ml of methanol. The mixture was ^{warmed to 0} ° C. and poured into 50 ml of saturated aqueous ammonium chloride solution. The solution was extracted with 3 × 50 ml of methylene chloride. The methylene chloride layers were washed with 50 ml of saturated saline solution, dried over anhydrous magnesium sulfate and evaporated to dryness to give an oil.

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The oil was purified by column chromatography on 10 g of silica gel (Silica gel; 0.05-0.20 mm). The early fractions eluted with diethyl ether yielded a mixture the 23 wt .- ^ of an oil of 1- / 3,3aR, 4,5,6,6aS-hexahydro-2R-methoxy-5R- (p-phenylbenzoyloxy) -2H-cyclopenta / b_7furan-4R-yl_7-1E- octene-3R-ol and the later ether fractions yielded 70% by weight of an oil of 1- / 3,3aR, 4,5,6,6aS-hexahydro-2R-methoxy-5R- (p-phenylbenzoyloxy) -2H-cyclopenta / b_7- furan-4R-yl_7-1 E-octene ~ 3S-o 1.

Example 60

A solution of 0.0464 g (0.00010 moles) of 1- / 3.3aR, 4,5,6,6aS-hexahydro-2R-methoxy-5R- (p-phenylbenzoyloxy) -2H-cyclopenta / b_7 furan-4R-yl_7-1E-octen-3S-ol, 1 ml (0.0010 mol) of aqueous 1.0 N sodium hydroxide solution and 5 ml of methanol was added for 16 hours stirred at room temperature.

The solution was poured into 25 ml of saline and with 4 × 25 ml of methylene chloride extracted. The methylene chloride extracts were washed with 50 ml of brine, over anhydrous Magnesium sulfate dried and evaporated to dryness, where 1 - (3 »3aR, 4, 5, 6, öaS-hexahydro ^ R-hydroxy ^ R-methoxy ^ H-cyclopenta / b_7furan-4R-yl) -1E-octen-3S-ol was obtained.

Example 61

A mixture of 3.30 g (0.0122 mol) of 4R- (2-hydroxyethyl) -5R- (3S-hydroxy-1E-octenyl) -cyclopentane-1R, 3S-diol and 25 ml of pyridine was cooled to ^{0 ° C} and 6.40 g (0.0610 mol) of 97% strength by weight acetic anhydride in 5 ml of pyridine was added dropwise. The mixture was ^{stirred at 0} ° C. for 2 hours and at room temperature for 16 hours.

The mixture was poured into 50 ml of water and 3 x 50 ml

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Extracted methylene chloride. The methylene chloride layers were mixed with 2 × 50 ml of 10% strength by weight aqueous sulfuric acid, 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated saline solution. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness, leaving oily 4R- (2-acetoxyethyl) -5R- (3S-acetoxy-1E-octenyl) -cyclopentane-1R, 3S-diol diacetate was obtained.

Example 62

A mixture of 2.50 g (0.00567 mol) of 4R- (2-acetoxyethyl) -5R- (3S-acetoxy-1E-octenyl) -cyclopentane-1R, 3> S-diol diacetate, 10 ml of water and 90 ml of tert .-Butyl alcohol was ^{stirred at 0} ° C. and 5 »67 ml (0.00567 mol) of aqueous 1.0 M sodium hydroxide solution were added dropwise. The mixture was ^{stirred at 0} ° C. for 4 hours and evaporated to dryness at room temperature: the residue was dissolved in 100 ml of methylene chloride. This solution was washed with 2 × 50 ml of water, dried over anhydrous magnesium sulfate and evaporated to dryness, 5R- (3S-acetoxy-1E-octenyl) -4-R- (2-hydroxyethyl) -cyclopentane-1R, 3S-diol diacetate was obtained.

Example 65

A mixture of 0.256 g (0.0020 mol) of 2R- (2-hydroxyethyl) -3-cyclopenten-1S-ol in 5 ml of pyridine was ^{cooled to O 0} O, and 0.210 g (0.0020 mol) of 97 wt .- ^ ige acetic anhydride in 1 ml pyridine added dropwise. The mixture was ^{stirred at 0} ° C. for 2 hours and at room temperature for 16 hours.

The solution was poured into 50 ml of saturated saline solution and extracted with 3 x 50 ml of methylene chloride. The methylene chloride layers were mixed with 2 χ 50 ml of 10 wt .- # aqueous

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ger sulfuric acid and 50 ml of saturated aqueous sodium bicarbonate solution washed, dried over anhydrous magnesium sulfate and evaporated to dryness to give an oil .

The oil was purified by column chromatography on 15 S silica gel (Silica gel; 0.05-0.20 mm). A total of 0.080 g of impurities was eluted with benzene and 2 vol .- # ethyl acetate in benzene. The fractions with 5 vol .- # Ethyl acetate-benzene yielded oily 2R- (2 ~ acetoxyethyl) -37 cyclopenten-1S-ol after distillation; K. = 85 C (0.1 mmHg).

Example 64

A mixture of 0.256 g (0.0020 mol) of 2S- (2-hydroxyethyl) -3-cyclopenten-1R-ol in 5 ml of pyridine was ^{cooled to 0} ° C., and 0.210 g (0.0020 mol) of 97 wt .- # Acetic anhydride in 1 ml of pyridine added dropwise. The mixture was stirred at 0 ° for 2 hours and at room temperature for 16 hours.

The solution was poured into 50 ml of saturated saline solution and extracted with 3 x 5 ° ml of methylene chloride. The methylene chloride layers were with 2 × 50 ml of 10 wt .- # aqueous Sulfuric acid and 50 ml of saturated aqueous sodium. bicarbonate solution extracted, dried over anhydrous magnesium sulfate and dried to dryness leaving an oil evaporated.

The oil was purified by column chromatography on 15 g of silica gel (silica gel; 0.05-0.20 mm). A total of 0.028 g of impurities was eluted with benzene and 10 vol .- ^ ethyl acetate-benzene. The fractions containing 25 % ethyl acetate-benzene gave oily 2S- (2-acetoxyethyl) -3-cyclopentene-1R-oil after distillation; K. = 85 ° C (0.1 mmHg).

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Example 65

A mixture of 0.093 g (0.00050 mol) of 2R- (2-acetoxyethyl) -3R, ^ ■ S-epoxy-IR-cyclopentanol, 4 ml of water and 1 ml (0.0010 mol) 1.0 N aqueous sodium hydroxide solution was stirred at room temperature for 16 hours.

The excess base was neutralized by adding 1 g of solid carbon dioxide and stirring the mixture for 10 minutes. The solution was evaporated to dryness and the residue was triturated with 3 x 25 ml methylene chloride. The methylene chloride solution was concentrated to dryness, oily / 2R ~ hydroxy-4S, 5R-epoxycyclopentane-1R-ethanol_7- (epoxydiol) being obtained. Distillation at 140 ⁰ C (0.1 mmHg) gave the pure epoxydiol.

Example 66

A mixture of 0.093 S (0.00050 mol) of 2S- (2-acetoxyethyl) -3S, 4R-epoxy-IS-cyclopentanol, 4 ml of water and 1 ml (0.0010 mol) of aqueous 1.0 N sodium hydroxide solution was used for 16 hours stirred at room temperature. The excess base was neutralized by adding 1 g of solid carbon dioxide (dry ice) and stirring the mixture for 10 minutes. The solution was concentrated to dryness and the residue was triturated with 3 x 25 ml of methylene chloride. The methylene chloride solution was concentrated to dryness, oily 2S-hydroxy-4R, 5S-epoxycyclopentane-1S-ethanol (epoxydiol) being obtained. Distillation at 140 ⁰ C (0.1 mmHg) gave the pure epoxydiol.

Example 67

A mixture of 0.170 g (0.0010 mol) of 2S- (2-acetoxyethyl) -3-cyclopenten-1R-ol, 4 ml of methylene chloride and 0.4-0 g of anhydrous sodium bicarbonate was ^{cooled to 0} ° C., and it was 0.224 g (0.0011 mol) m-chloroperbenzoic acid (purity

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of 85 wt .- ^) in 2 ml of methylene chloride added dropwise. The mixture was ^{stirred at 0 0} G for 1 hour and at room temperature for 16 hours in the dark.

The mixture was diluted with 75 ml of 1: 1 YoI. Parts of ethyl acetate-methylene chloride, and this solution was washed with 2 × 25 ml of aqueous 10% by weight sodium hydroxide solution and 2 × 25 ml of saturated saline solution. The solution was dried over anhydrous magnesium sulfate and concentrated to dryness, oily 2R- (2-acetoxyethyl) -3R, 4S-epoxy-1R-cyclopentanol being obtained. This product was purified by distillation at 100 ⁰ G (0.1 mmHg).

Example 68

A mixture of 0.170 g (0.0010 mol) of 2R- (2-acetoxyethyl) -3-cyclopenten-1S-ol, 4 ml of methylene chloride and 0.40 g of anhydrous sodium bicarbonate was ^{cooled to 0 0} G, and 0.224 g of ( 0.0011 mol) of m-chloroperbenzoic acid (purity of 85% by weight) in 2 ml of methylene chloride was added dropwise. The mixture was stirred at 0 G for 1 hour and at room temperature for 16 hours in the dark.

The mixture was diluted with 75 ml of 1 × 1 parts by volume of ethyl acetate-methylene chloride, and this solution was washed with 2 × 25 ml of aqueous 10% by weight sodium hydroxide solution and 2 × 25 ml of saturated saline solution. The solution was dried over anhydrous magnesium sulfate and concentrated to dryness, oily 2S- (2-acetoxyethyl) -3S, 4R-epoxy-1S-cyclopentanol being obtained. This product was purified by distillation at 100 ⁰ G (0.1 mmHg).

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Example 69

A solution of cyclopentadxenyl sodium was prepared from 20.5 S (0.90 g at) of sodium metal and 39.6 g (0.60 mol) of cyclopentadiene at -10 ° C. in 300 ml of tetrahydrofuran. The solution was filtered through glass wool and -tropfenweise, added to a solution of 91 ₅ 8 g (0.60 mol) of methyl bromoacetate and 50 ml of tetrahydrofuran which was maintained at -78 ⁰ C. The cold mixture was stirred at -78 ° C for 2.5 hours, then warmed to -60 ° C for 16 hours, with a. Solution of methyl 2,4-cyclopentadiene-i-acetate was formed.

A total of 200 ml (0.20 mol) of 1 M borane in tetrahydrofuran was added dropwise to the reaction mixture, which was kept at -60 ° C. The mixture was stirred to ⁰ ° C during a one hour period and allowed to warm at 0 C for 16 hours to yield racemic tris (trans-2-methpxycarbonylmethyl-3-cyclopenten-1-yl) borane.

A solution of 60 ml of aqueous 3N sodium hydroxide solution was added to the reaction mixture (0 ° C.), followed by the dropwise addition of 60 ml of -30% strength by weight hydrogen peroxide in water at ⁰ ° C.

A total of 5 g of sodium bisulfite and then 20 g of sodium chloride were added to the mixture. That The odor was then extracted with 2 × 250 ml of ether. The ethereal layers were combined and washed with 100 ml of water and 100 ml of saturated saline. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness, 72.1 g of an oil filing. The distillation at 80 to 83 ° C. (0.1 mm / 1 g) gave racemic methyl trans-2-hydroxy-4-cyclopentene-1-acetate.

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Example 70

A mixture of 4-.6O grams (0.0696 moles) of 85 weight percent potassium hydroxide in water, 25 ml of water, 25 ml of methanol and 5-44 g (0.0348 moles) racemic methyl trans ^ -hydroxy ^ -cyclopenten-1-acetate was stirred at room temperature for 48 hours to form a solution containing racemic sodium trans-2-hydroxy-4-cyclopentene-1-acetate contained.

The solution was diluted with 50 ml of water and 3 x 80 ml Diethyl ether extracted. The combined ether extracts were washed with 50 ml of water and discarded. The united layers of water were added with an excess of 1: 1 "parts by volume of a slurry of concentrated aqueous hydrochloric acid and ice acidified and extracted with 3 x 80 ml of diethyl ether. The combined ether layers were washed with 50 ml of water and discarded.

The combined water layers were concentrated to dryness and the solid residue was triturated with 3 × 15 ° ml of methylene chloride. The methylene chloride solution was filtered and evaporated to dryness, v / obeizemische trans-2-hydroxy-4-cyclopentene-1-acetic acid was obtained as a solid, m.p. 59 to 60 ^° C.

Example 71

To a solution of 1.00 g (0.00704 mol) of racemic trans-2-hydroxy-4-cyclopentene-1-acetic acid in 5 ml of pyridine at ⁰ ° C., 0.805 g (0.00773 mol) of methanesulfonyl chloride were added dropwise, and the mixture was ^{stirred at 0} ° C. for 4 hours and at room temperature for 48 hours to form a solution which contained chemical trans-2-methylsulfonyloxy-4-cyclopentene-1-acetic acid. To this dark solution, 0.5 g of ice was added and the mixture was stirred for 4 hours.

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The mixture was diluted with 50 ml of water and 3 x 50 ml Extracted methylene chloride. The combined methylene chloride layers were with 5 ° ml of aqueous 10 wt .- # strength sulfuric acid, 50 ml of saturated aqueous sodium bicarbonate solution and 50 ml of saturated saline solution. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness, 0.700 g of a dark oil being obtained.

The oil was dissolved in 100 ml of 1: 1 parts by volume of methylene chloride-ethyl acetate dissolved and with 5 ° ml 10 ^ iger sodium hydroxide solution, 50 ml of water and 50 ml of saturated saline solution washed. The solution was over anhydrous magnesium sulfate dried and evaporated to dryness, giving racemic cis-2-hydroxy-4-cyclopentene-1-acetic acid lactone when oil was produced; K. = 50 to 52 ° C (0.1 mmHg).

Example 72

To a solution of 0.325 g (0.0021 mol) of razemisehern methyl trans-2-hydroxy-l ^{i-cyclopentene-1-acetate} in 2 ml of pyridine at ⁰ ° C was added dropwise 0.260 g (0.0023 mole) of methanesulfonyl chloride in 0.5 ml of pyridine was added. The mixture was ^{stirred at 0} ° C. for 1 hour and poured onto crushed ice. The mixture was diluted with 50 ml of water and extracted with 3 × 50 ml of diethyl ether. The combined ether layers were washed with 50 ml of aqueous 10% strength by weight sulfuric acid, 50 ml of saturated sodium bicarbonate solution and 50 ml of saturated saline solution. The solution was then dried over anhydrous magnesium sulfate and evaporated to dryness at room temperature, with 0.4-65 g (94 #) of a colorless oil which solidified on standing at -10 g in the refrigerator.

Recrystallization from ether-hexane at ⁰ ° C. yielded a first amount of the product, ie racemic methyl-trans-2-methylsulfonyloxy-4-cyclopentene-i-acetate; F. = 36 to 37 ° G.

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Recrystallization of the mother liquor provided a second batch of product; F. = 34 to 36 ⁰ G.

An analytical sample was obtained by a further recrystallization from ether-hexane at O C, with fine, colorless needles of the product with a temperature of 37 to 38 ° C.

Example 73

To a solution of 0.290 g (0.00124 mole) of racemic methyl trans-2-methylsulfonyloxy-4-cyclopenten-i-acetate in 10 ml of tetrahydrofuran and 4 ml of water at ⁰ ° C was added dropwise 1.00 ml (0, 0020 mol) 2 N sodium hydroxide solution was added. The two-phase solution was stirred vigorously at 0 G for 1 hour and at room temperature for 16 hours, racemic sodium cis-2-hydroxy-4-cyclopentene-1-acetate mixed with racemic cis-2-hydroxy-4-cyclopentene-1- acetic acid lactone formed.

The mixture was diluted with 50 ml of water and extracted with 3 × 5 ° diethyl ether. The ether extracts were combined with one another and washed with 25 ml of water. The water layers were combined with one another, ^{cooled to 0} ° C. and acidified with excess, aqueous 6 N sulfuric acid. The acidic solution was saturated with sodium chloride and extracted with 3 × 50 ml of methylene chloride. The methylene chloride and ether layers were combined with one another and washed with 50 ml of saturated aqueous sodium bicarbonate solution. The solution was then dried over anhydrous sodium sulphate and evaporated to dryness, the product being obtained as a racemic cis-2-hydroxy-4-cyclopentene-i-acetic acid lactone in the form of an oil.

The distillation at 50 to 52 ⁰ G (0.1 mmHg) yielded the pure lactomo product.

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Example 74

A mixture of 0.760 g (0.0200 mol) of lithium aluminum hydride, 60 ml of diethyl ether and 2.48 g (0.0200 mol) of racemic cis-2-hydroxy-4-cyclopentene-i-acetic acid lactone was ^{stirred at 0} ° C. for 1 hour. At 0 ^° C., 1.5 ml of water and then 1.2 ml of aqueous 10% strength by weight sodium hydroxide solution were added dropwise to the solution, and the mixture was stirred at 0 C. for 1 hour. The solution was then stirred with 0.50 g of anhydrous magnesium sulfate for 0.5 hour, diluted with 50 ml of methylene chloride and filtered. The solid residue was triturated with 2 × 50 ml of methylene chloride and filtered. The combined filtrate was evaporated to dryness, 2.60 g of a colorless, viscous oil being obtained.

The oil was purified by column chromatography on 30 g of silica gel (silica gel; 0.05-0.20 mm). A total of 0.10 g of impurities was eluted with benzene and 10% ethyl acetate-benzene. The fractions with 25 vol .- # ethyl acetate-benzene gave racemic ice-2- (2-hydroxyethyl) -3-cyclopenten-1-ol as an oily product.

The distillation at 83 to 84 ⁰ C (0.1 mmHg) yielded the pure diol product.

Example 75

A mixture of 0.256 g (0.0020 mol) of racemic cis-2- (2-hydroxyethyl) -3-cyclopenten-1-ol, 5 ml of methylene chloride and 0.20 g of anhydrous sodium bicarbonate was ^{cooled to 0} ° C. and it 0.447 S (0.0022 mol) of m-chloroperbenzoic acid (purity 85% by weight) in 5 ml of methylene chloride was added dropwise. The mixture was ^{stirred at 0 0} O for 1 hour and at room temperature for 18 hours.

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The mixture was diluted with 100 ml of diethyl ether and this solution was washed with 4 × 25 ml of water. The water layers were combined and evaporated to dryness. The solid residue was triturated with 3 × 25 ml of hot methylene chloride and filtered. The methylene chloride filtrate was evaporated to dryness, 0.300 g of a colorless oil being obtained. The oil was purified by column chromatography on 30 g of silica gel (silica gel; 0.05-0.20 mm). The product, racemic cis-2-hydroxy-4-, 5-epoxycyclopentane-1-ethanol only, was eluted with 2 vol .- # methanol-chloroform. The distillation at 140 to 150 ^° C. (0.1 mmHg) yielded the pure product.

Example 76

A mixture of 0.513 g (0.0040 mol) of racemic cis-2- (2-hydroxyethyl) -3-cyclopenten-1-ol and 8 ml of Pyrün was ^{cooled to 0} ° C., and 0.461 g (0.0044 mol ) Acetic anhydride in 2 ml of pyridine was added dropwise. The mixture was ^{stirred at 0} ° C. for 1 hour and at room temperature for 18 hours.

The solution was poured into 50 ml of saturated saline solution and extracted with 3 x 50 ml of methylene chloride. The methylene chloride layers were with 2 χ 50 ml of aqueous 10 wt .- ^ iger Sulfuric acid and 50 ml of saturated aqueous sodium bicarbonate solution washed, dried over anhydrous magnesium sulfate and concentrated to dryness, 0.700 g of an oil being obtained.

The oil was purified by column chromatography on 30 g of silica gel (Silica gel; 0.05-0.20 mm). A total of 0.078 g of impurities was mixed with benzene and 10 vol .- # Ethyl acetate-benzene eluted. The fractions with 25 Vol.-7a Ethyl acetate-benzene yielded oily, racemic cis-2- (2-acetoxyethyl) -3-cyclopenten-1-ol after distillation; K. = 85 ° C (0.1 mmHg).

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Example 77

A mixture of 0.170 g (0.0010 mol) of racemic cis-2- (2-acetoxyethyl) -3-cyclopenten-1-ol, 4 ml of methylene chloride and 0.40 g of anhydrous sodium bicarbonate was ^{cooled to 0 0} G and it 0.224 g (0.0011 mol) of m-chloroperbenzoic acid (purity 85% by weight) in 2 ml of methylene chloride were added dropwise. The mixture was ^{stirred at 0 0} G for 1 hour and at room temperature for 18 hours in the dark.

The mixture was washed with 75 ml of 1: 1 yoI. Parts of ethyl acetate-methylene chloride diluted, and this solution was saturated with 2 χ 25 ml of aqueous, 10 wt .- ^ iger sodium hydroxide solution and 2 χ 25 ml Washed with saline. The solution was dried over anhydrous magnesium sulfate and evaporated to dryness, whereby oily, racemic cis-2- (2-acetoxyethyl) -3,4-epoxy-1-cyclopentanol only incurred. Distillation at 100-105 ° C (0.1 mmHg) provided the pure cyclopentanol product.

Example 78

A solution of 0.093 S (0.00050 mol) of racemic cis-2- (2-acetoxyethyl) -3,4-epoxy-1-cyclopentanol only, 4 ml of water and 1 ml (0.0010 mol) of aqueous 1, ON sodium hydroxide solution was over Stirred overnight at room temperature. The excess base was removed by adding 1 g of solid carbon dioxide (dry ice) and stirring the mixture for 10 minutes. The solution was evaporated to dryness and the residue became triturated with 3 x 25 ml of methylene chloride. The methylene chloride solution was evaporated to dryness, leaving oily only-cis-2-hydroxy ^^ - epoxycyclopentane-i-ethanol with K. = I4O up to 150 ° C (0.1 mmHg) was obtained.

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Example 79

According to the procedure of Examples 41, 43, 45, 47 and 5R- (3R-Hydroxy-1E-oetenyl) -4R- (2-trityloxyethyl) -cyclopentane-1R, 3S-diol in 15-epi-prostaglandin F ₀ with föc7 - +11 (tetrahydrofuran) via the following intermediate

D.
products converted:

5R- (3R-acetoxy-1E-octenyl) -4R- (2-trityloxyethyl) -cyclopentane-IR ^ S-diol diacetate;

5R- (3R-acetoxy-1E-octenyl) -4R- (2-hydroxyethyl) -cyclopentane-1R, 3S-diol diacetate;

2R- (3R-acetoxy-1E-octenyl) -3R, 5S-diacetoxy-1R-cyclopentane acetaldehyde and

7 - / ^ R- (3R-acetoxy-1E-octenyl) -3R, 5S-diacetoxy-1R-cyclopentyl_7-5Z-heptenoic acid.

Example 80

Following the procedure of Examples 50, 51, 52, 53 and 2R-hydroxy-4S, 5R-epoxycyclopentane-1R-ethanol in 5S- (3-oxo-1E-octenyl) ~ 4S- (2-trityloxyethyl) -cyclopentane-1S, 3R- diol converted via the following intermediates:

A mixture of 4S- (2-hydroxyethyl) -5R- (3R-tert-butyloxy-1 · octynyl) -cyclopentane-1S, 3R-diol and 4S- (2-hydroxyethyl) -5R- (3S-tert.- butyloxy-1-octynyl) -cyclopentane-1S, 3R-diol;

A mixture of 4S- (2-hydroxyethyl) -5R- (3R-hydroxy-1-octynyl) -cyclopentane-1S, 3R-diol and 4S- (2-hydroxyethyl) -5R- (3S-hydroxy-1-octynyl) -cyclopentane-1S, 3R-diol;

A mixture of 4S- (2-hydroxyethyl) -5S- (3R-hydroxy-1E-oct _e nyl) -cyclopentane-1S, 3R-diol and 4S- (2-hydroxyethyl) -5S-r (3S-hydroxy-1E -octenyl) -cyclopentane-1S, 3R-diol and

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5S- (3R-Hydroxy-1E-octenyl) -4-S- (2-trityloxyethyl) -cyclopentane-1S, 3R-diol and 5S- (3S-hydroxy-1E-octenyl) -4-S- (2-trityloxyethyl) -cyclopentane-IS, 3R-diol.

Example 81

Following the procedure of Example 55, the compound was obtained 5S- (3-Oxo-1E-octenyl) -4-S- (2-trityloxyethyl) -cyclopentane-1S, 3R-diol in a mixture of 3: 1 parts by weight of the following Isomers converted:

5S- (3R-Hydroxy-1E-octenyl) -4-S- (2-trityloxyethyl) -cyclopentane-1S, 3R-diol and

5S- (3S-hydroxy-1E-octenyl) -4S- (2-trityloxyethyl) -cyclopentane-1S,

These isomers are separated as described in Example 55 and isolated.

Example 82

Following the procedure of Examples 41, 4-3, 4-5 »4-7 and 4-9 5S- (3S-hydroxy-1E-octenyl) -4-S- (2-trityloxyethyl) -cyclopentane-1S, 3R-cLiol into an optically active antipode

of 15-repi-prostaglandin I ₀ -, / (/ '7 ² ^ = -11 ° (tetrahydro-

_D furan), converted via the following intermediates:

5S- (3S-acetoxy-1E-octenyl) -4-S- (2-trityloxyethyl) -cyclopentane-IS ^ R-diol diacetate;

5S- (3S-acetoxy-1E-octenyl) -4-S- (2-hydroxyethyl) -cyclopentane-IS ^ R-tiioldiacetate;

2S- (3S-acetoxy-1E-octenyl) -3S, 5R-diacetoxy-1S-cyclopentane acetaldehyde; and

7 - / ^ S- (3S-acetoxy-1E-octenyl) -3S, 5R-diacetoxy-1S-cyclopentyl_7-5Z-heptenoic acid.

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Example 83

Following the procedure of Examples 41, 43, 45, 47 and 49, 5S- (3R-hydroxy-1E-oetenyl) -4S- (2-trityloxyethyl) -cyclopentanes, 3R-diol was converted into an optically active antipode of prostaglandin ^ o ^ converted via the following intermediate products:

5S- (3R-acetoxy-1E-octenyl) -4S- (2-trityloxyethyl) -cyclopentane-1S, 3R-diol diacetate;

5S- (3R-acetoxy-1E-octenyl) -4S- (2-hydroxyethyl) -cyclopentane-IS ^ R-diol diacetate;

2S- (3R-acetoxy-1E-octenyl) -3S, 5R-diacetoxy-1S-cyclopentane acetaldehyde; and

7- / 2S- (3R-acetoxy-1E-octenyl) -3S, 5R-diacetoxy-1S-cyclopentyl_7-5Z-heptenoic acid.

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Claims (7)

Claims 1. Process for the production of an optically active borane following general formula: -C -OR. ι worm -C-OR _x , an ester protecting group, which m the Carboxy radical is convertible by hydrolysis, R ₁ - represents an optically active, organic radical, χ is an integer from 1 to 2 and y is an integer from 0 to 1, with the proviso that the sum of χ and y = 2 is, or its optically active antipode, characterized in that a compound of the following general formula It wherein R ^ has the meaning given above, with a treated optically active, organic borohydride or its optical antipode. ² . Process according to claim 1, characterized in that the organic borohydride used is (+) - di-3-pinanyloder (-) - bi-3-pinanylborane. • A09833 / 10A8 ³ . Method according to claim! , characterized in that the reaction is carried out in an ethereal solvent. 4. Optically active compound of the following general formula: J. where -C-OR _x , an ester protection gray, which is in the ti I • Carboxy radical can be converted by hydrolysis, R, is an optically active organic radical, χ represents an integer from 1 to 2, y is an integer from 0 to 1, with the proviso that the sum of χ and y = 2 ,
or its optically active antipode. 5. aR-Methoxy-carbonylmethyl ^ -cyelopenten-IS-yl-bis- {(1R, 2S, 3S, 5S) -2,6,6-trimethyl-bicyclo / J.1.1_7heptan-3-yl} -borane. 6. aS-Methoxycarbonylmethyl-J-cyclopenten-IR-yl-bis- {(1S, 2R, 3R, 5R) -2,6,6-trimethylbicyclo / 3.1.1_7heptan-3-yl } -borane. ^7th Racemate of the following formula: CH ₂ COR ₁ where -Ci-OR _x . represents an ester protection group, which in the carboxy moiety can be converted by hydrolysis, and the boron substituent is bonded to the cyclopentane unit on the opposite side of the plane as the methylene carboxy ester. ₄₀ g _833/1048