MXPA97007400A - Preparation of 2-cycloopentenol cis-4-protegi derivatives - Google Patents

Abstract

The present invention relates to a process for preparing a CIS compound of the formula II: wherein Pg is selected from the group consisting of benzyl, substituted benzyl, -CH2OCH3, -CH2SCH3-, -OCH2OCH2phenyl, -CH2OCH2CH2OCH3, -CH2OCH2CCI3, - CH (OCH2CH2CH3) 2, -CH2OCH2CH2Si (CH3) 3, -CH (OC2H5) CH3, -C (OCH3) (CH3) 2, -CH (CH3) OCH (CH3) 2, -CH2CCI3, -C (CH3) 3 , -CH2CH = CH2, -CH2CH = CH-phenyl, -CH (phenyl) 2, -C (phenyl) 3, tetrahydropyranyl, 4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydrothio-pyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl and SiR1R2R3, in wherein R1, R2 and R3 are each independently and SiR1R2R3, wherein R1, R2 and R3 are each independently C1-C4 alkyl, phenyl, benzyl, substituted phenyl and substituted benzyl, comprising: a) dissolving a compound of the Formula I: where Pg is as previously defined, in an appropriate organic solvent, and b) treat the solution with an appropriate Lewis acid and an agent e suitable reduction at a temperature of about -100 ° C to about 20

Description

PREPARATION OF 2-CICLOPENTENOL CIS-4-O-PROTECTED DERIVATIVES BACKGROUND OF THE INVENTION The present invention relates to a novel process for preparing cis-4-O-protected 2-cyclopentenol derivatives, which are useful intermediates in the preparation of various cyclopentanyl and cyclopentenyl purine analogs, which are useful as immunosuppressants, as described by Borcherding, et al., in European Patent Application Publication Nos. 0 475 41 1 A 1, published on March 18, 1992, 0 475 413 A2, published on March 18, 1992, and 0 545 413 A 1, published on June 9, 1993. In addition, derivatives of 2- Cyclopentenol cis-4-O-protected are useful intermediates in the preparation of various prostaglandins.

COMPENDIUM OF THE INVENTION The present invention provides a novel process for the preparation of a CIS compound of the formula (I I): formula (I I) wherein Pg is selected from the group consisting of benzyl, benzyl its substituted, -CH2OCH3-, -CH2SCH3-, CH2OCH2phenyl, -CH2OCH2CH2OCH3-, -CH2OCH2CCI3-, -CH (OCH2CH2CI) 2 > -CH2OCH2CH2Si (CH3) 3, -CH (OC2Hs) CH3, -C (OCH3 (CH3) 2, -CH (C H3) OCH (CH3) 2, -CH2CCI3, -C (CH3) 3, CH2CH = CH2, - CH2CH = CHphenyl, -CH (phenyl) 2, -C (phenyl) 3, tetrahydropyranyl, 4-methoxytetrahydropyranyl, 3-b rom or tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydrothio-pyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl and SiR? R2R3 l where , R 2 and R 3 are each independently C 1 -C 4 alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl, comprising: a) dissolving a compound of the formula (I): formula (I) wherein Pg is as defined above, in a suitable organic solvent; and b) treating the solution with a suitable Lewis acid and a suitable reducing agent at a temperature of from about -100 ° C to about 20 ° C. The present invention further provides a novel process for the preparation of the CIS enantiomer of the formula (1ia): formula (lia) wherein Pg is selected from the group consisting of benzyl, substituted phenyl, -CH2OCH3-, -CH2SCH3-, CH2OCH2phenyl , -CH2OCH2CH2OCH3-, -CH2OCH2CCI3-, -CH (OCH2CH2CI) 2, -CH2OCH2CH2Si (CH3) 3, -CH (OC2Hs) CH3, -C (OCH3 (CH3) 2, -CH (CH3) OCH (CH3) 2 , -CH2CCI3, -C (CH3) 3, CH2CH = CH2, -CH2CH = CHphenyl, -CH (phenyl) 2, -C (phenyl) 3 l tetrahydropyranyl, 4-methoxytetrahydropyranyl, 3-bromo tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl , tetrahydrofuran ilo, tetrah idrotiofuranyl and SiR? R2R3, wherein R 1 t R 2 and R 3 are each independently or independently C 1 -C 4 alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl, comprising: a) dissolving an enantiomeric compound of the formula (la): formula (la) wherein Pg is as defined above, in an organic solvent; and b) treating the solution with a suitable Lewis acid and a suitable reducing agent at a temperature of from about -100 ° C to about 20 ° C. In addition, the present invention provides a novel process for the preparation of the C-IS enantiomer of the formula (I lb): formula (Ilb) wherein Pg is selected from the group consisting of benzyl, substituted benzyl, -CH2OCH3-, -CH2SCH3-, CH2OC H2phenyl, -CH2OCH2CH2OCH3-, -CH2OCH2CCI3-, -CH (OCH2CH2CI) 2, -CH2OCH2C H2Si (CH3) 3, -CH (OC2H5) CH3, -C (OC H3 (C H3) 2, -CH (C H3) OCH (CH3) 2, -CH2CCI3, -C (CH3) 3, CH2CH = CH2, -CH2CH = CH-phenyl, -CH (phenyl) 2, -C (phenyl) 3, tetrahydropyranyl, 4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydrothio-pyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl and SiR? R2R3, wherein R ?> R2 and R3 are each independently C? -C4 alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl, which comprises: a) dissolving an enantiomeric compound of the formula (la): formula (Ib) wherein Pg is as defined above, in an organic solvent; and b) treating the solution with a suitable Lewis acid and a suitable reducing agent at a temperature of from about -100 ° C to about 20 ° C.

In addition, the present invention also provides a novel process for the preparation of the CIS compounds of the formulas (llb) and (IV): formula (Ilb) formula (IV) wherein Z is C2-C4 alkanoyl; and Pg is selected from the group consisting of benzyl, substituted benzyl, -CH2OCH3-, -CH2SCH3-, CH2OCH2fenilo, -CH2OCH2CH2OCH3-, -CH2OCH2CCI3-, -CH (OCH2 CH2CI) 2, -CH2OCH2CH2Si (CH3) 3, -CH ( OC2H5) CH3, -C (OCH3 (CH3) 2l -CH (CH3) OCH (CH3) 2, -CH2CCI3, -C (CH3) 3, CH2CH = CH2I -CH2CH = CH-phenyl, -CH (phenyl) 2, -C (phenyl) 3, tetrahydropyranyl, 4-methoxy tetrahydro pyre nor, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 4-metoxitetrahidrotio-pyranyl, tetrahydrofuranyl, tetrahydro-thiofuranyl and SiR? R2R3, where Ri, R2 and R3 are each independently alkyl C? -C, phenyl, benzyl, substituted phenyl or substituted benzyl, comprising: a) dissolving a compound a compound of the formula (I): formula (I) wherein Pg is as defined above, in an organic solvent; and b) treating the solution with a suitable Lewis acid and a suitable reducing agent at a temperature from about -100 ° C to about 20 ° C to produce the CIS compound of the formula (II); formula (II) wherein Pg is as defined above; c) treating the CIS compound of the formula (II) with a suitable enzyme and an excess of a suitable acylating agent, in a suitable solvent to produce a mixture of the compounds of the formulas (llb) and (IV), as defined earlier; and d) separating the compound of the formula (lb) from a compound of the formula (IV). The invention further provides a novel process for the preparation of a CIS compound of formulas (II), (lia), (llb) or (IV), as defined above, wherein a suitable alcohol is added to the reaction mixture. concomitantly with or before treating the compound of the formula (I) with the appropriate reducing agent.

The invention also provides a novel process for the preparation of the CIS compounds of the formulas (Vlb) and (Vil): formula (Vlb) wherein Z is C2C4 alkanoyl; and Pg is selected from the group consisting of benzyl, substituted benzyl, -CH2OCH3-, -CH2SCH3-, CH2OCH2fenilo, -CH2OCH2CH2OCH3-, -CH2OCH2CCI3-, -CH (OCH2 CH2CI) 2, -CH2OCH2CH2Si (CH3) 3, -CH ( OC2Hs) CH3, -C (OCH3 (CH3) 2, -CH (CH3) OCH (CH3) 2, -CH2CCI3, -C (CH3) 3, CH2CH = CH2, -CH2CH CHfenilo, -CH (phenyl) 2l - C (phenyl) 3, tetrahydropyranyl, 4-tetrahydropyranyl m ethoxy, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 4-metoxitetrahidrotio-pyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl and ISRRT? RS, wherein R R2 and R3 are each independently alkyl of C? C4 , phenyl, benzyl, substituted phenyl or substituted benzyl, comprising, treating the CIS compounds of the formula (IV): formula (VII) wherein Pg is as defined above, with a suitable enzyme and an excess of a suitable acylating agent in a suitable solvent, to produce a sample of compounds of the formulas (Vlb) and (VII), as defined earlier; and f) separating the compound of the formula (Vlb) from the compound of the formula (VII).

DETAILED DESCRIPTION OF THE INVENTION The term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. This includes geometric isomers (cis / trans), and isomers of compounds with more than one asymmetric center that are not mirror images of each other (distereomers). The terms "enantiomer" or "enantiomer" refer to a molecule that is not superimposable in its mirror image and therefore optically active, wherein the enantiomer rotates in the plane of polarized light in one direction and its image of mirror rotates in the plane of polarized light in the opposite direction. The terms "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers, or a racemic modification or racemic mixture are optically inactive., the prefixes "(+)" and "(-)" are used to designate the sign of rotation of the plane of light polarized by the compound, (+) meaning that the compound is dextrogiratorio and (-) meaning that the compound is levogiratorio . The term "enantiomeric enrichment" refers to the increase in the amount of the enantiomer compared to another enantiomer. A convenient method for expressing the enantiomeric enrichment achieved is the concept of "enantiomeric excess" or "ee", which is expressed by the following equation: ee = E1 - E2 x 100 wherein E1 is the amount of the first enantiomer, and E2 is the amount of the corresponding second enantiomer. For example, when the initial ratio of two enantiomers in a reaction is 50:50 (a racemic mixture) and the reaction produces enantiomeric enrichment with the final ratio of 90: 10, then ee with respect to the first enantiomer is 80%. It is preferred to obtain an ee greater than 90%. It is understood that the enantiomers of the formula (1 a) and the corresponding enantiomers of the formula (1 b) are mirror images of each other. It is further understood that the enantiomers of the formulas (1 a) and (1 lb) are also in the CIS configuration. In addition, the CIS compounds of the formula (I I) are racemic mixtures of the corresponding enantiomers of the formulas (1 a) and (1 Ib). It is also understood that the enantiomeric compounds of the formula (la) and the corresponding enantiomeric compounds of the formula (Ib) are mirror images of each other. For example, the enantiomer of the formula (la ') and the enantiomer of the formula (I b'), below, are mirror images of each other. formula ('') formula (Ib ') As used herein, the term "C 1 -C 4 alkyl" refers to a saturated straight or branched chain hydrocarbon radical having from 1 to 4 carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like. As used herein, the term "C2-C4 alkanoyl" refers to an acetyl, propionyl and butyryl group. As used herein, the term "C 1 -C 4 alkoxy" refers to a straight or branched alkoxy group containing 1 -4 carbon atoms and includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, and the like. As used herein, the term "halogen", "halo", "halogenide", or "hal", refers to a fluorine atom, chlorine atom, bromine atom or iodine atom. The term "TBDMS" refers to a tert-butyldimethylsilyl functionality of the formula: The term "phenyl" refers to the phenyl functionality of the formula: The terms "benzyl-" or "Bn" refers to the benzyl functionality of the formula: The term "substituted phenyl" refers to the substituted phenyl functionality of the formula: wherein R is C 1 -C alkyl, C 1 -C 4 alkoxy, NO 2, -CN, F, Cl, Br, or I, which may be located in the ortho, meta, or para position on the ring. The term "substituted benzyl" refers to the substituted benzyl functionality of the formula: wherein R is C? -C4 alkyl, C? -C4 alkoxy, N02, -CN, F, Cl, Br, or I, which may be located in the ortho, meta, or para position, on the ring. The term "THP" refers to the tetrahydro-pyran-2-yl functionality of the formula: The terms "acetyl", "propionyl", and "butyryl" refer to the following functional groups, respectively: As used herein, a CIS compound such as a compound A, means the hydrogens in positions 1 and 2 on the cyclopentenyl ring, both are on the same plane of the ring, and the substituents OH and OJ, where J is H or Pg, at positions 1 and 2, are also on the same plane of the ring between each other. In this way, OH and OJ are in the plane opposite to the hydrogens in positions 1 and 2. The designation "-" ^ - ft "refers to a link that exits out of the plane of the page. ,, u "refers to a link that exits backwards from the plane of the page. The designation "w?" Refers to a link for which the stereochemistry is not designated. The patent application of E. U.A. Series No. 08/41 1, 136, filed on March 27, 1995, entitled "PREPARATION OF CIS-4-0-PROTECTED-2-CYCLOPENTENOL DERIVATIVES "(Preparation of 2-cyclopentenol-CIS-4-0-protected derivatives), incorporated herein by reference. Scheme I describes the preparation of compounds of the formulas (I) , (II), and (III) All substituents, unless otherwise indicated, are as previously defined Reagents and starting materials are readily available to one skilled in the art.

SCHEME I Protection formula (I) Step c Reduction formula (II) 3 Step d Check out formula (III) In step a, the 4-hydroxy-2-cyclopentenone (2) is easily prepared from furfuryl alcohol (1) by one skilled in the art, following the procedure described by Masayoshi Nanni, Harima Ta-machi and Moriyama-shi, Japanese Patent Description Bulletin, KOKAI No. 57-62236, April 15, 1982, or alternatively as described by G. Piancatelli et al., Tetrahedron. 34. 2775 (1978). In step b 4-hydroxy-2-cyclopentenone (2) was protected with a suitable protecting group to provide the compound of formula (I), using techniques and procedures well known to one skilled in the art. Examples of suitable protecting groups are described by T.W. Greene, "Protective Groups in Organic Svnthesis", John Wiley & Sons, Inc., 1981, Chapter 2, such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxy-methyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3- b, tetrahydro pyra, tetrahydropylopyranyl, 4-methoxy tetrahydropyranyl, 4-methoxy tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 2,2,2-trichloroethyl, tert-butyl, alyl, cinnamyl, p-chlorophenyl, benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-chlorobenzyl, p-bromobenzyl, p-cyanobenzyl, diphenylmethyl, tri-phenylmethyltriethylsilyl, tri isopropyl silyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldi Isyl, dimethylethylsilyl, methyldiisopropylsilyl, methyl-di-tert-butylsilyl, tribenzylsilyl, triphenylsilyl, phenyldimethylsilyl, benzylmethylethylsilyl, phenylethylmethylsilyl, tri-o-tolylsilyl, tert-butyldiphenylsilyl, and the like. Preferred suitable protecting groups are tetrahydropyranyl and tert-butyldimethylsilyl. Suitable highly protective groups are tert-butyldimethylsilyl and trityl. The compounds of the formula (I) are readily prepared by one skilled in the art, using the methods described by T.W. Greene, "Protective Groups in Organic Svnthesis", John Wiley & Sons, Inc., 1981, Chapter 2. For example, the protective step can be carried out by dissolving the 4-hydroxy-2-cyclopentenone (2) in an inert, organic, substantially anhydrous solvent in the presence of an acid acceptor, preferably a base. of nitrogen such as triethyl, quinoline, lutidine, imidazole, or pyridine. The preferred acid acceptor is triethylamine. Examples of suitable solvents for the protection step are methylene chloride, tetrahydrofuran, chloroform, tetrachloroethane, nitromethane, benzene, diethyl ether, acetonitrile, dimethylformamide, and the like. The preferred suitable solvent is tetrahydrofuran. Optionally, a catalytic amount of 4-dimethylaminopyridine (DMAP) can be added to the solution. Then, the solution is cooled to about 0 ° C and about one equivalent of a suitable silylating agent is added to the solution. The reaction is allowed to stir for 2 to 14 hours and then the compound of the formula (I) is isolated and purified by well known techniques, such as extraction and distillation methods. For example, the reaction was poured into 0.5N aqueous hydrochloric acid, and the phases were separated. The aqueous phase was extracted with a suitable organic solvent, such as heptane. The organic extract was combined with the organic phase and rinsed with 5% sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was then purified by Kugelrohr distillation to provide the compound of formula (I). In step c, the compound of the formula (I) is selectively reduced to provide the CIS compound of the formula (I I). For example, the compound of the formula (I) and a suitable Lewis acid are dissolved in a suitable organic solvent under an inert atmosphere, such as argon, with agitation. The suitable organic solvent is essentially anhydrous and can be a mixture of suitable organic solvents or an individual organic solvent. Examples of a suitable organic solvent are diethyl ether, dipropyl ether, tert-butyl-methyl ether, toluene / tert-butyl-methyl ether, heptan / tert-butyl-methyl ether, toluene / diethyl ether, and the like. Preferred suitable organic solvents are diethyl ether, toluene / diethyl ether or toluene / tert-butyl-methyl ether. Suitable highly suitable organic solvents are toluene / diethyl ether or toluene / tert-butyl-methyl ether. The amount of suitable Lewis acid used is from about 0.10 eq to about 5 eq, with about 0.5 eq being preferred. Examples of a suitable Lewis acid are lithium chloride, lithium bromide, lithium iodide, lithium perchlorate, zinc chloride, magnesium bromide, cerium chloride (11), and the like. Preferred Lewis acids, preferred, are lithium iodide and lithium bromide, with lithium iodide being the preferred Lewis acid. The temperature of the solution, required for the selective reduction, is -100 ° C to 20 ° C, approximately. The preferred temperature is from about -78 ° C to about -10 ° C, with the temperature of the solution being -25 ° C being very preferred. Then, the solution is treated with a suitable reducing agent. The preferred amount of suitable reducing agent, used, is from about 0.4 eq to about 5 eq, with about 0.5 eq being very preferred. Examples of suitable reducing agents are aluminum hydride or aluminum, lithium trimetoxy aluminum hydride, REDAL® (Aldrich Chemical Company, Milwaukee, Wisconsin), lithium borohydride and the like. The preferred suitable reducing agent is lithium aluminum hydride. After the addition of the appropriate reducing agent, the reaction is stirred for about 1 hour to about 5 hours, with about 2 hours being preferred. The reaction was then cautiously quenched and the product isolated and purified using conditions well known in the art. For example, about 1 to 2 eq of aqueous sodium hydroxide (1 N) were added at a rate that kept the reaction temperature below 20 ° C. After the reaction was quenched, it was filtered through a diatomaceous earth pad, such as CELITE, (available from Aldrich Chemical Company, Milwaukee, Wisconsin). The diatomaceous earth pad was then rinsed with a suitable organic solvent, such as toluene. The filtrate was separated and the aqueous phase was extracted with a suitable solvent, such as toluene. The organic phases can be combined and washed sequentially with aqueous sodium hydroxide (1N), brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compound of formula (II), which can be purified by well-known techniques, such as chromatography or distillation. Gas chromatography (GC) can be used by one skilled in the art to determine the ratio of the CIS compound of the formula (II) to the by-products of the reduction, which are the compounds 2 and 3. Furthermore, in step c , the compound of the formula (I) can be selectively reduced to provide the CIS compound of the formula (II) by adding a suitable alcohol to the reaction mixture, described above, under conditions analogous to those described above, either in the presence of the appropriate Lewis acid, or alternatively, without the addition of the suitable Lewis acid. Examples of suitable alcohols are isopropanol, 2-methyl-1-propanol, 2-methyl-2-butanol, 2-methyl-1-butanol, 3-methyl-1-butanol, 3-methyl-2-butanol, triethyl-siianol, ter -butyldimethylsilanol, methyl-diisopropylsilanol, isopropyldimethylsilanol, triisopropylsilanol, methyl-di-tert-butylsilanol, tribenzylsilanol, triphenylsilanol, tert-butyldiphenylsilanol, phenyldimethylsilanol, benzylmethylethylsilane, phenylmethylethylsilane, tri-o-tolylsilanol, phenol and the like. Preferred suitable alcohols are isopropanol and tert-butyldimethylsilanol, with tert-butyldimethylsilanol being very preferred. The amount of alcohol added may vary from about 0 mole% to about 100 mole%. The preferred amount of added alcohol is from about 16 mol% to about 30 mol%, with about 20 mol% being very preferred. More specifically, for example, a suitable reducing agent, such as lithium aluminum hydride, is combined with a suitable Lewis acid, such as lithium iodide in a suitable organic solvent, such as toluene. The reaction mixture is cooled from about -40 ° C to about -20 ° C, and a mixture of a compound of the formula (I), such as 4-tert-butyldimethylsiloxy, is slowly added to the reaction mixture. 3-cyclopentanone, tert-butyldimethylsilanol and tert-butyl methyl ether. After stirring for about 4 hours, the reaction was quenched with aqueous ammonium chloride and the product isolated and purified by well known techniques, such as column chromatography on silica gel or by vacuum distillation. It is understood by one skilled in the art, that the reagents can be combined in various forms, provided that the suitable alcohol is present when the suitable reducing agent is combined with the compound of the formula (I). For example, the suitable Lewis acid can be combined with the suitable reducing agent and a suitable alcohol in a suitable organic solvent, such as toluene. The reaction mixture was then treated with a solution of a compound of the formula (I) in a suitable organic solvent, such as tert-butyl methyl ether to provide the CIS compound of the formula (II). In another example, the suitable Lewis acid can be combined with the suitable reducing agent, a suitable alcohol in a suitable organic solvent, such as toluene, and a compound of the formula (I) followed by the addition of a suitable organic solvent, such as tert-butyl methyl ether to provide the CIS compound of the formula (II). In step d, the CIS compound of the formula (I I) is deprotected under conditions well known in the art, to provide the CIS compound of the formula (III) [see, for example, T.W. Greene, "Protective Groups in Organic Svnthesis", John Wiley & amp;; Sons, Inc, 1981, Chapter 2]. For example, the compound of the formula (I I), wherein Pg is a trialkyl silyl group, such as a tert-butyldimethylsilyl group, was dissolved in a suitable organic solvent, such as tetrahydrofuran. Then, it was optionally treated with about 0.15 eq of a suitable amine, such as triethylamine, followed by treatment with about 1.1 eq of tetrabutylammonium fluoride (as a 1 N solution in tetrahydrofuran), at room temperature. The reaction was stirred for about 2 to 6 hours and then the product was isolated and purified by well known techniques. For example, the reaction was concentrated under vacuum and the residue was purified via flash chromatography on silica gel with a suitable eluent, such as 10% acetone / ethyl acetate. The purified material was then recrystallized from a suitable organic solvent, such as chloroform to provide cis-2-cyclonentenyl-1,4-diol of the formula (11).Further, in step d, the compound of the formula (II), wherein Pg is a tetrahydro-pyran-2-yl group, was dissolved in a suitable organic solvent, such as methanol or ethanol, and treated with an acid suitable, such as pyridinium p-toluenesulfonate (PPTS), at room temperature for 1 to 4 hours. The product was isolated and purified by well-known techniques. For example, the reaction is neutralized with a suitable base, such as sodium bicarbonate and concentrated under vacuum. The residue was then purified by flash chromatography on silica gel with a suitable eluent, such as 10% acetone / ethyl acetate. The purified material was then recrystallized from a suitable organic solvent, such as chloroform, to provide cis-2-cyclopenten-1, 4-dioI of the formula (III). In a manner analogous to that described in Scheme I, compounds of the formulas (1 a) and (1 b) can be prepared from the corresponding compounds of the formulas (la) and (Ib). The compounds of the formulas (la) and (Ib) can be prepared by one skilled in the art, for example, generally following the procedure described by M. Asami, Tetrahedron Letters, 26 (47), 5803-5806 (1985), or SP Khanapure and others, J. Org. Chem. 60, 7548-7551 (1995). In addition, the compounds of the formulas (la) and (Ib) can be prepared by one skilled in the art from the compounds of the formulas (Ib) and (IV) prepared in Scheme II shown below.

Scheme II describes the preparation of compounds of the formulas (llb) and (IV) from the compounds of the formula (II). The compounds of the formula (II) can be prepared following the procedure set forth in Scheme I. In addition, the compounds of the formula (II) can be prepared by converting the cyclopentadiene to cis-2-cyclopentenyl-1,4-diol, following the procedure described by Kaneko, C, et al., Svnthesis, 876, (1974), and then monoprotecting the diol with a suitable protecting group under conditions well known to those skilled in the art, for example, as described by Jain, S., et al., Chemistry and Industry, 17, 576, (September 1990), Rapoport, H. and Castello, A., J. Org. Chem., 51, 1006 (1986), McDougal, P., and others, J. Orq. Chem .. 51. 3388 (1986), and Roush et al., J. Org. Chem. 56, 1636 (1991). All substituents, unless otherwise indicated, were previously defined. Reagents and starting materials are readily available to those skilled in the art.

SCHEME II II) formula (Ilb) formula (lia) Step A Enantioselective acylation catalyzed by an enzyme Formula (Ilb) formula (IV) StepB Step C Hydrolyze Hydrolyze formula (lia) formula (V) In Scheme II, step A, a compound of formula (II) was subjected to an enantioselective acylation reaction catalyzed by an enzyme under analogous conditions well known in the art, such as those described by Johnson, CR and others, Tetrahedron Letters. 3_5 (12), 1833-1834 (1994), C. R. Johnson and S.J. Bis, Tetrahedron Letters. 33 (48), 7287-7290 (1992), Theil, and others, Liebiegs Ann. Chem. 195-200 (1991), Theil, and others, Tetrahedron. 47 (36), 7569-7582 (1991) and Theil et al., Svnthesis, 540 (1988), to provide the compound of formula (lb) and (IV). For example, a compound of formula (II) was dissolved in a suitable solvent or solvent mixture, such as tert-butyl methyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, cyclohexane, toluene, hexane, and the like. Preferred suitable solvents are tert-butyl methyl ether and cyclohexane. The solution was treated with a suitable enzyme and an excess of a suitable acylating agent. Examples of suitable acylating agents are isopropenyl acetate, isopropenyl propionate, isopropenybutyrate, vinyl acetate, vinyl propionate, vinyl butyrate., and similar. The preferred suitable acylating agent is vinyl acetate. Optionally, about 0.70 equivalents of an alkyl amine, such as triethylamine, can be added, with stirring, at a temperature of about 15 ° C to about 55 ° C. A suitable enzyme is an enzyme that catalyzes the enantioselective acylation of the compound of the formula (II), whereby essentially only a single enantiomer of the racemic mixture, such as the compound of the formula (lia), is acylated under the conditions described to produce a mixture of compounds of the formula (IV) and the formula (lb), wherein Z is acetyl, propionyl, or butyryl. Examples of suitable enzymes are pancreatin (available from Sigma Chemical Company), lipase B from Candida Antarctica (Novo Nordisk SP 435), lipozyme IM (available from Novo Nordisk), and the like. The preferred suitable enzyme is pancreatin. The preferred temperature is 22 ° C. The reaction is then stirred for about 6 hours to 24 hours, preferably about 8 hours. The reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum to provide a mixture of compounds of formulas (llb) and (IV). The resulting mixture of the compounds of formulas (llb) and (IV) are easily separated from one another by techniques and procedures well known to one skilled in the art, such as chromatography or distillation. For example, the mixture can be chromatographed on silica gel with a suitable eluent, such as ethyl acetate / hexane to provide a clean separation of the compounds of the formula (lb) from the compounds of the formula (VII). In Scheme II, step B, the compounds of the formula (IV) can be selectively hydrolyzed through procedures well known to one skilled in the art, to produce the compounds of the formula (lia). For example, the compound of the formula (IV), wherein Pg is a tetrahydro-pyran-2-yl protecting group, or a trialkylsilyl protecting group, such as a tert-butyl-i-methyl-yl group, can be dissolved in a suitable solvent or solvent mixture, such as TH F / methanol / water, and be treated with an equivalent of a suitable base, such as lithium hydroxide monohydrate. The reaction was stirred at room temperature for about 1 to 8 hours, and the product was then isolated and purified by well known techniques, such as extraction methods and chromatography. For example, the reaction is diluted with a suitable organic solvent, such as diethyl ether, rinsed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was then purified by chromatography on silica gel with a suitable eluent, such as ethyl acetate / hexane, to provide the compound of the formula (Ha). In Scheme I I, step C, the compounds of the formula (IV) can be selectively hydrolyzed by methods well known to one skilled in the art to produce compounds of the formula (V). For example, the compound of the formula (IV), wherein Pg is a tetrahydro-pyran-2-yl protecting group can be dissolved in an organic solvent such as ethanol, and treated with p-toluenesulfonic acid. In addition, the compound wherein Pg is a tert-butyldimethylsilyl group in the formula (IV), can be dissolved in a suitable organic solvent such as tetrahydrofuran, and treated with n-tetrabutylammonium fluoride. Any reaction is then stirred at room temperature for approximately 1 to 8 hours, and the product is then isolated and purified by well known techniques, such as extraction methods and chromatography. For example, any reaction is diluted with a suitable organic solvent, such as diethyl ether, rinsed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is then purified by chromatography on silica gel with a suitable eluent, such as ethyl acetate / hexane, to provide the compound of the formula (V). The compounds of formulas (llb) and (lia) can then be converted to the corresponding enantiomers of O-protected 4-hydroxy-2-cyclopentenone by methods known to one skilled in the art. For example, the procedures described by M. Asami, Tetrahedron Letters. 26 (47), 5803-5806 (1985), K. Laumen and M. Schneider, Tetrahedron Letters. 25 (51), 5875-5878 (1984), M. Nara et al., Tetrahedron. 36, 3161-3170 (1980), and J. Nokami and others, Tetrahedron Letters. 32 (21), 2409-2412 (1991), can be followed in an analogous manner to produce both enantiomers of 4-hydroxy-2-cyclopentenone O-protected. For example, the compound of the formulas (Na) or (llb) is dissolved in a suitable organic solvent, such as methylene chloride and treated with a suitable oxidizing agent, such as manganese dioxide (Mn02), pyridinium dichromate. (PDC) or pyridinium chlorochromate (PCC) to provide the ketones of formulas (la) and (Ib). The compounds of the formulas (Na) and (Ib) are useful synthetic intermediates for the enantioselective synthesis of prostaglandins, for example, see M. Asami, Tetrahedron Letters. 26 (47), 5803-5806 (1985). In addition, the enantiomers of the formulas (la) and (Ib) can be prepared, in general, following the procedure of Corey, E. J., et al., Tetrahedron Letters. 27. 2199 (1986), or S. P. Khanapure et al., J. Org. Chem..60.7548-7551 (1995). The compounds of the formulas (Via), (Vlb), (VII) and (VIII) can be prepared as described in Scheme Ill. All substituents, unless otherwise indicated, are previously defined. Reagents and starting materials are readily available to one skilled in the art.

SCHEME lll SAW) formula (VIb) formula (Via) Step A Enantioselective acylation catalyzed by an enzyme formula (VIb) formula (VII) StepB Step C Hydrolyze Hydrolyze formula (Vía) formula (VIII) In Scheme 1, the compound of the formula (VI) was prepared by one skilled in the art, for example, by reducing the double bond in the compound of the formula (II). More specifically, the compound of formula (I I) was combined with Ni2B in a suitable organic solvent, such as methanol, and the reaction mixture was stirred for about 15-20 hours at room temperature under a hydrogen atmosphere. The product was then isolated and purified by techniques and procedures well known in the art. For example, the hydrogen atmosphere was purged with nitrogen, the reaction mixture was filtered through diatomaceous earth, the solids were washed with methanol and the filtrate was concentrated under vacuum. The residue was then purified by column chromatography or vacuum distillation to provide the purified compound of the formula (VI). In Scheme 11, Step A, the compound of the formula (VI) was subjected to an enantioselective acylation reaction catalyzed with an enzyme under analogous conditions well known in the art, such as those described by Johnson, C.R. and others, Tetrahedron Letters. 35 (12), 1833-1834 (1994), C. R. Johnson and S.J. Bis, Tetrahedron Letters. 33 (48), 7287-7290 (1992), Theil, and others, Liebiegs Ann. Chem. 195-200 (1991), Theil, and others, Tetrahedron. 47 (36), 7569-7582 (1991) and Theil et al., Svnthesis. 540 (1988), to provide the compound of the formula (Vlb) and (Vi l). For example, a compound of the formula (VI) was dissolved in a suitable solvent or solvent mixture, such as tert-butyl methyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, cyclohexane, toluene, hexane, and the like. Preferred suitable solvents are tert-butyl methyl ether and cyclohexane. The solution was treated with a suitable enzyme and an excess of a suitable acylating agent. Examples of suitable acylating agents are isopropenyl acetate, isopropenyl propionate, isopropenybutyrate, vinyl acetate, vinyl propionate, vinyl butyrate, and the like. The preferred suitable acylating agent is vinyl acetate. Optionally, about 0.70 equivalents of an alkyl amine, such as triethylamine, can be added, with stirring, at a temperature of about 15 ° C to about 55 ° C. The preferred temperature is about 22 ° C. A suitable enzyme is an enzyme that catalyzes the enantioselective acylation of the compound of the formula (VI), whereby essentially only a single enantiomer of the racemic mixture, such as the compound of the formula (Via), is acylated under the conditions described to produce a mixture of compounds of the formula (VII) and the formula (VIIb), wherein Z is acetyl, propionyl, or butyryl. Examples of suitable enzymes are pancreatin (available from Sigma Chemical Company), lipase B from Candida Antarctica (Novo Nordisk SP 435), lipozyme IM (available from Novo Nordisk), and the like. The preferred suitable enzyme is pancreatin. The reaction is then stirred for about 6 hours to 30 hours, preferably about 8 hours. The reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum to provide a mixture of compounds of formulas (Vlb) and (Vi l). The resulting mixture of the compounds of the formulas (Vlb) and (Vi l) are easily separated from one another by techniques and procedures well known to one skilled in the art, such as chromatography or distillation. For example, the mixture can be chromatographed on silica gel with a suitable eluent, such as ethyl acetate / hexane to provide a clean separation of the compounds of the formula (Vlb) from the compounds of the formula VII). In Scheme l l l, step B, the compounds of the formula (Vi l) can be selectively hydrolyzed through procedures well known to one of ordinary skill in the art, to produce the compounds of the formula (Via). For example, the compound of the formula (Vi l), wherein Pg is a tetrahydro-pyran-2-yl protecting group, or a trialkylsilyl protecting group, such as a tert-butyldimethylsilyl group, can be dissolved in a suitable solvent or solvent mixture, such as THF / methanol / water, and treated with an equivalent of a suitable base, such as lithium hydroxide monohydrate. The reaction was stirred at room temperature for about 1 to 8 hours, and the product was then isolated and purified by well known techniques, such as extraction methods and chromatography. For example, the reaction is diluted with a suitable organic solvent, such as diethyl ether, rinsed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was then purified by chromatography on silica gel with a suitable eluent, such as ethyl acetate / hexane, to provide the compound of the formula (Via). In Scheme III, step C, the compounds of the formula (VII) can be selectively hydrolyzed by methods well known to one skilled in the art to produce compounds of the formula (VIII). For example, the compound of the formula (VII), wherein Pg is a tetrahydro-pyran-2-yl protecting group can be dissolved in an organic solvent such as ethanol, and treated with p-toluenesulfonic acid. In addition, the compound wherein Pg is a tert-butyldimethylsilyl group in the formula (IV), can be dissolved in a suitable organic solvent such as tetrahydrofuran, and treated with n-tetrabutylammonium fluoride. Any of the above reaction mixtures are then stirred at room temperature for about 1 to 8 hours, and the product is then isolated and purified by well known techniques, such as extraction methods and chromatography. For example, any of the above reaction mixtures are diluted with a suitable organic solvent, such as diethyl ether, rinsed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is then purified by chromatography on silica gel with a suitable eluent, such as ethyl acetate / hexane, to provide the compound of the formula (il). The compounds of the formulas (Vlb) and (Via) can then be easily converted to the corresponding enantiomers of O-protected 3-hydroxycyclopentanone through procedures known to one skilled in the art. For example, the compounds of the formulas (Via) or (Vlb) are dissolved in a suitable organic solvent, such as methylene chloride and are treated with a suitable oxidizing agent, such as pyridinium dichromate (PDC), pyridinium chlorochromate. (PCC) or Swern conditions to provide the corresponding ketones. The following examples present typical syntheses, as described in Schemes I, I I and ll l. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. The retention times of gas chromatography, reported here, are obtained under the following conditions: Hewlett Packard 5890 series II gas chromatography was used, with an interlaced column of 30 mx 0.32 mm HP-5, 5% PH ME silicon, equipped to it. The flow rate was set at 30 ml / min with helium as the carrier gas. The temperature of the injection port is 200 ° C, the temperature of the detector is 275 ° C and the program used is a gradient, where the initial temperature was set at 100 ° C for 10 minutes, and then increased to a speed of 10 ° C / minute at 200 ° C, where it was maintained for 5 minutes before completion. In addition, chiral chromatography was easily used by someone skilled in the art to determine the ee of a particular compound. For example, you can use a CDX-ß, i.d. 10 m x 0.25 mm (available from J &; W Scientific, Folson, CA) under normal conditions, such as a column temperature of 100 ° C, injector temperature of 200 ° C and detector temperature of 220 ° C. Alternatively, the ee of a particular compound can be determined by preparing the corresponding Mosher esters of the compounds of (R) - (+) - α-methoxy-a- (trifluoromethyl) phenyl acetic acid or (S) - (-) - α-methoxy-a- (trifluoromethyl) phenyl acetic, using techniques well known to those skilled in the art, for example, see, Dale, J. A., Dull, D. L. and Mosher, H. S., J. Org. Chem .. 34 (9), 2543-2549 (1969). The amounts of each resulting diastereomer can be determined by 19 F NMR or separation through column chromatography, chiral column chromatography or gas chromatography, as is well known in the art, thus allowing calculation of the ee of the compound. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmoles" refers to millimoles; "my" refers to milliliters; "pe" refers to boiling point; "pf" refers to melting point; "° C" refers to degrees Celsius; "mmHg" refers to millimeters of mercury; "μL" refers to microliters; "μg" refers to micrograms; and "μM" refers to micromolar; "Rf" refers to retention factor; "d" refers to parts per million down from tetramethylsilane; "[a] D20" refers to the specific rotation of line D of sodium at 20 ° C obtained in a cell of 1 decimeter; "c" refers to concentration in g / ml; "DMF" means dimethylformamide; "TH F" means tetrahydrofuran; "TBME" means tert-butyl methyl ether; "NMM" means N-methylmorpholine; "DMSO" means dimethyl sulfoxide; and "DMAP" means 4-dimethylamino pyridine.

EXAMPLE 1 Preparation of 4-hydroxy-2-cyclopentenone Scheme I, step a; a solution of furfuryl alcohol was treated (125 g, 1.27 moles) in water (3.7 I) with KH2P0 (6.3 g, 46.3 mmol). The pH of the solution was adjusted to a pH of 4.1 (pH meter) with H3P0 and then heated to 99 ° C under a nitrogen atmosphere for 40 hours. The solution was then cooled and washed with methylene chloride (2 x 500 mL). The organic layers were combined and extracted with water (2 x 500 mL). The aqueous layer and the aqueous extracts were combined and concentrated under vacuum (70 ° C, 20 mmHg) to provide an oil. The oil was dissolved in methylene chloride (1 L), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (66 g, 53%) as a dark oil; 1 H NMR (CDCl 3) d 7.61 (dd, J = 5.6, 4.8 Hz, 1 H), 6.20 (dd, J = 5.6, 4.8 Hz, 1 H), 5.01 -5.04 (m, 1 H), 3.61 (bs) , 1 H), 2.75 (dd, J = 18.5, 3.2 Hz, 1 H), 2.26 (dd, J = 18.5, 6.0 Hz, 1 H), 1 3 C NMR (CDCl 3) d 207.4, 164.0, 134.7, 70.1, 44.1; IR (net)? Max 3387, 2974, 1711 cm'1; MS (El) m / e (% relative intensity) 98 (M +, 100). Anal. Cale, for C5H6O2.0.16h2O: C, 59.47; H, 6.30, H20, 2.9. Found C, 59.56; H, 6.52, H20, 3.0.

EXAMPLE 2 Preparation of 4-tert-butyldimethylsiloxy-2-cyclopentenone MS Scheme I, step b; a solution of 4-hydroxy-2-cyclopentenone (191 g, 1.95 mol, prepared in Example 1) and triethylamine (430 mL, 3.09 mol) in anhydrous tetrahydrofuran (1 L), was treated with 4-dimethylaminopyridine (4.90 g, 40.0 mmoles). The solution cooled to 0 ° C and treated in portions, for 10 minutes, with tert-butyldimethylsilyl chloride (278 g, 1.84 moles) keeping the temperature at or below 10 ° C. Then, the mixture was allowed to stir overnight at room temperature. It was then emptied into aqueous HCl (0.5 N, 1L). The phases were separated and the aqueous phase was extracted with heptane (2 x 1 L). The organic phase and the organic extracts were combined, washed with HCl (0.5 n, 2 x 500 mL), then 5% sodium bicarbonate (500 mL), then brine (500 mL), dried over anhydrous magnesium sulfate. , filtered and concentrated under vacuum (40 ° C, 20 mmHg) to provide the title compound (325 g). This was purified by Kugeirohr distillation (70-80 ° C, 1 mmHg) to provide the title compound (282 g, 72% yield) as a light yellow oil, Rf = 0.55, 20% ethyl acetate / hexane, GC retention time is 14.97 minutes; 1 H NMR (CDCl 3) d 7.48 (dd, J = 5.7, 2.4 Hz, 1H), 6.20 (d, J = 5.7, Hz, 1H), 4.95-4.99 (m, 1H), 2.72 (dd, J = 18.2, 6.0 Hz, 1H), 2.25 (dd, J = 18.2, 2.3 Hz, 1H), 0.00 (S, 9H), 0.11 (s, 6H); 13 C NMR (CDCl 3) d 206.4, 163.8, 134.4, 70.8, 44.9, 25.7, 25.6, 18.0; IR (net)? Max 2957, 2931, 2887, 2858, 1725 cm'1; MS (El) m / e (% relative intensity) 212 (M +, 5), 155 (M * -57, 100). Anal. Cale, for CnH20O2Si: C, 62.21; H, 9.51. C, 62.39; H, 9.50.

EXAMPLE 3a Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol.

Scheme I, step c; a mechanically stirred solution of 4-tert-butyldimethylsiloxy-2-cyclopentenone (50.2 g, 236 mmol) in anhydrous toluene (1 L) under an argon atmosphere was treated with lithium iodide (160 g, 1.20 mol). The mixture was cooled to -20 ° C and treated with lithium aluminum hydride (9.0 g, 237 mmol) in one portion. The reaction was then stirred for 5 minutes and tert-butyl methyl ether (200 ml) was added at a rate that maintained the reaction temperature at or below -15 ° C (total addition time, about 3 minutes). The reaction was stirred for 1 hour at -20 ° C, and then quenched by the slow addition of aqueous sodium hydroxide (1 N, 250 ml) at a rate that kept the reaction temperature below 20 ° C. The resulting suspension was then filtered through a diatomaceous earth pad and the pad was subsequently rinsed with toluene (400 ml). The filtrate phases were separated and the aqueous phase was extracted with toluene (300 ml). The organic phase and the organic extract were combined, rinsed with aqueous sodium hydroxide (1 N, 300 ml), brine (300 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40 ° C). , 20 mmHg). The residue was then purified through Kugeirohr distillation (60-80 ° C, 1 mmHg) to provide the title compound (37.4 g, 74% yield) as a colorless oil.; addition of cis / trans / 1 -2 + 1 -4, 95.3 / 2.1 /2.6; Rf = 0.20, 20% ethyl acetate / hexane, retention time GC for the title compound is 13.95 minutes, while retention times for the byproducts corresponding to 3 (trans) and 4 (addition 1 -2 + 1 -4) in Esq uema I, where Pg is a group TBDMS are 14.45 minutes and 14.06 m inutes, respectively; for the title compound, 1 H NMR (CDCl 3) d 5.93 (dt, J = 5.5, 1.7 Hz, 1 H), 5.84 (dt, J = 5.5, 1.6 Hz, 1 H), 4.63- 4.68 (m, 1 H), 4.52-4.62 (m, 1 H), 2.76-2.86 (bs, 1 H), 2.69 (dt, J = 13.8, 7.1 Hz, 1 H), 1.52 (dt, J = 13.8, 4.7 Hz, 1 H); 0.90 (s, 9H), 0.90 (s, 6H) 1, 3J, C R M N (C DCI3) d 136.7, 135.6, 75. 1, 75.0, 44.5, 25.9, 1 8.1; I R (net)? Max 3373, 2957, 2932 cm "1; MS (El) m / e (% relative intensity) 157 (M * -57).

EXAMPLE 3b Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol Scheme I, step c; A mechanically stirred solution of 4-tert-butyldimethylsiloxy-2-cyclopentenone (175 g, 824 mmol) in anhydrous toluene (1.5 L) under an argon atmosphere was treated with lithium iodide (240 g, 1.79 moles). The mixture was cooled to -20 ° C and treated with lithium aluminum hydride (13.5 g, 356 mmol) in one portion. The reaction was then stirred for 5 minutes and anhydrous tert-butyl-methyl ether (300 ml) was added at a rate which maintained the reaction temperature at or below -15 ° C (total addition time, about 3 minutes) . The reaction was stirred for 3 hours at -20 ° C and then quenched by the slow addition of aqueous sodium hydroxide (250 ml) at a rate that kept the reaction temperature below 20 ° C. The resulting suspension was then filtered through a diatomaceous earth pad and the pad was subsequently rinsed with toluene (400 ml). The filtrate phases were separated and the aqueous phase was extracted with toluene (450 ml). The organic phase and the organic extract were combined, rinsed with aqueous sodium hydroxide (1 N, 450 mL), brine (450 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40 ° C). , 20 mmHg). The residue was then purified by Kugeirohr distillation (60-80 ° C, 1 mmHg) to provide the title compound (120 g, 68% yield) as a colorless oil; addition cis / trans / 1 -2 + 1 -4, 92/4/4.

EXAMPLE 3c Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol Scheme I, step c; A mechanically stirred solution of 4-tert-butyldimethylsiloxy-2-cyclopentenone (1.01 g, 4.76 mmol) in anhydrous diethyl ether (20 ml) under an argon atmosphere was treated with lithium iodide (3.20 g, 23.9 mmol). The mixture was cooled to -78 ° C and treated with lithium aluminum hydride (184 g, 4.85 mmol) in one portion. The reaction was then stirred for 90 minutes. It was then quenched by the slow addition of aqueous sodium hydroxide (1 N, 23 ml) at a rate that kept the reaction temperature below 20 ° C. The resulting suspension was then filtered through a diatomaceous earth pad and the pad was subsequently rinsed with ether. The filtrate phases were separated and the aqueous phase was extracted with ether (20 ml). The organic phase and the organic extract were combined, rinsed with aqueous sodium hydroxide (1 N, 20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40 ° C). C, 20 mmHg). The residue was then purified by Kugeirohr distillation (60-80 ° C, 1 mm Hg) to provide the title compound (820 mg, 80% yield) as a colorless oil; addition cis / trans / 1 -2 + 1 -4, 88.5 / 3.3 / 8.2.

EXAMPLE 3d Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol Scheme I, step c; a mechanically stirred solution of 4-tert-butyldimethylsiloxy-2-cyclopentenone (502 mg, 2.36 mmol) in anhydrous toluene (10 ml) under an argon atmosphere was treated with lithium bromide (1.06 g, 12.2 mmol). The mixture was cooled to -20 ° C with an ice / salt bath and treated with lithium-aluminum hydride (92.0 mg, 2.42 mmol) is a portion, followed by tert-butyl-methyl ether (1.0 mi) . The ice / salt bath was replaced with an ice bath, and the reaction was then stirred for 2 hours at 0 ° C. Then, it was quenched by the slow addition of aqueous sodium hydroxide (1 N, 7.0 ml) at a rate that kept the reaction temperature below 20 ° C. The resulting suspension was then filtered through a diatomaceous earth pad, and the pad was subsequently rinsed with toluene. The phases of the filtrate were separated and the aqueous phase was extracted with toluene. The organic phase and the organic extract were combined, rinsed with aqueous sodium hydroxide (1 N), brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum (40 ° C, 20 mmHg). The residue was then purified by Kugeirohr distillation (60-80 ° C, 1 mmHg) to provide the title compound (350 mg, 69% yield) as a colorless oil; addition cis / trans / 1 -2 + 1 -4, 92.7 / 6.3 / 1 .0.

EXAMPLE 3e Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol Scheme I, step c; A stirred solution of ZnCl 2 (19 mL, 19 mmol, 1 M in ether) was treated with 4-tert-butyldimethylsiloxy-2-cyclopentenone (2.0 g, 9.42 mmol) under an argon atmosphere. The solution was cooled to -20 ° C and treated, by dripping, with lithium-aluminum hydride (9.0 ml, 9.0 mmol, 1 M in ether) at such a rate in order to maintain the reaction temperature at or below -15 ° C After stirring for about 2 hours at -20 ° C, approximately 5 ml of 1 N NaOH was added. The reaction was filtered through diatomaceous earth, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.3 g); cis / trans / 1-2 + 1-4 addition, 81/3/16.

EXAMPLE 3f Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol Scheme I, step c; A stirred solution of 4-tert-butyldimethylsiloxy-2-cyclopentenone (2.0 g, 9.42 mmol) in anhydrous toluene (15 mL) under an argon atmosphere was treated with MgBr2 (3.5 g, 19.0 mol). The mixture was cooled to -25 ° C and treated with lithium aluminum hydride (178 mg, 4.69 mmol) in one portion, followed by the addition of anhydrous tert-butyl methyl ether (3.0 ml). The reaction was stirred at -20 ° C for 2 hours and then overnight at room temperature. Additional lithium aluminum hydride (178 mg, 4.69 mmol) was added at room temperature, and the reaction mixture was stirred for 2 hours. The reaction was quenched after a slow addition of 1 N NaOH (5 ml) followed by filtration through diatomaceous earth. The filtrate was dried over magnesium sulfate hydro, filtered and concentrated under vacuum to provide the title compound (1.3 g); addition cis / trans / 1 -2 + 1 -4, 90/3/7.

EXAMPLE 3q Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol with 2.8 molar of tert-butyldimethylsilane nol added to the reaction mixture Scheme I, step c; in a 100 ml flask equipped with a mechanical stirrer, a low temperature thermometer and a 60 ml addition funnel, the upper part with a nitrogen bubble former, was placed lithium-aluminum hydride (0.5 g, 0.01 3 moles), lithium iodide (6.7 g, 0.05 moles) and toluene (34 g). The slurry was cooled to -40 ° C and the addition funnel was charged with 4-tert-butyldimethylsiloxy-3-cyclopentanone (5.0 g, 0.024 mole, containing 2.8% tert-butyldimethylsilanol, as determined by gas chromatography in a for gas chromatography series IIH ewlett-Packard 5890, a Hewlett-Packard integrator, a Hewlett-Packard column, PH-1, 10 m, 0.53 mm ID, 2.56 μm, injection port at 190 ° C, detector at 270 ° C, using a gradient with a starting temperature of 50 ° C for 2 minutes, then increasing at a speed of 20 ° C / minute at 250 ° C for 5 minutes) and butyl-methyl ether (18 g, TBME) . The cyclopentenone / TBM E solution was added to the slurry for 5 minutes at said speed in order to maintain the internal reaction temperature between -30 ° C and -36 ° C. The reaction mixture was then allowed to warm to -30 ° C and stirred for 4 hours. The reaction was quenched by slow addition of a 5% by weight solution of ammonium chloride (20 g). Toluene (20 g) was added and the phases were separated. The aqueous phase was then extracted with toluene (30 g). The organic phases were combined, washed with water (30 g), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by vacuum distillation through a bead column (4 mm) packed glass, 14 cm, at 0.2 mmHg (63-66 ° C) to provide the title compound (3.9 g, 77%); addition cis / tra ns / 1 -2 + 1 -4, 95/4/1.

EXAMPLE 3h Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol with 16 mol% of tert-butyldimethylsilanol added to the reaction mixture Scheme I, step c; in a 100 ml flask equipped with a mechanical stirrer, a low temperature thermometer and a 60 ml addition funnel, the top part with a nitrogen bubble former, was placed lithium-aluminum hydride (0.5 g, 0.013 moles), lithium iodide (6.7 g, 0.05 moles) and toluene (34 g). The slurry was cooled to -30 ° C and the addition funnel was charged with 4-tert-butyldimethylsiloxy-3-cyclopentanone (4.3 g, 0.02 mole, containing 2.8% tert-butyldimethylsilanol, as determined in Example 3g), butyldimethylsilanol (0.6 g, 0.005 mole) and tert-butyl methyl ether (18 g, TBME). Additional tert-butyldimethylsilanol was added to adjust the solution to contain 16% tert-butyldimethylsilanol. The cyclopentenone / silanol / TBME solution was added in one portion resulting in an exotherm of 8 ° C. The reaction mixture was cooled and maintained between -28 ° C and -32 ° C for 1.5 hours. The reaction was then quenched by the slow addition of a 5% by weight solution of aqueous ammonium chloride (20 g) and the phases were separated. The aqueous phase was extracted with methylene chloride (2 x 20 g). The organic phases were combined, washed with water (20 g), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by vacuum distillation through a bead column (4 mm) packed glass, 14 cm, at 0.5 mmHg (67-70 ° C) to provide the title compound (3.5 g, 81%); addition cis / trans / 1-2 + 1-4, 96.3 / 2.8 / 0.9.

EXAMPLE 3e Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol with 17 mol% of tert-butyldimethylsilanol added to the reaction mixture Scheme I, step c; a lithium-aluminum hydride (0.5 g, 0.013 moles) was placed in a 100 ml flask equipped with a mechanical stirrer, a low temperature thermometer and a 60 ml addition funnel, the upper part with a nitrogen bubble former. ), lithium iodide (1.4 g, 0.010 mol) and toluene (34 g). The slurry was cooled to -33 ° C and the addition funnel was charged with 4-tert-butyldimethylsiloxy-3-cyclopentanone (4.3 g, 0.02 mole, containing 2.8% tert-butyldimethylsilanol, as determined in Example 3g), -butyldimethylsilanol (0.6 g, 0.005 mole) and tert-butyl methyl ether (18 g, TBM E). Additional tert-butyldimethylsilanol was added to adjust the solution to contain 17% tert-butyldimethylsilanol. The cyclopeptenone / silanol / TBME solution was added in one portion resulting in an internal temperature of -23 ° C. The temperature of the reaction mixture was maintained near -30 ° C for 23 hours, and extinguished with 5% by weight of aqueous ammonium chloride (21 g). The phases were separated and the aqueous phase was extracted with toluene (2 x 20 g). The organic phases were combined, washed with water (25 g), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by vacuum distillation through a bead column (4 mm) packed glass, 14 cm, at 0.4 mmHg (65-68 ° C) to provide the title compound (3.2 g, 74%); addition cis / trans / 1 -2 + 1 -4, 96.2 / 2.8 / 1.

EXAMPLE 3i Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol with 18 mol% of tert-bldildimethylsilanol added to the reaction mixture Scheme I, step c; a lithium-aluminum hydride (0.5 g, 0.013 moles) was placed in a 100 ml flask equipped with a mechanical stirrer, a low temperature thermometer and a 60 ml addition funnel, the upper part with a nitrogen bubble former. ), and toluene (30 g). The slurry was cooled to -30 ° C and the addition funnel was charged with tert-butyldimethylsilanol (0.6 g, 0.005 mole), and toluene (9 g).

The silanol / toluene solution was added in one portion resulting in a moderate gas evolution. Additional tert-butyldimethylsilanol was added to adjust the solution to contain 18% tert-butyldimethylsilanol. The mixture was stirred at a temperature between -25 ° C and -30 ° C for 15 minutes. The addition funnel was charged with 4-tert-butyldimethylsiloxy-3-cyclopentanone (4.3 g, 0.02 mole, containing 2.8% tert-butyldimethylsilanol, as determined in Example 3g) and tert-butyl-methyl ether (13 g, TBME ). The cyclopentenone / TBME solution was added in one portion to the resulting slurry in an exotherm of 9 ° C (-21 ° C internal reaction temperature). The temperature of the reaction mixture was maintained near -25 ° C for 1.5 hours and then extinguished with 5% by weight of aqueous ammonium chloride. Toluene (20 g) was added and the phases separated. The aqueous phase was extracted with toluene (30 g). The organic phases were combined, washed with water (30 g), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by vacuum distillation through a bead column (4 mm) of packed glass, 14 cm, at 0.5 mmHg (67-69 ° C) to provide the title compound (3.1 g, 72%); cis / trans / 1-2 + 1-4 addition, 95 / 3.9 / 1.1.

EXAMPLE 3k Preparation of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol with 20 mol% isopropanol added to the reaction mixture Scheme I, step c; a slurry of lithium-aluminum hydride (350 mg, 9 mmol) and lithium iodide (1.16 g, 8.7 mmol) in toluene (34), cooled to -30 ° C and treated with a 4-ter- butyldimethylsiloxy-3-cyclopentanone (3.509 g, 16.5 mmol) tert-butyl-methyl ether (17 ml) and isopropanol (0.25 ml, 20 mol%), dropwise, over 22 minutes. The temperature was increased to -25 ° C. The reaction was then stirred for 2.5 hours at -20 ° C to -25 ° C. After, saturated ammonium chloride (20 ml) was added to the reaction followed by water (50 ml). The reaction was warmed to room temperature and then filtered. The solids were rinsed with toluene (20 ml). The phases of the filtrate were separated. The aqueous phase was extracted with toluene (20 ml). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by Kugeirohr distillation (0.4 mmHg / 60-75 ° C) to provide a colorless oil (2.17 g, 61%); cis / trans / 1-2 + 1-4 addition, 95.9 / 3.1 / 1.

EXAMPLE 4 Preparation of cis-2-cyclopentenyl-1,4-diol Scheme I, step d; a solution of cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (50 g, 0.233 mole) in tetrahydrofuran (250 ml) at room temperature was treated sequentially with triethylamine (5.0 ml, 0.36 mole) and tetrabutylammonium fluoride (250 ml of a 1.0 N solution in tetrahydrofuran, 0.250 moles). The reaction was stirred for 3 hours and then concentrated under vacuum (40 ° C, 20 mmHg). The residue was then purified by chromatography (silica gel, 100 x 160 mm, 10% acetone / ethyl acetate) followed by recrystallization from chloroform to provide the title compound (18.0 g, 77%) as white needles.; mp 57-58 ° C, Rf = 0.25 (10% acetone / ethyl acetate); 1 H NMR (CDCl 3) d 6.01 (s, 2 H), 4.62-4.68 (m, 1 H). 4.02 (d, J = 7.3, 3.2 Hz, 1H), 2.736 (dt, J = 14.6, 7.3 Hz, 1H), 1.57 (dt, J = 14.5, 3.4 Hz, 1H); 13 C NMR (CDCl 3) d 136.3, 74.9, 43.3; IR (KBr)? Max 3402, 3391, 3364 cm'1; MS (Cl) m / e (% relative intensity) 83 (M * + H-H20, 100). Anal. Cale, for C5H802: C, 59.98; H, 8.05. Found C, 59.79; H, 8.36.

EXAMPLE 5 Preparation of 4- (tetrahydro-pyran-2-yloxy) -cyclopent-2-enone Scheme I, step b; a solution of 4-hydroxy-2-cyclopentenone (1.41 g, 14.4 mmol) in tetrahydrofuran (24 mL) was treated with 3,4-dihydro-2H-pyran (2 mL) and pyridinium p-toluenesulfonate (500 mg, PPTS ). The reaction was stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate (25 ml) and washed with 50% saturated brine (2 x 30 ml). The organic layer was dried over anhydrous sulfate, filtered and concentrated under vacuum. The resulting crude brown oil was purified by filtration through a plug of silica gel (25 g, 33% ethyl acetate / hexane) to provide the title compound as a yellow oil (2.00 g, 76%); 'H NMR (CDCl 3) d 7.46 (2 x dd, 1 H, J = 16.3, 5.7 Hz), 6.2 (m, 1H), 4.9 (m, 1H). 4.80 (d appt, 1H, J = 23.8, 2.9 Hz), 3.9 (m, 1H), 3.6 (m, 1H), 2.73 (2 x dd, 1H, J = 18.4, 6.2 Hz), 2.35 (2 xd, 1H, J = 18.4 Hz), 1.8 (m, 1H), 1.6 (m, 4H); IR (net)? Max 2944, 2870, 2899, 1723, 1348, 1202, 1182, 1152, 1128, 1078, 1032 cm'1; MS (Cl) m / e (% relative intensity) 183 (M + H \ 28), 85 (100).

EXAMPLE 6 Preparation of cis-4- (tetrahydro-pyp-2-yloxy) -cyclopent-2-enol Scheme I, step c; a slurry of lithium-aluminum hydride (222 mg, 5.8 mmol), lithium iodide (3.2 g, 24 mmol), tert-butyl methyl ether (6 ml) and toluene (16 ml), cooled to -15 ° C. C. A solution of 4- (tetrahydro-pyran-2-yloxy) -cyclopenten-2-enone (2179 g, 11.97 mmol, prepared in Example 5) in tert-butyl-methyl ether (2 ml) and toluene (2 ml) it was added dropwise over 40 minutes. The reaction mixture was allowed to stir for 30 minutes. Then, sodium hydroxide (1 N, 5 ml) was slowly added to the reaction mixture. The sludge was filtered and the resulting phases separated. The aqueous phase was extracted with ethyl acetate (2 x 10 mL). The organic extracts were combined with the organic phase, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude oil was then purified by chromatography (silica gel, 30 g, 50% ethyl acetate / hexane, 400 ml) to provide the title compound (1.62 g, 73%), cis / trans / 1-2 addition + 1-4, 88/8/4; 1 H NMR (CDCl 3) d 6.1 (m, 1 H), 4.7 (m, 1 H), 4.6 (m, 2 H), 3.9 (m, 1 H), 3.5 (m, 1 H), 2.7 (m, 1 H), 1.4- 2.0 (m, 8H); 13 C NMR (CDCl 3) d 137.2, 137.1, 134.8, 133.6, 98.3, 97.8, 79.7, 79.5, 74.7, 74.5, 62.6, 62.5, 42.0, 41.1, 31.1, 30.9, 25.4, 19.6, 19.5; IR (net)? Max 2944, 2870, 2855, 1723, 1348, 1202, 1182, 1152, 1128, 1078, 1032 cm "1; MS (Cl) m / e (% relative intensity) 183 (M + H \ 7 ), 167 (M + H + -H20, 40), 85 (100).

EXAMPLE 7 Preparation of cis-2-cyclopentenyl-1,4-diol Scheme I, step d; a solution of cis-4- (tetrahydro-pyran-2-yloxy) -cyclopent-2-enol (338 mg, prepared in Example 6) in ethanol (4 ml) was treated with p-toluenesulfonic acid monohydrate (38 mg , p-TsOH »H20). The mixture was stirred at room temperature for 2 hours. Potassium carbonate (116 mg) was added and the reaction mixture was diluted with 25% hexane / ethyl acetate (10 mL). This solution was emptied onto a plug of silica gel (10 g) and eluted with 25% hexane / ethyl acetate (3 x 30 mL) and ethyl acetate (2 x 40 mL) to provide the title compound (167 mg, 90%), cis / trans addition / 1-2 + 1-4, 88/8/4.

EXAMPLE 8 Preparation of 4-tert-butoxy-cyclopent-2-enone Scheme I, step b; a solution of 4-hydroxy-2-cyclopentenone (1.15 g, 11.7 mmol) in methylene chloride was cooled to 3 ° C and treated sequentially with tert-butyl trichloroacetimidate (4.2 ml, 23.7 mmol) and boron trifluoride-etherate of diethyl (0.15 ml). The reaction mixture was stirred at 3-10 ° C for 2 hours and then allowed to warm to room temperature and stirred for 22 hours. The reaction mixture was then treated with sodium bicarbonate (250 mg) and filtered. The filtrate was concentrated under vacuum and the residue was purified by chromatography (silica gel, 39 g, 20% ethyl acetate / hexane, 600 ml) to provide the title compound (355 mg, 40%) as a yellow oil; 1 H NMR (CDCl 3) d 7.44 (dd, 1 H J = 18 Hz), 6.2 (d, 1 H, J = 5.4 Hz), 4.8 (m, 1 H), 2.68 (dd, 1 H J = 5.8, 18 Hz), 2.25 (d, 1H J = 18 Hz), 1.27 (s, 9H); IR (net)? Max 2976, 2936, 1721, 1368, 1352, 1188, 1103, 1161 cm "1; MS (Cl) m / e (% relative intensity) 155 (M + H +, 22), 99 (100 ).

EXAMPLE 9 Preparation of cis-4-tert-butyloxy-cyclopent-2-enol Scheme I, step C; a slurry of lithium-aluminum hydride (55 mg, 144 mmol), lithium iodide (1.65 g, 5.76 mmol), tert-butyl methyl ether (2 mL) and toluene (3 mL) was cooled to -15 ° C. . The slurry was treated dropwise with 4-tert-butoxy-cyclopent-2-enone (430 mg, 2.79 mmol, dissolved in 1 ml of toluene) for 5 minutes. The reaction mixture was stirred at -20 ° C to -12 ° C for 2 hours, and then allowed to warm to room temperature and stirred for 30 minutes. Then, the reaction mixture was treated sequentially with sodium hydroxide (1 N, 1 ml), then with tert-butyl methyl ether (10 ml) and filtered. The filtrate phases were separated and the aqueous phase was extracted with tert-butyl-methyl ether (15 ml). The organic extracts and the organic phase were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 30 g, 33% ethyl acetate / hexane) to give the title compound (183 mg, 42%) as a yellow oil, cis / trans / 1-2 + addition 1-4, 87 / 9.8 / 3.2; 1 H NMR (CDCl 3) d 5.9 (m, 1H). 5.8 (m, 1H), 4.6 (m.1H), 4.5 (m.1H), 2.7 (m, 1H), 2.0 (d, 1H J = 9.6 Hz), 1.5 (d appt, 1H, J = 4.5, 14 Hz), 1.2 (s, 9H); 13 C NMR (CDCl 3) d 136.6, 136, 75.5, 74.4, 74, 44.6, 28.7; ? max 3393, 2974, 2938, 2907, 2878, 1389, 1364, 1117, 1169, 1022 cm'1; MS (Cl) m / e (% relative intensity) 155 (M + H * -H 2 O), 57, 83 (100).

EXAMPLE 10 Preparation of (-) - cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (A) and 4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester of - (-) - acetic acid (B) A B Scheme II, step A; cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (10.0 g, 46.6 mmol, prepared in Example 3a) was dissolved in tert-butyl-methyl ether (60 mL, anhydrous). To this solution was added triethylamine (4.5 ml, 42.3 mmol), pancreatin (30 g, available from Sigma Chemical Company), and vinyl acetate (22 ml, 239 mmol). The reaction was allowed to stir for 7 hours at room temperature. The reaction was then filtered through diatomaceous earth and the filtrate was concentrated under vacuum. The products were separated by chromatography on silica gel (5% to 20% ethyl acetate / hexane) to provide 4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester of (-) - acetic acid (B, 6.1 g, yield 51%, 99% ee), [α] D -0.2 °, (c = 0.52, chloroform) as a yellow oil and (-) - cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (A, 4.7 g , 47% yield,> 99% ee), [a] D -18.6 °, (c = 1.01, chloroform) as a yellow oil.

EXAMPLE 1 Preparation of (-) - cis-4- (tetrahydro-pyran-2-yloxy) -cyclopent-2-enol (A) and cis-4- (tetrahydropyran-2-yloxy) -cyclopent-2-enyl ester of (-) - acetic acid (B) B Scheme I I, step A; cis-4- (tetrahydro-pyran-2-yloxy) -cyclopent-2-enol (1.091 g, 5.92 mmol, prepared as in Example 6) was dissolved in tert-butyl-methyl ether (8.6 ml., anhydrous). To the solution were added triethylamine (0.59 ml, 4.2 mmol), pancreatin (3.2 g, available from Sigma Chemical Company), and vinyl acetate (2.7 ml, 29 mmol). The reaction was allowed to stir for 7 hours at room temperature. The reaction was then filtered through diatomaceous earth and the filtrate was concentrated under vacuum. The products were separated by chromatography on silica gel (10% to 20% ethyl acetate / hexane) to provide cis-4- (tetrahydro-pyran-2-yloxy) -cyclopent-2-enyl acid ester (-) -acetic (B, 601 mg, 45% yield, 91% ee), [a] D = -19.8 °, (c = 1.00, chloroform) as a yellow oil and (-) - cis-4- ( tetrahydro-pyran-2-yloxy) -cyclopent-2-enol (A, 560 mg, 50% yield, 94% ee), [a] D = -9.9 °, (c = 1.06, chloroform) as a yellow oil (-) - cis-4- (tetrahydro-pyran-2-uloxy) -cyclopent-2-enol Anal. Cale, for CnH16O3 »0.13H2O: C, 64.38; H, 8.78. It was found: C, 64.32; H, 8.97. cis-4- (tetrahydro-pyran-2-yloxy) -cyclopent-2-enyl acid ester (-) - acetic Anal. Cale, for C? 2H? ß04: C.63.70; H. 8.01. It was found: C, 63.42; H, 8.09.

EXAMPLE 12 Preparation of (+) - cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol Scheme II, step B; 4-tert-Butyldimethylsilyloxy-cyclopentene-2-enyl ester of (-) - acetic acid (2.3 mmol, prepared in Example 10) was dissolved in THF / methanol / water (2.7 / 0.9 / 0.9 ml). Lithium hydroxide monohydrate (2.5 mmol) was added with stirring. After stirring for about 3 hours at room temperature, the reaction was diluted with water (10 ml) and extracted with tert-butyl methyl ether. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 20% ethyl acetate / hexane) to provide the title compound (452 mg, 92% yield), [a] D20 = + 21.8 °, (c = 1.02, chloroform).

EXAMPLE 13 Preparation of (+) - cis-4- (tetrahydro-pyran-2-yloxy) -cyclopent-2-enol Scheme II, step B; cis-4- (tetrahydro-pyran-2-yloxy) -cyclopent-2-enyl ester of (-) - acetic acid (106 mg, 0.47 mmol, prepared in Example 11) was dissolved in THF / methanol / water (1.5 /0.5/0.5 mi). Lithium hydroxide monohydrate (0.57 mmol) was added with stirring. After stirring for about 3 hours at room temperature, the reaction was diluted with tert-butyl-methyl ester (10 ml) and water (10 ml). It was extracted with tert-butyl-methyl ether (2 x 10 mL). The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 2.5 g, 1.7 x 2.5 cm column, 50% ethyl acetate / hexane, 150 ml) to provide the title compound (80 mg, 93% yield). ), [s] D20 = + 9.9 °, (c = 0.98, chloroform).

EXAMPLE 14 Preparation of (-) - cis-4-tert-butyloxy-cyclopenten-2-enol (A) and cis-4-tert-butyloxy-cyclopent-2-enyl ester of (-) - acetic acid (B) B Scheme II, step A; cis-4-tert-butyloxy-cyclopent-2-enol (485 mg, 3.1 mmol, prepared in Example 9) was dissolved in tert-butyl methyl ether (8.6 ml, anhydrous). To the solution were added triethylamine (0.7 eq), pancreatin (3 eq by weight, available from Sigma Chemical Company), and vinyl acetate (5 eq). The reaction was allowed to stir for 17 hours at room temperature. The reaction was then filtered through diatomaceous earth and the filtrate was concentrated under vacuum. The products were separated by chromatography on silica gel (10% to 20% ethyl acetate (hexane) to provide cis-4-tert-butyloxy-cyclopent-2-enyl ester of (-) - acetic acid (B, 50 % yield, 76% ee), [a] D = -10.9 °, (c = 0.98, chloroform), 1 H NMR (CDCl 3) d 5.94 (d.lH, J = 5.5 Hz), 5.89 (d, 1H, J = 5.5 Hz), 5.46 (appt, 1H, J = 5.5 Hz), 4.52 (appt, 1H, J = 5.5 Hz), 2.8 (m, 1H, 2.0 (s, 3H), 1.6 (d appt, 1H, J = 4.8, 14 Hz), 1.22 (s 9H), 13C NMR (CDCI3) d 172.2, 138.6, 131.6, 77.4, 77.2, 41, 28.7, 28.6, 21.4, IR (net)? Max 2976, 1738, 1364 , 1242, 1196, 1067, 1020 cm'1, CIMS m / e (% relative intensity) 199 (M + H \ 4), 139 (M + H * -AcOH.70), 83 (100), and (- ) -cis-4-tert-butyloxy-cyclopent-2-enol (A), 194 mg, 40% yield,> 98% ee), [a] D = -17.2 °, (c = 1.09, chloroform) as a yellow oil. f-) cis-4-tert-butyloxy-cyclopent-2-enol Anal. Cale, for C9H? 602: C, 69.19; H. 10.32. Found: C, 69.07; H, 10.37. cis-4-tert-butyloxy-cyclopent-2-enyl ester of (-) acetic acid Anal. Cale, for: Cn H1803: C. 66.64; H. 9.15. Found: C, 67.1 1; H, 9.03.

EXAMPLE 15 Preparation of (+) - cis-4-tert-butyloxy-cyclopent-2-enol Scheme II, step B; cis-4-tert-butyloxy-cyclopent-2-enyl ester of (-) - acetic acid was dissolved (90 mg, 0.45 mmole, prepared in Example 14) in THF / methanol / water (1.5 / 0.5 / 0.5 ml). Lithium hydroxide monohydrate (23.7 mg) was added with stirring. After stirring for about 2 hours at room temperature, the reaction was diluted with water (10 ml) and extracted with tert-butyl methyl ether. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 2 g, 40% diethyl ether / hexane, 1.5 × 2.5 column) to provide the title compound (71 mg, quantitative yield, 76% ee) as a pale yellow oil, [a] D20 = + 14.6 °, (c = 1 .03, chloroform).

MPLO AXIS 16 Preparation of cis-4-benzyloxy-cyclopent-2-enol Scheme 1, step b; in a manner analogous to the procedure described in Example 8, 4-benzyloxy-2-cyclopent-2-enone was prepared from 4-hydroxy-2-cyclo-intenone, benzyl trichloroacetimidate and boron trifluoride diethyl etherate. Scheme I, step c; a solution of lithium-aluminum hydride (45 mg, 1.2 mmol) and lithium iodide (451 mg, 3.37 mmol) in diethyl ether (4 mL) was cooled to -30 ° C and treated, dropwise, for 5 minutes with a solution of 4-benzyloxy-2-cyclopent-2-enone (444 mg, 2.36 mmol, prepared above) in diethyl ether (1 ml). The reaction mixture was stirred for 1.5 hours at -25 ° C and then treated with 1 N sodium hydroxide (1 mL). The reaction mixture was then allowed to warm to room temperature and filtered. The filtrate was extracted with ethyl acetate (2 x 10 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography to provide the title compound (1 51 mg, 34% yield) as a pale yellow oil, 28/4/3, cis / trans / 1, 4 + 1, 2; 1 H NMR (CDCl 3) d 7.3 (m, 5 H), 6.05 (appt, 2 H, J = 7 Hz), 4.6 (m, 1 H), 4.56 (dd, 2 H, J = 11.7, 17 Hz), 4.44 (dd, 1H, J = 4, 6.8 Hz), 2.7 (m, 1H), 1.67 (d appt, 1H, J = 14 Hz); 13 C NMR (CDCl 3) d 138.6, 137.4, 128.7, 128.1. 127.9, 81.7, 75.3, 71.3, 41.3; IR (net)? Max 3381, 2918. 2851, 1360, 1072, 1051, 1028 cm "1; CIMS m / e (% relative intensity) 173 (M + H + -H20), 91 (100).

Anal. Cale, for C? 2Hi402: C, 75.77; H, 7.41 Found: C, 75.61; H, 7.78.

EXAMPLE 17 Preparation of (-) - cis-4-benzyloxy-cyclopent-2-enol (A) and cis-4-benzyloxy-cyclopent-2-enyl ester of (-) acetic acid (B) B Scheme II, step A; cis-4-benzyloxy-cyclopent-2-enol (500 mg, prepared in Example 16) was dissolved in tert-butyl-methyl ether (8.6 ml, anhydrous). To the solution were added triethylamine (0.7 eq), pancreatin (3 eq by weight, available from Sigma Chemical Comapny), and vinyl acetate (5 eq). The reaction was allowed to stir for 7 hours at room temperature. The reaction was then filtered through diatomaceous earth and the filtrate was concentrated under vacuum. The products were separated through chromatography on silica gel (20% ethyl acetate / hexane) to provide (-) - cis-4-benzyloxy-cyclopent-2-enol (A) (147 mg, 29% yield ), [a] D20 = -12 °, (c = 1.09, chloroform) and cis-4-benzyloxy-cyclopent-2-enyl ester of (-) acetic acid (B) (427 mg, yield 70%), [a] D20 = -5.2 °, (c = 0.97, chloroform), 1 H NMR (CDCl 3) d 7.3 (m, 5H). 6.13 (d, 1H, J = 5 Hz), 5.99 (d, 1H, J = 5 Hz). 5.5 (m. 1H). 4.59 (d, 1H, J = 11.8 Hz), 4.54 (d, 1H, J = 11.8 Hz), 4.5 (m, 1H), 2.78 (d appt, 1H, J = 7.2, 14.3 Hz), 2.05 (s, 3H), 1.76 (d appt, 1H, J = 4.4, 14.3 Hz); 13 C NMR (CDCl 3) d 171.1, 138.5, 136.4, 133.1, 128.7, 128, 127.9, 81.4, 77.1, 71.2, 37.8, 21.4.

EXAMPLE 18 Preparation of (+) - cis-4-benzyloxy-cyclopent-2-enol Scheme II, step B; cis-4-benzyloxy-cyclopent-2-enyl ester of (-) - acetic acid (158 mg, 0.68 mmol, prepared in Example 17) was dissolved in THF / methanol / water (1.5 / 0.5 / 0.5 ml). Lithium hydroxide monohydrate (0.75 mmol) was added with stirring. After stirring for about 2 hours at room temperature, the reaction was diluted with water (10 ml) and extracted with tert-butyl methyl ether. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 2 g, 20% ethyl acetate / hexane, 1.5 x 2.5 cm column) to provide the title compound (120 mg, 92% yield), [ a] D20 = + 5.0 °, (c = 0.93, chloroform).

EXAMPLE 19 Preparation of (-) - cis-4-acetoxy-cyclopent-2-enol Scheme II, step B; cis-4-tert-butyldimethyl-silyloxy-cyclopent-2-enyl ester of (-) - acetic acid was dissolved (11.53 g, 45 mmol, prepared in Example 10) in tetrahydrofuran (49.5 ml) and triethylamine (0.7 ml). The solution was treated with a tetra-n-butylammonium fluoride solution (49.5 ml of a 1M solution in THF, 49.5 mmol) and stirred for 2 hours at room temperature. The mixture was then concentrated under vacuum and the residue purified by chromatography (silica gel, 33% to 50% ethyl acetate / hexane) to provide a white solid (5.85 g), which was recrystallized from tert-butyl methyl ether / heptane (80 ml / 100 ml) to provide the title compound (4.99 g, 78% yield, >)90% ee), [a] D20 = -68 °, (c = 0.98, chloroform), mp 48-49 ° C; 1 H NMR (CDCl 3) d 6.12-6.14 (m, 1H), 5.99-6.01 (m, 1H), 5.49-5.54 (m, 1H), 4.70-4.77 (m, 1H), 2.83 (dt, 1H, J = 14.5, 7.3 Hz), 2.22 (d, 1H, J = 7.8 Hz), 2.08 (s, 3H), 1.6 (dt, 1H, J = 14.5, 3.8 Hz).

EXAMPLE 20 Preparation of cis-4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester of (+) -acetic acid (-) - Cis-4-tert-Butyldimethylsilyloxy-2-cyclopentenol (1 g, 4.67 mmol, prepared in Example 10) was dissolved in pyridine (20 mL) and treated with acetic anhydride (2 mL). The reaction was stirred overnight. The reaction was diluted with diethyl ether (100 mL), washed with 3 M hydrochloric acid (3 x 100 mL), saturated sodium bicarbonate (100 mL), brine (100 mL), dried over anhydrous magnesium sulfate, it was filtered and concentrated under vacuum to provide the title compound (1 g, 98% yield), Rf = 0.5 (5% ethyl acetate / hexane), [a] D20 = + 1.3 °, (c = 1.00 , chloroform), 1 HNMR (CDCl 3) d 5.9 (m.H), 5.5 (m.H), 4.7 (m.H), 2.8 (m, 1H), 2.05 (s, 3H), 1.6 (m, 1H) , 0.91 (s, 9H), 0.09 (s, 6H); 13 C NMR (CDCl 3) d 178.8, 138.8, 131.1, 76.9, 74.8, 41.1, 25.8, 21.1, 18.1, -4.7, -4.6; IR (net)? Max 2955, 2932, 2859, 1739, 1369. 1240, 1105, 1062, 1049 cm'1; CIMS m / e (% relative intensity) 256 (M + H +, 7), 197 (M + H + -AcOH, 100).

EXAMPLE 21 Preparation of cis-4- (tetrahydro-pyra n-2-y! Oxy) -cyclopent-2-enyl ester ester of (+) - acetic acid (B) It was dissolved (-) - cis-4- (tetrahydro-pyran-2-yloxy) -cyclopent-2-enol (292 mg, 1.59 mmol, prepared in Example 1 1) in pyridine (2.8 ml) and treated with acetic anhydride (0.39 ml) and dimethylamino pyridine (16 mg). The reaction was stirred overnight. The reaction was concentrated under vacuum, the residue was dissolved with ethyl acetate (10 mL). It was washed with 0.5 M hydrochloric acid which was saturated, Vi, with brine (2 x 10 mL), saturated sodium bicarbonate (10 mL), brine (10 mL), dried over anhydrous magnesium sulfate, filtered and it was concentrated under vacuum. The residue was purified by chromatography (silica gel, 10 g, 1.5 x 4 cm column, 20% ethyl acetate / hexane) to provide the title compound (290 mg, 81%.

EXAMPLE 22 Preparation of (-) - cis-4-acetoxy-cyclopent-2-enol The cis-4- (tetrahydro-pyran-2-yloxy) -cyclopent-2-enyl ester of (-) - acetic acid (192 mg, 0.85 mmol, prepared in Example 11) was dissolved in ethanol (1.5 ml) and treated with p-toluenesulfonic acid (11.7 mg). The reaction was stirred at room temperature for 2 hours. Carbonate or bicarbonate was added to neutralize the reaction mixture and concentrated in vacuo. The residue was purified by chromatography (silica gel, 3 g, 1.5 x 3 cm column, 33% ethyl acetate / hexane, 80 ml), to provide the title compound (90 mg, 75% yield). , 91% ee), [a] D20 = -66.1 °, (c = 0.63, chloroform).

EXAMPLE 23 Preparation of (-) - cis-3-acetoxy-cyclopentanol (-) - Cís-4-acetoxy-cyclopent-2-enol (11.0 g, 77.4 mmol, prepared in Example 19) was dissolved in ethanol (50 ml) and treated with Raney nickel (1.1 g, previously washed with water (2 x 50 mL) and ethanol (2.50 mL, Ra-Ni) The atmosphere was charged with hydrogen at 344.75 KPa) and the mixture was stirred. After 20 minutes, the solution was filtered and the filtrate was treated with triethylamine (1.0 ml, 7.2 mmol). After 1 hour, the solution was concentrated under vacuum and the residue was distilled through Kugeirohr distillation (60-80 ° C, 1 mmHg), to provide the title compound (9.74 g, 87%) as a colorless oil.

EXAMPLE 24 Preparation of 3-methanesulfonyloxy-cyclopentyl ester of (1S.3R) -acetic acid (1S, 3R) -cis-3-acetoxy-cyclopentanol (9.75 g, 67.6 mmol, prepared in Example 23) was dissolved in tert-butyl ether (80 mL, anhydrous, and cooled to -8 ° C with stirring. Methanesulfonyl chloride (5.7 ml, 73.6 mmol, mesyl chloride) was added over 5 minutes, followed by the dropwise addition of triethylamine (11.4 ml, 81.2 ml), for about 30 minutes, keeping the temperature below -20. C. The ice bath was then stirred and the mixture was stirred for 2 hours.The mixture was poured into a water / brine mixture (50 ml / 50 ml) .The layers were separated and the aqueous layer was extracted with water. tert-butyl methyl ether (100 ml) The organic layer and the extract were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (14.4 g) as a yellow oil; 1 H NMR (CDCl 3) d 5.1 (m, 2 H), 3.02 (s, 3 H), 2.41 (m, 1 H), 2.05 (s 3 H), 2.0 (m, 5 H).

EXAMPLE 25 Preparation (-) - cis-3-ter-bu tildimetilsili loxi-cic I opentanol (-) - Cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (28.85 g, 135 mmol, prepared in Example 10) was dissolved in ethanol (75 ml) and treated with Raney nickel (1.85 g, 32 mmol, previously washed with water (2 x 50 ml) and ethanol (2 x 50 ml)). The atmosphere was charged with hydrogen at 344.74 kPa) and the mixture was stirred. After 5.25 hours. The solution was filtered at 0 ° C and treated with sodium borohydride (0.54 g, 14.3 mmol). After stirring for 2 hours, the solution was concentrated under vacuum and the resulting oil was distilled through Kugeirohr distillation (40-60 ° C, 1 mmHg) to provide the title compound (25.5 g, 87%) as an oil. colorless, [a] D20 = -3.9 °, (c = 0.99, chloroform); ? NMR (CDCl 3) d 4.4 (m, 1H), 4.3 (m, 1H), 3.03 (d, 1H, J = 10.5 Hz), 1.9-1.6 (m, 6H). 0.89 (s, 9H), 0.07 (s, 6H); 3 C NMR (CDCl 3) d 74.9, 74.1, 44.4, 34.2, 34.1, 25.8, 17.9, -4.9, -5.0; IR (net)? Max 3405, 2957, 2932, 2888, 2858, 1256, 1081, 1069, 1038, 1026 cm'1; CIMS m / e (% relative intensity) 217 (M + H +, 81), 199 (M + H + -H20, 37), 67 (100). This (-) - enantiomer (title compound) could not be separated from the (+) - enantiomer (antipode) using the chiral column described above.

Anal. Cale, for CnH2402 Si: C, 61.06; H, 11.17. Found: C, 61.28; H. 10.85.

The above reductions in Examples 23 and 25 can also be effected using catalysts such as platinum on Al203l nickel boride, platinum on CaCO3, Wilkinson catalyst ([-C6Hs) 3P] 3RhCl).

EXAMPLE 26 Preparation of 3-tert-Butyldimethylsilyloxy-cyclopentyl ester of (1S.3R) -methanesulfonic acid (-) - Cis-3-tert-butyldimethylsilyloxy-cyclopentanol (9.20 g, 42.5 mmol) was dissolved in anhydrous tert-butyl-methyl ether (50 ml) and cooled to -5 ° C. The solution was treated with sulfonyl metal chloride (3.6 g, 46.5 mmol, mesyl chloride). followed by triethylamine (7.2 ml, 51.7 mmol), at such a rate in order to maintain the temperature between -5 ° C and -2 ° C with an ice bath. The ice bath was stirred and the solution was stirred for 2 hours. The mixture was then transferred to a separatory funnel and treated with brine / water (50 ml / 50 ml). The layers were separated and the aqueous layer was extracted with tert-butyl-methyl ether (2 x 50 mL). The organic layer was combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (12.1 g, 97% yield) as a colorless oil; 1 H NMR (CDCl 3) d 5.1 (m, 1 H), 4.2 (m, 1 H), 2.99 (s, 3 H), 2.3 (m, 1 H), 2.0 (m, 3 H), 1.8 (m, 2 H), 0.88 ( s, 9H), 0.04 (s, 6H).

EXAMPLE 27 Preparation of 4-trityloxy-2-cyclopentenone enil) 3 Scheme I, step b; a solution of triflyl chloride (3.44 g, 12.3 mmol) in methylene chloride (20 ml) was treated sequentially with 1,8-diazabicyclo [5.4.0] undec-7-ene (2.2 ml, 14.7 mmol, DBU) and 4-hydroxy-2-cyclopentenone (1.01 g, 10.0 mmol, in 5 ml of methylene chloride, prepared in Example 1. The reaction was stirred for 3 days at room temperature and then emptied onto ice (ca. 25 ml). The phases were separated and the organic phase was washed with water (25 ml) The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo.The residue was purified by column chromatography (silica gel, 20% ethyl acetate / hexane) to provide the title compound (1.26 g, 36%) as a pale yellow oil, 1 H NMR (CDCl 3) d 7.5 (m 6 H) 7.3 (m, 9 H), 6.85 (dd, 1H), 6.05 (d, 1H), 4.8 (m, 1H), 2.1 (m 2H), 13C NMR (CDCI3) d 206.6, 162.9, 144.3, 135.2, 128.8, 128.4, 127.7, 88.2, 73.1. , 43.4; IR (KBr)? Max 3061. 1719, 1491, 14 49, 1352, 1181, 1107, 1053 cm'1.

EXAMPLE 28 Preparation of (+ / -) - cis-4-trityloxy-2-cyclopentenol enyl) 3 Scheme I, step C; a sludge of 4-trityloxy-2-cyclopentenone (1.03 g, 3.03 mmol, prepared in Example 27) in toluene (8 mL) was cooled to -20 ° C and treated sequentially with lithium aluminum hydride (76 mg., 2.0 ml), lithium iodide (1.06 g, 7.9 mmol) and dropwise with tert-butyl methyl ether (2 ml, for 5 minutes). The reaction was stirred for 1 hour at -20 ° C, heated at 0 ° C for 30 minutes, and stirred at 0 ° C to 15 ° C for 4 hours. The mixture was quenched through the slow addition of 1 N NaOH (2 ml) and then the reaction was filtered. The solids were washed with tert-butyl methyl ether and the phases of the filtrate were separated. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20% ethyl acetate / hexane) to provide the title compound as a white foam (980 mg, 95%). 1 H NMR (CDCl 3) d 7.5 (m, 6H), 7.3 (m, 9H), 5.79 (d.1H). 5.14 (d, 1H), 4.5 (m, 1H), 4.4 (m, 1H), 2.2 (m, 1H). 1.42 (d, 1H); 13 C NMR (CDCl 3) d 145.1, 136.2, 135.9, 129.0. 128.1, 127.3, 87.7, 77.4, 74.9, 43.2; IR (KBr)? Max 3422, 3057, 1491. 1364, 1084. 1065, 1024 cm. "1.

EXAMPLE 28a Preparation of cis-2-cyclopentenyl-1,4-diol A solution of (+/-) - cis-4-trityloxy-2-cyclopentenol (200 mg, 0.58 mmol, prepared in Example 28) in ethanol (2 mL) was treated with p-toluenesulfonic acid (20 mg) and stirred at 55 ° C for 8 hours. The reaction mixture was then concentrated under vacuum (55 ° C / 15 mmHg) and the residue was purified by column chromatography (silica gel, 10% acetone / ethyl acetate) to provide the title compound (58). mg); addition cis / trans / 1-2 + 1-4, 30/1 / trace.

EXAMPLE 29 Preparation of (+/-) - cis-tert-butyldimethylsilyloxycyclopentanol Combine (+/-) - cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (2.50 g, 11.6 mmol, prepared in Example 3), and Ni2B (8.5 ml of a 0.14 M slurry in methanol, 10 mol%) ) in methanol (14 ml). The mud was stirred under a mud atmosphere for 18.5 hours. Then, the hydrogen atmosphere was replaced by nitrogen, filtered through diatomaceous earth and the solids were rinsed with methanol (50 ml). The filtrate was concentrated under vacuum (15 mmHg (40 ° C) and the residue was purified by Kugeirohr distillation (0.6 mmHg / 60-65 ° C) to provide the title compound as a colorless oil (2.31 g, 92%).

EXAMPLE 30 Preparation of (1S.3R) - (-) - cis -3-tert-butyldimethylsilyloxycyclopentanol (A) and (1R. 3S) - (+) - cis -tert-butyldimethylsilyloxy-cyclopentanyl acetate (B) B Scheme III, step A; (+/-) - cis-3-tert-butyldimethyl-silyloxycyclopentanol (2119 g, 9.8 mmol, prepared in Example 29), pancreatin (6.2 g, 3 equivalents by weight), triethylamine (0.9 ml, 6.5 mmol) was combined. and vinyl acetate (4.3 ml) in tert-butyl methyl ether (12 ml) and stirred for 27 hours at room temperature. Then, the reaction was filtered through diatomaceous earth and the filtrate was concentrated under vacuum (room temperature / 15 mmHg). The residue was purified by column chromatography [silica gel, 55 g, hexane (300 ml) followed by 5% ethyl acetate / hexane (500 ml)] to provide the acetate (1R, 3S) - ( +) - 3-tert-butyldimethylsilyloxycyclopentanyl (1.23 g, 49% yield, 98% ee, as determined from gas chromatography with a chiral column) and (1S, 3R) - (-) - 3-tert-butyldimethylsilyloxycyclopentanol (771 mg, 37% yield, 92% ee, as determined from its acetate derivative followed by GC chiral column analysis, see Example 30a.

Physical data for (1S.3R) - (-) - 3-tert-butyldimethylsilyloxycyclopentanol; [a] D20 = -3.7 °, (c = 1.20, chloroform); ? NMR (CDCl 3) d 4.4 (m, 1H), 4.3 (m, 1H), 3.03 (d, 1H), 1.9-1.6 (m, 6H), 0.89 (s, 9H), 0.07 (s, 6H); 13 C NMR (CDCl 3) d 74.9, 74.1, 44.4, 34.2, 34.1, 25.8, 17.9, -4.9, -5.0; IR (net)? Max 3405, 2957, 2932, 2888, 2858, 1256, 1091, 1069, 1038, 1026 cm "1.

Anal. Cale, for CnH2402 Si: C, 61.06; H, 11.18.

Found: C, 61.32; H, 11.13.

Physical data for (1R. 3S) - (+) - 3-tert-butyldimethylsilyloxy-cyclopentanyl acetate; [a] D 20 = + 7.0 °. (c = 1.12, chloroform).

Anal. Cale, for C? 3H2ß03Si: C, 60.42; H, 10.14. Found: C, 60.70; H, 10.51.

EXAMPLE 30a Preparation of (1 S, 3 R) - (-) - cis-3-tert-butyldimethylsilyloxy-cyclopentanyl acetate (1S, 3R) - (-) - cis-3-tert-butyldimethylsilyloxycyclopentanol (209 mg, 2.5 mmol, prepared in Example 30), pyridine (1 mL), acetic anhydride (0.1 mL) and DMAP (5 mg) were combined. ). The reaction was stirred at room temperature for 15.5 hours. Then, the reaction was diluted with diethyl ether (10 ml) and washed sequentially with 0.5 M HCl, Yt, saturated with sodium chloride (2 x 10 ml), saturated sodium bicarbonate (10 ml) and brine (10 ml). ). Analysis of the filtrate indicated 92% ee for the title compound. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. [a] D20 = -6-6 °, (c = 0.99, chloroform); 1 H NMR (CDCl 3) d 5.0 (m, 1 H), 4.2 (m, 1 H), 2.2 (m, 1 H), 2.02 (s 3 H), 1.9 (m, 1 H), 1.7 (m, 2 H), 0.89 ( s, 9H), 0.05 (s, 3H), 0.04 (s 3H); 13 C NMR (CDCl 3) d 171.3, 75.0, 72.7, 42.3, 34.3, 30.5, 26.0, 21.5, 18.3, -4.5; IR (net)? Max 2957, 2932, 2859, 1740, 1250, 1115, 1096. 1045 cm'1.

Claims (4)

1. REIVI NDICACIONE S 1 .- A procedure for preparing a CIS compound of the formula: formula (I I) wherein Pg is selected from the group consisting of benzyl, substituted benzyl, -CH2OCH3-, -CH2SCH3-, CH2OCH2phenyl, -CH2OCH2CH2OCH3-, -C H2OCH2CCI3-, -CH (OCH2CH2CI) 2,
2. -CH2OCH2CH2Si (CH3) 3, -CH (OC2H5) CH3, -C (OC H3 (CH3) 2, -CH (C H3) OCH (CH3) 2, -CH2CCI3. -C (CH3) 3 .CH2CH = CH2, -CH2CH = CHphenyl, -CH (phenyl) 2, -C (phenyl) 3, tetrahydropyranyl, 4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetra hydrothio-pyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl and SiR? R2R3, wherein Ri R 2 and R 3 are each independently C 1 -C 4 alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl, which comprises: a) dissolving a compound of the formula (I): formula (I) wherein Pg is as defined above, in a suitable organic solvent; and b) treating the solution with a suitable Lewis acid and a suitable reducing agent at a temperature of from about -100 ° C to about 20 ° C. 2 - A process according to claim 1, wherein the suitable reducing agent is lithium-aluminum hydride.
3. 3 - . 3 - A process according to claim 2, wherein the suitable organic solvent is toluene / diethyl ether. 4. A process according to claim 2, wherein the suitable organic solvent is diethyl ether. 5. A process according to claim 2, wherein the suitable organic solvent is toluene / tert-butyl-methyl ether. 6. A process according to claim 2, claim 3 or claim 4, wherein the suitable Lewis acid is lithium iodide. 7 '. - A process according to claim 6, wherein the mixture is cooled to a temperature of about -78 ° C to about -10 ° C. 8. - A process according to claim 6, wherein the mixture is cooled to a temperature of about -25 ° C. 9. A process according to claim 8, wherein Pg is tert-butyldimethylsilyl. 10. A process for the preparation of the CIS enantiomer of the formula: formula (lia) wherein Pg is selected from the group consisting of benzyl, substituted phenyl, -CH2OCH3-, -CH2SCH3-, CH2OCH2phenyl, -CH2OCH2CH2OCH3-, - CH2OCH2CCI3-, -CH (OCH2CH2Cl) 2, -CH2OCH2CH2Si (CH3) 3, -CH (OC2Hs) CH3, -C (OCH3 (CH3) 2. -CH (CH3) OCH (CH3) 2, -CH2CCI3, -C ( CH 3) 3, CH 2 CH = CH 2, -CH 2 CH = CH-phenyl, -CH (phenyl) 2, -C (phenyl) 3, tetrahydropyranyl,
4. 4-m-ethoxy-tetrahydropyranyl, 3-bromo-tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl and SiR? R2R3l wherein R1t R2 and R3 are each independently C? -C4 alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl, comprising: a) dissolving an enantiomeric compound of the formula (la): formula (la) wherein Pg is as defined above, in an organic solvent; and b) treating the solution with a suitable Lewis acid and a suitable reducing agent at a temperature from about -100 ° C to about 20 ° C 11.- A process for the preparation of the CIS enantiomer of the formula: formula (Ilb) in where Pg is selected from the group consisting of benzyl, substituted benzyl, -CH2OCH3-, -CH2SCH3-, CH2OCH2phenyl, -CH2OCH2CH2OCH3-, -CH2OCH2CCI3-, -CH (OCH2CH2CI) 2, -CH2OCH2CH2Si (CH3) 3, -CH (OC2Hs CH3, -C (OCH3 (CH3) 2, -CH (CH3) OCH (CH3) 2, -CH2CCI3, -C (CHj) 3. CH2CH = CH2.-CH2CH = CHPhenyl, -CH (phenyl) 2, - C (phenyl) 3, tetrahydropyranyl, 4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxy tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl and SiR? R2R3l wherein Ri, R2 and R3 are each independently C? -C4 alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl, comprising: a) dissolving an enantiomeric compound of the formula; wherein Pg is as defined above, in a suitable organic solvent; Y formula (Ib) b) treating the solution with a suitable Lewis acid and a suitable reducing agent at a temperature from about -100 ° C to about 20 ° C. 12. A process for the preparation of the CIS compounds of the formulas (llb) and (IV): formula (Ilb) formula (IV) wherein Z is C2-C4 alkanoyl; and Pg is selected from the group consisting of benzyl, substituted benzyl, -CH2OCH3-, -CH2SCH3-, CH2OCH2phenyl, -CH2OCH2CH2OCH3-, -CH2OCH2CCI3-, -CH (OCH2CH2Cl) 2, -CH2OCH2CH2Si (CH3) 3. -CH (OC2H5) CH3. -C (OCH3 (CH3) 2l -CH (CH3) OCH (CH3) 2. -CH2CCI3, -C (CH3) 3, CH2CH = CH2, -CH2CH = CH-phenyl, -CH (phenyl) 2, -C (phenyl) 3, tetrahydropyranyl, 4-methoxytetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydrothio-pyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl and SiR? R2R3, wherein R ,, R2 and R3 are each independently C? -C4 alkyl, phenyl, benzyl substituted phenyl or substituted benzyl, comprising: a) dissolving a compound a compound of the formula (I), wherein Pg is as defined above, in a suitable organic solvent; formula (I) b) treating the solution with a suitable Lewis acid and a suitable reducing agent at a temperature from about -100 ° C to about 20 ° C to produce the compound CI S of the formula (I I); formula (II) wherein Pg is as defined above; c) treating the CIS compound of the formula (II) with a suitable enzyme and an excess of a suitable acylating agent, in a suitable solvent to produce a mixture of the compounds of the formulas (llb) and (IV), as defined earlier; and d) separating the compound of the formula (lb) from a compound of the formula (IV). 13. A process according to claim 12, wherein the suitable acylating agent is vinyl acetate. 14. A method according to claim 13, wherein the suitable enzyme is pancreatin. 15. A process according to claim 14, wherein the suitable solvent is tert-butyl methyl ether. 16. A process according to claim 14, wherein the suitable solvent is cyclohexane. 17. A process according to claim 12, for preparing compounds of the formula, which further comprises, hydrolyses the compound of the formula (IV) formula (lia) formula (IV) wherein Z is C2-C4 alkanoyl; and Pg is selected from the group consisting of benzyl, substituted benzyl, -CH2OCH3-, -CH2SCH3-, CH2OCH2phenyl, -CH2OCH2CH2OCH3-, -CH2OCH2CCI3-, -CH (OCH2CH2Cl) 2, -CH2OCH2CH2Si (CH3) 3. -CH (OC2H5) CH3I-C (OCH3 (CH3) 2, -CH (CH3) OCH (CH3) 2, -CH2CCI3, -C (CH3) 3, CH2CH = CH2, -CH2CH = CH-phenyl, -CH (phenyl) 2, -C (phenyl) 3, tetrahydropyranyl, 4-methoxy tetrahydro pyranyl, 3-bromotetrahydro pyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydrothio-pyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl and SiR? R2R3, wherein R (l R2 and R3 are each independently C 1 -C 4 alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl 18. A process according to claims 1, 10, 11, 12 or 17, wherein a suitable alcohol is added to the reaction mixture concomitantly with or before the treatment of the compound of formulas (I), (a), or (Ib) with the appropriate reducing agent 19. A process according to claim 18, wherein the suitable alcohol is tert-butyldimethylsilanol . 20. - A process according to claim 18, wherein the suitable alcohol is isopropanol. 21. A process for the preparation of the CIS compounds of the formulas (Vlb) and (Vil): formula (Vlb) formula (VII) wherein Z is C2-C4 alkanoyl; and Pg is selected from the group consisting of benzyl, substituted benzyl, -CH2OCH3-, -CH2SCH3-, CH2OCH2phenyl, -CH2OCH2CH2OCH3-, -CH2OCH2CCI3-, -CH (OCH2CH2Cl) 2, -CH2OCH2CH2Si (CH3) 3. -CH (OC2H5) CH3, -C (OCH3 (CH3) 2, -CH (CH3) OCH (CH3) 2, -CH2CCI3, -C (CH3) 3, CH2CH = CH2, -CH2CH = CH-phenyl, -CH (phenyl) ) 2, -C (phenyl) 3, tetrahydropyranyl, 4-methoxy tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydrothio-pyranyl, tetrahydrofuranyl, tetrahydro-thiofuranyl and SiR? R2R3, wherein Ri, R2 and R3 are each independently C 1 -C 4 alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl, which comprises treating the CIS compound of the formula (VI); formula (VI) wherein Pg is as defined above, with a suitable enzyme and an excess of the appropriate acylating agent in a suitable solvent, to produce a mixture of compounds of the formulas (Vlb) and (Vl), as defined previously; and f) separating the compound of the formula (Vlb) from the compound of the formula (VII). 22. A process according to claim 21, wherein the suitable acylating agent is vinyl acetate. 23 - A method according to claim 22, wherein the suitable enzyme is pancreatin. 24 - A process according to claim 23, wherein the suitable solvent is tert-butyl methyl ether. SUMMARY The present invention relates to a novel process for preparing cis-O-protected-substituted 2-cyclopentenol derivatives comprising, (a) dissolving a 4-0-protected 2-cyclopentanone in a suitable solvent; and (b) treating the solution with a suitable Lewis acid and a suitable reducing agent at a temperature of about -10 ° C to about 20 ° C. The cis-4-O-protected-substituted 2-cyclopentenol derivatives are useful intermediates in the preparation of various cyclopentanyl and cyclopentenyl purine analogues, which are useful as immunosuppressants and in the preparation of various prostaglandins.