CA1198421A - Prostaglandin intermediates - Google Patents

Abstract

ABSTRACT
PROSTAGLANDIN INTERMEDIATES
A process for the preparation of a compound of formula (I) (I) wherein represents one of the divalent cyclic groups the letters a and b indicating in each case the points of attachment of the substituents R1 and respectively; R1 represents a 6-carboxyhex-2-enyl 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 accom-panied 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 derivative of the carboxy group; R2 represents hydrogen, a C1-10 aliphatic hydrocarbon group or a C1-10 aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group Ar, where Ar is a phenyl, napthyl. fluorenyl, dibenzo-cyclohexyl, dibenzocycloheptyl, pyridyl, benzothiazolyl, dihydrobenzothiazolyl, N-methyldihydroenzothinzolyl, benzoxazolyl, dihydrobenzoxazolyl or N-methyldihydrobenzoxazolyl group or such a group substituted by one or more substituents selected from C1-10 alkoxy, halogen, C1-10 halogen substituted alkyl, sulphamoyl, amino, hydroxyl, nitro and C1-10 alkyl groups; and either V and W together represent the oxygen atom of a carbonyl group or, when R2 is other than hydrogen, V represents hydrogen and W represents a hydroxy group; with the proviso that when R2 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 comprises reacting a compound of formula (II)

Description

PROSTAGLAN~IN INTERMEDIATES
This invention relates to intermediates for use in the synthesis of prostaglandins containing ~everal types of ring system.
In Cana~ian Patent Application Number 380,307 a group of biologicaliy active compounds is described and claimed which 05 contain a substituted bicyclo [2,2,2] octane, bicyclo [2,2,2J
oct-2~-ene t 6,6-dimethyl-bicyclo [3,1,1] heptane, 7-oxa-bicyclo [2,2,~ heptane, 7-oxa-bicyclo ~2,2,1] hept-2Z-ene, cyclohexene, cyclohexane or hydroxycyclopentane 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.
According to the present invention a process for the preparation of a compound of formula tI) I~P~

X I (I) --¦~C~R2)~' H W

H
~C
wherein ¦ represents one of the divalent cyclic X I groups I
H

;~@
.

lo I' I, SHEA

O O

SHEA

OH

~8L23L

the letters a and b indicating in each case the points of attachment of the substituents R and C(R ) W respectively; R represents a 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 optional.ly 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 bo~d, (c) shortening or lengthening of the carbon chain by one or two methylene groups, and (d) formation of an amide, ester or salt derivative of the carboxy group;
R represents hydrogen~ a C1 10 aliphatic hydrocarbon group or a C1 10 aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group Ar, where Ar is a phenyl, napthyl, fluorenyl, dibenzocyclohexyl, dibenzo-cycloheptyl, pyridyl, benzothiazolyl, dihydrobenzothiazolyl, N-methyldihydrobenzothiazoly~ benzoxazolyl, dihydrobenzoxazolyl or N-methyldihydrobenzoxazolyl group or such a group substituted by one or more substituents selected from Cl 10 alkoxy, halogen, C1 10 halogen substituted alkyl, sulphamoyl, amino, hydroxyl, nitro and C1 10 alkyl groups; and either V and W together rapresent the oxygen atom of a carbonyl group or, when R is other than hydrogen, V represents hydrogen and 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 ~3,1,1] heptane ring system which comprises reacting a compound of formula (II) C~ Y
X (II) H

~;

2~

in which Z represents (a) a formyl group in acetal form, (b) a hydroxymethyl group, (c) a formyl group or (d) a group CH(R )OH, Y is either R1as defined for (I) or a precursor for R and and R are as defined for (I), the said reaction consisting of 05 (a) effecting hydrolysis of the acetal to give a formyl group, (b) effecting oxidation of the hydroxymethyl group to give a formyl group, (c) effecting a Grignard reaction involving the fsrmyl group and a reagent R2MgHalogen to give a group CH(R OH), or (d) effecting oxidation of the group CH(R OH) to give a group C(R )=O, and where appropriate converting the group Y in the resultant product into a group Rl, the process optionally involving a change of stereochemistry of (I) to that of (II).
The various bridged ring systems indicated above may alternatively be represented in planar form, i.e. in the same order as ' ~1 (the two free valencies ln the third and fourth formulQe indicating methyl groups), bu~ ~he more usual convention has generally been followed throughout the speciflcation of representing these systems in non-pla~r form. It will be apprec~ated, however, that the 05 compounds (I) may e~ist in varlous stereoisomeric forms, which are included wlthin the ~cope of the invention, and in particular ~hat each geometric isomer of a bridged ring c~mpound (I) will exi~t in two enantiomorphic forms. These two forms will have the 6tr~cture illustrated hereinbefore and the mirror image of that structure. Taking the vicinally disubstituted bicyclo [2,2~2]
oct-2Z-enP ring system as an example, such pairs of enantiomorphs may be shown as foll~s (the rings being numbered according to the system used herein).

3 3 For the sake of added clarity it might be mentioned that alterna-tive, equivalent, modes of showing these non-planar structures may be used. Thus the right hand of ehe two formulae shown directly above is equivalent to 2 *~d ~Iso 3 " ~l989L2~

It will be seen that the modif~catlons of ehe 6-carboxyhex-2-enyl group which may be made in compo~nds according to the present ~nvention are of two types. Thus, the modiflcatlons elther involve ~he hex-2 enyl group or the 6-carboxy group. ~mong ~5 modifications of the firs~ fonm, wh~ch sre listed under (a) to (c) above, certain preferences may be lndicated. Ihu~, ~here the double bond 15 reduced and a carbon atom replac~d, the replacemen~
- is convenlently by an oxygen rather than a sulphur ~om and al80 is conveniently at ~he 2 or 3 position. ~oreover, where the position of the double bond is altered, thls is convenien~ly to the 3,4 posltion and where the carbon chain is shortened or leng~hened, this is conveniently at the end of the chain ad~acent to the carboxy group. Among the second fonm of modificatiou, listed under (d) above, examples of amide, ~ster and salt deriva-tives of partlcular interest are to be found in the prostaglandinart and ~nclude esters such as alkyl esters, amides 6uch as ~hose con~aining the group CONHS02CH3 and Yariants thereon, and sal~s wl~h var~ous physiologically acceptable cations. Specific examples of salts are those formed with an alkali metal such as sodium or with quaternary ammonium ions or amines cuch as tris (the symbol tris represents the compound 2-amino-2-hydroxymethylpropane-~,3-diol).
Examples of specific groups Rl are -CH2-CH=CH-(CH~)3C02~, -~CH2)6C02H and -(CH)20(cH~)3Co2H, as well as amide,~salt and partlcularly ster derivatives of both groups.
Groups R other than hydrogen are fully described in Canadian Patent Application Number 38Q,907, aliphatic hydrocarbon groups substituted directly by an aromatic group and particularly unsubstituted aliphatic hydrocarbon groups being of most interest.
The size of the group R can however influence the ease with which the final biologically active compounds may be prepared a~d 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 form3 for example ethyl and especially methyl. The hydrocarbon and heterocyclic aromatic groups present in groups R are described in further detail in Canadian Application 380,907 but 342~

pyridyl groups such as pyrid-l-yl and especi~lly phenyl and substituted phenyl groups are of particular interest. When the group R contains an aliphatic hydrocarbon gorup directly substituted by an aromatic group, then it is preferred that the aromatic group is 05 not attached to a carbon atom of the aliphatic group which is itself attached directly to the carbon atom of the group C(R )~ W Thus, for example, a 2-phenylethyl group is preferred to a l-phenylethyl or phenylmethyl (benzyl) group. Good levels of biological activity have been achieved with compounds prepared from intermediates of formula (I) in which R2 is one of hydrogen, ethyl and especially methyl.
The increase in biological activity resulting from the presence of a group R which is methyl rather than hydrogen has been found to be particularly marked in the case of those compounds described in Canadian Applieation 380,907 containing a group derived from the group C(~ ) ~W of the intermediate which is of the form C(R )=N-NHCO.NHR
or C(R )=N-NHCS.NHR .
As lndicated above, compounds according to the present inven-tlon may contain, in the order shown previously, one of the following types of ring syste~: b~cyc lo [2,2~2~ octane, bicyclo [2, 2,2]
20-; oct-~Z-ene, 6,6-dimethyl-bicyclo [3,1,11 heptane, 7-oxa-bicyclo ~2,291] heptane, 7-oxa-b1cyclo [2,2,1~ hept-2Z-ene, cyclohexane, ~yclohexene and hydroxycyclopentane. The 6,6-dimethyl-bicyclo 13,1,11 heptane ring system, unlike the others, may be substituted in either of two ways, corresponding to reversal of the substituents shown at the a and b positions. It will be appreciaeed that the bridged ring systems present in compounds according to the present invention show a range of degrees of asymmetry. Thus, the 6,6-dime~hyl-bicyclo [3,1,1] heptane ring system is sufficiently asymmetric for reversal of the substituents at the a and b positions 3~ to resul~ in a different structural isomer and thus a different compound (I), both types of compound (I) containing the 6,6-dimethyl-bicyclo 13,1,1] heptane ring system being covered by ~he present ~nvention. In the case of the 7-oxa-bicyclo [2,2,1~ hep~ane and 7-oxa-bicyclo 12,2,1] hept-2Z-ene ring systems, h~ever, reversal of these substituents would merely provide a struc~ure whleh represents an alternative stereoisomer, the invention, as has z~

_ 8 --p eviously been indlcated, extending ~o the compounds (I) in their various stereolsomeric forms. The situstion with the b~c~clo [2,2,2]
oct-2~-ene ring system is Qnalogous to thQt pertaining in the case of the 7-oxa-bicyclo 12,2,13 heptane and hept-2Z-ene rlng sgstems 05 but the bicyclo [2,2,2] octane rln~ system hRs a ~ufflcient degree of symmetry for such reYersal of the a and b 6ubstituents to glve the same compound ~) of identical stereochem~stry. Amang these ring systems, ~he bridged rlng systems are of particular interest and of the~e the blcyclo 12,2,21 octane and the 6,6-di~enthyl-bicyclo ~3,1,1] heptane ring subs~ituted at the 2-position by the group C~R ) W rather than the group R may be mentioned particularly.
Among those brldged rlng systems which may be ~aturated or unsatu-rated, ~he for~er are usually preferred, particularly in the case of the compounds con~aining an oxygen bridging group, as ~nsaturation generally confers lower stab~lity wh~lst the level of biological activity of the final compounds prepared fr~ intermediates of this invention is generslly substantially slmllar.
It will be appreciated that the ~tructures of the compounds described above prov~de varlous opportunities for the occurrence of stereoisomerism. The substituent groups R1 and C(R ) = m~y be in the cis or trans rela~ionship to each other, compounds of the latter configuration more generally being preferred. Moreover~
when the ring system is one which ls br~dged or contains a hydrogen substituent then, in m~st cases~ diferent isomers will exlst which vary a~cording to the way in which the substituent groups R
and C~R ) V are disposed in relation to the ~ridging groups or the substituent. Isomers of particular interest are shown below ln one of the two enantiomorphic forms which can exist in each case, the other enantiomorph having a structure which is the mirror ~mage of that shown. Ihe unsaturated rlng system is illustrated ~here the ring system may be saturated or unsatur~ted and the symbol B represents -C~2CH2-(positions 7 and 8) nr -0-~position 7). As indicated above, the bicyclo [2,2,2] ~ctane system possesses a greater degree of symmPtry than the o~her bridged ring systems~ 8S the two bridging groups at$ached $oge~her st the bridge positions (1 ~nd 4~ are identical, both being -CH2CH2-.

~.g8~

In this case therefore, although the trans isomer is preferred and can exist in two enantiomorphic Eorms, the endo, exo type isomerism which can occur with the other bridged ring systems cannot arise.
It will be seen that in the s~ructures shown below the numbering 05 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 unsatura~ed form is chosen so that the double bond in the unsaturated ring system receives the lowet number possible (2), the substituents Rl and C(R2) = V then being at the 5 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 [39]~]] heptane system.

B B

V ~o V
5-exo~ 6-endo W ~-endo~ 6-~xo -~RI or C(R~\

C~3 \~ C(~2~W or ~1 3Clc 9 ~oC

(RZ)~W

C(k~3~ or Rl 20c>~, 60c ~.

2~

OH
~RI

`C(R J~W
~,2,~, 30 ~RI

~C¢R J<~
oc, 3"~

Among the isomers illustrated above in two forms, one form is usually preferred to a somewhat greater extent than the other. In the case of the S-exo, 6-endo and 5~endo, 6-exo isomers the latter is most usually preferred but in the case where B is -O- the 05 5-exo, 6-endo isomer is also of considerable interest. In the case of the 2~, 3~, 6~, and 2~, 3~, 6~, 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 sy5 tem is the use of and to indicate the directions in 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 or (the position of the gem dimethyl groups at the 6-position -84~

is dlctated by that of the carbon atom to ~hlch they are attached)].
In the case of the , 2B9 3a and 1~, 2a~ 3~isomers the latter is agal~ of ~o~t lnt~re~t.
~here the substituen~ R ls a 6~carboxyhex-2-enyl group or a 05 group ~odified there~rom but stlll contalning the double bond, ~hen ~he configuration about this bond is preferably c16 (Z) rather than trans (E). In add~tion to the foregoing lsomerism, as indicated pre~iougly the compounds of the present lnvention wlll ln ~ost cases additlonally be resolvable i~to enantiomorphic forms aod one among these may be preferred by virtue of blological - activity or phycical properties of the final compoun~s prepared from lntermediates of the present invent~on. Single enant~amers ~ay be obtained either by ~he use of an optically active starting material or by resolution of a pair of enantiomorphs.
It ~ill be appreciated, however, that certain of the compounds of the present lnvent~on are capable of ep~meri~ation under parti-cular conditions and that in a few cases, as wlll be seen from Canadian Application 380,907, the stereochemistry of an intermediate may undergo some modification during conversion to a final, biologically active, compound.
Compounds of formula (I) in which R is hydrogen are of value not only for direct use as an intermediate in the preparation of biologically active compounds in which R is hydrogen but also as a suitable intermediate for the preparation of those compounds of formula (I) in which R is other than hydrogen. The preparation of such compounds in which the substituent C(R2)' W is a formyl group, is described in detail in the Examples and at the end of the Examples for various of the nine ring systems described hereinbefora. The formyl group may be generated by one of the two procedures referred to previously involving the hydrolysis, for example with aqueous hydrochloric acid, of a formyl group in acetal form, for example an acekal formed with ethylene glycol, methanol or ethanol, or the oxidation of a group CH(R2)0H, for example with pyridinium dichromate, the procedure used for any particular ring system depending upon the ease of synthesis of the precursor (II).

_ 12 --Co~pounds (II) containing the unsaturated blcyclo [2,2,23 ~ct-2X-ene rlng sys~em may be prepared by ~he procedure descrlbed in Example 1 for the preparation of a blcyclo [2,2,2] octane (II) but omitting the H2~Pd-C reduction step whlch is described in sectlon (4), 05 thereby retaining the double bond present in the bicyclo 12,2,2]
oct-2~-ene of section (3). Such a procedure ls similar to the synthesis of ~he analogous compound containing a bicyclo ~2,2,1]
hept-2Z-ene ring system ~A~hich is described in detail and illu-s~rated in UK Pa~ent 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 equil~brium of the reaction wi~h ethanol does not lie sufficiently towards the ring closed form. The compound (II~ containing the cyclohe~ane ring system l5 may be obtained by the introductlon of a H2~pd-C reduction step into the synth&sis 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 forma~ion of the monobenzyl ether. Alternatively, cyclohexane 1,2-dicarboxylic acid anhydride may be used as the starting materlal. 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 th~ literature ~hich yield compounds containing a 6-carboxyhex-2'Z-enyl or 6-carboxyhexyl substi~uent R , for example Eggelte et al, J.C.S. Perkin I, 1978, 980 Sprague et al, Advances in Prostaglandin and Thromboxane Research, 1980, 6, 493.
Other stereoisomers are obtainable by modified r~outes. Thus, for examp]e a-pinene ~ay 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 rlng unsaturated analogues modifications of the routes described in ~he literature may be used to produce other stereoisomers.
Modification of the 6-carboxyhex-2-enyl group may be effected ~hrough the initial introduction of a group R in modified form or t3 -by modificat~on of this group during or at the end of the 6ynthesls.
Thus, ester formation may conveniently be effected by esterlficatlon of a free carboxy group ~ust prior to conversion of an acetal group to a formyl group, for example using diazomethane to form 05 the ~ethyl ester. Amides may similarly be prepared by conventional procedures. Indeed, the procedures for effectlng the various modiflcations indicated above will be apparent from the considerable literature existing on prostaglandin chemistry. Thus, for example, in the case of a sa~urated ring system, where a precursor of structure ~/ =\/~/\CO 11 X

C
¦ CH0 (in acetal form) is involved in the synthesis of compounds containing a 6-carboxy-hex-2-enyl group, then a convenient rou~e to the analogous contain-ing a 6-carboxyhexyl group involves the reduction of this precursor, for example with H2/Pd-C. The preparation of compounds containing a 6-carboxyhexyl group in this ~anner is described in GB 2039909A.
Where the synthetic route initially involves compounds con~aining the corresponding unsaturated ring lt 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 unsaturated ring syste~s, 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 route for doing this involves the use of a compound of structure 11 .
CH
~3 ' Z'~

_ 14 ~herein the resldue ls a ~aturated one, such as 6,6-d~me~hyl-2-.. (2'-hydroxyethyl)-bicyclo [3,1,11 hept-2-ene, a6 8 ~tar~ing material.
Reac~lon ~ith ~crylonitrlle in the presence of Triton B ~benzyl-methylammonlu~ hydroxlde~ in a Michael reactlon i6 then used to 05 modify the 2 substitutent to fonm a 5' cyano-3'-oxapentyl gro~p whlch is then chain extended using, ~n turn, lithlum ~luminium hydride, toluene sulphonyl tTs) chloride in pyridine, sod~um hydride followed by Ts chlorlde, and cyanide ion to give a 6'-cya~o-3'-oxahexyl group by the sequence of reactions -(CH2)20(CH2)2 CN (cH2)2o~cH2)2cH2NH~ -(cH2)2o(cH2)3NHTs ( -(C~2~20(CH2)3MT (C~2)2(cH2~3cN
(2)'r~CL
Acid hydrolysig and esterification are then used to con~ert the cyano ~roup to a methoxycarbonyl ~roup snd the reactsnt 9-borabicyclo 13,3,1] nonane ls finally employed to effec~ reaction ~t the double bond to yield a compound of the ~ype (II) descrlbed herein-before having the structure H/\~ C~2C~13 /~

¦ \ C~O

When the desired compound of formula (I) contains a substituent C(R ) ~W in which R is other than hydrogen, its formation from the compound (II) may conveniently be effected by a Grignard reaction using a reagent of the form R MgHalogen, followed by oxidation of the resulting secondary alcohol of formula (II) in which Z is CH(R )OH, for example using Jones reagent, to give the desired compound of formula (I).
T~a~ U~C

It will be appreciated that the methods described above are not the only ones which may be ~sed for the preparation of compounds according to the present inventlon and that various alternatlve procedures ~ay be used as will be apparent to those skilled in the S art o~ prostaglandin chemistry.
The compounds (I) are used for the preparation of the compounds of Canadian Application 380,907 in procedures which are described therein.
This inYention is illustrated by the following Examples.
Where possible, t'ne stereochemistry whi~h the compounds are believed to possess has been indicated. However, some contam~natioa 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 ~ill be appreciated that the proportion of such con~aminants does not necessarily depend upon the ~tereochemical nature of the inter~ediaces in earlier stages of the synthesls. Thus, certain compounds are eapable of epimerisation under particular conditions, and the formyl compounds (II) in particular can undergo an epimerisation involving the formyl group, for example at the stage in the synthesis of so~e of these compounds where the formyl group is generated by the action oE 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 and 5 sn optically active starting ~aterial is used and these compounds are therefore also optically active. It should also be noted that the full ~tereochemistry has not been designated in the names of the compounds of Examples 3 and 4 in as far as no attempt has been ~ade to indicate the orien~ation of the substituents R
and C(R )' W relative eo the two bridging groups -CH2- and -C(CH3)~-, the full orientation being as shown in the structure designated , 3~, 6x, shown hereinbeEore. In the case of Example 5, this is also true for the stereochemistry of the compounds of sect;ons S
and 6, although in admixture with another isomer, but reference ~hould be made to the note at the end of this Example as regards the stereochemistry of the title ~ompound thereof.

-!
_ 16 -The mass spectroscopy data is generally obtained by direct inlet except for cases where the compound has a substituent R ~hich terminates in an ester grouplng when the data i8 obtained by gas chromatography mass spectroscopy. In certain ca~es, which are S indicated, the f~eP carboxy group of the substituent R is converted to a methyl ester group before the mass spectrum i8 run (by gas chromatography mass spectroscopy). Such conversion is readlly achieved by solution in methanol, using ~arming and addition of ~aHC03 as necessary, ollowed by ~he addition of an excess of ethereal diazomethane ~o the methanolic solution, standing, and the removal of sol~ent.
EXAMPLES
Following ~he Examples, the preparation -Is described of two compounds, 4-(6'-ethoxycarbonylhex-2'Z-enyl)-5-formylcyclohex-1-ene and 1-hydroxy~2a-(6'-carboxyhex-2'7-enyl)-3~Lformylcyclopentane, which may be used in a manner analogous to that of Examples 2 and

4 as starting materials for the preparation of compounds according to the present in~ention having a group R other than hydrogen and contain~ng a 4,5-substltuted cyclohex~l-ene or 2,3-substltuted 1-hydroxycyclopentane ring system.
Example 1: ~rans-$-~6'-Carboxyhex-2'Z-enyl)-6-formyl-bicyclo [2,2,2]
octane (1) aleinaldehydic 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 ~s irradla~ed 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.
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 msleinaldehydic acld pseudo-ethyl ester and cyclohexadlene Cyclohexadiene t4.5 g) and the maleinaldehydic acid pseudo-ethyl ester (1) (6.4 g) are heated together in a thick walled glass tube at 120 C for 10 hours and the produc~ ls distllled to give the Diels-Alder adduct of these two compounds in over 90~ yleld, b.p. 95 - 97 C/0.2 mm, M 208.
(3) 5-endo-HydrDx~ethyl 6-exo~(1',3'-dioxacyclopent o 12.2.2J oct-2Z-ene The Diels-Alder adduct (2) (10 g) is heated under a ~ean and 05 Stark apparatus wlth 12 ml of ethylene glycol in 100 ml toluene con-~aining a crystal of p-toluenesulphonic acid. After water has ceased to form, half of the solvent is distilled off and ~he resultant ~olution nf 5-endo-ethoxycarbonyl-6-exo-(1',3'-dloxacyclopent-2'-yl) bicyclo [2.2,2~ oct-2Z-ene is added to e~cess lithium aluminium hydride (3 g) in 200 ml ~f dry ether. The addition is perf~rmed a~ a rate whlch maintains a gentle boiling of the ether (30 to 60 m~nutes). After a further 1 hour of heating ~he excess hydride is destroyed by the careful addition of wet ether followed by water. The mixture is then treated with aqueous 10~ w/v sodlum hydroxide solution to precipitate aluminium salts. The mlxture ls dried over magnesiu~ 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-Hydr~y~thyl-6~ 3~-dioxacyclope -bicyclo ~2,2,2~ octane The crude alcohol/acetal obtained in (3) is dissolved in ethanol and hydrogenated at atmospheric pressure over 10~ palladium on charcoal. one molecular eqllivalent of hydrogen being absorbed.
The catalyst is filtered off and the solvent evaporated. Distilla-tlon 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'-dioxacyclopen~-2'-yl)-bicyclo ~2,2,2]
octane The alcohol/acetal (4~ (7.0 ~) ~n 15 ml dry pyrldine is added to 7.5 g of p-toluenesulphonyl chloride in 45 m~ of pyridine at 0 C with stirring. After 20 hours the mixture is poured ~nto ice/water and after 30 minutes stirrin~ the mixture is extracted with ether to give the tosy~ate ester of the alcohol as a colour-less oil ln good yield.

34~

he tosylate ester (12.0 g) ln di~ethyl sulphoxide (15 ml) is added to potassium cyanide (3.0 g) in dimethyl sulphoxide t20 ml).
The mixture is stirred and heated at 100 C under ~itrogen for

6 hours. The rea~tion mlxture is then poured into water and the 05 mixture is ex~racted with ether ~o give the title compound as an oil (7-2 8). ~max22o5 cm , which i6 purified by passage through a short Florisil~column with toluene as eluant.
(6) trans-5-Formylmethyl-6-(1',3'-dioxacyclopent-2'-yl)-bicyclo _2,2,2J octane The nitrlle/ace~al (5) (7.0 g) is stirred in 100 ml of dry toluene under nitrogen at -15 C. Di-isobutylaluminlum hydride9 ~42.5 ml of lM solu$ion in toluene) is added slowly over 25 minutes and the mixture ls allowed to wanm slowly to room temperature.
After 1 hour, methanol tlO ml) is slowly added, followed by 200 ml of saturated aqueous sodium hydrogen tartrate. The mixture is 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 C~gS04) and evaporated. The yellow oil obtained i8 chromatographed on Florisil in toluene to give the title compound as an oil (5.8 B, 83Z~,y a ~film) 1720 cm , ~(CDC13) 9.75 (t, J=2Hz, lH). 4.85 (d, J=8Hz, lH), 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 12,2,2~ 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 mlxture is stirred overnight at room temperature, and then the solvent is removed at 50 - 60 under vacuum. The residue is dissolved in water and the aqueous phase is extracted wlth ether to remove non-acidic material. The water layer is acidified (pH = 4) with 2N
aqueous hydrochloric acid and then extracted with ether. The i~ ~rQ~e Li9~Z~L

~9 --,/ ethereal solution i6 dried and e~aporated to give transr(6'-carboxyhex-2'Z-enyl)-6 (1',3'-dioxacyclopent-2'-yl)-bicyclo [2,2,2]
octane as an oil t3.5 g, 55%).
The acetal group is removed by stirr~ng this material (3 g) 05 with 200 ml of wa$er/dioxane (1:1 v/v) containlng 0.1N aqueous hydrochloric acid at 40 C. The mixture is extracted wlth ether and the ethereal extract is dried (MgSO4~ and evaporated to give a residue which ls purified by chromatography on 6ilica gel in toluene~ethyl acetate (g0:10 v/v) to give the title compound as an oil [2.3 g, 48~ from (6)], v ax (film) 1725 and 1710cm 1, ~(~DC13) 9.73 (6, lH), 5.5-5.3 (m, 2H), and 2.2-1.45 (m, 20H).
Example 2. trans-5-(6'-Carboxyhex-2'Z-enyl)-6-acety~bicyclo [2,2,2]
octane (1) trans-5-(6'-Carboxyhex-2'Z-enyl)~6-(1'-hydroxyethyl)-bicyclo 12,2,2] oc~ane trans-5-(6'-Carboxyhex-2'Z-enyl)-6-formyl-bicyclo [2,2,2~
octane is prepared as descrlbed in Example 1. This acidtaldehyde (2 g) is dissolved in dry tetrahydrofuran (20 ml) at 0 C and treated under nitrogen with lM solution of methyl magnesium bromide in ether (23 ml) during 2 hours. The reactlon is quenched by the addltion of dilute aqueous hydrochloric acid and the mixture is extracted with ether ~3 x). Ihe ethereal solution is dried and evapora~ed to gi~e a residue which is chomatographed on silica gel using increasing proportions o~ ethyl aceta~e 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 epimers differing in configuration at the asymmetric caroon atom of the group -CHOHCH3.
t2) 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 ~1 of a solution prepared by dissolving 26.7 g of chromic anhydride in 23 ml of concentrated sulphuric acid and dilutlng to 100 ml with water, followed by fil~ration~ and oxidation allowed to proceed at O C for 30 minu~es.

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), C (CDC13) 5.4 (m, 2H), 2.2 (s, 3H) 2.6-1.3 (m, 20H) M 292 and also 249 (M-43) and 151 05 (M-141) (as methyl ester).
Example 3: 2o-(6'-Carboxyhex-2'Z-enyl)-3~-formyl-6,6-dimethyl-_icyclo [3,1,1] heptane (1) 2-(2'-Benzy oxyethyl)-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 roum t-~mperature. After addition (ca. 1 hour), stirring is con-tinued for 4-5 hours until all hydrogen evolution has ceased.
Benzyl chloride (52 g, 46 ml) ls added over 1-2 hours at room temperature ~hen an exothermic reaction is observed. After the 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 follo~ed by distillation under vacuum to give the title compound as an oil (71 g, 70%), b.p. 128 - 131 C/0.2 mm.
(2) 2o-(2'-Benzyloxyethyl)-3~formyl-6,6-dimethyl-bicyclo [3,17 1] heptane The benzyl ether (1) (10.2 g) is placed in a large flas~
(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 ~emperature. 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 oYer 30-60 minutes with vigorous stirring maintaining a posltive 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 ~9~

_ 21 --97.5 g NaH2P0~.2H20 + 108.75 g K2HP04 dissolved ln 250 ml ~ater) is added with vigorous stirring. Flnally 15 ml of 30% hydrogen peroxide is carefully added while keeping the temperature of the mixture below 20 C. The mixture is stirred for a further 10 minutes 05 and then poured into water. The title co~pound is isola~ed by ether extraction and yurified by chromatography on Florisil eluting with petrol/ether, being obtained as an oil (8.9 g, 81~ max(film) 1718 cm (3) 2~-(2'-Ben~yloxyethyl)-3~-(dimethoxymethyl)-6,6-dimethyl-bicyclo ~3,1,1] heptane The benzyl ether/aldehyde (2) (10 g) is dissolved in 100 ml of methanol contalning 10 ml trimethyl orthoformate. A few crystals of p-toluene sulphonic acid are added and the mixture is kept overnight. The solution is treated wi~h 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 by ether extrac~ion in impure form as an oil in 100% yield, M 342.
(4) 2a-(2'-Hydroxyethyl?~3~-(dimethoxymethyl)-6,6-dimethyl-bicyclo [3~ heptane The benzyl ether/acetal (3) (10 g~ is dissolved in 100 ml of methanol and 300 ~g 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 ~he title compound is isolated in impure form as an oil in 100% yield by filtration oE the mixture through Celite~kand eYaporation of the ~ethanol.
(5) 2a-(2~-Formylmethyl)-3~-(dimethoxymethyl)-6,6-dimethyl-bicyclo 13,1,1~ heptane The alcohol/acetal (4) (S.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 cyclisa$ion of the debenzylated compound to give a cyclic acetal. In the event of this presenting difficulty, an alternatlve procedure is to use sodium in liquid ammonia for this s~age.
T~ade ~r~

84~

minutes to pyridinium chlorochromate (6.0 g) in 30 ml methylene chloride con-taining 0.5 g of dry finely divided sodium acetate. After 2 hourst 200 ml of dry ether is added to the mixture and after a further lS minutes, the mixture is poured into water. The ether layer is quickly washed with 3% aqueous sodium hydroxide (2 x 200 ml), followed by brine. The solution is dried over sodiurn sulphate, the ether evaporated and the residue chromatographed on Florisil with benzene/ether as eluant to give the title compound (2.1 g, 43%), vmax(film) 1720 cm , M 240.
(6) 2~-(6~-carboxyhex-2~z-enyl)-3~-(dimethoxymethyl)-6~6-dimethyl-bicyclo [3,1,1J
heptane The aldehyde/acetal (5) (0.5 g) is reacted with 2.2 equivalents of 4-carboxy-n-butyl-triphenyl-phosphonium bromide in the presence of dimesyl sodium in dimethyl sulphoxicle. The 4-carboxy-n-butyl-triphenyl-phosphonium bromide is mixed with 30 ml of dimethyl sulphoxide. A 2M solution of dimesyl sodium in dimethyl sulphoxide (50 ml) is added slowly while the mixture is maintained at 25C with a water bath. The aldehyde/acetal (5) is reacted with this mixture to give the title compound in a high purity (0.51 g, 72%)9 M 338.
(7) 2~-(6'-Carboxyhex-2'Z-enyl)-3~-formyl-6,6-dimethyl-bicyclo [3,1,1] heptane The acid/acetal (6) (0.5 g) is dissolved in 20 ml of dioxane-water mixture (1:1) and the solution is heated at 40C 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 , ~(CDC13) 0.7 (d, lH)~
1.2 (s 3H), 1.5-2.8 (m, 15H), 5.4 (m, 2H), 8.5 (s, very broad, lH), 9.6 (d9 lH), M 292 (methyl ester).

~.~

2~
- 22a -Example 4: 2a-(6'-carboxyhex-2~z-enyl)-3~-acetyl-6~6-dimethyl-bicyclo l3,1,1]
heptane (1) 2a-(6'--Carboxyhex-2'Z-enyl)-3~-(1'-hydroxyethyl)-6,6-dimethyl-bicyclo [3,1,1]

heptane 2~-(6'-Carboxyhex-2'Z-enyl)-3~-formyl-6,6-dimethyl-bicyclo 13,1,1~ heptane is prepared as described in Example 3. This acid/aldehyde ~1.1 g) is dis-solved in dry tetrahydrofuran (20 ml) and treated at 0C ~mder nitrogen with a lM 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 -

8~

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 asymmetric carbon atom of the group -CHOHCH3.
(2) _~-(6'-Carboxyhex-2'Z-enyl)~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 O C slowly whilst stirring with Jones reagent (1.25 ml, prepared as described in Example 2), the oxidation at O C being contlnued for 30 minutes. The reaction mixture is ~hen quenched with water and the product immediately extracted 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 frac~ion ~hich is evaporated to give the title compound (0.625 g), ~(CDC13) 5.35 (~, 2H), 218 (s; 3H), 3.0-1.6 (m~ 17H), 1.07 (s, 3H), 1.22 (s, 3H), 0.87 (d, lH), M 306 and also 2~3 (M-43), 165 (M-141) and 125 ~on ~ethyl 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 ions at m/e 377 ~M ), 320 (M-57), 304 (M-73), 142 and 116.
Example 5~: 3~(6'-Carboxyhex-2'~-enyl)-2-formyl-6,6-dimethyl-bicyclo _,1,1] heptane (1) 2-(6'-Vinyloxymethyl-6,6-dimeth~_-bicyclo ~3,1~1] hept-2-ene A mixture of ~-hydroxymethyl-6,6-dimethyl-bicyclo [3,3,1~
hept-2-ene [(-)-myrtenol~ ~26 g), mercuric acetate (2.S g) and ethyl vinyl ether (500 ~1) ls 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 filt~red, 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,~ ma (film) 2975, 2910, 2820 and 1605 cm 318~

(2) _~}(Formyl~ethyl 2-methylene=6~6-dimethyl-blcycio [3,1,1]
heptane The vinyl ether (1~ (2.0 g) is heated in a sealed tube at 200 C for 7 h~urs. The resultlng yellow oil is purified by chroma~
to~raphy on silica gel ~ith toluene as eluant to glve the title compound as an oil (1.4 g, 70%),vmax(film) 1720 cm 05 In an alternative procedure whlch 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 w~th glass wool aDd heated at lso c, the product being condensed ln a cold trap and distilled to give the title compound as an oil, b.p. 70 - 75 C/l mm.
(3) 3-~L(6'-Carboxyhex-21Z-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 ~nd the flask released to dry nitrogen. Dry dimethyl sulphoxide (DMS0) (25 ml) is added, followed by the slow addition of 18 ml of a 1.6 M solution of butylllthium in hexane. The temperature is held at 25 C and the aldehyde ~2~ (1.5 g) in DMS0 (5 ml) ls 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 e*her (3 x 75 ml), and the aqueous layer is then acidifled to pH 4 with 2N hydrochloric acid and re-extracted with ether ~3 x 50 ml). The extracts of the acidified aqueous layer are dried over magnèsium sulphate and evaporated to give the title compound as a yellow oil (2.0 g, 86%), ~CDCl3) 0.75 (s, 3H), 1.25 (s, 3H), 4.73 (m, 2H), 5.45 (m, 2H).
~4) 3-~L(6'-~etho~ycarbonylhex-2'Z-enyl)~2-methylene-6,6-dimethyl-bicyclo [3,1,1] heptane The acid (3~ (2.0 g) is treated with an ethereal solutio~ of 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 vacuu~ to give the title compound as a yellow oil (2.2 g, 100%).

(5) _-~-(Hydroxymethyl-3-~-(6'-methoxycarbonylhex-2'Z-enyl)-6,6-_imethyl-bicyclo [3,1,1 _heptane and 2-~-Hydro~ymethyl-3-~-( methoxycarbonylhex-2'Z-enyl)-6,6-dimethyl-bicyclo [3,1,1 heptalle 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 13,3,1] 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 r3.3 ml) over a period of 10 minutes, cooling being required to control the resulting exothermic reaction.
Th ixture is then stirred under air for 15 minutes, treated with 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, ~hich is stirred overnigh~ 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 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, 3~) 5.42 (m, 2H).
(6) 2~-(Formyl-3~-~6'-methoxycarbonyl-hex-2'Z-enyl)-6,6-dimethyl-bicyclo 13?1,1] heptane and 2~-formyl-3~-(6'-methoxycarbonyl-hex-2'Z-enyl)-6,6-dimethyl-bicyclo [3,1~1J heptane The mixture of epimeric alcohols (5) (0.~94 g) is dissolved in dry dichloromethane (1.5 ml) and pyridinlum dichromate (0.6 g) is added. The mixture is stirred for 22 hours at room tempera~ure and then dry ether (3 ml) and hexane (3 ml) are added. Stirring ls 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 (0-075 g, 25.4~), S(CDC13) 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 1~.

:~L9~3~Z~
- 26 _ (7) 3~-(6'-Carboxyhex-2'Z-enyl)-2-formyl-6,6-dimethyl-bicyclo [3,1~1] heptane The aldehyde ester (6) (0.075 g) is treated with 0.2N 5~ v/v aqueous methanolic potassium hydroxide at 40 C for 2 hours. The solution is then neutraliæed 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 sn oil (0.065 g, 65~ (CDC13) 0.75 (s, 3H), 1.22 (s, 3H), 5.45 (m, 2H)t 9.6 (br, lH), 9.71 (s or finely split d, lH).
This aldehyde/acid (7) is obtained as a compound having a 2-formyl substituent with either the aor ~configuration. The 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-esterifica~ion.
It has not been possib]e, however, ~o identify which of the two ]5 configurations should be assigned to the 2-formyl substituent of the aldehyde acid.
PREPARATIO~ OF FORMYL SUBSTITUTED STARTING MATERIAL
(A) Preparation of 4-(6'-ethoxycarbonylhex-2'~-enyl)-5-formylcyclohex-1-ene ~1) cis-4,5-bis-Hydroxymethylcyclohex-l-ene A solution of the anhydride of 3,4-dicarboxycyclohex-1-ene t25.8 g~ in THF (150 ml) is added with cooling to a stirred suspen-sion of LiAlH4 (~ g) in THF (200 ml) under N2 at a rate such as to maintain the temperatura at O 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 addi~ion of 1:1 THF-H2o mixture (100 ml). After dilut~on with chloroform (150 ml) the resulting mixture is filtered a~d ~he solid is washed with chlorofom ~3 x 25 ml). Concentration of ~he filtrate under reduced pressure yields an~oily residue which ls dissolved in benzene, dried over (MgS04) and reconcentrated in vacuo to give the title compound as an oil (22 g, ca. 90X), ~fllm) 3350 cm max `` 11984~

(2) cis-4-Hydroxymethyl-5-benzyloxymethylcyclohex-1-e~e The diol (1) (16.2 g) ln dimethylEormamide (50 ml) is added dropwise to sodium hydride (3.1 g) in dimethylformamide tDMF) (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 1~ 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 (MgS04) 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 - 145 C/0.03 mm,v a (film) 10 3440 and 1600 cm 1.
(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 shaking. The product is extracted with ether, washed consecutively with water, 0.1 M sodium carbonate and brine, dried (MgS04), 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.
spectrum shows the absence of a hydroxyl group.
(4) cis-4-Cyanomethyl-5-benzyloxymethylcyclohex-1-en_ The p-toluene sulphonyl ester/benzyl ether (3) (12 g) in dimethylsulphoxide (DMS0) (15 ml) is added with stirring to potas-sium cyanide (3 g) in DMS0 ~20 ml). The mixture is heated at 100 C under nitrogen for 6 hours and is ~hen cooled, poured into water and the product extracted with ether. The solvent is removed and the residue purified on a Plorisil column, eluting with petroleum ether-ben~ene (1:1) to give the tit~e compound as an oil (6.5 g, ca. B0~) v (film) 2220 and 1600 cm 1 max (5) cis-4-Formylmethyl-5-benzyloxymethylcyclohex-1-ene Di-isobutyl aluminium hydride (25 ml of a lM 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

- 28 _ under N2. After stirring for a further one hour at room tempera-ture, the reaction is terminated by the cautious addition of methanol (6 ml), followed by saturated aqueous sodium hydrogPn tartrate (95 ml). The mixture is then stirred and heated at 40 C
05 for 2 hours. The organic phase is separated and the aqueous layer is further extracted with ethyl acetate, the combined arganic solutions being dried and the solven-t evaporated to give an oil.
Chro~atography of the oil on Florisil, eluting with benzene gives the pure title compound as an oil (3.0 g 60%), a (film) 1715 cm 1.
(6) cis-4-(6'-Carboxyhex-2'Z-enyl)-5-benzyloxymethylcyclohex-1-ene (4-Carboxyl-n-butyl)-triphenylphosphonium bromide (7.0 g) is dried at 75 C under vacuum for 2 hours. The white solid is cooled, the vacuum is released to dry nitrogen and DMSO ~lO ml) is added followed by 9 ml of 2M solution of dimesyl sodium in DMS0. 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 HCl. The mixture is extracted with ether and the ethereal solution dried (MgSO4) and concentrated in vacuo to give the title compound (10 g), vma (film) 1700 cm (7) cis-4-(6~-Carboxyhex-2'Z-enyl)-5-hydroxymethylcyclohex-1-ene To a stirred suspension of 1.5 g of the acidtbenzyl ether (6) in lO0 ml of liquid ammonia is added a total of 1 g of sodium in portions over 10 - 12 mislutes at the end of which tlme the charac-teristic deep blue colour persists. The mixture is stirred for30 minutes, the blue colour is then dlscharged 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 3Q ls then dissolved in 40 ml of water. The aqueous solution is treated ~ith Nori then acidified with acetic acid and extracted with chloroform. Evaporation of the solvent gives the title compound as an oil (0.9 g), v a (film) 3350-3450 and 1700 cm 1.
r~R~

L91~Z~

(8) cis-4-(6'-Ethoxycarbonylhex-2'Z-enyl)-5_hydro~.y~ethyl~yclo-hex-]-ene The acid/alcohol (7) (0.75 g) is dissolved in ethanol, 0.3 ml o~ concentrated sulphuric acid is added and the mixture is heated under rerlux 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 (MgS04). Evaporation of the solvent gives the title compound as an oil (0.8 g),v (film) 1725 cm 1

(9) 4 6'-Ethoxycarbonylhex-2'Z-enyl)-5-formylcyclohex-1-ene The ester/alcohol (8) (1.3 g), dicyclohexylcarbiimide (3.5 g) DMS0 (5 ml) and dry benzene ~10 ml) are placed in a 125 ml flask under nitrogeD. 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 (Na2SO4). The solvent is evaporated to give a slurry ]5 residue which is redissolved in ben~ene. Solid particles separate fr~m the solution and the solvent is then evaporated to give the title compound as aD oil (l . O g), v tfilm) 1715 cm , ~(CDC13) 1.61-2.06 (m) 2.15-2.28 (t, lH). 2.4Q ~t, 2H), 5.40 (m, 2H), 5.70 (s, 2H~, 9.79 (d, lH~, M 250 (as methyl ester).
(B) P paration of l~-hydroxy-2~-~6'-Carboxyhex-2'Z-enyl)-3~-formylcyclopentane (1) 6-(1',3'-Dioxacyclopent-2'-yl)-2-oxabicyclo 13,3,0] octane-3-one 6-Formyl-2-oxabicyclo [3,3,03 octane-3-one ~2.0 g~ is heated at 6Q 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 NaHC03 (20 ml). The organic phase is separated, washed with ~ater, dried and concentrated to give the title compound in 95% yield,v a (film) 1750 cm 1.
The starting msterial is prepared by the treatment of 1,3-cyclohexadiene with dichloroacetyl chloride, followed by dechlorination with ~inc and acetic acid of the resulting adduct to ~ive bicyclo 14,2,0]-oct-2-en-7-one. This compound is subjected 2~L

to Baeyer-Villiger oxidation to give 7-oxablcyclo l4,3,0] non-2-en-~-one which is ~reated with thallium (III) nitrat~ under carefully controlled oonditions to give 6-formyl-2-oxabicyclo 13,3,0]
octane-3~one having properties identical with those reported by ~5 Corey and Ravindranathan, Tetrahedron ~etters, 1971, 4753.
(2) 6-(1',3'-Dioxacyclopent-2'-yl)-3 hydroxy-2-oxabicyclo 13,3,0 octane The lactone/acetal (1) (0.5 g) in dry toluene is cooled to -60 C and treated under N2 dropwise from a syringe with 2 ml of a 25% ~/v ~olution of diisobu~ylaluminium hydried in toluene. The reac~ion is quenched at -60 C after 2.5 hours by the careful addition of methanol (1 ml). The resction mixture is then diluted with ether (50 ml~ and is warmed to room temperature. Water (0.5 ml~ is added and stirring ls continued for 40 minutes followed by drying over anhydrous MgS04. Evaporation of the solvent in vacuo gives the tltle compound as an oil (0.42 g), v a (f~lm) 15 3400 cm (3)~ 1~-Hydroxy-2a-(6'-carboxyhex-2'Z-enyl)-3~-(1',3'-dioxa-cyclopent-2t-yl)-cyclopentane Dimesyl sodium in DMS0 (2.05 ml) is added dropwise to a solution of (4-carboxy-n-butyl)-triphenylphosphonium bromide (2.3 g3 (dried before use) in 3 ml of DMS0. 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 DMS0 and the m~xture is stirred overnight. The reaction mixture is then dil~ted wlth water ~50 ml) and extracted with ethyl acetate. The cooled aqueous layer is acidified with dilute HCl to pH 4 and extracted with e~hyl aceta~eO
The or~anic extracts are washed with water, dried ~MgS04) and 2~ concentrated. The resulting erude product ~s pu~ified by chroma-tography on Unisil using toluene-ether (1:1 v/v) as eluant to yield the title compound as sn oil (0-4 g)~ vma ~film~ 3350-3420 cm (4) la-Hydroxy-2~-(6'-carboxyhex-2'Z-enyl)-3~-formylcyclopentane The hydroxylacid/acetal (3) (0.15 g) Is hydrnlysed by d~ssolving it in 20 ml of dioxane-water mixture (1:1 v/v) and heated at 40 C
30 with 0.05M aqueous HCl for 3 hours. 100 ml of water is added and the product extracted with ether. The solve~t ~s e~aporated and the residue purified by silica gel chromatography, eluting with a gradient fro~ 10% v/v ethyl acetate in toluene to pure ethyl acetate, to give the title compound as an oil (95 mg), 35 ~(CDCl3) 4.30 (br, lH) 5.40 (m, 2H), 6.70 (br, lH), 9.60 (d, lH).
~de ~Q
, .

Claims (60)

- 31 -

1. A process for the preparation of a compound of formula (I) (I) wherein represents one of the divalent cyclic groups the letters a and b indicating in each case the points of attachment of the substituents R1 and respectively; R1 represents a 6-carboxyhex-2-enyl 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 accom-panied 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 derivative of the carboxy group; R2 represents hydrogen, a Cl-10 aliphatic hydrocarbon group or a Cl-10 aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group Ar, where Ar is a phenyl, napthyl, fluorenyl, dibenzo-cyclohexyl, dibenzocycloheptyl, pyridyl, benzothiazolyl, dihydrobenzothiazolyl, N-methyldihydrobenzothiazolyl, benzoxazolyl, dihydrobenzoxazolyl or N-methyldihydrobenzoxazolyl group or such a group substituted by one or more substituents selected from Cl-10 alkoxy, halogen, Cl-10 halogen substituted alkyl, sulphamoyl, amino, hydroxyl, nitro and Cl-10 alkyl groups; and either V and W together represent the oxygen atom of a carbonyl group or, when R2 is other than hydrogen, V represents hydrogen and W represents a hydroxy group; with the proviso that when R2 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 which comprises reacting a compound of formula (II) (II) in which Z represents (a) a formyl group in acetal form, (b) a hydroxymethyl group, (c) a formyl group or (d) a group CH(R2)OH, Y is either R1 as defined for (I) or a precursor for R1 and X and R2 are as defined for (I), the said reaction consisting of (a) effecting hydrolysis of the acetal to give a formyl group, (b) effecting oxidation of the hydroxymethyl group to give a formyl group, (c) effecting a Grignard reaction involving the formyl group and a reagent R2MgHalogen to give a group CH(R2OH), or (d) effecting oxidation of the group CH(R2)OH to give a group C(R2)=O, and where appropriate converting the group Y in the resultant product into a group R1, the process optionally involving a change of stereochemistry of (I) to that of (II).

2. A process according to Claim 1, in which Z represents an acetal group formed with ethylene glycol, methanol or ethanol.

3. A process according to Claim 1, in which Z represents a hydroxymethyl group which is oxidized with pyridinium dichromate.

4. A process according to Claim 1, in which Z represents a group CH(R2)OH
which is oxidized with Jones reagent.

5. A process according to Claim 1, in which Y is R1.

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

7. A process according to Claim 1, in which the divalent cyclic group is a bridged group.

8. A process according to Claim 1, in which (I) contains a bicyclo [2,2,2] octane or bicyclo [2,2,2] oct-2Z-ene ring system and any compound (I) containing a formyl group is produced by the hydrolysis of a compound (II) containing a formyl group in acetal form.

9. A process according to Claim 1, in which (I) contains a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system having the group R1 at the 3-position and any compound (I) containing a formyl group is produced by the oxidation of a compound (II) containing a hydroxymethyl group.

10. A process according to Claim 1, in which any modification of the 6-carboxyhex-2-enyl group of type (c) is a shortening or lengthening of the carbon chain by one methylene group.

11. A process according to Claim 1, in which R1 is a 6-carboxyhex-2Z-enyl group or a derivative thereof formed at the carboxy group.

12. A process according to Claim 1, in which R1 is a 6-carboxyhexyl group or a derivative thereof formed at the carboxy group.

13. A process according to Claim 1, in which R1 is a group terminating in a free carboxy group.

14. A process according to Claim 1, in which R1 is a group terminating in an ester derivative of the carboxy group.

15. A process according to Claim 1, in which the substituent is a group C(R2)=O.

16. A process according to Claim 1, in which R2 is hydrogen or an aliphatic hydrocarbon group.

17. A process according to Claim 8 or 9 in which (I) contains a bicyclo [2,2,2] octane or bicyclo [2,2,2] oct-2Z-ene ring system, or a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system having the group R at the 3-position, and in which the substituent is a formyl group.

18. A process according to Claim 1 in which (I) 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 is a group C(R2)=O wherein R2 is an aliphatic hydrocarbon group.

19. A process according to Claim 18, in which R2 is an alkyl group of 1 to 3 carbon atoms.

20. A process according to Claim 18, in which R2 is ethyl.

21. A process according to Claim 18, in which R2 is methyl.

22. A process according to Claim 1, in which the configuration about any double bond in the group R1 is cis.

23. A process according to Claim 1, in which groups R1 and are in a trans relationship.

24. A process according to Claim 1, in which the divalent cyclic group of (I) has the 5-endo, 6-exo configuration when it contains a bicyclo [2,2,2] oct-2Z-ene, 7-oxa-bicyclo [2,2,1] heptane or 7-oxa-bicyclo [2,2,1] hept-2Z-ene ring system, the 2.alpha., 3.beta., 6.alpha. configuration when it contains a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system and the 1.alpha., 2.alpha., 3.beta. configuration when it contains a l-hydroxycyclo-pentane ring system.

25. A process according to Claim 1, in which (I) is a trans 5,6-substituted bicyclo [2,2,2] octane, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 6-position being a formyl group.

26. A process according to Claim 1, in which (I) is a trans 5,6-substituted bicyclo [2,2,2] octane, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 6-position being an acetyl group.

27. A process according to Claim 1, in which (I) is a trans 5,6-substituted bicyclo [2,2,2] oct-2Z-ene, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 6-position being a formyl group.

28. A process according to Claim 1, in which (I) is a trans 5,6-substituted bicyclo [2,2,2] oct-2Z-ene, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 6-position being an acetyl group.

29. A process according to Claim 1, in which (I) is a 2.alpha., 3.beta.-substituted 6,6-dimethyl-bicyclo [3,1,1] heptane, the substituent at the 2-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 3-position being a formyl group.

30. A process according to Claim 1, in which (I) is a 2.alpha., 3.beta.-substituted 6,6-dimethyl-bicyclo [3,1,1] heptane, the substituent at the 2-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 3-position being an acetyl group.

31. A process according to Claim 1, in which (I) is a 3.beta., 2-substituted 6,6-dimethyl-bicyclo [3,1,1] heptane, the substituent at the 3-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'z-enyl group and that at the 3-position being a formyl group.

32. A process according to Claim 1, in which (I) is a 3.beta., 2-substituted 6,6-dimethyl-bicyclo [2,1,1] heptane, the substituent at the 3-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 3-position being an acetyl group.

33. A compound of formula (I) (I) wherein represents one of the divalent cyclic groups the letters a and b indicating in each case the points of attachment of the substituents R1 and respectively; R1 represents a 6-carboxyhex-2-enyl 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 accom-panied 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 derivative of the carboxy group; R2 represents hydrogen, a Cl-10 aliphatic hydrocarbon group or a Cl-10 aliphatic hydrocarbon group substituted directly or through an oxygen or sulphur atom by an aromatic group Ar, where Ar is a phenyl, napthyl, fluorenyl, dibenzo-cyclohexyl, dibenzocycloheptyl, pyridyl, benzthiazolyl, dihydrobenzthiazolyl, N-methyldihydrobenzthiazolyl, benzoxazolyl, dihydrobenzoxazolyl or N-methyldihydrobenzoxazolyl group or such a group substituted by one or more substituents selected from Cl-10 alkoxy, halogen, Cl-10 halogen .
substituted alkyl, sulphamoyl, amino, hydroxyl, nitro and Cl-10 alkyl groups; and either V and W together represent the oxygen atom of a carbonyl group or, when R2 is other than hydrogen, V represents hydrogen and W represents a hydroxy group; with the proviso that when R2 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 when prepared by the process of Claim 1 or an obvious chemical equivalent thereof.

34. A compound according to Claim 33, in which the divalent cyclic group is other than a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system having the group R1 at the 3-position when prepared by the process of Claim 6 or an obvious chemical equivalent thereof.

35. A compound according to Claim 33 in which the divalent cyclic group is a bridged group when prepared by the process of Claim 7 or an obvious chemical equivalent thereof.

36. A compound according to Claim 33, which contains a bicyclo [2,2,2]
octane or bicyclo [2,2,2] oct-2Z-ene ring system when prepared by the process of Claim 8 or an obvious chemical equivalent thereof.

37. A compound according to Claim 33,which contains a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system having the group R1 at the 3-position when prepared by the process of Claim 9 or an obvious chemical equivalent thereof.

38. A compound according to Claim 33, in which any modification of the 6-carboxyhex-2-enyl group of type (c) is a shortening or lengthening of the carbon chain by one methylene group when prepared by the process of Claim 10 or an obvious chemical equivalent thereof.

39. A compound according to Claim 33, in which R1 is a 6-carboxyhex-2Z-enyl group or a derivative thereof formed at the carboxy group when prepared by the process of Claim 11 or an obvious chemical equivalent thereof.

40. A compound according to Claim 33 in which R1 is a 6-carboxyhexyl group or a derivative thereof formed at the carboxy group when prepared by the process of Claim 12 of an obvious chemical equivalent thereof.

41. A compound according to Claim 33, in which R1 is a group terminating in a free carboxy group when prepared by the process of Claim 13 or an obvious chemical equivalent thereof.

42. A compound according to Claim 33, in which R1 is a group terminating in an ester derivative of the carboxy group when prepared by the process of Claim 14 or an obvious chemical equivalent thereof.

43. A compound according to Claim 33, in which the substituent is a group C(R2)=O when prepared by the process of Claim 15 or an obvious chemical equivalent thereof.

44. A compound according to Claim 33, in which R2 is hydrogen or an aliphatic hydrocarbon group when prepared by the process of Claim 16 or an obvious chemical equivalent thereof.

45. A compound according to Claim 33, which contains a bicyclo [2,2,2]
octane or bicyclo [2,2,2] oct-2Z-ene ring system, or a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system having the group R1 at the 3-position, and in which the substituent is a formyl group when prepared by the process of Claim 8 or 9 or an obvious chemical equivalent thereof.

46. A compound according to Claim 33, 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 is a group C(R2=O wherein R2 is an aliphatic hydrocarbon group when prepared by the process of Claim 18 or an obvious chemical equivalent thereof.

47. A compound according to Claim 33, 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 is a group C(R2)=O wherein R2 is an alkyl group of 1 to 3 carbon atoms when prepared by the process of Claim 19 or an obvious chemical equivalent thereof.

48. A compound according to Claim 33 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 is a group C(R2)=O wherein R2 is ethyl when prepared by the process of Claim 20 or an obvious chemical equivalent thereof.

49. A compound according to Claim 33 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 is a group C(R2)=O wherein R2 is methyl when prepared by the process of Claim 21 or an obvious chemical equivalent thereof.

50. A compound according to Claim 33, in which the configuration about any double bond in the group R1 is cis when prepared by the process of Claim 22 or an obvious chemical equivalent thereof.

51. A compound according to Claim 33, in which groups R1 and are in a trans relationship when prepared by the process of Claim 23 or an obvious chemical equivalent thereof.

52. A compound according to Claim 339 which has the 5-endo, 6-exo configuration when it contains a bicyclo [2,2,2] oct-2Z-ene, 7-oxa-bicyclo [2,2,1] heptane or 7-oxa-bicyclo [2,2,1] hept-2Z-ene ring system, the 2.alpha., 3.beta., 6.alpha. configuration when it contains a 6,6-dimethyl-bicyclo [3,1,1] heptane ring system and the 1.alpha., 2.alpha., 3.beta. configuration when it contains a l-hydroxycyclopentane ring system when prepared by the process of Claim 24 or an obvious chemical equivalent thereof.

53. A compound according to Claim 33, which is a trans 5,6-substituted bicyclo [2,2,2] octane, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 6-position being a formyl group when prepared by the process of Claim 25 or an obvious chemical equivalent thereof.

54. A compound according to Claim 33, which is a trans 5,6-substituted bicyclo [2,2,2] octane, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 6-position being an acetyl group when prepared by the process of Claim 26 or an obvious chemical equivalent thereof.

55. A compound according to Claim 33, which is a trans 5,6-substituted bicyclo [2,2,2] oct-2Z-ene, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 6-position being a formyl group when prepared by the process of Claim 27 or an obvious chemical equivalent thereof.

56. A compound according to Claim 33, which is a trans 5,6-substituted bicyclo [2,2,2] oct-2Z-ene, the substituent at the 5-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 6-position being an acetyl group when prepared by the process of Claim 28 or an obvious chemical equivalent thereof.

57. A compound according to Claim 33, which is a 2 .alpha., 3.beta.-substituted 6,6-dimethyl-bicyclo [3,1,1] heptane, the substituent at the 2-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 3-position being a formyl group when prepared by the process of Claim 29 or an obvious chemical equivalent thereof.

58. A compound according to Claim 33, which is a 2.alpha., 3.beta.-substituted 6,6-dimethyl-bicyclo [3,1,1] heptane, the substituent at the 2-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 3-position being an acetyl group when prepared by the process of Claim 30 or an obvious chemical equivalent thereof.

59. A compound according to Claim 33, which is a 3.beta., 2-substituted 6,6-dimethyl-bicyclo [3,1,1] heptane, the substituent at the 3-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylheX-2'Z-enyl group and that at the 3-position being a formyl group when prepared by the process of Claim 31 or an obvious chemical equivalent thereof.

60. A compound according to Claim 33, which is a 3.beta., 2-substituted 6,6-dimethyl-bicyclo [2,1,1] heptane, the substituent at the 3-position being a 6'-carboxyhex-2'Z-enyl or 6'-methoxycarbonylhex-2'Z-enyl group and that at the 3-position being an acetyl group when prepared by the process of Claim 32 or an obvious chemical equivalent thereof.
42.