Field of the invention The present invention relates to the process for preparation of 13,14- dihydro-PGF _2α derivatives of R or S configuration at carbon atom in omega chain substituted by hydroxyl, which are valuable biologically active substances or intermediates thereof. The invention especially relates to the process for preparation of 13,14-dihydro-15(R)-17-substituted-18,19,20-trinor-PGF _2α , known as latanoprost. This compound is used for the reduction of elevated intra-ocular pressure in patients with open angle glaucoma and ocular hypertension. Background of the invention

In a human organism, natural prostaglandins are present at very low concentration in almost all tissues and body fluids and play an important role in conditions such as pregnancy, arterial hypertension, osteoporosis, chronic ulcer disease, asthma or algesia. Some of the prostaglandins play some role in inflammatory processes and conditions related to myocardial infarction, in arthritis or affect adverse effects of antineoplastic chemotherapy.

Prostaglandins F _2α (PGF _2α ) are derivatives of 7-[3,5-dihydroxy-2-(3- hydroxy-l-octenyl)-cyclopentyl]-5-heptenoic acid, a cyclopentane ring which carries two hydroxy groups in cis configuration and two hydrocarbon side chains, alpha and omega. In prostaglandins F _2α one unsaturated bond is situated between carbons 13 and 14 in the omega chain, and additional double bond in the cis configuration is situated between carbons 5 and 6 of the alpha chain. Analogues of PGF ₂₀₁ and their use in the treatment of ocular hypertension and glaucoma are described in, among others, European patent applications EP- Al-0170258, EP-A1-0253094 and EP-A1-0364417. Review of medicines used in glaucoma treatment was undertaken by M.F. Sugrue (J. Med. Chem. 40 (1997), 2793-2809). Among PGF _2α analogues, an important therapeutic role plays latanoprost (CB. Tons et al. _; Ophtalomology 100 (1993), 1297-1304). Latanoprost, 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF _2α isopropyl ester or (Z)-7-{(lR,2R,3R,5S)-3,5-dihydroxy-2-[(R)-5-phenyl-3-

hydroxypentyljcyclopentyll-hept-S-enoic acid 2-propyl ester, having saturated omega side chain and esterified carboxylic group, has the structure

Latanoprost is described in European patent EP 0364417 Bl.

General issues related to chemistry of prostaglandins, including PGF _2α , are disccused, for example, in monographs in the field of organic chemistry: R. Noyori "Assymetric Catalysis In Organic Chemistry" John Wiley and Sons, Inc., New York, NY, 1994, chapter VI;; EJ. Corey, X-M. Cheng "The Logic of Chemical Synthesis" John Wiley and Sons, Inc. New York, NY, 1989; chapter XI and J.-H. Fuhrhop, G.Li "Organic Synthesis - Concepts and Methods" Wiley- VCH Verlag GmbH, Weinheim, 2003; Chapter II.

Numbering of carbon skeleton of prostaglandins, used in the present description, is discussed in the monograph of J.H. Fuhrhop, G. Li "Organic Synthesis - Concepts and Methods" Wiley- VCH Verlag GmbH, Weinheim, 2003 ; Chapter II.

In the synthesis of derivatives of prostaglandins, three strategies are generally used:

(a) Corey's method, so-called general method of synthesis of prostaglandins (EJ. Corey, X.-M. Cheng "The Logic of chemical Synthesis" John Wiley and Sons, Inc. New York, 1989; chapter XL EJ. Corey, Angew. Chem. Int. Ed. Engl. 30, (1991), 455),

(b) 1,4-addition method (S. Okamoto et al. J. Org. Chem 53 (1988), 5590; EJ. Corey et al. Tetrahedron Lett. 27 (1986), 2199; CJ. Sih et al. J. Am. Chem. Soc. 97 (1975), 865), and

(c) Noyori' s method consisting in 1,4-addition with enolate uptake (R. Noyori "Asymetric Catalysis In Organic Chemistry" John Wiley and Sons, Inc. New York, NY, 1994; chapter VI).

These strategies are demonstrated in a simplified way in Scheme 1.

Strategies of synthesis of prostaglandins

Corey's (-)-lactone

Corey's method

PGF 2a

1 ,4-addition method

PGF 2α

1,4-addition with enolate uptake (Noyori's) method PGF. 2α

Scheme 1

Among the above-mentioned methods, the most important in practice is Corey's method, constisting in attachement, first, of the omega chain, and then the alpha chain, to appropriately functionalized synthone of central cyclopentane ring. This, in turn, is prepared by uncomplicated modifications of Corey's (-)-lactone ((2S,3R ₎ 4S,5R)-4,5-dihydroxy-hexahydrocyclopenta[b]furan-2'-on e).

For example, synthesis of PGF _2α analogue latanoprost by Corey's method comprises the sequence of successive reactions:

(a) attachement of omega chain in the form of enone to synthone of. cyclopentane ring, eg. in Wittig's reaction;

(b) reduction of 13,14-en-15-one to 13,14-en-15-ol;

(c) hydrogenation of unsaturatted bond between carbons 13 and 14;

(d) attachement of alpha chain; and optionally

(e) further transformations of side chains.

According to the above methods, described, among others, in EP

0364417 Bl, EP 0544899 Bl and in B. Resul et al., J. Med. Chem. 36 (1993), p.

243-248 and 2242, from p-phenylbenzoiloxy-derivative of Corey's (-)-lactone, by sucessive reactions, diastereoisomeric mixture of latanoprost and its 15S epimer is obtained. That mixture requires chromatographic resolution.

Two other impurities of latanoprost may be 15S, 5,6.Z?-isomer and 15R, 5,6E-isoraer.

In view of regulatory requirements relating to chemical purity of pharmacologically active substances, especially ophtalmic substances, there is a necessity to develop improved methods of synthesis of appropriate diastereoisomer of PGF _2α derivative, not only devoid of residual intermediates and reagents used in multi-step synthesis, but also free of diastereoisomeric derivatives of side-formed prostaglandins of potentially potent biological activity, which may exert their own therapeutic effect. International Patent publication WO 93/00329 (EP 0544899 Bl) resolves the problem of diastereoisomeric purity of latanoprost by partially regioselective hydrogenation of carbonyl group in omega chain with use of boronhydride and isolation of the desired 15R diastereoisomer of intermediate alcohol by selective crystallization in diisopropyl ether. Further improvements of that approach to synthesis of PGF _2α derivatives are proposed in the art, consisting in use of more preferable and/or additional hydroxyl protecting groups, or in different order of their introduction and/or removal (WO 01/55101, WO 92/02496, WO02/96898); other, more selective, methods of carbonyl group reduction (WO 02/96868) or methods of double bond in omega chain reduction (WO 03/037857, US 668901).

Despite development of stereoselective methods of generation of asymmetry centre at position corresponding to carbon atom of carbonyl group of coupled enone, described, for example, in monograph of EJ. Corey, X.-M. Cheng "The Logic of Chemical Synthesis" John Wiley and Sons, Inc. New York, NY, 1989, chapter XI; US 6,689,901 patent and publications of J. Hutton, Synthetic Commun. 9 (1979), 483 and M. Node et al. J. Am. Chem. Soc. 122 (2000), 1927- 1936, reduction always results in undesired side formation of diastereoisomer of opposite configuration. In practice, it means that the prepared crude compound

needs to be purified of undesired isomer, and this is more laborious and more difficult, the greater its amount in the mixture is.

En the case of latanoprost, this difficulty is greater because 15S, 5,6Z isomer is difficult to detect even with use of HPLC analysis due to similar retention times of both isomers (relative value of R _F(15S > = 0.95 x R _F( ^ _R.) (WO 02/0968989). In practice, it means that preparative separation of 15S, 5,6Z isomer from latanoprost is difficult, both by column chromatography and by preparative HPLC.

The attempts to introduce to Corey's lactone first the omega chain, having in its structure the ready asymmetry centre corresponding to desired 15R configuration, and subsequent, to introduce to synthone the alpha chain, are described, by the way of example of PGE ₃ and PGF _3α analogues, in the publication of EJ. Corey et al., J. Am. Chem. Soc. 93 (1971), 1490. However, due to the low total yield, these methods are not useful in industrial scale. The strategy of introducing at first the omega chain to

(phenylsulfonyl)methyl derivative of Corey's (-)-lactol in the reaction with optically active α-hydroxy-aldehydes, is used also for preparation of racemic and non-racemic PGF _2α . From thus obtained 14,15-dihydroxy-13-sulfone, sulfonate and 14-hydroxy groups are removed reductively, to give 13,14-alkenes, to which alpha chain is then added (B. Achmatowicz et al., Tetrahedron 44 (1988), 4989- 98).

Precursors of prostaglandins, having β-hydroxysulfone moiety in the omega chain which is first introduced, are also prepared in the reaction of (phenylsulfonyl)methyl derivative of Corey's (-)-lactol with bases and epoxys. According to Polish patent PL 149389, hydroxy group in omega chain is then oxidized to ketone, whereas as the result of sulfone elimination, prostaglandin synthones are prepared, having omega chain in the form of 13,14-en-15-one. Use of this strategy for synthesis of PGF _2n derivatives is not practically more adavntageous than analogical method of introducing 13,14-en-15-one in the Wittig's reaction, because it requires stereoselective reduction of carbonyl group and, then, introducing of alpha chain, what is related to the difficulties described above.

The strategy of attachement of alpha chain first and then omega chain is used in PGF _lα and PGD ₂ synthesis from the derivatives of Corey's (-)-lactone (T.K. Schaaf, E. J. Corey, J. Org. Chem. 37 (1972), 2921; E. J. Corey et al., J. Am. Chem. Soc. 93 (1971), 4326; E. J. Corey, K. Shimoji, J. Am. Chem. Soc. 105 (1983), 1662). In this way, in the case of synthesis of PGF derivatives, the 5,6- saturated compounds of 13,14-en-15-one structure are obtained, requiring reduction of ketone group of enone to allyl alcohol of 15R configuration. The above process, in the case of adaption for synthesis of PGF _20I analogues, would be burdened with significant difficulties related to occurrence of 15S isomer and the the need of stereoselective reduction of 13,14-alkene in the presence of 5,6- alkene.

Summary of the invention

Search for stereoselective and practically useful method of preparation of 13,14-dihydro-PGF _2α derivatives lead the present inventors to the attempt of introducing to Corey's (-)-lactone omega chain of target prostaglandin, having formerly generated asymmetry centre at carbon atom substituted by hydroxyl, which process would allow elimination of need for regioselective reduction of enone moiety and separation of undesired regioisomers from the final product. This aim has been realized in the process according to the invention, in which to the starting derivative of Corey's (-)-lactone alpha chain is introduced first, and subsequently, omega chain of target derivative of F _2ce prostaglandin is attached, having chiral centre at carbon atom substituted by hydroxyl. Process acording to the invention provides derivatives of 13,14-dihydro-PGF _2α of high diastereoisomeric excess of desired isomer of R or S configuration, respectively, at carbon atom substituted by hydroxyl. This process especially allows preparation of 13,14-dihydro-15(R)-17-substituted-18,19,20-trinor-PGF _2α derivatives of high diastereoisomeric excess.

The invention provides process for preparation of prostaglandin F _2α derivatives of R or S configuration at carbon atom in omega chain substituted by hydroxyl, of high diastereoisomeric excess, represented by general formula (VIII),

(VIII) wherein:

R represents COOH or COOY, wherein Y is Ci- ₆ -alkyl, alkylphenyl or phenyl, optionally substituted by d- ₃ -alkyl; Z represents H, methyl or phenyl, optionally substituted by d. ₃ -alkyl, C ₁ .

₃ -alkoxy or at least one halogen atom;

R ₃ represents H or hydroxyl protecting group, and n represents an integer from. O to 6, characterized in that (a) anion is generated, at α position in relation to sulfonyl group, from sulfone of formula (V)

OR ₁

(V) wherein

Ri and R ₂ , independently, represent hydroxyl protecting group, Ar represents substituted or unsubstituted aryl or heteroaryl containing at least one heteroatom selected from the group consisting of O, N, P and S atoms, R ₄ is orthoester group represented by the general formula (Va),

( Va ) wherein

R ₅ represents H, substituted or unsubstituted d-Cβ-alkyl or aryl, or R ₄ is -C(ORe) ₃ orthoester group, wherein R ₆ is substituted or unsubstituted

Ci-C ₁₀ -alkyl or aryl; and then

(b) anion is reacted with an alkylating agent of configuration at carbon atom substituted by hydroxyl corresponding to a configuration of a target prostaglandin, of general formula (VI),

(Vl) wherein

LG represents a leaving group; and R ₃ represents a hydroxyl protecting group; or LG and R ₃ represent bonds and, together with -S(O)- or -SO ₂ - group attached to them, form sulfite or sulfate ring; or

LG and R ₃ represent bonds and, together with oxygen atom of OR ₃ , constitute an epoxy ring; and n and Z have the meaning defined for formula (VIII);

(c) compound obtained at step (b) of general formula (VII):

(VII)

wherein:

R ₇ represents R ₄ group defined for formula (V) or R ₇ represents C(=0)- 0R ₈ , wherein Rg represents H, substituted or unsubstituted d-io-alkyl or phenyl, or R ₇ represents -CH ₂ -C(CH ₂ OH) ₂ -R ₅ , Ar, R ₁ -R ₃ , R ₅ , n and Z have the meaning defined above; is reductively desulfonated to give the compound of general formula (Vila):

(Vila)

wherein R ₁ -R ₃ , R ₇ , n and Z have the meaning defined for formula (VII); then

(d) hydroxyl protecting groups are removed, to give the compound of formula (VIIb):

(VIIb)

wherein R ₁ -R ₃ are H, and n, Z and R ₇ have the meaning defined for formula (VII), (e) R ₇ group is converted into R group, to give the compound of formula (VIII),

(VIII) wherein R is COOH, and n and Z have the meaning defined for formula (VII); and

(f) if needed, the compound of formula (VIII), obtained at step (e), is subjected to esterification by the process known per se, leading to the preparation of the compound of formula (VIII), wherein R represents COOY ₅ wherein Y is C _1-6 - alkyl, alkylphenyl or phenyl, optionally substituted by Q- ₃ -alkyl; Z represents H, methyl or phenyl, optionally substituted by C _1-3 -alkyl or Ci-3-alkoxy or at least one halogen atom; and n represents an integer from O to 6.

The invention also provides starting compounds used in the above process, represented by general formula (V)

wherein:

R ₁ and R ₂ , independently, represent H or hydroxyl protecting group;

Ar represents substituted or unsubstituted aryl or heteroaryl containing at least one heteroatom selected from the group consisting of O, N, P and S atoms;

R ₄ is orthoester group defined by general formula (Va),

( Va ) wherein R ₅ represents H, substituted or unsubstituted Cj-C _ό -alkyl or aryl, or

R ₄ is -C(OR _O ) ₃ orthoester group, wherein RQ is substituted or unsubstituted

Q-Qo-alkyl or aryl.

The invention further provides process for preparation of the compound of formula (V)

OR ₁

(V)

wherein

R ₁ and R ₂ , independently, represent H or hydroxyl protecting group, Ar represents substituted or unsubstituted aryl or heteroaryl containing at least one heteroatom selected from the group consisting of O, N, P and S atoms; R ₄ is orthoester group defined by general formula (Va),

( Va )

wherein R ₅ represents H, optionally substituted or unsubstituted C ₁ -C ₆ - alkyl or aryl, or

R ₄ is -C(ORe) ₃ orthoester group, wherein R ₆ is substituted or unsubstituted Ci-Qo-alkyl or aryl, characterized in that

(a) derivative of Corey's (-)-lactone of formula (I)

O

OR ₁

(I) wherein R ₁ is as defined for formula (V), is converted into sulfide of formula (II),

O

OR ₁

(H) wherein R ₁ i Ar have the meaning defined for formula (V),

(b) sulfide obtained at step (a) is selectively oxidized to sulfone o formula (III);

O

OR ₁

("I) wherein R ₁ and Ar have the meaning defined for formula (V);

(c) carbonyl group of sulfone of formula (IH) is reduced and the derivative of lactol of formula (IV) of a proper configuration is isolated,

OR ₁

(IV) wherein R ₁ and Ar have the meaning defined for formula (V);

(d) lactol of formula (IV) is reacted in a Wittig's reaction with the derivative of the compound, which is a precursor of alpha side chain of the target prostagladin, to obtain the compound of formula (V),

(V) wherein R ₂ represents H; R ₁ , R ₄ and Ar have the meaning defined for formula

(V); and

(e) product of Wittig's reaction of formula (V) is isolated and, optionally, the remaining hydroxyl group is protected.

The invention also provides novel compounds which are precursors of a synthone of omega side chain of PGF _2α , of R or S configuration at carbon atom substituted by hydroxyl, represented by the general formula (VI)

(Vl) wherein

LG represents halogen atom, alkyl-, alkylaryl- or arylsulfonyloxy group; R ₃ represents H or a hydroxyl protecting group; or

LG and R ₃ represent bonds and, together with -S(O)- or -SO ₂ - group atttached to them, form sulfite or sulfate ring; or

LG and R ₃ represent bonds and, together with oxygen atom of OR ₃ group, constitute an epoxy ring;

Z represents H, methyl or phenyl, optionally substituted by C _1-3 -alkyl, C ₁ . ₃ -alkoxy or at least one halogen atom; and n represents an integer from O to 6.

Preferred starting compounds of formula (VI) are those, in which LG represents iodine or bromine atom or p-toluenesulfonyloxy group, and R ₃ represents a hydroxyl protecting group, which compounds have S configuration at carbon atom substituted by hydroxyl.

The invention also provides processes for preparation of the compounds of general formula (VI), of R or S configuration at carbon atom substituted by hydroxyl, especially compounds (VI) of high enantiomeric excess.

Another aspect of the invention are intermediates prepared in consecutive steps of the process for preparation of 13,14-dihydroxy-derivatives of PGF _2α according to the invention.

One group of novel compounds are those represented by general formula (VII)

(VII)

wherein

R ₁ , R ₂ and R ₃ , independently, represent hydroxyl protecting groups, Ar represents substituted or unsubstituted aryl or heteroaryl containing at least one heteroatom selected from a group comprising oxygen, nitrogen, phosphorus and sulfur,

R ₇ represents R ₄ group, which is orthoester group, defined by general formula (Va),

( Va ) wherein R ₅ represents H, substituted or unsubstituted Ci-C ₆ -alkyl or aryl, or

R ₄ is -C(ORe) ₃ orthoester group, wherein Rg is a substituted or unsubstituted Q-Cio-alkyl or aryl; or

R ₇ is C(=O)-ORg group, wherein R ₈ represents hydrogen atom, substituted or unsubstituted C ₁ -C ₁₀ alkyl, phenyl or -CH ₂ -C-(CH ₂ OH) ₂ -R ₅ group and

R ₅ has the meaning defined above;

Z represents H, methyl or phenyl, optionally substituted by Q-3-alkyl, C ₁ .

₃ -alkoxy or at least one halogen atom; n represents an integer from 0 to 6. Another group of novel compounds are those represented by general formula (Vila)

(Vila) wherein:

Ri ₅ R ₂ and R ₃ , independently, represent H or hydroxyl protecting group, Ar represents substituted or unsubstituted aryl or heteroaryl containing at least one heteroatom selected from a group comprising oxygen, nitrogen, phosphorus and sulfur,

R ₇ represents R ₄ group, which is orthoester group, defined by general formula (Va),

( Va ) wherein R ₅ represents H, substituted or unsubstituted Ci-Cβ-alkyl or aryl, or

R ₄ is -C(OR _O ) ₃ orthoester group, wherein R ₆ is substituted or unsubstituted Ci-Cio-alkyl or aryl; or R ₇ is C(=O)-OR ₈ group, whrein R ₈ represents hydrogen atom, substituted or unsubstituted Ci-C ₁ O alkyl, phenyl or -CH ₂ -C-(CH ₂ OH)-R ₅ group, and R ₅ has the meaning defined above;

Z represents H, methyl or phenyl, optionally substituted by Ci- ₃ -alkyl, C ₁ . ₃ -alkoxy or at least one halogen atom; and n represents an integer from 0 to 6.

Brief description of the figures

Fig. 3 presents the general route of the process for preparation of of 13,14- dihydro-PGF _2α derivatives according to the invention, by example of latanoprost, ie. 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF _2α isopropyl ester.

Fig. 4 presents the synthesis of latanoprost with use of starting compound of formula (V), wherein R ₄ is orthoester group (OBO) is presented.

Detailed description of the invention

Starting compound in the process for preparation of derivatives of 13,14- dihydro-F2 _α prostaglandins, is sulfone of general formula (V)

OR ₁ (V) wherein

Ri and R ₂ , independently, represent H or hydroxyl protecting group; Ar represents substituted or unsubstituted aryl or heteroaryl containing at least one heteroatom selected from the group consisting of O, N, P and S atoms; R ₄ is orthoester group defined by general formula (Va),

( Va ) wherein

R5 represents H, substituted or unsubstituted Q-Co-alkyl or aryl, or R ₄ is -C(OR _O ) ₃ orthoester group, wherein R ₆ is substituted or unsubstituted

Ci-do-alkyl or aryl.

The term "aryl" used hereby with reference to Ar group means phenyl group, naphthyl group or 9,10-methaneanthracen-(10H)-yl group, each of them may be optionally substituted by one or more of the following substituents: halogen, C^-alkyl or alkoxyl.

The term "heteroaryl" used hereby with reference to Ax group means aromatic five- or six-membered group, containing at least one heteroatom selected from the group including oxygen, phosphorus and sulfur, such as thienyl, furanyl, pyrrolil, pyridinyl, pyridazil, quinolinyl, indolyl, imidazolyl, oxazolyl, izoxazolyl, benzofuranyl, benzo[b]thienyl and the like.

The term "alkyl group" used hereby, unless otherwise specified, means streight or branched hydrocarbon group, containing detailed number of carbon atoms.

Unless otherwise specified, each alkyl group, aryl group or heteroaryl group may be optionally substituted by one or more of the following substituents: halogen, C _1-4 -alkyl, C _1-4 -alkoxyl or nitro group.

Hydroxy groups in the starting compound (V) are protected by introduction of protecting groups, which may be the same or different.

Introduction and removing of groups protecting hydroxy groups of alcohols is well known in the art of organic synthesis (T. W. Greene, P.G.M. Wuts "Protective Groups in Organic Synthesis", ed. 3, John Wiley and Sons, Inc., New York, NY, 1999; PJ. Kocienski "Protecting Groups", Georg Thieme Verlag, Stuttgart, 1994; J. March, Advanced Organic Chemistry'', John Wiley and Sons, New York, NY, 1982).

IQ the process of the invention, typical protecting groups are independently used, of sufficient stability in the presence of bases and acids, such as alkyl- or arylsilyl groups, alkyl- and arylcarbonyl groups (ester groups); acyl groups; alkylaminocarbonyl (carbamate) groups; alkyl groups; alkoxy groups and other. Silyl groups are trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilyl groups, such as, for example, trimethylsilyl, tiethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl. Acyl groups include alkanoyl groups and carboxyalkanoyl groups, having 1 to 6 carbon atoms, such as acetate group. Typical alkoxyalkyl groups are, for example, methoxymethyl, ethoxymethyl, tetrahydrofuranyl and tetrahydropyranyl.

Carboxyl group in the starting compound (V) is protected, for example, in the form of orthoester group or oxabicyclo[2.2.2]octane group (OBO).

Use of orthoesters and oxabicyclo[2.2.2]octane group as protecting carboxyl group is discussed in the monograph of T.W. Greene, P.G.M. Wuts "Protective Groups in Organic Synthesis", 3 ed., John Wiley and Sons, Inc. New York, NY, 1999; chapter V, and in the publication of U. Pindur; J. Mueller, C. FiIo, H. Witzell Chem. Soc. Rev. 1987, 75. However, there are few examples of oxabicycleoctane group use in the art of prostaglandin synthesis (G. H. Verdoorn et al. South African Journal of Chemistry 40 (1987), 134-8; E. J. Corey, X. -M. Cheng "The Logic of Chemical Synthesis" John Wiley and Sons, Inc., New York, NY, 1989; chapter XI), due to limited stability of oxabicyclooctane moiety in acidic conditions. Compounds of 4-methyl-2,6,7-trioxabicyclo[2.2.2]octane structure easily hydrolyze to corresponding esters of 2,2-bis(hydroxymethyl)-l- propyl, which may be then converted into other esters, for example, alkyl esters, into salts of corresponding acids or into corresponding carboxylic acids (P. J. Kocienski "Protecting Groups", Georg Thienie Verlag, Stuttgart, 1994; T. W. Greene, P. G. M. Wuts "Protective Groups in Organic Synthesis", 3 ^rd ed., John Wiley and Sons, Inc., New York, NY, 1999; J. March "advanced Organic Chemistry" John Wiley and Sons, New York, NY, 1992). In the suitably selected conditions, 4-alkyl-2,6,7-trioxabicyclo[2.2.2]octane groups and other orthoesters are very useful carboxyl protecting groups, especially in the basic conditions.

Methods of alkylation of compound containing active methylene groups, such as (arylsulfonyl)methyl group, with use of alkyl sulfonates or alkyl halides, are discussed, for example, in the moograph of H. O. House "Modern Synthetic

Reactions", W. A. Benjamin, Inc., Menlo Park, CA, USA, 1972; Chapter 9. Activation of such group (generation of stabilized carbanion -CH-SO ₂ -Ar) is known in the art and proceeds under influence of bases: P.E. Magnus, Tetrahedron 33 (1977), 2019; B.M. Trost Bull. Chem. Soc. Jpn. 61 (1988), 107; N. S. Simpkins Tetrahedron 46 (1990), 6951. Bases used for generating carbanions stabilized by (arylsulfonyl)methyl group are, for example, butyllithium or lithium hexamethyldisilazide (lithium bis(trimethylsilyl)amide (LiHMDS), Me ₃ -Si-N(Li)-Si-Me ₃ , cited, for example, in I. R. Baldwin, R. J. Whitby Chem. Commun. (2003), 2786-2787. In a preferred embodiment of the invention, sulfone anion of formula (V) is generated in situ, with use of strong organic base, for example, metal bis(trimethylsilyl)amide, preferably lithium bis(trimethylsilyl)amide, in nonaqueous solvent.

Activation of sulfone (V) allows its effective alkylation with use of alkylating agent of R or S configuration at carbon atom substituted by hydroxyl, of general formula (VI)

(Vl) wherein LG represents halogen atom, alkyl-, alkylaryl- or arylsulfonyloxy group;

R ₃ represents H or a hydroxyl protecting group; or

LG and R ₃ represent bonds and, together with -S(O)- or -SO ₂ - group atttached to them, form sulfite or sulfate ring; or

LG and R ₃ represent bonds and, together with oxygen atom of OR ₃ group, constitute an epoxy ring;

Z represents H, methyl or phenyl, optionally substituted by C _1-3 -alkyl, C _1-3 - alkoxy or at least one halogen atom; and n represents an integer from 0 to 6.

Good LG leaving group in the compound (VI) may be halogen atom, such as iodine, bromine, chlorine, fluorine; alkyl- alkylaryl- or arylsulfonyl group, such as benzenesulfonyl, p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, alkylsulfonyl, substituted alkylsulfonyl, naphthylsulfonyl, substituted phenylsulfonyl, chlorosulfonyl, substituted naphthylsulfonyl or another group easily leaving with electron pair, such as, for example, oxygen atom of epoxy ring.

In the alkylation reaction in step (b), the compound (VI) is used, of R or S configuration at carbon atom substituted by hydroxyl, corresponding to configuration of a derivative of target prostaglandin of formula (VIII), of high enantiomeric excess (defined accorrding to the definition in the monograph of E. L. Eliel; S. H. Wilen; L. N. Mander "Stereochemistry of Organic Compounds" John Wiley and Sons, Inc. Preferably, the compound (VI) of enantiomeric excess above 99% is used, more preferably, above 99.5%.

In the process according to the invention, preferred alkylating agents are those, in which LG represents iodine atom, bromine atom or p-toluenesulfonyloxy group, and R ₃ represents a hydroxyl protecting group.

Preferably, in the compounds (VI) R ₃ group is Si(R) ₉ (R ₁ O)(Rn), wherein R ₉ -Rπ are the same or different and represent Ci-C ₆ -alkyl or phenyl.

As a result of alkylation in step (b), the compound of (R) or (S) configuration at carbon atom substituted by hydroxyl is obtained, represented by general formula (VII)

(VII) wherein

R ₁ , R ₂ and R ₃ , independently, represent hydroxyl protecting groups, Ar represents substituted or unsubstituted aryl or heteroaryl containing at least one heteroatom selected from a group including oxygen, nitrogen, phosphorus and sulfur,

R ₇ represents R ₄ group, which is orthoester group, defined by general formula (Va),

( Va ) wherein R ₅ represents H, substituted or unsubstituted Ci-C ₆ -alkyl or aryl, or

R ₄ is -C(ORe) ₃ orthoester group, wherein R ₆ is a substituted or unsubstituted Cj-Ci _O -alkyl or aryl; or R ₇ is group, wherein R ₈ represents hydrogen atom, substituted or unsubstituted C ₁ -Ci _O alkyl, phenyl or -CH ₂ -C-(CH ₂ OH) ₂ -R ₅ group and R ₅ has the meaning defined above;

Z represents H, methyl or phenyl, optionally substituted by C^-alky! or d-3-alkoxy or ate least one halogen atom; n represents 0-6 integer.

In the step (c), the compound of formula (VIII) is subjected to the reaction of selective desulfonation, to obtain the compound of general formula (Vila)

(Vila) wherein: R ₁ , R ₂ and R ₃ , independently, represent H or hydroxyl protecting group,

Ar represents substituted or unsubstituted aryl or heteroaryl containing at least one heteroatom selected from a group comprising oxygen, nitrogen, phosphorus and sulfur,

R ₇ represents R ₄ group, which is orthoester group, defined by general formula (Va),

( Va )

wherein R ₅ represents H, substituted or unsubstituted d-Cg-alkyl or aryl, or

R ₄ is -C(OR _O ) ₃ orthoester group, wherein R ₆ is substituted or unsubstituted Ci-Qo-alkyl or aryl; or

R ₇ is group, whrein R ₈ represents hydrogen atom, substituted or unsubstituted C ₁ -C ₁₀ alkyl, phenyl or -CH ₂ -C-(CH ₂ OH)-R ₅ group, and

R ₅ has the meaning defined above;

Z represents H, methyl or phenyl, optionally substituted by Cμ ₃ -alkyl or C _1-3 -alkoxy or at least one halogen atom; and n represents 0-6 integer. Arylsulfonate group may be reductively removed from sustituted

(arylsulfbnyl)alkanes in various conditions, depending on starting compound structure (Y. Liu, Y. Zhang, Org. Prep. Proc. Int. 33 (2001), 372). Among methods of more general meaning, reduction with use of metals dissolved in liquid ammonia should be mentioned (eg. J.R. Hwu et al., J. Org. Chem. 61 (1996), 1493-1499); reduction with use of Mg / MeOH or Mg / EtOH+HgCl ₂ (G. H. Lee et al., Tetrahedron Lett. 34 (1993), 4541-2; A. C. Brown, L. A. Carpino, J. Org. Chem. 50 (1985), 1749-50), and reduction with use of sodium amalgam in MeOH in Na ₂ HPO ₄ buffering conditions (B. M. Trost et al., Tetrahedron Lett. 17 (1976), 3477-8). In the reactions of reductive desulfonation, by-products of structure of alkene, which is a product of elimination of ArS(O)OH, may be generated. (B. M. Trost et al., Tetrahedron Lett. 17 (1976), 3477-8).

In the preferred embodiment of the invention, reductive desulfonation is carried out with use of sodium amalgam (Na/Hg).

In step (d), hydroxy groups of the thus obtained compound (Vila) are deprotected, by the method known to those skilled in the art, to give the compound of formula (VIIb)

(VIIb) wherein the meaning of R ₇ , Z and n was defined above for the compound (VII).

Deprotection of hydroxy groups is carried out, depending on type of protecting groups used, in acidic or basic conditions. The silyl groups are removed, for example, in acidic conditions by the use of protonic acids solutions or their salts with organic bases, in organic solvents, such as THF or acetone, optionally in the presence of water.

Removing of hydroxyl protecting groups in acidic conditions in the process according to the invention is accompanied by hydrolysis of orthoester or ester (R ₇ ) group to carboxyl group.

If needed, protecting group from R ₇ substituent maybe removed in step (e) by use of strong base solution, for example, lithium hydroxide in the mixture of solvents, such as methanol, ethanol, THF, dioxane or water.

As a result of the reactions carried out, in the process of the invention, 13,14-dihydro-PGF _2α represented by formula (VIII), is prepared

(VIII) wherein R represents COOH, R ₃ is H and Z has the above defined meaning, characterized by high diastereomeric excess (defined according to the monograph of E. L. Eliel; S. H. Wilen; L. N. Mander "Stereochemistry of Organic

Compounds" John Wiley and Sons, Inc., New York, NY, 1994), exceeding 99%, preferably exceeding 99.5%.

Then, a carboxyl group of thus obtained compound (VIII) is esterified, to give the compound (VIII), in which Y represents Ci-6-alkyl, alkylphenyl or phenyl, optionally substituted by Ci _-3 -alkyl groups; Z represents H, methyl or phenyl, optionally substituted by Ci-3-alkyl groups or C _1-3 -alkoxy groups or ate least one halogen atom; and n represents 0-6 integer.

Steps (e) and (f) according to the invention may be carried out simultaneously, if a salt of an acid of formula (VIII), wherein Y represents metal cation or quaternary ammonium cation, is used directly for the reaction with the esterifying agent.

Esterification reaction is carried out according to the method known for those skilled in the art of chemistry of PGF _2α derivatives, for example, according to the method described in the publication of B. Resul et al., J. Med. Chem. 36 (1993), 243-248 or in International Patent publications WO 92/02496; WO 93/00329; WO 01/55101; WO 01/87816; WO 02/096868. Typical esterifying agents are alkyl or phenyl halides and sulfonates. The reaction is carried out in non-aqueous solvents, preferably in aprotic non-aqueous solvents.

Process according to the invention allows preparation of PGF ₂₀₁ derivatives of high diastereomeric excess of a desired isomer of R or S configuration at carbon atom substituted by hydroxyl in omega chain, by the method including addition synthone of alpha chain first, and then synthone of omega chain, to synthone derivative of Corey's (-)-lactone. Optical purity of the product obtained depends on optical purity of compound of formula (VI), used in the process. In the preferred embodiment the process according to the invention is employed for preparation of latanoprost of high diastereomeric excess and advantageous profile of by-products and impurietes. Contrary to processes knonw in the art, purification of latanoprost prepared in the process according to the invention is relatively simple, due to very low content of undesired 15S, 5,6Z diasteroisomer of latanoprost, which depends on controllable degree of optical purity of compounds of formula (VI). In this way, difficulties related to use of preparative HPLC are avoided.

In the process according to the invention, starting compounds of formula (V)

wherein

R ₁ and R ₂ , independently, represent H or hydroxyl protecting group; Ar represents substituted or unsubstituted aryl or heteroaryl containing at least one heteroatom selected from the group comprising oxygen, nitrogen, phosphorus and sulfur; R ₄ is orthoester group defined by general formula (Va),

^{( Va )} wherein

R ₅ represents H, optionally substituted or unsubstituted Q-Cβ-alkyl or aryl, or

R ₄ is -C(ORe) ₃ orthoester group wherein R ₆ is substituted or unsubstituted C ₁ - C ₁₀ -alkyl or aryl, are prepared from Corey's (-)-lactone protected derivatives.

Process for preparation of compounds of formula (V) is characetrized in that:

(a) derivative of Corey's (-)-lactone of formula (I)

OR ₁

(I) wherein R ₁ is as defined for formula (V), is converted into sulfide of formula (II),

OR ₁ (II) wherein R ₁ i Ar have the meaning defined for formula (V),

(b) sulfide of step (a) is selectively oxidized to sulfone o formula (III);

OR ₁

(III) wherein R ₁ and Ar have the meaning defined for formula (V);

(b) carbonyl group of sulfone of formula (III) is reduced and the proper derivative of lactol of formula (IV) is isolated,

OR ₁

(IV) wherein Rj and Ar have the meaning defined for formula (V);

(c) lactol of formula (IV) is reacted in a Wittig's reaction with the derivative of the compound, which is a precursor of alpha side chain of the target prostagladin, to obtain the compound of formula (V),

OR ₁

(V) wherein R ₂ represents H; R ₁ , R ₄ and Ar have the meaning defined for formula

(V); and

(d) the product of Wittig's reaction of formula (V) is isolated and, optionally, the remaining hydroxyl group is protected.

Starting derivatives of Corey's (-)-lactone of general formula (I)

OR ₁

(D wherein Ri is as defined for formula (V), are commercially available or may be obtained by the methods described, for example, in the monograph of E. J. Corey, X-M. Cheng "The Logic of Chemical" John Wiley and Sons, Inc., New York, NY, 1989; chapter XI, and in the publication of E. J. Corey, Angew. Chem. Int. Ed. Engl. 30, (1991), 455.

These compounds may be converted into sulfides of formula (II)

OR ₁

(H) wherein Ri and Ar have the above defined meaning, in the reaction of nucleophilic substitution, allowing the interconversion of primary hydroxyl group of the compound (I) for leaving group LG. Conveniently, this reaction is carried out in Mitsunobu reaction conditions (Mitsunobu, O. Synthesis 1981, 1), consisting in activation of hydroxyl by dialkyl diazocarboxylate in the presence of PPh ₃ or Bu ₃ P. In these conditions, addition of suitable thiophenol results in sulfide forming (D. J. Cundy et al. Org. Prep. Proc. Ml. 32 (2000), 461, P. R. Blakemore et al. Synlett 1998, 26). In order to convert primary alcohol into aryl sulfide, the conditions which do not require participation of diazocaboxylate are also used, for example, PhSSPh/Bu ₃ P/C ₅ H ₅ N (H. Miayaoka et al., Tetrahedron Lett. 42 (2001), 9233).

Oxidation of sulfides to sulfones (K. R. Guertin, A. S. Kende, Tetrahedron Lett. 34 (1993), 5369 and cited references) is a convertion often used in organic synthesis due to great usefulness of sulfone in the synthesis (P. E. Magnus, Tetrahedron 33 (1977), 2019; B.M. Trost Bull. Chem. Soc. Jpn. 61 (1988), 107; N. S. Simpkins, Tetrahedron 46 (1990), 6951). Suitable oxidizing agents are, for example, organic peracids (J. Lamsa, FR 2604707); V. Meladinis et al., Zeitschrift fur Naturforschung, B: Chemical Sciences 44 (1989), 1453: M,-Y. Chen et al., Journal of Organic Chemistry 69 (2004) 2884; M. Therien, Synthesis 2001, 1778). In a preferred embodiment of the invention, oxidation step is carried out in a two- phase system: organic solvent non-miscible with water / water, using magnesium monoperoxyphatalate in anhydrous or hydrate form.

Preferably, oxidation reaction, according to the invention, is carried out in water / methylene chloride medium, in the temperature range of 0-40 ⁰ C.

Such conditions of oxidation reaction eliminate the need for catalysts use and allow easy isolation of product by simple separation of phases after the reaction.

Reduction of lactones to Iactols (cyclic hemiacetals of aldehydes) may be carried out, for example, with use of alkyl aluminium hydrides, such as diisobutyl aluminum hydride (i-Bu) ₂ AlH (DEBAL, DIBAL-H). Use of this reagent for reduction of lactones is widely documented in the art of prostaglandin chemistry, especially in Corey's method (E. J. Corey, X.-M. Cheng "The Logic of Chemical Synthesis" John Wiley and Sons, Inc., New York, NY, 1989; chapter XI).

Properties of the compounds (II) and the reaction conditions used allow preparation of Iactols of gneral formula (IV)

OR ₁

(IV)

to which alpha chain of the target derivative of prostaglandin F _2α is introduced, for example, in the typical reaction of Wittig's type, with use, eg. quaternary phosphonium salts.

Quaternary phosphonium salts used as reagents in Wittig's reaction are suitable alkylphosphonium halides, such as bromide, iodide or chloride. Mechanism and compounds used in Wittig's reaction are generally known. For example, reaction of [4'-[4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-l- yl)butyl]triphenylphosphonium bromide with aldehydes is described in: G. H. Verdoorn et al., South African Journal of Chemistry 40 (1987), 134-8. [4-Methyl-2,6,7-trioxabicyclo[2.2.2]oct-l-yl)butyl]triphenyl phosphonium iodide has not been described in the prior art. Synthesis of the potentially useful starting compound for synthesis of this Wittig's salt, l-(4'-iodobutyl)-4-methyl- 2,6,7-trioxabicyclo[2,2,2]octane, is described in US 5,538,995. Preparation of quaternary phosphonium salts useful for Wittig's reaction is usually based on the reaction of triphenylphosphine with alkyl halide (A. Maeycker, Organic reactions, Wiley, New York, NY, 1965, torn 14, p. 270). Reaction of alkyl iodides of complex structure with triphenylphosphine resulting in quaternary phosphonium salts proceeds especially easily in the presence of sulfolane ((LA. Secrist III, S.R. Wu J. Org. Chem. 44 (1979) 1434). Wittig's reaction of aldehydes and ylides uncoupled with electron accepting groups, carried out without excess of lithium salts, magnesium salts or salts of other metal of Lewis acid character, results exclusively or with high excess in formation of alkens of Z configuration (E. L. Eliel; S. H. Wilen; L.N. Mander ,,Stereochemistry of Organic Compounds" John Wiley and Sons, Inc., New York, NY, 1994; Chapter 9 and Chapter 12). Wittig's reaction of phosphonium salts with γ-hydroxy-aldehydes or their equivalents, which are five-

membered lactols, is described, among others, in the case of prostaglandins (H.O. House ,,Modern Synthetic Reactions", W.A. Benjamin, Inc., Menlo Park, CA ₃ USA, 1972; E. J.Corey, X.-M.Cheng ,,The Logic of Chemical Synthesis", John Wiley and Sons, Inc., New York, NY, 1989; chapter XI). In such reactions, for generation of anion (ylide) bases are used, such as potassium t-butanolate (t- BuOK), butyllithium (BuLi), lithium hexamethylsilazide (LiHMDS), dimsilate anion, tertiary amines.

In the preferred embodiment of the invention, Wittig's reaction is carried out in the presence of aluminium organo-compounds, preferably in the presence of Al Ct-BuO) ₃ .

Use of aluminum organo-compounds, such as Al Ct-BuO) ₃ , in the reactions of this type, has not been described in the prior art. However, high chemical affinity of many aluminium(III) salts for oxygen atoms present in organic compounds molecules is known (H. Yamarnoto ,,Organoaluminum Compounds", in: M. Schlosser, ed.: ,,Organometallics in Synthesis", John Wiley and Sons, New

York, NY, 1994; Chapter 7), as well as strong basic character of tert-BuO ^' ion

(H.O. House ,,Modern Synthetic Reactions", W.A. Benjamin, Inc., Menlo Park,

CA, USA, 1972; J. March ,,Advanced Organic Chemistry" John Wiley and Sons,

New York, NY, 1992), on which the concept of their use in the synthesis according to the invention is based.

Essential for the course of preparation of PGF _2α and especially for purification of the final product is the use of the compound (VI) of high enantiomeric purity for the reaction with Corey's (-)-lactone.

Compounds (VI), of R or S configuration at carbon atom substituted by hydroxyl, represented by the general formula (VI):

(Vl) wherein

LG represents halogen atom, alkyl-, alkylaryl- or arylsulfonyloxy group;

R ₃ represents H or a hydroxyl protecting group; or

LG and R ₃ represent bonds and, together with -S(O)- or -SO ₂ - group attached to them, form sulfite or sulfate ring; or LG and R3 are bonds and, together with oxygen atom of OR ₃ group, constitute an epoxy ring;

Z represents H, methyl or phenyl, optionally substituted by d- ₃ -alkyl, Ci-

₃ -alkoxy or at least one halogen atom; and n represents an integer from 0 to 6, are prepared in a process characterized in that:

(a) a primary hydroxyl group of a corresponding (2S)- or (2i?)-4-phenyl-l,2- alkyldiol of formula 0H-CH-CH(0H)-(CH ₂ ) _n -Z, wherein n and Z have the meaning defined for formula (VI), is converted selectively into ArSO ₂ O- group, wherein Ar represents substituted or unsubstituted aryl or heteroaryl, to obtain the compound of formula (VI), wherein LG represents substituted or unsubstituted aryl or heteroaryl,

(b) secondary hydroxyl group of the compound (VI) obtained at step (a) is protected by introducing of R ₃ protecting group,

(c) ArSO ₂ O- group of compound (VI) is substituted by halogen atom, to obtain the compound (VI), wherein LG is halogen atom,

(d) the compound (VI), wherein LG represents halogen atom or ArSO ₂ O- group, and R ₃ represents protecting group, is converted into the compound (VI), wherein LG and OR ₃ together form cyclic epoxy ring, or, optionally,

(e) (2S)- or (2i?)-4-phenyl- 1 ,2-alkyldiol of formula 0H-CH-CH(0H)-(CH ₂ ) _n - Z, wherein n and Z have the meaning defined for formula (VI), is converted into the compound (VI) ₅ wherein LG and R ₃ form a sulfite (S(O)-) ring, and then, optionally,

(f) the compound (VI) of step (e) is oxidized to the compound (VI), wherein LG and R ₃ form a sulfate (-S(O ₂ )-) ring, and, optionally,

(g) hydroxyl group is protected. Oxidation in step (f) may be carried out with use of strong inorganic oxidizing agent, such as NaIO ₄ ZRuCl ₃ .

Optionally, cyclic sulfate may be prepared directly in the reaction of 2(S)- or 2(R)-phenyl-l ,2-alkyldiol with sulfuryl chloride.

Alternative process for preparation of the compound of R or S configuration at carbon atom substituted by hydroxyl, of general formula (VI)

(Vl) wherein

LG represents halogen atom, alkyl-, alkylaryl- or arylsulfonyloxy;

R ₃ represents a hydroxyl protecting group; or

LG and R ₃ represent bonds and, together with -S(O)- or SO ₂ - group attached to them, form sulfite or sulfate ring; or

LG and R ₃ represent bonds and, together with oxygen atom of OR ₃ group, constitute an epoxy ring; Z represents H, methyl or phenyl, optionally substituted b

₃ -alkoxy or at least one halogen atom; and n represents an integer from 0 to 6, is characterized in that:

(a) a derivative of D- or L-glyceric aldehyde of formul CHO, wherein Ri and R ₂ represent a hydroxyl protecting group or together constitute a fragment of dioxolane ring, is reacted in a Wittig's reaction with tertiary phosphonium salt of formul wherein Z and n have the meaning defined for formula (VI), and X^ represents bromide, iodide or chloride anion,

(b) alken obtained in step (a) is hydrogenated,

(c) hydroxyl protecting groups are removed, to obtain a derivative of 1,2-diol, (d) primary hydroxyl group of (2S)- or (2i?)-4-ρhenyl-l,2-alkyl-diol of formula

OH-CH-CH(OH)-(CH ₂ ) _n -Z ₅ wherein n and Z have the meaning defined for formula (VT), obtained at step (b) or (c), is converted into ArSO ₂ O-, Cl-

SO-O- or Cl-SO ₂ -O- group, wherein Ar represents aryl or heteroaryl,

(e) secondary hydroxyl group of the compound prepared in step (d) is protected, and, optionally,

(f) ArSO ₂ O- group is substituted by halogen atom.

Process for preparation of the preferred compound of S configuration, of formula (VI), wherein n=2, and Z represents phenyl, being a valuable starting compound in the process of latanoprost preparation according to the invention, is illustrated by scheme:

Ph

ArSO ₂ OH

( VI)

Using of 2(S)-4-ρhenyl-l,2-butanediol of enantiomeric excess above 99%, preferably above 99.5%, as the starting compound in the above process, provides compounds (Vi) useful for latanoprost preparation.

Generally, derivatives of terminal 1,2-diols of high degree of optical purity are prepared, for example, in the reaction of asymmetrical dihydroxylation of terminal alkenes (H. Becker, K.B. Sharpless, Angew, Chem. Int. Ed. Engl. 35 (1996), 448-450; TJ. Hodgkinson, M. Shipman, Synthesis 1998, 1141-1144; H. C. KoIb et al., Chem. Rev. 94 (1994)). Synthesis of (2R)-l,2-dihydroxy-4- phenylbutane of ee=84% enantiomeric excess, with use of (DHQD) ₂ PHAL catalyst, is described in Z.-M. Wang et al., Tetrahedron Lett. 34 (1993), 2267- 2270. Preparation of non-racemic (2S)-l,2-dihydroxy-4-phenylbutane is also described in: J. Hasegawa at al., Agric. Biol. Chem. 54 (1990), 1819-1827; T. Tsujigami at al., Tetrahedron: Asymmetry 12 (2001), 2543-2549; B.P. Branchaud, H.S. Blanchette, Tetrahedron Lett. 43 (2002), 351-353; T. Ishida at al., Adv. Synth. Catal. 345 (2003), 576-579; M. Rezaei at al., Tetrahedron Lett. 44 (2003), 7513-7516.

Optically active 2,3-O-isopropylidene-D-glyceric aldehyde, starting compound in one of variants of the synthesis of the compounds (VI), may be prepared in the process described in C. R. Schmid et al., Organic Syntheses, Coll. Vol. 9 (1998), 450, from easily available .D-mannitol, which is first convereted into bis-acetonide, and then into 2,3-O-isoproρylidene-Z>-glyceric aldehyde, by use of sodium periodate. 2,3-Isoρropylidene-Z>-glyceric aldehyde may be used as chiral synthone of 1,2-diol in the reaction of chain extension. One method of the extension of chain of defined functionalization and stereochemistry is Wittig's reaction of functionalized aliphatic aldehydes with ylides prepared from

alkyltriphenylfosphonim salts. It results in the formation of alkene, often in the form of mixture of E and Z isomers, which may be then further reacted, for example, in hydrogenation reaction on palladium catalyst (H. O. House "Modern Synthetic Reactions", W.A. Benjamin, Inc., Menlo Park, CA, USA, 1972), to give alkanes of longer carbon chain with mainatenance of substitutents which are primarily attached to starting alkyl chain of aldehyde. Use of such process for synthesis of non-racemic (2<S)-l,2-dihydroxy-4-phenylbutane is described in the publications of J. Hasegawa et al., Agric. Biol. Chem., 54 (1990); M. Rezaei et al., Tetrahedron Lett 44 (2003), 7513-7516. 1,2-O-isopropylidene derivatives easily hydrolize, for example, in the presence of protonic acids (T. W. Greene, P. G. M. Wuts "Protective Groups in Organic Synthesis", 3 ^rd ed., John Wiley and Sons, Inc., New York, NY, 1999), resulting in 1,2-diols formation with good yield.

1,2-Diol thus prepared is reacted with thionyl chloride or with sulfuryl chloride with formation of cyclic sulfite or sulfate, respectively (H. C. KoIb et al., Chem. Rev. 94 (1994) and cited references). Optionally, cyclic sulfate is prepared in the process of oxidation of cyclic sulfate.

1,2-Diol of high enantiomeric excess is then converted into alkylating agent of formula (VI), wherein LG represents a good leaving group. Good leaving groups are, for example, sulfonate groups and halogen atoms (J. March "Advanced Organic Chemistry", John Wiley and Sons, New York, NY, 1992; H. O. House "Modern Synthetic Reactions", W. A. Benjamin, Inc., Menlo Park, CA, USA, 1972), especially if they are attached directly to methylene group of small steric hindrance. Both primary halides and primary alkyl sulfonates easily react in nucleophilic substitution reactions, ha the same publications processes for convertion of sulfonates into corresponding iodides or bromides are described.

However, preparation of (S)-2-hydroxy-4-phenylbutyl 4- mehtylbenzenesulfonate from 2(S)-l,2-epoxy-3-p-toluenesulfonyloxypropane in the reaction of substitution by benzyl anion, described by J. M. Klunder et al., J.

Org. Chem. 54 (1989), 1295-1304), usually results in formation of compounds of low enantiomeric excess (ee= 94%, 3% of isomer 3(R).

Process according to the invention allows preparation of 3(»S}-l-ρhenyl-3- hydroxy-4-p-toluenesulfonyloxybutane of very high enantiomeric excess, when starting 2(»S)-4-phenyl-l,2-butanediol of high optical purity (ee> 99%) is used.

Conversion of 2-hydroxy-l-sulfonyloxyalkanes into primary alkyl halides in the presence of a base is accompanied by the reaction of formation of 1,2- epoxys, which may be also useful as alkylating agents (H. C. KoIb et al., Chem. Rev. 94 (1994); B. Achmatowiczet al., J. Chem. Soc. Chem. Commun. (1987), 1226-8). However, this reaction may be avoided, after prior introduction of 2- hydroxyl protecting group, eg. O-silyl group.

The following examples are provided to illustrate the invention. The examples are not meant to limit the scope of the invention as defined in the claims.

Examples As starting compound, protected Corey's (-)-lactone, (3aR,4S,5R,6aS)-4- hydroxymethyl-5-triethylsilyloxy-hexahydrocyclopenta[b]furan -2-one was used, available from Pharma Tech International Inc.: [α] _D = (-)47.5° (CHCl ₃ , 2O ⁰ C, c= 1); ¹ H-NMR (CDCl ₃ ; 200 MHz) δ 0.59 (6H, q, 8Hz), 0.95 (9H, t, 8Hz), 2.00 (3H, m), 2.28 (IH ₃ m), 2.54 (IH, dd: 16.7, 1.8Hz), 2.74 (2H, m), 3.60 (2H ₅ bd: 5.8 Hz), 4.13 (IH, q, 5.7 Hz), 4.93 (IH, ddd: 7.0, 7.0, 2.8 Hz); ¹³ C-NMR (CDCl ₃ ; 50 MHz) δ 4.7 (3C), 6.7 (3C) ₅ 35.4, 38.8, 41.0, 56.2, 62.7, 74.6, 83.5, 177.1.

Example 1

φhenylthio)methyl-5-

(Methylsilyloxy)hexahydrocyclopenta[&]furan-2-one

ydroxymethyl-5-(triethylsilyloxy)- hexahydrocyclopenta[6]furan-2-one (11.45 g, 40.0 mM) was dissolved in anhydrou L). Then, anhydrous tetrahydrofurane (20 niL) and Ph ₃ P (13,l,g, 50 Mm) were added and stirred at room temperature. After dissolution, the reaction mixture was coolled to +15°C and PhSH was added (5.51 g, 5.15 mL, 50 mM). After stirring for 5 minutes, solution of diisopropyl diazocarboxylate (DIAD, 95%; 10.4 mL, 50 mM) in anhydrous THF from syringe was added slowly, over 5 minutes. The reaction mixture was allowed, with stirring, for slow heating +25°C. After 15 hours, THF (25 mL) was added and the mixture was heated to +40°C under argon for 9 hours, and then it was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum to give 41 g mass (oil), which was purified by "flash" chromatography on silica gel column 230-400 mesh (440 g). Product was eluated with hexane (75%) - EtOAc (12,5%)- CH ₂ Cl ₂ (12.5%) mixture of solven -(phenylthio)methyl-5- (triethylsilyloxy)hexaliydrocyclopenta[έ]furan-2-one (10.84 g, 71.6%) was obtained as colourless, thick oil; [α] _D = (-)31.0° (CHCl ₃ , 25°C, c=l); ¹ H-NMR

(CDCl ₃ ; 200 MHz) δ 0.56 (6H ₃ q: 8.0 Hz), 0.92 (9H, t: 8.0 Hz), 2.00 (IH, m), 2.08 (IH ₅ m), 2.22 (IH, m), 2.45-2.85 (4H, m), 3.02 (IH, dd: 13.2, 5.9 Hz), 4.08 (IH, q: 5.0 Hz), 4.95 (IH, ddd: 7.0, 6.8,2.8 Hz), 7.31 (5H, m); ¹³ C-NMR (CDCl ₃ ; 50 MHz) δ 4.6 (3C), 6.7 (3C), 35.8, 36.1, 40.6, 41.8, 54.0, 76.3, 83.1, 126.2, 129.0 (2C), 129.1 (2C), 135.4, 176.9; EI MS m/z 379 (M+H, 2%); Elem. analysis: for C ₂₀ H ₃₀ O ₃ SSi calc. %C: 63.45, %H: 7.99, %S: 8.47; found. %C: 63.37, %H 8.03, %S: 8.46. Example 2

(3ai?,4/?,5i?,6aS}-4-(phenylosulfonyl)methyl-5-triethylsi lyloxy)liexahydro- cyclopenta[ό]furan-2-one

C ₂₀ H ₃₀ O ₃ SSi C ₂₀ H ₃₀ O ₅ SSi

MoI. Wt: 378,60 MoI. Wt: 410,60

(3ai?,4i?,5i?,6a ₎ S}-4-(Phenylthio)methyl-5-(triethylsilyloxy)- hexahydrocyclopenta[&]furan-2-one (9.55 g, 25.2 mM) was dissolved in CH ₂ Cl ₂ (150 niL). The solution was cooled in water bath (17°C). Upon intensive stirring, over 2 minutes, suspension of magnesium monoperoxyphtalate hexahydrate (MMPP x 6H ₂ O) (89.7 g, 80%, approx. 145 mM, approx. 5.7 of equivalent) in H ₂ O) (230 niL) was added. Stirring was continued for 65 minutes, CH ₂ Cl ₂ (100 mL) was added, and upon intensive stirring and cooling (17°C), unsaturated aqueous solution of NaHCO ₃ (350 mL) was added dropwise over 20 minutes.

After dropwise addition was completed, it was stirred for 15 minutes more, then the layers were separated, the aqueous layer was extracted with CH ₂ Cl ₂ (40 mL), organic layers were combined and extracted again with saturated aqueous NaHCO ₃ (300 mL) solution. Phases were separated, the aqueous phase was washed with CH ₂ Cl ₂ (40 mL). The combined organic phases were extracted with 10% Na ₂ S ₂ O ₃ aqueous solution (500 mL), phases were separated, aqueous phase was washed with CH ₂ Cl ₂ (40 mL). The combined organic phases were extracted with NaHCO ₃ solution (300 mL), dried over MgSO ₄ (50 g), the drying agent was filtered and washed with CH ₂ Cl ₂ (5 mL). The filtrates were combined, concentrated and dried over vacuum (1 mm Hg, 30 ⁰ C, 30 min.). The colourless oil was prepared (11.86 g). This sample was purified by "flash" chromatography on silica gel column 230-400 mesh (350 g), eluent: 40% EtOAc in hexane. The prepared fractions were concentrated and dried over vacuum (1 mm Hg, 30 ⁰ C, 60 min.). (3&R,4R,5R, 6a,S)-4-(Phenylosulfonyl)rnethyl-5-

(triethylsilyloxy)hexahydrocyclo-penta[&]furan-2-one, colourless solidifying oil, was obtained (9.81 g, 94.8%); [α] _D = (-) 24.9°(CHC1 ₃ , 25°C, c=l); ¹ H-NMR (CDCl ₃ ; 200 MHz)δ 0.53 (6H, q: 8.0 Hz) ₃ 0.89 (9H, t: 8.0 Hz), 1.98 (IH, m), 2.15 (IH, m), 2.33 (IH, m), 2.62-2.98 (4H, m), 3.18 (IH ₅ dd: 13.9, 4.4 Hz), 4.01 (IH, q: 5.1 Hz), 4.98 (IH, ddd: 7.1, 6.8, 3.5 Hz); ¹³ C-NMR (CDCl ₃ ; 50 MHz) δ 4.6 (3C), 6.7 (3C), 35.8, 40.4, 41.9, 49.4, 58.5, 76.7, 82.6, 127.7 (2C), 129.4 (2C), 133.9, 139.0, 176.6.; ESI HRMS m/z 433.1497 (M+Na*); 411.1676 (M+H ⁺ ), for C _2O H ₃ ]O ₅ SSi 411.1662 was calculated, for C ₂₀ H ₃₀ O ₅ SSiNa 433.1481 was calculated; elem. analysis: for C ₂₀ H ₃₀ O ₅ SSi calc. %C: 58.50, %H: 7.36, %S: 7.81; found. %C: 58.36, %H 7.22, %S: 8.01.

Example 3

(2i?/5',3ai?,4i?,5i?,6a5)-4-(phenylosulfonyl)methyl-5-(tr ietliylsilyloxy)hexahydro-

2H-cyklopenta[ό]furan-2-ol

C ₂₀ H ₃₀ O ₅ SSi C ₂₀ H ₃₂ O ₅ SSi

MoI. Wt, 410,60 MoI. Wt: 412,62

(3ai?,4i?,5i?,6a5)-4-(Phenylsulfonyl)methyl-5-(triethylsi lyloxy)hexahydro- cyclopenta[6]furan-2-one (9.26 g, 22.55 mM) was dissolved in anhydrous THF (120 niL). The solution was coooled under argon to -75°C. DIBALH solution (1.4 M in toluene; 35 mL, 49.6 mM) was added slowly, over 5 minutes. The solution was stirred under argon at - 75 ⁰ C. After 2 hours, upon continuation of vigorous stirring and cooling in C0 ₂ /Me0H bath, MeOH (9.5 mL, 234 mM) was slowly added dropwise. Then the cooling bath was removed and stirring was continued, allowing for slow heating of the mixture to - 5°C. H ₂ O (130 mL) and 2M aqueous solution of NaHSO ₂ (100 mL) were consecutively added dropwise and stirring was contiued for 5 minutes. EtOAc (100 mL) was added, phases were separated after extraction, aqueous phase extracted twice with EtOAc (2 x 80 mL). Organic layers were combined and extracted twice with saturated brine (2 x 200 mL), then they were dried over anhydrous Na ₂ SO ₄ (50 g), drying agent was filtered, washed with EtOAc (40 mL), the combined filtrates were concentrated and dried under vacuum (5 mm Hg, 30°C, 30 min. and 1 mm Hg, 30 ⁰ C, 1 hour). Thick, colourless

oil (10.1 g) was obtained. This sample was purified by "flash" chromatography on silica gel column 230-400 mesh (200 g), eluent: 42% EtOAc in hexane + 0.02% C5H ₅ N. Upon resolution, EtOAc concentration was gradient-increased up to 50%. The product was dried under vacuum (1 mm Hg, 3O ⁰ C, 90 nun.). (2i?/,y,3ai?,4i?,5i?,6a _J S)-4-(Phenylsulfonyl)methyl-5-(triethylsilyloxy)hexahy dro- 2H-cyclopenta[&]furan-2-ol was obtained (approx. 3:1 mixture of two epimers), as colourless thick oil (8.50 g, 91.3%); ¹ H-NMR (CDCl ₃ ; 200 MHz)δ 0.52 (6H, 2 x q), 0.89 (9H, 2 x t), 1.62 (0.75H, m), 1.98-2.37 (4H, m), 2.62 (1.25H, m), 2.90- 3.04 (1.75H, m), 3.23 (0.25H, dd: 14.1, 4.4 Hz), 3.36 (0.75H, dd: 14.0, 3.1 Hz), 3.78 (0.75H, ddd: 8.8, 8.6, 5.8 Hz), 3.98 (0.25H, bq: 5.1 Hz), 4.60 (1.25H, m), 5.48 (0.25H, ddd: 6.4, 4.5, 1.7 Hz), 5.62 (0.75H, dd: 3.7, 3.5 Hz), 7.91 (2H, m), 7.61 (3H, m); ¹³ C-NMR (CDCl ₃ ; 50 MHz) δ 4.45,4.73, 6.63, 6.73, 40.36, 40.68, 40.99, 42.54, 44.18, 46.43, 48.45, 49.08, 59.04, 59.80, 77.39, 78.46, 79.90, 83.62, 100.42 i 101.22 (hemiacetal), 127.61, 127.80, 129.19, 129.23, 133.54, 133.66, 139.28, 139.58; Elem. anal: for C ₂₀ H ₃₂ O ₅ SSi calc. %C: 58.22, %H: 7.82, %S: 7.77; found. %C: 57.98, %H 7.78, %S: 8.05.

Example 4

[4-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-l-yl)butyl]tri phenylphosphonium iodide

C _1O H ₁₇ IO ₃ C2&H32IO3P MoI. Wt: 312,14 MoI. Wt.: 574,43

In 250 mL flask, l-(4-iodobutyl)-4-methyl-2,6,7- trioxabicyclo[2.2.2]octane prepared according to process of US 5,538,995 (15.8 g, 50.6 mM), triphenylphosphine (14.6 g, 55.66 mM), sulfolane (20 mL) and C ₅ H ₅ N (0.10 mL) were placed under argon. The content of the flask was stirred and heated under argon at 8O ⁰ C. After 70 minutes, the mixture was cooled to 40°C and CHCl ₃ containing 0.3% of pyridine (70 mL) was added. This solution was added dropwise over 10 minutes to the mixture OfEt ₂ O (1.5 L) and EtOAc (0.6 L) and vigorously stirred under argon. The reaction mixture was vigorously stirred (600 r.p.m.) for 15 minutes at room temperature, then it was stirred more slowly (150 r.p.m.) for 15 minutes, and the solution was decanted. The thus obtained precipitate was dissolved in CHCl ₃ containing 0.2% of C ₅ H ₅ N (75 mL). This solution was added dropwise to vigourosly stirred mixture of Et ₂ O (1.2 L) and EtOAc (0.5 L). It was stirred under argon at room temperature. After 20 minutes, stirring was stopped. After 10 minutes, the solution was decanted, the precipitate was washed with Et ₂ O (100 mL) and Et ₂ O layer was decanted again. The obtained precipitate was dried under vacuum (1 mm Hg, 25°C, 1.5 h). The crude product (28.95 g, 100%) was obtained. This sample was dissolved in MeOH containing 0.04% OfC ₅ H ₅ N (35 mL), EtOAc containing 0.04% OfC ₅ H ₅ N (65 mL) was added and it was allowed for crystallization at + 4 ⁰ C. After 1.5 h, the precipitate was

filtered and dried (1 mm Hg, 25°C, 1 h). [4-(4-methyl-2,6,7- trioxabicycloP^^oct-l-ytybutyljtriphenylphosphomum iodide was obtained (14.01 g, 48.3%) as colourless, thick heaps, t.t.= 130-134°C; ¹ H-NMR (CDCl ₃ ; 200 MHz) δ; 0.78 (3H, s), 1.58-1.80 (6H, m), 3.45 (2H, m), 3.79 (6H, s), 7.70- 7.88 (15H, m); ¹³ C-NMR (CDCl ₃ ; 50 MHz) δ 14.5, 21.7 (d: 4.0 Hz), 22.7 (d: 50.8 Hz), 24.0 (d: 16.8 Hz), 30.2, 34.7, 72.3 (3 x C), 108.5, 117.8 (3 x C, d: 86 Hz), 130.5 (6 x C, d: 12.4 Hz), 133.5 (6 x C, d: 10.0 Hz), 135.1 (3 x C, d: 2.8 Hz).

Example 5 methyl-2,6,7-trioxabicyclo[2.2.2]octan- 1 ~yl)hex-2- enyl]-5- [(phenylosulfonyl)methyl]cycloρentane-l ₅ 3-diol and the mixture of

trioxabicyclo[2.2.2]octan-l-yl)hex-2- enyl]-2-[(phenylsulfonyl)methyl]-4-(triethylsilyloxy)cyclope ntanol and

trioxabicyclo[2.2.2]octan-l-yl)hex-2- enyl]-3-[(phenylsulfonyl)methylo]-4-(triethylsilyloxy)cyclop entanol.

0 ₂₄ !! ₃ 4O ₇ S

MoI. Wt.: 412,62 MoI. Wt.: 466,59

+

Rl= TES, R2=H; 65% Rl= H; R2= TES; 35%

[4-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-l- yl)butyl]triphenylphosphonium iodide (7.98 g, 13.9 mM) and anhydrous THF were stirred under argon at room temperature for 30 minutes. Then the mixture was coolled under argon to O ⁰ C and t-BuOK was added by several portions (Fluka > 97%, 3.85 g total, approx. 34 mM). The mixture was stirred at O ⁰ C for 5 minutes, then the cooling bath was removed, anhydrous THF (10 mL) was added, and it was stirred over 20 minutes, allowing the mixture to heat to approx. 2O ⁰ C. Then the mixture was cooled again to 0 ⁰ C and, over 3 minutes, while stirring vigorously, the solution of (2/?/ ₎ S',3aR,4i?,5i?,6a5)-4-(ρhenylsulfonyl)methyl-5- (triethylsilyloxy)hexahydro-2H-cyclopenta[ό]furan-2-ol (mixture of epimers) (2.70 g, 6.54 mM) in anhydrous TΗF (10 mL) was aded dropwise. Stirring at 0°C was continued for 15 minutes, then the cooling bath was removed and it was

vigorously stirred under argon, allowing the mixture to heat to 20 ⁰ C. In 80 minutes after lactol was added dropwise, Al(t-BuO) ₃ (420 mg, approx. 1.7 mM) was added and stirring was continued at 20 ⁰ C under argon. Exactly in 5 hours after the reaction started, the reaction mixture was cooled to 0 ⁰ C and 3% solution of pyridine in H ₂ O (10 mL) was added very slowly. It was stirred for 5 minutes, then the mixture was trasferred to the separator containing EtOAc (70 mL) and saturated aqueous solution OfNaHCO ₃ (70 mL). After extraction, the layers were separated, the aqueous layer was extracted twice with EtOAc (50 mL, 30 mL), then the organic layers were combined and extracted twice with saturated brine (50 mL, 50 mL). 3 drops of pyridine were added to the organic layer, and it was dried over anhydrous Na ₂ SO ₄ (25 g) at + 4 ⁰ C over night. Then the drying agent was filtered, washed with EtOAc (30 mL), the combined filtrates were concentrated and dried under vacuum. Thick oil (8.2 g) was obtained, which was dissolved in CH ₂ Cl ₂ (20 mL) and injected on "flash" chromatographic silica gel column 230-400 mesh (250 g), previously prepared in the mixture of 70% EtOAc- 30% hexane + 0.15% C ₅ H ₅ N (Phase I). After collecting of 2 L of eluate washed out with Phase I, mobile phase was exchanged for Phase II: 84% EtOAc - 16% hexane + 0.15% C ₂ H ₅ N. Fractions obtained by washing out with Phase I were combined on the basis of TCL chromatograms, concentrated and dried under vacuum. The mixture of (li?,2i.,3i?,45)-3-[(Z)-6-(4-methyl-2,6,7- trioxabicyclo[2.2.2]octan-l-yl)hexe-2-nyl]-2-[(phenylsulfony l)methyl]-4- (triethylsilyloxy)cyclopentanol (ca. 65%) and (15,2/?,3i?,4i?)-2-[(Z)-6-(4-methyl- 2,6,7-trioxabicyclo[2.2.2]octan-l-yl)hex-2-enyl]-3-[(phenyls ulfonyl)methyl]-4- (triethylsilyloxy)cycloρentanol (ca. 35%) (584 mg of the mixture, yield 15.4%), colourless glaze was obtained; ¹ H-NMR (CDCl ₃ ; 200 MHz) δ 0.57 (6H ₅ 2 x q),

0.79 (1.95H, s), 0.80 (1.05H ₅ s), 0.93 (9H, 2 x t), 1.34-1.54 (3.5H, m), 1.56-1.78 (3H, m), 1.82-2.20 (6.6H, m), 3.01 (0.65H, dd: 14.4, 11.2 Hz), 3.32 (0.65H, dd: 14.4, 2.6 Hz), 3.56 (0.65H, m), 3.88 (3.9H, s), 3.89 (2.1H, s), 3.90 (0.35H, m), 4.13 (1.30H, m), 5.15-5.38 (2H, m), 7.54-7.74 (3H, m), 7.93-7.99 (2H, m); fractions prepared after washing out with Phase II were combined on the basis of TLC chromatograms, concentrated and dried under vacuum. Glaze was obtained (3.597 g) containing slight amount of triphenylphosphine oxide, which was removed by two-time maceration with Et ₂ O (8 mL, 4 mL). (li?,3S,4i?,5i?)-4-[(Z> 6-(4-Methyl-2,6,7-trioxabicyclo[2.2.2]octan-l-yl)hex-2-enyl] -5- [(phenylsulfonyl)methyl]cyclopentane-l,3-diol was prepared (2.0 g, 65.5 %); ¹ H- NMR (CDCl ₃ ; 200 MHz) δ 0.80 (3H, s), 1.36-1.52 (3H, m), 1.61 (2H, m), 1.8- 2.29 (8H, m), 3.05 (IH, dd: 14.3, 11.2 Hz), 3.33 (IH, dd: 14.3, 2.6 Hz) ₃ 3.53 (IH, bs, OH), 3.88 (6H, s), 4.09 (IH, m), 4.31 (IH, m), 5.17-5.39 (2H, m), 7.47-7.74 (3H, m), 7.93-7.99 (2H, m).

Example 5a

(2 _J R/6',3ai-,4i?,5i-,6a ₎ S)-4-(Phenylsulfonyl)methyl-5-(triethylsilyloxy)hexahy dro- 2H-cyclopenta[&]furan-2-ol (mixture of two epimers) (1.74 g, 3.03 mM) was reacted in Wittig's reaction in conditions described above, with the difference that addition of Al(t-BuO) was not used. After processing and chromatographic purification (as above), the following was obtained: mixture of (a) (1R,2R,3R,4S)- 3-[(Z)-6-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-l-yl)hex- 2-enyl]-2- [(phenylsulfonyl)methyl]-4-(triethylsilyloxy)cyclopentanol (ca. 65%) and (l,S',2 _J R,3i?,4 _J R)-2-[(Z)-6-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan- l-yl)hex-2- enyl]-3-[(phenylsulfonyl)methyl]-4-(triethylsilyloxy)cyclope ntanol (ca. 35%)

(140 mg of the mixture, yield. 5.7%), (b) (li?,3S,4i?,5i?)-4-[(Z)-6-(4-methyl-2,6,7- trioxabicyclo[2.2.2]octan-l-yl)hex-2-enyl]-5-

[(phenylsulfonyl)methyl]cyclopentane-l,3-diol (499 mg, 25.4%); and (c) (2i?/5',3aR,4i?,5R,6aS)-4-[(phenylsulfonyl)methyl]liexahydro -2H- cyclopenta[δ]furano-2,5-diol

Ci ₄ H ₁₈ O ₅ S MoI. Wt.: 298,36

(mixture of isomers approx. 1:1) (127 mg, 10.1%), colourless glaze; ¹ H-NMR (CDCl ₃ ; 200 MHz) δ 1.78-2.42 (5H, m), 2.48-2.75 (2H, m), 3.07 (IH, dd: 14.2, 7.5 Hz), 3.26 (IH, dd: 14.2, 6.8 Hz), 3.61 (IH, bs, OH), 3.99 (IH, m, W^ ₂ = 14Hz), 4.61 (IH, m, ddd: 13.5, 6.8, 4.2 Hz), 5.53 (0.5H, d: 5.1 Hz), 5.62 (0.5H, bd: 4.0 Hz), 7.41-7.72 (3H, m), 7.91-7.96 (2H, m); EI MS m/z 298 (M ⁺ , 3%); ¹³ C- NMR (CDCl ₃ ; 50 MHz) δ 39.65, 39.81, 40.09, 42.38, 46.34, 47.04, 48.43, 48.51, 59.79, 60.43, 78.35, 78.46, 80.49, 83.86, 99.87, 100.8, 127.99 (2C), 129.46, 129.50, 134.01, 134.08, 138.99, 139.14 ; elem. analysis: for C ₁₄ H ₁₈ O ₅ S calc. %C: 56.36, %H: 6.08, %S: 10.75; found. %C: 56.43, %H 6.09, %S: 10.57.

Example 6

1. {(Z)-6-[(li?,2i.,3i?,5 _J S)-2-((phenylsulfonyl)methyl)-3,5-bis- -triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7- trioxabicyclo[2.2.2]octane.

(l/-,3<S',4i?,5i-)-4-[(Z)-6-(4-methyl-2,6,7-trioxabicy clo[2.2.2]octan-l-yl)hex-2- enyl]-5-[(phenylsulfonyl)methyl]cyclopentane-l,3-diol (279 mg, 0.58 mM) was dissolved in anhydrous DMF (10 mL). The solution was cooled under argon to 0 ⁰ C. Imidazole was added (160 mg, 2.34 mM), and then Et ₃ N (300 μL, 218 mg, 2.15 mM). The mixture was stirred at 0 ⁰ C under argon and TES-Cl (420 μL, 377 mg, 2.5 mM) was added. After 2 hours and 20 minutes, pyridine (0.50 mL) was added and the reaction mixture was transferred quantitatively to the separator containing saturated aqueous solution OfNaHCO ₃ (60 mL). It was extracted with the mixture of EtOAc-hexane (1:1; 60 mL). Layers were separated, the aqueous layer was extracted with hexane (40 mL). Organic layers were combined and extracted with saturated aqueous solution of NaHCO ₃ (60 mL). The layers were separated, the organic layer was dried over anhydrous Na ₂ SO ₄ (12 g). The drying agent was filtered, washed with hexane (15 mL), the combined filtrates were concentrated and dried under vacuum. The crude product obtained in this way was purified by "flash" chromatography on silica gel column 230-400 mesh gel (60 g), eluent 18% EtoAc in hexane + 0.07% CsH ₅ N. The fractions, which were pure on TCL, were combined, concentrated under vacuum and dried under vacuum (1 mm Hg, 25°C, 3 hours). l-{(Z)-6-[(li?,2 _J R,3i?,5 ₁ S)-2-((phenylsulfonyl)methyl)-3,5-bis- (triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7-

trioxabicyclo[2.2.2]octane (361 mg, 87 %) was obtained, as pale yellowish, thick oil; [α] _D = (+)9.3°(CHC1 ₃ , 22°C, c= 1); ¹ H-NMR (CDCl ₃ ; 200 MHz)δ 0.55 (12H, 2 x q: 8.0 Hz), 0.80 (3H, s), 0.92 (18H, t: 8.0 Hz), 1.39-1.72 (6H, m), 1.84 (IH, m), 1.98 (IH, m), 2.16 (4H, m), 3.19 (2H, bd: 5.3 Hz, CH ₂ SO ₂ Ph), 3.89 (6H, s), 4.14 (2H, m), 5.33 (2H, m, W _h/2 = 10.6 Hz), 7.50-7.68 (3H ₃ m), 7.89-7.95 (2H, m). ¹³ C- NMR (CDCl ₃ ; 50 MHz) δ 4.69 (3C), 4.82 (3C), 6.77 (3C), 6.82 (3C), 14.49, 23.15, 25.18, 26.94, 30.12, 36.16, 43.65, 46.73, 47.15, 57.40, 71.40, 72.47 (3C), 74.74, 108.95, 127.95 (2C), 128.54, 129.08 (2C), 130.28, 133.38, 140.27; elem. analysis: for C ₃₆ H ₆₂ O ₇ SSi ₂ calc. %C: 62.20, %H: 8.99; found %C: 62.04, %H 8.68.

Example 7

1 - {(Z)-6-[(li?,2i?,3i?,5,S)-2-((phenylsulfonyl)methyl)-3,5-bis - (triethylosilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7- trioxabicyclo[2.2.2]octane and (Z)-7-[(li?,2i?,3i?,5S)-2-((phenylsulfonyl)methyl)- 3,5-bis-(triethylsilyloxy)cyclopentyl]hept-5-enoic acid 2,2- bis(hydroxymethyl)propyl ester.

In the 100 mL flask, (li?,35 ^l ,4i2,5i?)-4-[(Z)-6-(4-methyl-2,6,7- trioxabicyclo[2.2.2]octan-l-yl)hex-2-enyl]-5-

[(phenylsulfonyl)methyl]cyclopentane-l,3-diol (2.0 g, 4.28 mmola) and the mixture of (li?,2i?,3i?,45)-3-[(Z)-6-(4-methyl-2,6,7-trioxabicyclo[2.2. 2]octan-l- yl)hex-2-enyl]-2-[(phenylsulfonyl)methyl]-4-(triethylsilylox y)cyklopentanol and (15',2i?,3i?,4i?)-2-[(Z)-6-(4-methyl-2,6,7-trioxabicyclo[2.2 .2]octan-l-ylo)hex-2- enyl]-3-[(phenylsulfonyl)methyl]-4-(triethylsilyloxy)cyclope ntanol (0.558 g, 0.961 niM) were placed. Anhydrous DMF (35 mL) was added. After dissolution, imidazole (2.396 g) was added, the mixture was cooled under argon to O ⁰ C, Et ₃ N was added (4.20 mL), then TES-Cl (5.05) was added. After 4 hours, processing was carried out. The crude product (approx. 7 g) was maintained at +4°C until the next day. Then, chromatographic purification was carried out similarly to Example 6 ("flash" chromatography on silica gel column 230-400 mesh (250 g),

eluent 18% EtOac in hexane + 0.07% C ₅ H ₅ N). Polar by-product was washed out with the mixture of EtOAc-hexane solvents (1:1). After drying of pure fractions on TCL, the following compounds were obtained: (a) l-{(Z)-6-[(lR,2R,3R,5S)-2- ((phenylsulfonyl)methyl)- 3,5-bis-(triethylsilyloxy)cyclopentyl]hex-4-enyl}-4- methyl-2,6,7-trioxabicyclo[2.2.2]octane (2.422 g, 66.5%), pale yellowish, thick oil; ¹ H-NMR (CDCl ₃ ; 200 MHz) identical with described in Example 6, and (b) (Z)-7-[(lR,2R,3R,5S)-2-((phenylsulfonyl)methyl)-3,5-bis- (triethylsilyloxy)cyclopentyl]hept-5-enoic acid 2,2-bis(hydroxymethyl)propyl ester (1.18 g, 31.5 %), colourless glaze; ¹ H-NMR (CDCl ₃ ; 200 MHz) δ 0.55 (12H ₅ 2 x q: 8.0 Hz), 0.84 (3H, s), 0.93 (18H, t: 8.0 Hz), 1.42-1.82 (6H, m), 1.86-2.40 (7H, m), 3.19 (3H, m), 3.55 (4H, bs), 3.89 (IH, d:1.4 Hz), 4.12 (3H, m), 5.39 (2H, m, Wh/2= 34 Hz), 7.51-7.68 (3H, m), 7.89-7.94 (2H, m).

Example 8 Preparation of omega chain synthones of general flrmula (VI), of high enantiomeric excess

S/R> 4:1

Ph

%

Example 8a (2.S)-4-phenylbutane-l ₅ 2-diol

C10H12 Ci ₀ H ₁₄ O ₂

MoI. Wt: 132,20 MoI. Wt.: 166,22

In the three-neck flask 21, t-butanol (450 mL), distilled water (450 mL),

(DHQ) ₂ AQN (Aldrich, 95%; 990 mg, 1.10 mM), K ₃ Fe(CN) ₆ (93.1 g, 280 niM), K ₂ CO ₃ (38.7 g, 280 mM) and K ₂ OsO ₂ (OH) ₄ (133 mg, 0.36 mM) were placed. The

mixture was stirred at room temperature over 1.5 h, then cooled to 0 ⁰ C (ice-water bath). Then, 4-phenyl-butene (11.90 g, 13.52 mL, 90.0 mM) was added and stirring was continued at 0 ⁰ C. After 17 hours, upon continuation of stirring and cooling at 0 ⁰ C, Na ₂ S ₂ O ₅ (130 g, 680 mM) was added. Cooling bath was removed and stirring was continued, allowing the mixture to heat to romm temperature. After 1 hour, EtOAc (400 mL) was added, vigourous stirring was carried out for 10 minutes, then phases were separated, aqueous phase was extracted with EtOAc (100 mL), organic phases were combined and dried over Na ₂ SO ₄ (100 g). Then the drying agent was filtered and washed with EtOAc (100 mL). The combined filtrates were concentrated under vacuum, nearly completely removing the solvents. Yellow oil obtained in this way was purified by "flash" chromatography on silica gel column (350 g), EtOAc as eluent. Fractions pure on TLC were concentrated and dried under vacuum (1 mm Hg, 30 ⁰ C, 1 hour). As a result, (2,S)-4-phenyl-l,2-butanediol (14.70 g, 98%) was prepared as pale yellowish, thick oil; ¹ H-NMR (CDCl ₃ ; 200 MHz)δ 1.72 (2H, m, Ww ₂ = 23 Hz), 2.70 (2H, m, W _h/2 = 42 Hz), 3.31 (2H, bs, 2 x OH), 3.42 (IH, dd: 11.2, 7.7 Hz), 3.61 (IH, dd: 11.2, 2.9 Hz), 3.69 (IH, m, Ψ _m = 18 Hz), 7.13-7.31 (5H, m); ¹³ C- NMR (CDCl ₃ ; 50 MHz) δ 31.8, 34.6, 66.6, 71.5, 125.8, 128.2 (2C), 128.3 (2C), 141.5. Analysis of this sample, by use of chiral HPLC chromatography, was carried out on Chiracel OD column (250+20) x 4.6 mm, 10 μm, eluent: hexane (80% vol) - 2-propanol (20% vol), flow rate 1.0 mL/min.: R _t 8.47 min. (17.2%), R _t 11.06 min. (81.9%), enantiomeric excess ee= 65.3%. As a standard for calibration of HPLC measurement, racemic 4-phenylbutane-l,2-diol was used, prepared from 4-phenyl-l-butene in the hydroxylation reaction accordiing to the above procedure, in which DABCO was used instead of (DHQ) ₂ AQN).

Example 8b (S)-2-hydroxy-4-phenylbutyl 4-methylbenzenesulfonate

(2S)-4-Phenyl-l,2-butanediol (13.58 g, 81.7 mM) was dissolved in anhydrous CH ₂ Cl ₂ (190 niL). To this solution, stirred under argon, Bu ₂ SnO (720 mg, 2.89 mM) was added. The suspension was stirred for 5 minutes, then Et ₃ N was added (11.40 mL, 8.276 g, 81.79 mM) and, upon continuation of stirring, the reaction mixture was cooled to O ⁰ C, then p-toluenesulfonyl chloride was added (16.03 g, 84.08 mM). The whole was stirred at 0 ⁰ C for 5 minutes more, the the cooling bath was removed and stirring was continued under argon, allowing for slow heating of the mixture to room temperature. After 1.5 h, the mixture was put away at +4°C for 18 hours. Then the mixture was concentrated to the vol of 100 mL and injected on "flash" chromatographic silica gel column 230-400 mesh (500 g). As a mobile phase, the solution of 25% EtOAc in hexane was used. On the basis of TLC analysis, the pure fractions were combined, concentrated and dried under vacuum (1 mm Hg, 30°C, 2 hours). Partly racemic (35)-l-phenyl-3- hydroxy-4-p-toluenesulfonyloxybutane was obtained (20.10 g, 76.8%) as colourless, thick oil; ¹ H-NMR (CDCl ₃ ; 200 MHz)δ 1.73 (2H, m), 2.19 (IH, d: 4.6

Hz ₅ OH), 2.45 (3H, s), 2.70 (2H, m), 3.85 (2H, m), 4.02 (IH, dd: 9.5, 2.9 Hz), 7.11-7.37 (7H, m), 7.79 (2H, ddd: 8.4, 2.0, 1.8 Hz); ¹³ C-NMR (CDCl ₃ ; 50 MHz) δ 21.6, 31.3, 34.1, 68.5, 73.8, 125.9, 127.8 (2C), 128.2 (2C), 128.3 (2C), 129.8 (2C), 132.4, 140.9, 144.9. Analysis of this sample, with use of chiral HPLC chromatography, was carried out on Chiracel OD column (250+20) x 4.6 mm, 10 μm, eluent: hexane (80% vol) - 2-propanol (20% vol), flow rate 1.0 mL/min.: Rt 13.10 min. (83.7%), R _t 15.53 min. (16.14%), enantiomeric excess ee=67.7%.

This sample of tosylate (ee= 67.7%; 19.85 g) was crystallized from Et ₂ O (60 mL). The prepared crystalline product (10.51 g) was crystallized twice with Et ₂ O in analogical conditions. As a result of these operations, optically pure (ee= 99.26%) (35)-l-phenyl-3-hydroxy-4-p-toluenesulfonyloxybutane was prepared (4.77 g, 18.45%) as colourless needles, m.p. 68-69°C; [α] _D = (+) 0.70° (CHCl ₃ , 25 ⁰ C, c= 1); ¹ H-NMR (CDCl ₃ ; 200MHz), spectrum identical with that described above. Analysis of this sample, with use of chiral HPLC chromatography, was carried out on Chiracle OD column (250+20) x 4.6 mm, 10 μm, eluent: hexane(80% vol) - 2-propanol (20% vol), flow rate 1.0 mL/min.: R _t 13.28 min. (99.59%), R ₁ 15.88 min. (0.37%), enantiomeric excess ee=99.26%; elem. analysis: for C ₁₇ H ₂₀ O ₄ S calc. %C: 63.73, %H: 6.29, %S: 10.01; found. %C: 63.79, %H 6.19, %S: 10.16.

Example 8c (S)-2-(Triethylsilyloxy)butyl 4-methylbenzenesulfonate

(3S)-l-Phenyl-3-hydroxy-4-p-toluenesulfonyloxybutane (ee= 99.26%; 4.537g, 14.16 niM) was dissolved in anhydrous DMF (38 niL). The solution was cooled under argon to 0°C, imidazole (1.069 g) and Et ₃ N (2.00 niL) were added. The mixture was vigorously stirred under argon at O ⁰ C and TES-Cl was added dropwise (2.52 mL). The mixture was stirred at O ⁰ C for 1 hour, then at room tempearture for 20 minutes, then hexane was added (100 mL) and satureted aqueous solution OfNaHCO ₃ (90 mL). After extraction, the layers were separated, the aqueous layer was again extracted twice extracted with hexane (2 x 40 mL). The combined aqueous layers were extracted with aqueous solution of NaHCO ₃ (100 mL). The layers were separated, the organic layer was dried over Na ₂ SO ₄ (20 g). The drying agent was filtered and washed on the filter with hexane (20 mL). The combined filtrates were concentrated and dried under vacuum to give an oil (7.0 g), which was purified by "flash" chromatography on silica gel column 230- 400 mesh (185 g), eluent: 10% EtOAc in hexane. Fractions, which were pure on TLC, were combined, concentraed and dried under vaccum (1 mm Hg, 27°C; 2 hours). (3iS)-l-Phenyl-4 _: p-toluenesulfonyloxy-3-triethylsilyloxybutane (6.127 g, 99.5%) was obtained as colourless, thick oil; [α] _D = (+)4.9°(CHC1 ₃ , 25 ⁰ C, c= 1); ¹ H-NMR (CDCl ₃ ; 200 MHz) δ 0.56 (6H, q: 8.0 Hz), 0.91 (9H, t: 8.0 Hz), 1.74 (ZH, m), 2.44 (3H, s), 2.60 (2H, m), 3.90 (3H, bs), 7.09-7.36 (7H, m), 7.78 (2H, ddd: 8.4, 2.0, 1.8 Hz); ¹³ C-NMR (CDCl ₃ ; 50 MHz) δ 4.8 (3C), 6.8 (3C), 21.6,

31.0, 35.8, 69.4, 72.8, 125.8, 127.8 (2C), 128.1 (2C), 128.3 (2C), 129.7 (2C), 132.7, 141.4, 144.7;

Elem. analysis: for C ₂₃ H ₃₄ O ₄ SSi calc. %C: 63.55, %H: 7.88, %S: 7.38; found. %C: 63.62, %H 7.72, %S: 7.40.

Example 8d

(3S)- 1 -Phenyl-4-iodo-3 -triethylsilyloxybutane

0,37

Example 8d.l

(35)-l-Phenyl-4-j9-toluenesulfonyloxy-3-triethylsilyloxyb utane (ee=

99.26%; 3.145 g; 7.23 niM) was dissolved in anhydrous DMF (30 mL). The solution was stirred vigorously at room temperature under argon and sodium iodide was added (4.60 g, 30.7 mM). Upon vigorous stirring, content of the flask was heated to +80°C under argon. After 2 hours, the mixture was cooled to room temperature, saturated aqueous solution OfNaHCO ₃ (70 mL) and hexane (70 mL) was added. Phases were separated after extraction. The aqueous phase was extracted with hexane twice ( 2 x 40 mL). The combined organic layers were extracted with hexane (2 x 40 mL). The combined organic layers were extracted with aqueous solution Of NaHCO ₃ (70 mL), then dried over Na ₂ SO ₄ (16 g), the drying agent was filtered, washed with hexane (15 mL), the combined filtrates

were concentrated and dried under vacuum. Pale yellowish oil was obtained (2.88 g), which was purified by "flash" chromatography on silica gel column 230-400 mesh (100 g), eluent: 3-10% EtOAc in hexane. After drying (1 mm Hg, 25 ⁰ C, 2 hours) of pure fractions on TCL, the following compounds were prepared: (a) (35)-l-phenyl-4-iodo-3-triethylsilyloxybutane (ee= 99.2%; 2.423 g, 85.8 %), colourless oil; [α] _D = (-)9.1° (CHCl ₃ , 2O ⁰ C, c= 1); ¹ H-NMR (CDCl ₃ ; 200 MHz) δ 0.62 (6H, q: 7.6 Hz), 0.98 (9H, t: 7.6 Hz), 1.78 (2H, m), 2.65 (2H, m), 3.23 (2H, dd: 5.1, 0.6 Hz), 3.66 (IH, m), 7.14-7.33 (5H, m); ¹³ C-NMR (CDCl ₃ ; 50 MHz) δ 5.05 (3C), 6.90 (3C), 13.25, 31.26, 38.61, 71.01, 125.73, 128.16 (2C), 128.25 (2C), 141.58.; HR ESI MS for C ₁₆ H ₂₇ IOSiNa calc. (M + Na ⁺ ) m/z 413.07736, found. 413.0764, and (b) (3£)-l-phenyl-4-/?-toluenesulfonyloxy-3- triethylsilyloxybutane (recovered substrate; 317 mg, 10.1%); ¹ H-NMR (CDCl ₃ ; 200 MHz) identical with cited above for this compound.

Example 8d.2

(35)-l-Phenyl-4 _: p-toluenesulfonyloxy-3-triethylsilyloxybutane (ee= 99.26%; 5.90 g; 13.57 mM) was dissolved in anhydrous DMF (60 mL). The solution was stirred vigorously at room temperature under argon and sodium iodide was added (8.8 g, 58.7 mM). Upon vigorous stirring, the content of the flask was heated to +85 ⁰ C under argon. After 3 hours, lack of substrate and presence of unexpected polar product was determined by TLC in the amount approximately 50%. The reaction mixture was cooled to room temperature, diisopropyl ether (70 mL) and H ₂ O (120 mL) were added. After extraction, the phases were separated, the aqueous phase was extracted twice with disopropyl ether (2 x 50 mL). The organic phases were combined and extracted with H ₂ O (80 mL), the organic phase was dried over

Na ₂ SO ₄ (22 g). The drying agent was filtered and washed with diisopropyl ether (25 mL). The filtrates were combined, concentrated and dried under vaccum to the mass of 5.51 g (crystallizing oil).

This sample was dissolved in anhydrous DMF (40 mL). The solution was cooled under argon to 0 ⁰ C, then imidazole was added (1.63 g; 23.9 mM). The mixture was stirred until dissolution, then TES-Cl was added (2.0 mL, 11.9 mM). The solution was stirred under argon in 0 ⁰ C. After 30 minutes, the cooling bath was removed and stiring was continued while allowing the sample to heat to room temperature. After the complete reaction time of 1 hour, diisopropyl ether (100 mL) and then saturated aqueous solution Of NaHCO ₃ were added (150 mL). The mixture was transferred to the separator. The phases were separated after extraction, the aqueous phase was extracted twice with disopropyl ether (2 x 50 mL).

The organic phases were combined and extracted with saturated aqueous solution of NaHCO ₃ (100 mL). The organic phase was dried over anhydrous Na ₂ SO ₄ (25 g), the drying agent was filetered and washed with diisopropyl ether. The filtrates were combined and concentrated under vacuum. The crude product was purified by "flash" chromatography on silica gel column 230-400 mesh (200 g), eluent: 2% EtOaAc in hexane. After drying (1 mm Hg, 25 ⁰ C, 2 hours) of the pure fractions on TLC, the following compounds were obtained: (a) (3 S)-I- phenyl-4-iodo-3-triethylsilyloxybutane (ee= 99.2%; 5.09 g, 96%), colourless oil; [α] _D = (-)9.1°; ¹ H-NMR (CDCl ₃ ; 200 MHz): spectrum identical with that described in Example 8d.l.

Example 8e

(35)- 1 -Phenyl-4-/?-toluenesulfonyloxy-3 -triethylsilyloxybutane and (3.S)-I- phenyl-4-iodo-3-triethylsilyloxybutane.

(D)-mannitol

Organic Syntheses, Coll. Vol. 9 (1998), p. 450

2,3-0-Isopropylidene derivative of (i?)-glyceric aldehyde was prepared from jD-mannitol according to the procedure described in the publication of CR.

Schid et al., Organic Syntheses, Coll. Vol. 9 (1998), 450. The obtained adehyde was distilled directly prior use in the reaction described in Example 8e.l (boiling temperature: 47-51 °C/20 mm Hg).

Example 8e.l

(£/Z,4S)-2,2-Dimethyl-4-styryl-[ 1 ,3]dioxolane.

QHi _O O ₃ C13H16O2

MoI. Wt.: 130,14 MoI. Wt.: 204,26

In a 2 L thre-necked flask, provided with a magnetic stirrer, a thermometer, a dropper with pressure compensation and argon inlet, tetrahydrofurane (1.21 L) and benzyltriphenylphosphonium bromide (189.4 g, 0.437 niM) were placed. The suspension was vigorously stirred in argon atmosphere and cooled to O ⁰ C. Then, 2.5 M solution of hexyllithium in hexane (170 mL, 0.425 M), maintaining the temperature of the mixture below 5 ⁰ C. Over 1 hour, the mixture was heated to 15°C, stirred for 30 minutes at this temperature, then cooled to 0°C. Then, the cooled below 5°C solution of freshly distilled 2,2,- O-isopropylidene derivative of (i?)-glyceryl aldehyde (52.3 g, 0.402 M) in tetrahydrofurane (150 mL) was added dropwise. After completion of dropwise addition, the mixture was heated to 20 ⁰ C and stirred at this temperature for 2 hours, then methanol (10 mL) was slowly added. The prepared suspension was filtered through Celite (100 g), the solid was washed twice with the mixture of hexane-EtOAc (2:1; 2 x 200 mL). The combined filtrates were concentrated under vacuum to viscous oil, which was then purified by "flash" chromatography on silica gel column 230-400 mesh (500 g). Eluent: hexane-EtOAc (1:1). After concentration of pure fractions and drying under vacuum, (J?/Z,45)-2,2-dimethyl- 4-styryl-[l,3]dioxolanes were prepared (mixture of isomers; 50.9 g, 62%);

colourless, thick oil; ; ¹ H-NMR (CDCl ₃ ; 200 MHz) δ 1.39 (2.3H ₅ s, CH ₃ ), 1.43 (0.7H ₅ s, CH ₃ ), 1.47 (3H, bs, CH ₃ ), 3.68 (IH, m), 4.08 (0.3H, m), 4.16 (0.7H, m), 4.67 (0.3H ₅ m), 4.92 (0.7H, m), 5.70 (0.7H, dd: 11.6, 9.0 Hz), 6.16 (0.3H, dd: 15.8, 7.6 Hz), 6.70 (IH, m), 121-1 Al (5H, m); ¹³ C-NMR (CDCl ₃ ; 50 MHz) δ 25.89, 25.94, 26.75, 26.86, 69.51, 69.7O ₅ 72.41, 77.24, 109.37, 109.43, 126.61, 126.71, 127.52, 127.98, 128.29, 128.57, 128.70, 129.20, 133.38, 133.97, 136.13, 136.24.

Example 8e.2 (4S)-2,2-Dimethyl-4-phenetyl-[l,3]dioxolane.

C ₁₃ H ₁₆ O ₂ C ₁₃ H ₁₈ O ₂

MoI. Wt.: 204,26 MoI. Wt: 206,28

The mixture of (E)I(Z) (4 ₁ S)-2,2-dimethyl-4-styryl-[l,3]dioxolanes (50.0 g) was dissolved in methanol (0.50 L). The solution was placed in autoclave (Parr, 1.6 L), 10% Pd/C catalyst was added (5.0 g). Hydrogenation was carried out under the pressure of 10 bars, at the temperature of 30 ⁰ C, for 24 hours. The catalyst was filtered and washed three times with methanol (3 x 50 mL). The filtrates were combined and concentrated under vacuum, then dried under vacuum. (45)-2 ₅ 2-dimethyl-4-phenethyl-[l,3]dioxolane (49.9 g, 98.8%) was obtained as colourless oil; [α] _D = (+)3.8"(CHCl ₃ , 2O ⁰ C, c= 1); ¹ H-NMR (CDCl ₃ ; 200 MHz)δ 1.36 (3H, bs), 1.43 (3H, bs), 1.88 (2H, m, W= 66 Hz), 2.70 (2H, m, W= 57 Hz), 3.52 (IH ₅ dd: 7.5, 7.0 Hz) ₅ 4.05 (2H, m, W= 39 Hz), 7.14-7.33 (5H,

m); ¹³ C-NMR (CDCl ₃ ; 50 MHz) δ 25.73 (CH ₃ ), 26.99 (CH ₃ ), 32.02 (CH ₂ ), 35.33 (CH ₂ ), 69.31 (CH ₂ ), 75.35 (CH), 108.71(quat. C), 125.95 (CH) ₅ 128.35 (2xCH), 125.41(2xCH), 141.53 (quat. C).

Example 8e.3 β)-4-Phenylbutane- 1 ,2-diol.

_r TT _n Ci ₀ H ₁₄ O ₂

^{13 18 2} MoI Wf 16622

MoI. Wt: 206,28 ^{0L WT} " ^100>/Z

(4»S)-2,2-Dimethyl-4-phenetyl-[l,3]dioxolane, obtained according to example 8e.2 (49.8 g, 0.241 mM) was disoolved in methanol (0.60 L), p-toluenesulfonic acid (0.50 g) was added and stirring was carried out at 40 ⁰ C for 4 hours. Then, Et ₃ N (2 mL) was added to the mixture and the solvent was evaporated under vacuum. The prepared oil was purified by "flash" chromatography silica gel column (500 g), EtOAc was used as eluent. (S)-4-Phenylbutane-l,2-diol (40.0 g, 99%) was obtained as colourless, thick oil, solidifying at +4°C; m.p. = 34-36 ⁰ C; [α]o= (- )13.6°(CHC1 ₃ , 20 ⁰ C, c= 1); [α] _D = (-)33.1°(EtOH, 2O ⁰ C, c= 1); ¹ H-NMR (CDCl ₃ ; 200 MHz): spectrum identical with spectrum described for (35)-l-phenyl-3,4- butanediol in Example 8 a.

Analysis of this sample by chiral HPLC chromatography was carried on Chiracel OD column (250+20)x4.6 mm, 10 μm, eluent: hexane (80% vol) - 2- propanol (20% vol), flow rate 1.0 mL/min.: R _t 8.5 min. (0.33%), R, 11.1 min. (98.86%), ee = 99.3%. In order to calibrate HPLC measurement, racemic 4- phenyl-l,2-butanediol was used, as in Example 8a above.

Example 8e.4 (S)-2-Hydroxy-4-ρhenylbutyl 4-methylbenzenesulfonate

C ₁₀ H ₁₄ O ₂ C ₁₇ H ₂ o0 ₄ S MoI. Wt: 166,22 MoI. Wt: 320,40

(S)-4-Phenyl-3,4-butane-l,2-diol obtained according to procedure described in Example 8e.3 of enantiomeric excess ee= 99.3% (40 g) was subjected to the reaction of monotosylation, as in Example 8b. After processing, the mixture was concentrated to 200 mL vol and injected on "flash" chromatographic column with silica gel 230-400 mesh (1000 g). As a mobile phase, the solution of 25% EtOac in hexane was used. (3,S)-l-Phenyl-3-hydroxy-4-p- toluenesulfonyloxybutane was obtained (60 g, 77.8%) as colourless, thick oil; ¹ H- NMR (CDCl ₃ ; 200 MHz): spectrum identical with that described in Example 8.b. This sample of tosylate (ee =99.7%) was crystallized from Et ₂ O (VEt2o : m = 3.5). Crystalline (S)-2-hydroxy-4-phenylbutyl 4-methylbenzenesulfonate was obtained (52 g, 67.4%) as colourless needles; [α] _D = (+) 1.0° (CHCl ₃ , 20 ⁰ C, c= 1). Analysis of this sample by chiral HPLC chiral chromatography was carried out on Chiracel OD column OD (250+20)x4.6 mm, 10 μm, eluent: hexane (80% obj.) - 2-propanol (20% obj.), flow rate 1.0 mL/min.: R _t 13.2 min. (98.37%), R ₄ 15.9 min. (0.039%); ee- 99.92 %.

Example 8e.5

(S)-2-(Triethylsilyloxy)-4-phenylbutyl and (iS)-l-phenyl-4-iodo-3-

(triethylsilyloxy)butane 4-methylbenzenesulfonate.

ee » 99% ee » 99%

67

ee » 99%

C ₁₆ H ₂₇ IOSi MoI. Wt.: 390,37

Crystalline (S)-2-hydroxy-4-phenylbutyl 4-methylbenzenesulfonate (ee=99.92%, 10.0 g) was silylated with chlorotriethylsilane according to the procedure described in Example 8c. (5)-2-(Triethylsilyloxy)-4-phenylbutyl A- methylbenzenesulfonate (13.43 g, 99%); ee=99.2%; spectrum ¹ H-NMR identical with that described for this compound in Example 8c. was obtained. This sample of (3,S)-l-phenyl-4-p-toluenesulfonyloxy-3-triethylsilyloxybuta ne (13.2 g) was reacted with Nal/DMF according to the procedure described in Example 8d.l, while heating at 75-80°C was carried out for 2.5 h. After processing and chromatographic purification, as in Example 8d.l, (S)-l-phenyl-4-iodo-3-

(triethylsilyloxy)butane was prepared (10.55 g, 89%); ee= 99.92%; spectrum ¹ H- NMR identical with that described for this compound in Example 8d.

Example 8.f (2R/S, 4S)-4-Phenethyl-[l,3,2]dioxathiolate-2-oxide

C ₁₀ H ₁₄ O ₂ C _1O H ₁₂ O ₃ S

MoI. Wt: 166,22 MoI. Wt: 212,27

To a round-bottom flask of 1 L vol, provided with a magnetic stirrer, a thermometer, argon inlet and a dropper with pressure compensation, 13.4 g of (S)- 4-phenylbutane-l,2-diol (ee= 99.92%) and 600 mL if dichloromethane were added, and stirring was continued for 5 minutes. The solution of 28.2 mL of N ₅ N- diisopropyylethylamine was added, the mixture was cooled to 5 ⁰ C. Then, over 10 minutes, thionyl chloride (6.20 mL) was added dropwise under the surface of the solution, so that the temperature was maintained in the range of 0 - 5 ⁰ C. Stirring was continued at this temperature for 1 hour. The reaction mixture was poured into 500 mL of 0.1 M phosphate buffer of pH 7.2 of the temperature of O ⁰ C. Organic layer was separated and washed with 500 mL of 2% NaCl solution. The mixture was dried with anhydrous sodium sulfate, concentrated and dried under the reduced pressure. The cyclic sulfite of (2R/S, 4S)-4-phenethyl-

[l,2,3]dioxathiolate-2-oxide in the from of oil (16.5 g, 96% yield), two diastereoisomers (approx. 1:1) was obtained; ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.83-2.38 (2H, m), 2.62-2.97 (2H, m), 3.90 (0.5H, dd: 8.1, 6.8 Hz), 4.24-4.52 (IH, m), 4.62 (0.5H, dd: 8.5, 6.4 Hz), 4.87-5.00 (0.5H, m), 7.16-7.35 (5H, m); ¹³ C- NMR (50 MHz, CDCl ₃ ) δ: 31.58, 31.99, 34.09, 35.13, 70.20, 71.50, 79.41 (CH), 82.98 (CH), 126.45, 126.49, 128.42, 128.46, 128.6, 128.70, 140.06, 140.16.

Example 8.g

(5)-4-Phenethyl-[l,3,2]dioxathiolate-2,2-dioxide

ee » 99%

C ₁₀ H ₁₂ O ₃ S C ₁₀ H ₁₂ O ₄ S MoI. Wt.: 212,27 MoI. Wt: 228,27

To the vigorously stirred solution of (2R/S, 4S)-4-phenethyl- [l,3,2]dioxathiolate-2-oxide prepared according to the procedure described in Exammple 8.f (7.8 g) in 100 mL of acetonitrile, 11.0 g of sodium periodate, 81 mg of rhutenium chloride hydrate RuCl ₃ x 3H ₂ O and 20 mL of water were added. The reaction mixture heated from 20° to approx. 40 ⁰ C over 10 minutes, and after this time complete oxidation of sulfite to sulfate was found on the basis of TLC (hexane/AcOEt 2:1). After cooling to the temperature of 2O ⁰ C, 100 mL of diethyl ether and 80 mL of water were added. Layers were separated, aqueous phase was extracted with Et ₂ O (2 x 100 mL). The combined ether soluions were dried over anhydrous sodium sulfate, the solvents were evaporated under the reduced pressure. 7.9 g of dark precipite was obtained, which was crystallized from 20 mL

of Et ₂ O. (S)-4-Phenethyl-[l,3,2]dioxathiolate-2,2-dioxide was obtained (3.5 g, 42%); white crystals, t.t.= 50-51 ⁰ C; [α] _D = (-)42.9° (MeOH, 2O ⁰ C, c= 1); IR (KBr) 651, 702, 757, 783, 853 (s), 965 (s), 1013, 1038, 1210 (s), 1381 (s), 1602 cm ¹ ; ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.93-2.11 (IH, m), 2.19-2.37 (IH, m), 2.65-2.94 (2H, m), 4.28 (IH, t: 8.1Hz), 4.60 (IH, dd: 9.0, 6.0 Hz), 4.85-4.98 (IH, m), 7.16- 7.38 (5H, m); ¹³ C-NMR (50 MHz, CDCl ₃ ) δ: 30.73, 33.86, 72.68, 81.99 (CH), 126.68, 128.31, 128.76, 139.07. Elem. analysis: for C ₁₀ Hi ₂ O ₄ S calc. %C: 52.62, %H: 5.30; %S: 14.05; found. %C: 52.66, %H 5.34, %S: 14.09. Analysis of this sample by chiral HPLC chromatography was carried out on Chiracel OD column (250+20) x 4.6 mm, 10 μm, eluent: hexane (85% vol) - 2- propanol (15% vol), flow rate 1.0 mL/min.: R _t 41.0 min. (100%), peak of the second isomer was not found; and also on Chiracel AD column (250+20) x 4.6 mm, 10 μm, eluent: hexane (85% vol) - 2-propanol (15% vol), flow rate 1.0 mL/min.: R _t 10.5 min. (100%), peak of the second isomer was not found; ee= approx. 100%.

Example 8.h

(S)- 1 ,2-Epoxy-4-phenylbutane

Example 8.h.l

(S)-4-phenyl- 1 -iodobutan-2-ol

C ₁₀ H ₁₃ IO

C ₁₆ H ₂₇ IOSi

MoI. Wt: 276,11 MoI. Wt.: 390,37

(ιS)-l-Phenyl-4-iodo-3-triethylsilyloxybutane of enantiomeric excess ee= 99.2% (3.52 g, 9.0 niM) was dissolved in acetone (20 mL). H ₂ O was added (2 mL). The solution was stirred at 20 ⁰ C under argon and pyridynium p- toluenesulfonate was added (200 mg). After 20 hours, the mixture was poured on 3% aqueous solution OfNaHCO ₃ (150 mL), and the mixture OfEt ₂ O-EtOAc was added (1:1, 100 mL). After extraction, the layers were separated, the organic layer was dried over Na ₂ SO ₄ (15 g), the drying agent was filtered and washed with EtOAc (20 mL). The filtrates were combined and concentrated under vaccum. The prepared oil was purified by "flash" chromatography on silica gel column 230-400 mesh, 120 g, eluent: 15% EtOAc/hexane. The obtained fractions, which were pure on TLC, were concentrated to the volume of 10 mL and put away at 0 ⁰ C for 2 hours. The obtained crystals were filtered and dried. (S)-4-Phenyl-l- iodobutane was prepared (1.80 g, 72%), white needles, t.t.= ⁰ C; [α] _D = (-)15,8° (CHCl ₃ , 20 ⁰ C, c= 1); ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.87 (2H, m), 2.74 (2H, m), 3.24 (IH, dd: 10.2, 6.8 Hz), 3.38 (IH, dd: 10.1, 3.5 Hz), 3.52 (IH, m, W= 28 Hz), 7.15-7.34 (5H, m); ¹³ C-NMR (50 MHz, CDCl ₃ ) δ: 16.59, 31.91, 38.14, 70.12, 126.07, 128.42 (2C), 128.50 (2C), 141.26. Elem. analysis: for C ₁₀ H ₁₃ IO ₃ calc. %C: 43.50, %H: 4.75; %I: 45.96; found. %C: 43,49, %H 4,61, %I: 46,00.

Analysis of this sample by chiral HPLC chromatography was carried out on Chiracel OD column (250+20) x 4.6 mm, 10 μm, eluent: hexane (85% vol) - 2-

propanol (15% vol), flow rate 1.0 niL/min.: R _t 8.20 min. (99.867%), R _t 11.1 (0.073%); ee= 99.85%.

Example 8.h.2 (S)-l,2-Epoxy-4-phenylbutane

C ₁₀ H ₁₃ IO C ₁₀ H ₁₂ O MoI. Wt: 276,11 MoI. Wt: 148,20

Crystalline (S)-4-phenyl-l-iodobutan-2-ol (ee= 99.85%) (1.61 g, 5.84 rnM) was dissolved in THF (12 mL). H ₂ O (1.5 mL) and solid KOH (1.95 g) were added. The reaction mixture was stirred at 20 ⁰ C under argon. After 7 hours, the mixture was quantitatively transferred to the separator, in which brine (50 mL), water (100 mL) and Et ₂ O (120 mL) were previously placed. After extraction, the phases were separated, the organic phase was extracted with H ₂ O (150 mL), the organic phase was dried over anhydrous Na ₂ SO ₄ (20 g, O ⁰ C, 16 hours), the drying agent was filtered and washed with Et ₂ O (20 mL), the filtrates were combined and concentrated at O ⁰ C, then they were dried (1O ⁰ C, 5 mm Hg, 15 minutes). (S)- 1,2- Epoxy-4-phenylbutane was obtained as pale yellowish oil; [α]o= (-)19,9° (CHCl ₃ , 20 ⁰ C, c= 1); ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.79-1.92 (2H, m), 2.47 (IH, dd: 4.9, 2.6 Hz), 2.66-2.87 (3H, m), 2.91-3.00 (IH, m), 7.15-7.34 (5H, m); ¹³ C-NMR (50 MHz, CDCl ₃ ) δ: 32.25, 34.29, 47.25 (CH ₂ ), 51.79 (CH), 126.02, 128.38 (2C), 128.45 (2C), 141.26. Elem. analysis: for Ci ₀ H ₁₂ O calc. %C: 81.04, %H: 8.16; found. %C: 80,25, %H: 8,20. Analysis of this sample by chiral HPLC chromatography was carried out on Chiracel OD column (250+20) x 4.6 mm, 10 μm, eluent: hexane (85% vol) - 2- propanol (15% vol), flow rate 1.0 niL/min.: R _t 8.86 min. (97.34%), R _t 10.6 min. (1.48%); ee= 97.00%.

Example 9

(phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)cyclope ntyl]hex-4-enyl}-4- methyl-2,6,7-trioxabicyclo[2.2.2]octane and 2,2-bis(hydroxymethyl)propyl [Z)-I-

(phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)cyclopenty l]hept-5-enate.

l-{(Z)-6-[(lR,2R,3R,5S)-2-((Phenylsulfonyl)methyl)-3,5-bis- (triethylsilyloxy)cyclopentyl]hex-4-enyl} -4-methyl-2,6,7- trioxabicyclo[2.2.2]octane (2.29 g, 3.29 mM) was dissolved in anhydrous THF (Aldrich, containing inhibitor); 15 mL). The solution was cooled to -75°C under

argon. Upon vigorous stirring, 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (14 rnL, 14 mM) was added over 3 minutes. It was stirred at -78°C under argon (20 minutes), then the solution was heated to 0 ⁰ C and stirred at this temperature for 10 minutes, then the mixture was cooled again to -78 ⁰ C. After 5 minutes of stirring at this temperature, the solution of (S)-l-phenyl-4-iodo-3- triethylsilyloxybutane (ee= 99.2%, 4.96 g, 12.7 mM) in anhydrous THF (4mL) was slowly added dropwise. It was stirred under argon at -78 ⁰ C for 10 minutes, then at 0 ⁰ C for 80 minutes. The cooling bath was removed and stirring was continued, allowing slow heating of the reaction mixture to +20 ⁰ C. After the total reaction time of 5 hours and 10 minute, the reaction mixture was cooled again under argon to -78°C and 1% solution of C ₅ H ₅ N in the brine-saturated aqueous solution OfNaHCO ₃ mixture (1:1) (4 mL) was added dropwise, then the mixture Of EtOAc-CH ₂ Cl ₂ (6:1); 50 mL) was added and the cooling bath was exchanged for water bath (+1O ⁰ C). Upon stirring of flask content, 1% solution of C ₅ H ₅ N in brine-saturated aqueous solution Of NaHCO ₃ mixture (1:1) (20 mL) was added. Then the mixture was transferred to the separator containing 1% solution of C ₅ H ₅ N in saturated aqueous solution Of NaHCO ₃ mixture (1:1) (30 mL) and mixture of EtOAc-CH ₂ Cl ₂ (6:1; 60 mL). After extraction, the phases were separated, the aqueous phase was extracted with EtOAc-CH ₂ Cl ₂ mixture (6:1; 30 mL). The organic phases were combined and extracted with 1% solution of C ₅ H ₅ N in brine-saturated aqueous solution Of NaHCO ₃ mixture (1:1) (50 mL). The phases were separated, the organic phase was dried over anhydrous Na ₂ SO ₄ (15 g). The drying agent was filtered and washed with EttOAc (20 mL). The filtrates were combined, concentrated and dried (6.92 g, oil). This sample was separated by "flash" chromatography on silica gel column 230-400 mesh (250 g).

As eluent, the following mixtures of solvents (phases) were subsequently used, I: 5% EtOAc in hexane + 0.1% tOAc in hexane + 0.1 III: 16.3% EtOAc in hexane : 100% EtOAc + 0.1% C ₅ H ₅ N. Concentration and drying of fractions pure on TLC eluted with Phase I gave (S)- l-phenyl-4-iodo-3-triethylsilylbutane (ee = 99.2%; 3.757 g), ¹ H-NMR (CDCl ₃ ; 200 MHz) identical with that described in Example 8d.l; concentration and drying of fractions pure on TLC eluted with Phase III gave: (a triethylsilyloxy-S-phenyl-l-φhenylsulfony^pentyO-SjS-bis- (triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7- trioxabicyclo[2.2.2]octane (mixture of two epimers in a ratio of 5:2, of different configurations at carbon atom, to which phenylsulfonyl is attached) (1.456 g, 46.2%); elem. analysis: found. %C: 65.58, %H 9.37, %S: 3.55. Content of each isomer in this mixture was determined on the basis of integration of olefinic signals in ¹ H-NMR spectrum (CDCl ₃ ; 500 MHz); and ( (phenylsulfonyl)metyl)- 3,5-bis-(triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2 ,6,7- trioxabicyclo[2.2.2]octane (recovered substrate; 165 mg, 7.2%), colourless glaze; ¹ H-NMR spectrum (CDCl ₃ ; 200 MHz) identical with that described in Example 6; concentration and drying of fractions pure on TLC eluted with Phase IV allowed for preparartion of ήethy\sily\oxy-5- phenyl-l-(phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)- cyclopentyl]hept-5- enoic acid 2,2-bis(hydroxymethyl)propyl ester (mixture of two isomers in a ratio of approx. 5:2, of different configurations at carbon atom, to which phenylsulfonyl is attached) (435 mg, 13.5%), pale yellowish, thick oil; ¹ H-NMR (CDCl ₃ + 0.1 % C ₅ D ₅ N; 200 MHz) δ 0.57 (18H, m), 0.83 (3H, s, CH ₃ ), 0.94 (27H,

m), 1.40-1.82 (5H, m), 1.90 (2H, m), 1.98-2.45 (1OH, m), 3.10 (IH, bs, OH), 3.22 (0.29H, m), 3.47 (0.71H, m), 3.55 (4H, bs), 3.87 (IH, m), 3.89 (IH, bs), 4.18 (4H, m), 4.41 (0.29H, m), 4.53 (0.71H, m), 5.26-5.53 (2H, m), 7.08-7.33 (5H, m), 7.46- 7.72 (3H, m), 7.84-7.94 (2H, m). Sample of triethylsilyloxy-S- phenyl-l-(phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)c yclopentyl]hex-4- enyl}-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (mixture of two isomers in a ratio of 5:2, 90 mg) was separated, by repeating twice a procedure on "flash" column LiChroprep (25-40 μm, 7 g), using 10% EtOAc in hexane +0.1% C ₅ H ₅ N as eluent. The following compounds were prepared: (a) major isomer l-{(Z)-6-

ethylsilyloxy-5-phenyl-l-(phenylsulfonyl)pentyl)- 3,5-bis-(triethylsilyloxy)cyclopentyl]hex-4-enylo}-4-methyl- 2,6,7- trioxabicyclo[2.2.2]octane (27.6 mg), colourless, thick oil; ¹ H-NMR (CDCl ₃ + 1% C ₅ D ₅ N; 500 MHz) δ 0.572 (18 H, m), 0.798 (3H, s), 0.940 (27H, m), 1.560 (4H, m), 1.654 (3H, m), 1.730 (2H, m), 1.992 (IH, m), 2.074-2.238 (5H, m), 2.362 (IH, ddd: 10.1, 8.2, 1.9 Hz), 2.494 (IH, ddd: 13.6, 11.0, 5.2 Hz), 2.584 (IH, ddd: 13.6, 11.0, 6.1 Hz), 3.471 (IH, ddd: 7.2, 5.2, 2.0 Hz; CHSO ₂ Ph), 3.898 (6H, s), 3.92 (IH, m, W= 7.7 Hz), 4.168 (IH, m, W= 8.2 Hz), 4.582 (IH, m, W= 6.8 Hz), 5.402 (2H, m, W= 15.7 Hz), 7.132 (2H, bd: 7.1 Hz), 7.181 (IH, bt: 7.3 Hz), 7.276 (2H, bt: 7.6 Hz), 7.532 (2H, bt: 7.8 Hz), 7.594 (IH, ddd: 7.4, 2.0, 1.6 Hz), 7.886 (2H, bdd: 7.2, 1.5 Hz). ¹³ C-NMR (CDCl ₃ + 1% C ₅ D ₅ N; 125 MHz) δ 4.96 (3C), 5.04 (3C), 5.22 (3C), 6.87 (6C), 6.93 (3C), 14.51, 23.21, 25.69, 27.24, 30.16, 31.11, 34.35, 36.30, 39.07, 44.14, 45.78, 50.44, 60.74, 69.04, 71.09, 72.52 (3C), 73.03, 109.02, 125.67, 128.22 (2C), 128.28 (2C), 128.37 (2C), 128.54, 128.91 (2C), 130.20, 133.10, 140.13, 142.17; and (b) minor isomer l-{(Z)-6-

[(li?,27?,3i?,5S)-2-((15' _J 35)-3-triethylsilyloxy-5-ρhenyl-l-(phenylsulfonyl)ρe ntyl)- 3,5-bis-(1riethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2 ,6,7- trioxabicyclo[2.2.2]octane (17.9 mg), colourless, thick oil; ¹ H-NMR (CDCl ₃ + 1% C ₅ D ₅ N; 500 MHz) δ 0.580 (18H, m), 0.783 (3H, s, CH ₃ ), 0.950 (27H, m), 1.420- 1.609 (6H ₅ m), 1.677 (3H, m), 1.805 (IH, quintet 7.1 Hz), 1.924-2.374 (7H, m), 2.475 (IH, ddd: 13.8, 11.4, 4.8 Hz), 3.240 (IH, ddd: 7.0, 4.8, 1.9 Hz; CHSO ₂ Ph), 3.882 (6H, s), 3.896 (IH, m, W= 24 Hz), 4.183 (IH, dd: 9.9, 5.1 Hz), 4.484 (IH, ddd: 12.6, 7.8, 5.9 Hz), 5.265 (2H, bdd: 5.0, 4.4 Hz), 7.027 (2H, dddd: 7.0, 2.2, 1.8, 1.4 Hz), 7.161 (IH, dd: 7.4, 1.4 Hz), 7.239 (2H, dddd: 7.4, 7.0, 2.2, 1.6 Hz), 7.494 (2H, dddd: 7.6, 7.1, 1.6, 1.2 Hz), 7.550 (IH, dd: 7.5, 1.3 Hz), 7.912 (2H, dddd: 7.1, 2.0, 1.5, 1.2 Hz). ¹³ C-NMR (CDCl ₃ + 1% C ₅ D ₅ N; 125 MHz) δ 4.97 (3C), 4.99 (3C), 5.05 (3C), 6.86 (3C), 6.92 (3C), 6.94 (3C), 14.53, 23.17, 25.70, 26.18, 27.07, 29.65, 30.16, 30.37 (quaternary C), 34.93, 36.29, 37.74, 43.57, 46.32, 51.51, 61.23, 69.49, 71.86, 72.53, 73.64, 109.05, 125.61, 128.13, 128.16 (2C), 128.19 (2C), 128.90 (2C), 128.92 (2C), 130.48, 133.31, 139.44, 142.10.

Example 9. a l-{(Z)-6-[(lR,2R,3R,5S)-2-((Phenylsulfonyl)methyl)-3-hydroxy -5- (triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7- trioxabicyclo[2.2.2]octane.

l-{(Z)-6-[(lR,2R,3R,5S)-2-((Phenylsulfonyl)methyl)-3,5-bi s- (triethylsilyloxy)cyclopentylo]hex-4-enyl}-4-methyl-2,6,7- trioxabicyclo[2.2.2]octane (345 mg) was dissolved in anhydrous THF (2 niL). The solution was cooled to -78°C and the solution of n-BuLi in hexane was added (2.4 M, 0.42 niL, 1.0 niM). After 1 hour of stirring at this temperature, solution of (S)- l-phenyl-4-iodo-3-triethylsilylbutane was added dropwise (ee = 99.2%; 0.50 niL, approx. 0.62 g, 1.58 niM) in THF (0.50 niL). The mixture was stirred and slowly heated to room temperature over 2 hours. After processing similar to that of Example 9 above, the crude product was purified on chromatographic silica gel column 230-400 mesh (100 g), eluent gradient 10%-90% EtOAc in hexane + 0.15% C ₅ H ₅ N. The following compounds were obtained: (a) unreacted alkyl iodide (532 mg) and (b) l-{(Z)-6-[(li?,2 _J R,3i?,55)-2-((phenylsulfonyl)methyl)-3- hydroxy-5-(triethylsilyloxy)cyclopentyl]hex-4-enyl} -4-methyl-2,6,7- trioxabicyclo[2.2.2]octane (139 mg, 48.2%), colourless glaze; ¹ H-NMR (CDCl ₃ ; 200 MHz) δ 0.60 (6H, q: 8.0 Hz), 0.80 (3H, s), 0.93 (9H, t: 8.0 Hz), 1.42 (3H ₃ m), 1.60 (2H, m), 1.82 (4H ₃ m), 1.97-2.23 (4H, m), 3.02 (IH ₃ dd: 14.5, 11.0 Hz; CHSO ₂ Ph), 3.33 (IH, dd: 14.5, 2.6 Hz; CHSO ₂ Ph), 3.89 (6H, s), 4.12 (2H ₃ m), 5.23 (2H, m), 7.60 (3H, m), 7.96 (2H, m). The second regioisomer (5-OH cyclopentane) of this compound was not isolated.

Example 10

thylsilyloxy-5-phenylpentyl)-3,5-bis- (triethylsilyloxy)cycloρentyl]hex-4-enyl}-4-methyl-2,6,7- trioxabicyclo[2.2.2]octane and 2,2-bis(hydroxymethyl)propyl (Z)-7-

triethylsilyloxy-5-ρhenylρentyl)-3,5-bis- (triethylsilyloxy)cyclopentyl]hept-5-enate.

Triethylsilyloxy-5-phenyl-l -

(phenylsulfonyl)ρentyl)-3,5-bis-(triethylsilyloxy)cyclop entyl]hex-4-enyl}-4- methyl-2,6,7-trioxabicyclo[2.2.2]octane (the mixture of two epimers in a ratio of 5:2, of different configuration at C-I carbon atom of omega chain) (770 mg, 0.80

niM) was dissoled in anhydrous MeOH (30 mL) and Na ₂ HPO ₄ was added (1.00 g, 7.0 mM). The mixture was stirred in argon atmosphere at room temperature. After 10 minutes, the mixture was cooled under argon to 0 ⁰ C and 10% Na/Hg amalgam was added (2.86 g). The mixture was stirred at 0 ⁰ C for 1 hour, then the cooling bath was removed and stirring was carried out under argon, allowing the mixture to heat slowly to 20 ⁰ C. After the total reaction time of 110 minutes, the mixture was cooled, vigorously stirring, again to 0 ⁰ C and, saturated aqueous solution of NH ₄ Cl (2.0 mL) was added dropwise. Immediately after the end of dropwise addition, 1% C ₅ H ₅ N solution in EtOAc (25 mL) was added. The mixture was vigorously stirrred for 15 minutes, H ₂ O (5mL) was added and stirring was carried out for further 10 minutes. Then the mixture was transferred to the separator containing saturated aqueous solution OfNH ₄ Cl (40 mL) and 1% C ₅ H ₅ N solution in EtOAc (30 mL). Mercury was removed and secured. After extraction the phases were separated, the aqueous phase was extracted with EtOAc (30 mL), the organic phases were combined and dried over the anhydrous Na ₂ SO ₄ (15 g, +4°C, over night). The drying agent was filtered and washed with EtOAc (15 mL). The combined filtrates were concentrated and dried under vacuum (5 mm Hg, 30 minutes, 25 ⁰ C). The crude product was purified by "flash" chromatography on LiChroprep column (25-40 μm; 70 g), eluent: gradient 7% - 70% EtOAc in hexane +0.12% C ₅ H ₅ N. After concentration and drying of homogenous fractions on TLC, the following compounds were obtained: (a) l-{(Z)-6-[(li?,2i?,3i?,55)-2- ((/?)-3-triethylsilyloxy-5-phenylpentyl)-3,5-bis-(triethylsi lyloxy)cyclopentyl]hex- 4-enyl}-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (420 mg, 69.6%), colourless glaze; [α] _D = (+)10°(CHCl ₃ + 0.1% Et ₃ N, 2O ⁰ C, c= 1); ¹ H-NMR (CDCl ₃ + 0.1% C ₅ H ₅ N; 200 MHz) δ 0.60 (18H, m), 0.79 (3H, s), 0.96 (27H, m), 1.30-1.61 (8H,

m), 1.65-1.82 (5H, m), 2.01-2.32 (5H ₅ m), 2.68 (2H, m), 3.73 (2H, m), 3.88 (6H, s), 4.09 (IH, bdd: 11.5, 5.8 Hz), 5.39 (2H, m, W= 40 Hz), 7.20 (3H, m), 7.28 (2H ₃ m); ¹³ C-NMR (CDCl ₃ + 0.1% C ₅ H ₅ N; 50 MHz) δ 4.87 (3C), 4.90 (3C), 5.09 (3C), 6.85 (3C), 6.86 (3C), 6.97 (3C), 14.49, 23.22, 25.74, 27.00, 27.93, 30.11, 31.66, 34.35, 36.21, 39.08, 44.19, 48.15, 50.10, 71.72, 72.34, 72.47 (3C), 76.23, 108.96, 125.51; 128.23 (2C), 128.26 (2C), 129.32, 129.71, 142.73; Elem. analysis: for C ₄₆ H ₈₄ O ₆ Si ₃ calc. %C: 67.59, %H: 10.36; found. %C: 67.62, %H 10.40; and (b) 2,2-bis(hydroxymethyl)propyl (Z)-7-((li?,2i?,3i?,5δ)-2-(( _J R)-3-triethylsilyloxy-5- phenylpentyl)-3,5-bis-(triethylsilyloxy) cyclopentyl]hept-5-enate (68 mg, 10.1%), pale yellowish glaze; TLC (Merck plates No. 1.05549; 25% EtOAc/hexane + 0.1% C ₅ H ₅ N) R _f = 0.07; ¹ H-NMR (CDCl ₃ + 0.1% C ₅ H ₅ N; 200 MHz) δ 0.58 (18H, 9 x 2H, q), 0.92 (30H, m: 9 x 3H, t+1 x 3H, s), 1.25-1.42 (2H, m), 1.43-1.90 (12H, m), 2.06-2.40 (6H, m), 2.64 (2H, m, W= 60 Hz), 3.03 (IH, bs, OH), 3.54 (3H, m), 3.88 (2H ₅ m), 4.04 (IH, m), 4.18 (2H, m), 5.40 (2H, m), 7.19 (3H, m), 7.27 (2H, m).

Example 11 l-{(Z)-6-[(li?,2i?,3Λ,5 ₎ S)-2-((i?)-3-Triethylsilyloxy-5-phenylρentyl)-3,5-bis - (txiethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7- trioxabicylo[2.2.2]octane.

Example 11a:

ethylsilyloxy-S-phenylpentyO-S^-bis- (triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7- trioxabicyclo[2.2.2]octane. -Triethylsilyloxy-S-phenyl-l- (phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy) cyclopentyl]hex-4-enyl}-4- methyl-2,6,7-trioxabicyclo[2.2.2]octane (the mixture of two epimers in a ratio of 5:2) (116 mg, 0.121 mM) was dissolved under argon in anhydrous MeOH (5.0 niL) and Na ₂ HPO ₄ was added (150 mg, 1.06 mM). The mixture was stirred in argon atmosphere at room temperature. After 20 minutes, the mixture was cooled under argon to 0 ⁰ C and 10% Na/Hg amalgam was added (360 mg, approx. 1.5 mM of Na). The mixture was stirred at O ⁰ C for 1 hour, then the coolimg bath was removed and stirring was carried out under argon, allowing the mixture to heat to 2O ⁰ C. After the total reaction time of 100 minutes (starting from the moment of amalgam addition), the mixture was cooled again to 0 ⁰ C and, upon vigorous stirring, and saturated aqueous NH ₄ Cl solution (3.0 mL) was added. The mixture

was stirred for 10 minutes, then H ₂ O (3 mL) was added and stirring was carried out under argon for 15 minutes. Then the the mixture was transferred to the separator containing saturated aqueous NH ₄ Cl solution (4 mL) and 1% solution of C ₅ H ₅ N in EtOAc (40 mL). Mercury was removed and secured. After extraction, the phases were separated, the aqueous phase was extracted with EtOAc (30 mL), the organic phases were combined and extracted with saturated aqueous NH ₄ Cl solution (30 mL). The layers were separated, the aqueous layer was dried over the anhydrous Na ₂ SO ₄ (10 g, + 4°C, over night). The drying agent was filtered and washed with EtOAc (10 mL). The combined filtrates were concentrated and dried under vacuum (1 mm Hg, 40 minutes, 25°C) to give l-{(Z)-6-[(li?,2R,3i?,55)-2- ((jR)-3-triethylsilyloxy-5-phenylpentyl)-3,5-bis-(triethylsi lyloxy) cyclopentyl]hex- 4-enyl}-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (106 mg, 99%), pale yellowish glaze; [α] _D = (+)9.9°(CHC1 ₃ + 0.1% Et ₃ N, 2O ⁰ C, 0= 1); ¹ H-NMR (CDCl ₃ + 0.1% C ₅ H ₅ N; 200 MHz): spectrum identical with that described for this compound in Example 10.

Example lib l-{(Z)-6-[(li?,2i?,3i?,5,S)-2-((i?)-3-Triethylsilyloxy-5-phe nylpentyl)-3 ₅ 5-bis-

(triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7- trioxabicyclo[2.2.2]octane.

In a three-necked flask provided with a reflux condeser for dry ice and placed in a dry ice - methanol cooling bath in argon atmosphere, anhydrous NH ₃ was condensed (Fluka; 50 mL). Then metallic calcium was added (20 mg, 5.5 niM), stirring was carried out for 25 minutes under argon, then the solution of 1- {(Z)-6-[(li?,2/?,3i?,5 _l S)-2-((li?/l ₁ S;3 ₎ S)-3-triethylsilyloxy-5-phenyl-l-

(phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)cyclopenty l]hex-4-enyl}-4- methyl-2,6,7-trioxabicyclo[2.2.2]octane was added (the mixture of two epimers in a ratio of 5:2) (80 mg, 0.0835 mM) in anhydrous THF (5 mL). The mixture was stirred at -78 ⁰ C for 5 hours, then THF was added (5 mL), the cooling bath was removed and stirring was carried out over night, allowing ammonia to evaporate slowly. After 16 hours, THF was added (20 mL), the mixture was cooled to 0 ⁰ C and saturated aqueous NH ₄ Cl solution (5 mL) was slowly added dropwise. EtOAc (30 mL) and NH ₄ Cl (30 mL) were added, phases were separated after the extraction. The aqueous phase was extracted again with EtOAc (10 mL), the organic phases were combined and extracted with saturated aqueous NH ₄ Cl solution (25 mL). The ogranic phase was dried over Na ₂ SO ₄ (7 g), the drying agent was filtered, the filtrate was concentrated under vacuum (1 mm Hg, 50 ⁰ C, 1 hour). Pale yellowish glaze (64 mg) was obtained, which was purified by "flash" chromatography on silica gel column (10 g), eluent: gradient 5-50% EtOAc in hexane + 0.1% C ₅ H ₅ N. l-{(Z)-6-[(li?,2i?,3i?,5 _J S)-2-((i?)-3-Triethylsilyloxy-5- phenylpentyl)-3,5-bis-(triethylsilyloxy)cyclopentyl]hex-4-en yl}-4-methyl-2,6,7- trioxabicyclo[2.2.2]octane was obtained (35.8 mg, 52.4%), colourless glaze; ¹ H- NMR (CDCl ₃ + 0.1% C ₅ H ₅ N; 200 MHz): spectrum in accordance with that described for this compound in Example 10, however, additional signals, indicating presence of unknown olephinic impurity, were observed (approx. 25% mol.): δ 5.71 (bs), 3.89 (s, OBO-CH ₂ ), 0.79 (s, OBO-CH ₃ ).

Example lie

l-{(Z)-6-[(li?,2R,3 _J R,55)-2-((R)-3-Triethylsilyloxy-5-phenylpentyl)-3,5-bi s-

(triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7- trioxabicyclo[2.2.2]octane.

In a three-necked 100 mL flask provided with a reflux condeser for dry ice and placed in a dry ice - methanol cooling bath in argon atmosphere, anhydrous NH ₃ was condensed (Fluka; 50 mL). Then metallic lithium was added (71 mg, 10.2 mM), stirring was carried out for 20 minutes under argon, then the solution of l-{(2)-6-[(lΛ,2i.,3i.,5 _ι S)-2-((lΛ/l ₁ S;35)-3-triethylsilyloxy-5-phenyl-l-

(phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)cyclope ntyl]hex-4-enyl}-4- methyl-2,6,7-trioxabicyclo[2.2.2]octane was added (the mixture of two epimers in a ratio of 5:2) (92 mg, 0.095 mM) in anhydrous THF (5 mL). The mixture was stirred at -78 ⁰ C for 1 hour, then the cooling bath was removed and stirring was carried out, allowing ammonia to evaporate. After 3 hours, THF (5.5 mL) was added and anhydrous MeOH (0.90 mL) was slowly added dropwise. The mixture was left over night for slow ammonia evaporation. Then saturated aqueous NH ₄ Cl (30 mL) solution and EtOAc (40 mL) were added, the phases were separated after extraction. The aqueous phase was extracted again with EtOAc (10 mL), the organic phases were combined and extracted with saturated aqueous NH ₄ Cl solution (25 mL). The organic phase was dried over Na ₂ SO ₄ (6 g), the drying agent was filtered, the filtrate was concentrated under vacuum (1 mm Hg, 30 ⁰ C, 30 min.). 1 - {(Z)-6-[(lR,2i?,3i?,55)-2-((i?)-3-triethylsilyloxy-5-ρhenyl pentyl)-3,5- bis-(triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7 - trioxabicyclo[2.2.2]octane was obtained as colourless, thick oil (73 mg); ¹ H-NMR (CDCl ₃ + 0.1% C ₅ H ₅ N; 200 MHz): spectrum in accordance with that described for this compound in Example 10; additional signals, indicating presence of unknown

olephinic impurity, were observed (approx. 20% mol.): δ 5.71 (bs), 3.89 (s, OBO- CH ₂ ), 0.79 (s, OBO-CH ₃ ).

Example Hd l-{(Z)-6-[(li?,2i?,3R,55)-2-((R)-3-Triethylsilyloxy-5-phenyl pentyl)-3,5-bis- (triethylsilyloxy)cyclopentyl]hex-4-enyl}-4-methyl-2,6,7- trioxabicyclo [2.2.2] octane.

To a 100 niL flask, placed in the ice- water coolling bath, n-propylamine (Fluka, 20 niL) was added in argon atmosphere. Then metallic lithium was added (90 mg, 13 HiM), stirring was carried out for 30 minutes under argon, then the solution of l-{(Z)-6-[(li?,2i?,3i?,5 ₁ S)-2-((li?/l ₁ S',35)-3-triethylsilyloxy-5-ρhenyl-l- (phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)cyclopenty l]hex-4-enyl}-4- methyl-2,6,7-trioxabicyclo[2.2.2]octane was added (the mixture of two epimers in a ratio of 5:2) (77 mg, 0.08 mM) in anhydrous THF (3 mL). Stirring was carried out at 0 ⁰ C for 4 hours, then the cooling bath was removed and stirring was carried out for 1 hour. THF (5.5 mL) was added and anhydrous MeOH (1 mL) was very slowly added dropwise. Stirring was carried out for 0.5 hour, then the mixture was concentrated under vacuum to approx. 7 mL, saturated aqueous NH ₄ Cl solution (30 mL) and EtOAc (40 mL) were added, the phases were separated after extraction. The aqueous phase was extracted again with EtOAc (10 mL), the organic phases were combined and extracted with saturated aqueous NH ₄ CL soluion (25 mL). The organic phase was dried over Na ₂ SO ₄ (6 g), the drying agent was fileterd, the filtrate was concentrated under vacuum. (1 mm Hg, 3O ⁰ C, 2 godz.). l-{(Z)-6-[(li?,2i?,3i?,5 ₍ S)-2-((i?)-3-triethylsilyloxy-5-phenylpentyl)-3,5-bis- (triethylsilyloxy)cyclopentyl]hex-4-enyl} -4-methyl-2,6,7-

trioxabicyclo[2.2.2]octane was obtained as pale yellowish, thick oil (59 mg); ¹ H-

200 MHz): spectrum in accordance with that described for this compound in Example 10; additional signals, indicating presence of unknown olephinic impurity, were observed (approx. 27% mol): δ 5.71 (bs), 3.89 (s, OBO-CH ₂ ), 0.79 (s, OBO-CH ₃ ).

Example 12 riethylsilyloxy-5-phenyl-l- (phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)cyclopenty l]hex-4-enyl}-4- me1hyl-2,6,7-trioxabicyclo[2.2.2]octane.

iethylsilyloxy-S-phenyl-l-

(phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)cyclope ntyl]hex-4-enyl}-4- niethyl-2,6,7-trioxabicyclo[2.2.2]octane (the mixture of two epimers in a ratio of approx. 5:2) (82 mg, 0.856 mM) was dissolved under argon in anhydrous EtOH (0.50 mL). Mg was added (powder, 50 mesh; 12.7 mg. 0.52 mM) and HgCl ₂ (3.1 mg). Stirring was carried out in a tightly closed flask for 48 hours. Then, C ₅ H ₅ N

was added (0.3 mL) and the mixture was concentrated under vacuum nearly to dryness, then it was purified by "flash" chromatography on silica gel column 230- 400 mesh, eluent: gradient 7%-18% EtOAc in hexane. The following compounds were obtained: (a) (Z)-7-((lR,2R,3R,5S) _r 2-((lR/lS,3S)-3-tήethy\sϊlyloxy-5- phenyl-l-(phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)c yclopentyl]hept-5- enoic acid ethyl ester, 5:2 mixture, epimers at C-I of omega chain (30.3 mg, 39.2%), colourless thick oil; TLC (Merck plates No. 1.05549; 10% EtOAc/hexane + 0.1% C ₅ H ₅ N) Rf= 0.38; ¹ H-NMR (CDCl ₃ + 0.1% C ₅ H ₅ N; 200 MHz) δ 0.58 (18H, 9 x 2H, q), 0.92 (27H, m: 9 x 3H, t), 1.25 (3H, t: 7.3 Hz), 1.43-1.78 (5H, m), 1.90-2.36 (HH, m), 2.50 (2H, m, W= 62 Hz), 3.23 (0.29H, m), 3.45 (0.71H, m), 3.90 (IH, m), 4.12 (2H, q: 7.2 Hz), 4.14 (IH, m), 4.48 (IH, ddd: 13.4, 7.8, 5.5 Hz), 5.40 (2H, m, W= 47 Hz), 7.11 (2H,m), 7.23 (3H, m), 7.55 (3H, m), 7.87 (2H, bdd: 8.0, 1.5 Hz); and (b) l-{(Z)-6-[(li?,2i?,3i?,56)-2-((li?/16',3 _i S)-3-triethylsilyloxy-5-phenyl-l- (phenylsulfonyl)pentyl)-3,5-bis(triethylsilyloxy)cyclopentyl ]hex-4-enyl}-4- methyl-2,6,7-trioxabicyclo[2.2.2]octane (the mixture of two epimers in a ratio of approx. 5:2) (34.9 mg, 42%; substrate recovery), thick, colourless oil, ¹ H-NMR spectrum identical with that described in Example 9.

Example 13

(Z)-7-{[(li?,2i?,3i?,5 _J S)-3,5-Dihydroxy-2-((i?)-3-hydroxy-5- phenylpentyl]cycloρentyl}hept-5-enoic acid.

ethylsilyloxy-5-phenyl-l- (phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)cyclopenty l]hept-5-enoic acid 2,2-bis(hydroxymethyl)propyl ester (the mixture of two epiemrs in a ratio of approx. 5:2) (305 mg, 0.313 mM) was dissolved under argon in anhydrous MeOH (10 mL). The solution was stirred and Na ₂ HPO ₄ was added (334 mg, 2.35 mM). Stirring was continued for 10 minutes, then the reaction mixture was cooled under argon to 0°C and 10% Na(Hg) amalgam was added (956 mg). Stirring was carried out at 0°C for 1 hour, then the cooling bath was removed and stirring was carried out while allowing the raction mixture to heat slowly to 20°C. After the total reaction time of 120 minutes from the moment of amalgam addition, the mixture was cooled again to 0°C and, upon vigorous stirring, saturated aqueous NH ₄ Cl

solution (1 mL) was added dropwise. EtOAc (5 niL) and saturated aqueous solution Of NH ₄ Cl (5 mL) were added, stirring was carried out for 15 minutes. Then H ₂ O was added (1.5 mL), stirring was carried out for 10 minutes, then the reaction mixture was transferred to the separator containing saturated aqueous NH ₄ Cl solution (20 mL) and EtOAc (10 mL). Mercury was removed and secured. The phases were separated after extraction, the aqueous phase was extracted with EtOAc (20 mL). The organic phases were combined and extracted with brine (30 mL). The organic layer was separated and dired over the anhydrous Na ₂ SO ₄ (10 g), then the drying agent was filtered and washed on the filter with EtOAc (10 mL), the combined filtrates were concentarted and dried under vacuum. The colourless, thick oil was prepared (227 mg). This sample was dissolved in acetone (6 mL), then H ₂ O (0.9 mL) and PPTS (122 mg) were added. Stirring was carried out in argon atmosphere, at room temperature, for 6 hours. Then the reaction mixture was concentrated to approx. 1 mL, EtOAc (10 mL) and saturated aqueous NaHCO ₃ solution (10 mL) were added. The phases were separated after extraction, saturated brine (25 mL) was added to the aqueous phase and two-time extraction with EtOAc was carried out (2 x 10 mL). The organic phases were combined and washed with saturated brine (25 mL). After separation of the layers, the organic layer was dried over anhydrous Na ₂ SO ₄ (10 g). The drying agent was filtered and washed with EtOAc (5 mL). The combined filtrates were concentrated and dried under vacuum. Thick oil was obtained (177 mg), which was purified by chromatography on LiChroprep column (25-40 μ,; 9.0 g), eluent: 5% (vol) of MeOH in EtOAc. The fractions, which were pure on TLC, were combined, concentrated and dried under vacuum (1 mm Hg, 20°C, 2 hours). (Z)-I- {[(l _J R,2Λ,3.R,55)-3,5-dihydroxy-2-((Λ)-3-hydroxy-5-

phenylpentylJcyclopentyllhept-S-enoic acid methyl ester was obtained (45 mg, 36%), thick, colourless oil; ¹ H-NMR (CDCl ₃ ; 200 MHz) δ 1.37 (2H, m), 1.50- 1.81 (7H, m), 1.86 (2H, m, W= 9 Hz), 1.97-2.40 (8H, m), 2.56-2.88 (3H, m), 3.66 (3H, s), 3.67 (IH, m, W= 8 Hz), 3.95 (IH, m), 4.15 (IH, m), 5.42 (2H, m, W= 45 Hz), 7.20 (3H, m), 7.27 (2H, m); ¹³ C-NMR (CDCl ₃ ; 50 MHz) δ 24.83, 26.61, 26.89, 29.62, 32.14, 33.41, 35.80, 39.05, 42.49, 51.64, 51.87, 52.80, 71.31, 74.65, 78.74, 125.83, 128.42 (4C), 129.45 (2C), 142.11, 174.46.

Sample of (2)-7-{[(li?,2i?,3i?,55)-3,5-dihydroxy-2-((R)-3-hydroxy-5- phenylpentyl]cyclopentyl}hept-5-enoic acid methyl ester (28 mg, 0.069 mM) was disoolved in MeOH (3 mL). H ₂ O (0.15 mL) and LiOH x 1 H ₂ O (60 mL, 1.43 mM) were added to the solution, stirred at room temperature, in argon atmosphere. After 20 hours, the reaction mixture was transferred to the separator containing saturated aqueous NH ₄ Cl solution (15 mL), 2M aqueous NaHSO ₄ solution (10 mL) and EtOAc (15 mL). The phases were separated after extraction. 2M aqueous NaHSO ₄ solution (5 mL) and EtOAc (10 mL) were added to the aqueous phase. The phases were separated after extraction. The ogranic phases were combined and extracted with the mixture of saturated aqueous NH ₄ Cl solution (10 mL) and 2M aqueous NaHSO ₄ solution (5 mL). The organic phase was dried over Na ₂ SO ₄ (5 g). The drying agent was filtered, the filtrate was concentrated and dried under vacuum (1 mm Hg, 25°C, 3 hours). (Z)-I- {[(li?,2 _J R,3i?,55}-3,5-dihydroxy-2-((i?)-3-hydroxy-5- phenylpentyl]cyklopentyl}hept-5-enoic acid was obtained (26.0 mg, 96%) as pale yellowish glaze; [α] _D = (+)29.7° (MeOH, 2O ⁰ C, c= 1); ¹ H-NMR (CDCl ₃ + 1% C ₅ D ₅ N; 200 MHz) δ 1.35 (2H, m), 1.45-1.86 (1OH, m), 2.07-2.37 (7H, m), 2.71

(2H, m, W= 61 Hz), 3.66 (IH, m), 3.94 (IH, m), 4.14 (IH, m), 4.94 (3H, bs), 5.43 (2H, m, W= 60 Hz), 7.21 (5H, m).

Example 14 (Z)-7-{[(li?,2i?,3i? ₅ 55)-3,5-Dihydroxy-2-((i?)-3-hydroxy-5- phenylpentyl]cyclopentyl}hept-5-enoic acid 2,2-bis(hydroxymethyl)propyl ester

l-{(Z)-6-[(li? _J 2i?,3i?,55)-2-((lJ?/15',35)-3-Triethylsilyloxy-5-pheny l-l- (phenylsulfonyl)pentyl)-3,5-bis-(triethylsilyloxy)cyclopenty l]hex-4-enyl}-4- methyl-2,6,7-trioxabicyclo[2.2.2]octane (378 mg, 0.462 niM) was dissolved in acetone (11 mL). The solution was stirred in argon atmosphere, H ₂ O was added (1.5 mL), then pyridynium p-toluenesulfonate (PPTS, 210 mg, 0.836 niM) was added. Stirring was carried out at the temperature of 18°C for 5 hours, then the solution was concentrated to the volume of 1.5 mL, EtOAc (40 mL), brine (30 mL) and saturated aqueous solution of NaHCO ₃ (20 mL) were added. The layers were separated after extraction, the aqueous layer was extracted twice with EtOAc (2 x 20 mL). The organic layers were combined and extracted with saturated brine

(50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ (7 g). The drying agent was filtered and washed with EtOAc (10 mL). The filtrates were combined, concentrated and dried under vacuum (1 mm Hg, 35°C, 1 hour). The prepared crude product was purified by "flash" chromatography on silica gel column 230- 400 mesh (14 g), eluent: 5% MeOH/ EtOAc. The fractions, which were pure on TLC, were concentrated and dried under vacuum do the constant mass. (Z)-I-

ihydroxy-2-((R)-3-hydroxy-5- phenylpentyl]cycloρentyl}hept-5-enoic acid 2,2-bis(hydroxymethyl)propyl ester, colourless glaze was obtained (217 mg, 95%); [α] _D = (+)29.7° (CHCl ₃ , 20 ⁰ C, c= 1.8); ¹ H-NMR (CDCl ₃ ; 200 MHz) δ 0.85 (3H, s), 1.36 (2H, m), 1.48-1.88 (HH, m), 2.02-2.39 (6H, m), 2.71 (2H, m, W= 60 Hz), 3.42 (4H, bs), 3.55 (4H, s), 3.63 (IH, m), 3.95 (IH, m), 4.12 (2H, bs), 5.41 (2H, m, W= 50 Hz), 7.18 (3H, m), 7.28 (2H, m); ¹³ C-NMR (CDCl ₃ + 1% C ₅ D ₅ N; 50 MHz) δ 16.88, 24.80, 26.52, 27.02, 29.61, 32.15, 33.54, 35.74, 39.05, 40.51, 42.51, 51.70, 52.63, 66.55, 67.00 (2C), 71.15, 74.53, 78.53, 125.78, 128.39 (2C), 128.42 (2C), 129.21, 129.77, 142.23, 174.56; HR ESI MS for C ₂₈ H ₄₄ O ₇ Na calc. (M + Na ⁺ ) m/z 515.29847, found. 515.2962.

Przyklad l5

phenylpentyl]cyclopentyl}hept-5-enoic acid.

l-{(Z)-6-[(l^,2i?,3i?,5S)-2-((li?/l ₁ S:3S)-3-Tπethylsilyloxy-5-phenyl-l- (phenylsulfonyl)pentyl)-3,5-bis(triethylsilyloxy)cyclopentyl ]hex-4-enyl}-4- methyl-2,6,7-rioxabicyclo[2.2.2]octane (99 mg, 0.121 niM) was dissolved in acetone (17 niL). The solution was stirred in argon atmosphere, H ₂ O was added (1 mL), then pyridynium p-toluenesulfonate (PPTS, 77 mg) was added. Stirring was carried out at 18 ⁰ C for 16 hours, then the solution was concentrated to the volume of approx. 1 mL, MeOH (10 mL) and H ₂ O were added. Stirring was carried out under argon at room temperature and LiOH x IH ₂ O was added (320 mg, 7.62 mM). After 5.5 h, the mixture was transferred to the separator containing saturated aqueous NH ₄ Cl solution (50 mL), 2M aqueous NaHSO ₄ solution (15 mL) and EtOAc (45 mL). The phases were separated after extraction, 2M aqueous NaHSO ₄ solution was added to the aqueous phase and extraction with EtOAc (30 mL) was carried out again. The organic phases were combined, dried over anhydrous Na ₂ Sθ ₄ (12 g), the drying agent was filtered, the filtrate was concentrated and dried under vacuum. Pale yellowish glaze was obtained (62 mg). This sample was purified by "flash" chromatography on LiChroprep column (25- 40 μm; 10 g), eluent: 0.5% AcOH in EtOAc. The fractions, which were pure on

TLC, were combined, concentrated and dried under vacuum (1 mm Hg, 30 ⁰ C, 2 hours) to the constant mass. (Z)-7-{[(lR,2R,2>R,5S)-3,5-Oihydroxy-2-((R)-3- hydroxy-5-phenylpentyl]cyclopentyl}hept-5-enoic acid was obtained (20.0 mg, 42.3%) as thick, colourless oil; [α] _D = (+)30° (MeOH, 2O ⁰ C, c= 1); ¹ H-NMR (CDCl ₃ + 1% C ₅ D ₅ N; 200 MHz) δ 1.35 (2H, m), 1.45-1.86 (1OH, m), 2.07-2.37 (7H, m), 2.71 (2H, m, W= 61 Hz), 3.66 (IH, m), 3.94 (IH, m), 4.14 (IH, m), 5.42 (2H, m, W= 60 Hz), 5.70 (3H, bs), 7.21 (5H, m); ¹³ C-NMR (CDCl ₃ + 1% C ₅ D ₅ N; 50 MHz) δ 24.82, 26.50, 26.68, 29.23, 32.10, 33.49, 35.38, 38.86, 42.44, 51.62, 52.32, 71.33, 74.28, 78.42, 125.74, 128.35 (2C), 128.41 (2C), 129.44, 129.50, 142.21, 177.10; HR ESI MS for C ₂₃ H ₃₄ O ₅ Na calc. (M + Na ⁺ ) m/z 413.23039, found. 413.2279.

Example 16

phenylpentyl]cyclopentyl}hept-5-enoic acid.

ρhenylpentyl]cyclopentyl}hept-5-enoic acid 2,2-bis(hydroxymethyl)propyl ester, (120 mg, 0.243 mM) was dissolved in MeOH (5 mL). H ₂ O was added (0.50 mL),

the solution was stirred under argon at room temperature and LiOH x IH ₂ O was added (240 mg, 5.72 niM). Stirring was carried out under argon for 8 hours, then the reaction mixure was quantitatively transferred to the separator containing saturated aqueous NH ₄ Cl solution (50 mL), 2M aqueous NaHSO ₄ solution (30 mL) and EtOAc (50 mL). The phases were separated after extraction, 2M aqueous NaHSO ₄ solution (20 mL) and EtOAc (30 mL) were added to the aqueous phase. The phases were separated after extraction, the organic phases were combined and extracted with the mixture of saturated aqueous NH ₄ Cl solution (20 mL) and 2M aqueous NaHSO ₄ solution (10 mL). The organic phase was dried over Na ₂ SO ₂ (10 g), the drying agent was filtered and washed with EtOAc (10 mL). The filtrates were combined, concentrated under vacuum (5 mm Hg, 30 ⁰ C) and dried under vacuum (1 mm Hg, 25°C, 3 hours). (Z)-7-{[(li?,2i-,3i?,55)-3,5-Dihydroksy-2- ((i?)-3-hydroksy-5-fenylopentylo]cyklopentylo}hept-5-enoic acid was obtained (94.1 mg, 99%) as thick, pale yellowish oil; [α] _D = (+)29.7° (MeOH, 20 ⁰ C, c= 1); ¹ H-NMR (CDCl ₃ + 1% C ₅ D ₅ N; 200 MHz) identical with that described for this compound in Example 15.

Example 17

(Z)-7-{[(li?,2Λ,3i?,55)-3,5-Dihydroxy-2-((i?)-3-hydroxy- 5- phenylρentyl]cyclopentyl}hept-5-enoic acid isopropyl ester

C23H34O5

MoI. Wt.: 390,51 C26H40O5

MoI. Wt: 432,59

(Z)-7-{[(\R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5- phenylpentyl]cyclopentyl}hept-5-enoic acid (20.0 mg, 0.051 mM) was dissolved in acetone (2.0 mL). The solution was stirred under argon for 10 minutes, then DBU was added (100 μL, 102 mg, 0.67 mM). After 3 minutes of stirring, 2- iodopropane was added (100 μL, 170 mg, 1.0 mM). The solution was stirred under argon at 20 ⁰ C for 14 hours. Then the reaction mixture was concentrated to the volume of approx. 0.50 mL, 4% aqueous citric acid solution (4 mL) and EtOAc (10 mL) were added. The mixture was quantitatively transferred to the separator containing EtOAc (20 mL), brine (30 mL) and 4% aqueous citric acid solution (2 mL). The layers were separated after extraction, the aqueous layer was extracted again with EtOAc (10 mL).

The organic layers were combined and extracted with the mixture of brine (20 mL) and saturated aqueous NaHCO ₃ solution (20 mL). The organic layer was dried over Na ₂ SO ₄ (7 g), the drying agent was filtered and washed on the filter with EtOAc (5 mL). The filtrates were combined, concentrated under vacuum (5 mm Hg, 30 ⁰ C) and dried under vacuum (1 mm Hg, 20°C, 1 hour). The colourless, thick oil was obtained (24 mg). This sample was purified by chromatography on LiChroprep column (25-40 μm; 4.0 g), eluent: 20% vol of hexane in EtOAc. The fractions, which were pure on TLC (Merck plates No. 1.05549, mobile phase:

EtOAc-hexane 6:1) were combined, concentrated and dried under vacuum (1 mm Hg, 20 ⁰ C, 4 hours, in darkness). The obtained product (91% HPLC purity) was purified by preparative HPLC (Example 17a). (Z)-7-{[(lR,2R,3R,5S)-3,5- Dihydroxy-2-((i?)-3-hydroxy-5-phenylpentyl]cyclopentyl}hept- 5-enoic acid isopropyl ester (latanoprost) was obtained (14.0 mg, 63.2%) as thick, colourless oil; 99.83% HPLC purity; [(X] _n = (+) 32.5 +/- O.5°(CHC1 ₃₎ 20 ⁰ C, c= 1); signals in spectrums of ¹ H-NMR (CDCl ₃ ; 500 MHz) and ¹³ C-NMR (CDCl ₃ ; 125 MHz): Table 1:

Table 1 Assingment of signals ¹ H-NMR (CDCl ₃ ; 500 MHz) and ¹³ C-NMR of latanoprost (CDCl ₃ ; 125 MHz); based on DEPT, H ₅ H-COSY 90, C ₅ H-HETCOR and LR C ₃ H- HETCOR spectra.

HR ESI MS for C ₂₆ H ₄₀ O ₅ Na: calc. (M + Na ⁺ ) m/z 455.27734, found 455.2756.

Example 17a Synthesis of latanoprost according to the above procedure of Example 17 was repeated, starting from the appropriate acid (84 mg). The reaction was carried out over 5.5 h. After processing and purification on LiChroprep column (25-40 μm, 5.0 g; eluent: 20% vol of hexane in EtOAc). The fractions, which were pure on TLC (Merck plates No. 1.05549, mobile phase: EtOAc-hexane 6:1), were combined, concentrated and dried under vacuum. The product (59 mg) thus obtained was purified to the purity above 99.8% with use of preparative HPLC. After drying of isolated pure fraction under vacuum (1 mm Hg, 25°C, 4 hours), latanoprost was prepared (35 mg) as colourless, thick oil; 99.82% HPLC purity; [α] _D = (+) 32°+/-0.5°(CHCl ₃ , 2O ⁰ C, c= 1); ¹ H-NMR (CDCl ₃ ; 500 MHz): spectrum identical with that described in Example 17.

HPLC analyses of the prepared latanoprost samples were carried out on 4.0 x 250 mm column, Waters Spherisorb 5 μm Silica; UV detection (210 nm). As a mobile phase (flow rate 1 niL/min.), the following mixtures were used: (a) the mixture of hexane (91.50% vol), isopropanol (8.40% vol) and acetic acid (0.10% vol), retention time of latanoprost: 16.6 min., retention time of Impurity I: 15.4 min., of Impurity II: 18.8 min., or (b) the mixture of heptane (94% vol), CH ₃ CN (2.5%) and isopropanol (3.5%), retention time of latanoprost: 18.8 min., retention time of Impurity I: 16.9 min., of Impurity II: 22.2 min.

Latanoprost samples, synthesized in the process according to the invention before purification by preparative HPLC were of purity (HPLC) approx. 91%, Impurity I: approx. 0.5-0.7%, hnpuruty II: approx. 5-8%.

Preparative purificaton of latanoprost samples was carried out on Waters

RCM 40 mm set, 2 Nova-Pak 4O x 100 mm cartridges, (HR Silica, 6 μ, 60 A), mobil phase (flow rate of 35 mL/min.): the mixture of hexane (91.50 vol), isopropanol (8.40% vol) and acetic acid (0.10% vol) or the mixture of heptane

(94% vol), CH ₃ CN (2.5%) and isopropanol (3.5%).

After purification by preparative HPLC (single), latanoprost of 99.83% purity (HPLC) was isolated.

As a result of preparative HPLC purification of consecutive batches of latanoprost, samples of Imurity I and Impurity II were isolated (HPLC data presented above).

Characteristics of Impurity I (data in accordance with B. Resul et al.; J. Med. Chem. 36 (1993), 243-248):

Impurity I

Impurity I: ,5-dihydroxy-2-((5 ^r )-3-hydroxy-5- phenylpentyl]cyclopentyl}hept-5-enoic acid isopropyl ester [α]o= + 34.3° (CHCl ₃ , MR data: Table 2;

Table 2 Assignment of signals of Impurity I in ¹ H-NMR (CDCl ₃ ; 500 MHz) and ¹³ C-NMR (CDCl ₃ ; 125 MHz) spectra; based on DEPT, H ₅ H-COSY 90, C,H-HETC0R i LR C ₅ H-HETCOR spectra.

HR ESI MS for ₂₆ H ₄₀ O ₅ Na: calc. (M + Na ⁺ ) m/z 455.27734, found. 455.2763.

Characteristics of Impurity II:

Impurity II:

Table 3 Assignment of signals of Impurity II in ¹ H-NMR (CDCl ₃ ; 500 MHz) and ¹³ C- NMR (CDCl ₃ ; 125 MHz) spectra; based on DEPT, H ₅ H-COSY 90, C ₃ H-HETCOR i LR C ₅ H-HETCOR spectra.

HR ESI MS for C ₂₆ H ₄₀ O ₅ Na: calc. (M + Na ⁺ ) m/z 455.27734, found. 455.2791.

Example 18

Preparation of latanoprost from (3ai?,4i?,5i?,6aS)-hexahydro-5-triethylsilyloxy-4- [(R)-3-triethylsilyloxy-5-phenylpentyl]cyclopenta[b]furan-2- one.

Latanoprost was prepared according to the procedure described in WO 02/096898, starting from (3ai?,4R,5R,6aS)-hexahydro-5-triethylsilyloxy-4-[(R)-3- triethylsilyloxy-5-plienylpentyl]cyclopenta[b]furan-2-one. Latanoprost yield: 45-

59% equivalent to (3ai?,4i?,5i?,6aS)-hexahydro-5-triethylsilyloxy-4-[(R)-3- triethylsilyloxy-5-phenylpentyl]cyclopenta[b]furan-2-on. Latanoprost samples prepared in this way (70-94% purity, HPLC) were analyzed as in Example 17a. Presence of Impurity I, Impurity II and Impurity III was determined.

In the case of use of mobil phase composed of heptane (94% vol), CH ₃ CN

(2.5%), isopropanol (3.5%), latanoprost R _t : 18.9 min., Impurity I R _t : 17.1 min.,

Impurity II Rt: 23.1 min., Impurity III R _t : 31 min. Amount of impurities determined on the basis of integration at 210 nm: Impurity I (1.2-8.1%), Impurity II (1.3-4.6%), Impurity III (0.3-2.8%).

Preparative purification by HPLC, both in conditions of Example 17a of the present invention and in conditions described in WO 02/096898 A2, does not allow purification of latanoprost samples of Impurity I. For example, in the sample of Impurity I content = 1.2%, its content after the first purification was 0.9%, whereas content of Impurity II and Impurity III was below 0.1%. Reduction of content of Impurity I to the level of below 0.1% required repeating of preparative resolution.