NZ218877A - Protected cyclopentanols - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £18877 218877 Class: F^?.7 Priority Date(s): .... ^ .7;. . X .*? Compieto Specification Filed: . !S 11 P.O. Journal, No: Under the provisions cf Reglft lation 23 (I) the ^ _ ..Lz^Jejx ^ NO DRAWINGS to JA-Aefiirjz.hzz. 19.^ Specification has been ante-date<J Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION PROTECTED CYCLOPENTANOLS fc/We' GLAXO GROUP LIMITED, a British company of Clarges House, 6-12 Clarges Street, London Wiy 8DH, England, hereby declare the invention, for which JE/we pray that a patent may be granted to hh/us, and the method by which it is to be performed, to be particularly described in and by the following statement: 1 r(fo/fowed by page 1A.) * - 3^- 13Q 50 147 218877 This invention relates to new protected cyclopentanols of use as intermediates in preparing uracil der ivatives 5 having antiviral activity.

Deoxyuridine derivatives such as 2'-deoxy-5-iodouridine (Prussoff and Gozs Handbook of Experimental Pharmacology, Part II of Antineoplastic and Immunosuppressive Agents, Springer-Verlag, New York 1975, pages 272-347) and 2'-deoxy-5-vinyluridine (Cheng et alf Antimicrobial Agents and Chemotherapy 10, 1, 119-122 (1976) have been found to possess antiviral activity. The activity of these compounds, however, is not very specific. British Patent Specification 15 No. 1,601,020 discloses E-5-(2-bromo and iodo-vinyl)-2'-deoxyuridine which are described as having selective antiviral activity against herpes simplex viruses.

There is a need, however, for compounds with better and more selective antiviral activity.

We have now found a small group of uracil derivatives which have improved selective activity against viruses, especially Herpetoviridae which compounds have the general formula (I): O (I) wherein R is a chlorine, bromine or iodine atom and physiologically acceptable salts thereof with bases.

In the compounds of formula (I) the halovinyl tiwjiii iinniniw-iir--finrrtiin*'S > i ncnii'■ nn■ * yf wi'nimwiini .-.v-t ^ * / X o 2 1 8877 group is in the E-configuration and the pyrimidine ring is in the 8-configuration relative to the cyclopeatane ring.

The compounds of formula (I) as well as processes 5 for their preparation and compositions containing them ar« described and claimed in our co-pending Application No. 205619.

In the present application we claim intermediates of use in preparing the compounds of formula 10 (I).

As described in Application No. 205619 fche compounds of formula (I) nnay be prepared by treatment of a compound of formula (II): COjH (ID a'o 12 o or a salt thereof (where R , R and R , which may be the same or different, represent hydrogen atoms or protecting groups) with a halogenating agent followed where necessary by removal of any protecting groups.

The compounds of formula (II) may be prepared by deprotection of the carboxyl group of a compound of formula (III): 218877 R3S COaR" (III) 12 3 (where R , R and R are as previously defined 4 and R represents a carboxyl protecting group).

The compounds of formula (III) may be prepared by reaction of a compound of formula (IV): OR1 HgX (IV) r3Ov 12 3 (where R , R and R are as previously defined and X is an anion e.g. chloride ion) with an ester of acrylic acid: ch2=chco2r4 4 (where R is as previously defined).

The compounds of formula (IV) may be prepared by reaction of a compound of formula (V): - A - o 2 1 8877 (V) 12 3 (where R , E and R are as previously defined) with a mercury salt HgX2 (where X is as previously defined).

According to one embodiment described in Application No. 205619 > the compounds of formula 2 3 (V) wherein R and R each represents a protecting group may alternatively be prepared by reacting 10 compounds of formula (XIX), (XIX) ■—' Z R2aO S 2s 3d. (where R and R ■ represent protecting groups 2 3 as previously defined in relation to R and R and Z represents a leaving group) with a compound 15 of formula (XX): (XX) l. » - . .... ~ y.; i (> 11 . ' - i ' ' ' •'■••■' '. - / . -..'•jr.';./ ' y -* - : • ... v'.-S'ufc. 21 8877 (where R*" is as previously defined) or a base salt thereof. Such compounds may then, if desired, be deprotected as described in Application No. 205619.

The reaction may be effected in an organic 5 solvent such as for example a sulphoxide e.g. dimethyl-sulphoxide, an amide such as dimethylformamide, an ether e.g. tetrahydrofuran or water. The reaction is generally carried out at a temperature in the range 0° to 120°C e.g. 30°-100°C and in the presence 10 of an organic or inorganic base such as sodium or potassium hydride, carbonate or bicarbonate or triethylamine. The leaving group represented by z may, for example be a halogen atom e.g. CI, Br or an acyloxy group such as a hydrocarbylsulphonyloxy 15 group e.g. methanesulphonyloxy or p-toluenesulphonyloxy.

Compounds of formula (XIX) may be prepared by treatment of compounds of formula (XXI): OH R2a O # (XXI) 2a 3a (where R and R are as previously defined) with 20 a reagent serving to introduce the desired group Z. Thus, for example, a halogen atom may be introduced by halide ion displacement or using an oxyhalide reagent such as thionyl chloride. Alternatively an acyloxy group Z may be introduced by reaction with an appropriate 25 acyl halide such as e.g. tosyl chloride. The reaction may, if desired, be carried out in the presence of a base e.g. pyridine or triethylamine and is conveniently effected in a medium such as water; an alcohol e.g. methanol or ethanol; a halogenated 30 hydrocarbon e.g. chloroform, or carbon tetrachloride; or a substituted amide e.g. N,N-dimethylformamide, ■'.s w"V'~ - 218877 or a ketone e.g. acetone. Temperatures are generally in the range -20#C to +70°C e.g. 0°C to +50°C. Alternatively, the base itself may be the solvent. Compounds of formula (XXI) may be prepared 5 by deprotecting compounds of formula (XXII): »3a '"Ov.

J OR (XXII) a2a R o (where R2a and R^a are as previously defined and ,11 R" represents a protecting group such as those 2 3 described in relation to R and R ). It will be appreciated that the group should be one which can be selectively removed, for example a trialkylsilyl group such as a dimetfr 'tertiarybutylsilyl group.

Such a group may be removed by reaction with tetraalkyl- ammonium halides e.g. tetra-n-butylammonium fluoride or with hydrogen fluoride in aqueous acetonitrile.

The reaction may conveniently be carried out in solvents such as ethers, e.g. tetrahydrofuran arid at a temperature in the range -50°C to +50°C e.g. -20°C to +20°C.

Compounds of formula (XXII) may be prepared by the introduction of hydroxyl protecting groups 2a 3a R and R into a compound of formula (XXIII)z HO ho OR 11 (xxirr) ]r •i-Av > 21 8877 (where R11 is as previously defined) .

Introduction of the hydroxyl protecting groups A M R a and R a may be carried out according to any appropriate conventional method. Suitable reagents 5 for the introduction of protecting groups include alkyl and aralkyl halides such as methoxymethyl chloride and benzyl bromide. The reaction is optionally carried out in the presence of a base such as diiso-propylethylamine and in organic solvents such as 10 ethers e.g. tetrahydrofuran, hydrocarbons e.g. benzene, halogenated hydrocarbons e.g. dichloromethane. The reaction may be carried out in the temperature range -50°C to +50°C e.g. -20°C to +20°C.

Compounds of formula (XXIII) may be prepared 15 by ozonolysis of compounds of formula (XXIV) i t - • (where R^ is as previously defined) followed by the reduction of the products formed therefrom with an alkali metal borohydride such as sodium borohydride. The reaction may be carried out in organic solvents such as an alcohol e.g. methanol, halogenated hydrocarbons e.g. dichloromethane; ethers e.g. tetrahydrofuran or mixtures thereof and at a temperature in the range -70°C to +50°C.

Compounds of formula (XXIV) may be prepared from compounds of formula (XXV): wwnwnjniwiwi ' ' ' . / **-**» w^vfiBWgfrMy 218877 '"A__/ OR 11 (XXV) (where R** is as previously defined) using a Grignard reagent capable of introducing a vinyl group, for 5 example vinyl magnesium bromide. The reaction may conveniently be carried out in the presence of a catalyst such as cuprous iodide and in an organic solvent such as a halogenated hydrocarbon e.g. dichloromethane; an ether e.g. tetrahydrofuran 10 or mixtures thereof and at a temperature in the range -70®C to +50°C.

Compounds of formula (XXV) may be prepared from the known compound of formula (XXVI): .-"Ch 0# 11 > ^01 OH <**"> by reaction with a reagent serving to introduce the protecting group R^.

The reaction may be carried out in the presence of a coupling agent such as an imidazole and in an organic solvent such as an amide for example 20 dimethylformamide and at a temperature in the range -50°C to +50°C for example -20°C to -f-20°C.

According to an alternative embodiment described in Application No. 205619 the compounds of formula (I) may be obtained by reacting compounds of formula (XXVII) - v - 5 ' ' V 218877 (XXVII) (where R and R* are as previously defined) or a base salt thereof with a compound of formula (XIX) 5 as defined above. The reaction is analogous to that described above to obtain compounds of formula (V) by reaction of compounds of formula (XIX) with compounds of formula (XX). The preferred conditions are as described for that reaction. The reaction 10 is followed, where necessary by removal of any protecting groups as described in Application No. 205619.

Alternatively the compounds of formula (XIX) may be prepared in situ by treatir. nt of a compound 15 of formula (XXI) with a dialkylazodicarboxylate, e.g. diethylazodicarboxylate, and a tertiary phosphine e.g. triphenylphosphine in a solvent such as tetrahydrofuran or acetonitrile.

Mixtures of isomers may be separated at any 20 convenient stage of the synthesis, for example, either before or after removal of protecting groups.

Thus the desired epimer may, where necessary, be separated from the corresponding epimer by conventional means, for example, by fractional crystallisation 25 and/or chromatography. Optically active isomers of the compounds may be obtained by resolution of the racemic mixtures using conventional means; see for example 'Stereochemistry of Carbon Compounds' by E. L. Eliel (McGraw Hill, 1962) and 'Tables 30 of Resolving Agents' by S.H. Wilen.

The intermediates of formulae (XIX), (XXI) , (XXII), (XXIII) and (XXIV) are closely related » 21 8877 chemically and may be expressed as having the formula (C): where either RD represents a hydroxymethyl group E D and R represents a hydroxyl group or R represents E a protected hydroxymethyl group and R represents a protected hydroxyl group 0£ R represents a hydroxyl D F group and R represents an ethenyl group and R represents a hydroxyl or protected hydroxyl group or a group Z as defined above with the proviso that either RD represents a protected hydroxymethyl E group and R represents a protected hydroxyl group P or R represents a protected hydroxyl group. Thes« intermediates of formula (C) are novel and constitute 15 features of the present invention.

The following examples illustrate the invention. Temperatures are in °C. The nomenclature used is in accordance with the Chemical Abstracts system.

Solutions were dried by use of magnesium 20 sulphate. Plash column chromatography was carried out over silica using the method described by w.E.

Still et al, J. Org. Chem. 1978, 14, 2923. i.. , t ... -,^ 218877 Intermediate A (la,3g, 5ot) - (—) -3-[ f (1,1-Dimethylethyl)d imethylsilyl loxy]-6-oxabicyclo[3,1,0]hexaae A. solution of (lar38#5a)-(+)-3-hydroxy-6-5 oxabicyclo[3,l,0]hexane (2.5 g) in dry DMF (25 ml) was treated with imidazole (3.40 g), the solution cooled to 0° under N2 and t-butyldimethylsilyl chloride (4.15 g) added. The solution was stirred at 0° for 10 minutes, allowed to-warm up to room 10 temperature and stirring continued for a further 18 hours. The mixture was poured into water (150 ml) and extracted with pentane (2 x 150 ml). The organic phase was washed with water (2 x 150 ml), dried and concentrated to afford the crude product as 15 a colourless oil. The latter was purified by flash chromatography, elution with 7% EtOAc/hexane affording the title compound as a colourless mobile oil (3^9 g); t (CDC13) 5.56 (1H, ABX, CHOSi), 6.52 (2H,s, CH -CH) , 7.86-8.08 (4H, ABX, CHj) , 9.1 (9H,s, CMe-j), 9.96 20 (6H,s,Me) J ■ ' ' - . . v ' v r V , as-. . , I J 1,1 mm immwmii <m-r-«»v> *.MUtt' r -u- 2 18877 Example 1 (lot,28 ,4a) ,-(—)-4-[ [ (l,l-Dimethylethyl)diniethylsilyl]-oxy]-2-ethenylcyclopentanol A stirred suspension of cuprous iodide (190 mg) 5 in dry THF (10 ml) at -30° under N2 was treated dropwise with a solution of vinylmagnesium bromide(1M in THF, 10 ml) causing a greyish coloured suspension to form. The latter was stirred at -30° for 15 minutes and then a solution of Intermediate A (1.50 g) in dry THF (5 ml) added dropwise. The resulting dark coloured solution was stirred at -30° for 15 minutes, the mixture allowed to slowly warm to 0° (ca. 0.5h) and then stirred for a further 2 hours. The reaction was quenched by pouring 15 into saturated NH^Cl solution (100 ml) and extracted with ether (2 x 100 ml). The combined organic extracts were washed with further saturated NH^Cl solution (100 ml), dried and concentrated to afford the crude product as a pale yellow oil. The latter 20 was purified by flash chromatography, elution with 8% EtOAc/hexane yielding the title compound as a colourless oil (1.25 g) .

Analysis Found : C, 64.54? H, 11.07% C13H26°2Si re(3uires: c' 64.40; H, 10.81% Example 2 (la,28,48)-(—)-[C(l#l-Dimethylethyl)dimethylsilylloxy]-2-hydroxylcyclopentanemethanol Oxygenated ozone was bubbled through a solution of 30 the product of Example 1 (6.68 g) in dry methanol (100 ml) and dichloromethane (50 ml) cooled to -70° until a deep blue colouration appeared. Sodium borohydride (1.05 g) was then quickly added in f one portion and stirring at -70° continued for 35 30 minutes. Further sodium borohydride (1.05 g) was then added, the mixture allowed to slowly warm to room temperature (ca. lhr.) and then stirred - L3 - 218877 for a further 30 minutes. The solvents were evaporated and the residue partitioned between dichloromethane (2 50 ml) and saturated ammonium chloride solution (250 ml). The aqueous layer was further extracted 5 with dichloromethane (1 x 250 ml), the combined organics dried and concentrated to afford the crude product as an opaque viscous oil. The latter was purified by flash chromatography, elution with 5% MeOH/CHgClg yielding the title compound as a 10 viscous colourless oil (5.34 g.) Analysis Found: C, 52.94; H, 10.89% C12H26°3S**0,1 H2° requires: C, 58.06; H, 10.64% Example 3 (la,36,4a)-(—)-(1,1-Dimethylethyl)dimethylT T 4-(methoxy-methoxy)-3-[(methoxymethoxy)methyl]cyclopentyl]oxy]silane To a solution of the product of Example 2 (5.0 g), and N,N-diisopropylethylamine (7.87 g, 10.6 ml) in dry dichloromethane (100 ml), cooled 20 to 0° under nitrogen, was added chloromethylmethyl ether (90%: 5.44 g, 5.19 ml,) dropwise over 10 minutes. The mixture was stirred at 0° for 5 minutes, allowed to warm up to room temperature and stirring continued overnight. The solution was washed with 25 water (100 ml), the aqueous layer extracted with further dichloromethane (1 x 50 ml) and the combined organic layers dried. Concentration afforded the crude product as an orange oil which was purified by flash chromatography, elution with 10% EtOAc/hexane 30 yielding the title compound as a colourless mobile oil (5.1 g) Analysis Found: C, 57.51; H, 10.75% C16H34°5S* re<Iuiresi C, 57.44; H, 10.55% if I I 218877 Example 4 (la,3a,4g)-(—)-3-(Methoxymethoxy)-4-f(methoxyroethoxy)-methyl]cyclopentanol.

A solution of the product of Example 3 (5.0 g) in THF (150 ml), stirred and cooled to 0°, was treated with tetra-n-butylammonium fluoride (1M in THF, 16 ml). The solution was allowed to warm up to room temperature and stirred for a further 4 hours. The mixture was concentrated to ca. 30 10 ml and subjected to flash chromatography. Elution with EtOAc/hexane (9:1) afforded the title compound as a pale yellow oil (3.2 g).

(CDC13)5.24-5.4 (4H,2xAB, OCHjO), 5.67 (lH,m,CH0CH2)r 5.9 (lH,m,CH0H), 6.4—6.7(8H,m+2s, OMe, CHjO), 7.45(lH,m,CHCH20) 15 7.6 (lH,d,OH), 7.9-8.4 (4H,m,2xCH2) Example 5 (la, 3ot,4g) - (—) -3-(Methoxymethoxy) -4- [ (methoxymethoxy) -methyl]cyclopentanol, 4-methylbenzenesulphonate 20 A mixture of the product of Example 4 (1 g), para- toluenesulphonyl chloride (0.96 g) and dry pyridine (20 ml) was stirred at room temperature overnight.

The pyridine was removed iji vacuo at 35°, the residue taken up in dichloromethane (50 ml) and the solution 25 washed with copper (II) sulphate solution (3 x 50ml). The organic phase was dried and concentrated to afford the crude product as a yellow oil. The latter was purified by flash chromatography. Elution with EtOAc/hexane (1:1) afforded the title compound 30 as a colourless oil (1.18 g) Analysis Found: C, 54.68; H, 6.57% C17H26°7S re^u^res : c' 54.52? H, 6.99% - .riwttG-- ^W**' Vm imW''^"^. 218877 Example 6 (la,3B» 4a)-(-)-l-[3-(Methoxymethoxy)-4-[(methoxymethoxy)-methyl]cyclopentyll-2,4(1H,3H)-pyrimidinedione A mixture of the product of Example 5 (374 mg), finely ground anhydrous potassium carbonate (414 mg) and uracil (336 mg) in dry DMSO (5 ml) was stirred under nitrogen at 90° for 15 hours. The resulting dark coloured solution was poured into brine (ca. 50 ml) and the mixture extracted with dichloromethane (3 x 30 ml). The organic phase was washed with brine (1 x 50 ml), dried and concentrated to afford the crude product as a yellow oil. The latter was purified by flash chromatography. Elution with 5-8% MeOH/CHjClj afforded the title compound as a pale yellow oil (138 mg) (CDC13) 1.13 (1H, br s, NH), 2.68 (1H, d, N-CH=CH), 4.25 (lH,d, N-CH=CH), 4.88 (1H, quin., H-l'), 5.35 (4H, s, OCHjO), 5.88 (1H, dt, CH-0-CH2 5.3-5.46 (2H, m, CH20), 6.62 (6H, s, OMe).

Example 7 (la,3S,4a)-(-)-!-[3-Hydroxy-4-(hydroxymethyl)cyclo-pentyl]-2,4(1H,3H)-pyrimidinedione A mixture of the product of Example 6 and p-toluenesulphonic acid (1.40 g) in methanol (100 ml), was heated under gentle reflux on a steam bath for 1 hour. The solution was cooled, stirred and treated with R8050 polyvinylpyridine resin (Reilly Corporation) until pH6 was attained (ca. 2 g resin). Filtration and concentration yielded the crude product as a pale yellow oil. The latter was purified by flash chromatography. Elution with 15% MeOH/CHjC^ afforded the title compound as a white crystalline powder (1.1 g) m.p. 159-162° llflWi rtiiin Example 8 (—)-Chloro-[1,2,3,4-tetrahydro-l-[f 30,4a) -3-hydroxy-4-(hydroxymethyl)cyclopentyl1-2,4-d ioxo-5-pyr imid inyl1-mercury To the product as prepared in Example 7 (400 mg) in water (1.5 ml) was added mercuric acetate (595 mg) in water (4.5 ml) and the solution stirred at 50° for 4h. Sodium chloride (256 mg) in water (1 ml) was added at 40° and the reaction mixture cooled (ice bath). Filtration of the solid, followed by drying at 60° iji vacuo, afforded the title compound as a white solid which was used directly in the next stage.

Example 9 (-)-(E)-Ethyl-3-T1,2,3,4-tetrahydro-l-f(36, 4a)-3-hydroxy-4-(hydroxymethyl)cyclopentyll-2,4-dioxo-5-pyrimidinvn-2-propenoate The product of Example 8 (390 mg), ethyl acrylate (0.75 ml) and dilithium palladium tetrachloride (0.1M solution in methanol, 8.7 ml) were stirred for 16h under nitrogen. The reaction mixture was filtered, the precipitate washed with warm methanol (20 ml) , and hydrogen sulphide gas bubbled through the combined methanol filtrate and washings to precipitate mercuric sulphide. The resulting mixture was filtered through Hyflo (registered Trade Mark) and the solvent removed jji vacuo. Water (5 ml) was added, and then removed iji vacuo at 30°. The residue was purified by flash chromatography eluting with chloroform-ethanol (6:1) to give the title compound (19 5 mg). "f ([^Hg] DMSO)(Mixture of epimers) 1.56, 1.70(lH,s,H-6), 2.54, 2.61(lH,d,CH=CHC02Et), 3.08, 3.14 (lH,d,=CHC02Et). 16 21 J ■■ ■ k ; %C * '. v - 2 1 8877 Example 10 (—)-(E)-3-[l,2,3,4-Tetrahydro-l-r(3(3, 4a)-3-hydroxy-4- (hydroxymethyl)cyclopentyl1-2>4-dioxo-5-pyrimidinyl]-2-propenoic acid 5 The product of Example 9 (180 mg) in 0.5 N aqueous sodium hydroxide (2.5 ml) was stirred at room temperature for 4h. Dowex 50G-X8 cation exchange resin was added until the solution had pH4. The resin was filtered off and the filtrate evaporated 10 in vacuo at 30-35° to give the title compound as an off-white solid (131 mg); ([^HgjDMSO) (mixture of epimers) 1.70, 1.86(lH,s,H-6) , 2.80, 2.86(lH,d,CH=CHC02H), 3.23, 3.34 (lH,d, =CHC02H).

Example 11 f—)-(E)-5-(2-Bromoethenyl)-l-[(la,38,4a)-3-hydroxy-4- (hydroxymethyl)-cyclopentyll-2,4-(1H,3H)-pyrimidinedione The product of Example 10 (110 mg) and potassium acetate (77 mg) in water (5 ml) were heated to 60°. N-20 bromosuccinimide (69.5 mg) was added in small portions over 5 min and the clear solution stirred at 60° for 10 min and then at room temperature for 2h.

■The solvent was removed and the residue purified by column chromatography, eluting with chloroform-25 ethanol (9:1), to give the title compound (10 mg); X (CD3OD) 2.24(1H,s,H-6), 2.66(lH,d,CH=CHBr), 3.19(lH,d,CH=CHBr, 4.93(lH,m,H-1'), 5.81(lH,m,H-3'), 6.2-6.4(2H,m,H-5f,5").

Claims (7)

.. • f: m~V y\- : . . , 218877 - 18 - Example 12 (—)-(E)-5-(2-Bromoethenyl)-1-[(la,38,4a)-3-hydroxy- 4-(hydroxymethyl)-cyclopentyll-2,4-(1H,3H)-pyrimidinedione A mixture of the product of Example 5 (374 mg) , (E)- 5-(2-bromovinyl)uracil (326 mg) and finely ground anhydrous potassium carbonate (207 mg) was stirred in dry DMSO (5 ml) at 90° under nitrogen for 4h. The dark coloured mixture was poured into water (50 ml) and extracted with dichloromethane (3 x 25 ml). The combined organic phases were washed with brine (50 ml), dried and concentrated to afford a yellow oil. The latter was purified by flash chromatography eluting with 2% methanol/dichloromethane to give crude (+)-(E)-5-(2-bromoethenyl)-1-[(la,30,4a)-3-methoxymethoxy-4-[(me thoxyme thoxy)methyl]-cyclopentyl]-2,4(1H,3H)-pyrimidinedione (42 mg) which was taken up in methanol (5 ml), para-toluenesulphonic acid (50 mg) was added and the solution refluxed for lh. The mixture was neutralised by the addition of R8050 polyvinylpyridine resin (Reilly Corporation) and subsequently evaporated onto flash silica (ca 1 g). The latter was applied to a flash chromatography column eluting with 10% methanol/dichloromethane to yield the title compound (11 mg). m.p. 179-183°(d). ■ . I : " 19 ~ WHAT +/WE CLAIM 1S> Claimc 218877

1. Compounds of formula (C) "t> RE^ 0/RP (C) where either R° represents a hydroxymethyl group E D 5 and R represents a hydroxyl group or R represents E a protected hydroxymethyl group and R represents e a protected hydroxyl group or R represents a hydroxyl D F group and R represents an ethenyl group and R represents a hydroxyl or protected hydroxyl group 10 or a leaving group with the proviso that either RD represents a protected hydroxymethyl group and E P R represents a protected hydroxyl group or R represents a protected hydroxyl group.

2. Compounds of formula (XIX) 3a, 15 ^ / 'z (XIX) R2aO ^ 2a 3a where R and R represent protecting groups and Z represents a leaving group.

3. Compounds of formula (XXI) .3a, ^' 0„ (XXI) R2a O 2a 3a 20 where R and R represent protecting groups.

4. Compounds of formula (XXII) 1 ¥( V r' S— - 20 - ®3a _ R 0 R 0 2 1 88 77 OR" (XXII) 2a 3a ]l where R , R and R represent protecting groups.

5. Compounds of formula (XXIII) HO HO OR 11 where R*1 represents a protecting group.

6. Compounds of formula XXIV;(XXIII);(XXIV);OR;11;HO;where R1* represents a protecting group. 10

7. Compounds as claimed in claim 1, as herein specifically disclosed in any one of Examples 1 to 5. P. LIMITED eys arey