NZ207025A - Prostaglandin intermediates - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £07025 267 OZ 5 Priority Date^s): A .7. na / a | Complete Specification Filed: .......

C01C53 Co7CS7 C07c-56i Class: f«W 7? „ .. 3 1 MAY 1985' Publication Date: ....

P.O. Journal, ISSo: P.

H S Hi I fil Under the provisions of Regu^ lation 23 (I) the Specification has been ante-dated ,9^l -J& ,^-J ^..Initiate NEW ZEALAND PATENTS ACT, 1953 No.: Divided out of 197 , 558 Date: 29 June 1981 COMPLETE SPECIFICATION INTERMEDIATES FOR USE IN THE SYNTHESIS OF PROSTAGLANDINS Ai We, NATIONAL RESEARCH DEVELOPMENT CORPORATION, a British Corporation established by Statute, of Kingsgate House, 66-74 Victoria Street, London SW1, England hereby declare the invention for which "f" / we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (-QUffujeel fey '<t>) 207025 - i a.

PROSTAGLANDIS This invention relates to intermediates for use in the synthesis of prostaglandins containing several types of ring system. This is a divisional of Mew Zealand Patent Specification 197,558.

In NZ Patent Specification No. 197,558, a group of biologically active compounds is described and claimed which contain a substituted bicvclo [2,2,2] octane, bicyclo [2,2,2] oct-2Z-ene, 6,6-dimethyl-bicyclo [3,1,1] heptane, 7-oxa-bicyclo [2,2,1] heptane, 7-oxa-bicyclo [2,2,1] hept-2Z-ene, cvclo'nexene, cvclohexane" or hvdroxvcyclopentane ring system. The compounds of the present invention constitute intermediates in a synthetic route of particular value for the preparation of various of these biologically active compounds.

Accordingly the present invention comprises a compound of formula (I) (I) wnerem represents one of the divalent cyclic groups 207025 the letters a and b indicating in each case the points of attachment 1 2 V 1 of the substituents R and C(R )-C^w respectively; R represents a 6-carboxyhex-2-eny1 group or a modification thereof in which the group is altered by one, or where appropriate by a combination, of the following: (a) reduction of the double bond optionally accompanied by replacement of a carbon atom at the 1, 2 or 3 position by a sulphur or oxygen atom, (b) alteration of the position of the double bond, (c) shortening or lengthening of the carbon chain by one or two methylene groups, and (d) formation of an amide, ester or salt 2 derivative of the carboxy group; R represents hydrogen, an aliphatic hydrocarbon group or an aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group; and either V and W together represent the oxygen atom of 2 a carbonyl group or, when R is other than hydrogen, V represents 15 hydrogen and V represents a hydroxy group; with the proviso that when R is hydrogen then the divalent cyclic group Is a bicyclo [2,2,2] octane, a bicyclo [2,2,2] oct-2Z-ene or a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system.

The various bridged ring systems indicated above nay alterna-20 tively be represented in planar form, i.e. in the sace order as " } . ^ 207025 - A - (the two free valencies in the third and fourth formulae indicating methyl groups), but the more usual convention has generally been folloved throughout the specification of representing these systems in non^-planar form. It will be appreciated, however, that the 05 compounds (I) may exist in various stereoisoineric forms, which are included within the scope of the invention, and in particular that each geometric isomer of a bridged ring compound (I) will exist in two enantiomorphic forms. These two forms will have the structure illustrated hereinbefore and the mirror image of that 10 structure. Taking the vicinally disubstituted bicyclo [2,2,2] oct-2Z-ene ring system as an example, such pairs of enantiomorphs may be shown as follows (the rings being numbered according to the system used herein). 8 8 For the sake of added clarity it might be mentioned that alteraa-15 tive, equivalent, modes of showing these non-planar structures may be used. Thus the right hand of the two formulae shown directly above is equivalent to 7 3 2n ^ It will be seen that the modifications of the 6-carboxyhex-2-enyl group which may be made in compounds according to the present invention are of two types. Thus, the modifications either involve the hex-2-envl group or the 6-carboxy group. Among modifications of the first form, which are listed under (a) to (c) above, certain preferences may be indicated. Thus, where the double bond is reduced and a carbon atom replaced, the replacement is conveniently by an oxygen rather than a sulphur atom and also is conveniently at the 2 or 3 position. Moreover, where the position of the double bond is altered, this is conveniently to the 3,4 position and where the carbon chain is shortened or lengthened, this is conveniently at the end of the chain adjacent to the carboxv group. Among the second form of modification, listed under (d) above, examples of amide, ester and salt derivatives of particular interest are to be found in the prostaglandin art and include esters such as alkyl esters, amides such as those containing the group -CONHSC^CH^ and variants thereon, and salts with various physiologically acceptable cations. Specific examples of salts are those formed with an alkali metal such as sodium or with quaternary ammonium ions or amines such as tris (the symbol tris represents the compound 2-amino-2-hydroxymethylpropane-l, 3-diol) Examples of specific groups R^" are -CR2-CH=CH-(CH2) ^GO^H, -(CH2)6C02H and -(CH) 20(CH2) 3C02H, as well as amide, salt and particularly ester derivatives of both groups. 2 Groups R other than hvdrogen are fully described in NZ Patent Specification No. 19 7,558, aliphatic hydrocarbon groups substituted directly by an aromatic group and particularly unsubsti- tuted aliphatic hydrocarbon groups being of most interest. The size 2 of the group R can however influence the ease with which the final 2 biologically active compounds may be prepared and R is preferably either hydrogen or one of the smaller alkyl groups, for example of 1 to 3 carbon atoms, in substituted form, or particularly in unsubstituted form, for example ethyl and especially methyl. 2 Aromatic groups.present .in grouos R are described in detail in NZ Patent Specification No. 19 7,558 but foe hydrocarbon or 207025 heterocyclic groups, for example phenvl and substituted phenyl 2 groups and pyridyl groups such as pyrid-l-yl. When the group R contains an aliphatic hydrocarbon group directly substituted by an aromatic group, then it is preferred that the aromatic group is not 05 attached to a carbon atom of the aliphatic group which is itself 2 V attached directly to the carbon atom of the group C(R ) . w Thus, for example, a 2-phenvlethyl group is preferred to a 1-phenylethvl or phenvlmethyl (benzyl) group. Good levels of biological activity have been achieved with compounds prepared from intermediates of formula (I) in which R is one of hydrogen, ethyl and especially methyl. The increase in biological activity 2 resulting from the presence of a group R which is methyl rather than hydrogen has been found to be particularly iparked in. the case of those compounds described in jjg Patent Specification £fo-z 197,558 2 - V containing a group derived from the group C(R )— of the inter- 2 3 2 3 mediate which is of the form C(R )=N-NHC0.NHR or C(R )=N-NHCS.NHR .

As indicated above, compounds according to the present invention may contain, in the order shown previously, one of the following types of ring system: bicyclo [2,2,2] octane, bicyclo [2,2,2] 20 oct-2Z-ene, 6,6-dimethyl-bicvclo [3,1,1] heptane, 7-oxa-bicyclo [2,2,1] heptane, 7-oxa-bicvclo [2,2,1] hept-2Z-ene, cyclohexane, cyclohexene and hydroxycyclopentane. The 6,6—dimethyl-bicvclo [3,1,1] heptane ring system, unlike the others, may be substituted in either of two ways, corresponding to reversal of the substituents 25 shown at the a and b positions. It will be appreciated that the bridged ring systems present in compounds according to the present invention show a range of degrees of asymmetry. Thus, the 6,6-dimethyl-bicyclo [3,1,1] heptane ring system is sufficiently asynmetric for reversal of the substituents at the a and b positions 30 to result in a different structural isomer and thus a different compound (I), both types of compound (I) containing the 6,6-dimethyl-bicyclo [3,1,1] heptane ring system being covered by the present invention. In the case of the 7-oxa-bicyclo [2,2,1] heptane and 7-oxa-bicyclo [2,2,1] hept-2Z-ene ring systems, however, reversal 35 of these substituents would merely provide a structure which represents an alternative stereoisomer, the invention, as has I. 24JANI985 207025 previously been indicated, extending to the compounds (I) in their various stereoisoraeric forms. The situation with the bicyclo [2,2,2] oct-2Z-ene ring system is analogous to that pertaining in the case of the 7-oxa-bicyclo [2,2,1] heptane and hept-2Z-ene ring systems 05 but the bicyclo [2,2,2] octane ring system has a sufficient degree of symmetry for such reversal of the a and b substituents to give the same compound (I) of identical stereochemistry. Among these ring systems, the bridged ring systems are of particular interest and of these the bicyclo [2,2,2] octane and the 6,6-dimenthyl-bicyclo [3,1,1] heptane ring substituted at the 2-positioa by the group 2 V 1 C(R )\_w rather than the group R be msntioned particularly Anong those bridged ring systems which may be saturated or unsaturated, the forcer are usually preferred, particularly in the case of the compounds containing an oxygen bridging group, as unsaturation 15 generally confers lower stability whilst the level of biological activity of the final compounds prepared from Intermediates of this Invention is generally substantially similar.

It will be appreciated that the structures of the compounds described above provide various opportunities for the occurrence 1 2 V of stereoisomerism. The substituent groups R and C(R be In the cis or trans relationship to each other, compounds of the latter configuration more generally being preferred. Moreover, when the ring system is one which is bridged or contains a hydrogen substituent then, in most cases, different isomers will exist which vary according to the way In which the substituent groups R 2 and C(R ) are disposed in relation to the bridging groups or the substituent. Isomers of particular interest are shown below in one of the two enantiomorphic forms which can exist in each case, the other enantloraorph having a structure which Is the 30 mirror image of that shown. The unsaturated ring system is illustrated where the ring system may be saturated or unsaturated and the symbol B represents -CH^CH^-Cpositions 7 and 8) or -0-(position 7). As indicated above, the bicyclo [2,2,2] octane system possesses a greater degree of symmetry than the other 35 bridged ring systems, as the two bridging groups attached together at the bridge positions (1 and A) are identical, both being -CH^CH^-. ' ",\r In this case therefore, although the trans Isomer is preferred and can exist In two enantlomorphlc forms, the endo, exo type isomerism which can occur with the other bridged ring systems cannot arise.

It will be seen that in the structures shown below the number- 05 lng applied herein to the various positions of the ring system has been indicated. It should be noted that the system of numbering adopted for the bridged ring systems which can exist in both saturated and unsaturated form is chosen so that the double bond in the unsaturated ring system receives the lowest number 1 2 . V possible (2), the substituents R and C(R then being at the 5 -» W and 6 positions respectively. For conformity, a similar system of numbering is followed for the analogous saturated ring systems, the substituents again being described as at the 5 and 6, rather than the 2 and 3 positions as in the 6,6-dimethyl [3,1,1] heptane 15 6ystem. b b 3 S- exo, 6-endo -endo, 6-exo 7 2/R1 or C(R2)- NR 2ji, 3cc, 6cc or R1 7 ch Zee, 3j3, 6oc 207^** i ^c(r2)=nr ice, 2£, 3oc OH l 2 >c(r2)=nr 4cc; 2cc; 3J3 Among the isomers illustrated above in two forms, one form is usually peferred to a somewhat greater extent than the other. In the case of the 5-exo, 6-endo and 5-endo, 6-exo isomers the latter is most usually preferred but in the case where B is -0- the 05 5-exo, 6-endo isomer is also of considerable Interest. In the case of the 2/9, 3a, 6a, and 2a, 3/3, 6a» isomers the latter is of most interest. [The convention applied herein for naming the compounds (I) containing a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system is the use of a and $3 to indicate the directions in 10 which the substituents at the 2- and 3-positions are directed. In the designations used above the position of the bridging carbon atom at position 6 has for simplicity also been Indicated by an a or P (the position of the gem dimethyl groups at the 6-position 207025 is dictated by that of the carbon atom to which they are attached)]. In the case of the la, 20, 3a and ia, 2a, 33 isomers the latter is again of most interest.

Where the substituent r'" is a 6-carboxyhex-2-envl group or a group modified therefrom but still containing the double bond, then the configuration about this bond is preferably cis (Z) rather than trans (E) . In addition to the foregoing isomerism, as indicated previously the compounds of the present invention will in most cases additionally be resolvable into enantiomorphic forms and one among these may be preferred by virtue of biological activity or physical properties of the final conpounds prepared from intermediates of the present invention. Single enantioners may be obtained either by the use of an optically active starting material or by resolution of a pair of enantiomorphs.

It will be appreciated, however, that certain of the compounds of the present invention are capable of epimerisation under particular conditions and that in a few cases, as will be seen fron "2 Patent Specification No. 197,558, t^e stereochemistry of an intermediate may undergo some modification during conversion to a final, biologically active, compound. 2 Compounds according to the present invention in which R~ is hydrogen are of value not only for direct use as an interaediate 2 in the preparation of a final compound in which R~ is hydrogen but also as a suitable intermediate for the preparation of those coo- 2 pounds according to the present invention in which R is other 2 than hydrogen. The preparation of such compounds in which R is hydrogen, shown as (II) below, is described in detail in the Examples and at the end of the Examples for various of the ring systems.

H 207025 Compounds (II) containing the unsaturated bicyclo [2,2,2] oct-2Z-ene ring system may be prepared by the procedure described In Example 1 for the preparation of a bicyclo [2,2,2] octane (II) but omitting the H^/Pd-C reduction step which is described in section (4), thereby retaining the double bond present in the bicyclo [2,2,2] oct-2Z-ene of section (3). Such a procedure is similar to the synthesis of the analogous compound containing a bicyclo [2,2,1] hept-2Z-ene ring system which is described in detail and illustrated in UK Patent Application 8000279, published under the serial number GB 2039909A, except that for the eight membered ring system it is preferred to use an acetal prepared from ethylene glycol rather than ethanol since the equilibrium of the reaction with ethanol does not lie sufficiently towards the ring closed form. The compound (II) containing the cyclohexane ring system may be obtained by the introduction of a H^/Pd-C reduction step into the synthesis of the equivalent cyclohexene compound, reducing the cis-4,5-bIs-hydroxymethylcyclohex-l-ene to give cis-4,5-bis-hydroxymethylcyclohexane before proceeding with the formation of the monobenzyl ether. Alternatively, cyclohexane 1,2-dicarboxylic acid anhydride may be used as the starting material. The 7-oxa-bicyclo [2,2,1] heptane and hept-2Z-ene compounds of formula (II) are obtainable, for example in the 5-endo, 6-exo form, by routes described in the literature which yield compounds containing a 6-carboxyhex-2'Z-enyl or 6-carboxyhexyl substituent R , for example Eggelte et al, J.C.S. Perkin I, 1978, 980 Sprague et al, Advances in Prostaglandin and Thromboxane Research, 1980, Jj, 493.

Other stereoisomers are obtainable by modified routes. Thus, for example a-pinene may be obtained in both optically active forms thus providing a route to (+)-nopol and (+)-myrtenol as alternative starting materials for use in the routes described in Examples 3, 4 and 5. Also, in the case of the 7-oxa-bicyclo [2,2,1] heptane compounds and their ring unsaturated analogues modifications of the routes described in the literature may be used to produce other stereoisomers.

Modification of the 6-carboxyhex-2-enyl group may be effected through the initial introduction of a group R in modified form or 207025 by modification of this group during or at the end of the synthesis. Thus, ester formation may conveniently be effected by esterification of a free carboxy group just prior to conversion of an acetal group to a formyl group, for example using diazomethane to form 05 the methyl ester. Amides may similarly be prepared by conventional procedures. Indeed, the procedures for effecting the various modifications indicated above will be apparent from the considerable literature existing on prostaglandin chemistry. Thus, for example, in the case of a saturated ring system, where a precursor of 10 structure H CHO (in acetal form) is involved in the synthesis of compounds containing a 6-carboxy— hex-2-enyl group, then a convenient route to the analogous containing a 6-carboxyhexyl group involves the reduction of this precursor, for example with H^/Pd-C. The preparation of compounds containing 15 a 6-carboxyhexyl group in this manner is described in GB 2039909A. Where the synthetic route initially involves compounds containing the corresponding unsaturated ring it may be possible, if desired, to reduce both the ring and chain double bonds at this stage in one step. In the case of other ring systems, particularly the 20 unsaturated ring systems, a 6-carboxyhexyl group is best introduced at an earlier stage of the synthesis, for example by a modification of the Initial Diels Alder reaction where such a reaction is employed. Introduction of a 3-oxa-6-carboxyhexyl group is similarly best effected at an early stage of the synthesis. A convenient 25 route for doing this involves the use of a compound of structure C - CH CH20H.

■CH 24JANJ985 207C2 5 wherein the residue X is a saturated one, such as 6,6-dimethyl-2-(2'-hydroxyethyl)-bicyclo [3,1,1] hept-2-ene, as a starting material. Reaction with acrylonitrile in the presence of Triton B (benzyl-methylammonlum hydroxide) In a Michael reaction Is then used to 05 modify the 2 substltutent to form a 5'-cyano-3'-oxapentyl group which Is then chain extended using, in turn, lithium aluminium hydride, toluene sulphonyl (Ts) chloride in pyridine, sodium hydride followed by Ts chloride, and cyanide ion to give a 6'-cyano-3'-oxahexyl group by the sequence of reactions -(CH2)20(CH2)2 CNL1A1H^ -(CH2)20(CH2)2CH2NH2^^ -(CH2)20(CH2)3NHTs O)NaH^-(CH2)20(CH2)3NTs2 CN- -(CHo)o0(CH?)QCN (2)TsCL Acid hydrolysis and esterification are then used to convert the cyano group to a methoxycarbonyl group and the reactant 9-borabicyclo [3,3,1] nonane is finally employed to effect reaction at the double bond to yield a compound of the type (II) described hereinbefore having the structure X | ^CHO H When the desired compound of formula (I) contains a substituent 2 V 2 C(R yzl „ in which R is other than hydrogen, "the compound (II) "~-W may conveniently be reacted with a Grignard reagent of the form 2 R MgHalogen, followed by oxidation of the secondary alcohol of formula (III) so formed, for example using Jones reagent, to give 20 the desired compound of formula (I).

H I ' V It will be appreciated that the methods described above are not the only ones which may be used for the preparation of compounds according to the present invention and that various alternative procedures may be used as will be apparent to those skilled in the 05 art of prostaglandin chemistry.

The compounds (I) are used for the preparation of the compounds of NZ Patent Specification No. 197,558 £n procedures which are described therein.

This invention is illustrated by the following Examples. 10 Where possible, the stereochemistry which the compounds are believed to possess has been indicated. However, some contamination of a minor nature by other isomers may often be present i.e. by the other of the pairs of preferred isomers shown hereinbefore or particularly by the corresponding cis isomer. It will 15 be appreciated that the proportion of such contaminants does not necessarily depend upon the stereochemical nature of the intermediates in earlier stages of the synthesis. Thus, certain compounds are capable of epimerisation under particular conditions, and the formyl compounds (II) in particular can undergo an epimerisation 20 involving the formyl group, for example at the stage in the synthesis of some of these compounds where the formyl group is generated by the action of acid on an acetal.

In most cases the compounds are obtained in the form of a racemic mixture but in the case of the compounds of Examples 3, 4 25 and 5 an optically active starting material is used and these compounds are therefore also optically active. It should also be noted that the full stereochemistry has not been designated in the names of the compounds of Examples 3 and 4 in as far as no attempt has been made to indicate the orientation of the substituents R^" 2 and C(R )=NR relative to the two bridging groups -CH^- and full orientation being as shown in the structure designated 2a, 3g, 6a, shown hereinbefore. In the case of Example 5, this is also true for the stereochemistry of the compounds of sections 5 and 6, although in admixture with another 35 isomer, but reference should be made to the note at the end of this Example as regards the stereochemistry of the title compound thereof.

The mass spectroscopy data is generally obtained by direct inlet except for cases where the compound has a substituent R* which terminates in an ester grouping when the data is obtained by gas chromatography mass spectroscopy. In certain cases, which are 05 indicated, the free carboxy group of the substituent R* is converted to a methyl ester group before the mass spectrum is run (by gas chromatography mass spectroscopy). Such conversion is readily achieved by solution in methanol, using warming and addition of NaHCO^ as necessary, followed by the addition of an excess of 10 ethereal diazomethane to the methanolic solution, standing, and the removal of solvent.

EXAMPLES Following the Examples, the preparation is described of two compounds, 4-(6'-ethoxycarbonylhex-2'Z-enyl)-5-formylcyclohex-l-ene and la-hydroxy-2a-(6'-carboxyhex-2'Z-enyl)-3/S-formylcyclopentane, which may be used in a manner analogous to that of Examples 2 and 4 as starting materials for the preparation of compounds according 2 to the present invention having a group R other than hydrogen and containing a 4,5-substituted cyclohex-l-ene or 2,3-substituted 1-hydroxycyclopentane ring system.

Example 1; trans-5-(6 '-Carboxyhex-2'Z-enyl)-6-formyl-bicyclo [2,2,2] octane (1) Maleinaldehydic acid pseudo-ethyl ester 30 g of redistilled furan-2-aldehyde is mixed with 600 ml dry ethanol and 300 mg of methylene blue is added. Dry air is blown gently through the solution and the material is irradiated with a 300 W tungsten lamp for about two days until t.l.c in a silica gel/ether system shows essentially no remaining starting material. 25 The solution is then stirred with vanadium pentoxide for four hours, filtered, and the solvent removed under reduced pressure. The residual oil is distilled under high vacuum to give the title compound as an oil (23.6 g, 76%), b.p. 90 - 92°C/0.2 mm. (2) Diels-Alder reaction between maleinaldehydic acid pseudo-ethyl ester and cyclohexadiene Cyclohexadiene (4.5 g) and the maleinaldehydic acid pseudo-ethyl 30 ester (1) (6.4 g) are heated together in a thick walled glass tube at 120°C for 10 hours and the product is distilled to give the Diels-Alder adduct of these two compounds in over 903! yield, b.p. 95 - 97°C/0.2 mm. M+ 208. (3) 5-endo-Hyd roxyme thyl-6-exo-(1', 3'-dioxaeyelopen t-2'-yl)-b icyclo I2 »A.._2 ] _oct-2Z-ene The Diels-Alder adduct (2) (10 g) is heated under a Dean and 05 Stark apparatus with 12 ml of ethylene glycol in 100 ml toluene containing a crystal of p-toluenesulphonic acid. After water has ceased to form, half of the solvent is distilled off and the resultant solution of 5-endo-ethoxycarbonyl-6-exo-(l',3'-dioxaeyelopent-2'-yl) bicyclo [2.2,2] oct-2Z-ene is added to excess lithium aluminium '0 hydride (3 g) in 200 ml of dry ether. The addition is performed at a rate which maintains a gentle boiling of the ether (30 to 60 minutes). After a further 1 hour of heating the excess hydride is destroyed by the careful addition of wet ether followed by water. The mixture is then treated with aqueous 10? w/v sodium '5 hydroxide solution to precipitate aluminium salts. The mixture is dried over magnesium sulphate and then filtered. The organic solvent is evaporated to give the title compound as an oil which is used directly in step (4). (4) trans-5-Hydroxymethyl-6-(1',3'-dioxacyclopent-2'-yl)~ bic^clo [2,2,2J_ octane The crude alcohol/acetal obtained in (3) is dissolved in 20 ethanol and hydrogenated at atmospheric pressure over 10Z palladium on charcoal, one molecular equivalent of hydrogen being absorbed. The catalyst is filtered off and the solvent evaporated. Distillation of the residue gives the title compound as a colourless oil (6.1 g, 60%), b.p. 110 - 112° C/0.15 mm. (5) trans-5-Cyano-6-(1',3'-dioxacyclopent-2'-yl)-bicyclo [2,2,2] octane The alcohol/acetal (4) (7.0 g) in 15 ml dry pyridine is added to 7.5 g of p-toluenesulphonyl chloride in 45 ml of pyridine at o 0 C with stirring. After 20 hours the mixture is poured into ice/water and after 30 minutes stirring the mixture is extracted with ether to give the tosylate ester of the alcohol as a colour-30 less oil in good yield.

The tosylate ester (12.0 g) in dimethyl sulphoxide (15 ml) Is added to potassium cyanide (3.0 g) In dimethyl sulphoxide (20 ml). The mixture is stirred and heated at 100°C under nitrogen for 6 hours. The reaction mixture Is then poured into water and the 05 mixture is extracted with ether to give the title compound as an oil (7.2 g), Vfflax2205 cm \ which is purified by passage through a short Florlsil column with toluene as eluant. (6) trans-5-Formylmethyl-6-(l',3'-dloxacyclopent-2l-yl)-blcyclo [2,2,2] octane The nitrile/acetal (5) (7.0 g) is stirred in 100 ml of dry toluene under nitrogen at -15°C. Di-isobutylaluminium hydride, (42.5 ml of 1M solution in toluene) is added slowly over 25 minutes and the mixture is allowed to warm slowly to room temperature.

After 1 hour, methanol (10 ml) is slowly added, followed by 200 ml of saturated aqueous sodium hydrogen tartrate. The mixture is o stirred at 40 C for 2 hours and the upper organic layer is then separated and the aqueous phase further extracted with ethyl acetate. The combined organic solutions are dried (MgSO^) and evaporated. The yellow oil obtained is chromatographed on Florisil in toluene to give the title compound as an oil (5.8 g, 83X),v 1 max (film) 1720 cm" , £(CDC13) 9.75 (t, J-2Hz, 1H), 4.85 (d, J=8Hz, 1H), 3.9 (m, 4H), 2.8-2.4 (m, 2H), 2.1-1.2 (m, 12H). (7) trans-5-(6'-Carboxyhex-2'Z-enyl)-6-formyl-bicyclo [2,2,2] octane 4-Carboxy-n-butyltriphenylphosphonium bromide (17.0 g) is dried at 75°C for 3 hours under vacuum. The solid is cooled and the vacuum released to argon. Dimethyl sulphoxide (50 ml) is added and butyllithium (270 ml of a 1.5 M solution in pentane) is added slowly over 1 hour. The deep red ylide thus formed is stirred at room temperature for 15 minutes and then the aldehyde/ acetal (6) (4.6 g) is added slowly over 15 minutes. The mixture is stirred overnight at room temperature, and then the solvent is o removed at 50 - 60 under vacuum. The residue is dissolved in 30 water and the aqueous phase is extracted with ether to remove non-acidic material. The water layer is acidified (pH * 4) with 2N aqueous hydrochloric acid and then extracted with ether. The ethereal solution Is dried and evaporated to give trans-(6'- carboxyhex-2'Z-enyl)-6-(1',3'-dioxaeyelopent-2'-yl)-bicyclo [2,2,2] octane as an oil (3.5 g, 55%).

The acetal group is removed by stirring this material (3 g) 05 with 200 ml of water/dioxane (1:1 v/v) containing 0.1N aqueous o hydrochloric acid at AO C. The mixture is extracted with ether and the ethereal extract is dried (MgSO^) and evaporated to give a residue which is purified by chromatography on silica gel in toluene/ethyl acetate (90:10 v/v) to give the title compound as an oil [2.3 g, 48% from (6)], v (film) 1725 and 1710cm'1, £(CDC1J max 3 9.73 (s, 1H), 5.5-5.3 (m, 2H), and 2.2-1.45 (in, 20H).

Example 2: trans-5-(6'-Carboxyhex-2,Z-enyl)-6-acetyl-bicyclo [2,2,2] octane (1) trans-5-(6'-Carboxyhex-2'Z-eny1)-6-(1'-hydroxyethyl)-bicyclo [2,2,2] octane trans-5-(6'-Carboxyhex-2'Z-enyl)-6-formyl-bicyclo [2,2,2] octane Is prepared as described in Example 1. This acid/aldehyde (2 g) is dissolved in dry tetrahydrofuran (20 ml) at 0°C and 15 treated under nitrogen with 1M solution of methyl magnesium bromide in ether (23 ml) during 2 hours. The reaction is quenched by the addition of dilute aqueous hydrochloric acid and the mixture is extracted with ether (3 x). The ethereal solution is dried and evaporated to give a residue which is chomatographed on silica gel 20 using increasing proportions of ethyl acetate in toluene as eluant. Traces of the starting material are eluted with 20% v/v ethyl acetate in toluene and 50% v/v ethyl acetate in toluene elutes the title compound. Evaporation of the solvent from the 50% v/v ethyl acetate/toluene gives the title compound as an oil (1.6 g) which consists of a mixture of the two eplmers differing in configuration * at the asymmetric carbon atom of the group -CHOHCH^. (2) trans-5-(6'-Carboxyhex-2'Z-enyl)-6-acetyl-bicyclo [2,2,2] octane A solution of the epimeric alcohols from (1) in acetone (20 ml) is treated with Jones reagent (2.2 ml of a solution prepared by dissolving 26.7 g of chromic anhydride in 23 ml of concentrated 30 sulphuric acid and diluting to 100 ml with water, followed by filtration) and oxidation allowed to proceed at 0°C for 30 minutes. <0% ^ A The reaction mixture is then poured into water and the product extracted with ether. The ether solution is dried and evaporated to give the title compound as an oil (1.3 g) , S (CDCl^) 5.4 (m, 2H), 2.2 (s, 3H) 2.6-1.3 (m, 20H) M+ 292 and also 249 (M-43) and 151 (M-141) (as methyl ester).

Example 3: 2a-(6'-Carboxyhex-2'Z-enyl)-3ff-formyl-6,6-dimethyl-bicyclo [3,1,1] heptane (1) 2-(2'-Benzyloxyethyl)-6,6-dimethyl-bicyclo [3,3,1]-hept-2-ene 2-(2'-Hydroxyethyl)-6,6-dimethyl-bicyclo [3,3,1] hept-2-ene [(-)-nopol] (66 g) is added slowly with stirring to 12.5 g of 80% sodium hydride dispersion in oil in 300 ml of dimethylformamide at room temperature. After addition (ca. 1 hour), stirring is continued for 4-5 hours until all hydrogen evolution has ceased.

Benzyl chloride (52 g, 46 ml) is added over 1-2 hours at room temperature when an exothermic reaction is observed. After the o addition, the mixture is heated at 80 C for 4 hours. The material is then cooled, poured into water and the product isolated by ether extraction followed by distillation under vacuum to give the title compound as an oil (71 g, 70%), b.p. 128 - 131° C/0.2 mm. (2) 2g-(2'-Benzyloxyethyl)-3 ft-formyl-6,6-dimethyl-bicyclo [3,1,1] heptane The benzyl ether (1) (10.2 g) is placed in a large flask (1 litre) with 30 ml THF (dry) under argon and 9-bora-bicyclo [3,3,1] nonane (9-BBN) in THF (90 ml of 0.5M solution) is added over 5-10 minutes at room temperature. The solution is refluxed for 30 hours maintaining the inert atmosphere, after which most of the compound has reacted at the double bond.

The hydroborated benzyl ether is cooled to 0°C while the argon atmosphere is replaced by carbon monoxide. A solution of lithium trimethoxyaluminium hydride (62 ml of 0.7M) is prepared from lithium aluminium hydride and methanol in THF and added over 30-60 minutes with vigorous stirring maintaining a positive pressure of carbon monoxide in the system. A vigorous uptake of gas is observed (ca. 1,000 ml) and after a further 1 hour of vigorous stirring the argon atmosphere is re-established and 82 ml of pH7 aqueous saturated phosphate buffer (buffer prepared from 97.5 g NaH^PO^.2H^0 + 108.75 g K^HPO^ dissolved in 250 ml water) is added with vigorous stirring. Finally 15 ml of 30% hydrogen peroxide is carefully added while keeping the temperature of the o mixture below 20 C. The mixture is stirred for a further 10 minutes 05 and then poured into water. The title compound is isolated by ether extraction and purified by chromatography on Florisil eluting with petrol/ether, being obtained as an oil (8.9 g, 81%),v (film) , max 1718 cm" . (3) 2a- ( 2 '-Benz yloxye thyl) -3/3- (dime thoxyme thyl) -6,6-dime thyl-bicyclo [3,1,1] heptane The benzyl ether/aldehyde (2) (10 g) is dissolved in 100 ml 10 of methanol containing 10 ml trimethyl orthoformate. A few crystals of p-toluene sulphonic acid are added and the mixture is kept overnight. The solution is treated with anhydrous sodium carbonate (0.5 g) and water (20 ml) is slowly added with efficient mixing. The mixture is added to excess water and the title compound isolated 15 by ether extraction in impure form as an oil in 100% yield, M 342. (4) 2a- ( 2' -Hydr oxyethy 1)-3/3- (dime thoxyme thyl) -6,6-dimethyl-bicyclo [3,1,1] heptane The benzyl ether/acetal (3) (10 g) is dissolved in 100 ml of * methanol and 300 mg of 10% palladium on charcoal is added. The mixture is then hydrogenated at room temperature and atmospheric pressure. After take up of 1 molar equivalent of hydrogen the 20 title compound is isolated in impure form as an oil in 100% yield by filtration of the mixture through Celite and evaporation of the methanol. (5) 2a- ( 2' -Formylme thyl) -3/9- (d ime thoxyme thyl) -6,6-dime thyl-bicyclo [3,1,1] heptane The alcohol/acetal (4) (5.0 g) is dissolved in dry methylene chloride (10 ml) and the solution is added with stirring over 10 * Some samples of catalyst may be found to encourage cyclisation of the debenzylated compound to give a cyclic acetal. In the event of this presenting difficulty, an alternative procedure is to use sodium in liquid ammonia for this stage. 207025 minutes to pyridiniura chlorochroroate (6.0 g) in 30 ml methylene chloride containing 0.5 g of dry finely divided sodium acetate.

After 2 hours, 200 ml of dry ether is added to the mixture and after a further 15 minutes, the mixture is poured into water. The ether layer is quickly washed with 37. aqueous sodium hydroxide (2 x 200 ml), followed by brine. The solution is dried over sodium sulphate, the ether evaporated and the residue chrocato graphed on Florisil with benzene/ether is eluant to give the title compound (2.1 g, 4 3%),v (film) 1720 cm"1. M+ 240. ma x * (6) 2 a— (6 — Ca rboxyh ex—2 ' Z—eny 1)—3 (d ime thoxyme thyl)—6,6—dimethyl— bicyclo [3,1,1] heptane The aldehyde/acetal (5) (0.5 g) is reacted with 2.2 equivalents of 4-carboxy-n-butyl-triphenyl-phosphoniuni bromide in the presence of dimesyl sodium in dimethyl sulphoxide as. described for.the bicyclo [2,2,1] heptane acid/acetal in Example 1(8) of New Zealand Patent Application No. 197,558 to give the title compound in a high purity (0.51 g, 72%), M+ 338. (7) 2°-(6 '-Carboxyhex-2 'Z-enyl)-3 £-formvl-6,6-dime thyl-bicyclo [3,1,1] heptane The acid/acetal (6) (0.5 g) is dissolved in 20 ml of dioxane- o water mixture (1:1) and the solution is heated at 40 C for 2.5 hours with an excess of 0.2M aqueous hydrochloric acid. The title compound is isolated as an oil by extraction with ether followed by chromatography on silicic acid eluting with 5% ether in toluene (0.36 g, 72%),v (film) 1720 cm_1, £(CDCl,) 0.7 (d, 1H), 1.2 max 3 (s 3H) , 1.5-2.8 (m, 15H), 5.4 (m, 2H), 8.5 (s, very broad, 1H) , 9.6 (d, 1H), M+ 292 (methyl ester).

Example 4 : 2cc— C6 '-Carboxyhex-2 'Z-enyl)-3 fracetyl-6,6-dimethyl-bicyclo [3,1,1] heptane (1) 2a-(6 '-Carboxyhex-2 'Z-enyl)-3ft-(l '-hydroxyethyl)-6,6-dimethyl-bicyclo [3,1,1] heptane 2a- (6 '-Carboxyhex-2 ' Z-enyl) -3 fhf ormyl-6,6-dime thyl-bicyclo [3,1,1] heptane is prepared as described in Example 3. This acid/aldehyde (1.1 g) is dissolved in dry tetrahydrofuran (20 ml) and treated at 0°C under nitrogen with a 1M solution of methyl magnesium bromide in diethyl ether (12 ml). The mixture is stirred overnight and is then allowed to come to room temperature and is quenched by the addition of dilute aqueous hydrochloric acid. The mixture is extracted with ether (3x) and the ether solution is dried and evaporated to give, as an oil the title compound in the form of an epimeric mixture differing in configuration at the it asymmetric carbon atom of the group -CHOHCH^. (2) 2g-(6 '-Carboxyhex-2 ' Z-enyl)-3/3-acetyl-6,6-dimethyl-bicyclo [3,1,1] heptane 05 The mixture of epimeric alcohols obtained in (1) is dissolved in acetone and treated at 0°C slowly whilst stirring with Jones reagent (1.25 ml, prepared as described in Example 2), the oxidation at 0°C being continued for 30 minutes. The reaction mixture is then quenched with water and the product immediately extracted 10 with ether. The ether solution is dried and evaporated and the oily residue is chromatographed on silica gel using increasing concentrations of ethyl acetate in toluene as eluant. The bulk of the desired product is contained in the 20% v/v ethyl acetate/toluene fraction which is evaporated to give the title compound (0.625 g), 15 £(CDC13) 5.35 (m, 2H), 218 (s, 3H) , 3.0-1.6 (m, 17H), 1.07 (s, 3H), 1.22 (s, 3H), 0.87 (d, 1H), M+ 306 and also 263 (M-43), 165 (M-141) and 125 (on methyl ester). The methyl ester-butyl oxime derivative, unlike the methyl ester, shows twin peaks on gas chromatography (syn/anti isomers). The major compound on g.c.m.s shows prominent 20 ions at m/e 377 (M+), 320 (M-57), 304 (M-73), 142 and 116.

Example 5: 3/?- (6 '-Carboxyhex-2 'Z-enyl)-2-f ormyl-6,6-dime thyl -bicyclo [3,1,1] heptane (1) 2-(6 '-Vinyloxymethyl-6,6-dimethyl-bicyclo [3,1,1] hept-2-ene A mixture of 2-hydroxymethyl-6,6-dimethyl-bicyclo [3,3,1] hept-2-ene [(-)-myrtenol] (26 g), mercuric acetate (2.6 g) and ethyl vinyl ether (500 ml) is heated under reflux in an atmosphere of argon for 16 hours. On cooling, anhydrous potassium carbonate (4.5 g) is added and the excess ethyl vinyl ether is removed by distillation. The residue is filtered, the solid washed with hexane (2 x 20 ml) and the combined filtrate and washings are distilled to give the title compound as an oil (22 g, 72%), b.p. 105 - 109°C/17 mm,v (film) 2975, 2910, 2820 and 1605 cm'1. max (2) 3 /3-( Formyl me thyl -2-me thylene-6,6-diraethyl-bicyclo [3,1,1] heptane The vinyl ether (1) (2.0 g) is heated in a sealed tube at 200°C for 7 hours. The resulting yellow oil is purified by chromatography on silica gel with toluene as eluant to give the title compound as an oil (1.4 g, 70%),v (film) 1720 cm max 05 in an alternative procedure which may produce higher yields the vinyl ether (1) is passed in a stream of argon or nitrogen through a tube (1 cm x 10 cm) packed with glass wool and heated at 190°C, the product being condensed in a cold trap and distilled to give the title compound as an oil, b.p. 70 - 75°C/1 mm. (3) 3± -(6'-Carboxyhex-2'Z-enyl)-2-methylene-6,6-dimethyl-bicyclo [3,1,1] heptane (4-Carboxy-n-butyl)triphenylphosphonium bromide (7.0 g) is dried at 75°C under vacuum for 90 minutes, cooled and the flask released to dry nitrogen. Dry dimethyl sulphoxide (DMSO) (25 ml) is added, followed by the slow addition of 18 ml of a 1.6 M solution of butyllithium in hexane. The temperature is held at 25°C and 15 the aldehyde (2) (1.5 g) in DMSO (5 ml) is added to the red ylide solution. The mixture is stirred overnight under nitrogen, then poured into 10% w/v aqueous sodium chloride (200 ml). The aqueous mixture is extracted with ether (3 x 75 ml), and the aqueous layer is then acidified to pH 4 with 2N hydrochloric acid and re-extracted 20 with ether (3 x 50 ml). The extracts of the acidified aqueous layer are dried over magnesium sulphate and evaporated to give the title compound as a yellow oil (2.0 g, 86%), ^CDCl^) 0.75 (s, 3H), 1.25 (s, 3H), 4.73 (m, 2H), 5.45 (m, 2H). (4) 3 jS -(6'-Methoxycarbonylhex-2'Z-enyl)-2-methylene-6,6-dimethyl-bicyclo [3,1,1] heptane The acid (3) (2.0 g) is treated with an ethereal solution of 25 diazomethane (120 ml) and a few drops of methanol are added. The solution is stirred for 20 minutes and the solvent is then removed under vacuum to give the title compound as a yellow oil (2.2 g, 100%). (5) 2d -(Hydroxymethyl-3ft -(6' -me thoxycarbonylhex-2'Z-enyl)-6,6-dimethyl-bicyclo [3,1,1] heptane and 2-Hydroxymethyl-3P (6'-methoxycarbonylhex-2'Z-enyl)-6,6-dimethyl-bicyclo [3,1,1] heptane The ester (4) (0.92 g) is placed in a dry 100 ml round-bottomed flask under nitrogen and is treated at 0°C over 5 minutes using magnetic stirring with 9-bora-bicyclo [3,3,1] nonane (a-BBN) in tetrahydrofuran (20 ml of 0.5M solution). The reaction mixture is 05 stirred at room temperature for 3 hours, and then 3N aqueous sodium hydroxide (3.3 ml, 10 mmol) is added, followed by 30% v/v aqueous hydrogen peroxide (3.3 ml) over a period of 10 minutes, cooling being required to control the resulting exothermic reaction. The mixture is then stirred under air for 15 minutes, treated with 10 potassium carbonate (3 g), and the organic upper layer separated off and dried over potassium carbonate. Evaporation of the solvent gives a cloudy yellow oil, which is stirred overnight in a 10:1 v/v toluene:light petroleum mixture (30 ml). The upper layer is decanted and evaporated to give a mixture of the title compounds 15 as an oil (0.4 g, 41%), £(CDC13) 0.92 (s) and 0.98 (s, total of 3H), 1.23 (s, 3H), 3.6-3.9 (m, 2H), 3.67 (s, 3H) 5.42 (m, 2H). (6) 2a-(Formyl-3ft-(6'-me thoxycarbonyl-hex-2'Z-enyl)-6,6-dime thyl-bicyclo [3,1,1] heptane and 2ft-formyl-3ft-(6'-methoxycarbonylhex-2 'Z-enyl) -6 , 6-dimethyl-bicyclo [3,1,1] heptane The mixture of epimeric alcohols (5) (0.294 g) is dissolved in dry dichloromethane (1.5 ml) and pyridinium dichromate (0.6 g) is added. The mixture is stirred for 22 hours at room temperature 20 and then dry ether (3 ml) and hexane (3 ml) are added. Stirring is continued for 15 minutes, and the mixture is then filtered. The last traces of the chromium salt are removed by passing the filtrate through anhydrous magnesium sulphate (5 g). Evaporation of the filtrate gives a mixture of the title compounds as an oil 25 (0.075 g, 25.4%), <?(CDCl3) 0.75 (s) and 0.96 (s, total of 3H), 1.21 (s, 3H), 3.67 (s, 3H), 5.42 (m, 2H), 9.70 (d) and 9.87 (d, total of 1H). f}2 B (7) 3ft-(6 '-Carboxyhex-2'Z-enyl)-2-fonnyl-6,6-dinie thyl-bicyclo [3,1,1] heptane The aldehyde ester (6) (0.075 g) is treated with 0.2N 5% v/v o aqueous methanolic potassium hydroxide at AO C for 2 hours. The solution is then neutralized with 2N aqueous hydrochloric acid and extracted with ether (3 x 20 ml). The extracts are dried over 05 magnesium sulphate and the solvent evaporated to give the title compound as an oil (0.065 g, 65%), ^(CDCl^) 0.75 (s, 3H), 1.22 (s, 3H), 5.45 (m, 2H), 9.6 (br, 1H), 9.71 (s or finely split d, 1H).

This aldehyde/acid (7) is obtained as a compound having a 2-formyl substituent with either the aor £configuration. The 10 formation of a single compound from the aldehyde ester (6) which is a mixture of compounds having a 2-formyl substituent with either an exo or an endo configuration is due to the epimerisation resulting from the use of the base to effect de-esterification. It has not been possible, however, to identify which of the two 15 configurations should be assigned to the 2-formyl substituent of the aldehyde acid.

PREPARATION OF FORMYL SUBSTITUTED STARTING MATERIALS (A) Preparation of 4-(6'-ethoxycarbonylhex-2'Z-enyl)-5-formylcyclohex-l-ene (1) c i s-4,5-b i s-Hy d r ox yme thy 1 c y c lohex-1 - ene A solution of the anhydride of 3,4-dicarboxycyclohex-l-ene (25.8 g) in THF (150 ml) is added with cooling to a stirred suspension of LiAlH^ (9 g) in THF (200 ml) under at a rate such as to 20 maintain the temperature at 0°C• After stirring for 18 hours at room temperature the mixture is gently refluxed for 1 hour and cooled in ice. The excess lithium aluminium hydride is decomposed by the careful addition of 1:1 THF-H^O mixture (100 ml). After dilution with chloroform (150 ml) the resulting mixture is filtered 25 and the solid is washed with chlorofom (3 x 25 ml). Concentration of the filtrate under reduced pressure yields an oily residue which is dissolved in benzene, dried over (MgSO^) and reconcentrated in vacuo to give the title compound as an oil (22 g, ca. 90%), • max v (film) 3350 cm"1. (2) cis-4-Hydroxymethyl-5-benzyloxymethyleyelohex-l-ene The diol (1) (16.2 g) in dimethylforraamide (50 ml) Is added dropwise to sodium hydride (3.1 g) in dimethylformamide (DMF) (50 ml). The mixture is stirred for 20 minutes and then benzyl chloride (16 g) is added and stirring is continued for a further 05 18 hours at 70°C. After removing the DMF in vacuo, water is added and the mixture is extracted with ether. The combine extracts are dried (MgSO ) and the solvent is evaporated to give a residue which is distilled under reduced pressure to give the title compound as an oil (16.5 g, ca. 60%), b.p. 140 - l45°C/0.03 mm,v (film) 10 3440 and 1600 cm (3) cis-4-p-Toluenesulphonyloxymethyl-5-benzyloxymethyl-cyclohex-l-ene The alcohol/benzyl ether (2) (10 g) in 20 ml of dry pyridine is added slowly at 0°C to p-toluenesulphonyl chloride (10.4 g) in pyridine (60 ml). The mixture is kept overnight at room temperature and is then quenched by pouring over crushed ice with vigorous 15 shaking. The product is extracted with ether, washed consecutively with water, 0.1 M sodium carbonate and brine, dried (MgSO^), and concentrated in vacuo at room temperature. The crude product is purified on a silica gel column, eluting with benzene-ethyl acetate (95%: 5% v/v) to give the title compound (14 g, 90%). The i.r. 20 spectrum shows the absence of a hydroxyl group. (4) ci s-4-Cya noroe thyl-5-b enz yl oxyme thyl eye lohex- 1-ene The p-toluene sulphonyl ester/benzyl ether (3) (12 g) in dimethylsulphoxide (DMSO) (15 ml) is added with stirring to potassium cyanide (3 g) in DMSO (20 ml). The mixture is heated at o 100 c under nitrogen for 6 hours and is then cooled, poured into water and the product extracted with ether. The solvent is removed and the residue purified on a Florisil column, eluting with petroleum ether-benzene (1:1) to give the title compound as an oil (6.5 g, ca. 80%) v (film) 2220 and 1600 cm"1. tqclx (5) cis-4-Formylmethyl-5-benzyloxymethylcyclohex-l-ene Di-isobutyl aluminium hydride (25 ml of a 1M solution in hexane) is added with stirring over a 15 minute period to the cyano/benzyl ether (4) (5.0 g) in dry toluene (70 ml) at -10°C under N^« After stirring for a further one hour at room temperature, the reaction is terminated by the cautious addition of methanol (6 ml), followed by saturated aqueous sodium hydrogen tartrate (95 ml). The mixture is then stirred and heated at 40°C for 2 hours. The organic phase is separated and the aqueous layer is further extracted with ethyl acetate, the combined organic solutions being dried and the solvent evaporated to give an oil. Chromatography of the oil on Florisil, eluting with benzene•gives the pure title compound as an oil (3.0 g 60%), v (film) 1715 cm \ max (6) cis-4-(6'-Carboxyhex-2'Z-enyl)-5-benzyloxymethylcyclohex-l-ene (4-Carboxyl-n-butyl)-triphenylphosphonium bromide (7.0 g) is o dried at 75 C under vacuum for 2 hours. The white solid is cooled, the vacuum is released to dry nitrogen and DMSO (10 ml) is added followed by 9 ml of 2M solution of dimesyl sodium in DMSO. The temperature is maintained at 25°C and the aldehyde/benzyl ether (5) (1.5 g) in DMSO is added to the deep red ylide solution.

After stirring overnight the solvent is removed at 55 - 60°C under reduced pressure. The residue is dissolved in water, extracted with ether, and the aqueous phase carefully acidified to pH 4 with 2N HC1. The mixture is extracted with ether and the ethereal solution dried (MgSO ) and concentrated in vacuo to give the title 4 -1 compound (10 g), v (film) 1700 cm max (7) cis-4-(6'-Carboxyhex-2'Z-enyl)-5-hydroxymethylcyclohex-l-ene To a stirred suspension of 1.5 g of the acid/benzyl ether (6) in 100 ml of liquid ammonia is added a total of 1 g of sodium in portions over 10-12 minutes at the end of which time the characteristic deep blue colour persists. The mixture is stirred for 30 minutes, the blue colour is then discharged by the careful addition of ammonium chloride and the reaction mixture is evaporated to dryness under a stream of nitrogen. The solid residue is triturated with 50 ml of benzene (to remove benzyl alcohol) and it is then dissolved in 40 ml of water. The aqueous solution is treated with Norit, then acidified with acetic acid and extracted with chloroform. Evaporation of the solvent gives the title compound as an oil (0.9 g), v (film) 3350-3450 and 1700 cm /z\' (8) cis-4-(6 '-Ethoxycarbonylhex-2 'Z-enyl)-5-hydroxyroethy] cyclo-hex-I-ene The acid/alcohol (7) (0.75 g) is dissolved in ethanol, 0.3 ml of concentrated sulphuric acid is added and the mixture is heated under reflux for 18 hours. The mixture is then diluted with water and extracted with ether. The ethereal extracts are washed with 05 water, saturated aqueous sodium bicarbonate and aqueous sodium chloride, and then dried (MgSO ). Evaporation of the solvent 4 -i gives the title compound as an oil (0.8 g),v (film) 1725 cm TDciX (9) A-(6 '-Ethoxycarbonylhex-2 'Z-enyl)-5-formylcyclohex-l-ene The ester/alcohol (8) (1.3 g), dicyclohexylcarbiimide (3.5 g) DMSO (5 ml) and dry benzene (10 ml) are placed in a 125 ml flask under nitrogen. Pyridinium trifluoroacetate (0.8 g) is added in one portion and the mixture is stirred for 18 hours. Ethyl acetate (50 ml) is added and the reaction mixture is then filtered. The filtrate is washed with water, saturated aqueous sodium chloride, and dried (Na^SO^). The solvent is evaporated to give a slurry residue which is redissolved in benzene. Solid particles separate from the solution and the solvent is then evaporated to give the title compound as an oil (1.0 g), vmax (film) 1715 cm fi^CDCl^) 1.61-2.06 (m) 2.15-2.28 (t, 1H), 2.AO (t, 2H), 5.AO (m, 2H), 5.70 (s, 2H), 9.79 (d, 1H), M+ 250 (as methyl ester).

(B) Preparation of la-hyd roxy-2a-(6'-Carboxyhex-2'Z-enyl)~ 3ff-formylcyclopentane (1) 6-(l ',3'-Dioxacyclopent-2'-yl)-2-oxabicyclo [3,3,0] octane-3-one 6-Formyl-2-oxabicyclo [3,3,0] octane-3-one (2.0 g) is heated o at 60 C in benzene (50 ml) with ethylene glycol (1 ml) and a trace of toluene-p-sulphonic acid under a Dean and Stark head. When reaction ceases, the reaction mixture is cooled and treated with water (20 ml) and 10% w/v aqueous KaHCO^ (20 ml). The organic 25 phase is separated, washed with water, dried and concentrated to give the title compound in 95% yield, v (film) 1750 cm H)3X The starting material is prepared by the treatment of 1,3-cyclohexadiene with dichloroacetyl chloride, followed by dechlorination with zinc and acetic acid of the resulting adduct 30 to give bicyclo [A,2,0]-oct-2-en-7-one. This compound is subjected ™" , «-«-* to Baeyer-Villiger oxidation to give 7-oxabicyclo [A,3,0] non-2-en-8-one which is treated with thallium (III) nitrate under carefully controlled conditions to give 6-formyl-2-oxabicyclo [3,3,0] octane-3-one having properties identical with those reported by 05 Corey and Ravindranathan, Tetrahedron Letters, 1971, A753. (2) 6-(1',3'-Dioxaeye1opent-2'-yl)-3-hydroxy-2-oxabicyclo [3,3,0] octane The lactone/acetal (1) (0.5 g) in dry toluene is cooled to -60°C and treated under dropwise from a syringe with 2 ml of a % w/v solution of diisobutylaluminium hydried in toluene. The o reaction is quenched at -60 C after 2.5 hours by the careful addition of methanol (1 ml). The reaction mixture is then diluted with ether (50 ml) and is warmed to room temperature. Water (0.5 ml) is added and stirring is continued for AO minutes followed by drying over anhydrous MgSO . Evaporation of the solvent in A vacuo gives the title compound as an oil (0.A2 g), v (film) « max 3A00 cm" . (3) - la-Hydroxy-2q-(6 '-carboxyhex-2 'Z-enyl)-3,5-(11,3'-dioxa- cyclopent-2'-yl)-cyclopentane Dimesyl sodium in DMSO (2.05 ml) is added dropwise to a solution of (A-carboxy-n-butyl)-triphenylphosphonium bromide (2.3 g) (dried before use) in 3 ml of DMSO. To the resultant red solution of the ylide is added dropwise a solution of the hydroxy/ 20 acetal (2) (0.5 g) in 5 ml of DMSO and the mixture is stirred overnight. The reaction mixture is then diluted with water (50 ml) and extracted with ethyl acetate. The cooled aqueous layer is acidified with dilute HCl to pH A and extracted with ethyl acetate. The organic extracts are washed with water, dried (MgSO^) and 25 concentrated. The resulting crude product is purified by chromatography on Unisil using toluene-ether (1:1 v/v) as eluant to yield the title compound as an oil (0.A g), v (film) 3350-3A20 cm max (A) lg-Hydroxy-2g-(6'-carboxyhex-2'Z-enyl)-3^-formylcyclopentane The hydroxy/acid/acetal (3) (0.15 g) is hydrolysed by dissolving it in 20 ml of dioxane^water mixture (1:1 v/v) and heated at A0°C 30 with 0.05M aqueous HCl for 3 hours. 100 ml of water is added and the product extracted with ether. The solvent is evaporated and

Claims (7)

- 30 - the residue purified by silica gel chromatography, eluting with gradient from 10% v/v ethyl acetate in toluene to pure ethyl acetate, to give the title compound as an oil (95 mg), S(CDC13) 4.30 (br, 1H) 5.40 (m, 2H), 6.70 (br, 1H), 9.60 (d, 1H) 207025 - 32 - and the letters a and b indicating in each case the points of attachment

1 2 -V 1 of the substituents R and C(R ) respectively; R represents a > w 6-carboxyhex-2-enyl group or a modification thereof in which the group is altered by one, or where appropriate by a combination, of 05 the following: (a) reduction of the double bond optionally accompanied by replacement of a carbon atom at the 1, 2 or 3 position by a sulphur or oxygen atom, (b) alteration of the position of the double bond, (c) shortening or lengthening of the carbon chain by one or two methylene groups, and (d) formation of an amide, ester 2 10 or salt derivative of the carboxy group; R represents hydrogen, an aliphatic hydrocarbon group or an aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group; and either V and W together represent the oxygen atom of a carbonyl 2 group or, when R is other than hydrogen, V represents hydrogen and 2 15 W represents a hydroxy group; with the proviso that when R is hydrogen then the divalent cyclic group is a bicyclo [2,2,2] octane, a bicyclo [2,2,2] oct-2Z-ene or a 6,6-dimethyl-bicyclo [3,l,l] heptane ring system.

2. A compound according to Claim 1, in which the divalent cyclic 20 group is other than a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system having the group R1 at the 3-position.

3. A compound according to Claim 1 or 2, in which the divalent cyclic group is a bridged group.

4. A compound according to Claim 1, which contains a bicyclo 25 [2,2,2] octane or bicyclo [2,2,2] oct-2Z-ene ring system. 207025 - 33 - :

5- A compound according to Claim 1, which contains a 6,

6-dimethyl-bicyclo [3,1.1] heptane ring systcn having the group R^ at the 3-position. 6. A compound according to any of Claims 1 to 5, in which any 05 modif ication of the 6-carboxyhex-2-enyl group of type (c) is a shortening or lengthening of the carbon chain by one methylene group. 7. A compound according to any of Claims 1 to 5, in which"R is a 6-carboxyhex-2Z-enyl group or a derivative thereof formed at the 10 carboxy group. 8. A compound according to any of Claims 1 to 5, in which R* is a 6-carboxyhexyl group or a derivative thereof formed at the carboxy group. 9. A compound according to any of Claims 1 to 8, in which R* is 15 a group terminating in a free carboxy group. 10. A compound according to any of Claims 1 to 8j in which R* is a group terminating in an ester derivative of the carboxy group. 11. A compound according to any of the preceding claims in which 2 ^ V 2 the substituent C(R ) is a group C(R )»0. w 20 12. A compound according to any of the preceding claims, in which 2 R is hydrogen or an aliphatic hydrocarbon group. 13. A compound according to Claim 1, which contains a bicyclo C2,2,2j octane or bicyclo £2,2,2] oc+-2Z-ene ring system, and In which the substituent Is a formyl group. 14. A compound according to claim 1, which contains a 6,6-d I methyl-bicyclo £3,1,1] heptane ring system having the group at the 3-position, and In which the substituent C(R^)C!v/ 's a formyl group. 15. A compound according to claim 1, which contains a bicyclo £2,2,2] octane, bicyclo £2,2,2] oct-2Z-ene or 6,6-dImethyl-bicyclo £3,1,1] heptane ring system, and In which the substituent C(R2)CT^ Is a group C(r2)=0 wherein Is an aliphatic hydrocarbon group. 16. A compound according to any one of claims 1 to 12 and 14, In which R^ Is an a Iky I group of 1 to 3 carbon atoms. 17. A compound according to claim 16, In which R^ Is ethyl. 18. A compound according to claim 16, in which R^ is methyl. - 34 - 207025 19. A compound according to any one of claims 1 to 7 and 9 to 18, In which the configuration about any double bond In the group Is els. 20. A compound according to any one of the preceding claims, In which groups fO and C(R^)Cw are ,n a trans relationship. 21. A compound according to claim 20, which has the 5-endo, 6-exo configuration when It contains a bicyclo £2,2,2] oct-2Z-ene, the 5-endo, 6-exo or 5-exo, 6-endo configuration when It contains a

7-oxa-blcyclo £2,2,1] heptane or 7-oxa-blcyclo £2,2,1] hept-2Z-ene ring system, the 2OZ, 6 configuration when It contains a 6,6-d 1 methyl-bicyclo £3,1,1] heptane ring system and the 1 o(, 2£K, configuration when It contains a 1-hydroxyeye Iopentane ring system. 22. trans-5-(61-Carboxyhex-2'Z-enyI)-6-formyI-bicyclo £2,2,2] octane and Its methyl ester. 23. trans-5-(6,-Carboxyhex-2,Z-enyI)-6-acetyI-bicyclo £2,2,2] octane and Its methyl ester. 24. 5-endo-(6*-Carboxyhex-2'Z-enyI)-6-exo-formyI-bicyclo £2,2,2] oct-2Z-ene and Its methyl ester. 25. 5-endo-(6*-Carboxyhex-2'Z-enyI)-6-exo-acetyI-bicyclo £2,2,2] oct-2Z-ene and Its methyl ester. 26. 2*-(61-Carboxyhex-2'Z-enyI-formyI-6,6-d1methyl-bicyclo £3,1,1] heptane and Its methyl ester. 27. 2o( -(6-Carboxyhex-2'Z-enyI)-3>0 -acetyl-6,6-dImethyl-bicyclo £3,1,1] heptane and Its methyl ester. 28. 3^ -(e'-Carboxyhex-^'Z-enyI)-2-formyI-6,6-dImethyl-bicyclo £3,1,1,] heptane and Its methyl ester. 29. 3^ -(6'-Carboxyhex-2'Z-enyI)-2-acety1-6,6-dlmethyl-bicyclo £3,1,1] heptane and Its methyl ester. By>Ms/their Authorised Agents, A. J. PARK & SON