IE48736B1 - Ethers of which the organic residues contain chiral atoms,a process for preparing them and their use in the resolution of alcohols,phenols or certain compounds of lactone structure - Google Patents

Description

» 48736 "Ν The present invention relates to new ethers of which the organic residues contain chiral atoms, a process for preparing them and their use in the resolution of alcohols, phenols or certain compounds of lactone st cture.

The subject of the invention is the optically active canpounds of the general formula I: zo. /-ΑΛ XC-H 0=0 (I) - : 0 in which formula the symbol A represents a hydrocarbon chain containing from 1 to 10 links, this chain being capable of 10 containing one or more heteroatoms or one or more unsaturations, all of the links constituting the chain being capable of representing a mono or polycyclic system including' a system of the spiro or endo type, the chain A being capable of containing one or more chiral atoms or else the lac- · 15 ton© component being capable of displaying chirality due to 2 ________ j .4873 6 the dissymmetric special configuration of the whole of the molecule, and the symbol Z represents either a primary, residue/ secondary or tertiary alcohol/containing at least one asymmetric carbon atom or a substituted phenolic residue 5 containing at least one asymmetric carbon atom, or an alcoholic or substituted phenolic residue of which the chirality is due to the dissymmetric spacial configuration of the whole of the molecule, it being understood that Z cannot represent a (E) or (S) α-eyano 3-phenoxy benzyl radical | 10 when A represents a hydrocarbon chain of structure; i i OH, GH, 5\ X 5 /° ϋ \ ^ H ^ (s^ C J Among the compounds of formula (I) there may be mentioned those in which the chain A contains one or more asymmetric carbon atoms and of which the chemical structure 15 imposes on the hydroxyl an unequivocal spacial disposition.

In this type of compound the two different atoms or radicals which farm the substituents on carbon atoms of the chain are selected from one or otherOf the following groups; a) the group constituted by hydrogen, the halogen atoms, the 20 nitro group, the alkyl radicals containing from 1 to 10 carbon atoms, the cycloalkyl radicals containing from 3 to 6 carbon atoms, the phenyl radical, the phenyl radicals substituted by at least one of the member of the group constituted by the halogen atoms, the alkyl radicals 3 48736 containing from 1 to 6 carbon atoms, the carboxyl group, the nitrile group, the -CHO group, the acyl groups, the -C~CF^ group, the S-alk and O-alk ,groups in which alk represents an alkyl group containing from 1 to 6 carbon 5 atoms, b) the group constituted by the radicals: .y , \ in which represents hydrogen, an alkyl radical containing from 1 to 6 carbon atoms, 10 the radical: 9 ^ s the radical: -C-CF, i 3’ 0 the radical: -C-CH0-NH0, the radical: -C-CH0C1, II 2 2 i 2 o o or a radical -C-alk in which alk represents an alkyl radical ‘ 0 15 containing from 1 to 6 carbon atoms, c) the group constituted by the radicals: R5 .each in which I?2 and Κ3» being the same or different, /represents*an 4 4*87 3 6 alkyl radical containing from 1 to 6 carbon atoms, or in which Rg and Rj represent, together with the nitrogen atom to which they are bonded, a heterocycle containing 6 atoms, or Eg represents a carboxyl group and R^ represents a 5 benzyl radical.

As particularly interesting family of compounds I there may be indicated: * - that which is characterised in that the chain A is an aliphatic hydrocarbon chain containing 2 or 3 carbon atoms; 10 - that which is characterised in that the chain A is an aliphatic hydrocarbon chain interrupted by a heteroatom; - that which is characterised in that the chain A is an aliphatic hydrocarbon chain containing a double bond; - that which is characterised in that the chain A is a 15 monocyclic hydrocarbon chain containing from 3 to 6 carbon atoms possessing, possibly, nn unsaturation; - that which is characterised in that the chain A is a bicyclic hydrocarbon chain containing from 5 to 10 carbon atoms possessing, possibly, an unsaturation.

As compound I of particular interest there may be mentioned; - those which are characterised in that the chain A has as its structure: CH, 3 \ 3 H ^ \ I I - those which are characterised in that the chain A has as its structure: 5 «'4 87 36 Υ Υ' Η /\ Η-C— I I Υ and Υ1, being the same or different, representing hydrogen, fluorine, chlorine or bromine atoms or an alfcyl radical containing from 2 to 6 carbon atoms, or else Y.and Y' being 5 capable of forming, together with the carbon atom to which they are bonded, a carbon homocycle containing from 3 to 7 carbon atoms; - those which are characterised in that the chain A has as its structure: \/V 1° ? f B representing an oxygen or sulphur atom, a -MH or -HR' group, R' being an alkyl radical containing from 1 to 6 carbon atoms; - those which are characterised in that the symbol Z has 15 as its structure: CV /\/ Xx. - those which are characterised in that the symbol 2 has as its structure: 6 4 Λ8736 β" __ν _“~0 R" representing an alkyl radical containing from 1 to 6 carbon atoms, an alkenyl radical containing from 2 to 6 carbon atoms, an alkynyl radical containing from 2 to 6 • 5 carbon atoms or a cyano radical.

In the compounds of formula 1, according to tbe invention, tbe residue Z can be an alcohol residue. In this case this alcohol can be primary, secondary or tertiary, of aliphatic, cycloaliphatic or aromatic, mono or polycyclic, , 10 nature.

Among these alcohols there will be mentioned especially the cyanhydrins.

The residue Z can also be a substituted phenyl residue in which the substituent group or groups contain at least one ]5 asymmetric carbon atom.

Among the compounds of formula I there will be mentioned more particularly those described in the examples and especially the compounds or mixtures of compounds of general formula I of which the names are as follows; 20 - mixture of (1R, 5S) 6,6-dimethyl-A(R) - Cl (S) - 2-methyl— 4-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxyl-3-oxa-bicyclo-(3.1.D)hex,·m-2-one and (1R,5S) 6,6-dimethyl-ft(R)-[l(R)-2--methyl-'i-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy]-3-oxa-bicyclo-(3.1.0)hoxan-2-one, 7 . 48736 - mixture of (IS, 5R) 6,6-dimethyl-4(R)~Cl (S)-2-methyl- 4-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy3—3-oxa-bicyclo-(3ο 1=0)-hexan-2-one and (1S,5R) 6,6-dimethyl-4(H)"Cl(R)-2--methyl-4-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy3-3-oxa - 5 hicyclo-(3.1.0)'hexan-2-one, - (1R, 5S) 6,6-dimethyl-4(R)_Cl(S)-.2-methyl-4-oxo-3-(2-propen--1-yl)-cyclopent-2-enyloxy]-3~oxa-bicyolo-C3.1.0)-hexan-2-one, - (1S,5R) 6,6-dimethyl-4(R)-[l(R)-2-methyl-4~oxo-3-(2-propen--l-yl)-cyclopent-2-enyloxy3-3-oxa-bicyclo-(3.1.0)-hexan-2-one, 10 - (1R,5S) 6,6-dimethyl-4(R)"C31,31-dimethyl-butyrolactone— 2‘-(S)oxy3-3-oxa-bicyclo-C3.1.03-hexan-2-one, - (1R,5S) 6,6-dimethyl-4(R)-E31,31-dimethyl-butyrolactone -2'-(R)oxy]-3-oxa-bicyclo-[3.1.03-hexan-2-one, as well as the mixture of the two latter compounds, IS - (3R) (3aR) (4S) (7R) (7aS) 3-C(l'R) (2‘S) (5'R) 2'-isopropyl-5' -methyl- cyclbhexyloxyj -tetrahydro-4,7-methano-isobenzo-furan-l-one, - (3R) (3aH) (nS) (7R) (7aS) 3-E(l'S) (2'R) (5'S) R'-iso-propyl-5'-methyl- cyclohsxylo.xy h-tetrahydro-4,7-methano- 2o isobenzofuran-l-one, as well as the mixture of the two latter compounds, - (1R,5S) 6,6-dimethyl-4(H)-[(l'R) (2'S) (5'R)-2'-isopropyl-51 -methyl- cyclohsxylaxy 3- 3-oxabicyclo-C3.1.03hexan-2-one, - (1R,53) 6,6-dimethyl-4(R)-C(1'S) (2'R) (5'S)-2'-isopropyl-25 5,-aethyl- cyclohexyLoxy 3-3-oxabicyclo-[3.1.03-hexan-2-one, as well as the mixture of the two latter compounds.

The subject of the invention is also a process for preparing the compounds of general formula (I), characterised 8 48736 in that a lactone compound of general formula II : «./'Λ ψ y «ο 0 in which formula 1 represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms and A keeps the 5 aforementioned meanings, in the presence of an acid, is reacted with an alcohol or a substituted phenol of general formula III: s ZOH (III) in which formula Z keeps the aforementioned meanings to 10 obtain: - either a compound of formula (I), called (Ift) in which all .the chiral atoms have well-defined configurations V up \/ when the lactone and the alcohol or the phenol possess 15 one or more chiral atoms of well defined configuration, - or a mixture of diastereoisomers, called (Ig), when the lactone is a well defined optical isomer and the chiral centres of the alcohol or of the phenol are not all of unequivocal configuration, 20 - or a mixture of diastereoisomers, called (Ις), when the 9 ---- 4 8 7 3 6 alcohol or the phenol is a well-defined optical isomer and the chiral atoms of the lactone are not all of unequivocal there are configuration, then/separated by a physical method the diastereoisomeric ethers contained either in the mixtures of 5 type Ig or in the mixtures of type Iq and, especially, the ether called I. of which the chiral centres are all of A unequivocal configuration.

The acid agent in the presence of which the alcohol or the phenol is reacted with the lactone compound is, for 10 example, selected from the group constituted by Sulphorric acids, perchloric acid and 5-sulnhosalicylic acid.

The reaction of the alcohol or· of the phenol with the lactone compound is carried out, preferably, by removing the water or the nlcchol formed, by azeotropic decantation,at 15 reflux of a solvent selected from the group constituted . by chlorinated solvents, aromatic or aliphatic hydrocarbons and ethers.

This reaction can also be carried out advantageously operating under reduced pressure and without a solvent.

The separation of the diastereoisomeric ethers (I) is carried out advantageously by crystallisation or chromatography.

If the chiral atom or atoms of the lactone (II) are each of fixed steric configuration (R) or (3), when the 25 asymmetric carbon atom or atoms of the alcohol or of the substituted phenol (III) are also, individually, of fixed steric configuration (R) or (a), corresponding compounds I, called (ΙΛ) are obtained directly with retention of 10 48736 configuration.

When, in this process, the alcohol or the substituted phenol (III) possesses one or more unresolved asymmetric carbon atoms, a mixture of diastereoisomeric ethers (I), 5 called (Ig), is obtained which can then be separated by physical treatment, especially by chromatography or by crystallisation from a solvent (diagram I).

The latter ease is particularly interesting.

After separation of the diastereoisomeric ethers 10 forming (IB), for example after separation of (1^), simple hydrolysis or alcoholysis, as is indicated hereinafter, enables the alcohols or substituted phenols resolved with respect to the racemic asymmetric carbon atom or atoms which they contained initially,to be obtained. When the alcohol Ψ 15 or the substituted phenol possess m unresolved chiral centres, 2m diastereoisomers similar to are formed which can, possibly, be separated into individual ones such as 1^.

In addition, the lactone compound (II) used, of which the chiral atom or atoms is/are fixed steric configuration 20 (R) or (S), is recovered as it existed at the beginning in the compounds (II).

Similarly, in the process for preparing the compounds I, if the asymmetric carhon atom or atoms of the alcohols or substituted phenols (HI)is/aBof fixed steric configuration 25 (E) or (s), when the chiral atom or atoms of the lactone moiety are also of fixed steric configuration (R) or (S), corresponding compounds called (1,) (diagram II) are obtained directly with retention of configuration. I 11 ! I. ---487 36 When, in this process, the lactone moiety is of racemic configuration (fiS), because of one or more unresolved chiral centres, a mixture of diactereoisomeric ethers (X), called (Iq), is obtained which can then be separated by 5 physical treatment, especially by chromatography or by crystallisation from a solvent.

♦ The latter case is particularly interesting.

After separation of the diastereoisomeric ethers formed (Ιβ), for example after separation of (1^), simple 10 hydrolysis or alcoholysis, as is indicated hereinafter, enables the lactone compound resolved with respect to the chiral atom or atoms of racemic configuration (RS) which it contained initially, to be obtained. When the lactone possesses n unresolved chiral centres, 2n diastereo-15 isomers similar to are formed which can, possibly, be separated into individual ones such as (1^).

In addition, the alcohol or the substituted phenol (III) used, of which the asymmetric carbon atom or atoms is/are of fixed steric confijuiration (H) or (6), is 20 recovered as it existed at the beginning in the compound ZOH.

In all the foregoing, the presence of one or more resolved or unresolved chiral centres in the compounds (II) or (III) inchesthe following different possibilities: 25 - either none of the chiral centres possesses unequivocal (H) or (3) configuration and the molecule is then a mixture of racemates containing enantiomers; - or some of the chiral centres possess an unequivocal 12 48736 configuration either (R) or (S) and the molecule is then a mixture of diastereoieoaers{ - or all the chiral centres have an unequivocal configuration either (R) or (S) and the molecule is then considered to be 5 a well-defined optical isomer.

In addition to the asynraefcric due to the presence of chiral centres in the molecules of the compounds (II) or (III), the latter can display geometric isomerism due to the presence of one or more double bonds (Ξ) or (Z), as well as 10 an additional chirality due to the spacial structure of the whole of the molecule of which the constituent atoms can, for example, be disposed in two orthogonal planes.

The process of the invention also applies in this case to a resolution of compounds into one or more racemic asymmetric 15 carbon atoms, present in one of the eomponatsof the ether (I) due to the chirality of the other part of the ether (I), The subject of the invention is, especially, a process for preparing the compounds of general formula I, as defined above, characterised in that the compound of formula 20 II is the lactone of a racemic or optically-active cis 2,2-dimethyl-3-(dihydroxymethyl)cyclopropane-l-carboxylic acid, the compound of formula III is racemic or optically-active l-hydroxy-2-metbyl-3-(2-propen-l-yl)cyclopent-2-en- 4-one and in that the possible separation of the diastereo-25 isomeric compounds I is carried out by crystallisation from an or»jnic solvent, a process for preparing the compounds of general formula I, as defined above, characterised in 13 - 481*36 that the compound of formula II is the racemic or optically- . active lactone of acis 2,2-dimethy1-3-(dihydroxymethyl)-cyclopropane-l-carboxylie acid, the compound of formula III is racemic or optically-active 2-hydroxy-3,3“dimethyl— 5 butyrolactone (or pantolactone) and the possible separation of the diastereoisomeric compounds is carried out by chromatography, a process for preparing the compounds of general formula I, as defined above, characterised in that the compound of formula II is racemic or optically-active 3-hydroxy— 10 tetrahydro-4,7-methanoisobenzofuran-l-one, the compound of formula III is racemic or optically-active menthol and the possible separation of the diastereoisomeric compounds is carried out by chromatography as well as a process for preparing the compounds of general formula I, as defined above, * ;' i 15 characterised in that the compound of formula II is the racemic * or optically-active lactone of a cis 2,2-111^41171-3-(dihydroxymethyl )-cyclopropane-l-carboxylic acid, the compound of formula III is racemic or optically-active menthol and the possible separation of the diastereoisomeric compounds is carried out 20 by chromatography.

The subject of the invention is also the use of the compounds of general formula (I) in the resolution of the compounds of formula (II) or (III), a use which consists in reacting a lactone compound of general formula (II) « Λι^Ύο ¥ c* (II) \/ H 48736 ia which formula X represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms and A keeps the aforementioned meanings, in the prenonce of an acid, with an alcohol or a substituted phenol of general 5 formula (III) ZOH (III) in which formula Z keeps the aforementioned meanings, to obtain either a mixture of diastereoisomers, called (Ig), when the lactone is a well-defined optical isomer and the 10 chiral centres of the alcohol or of the phenol 'are not all of unequivocal configuration, or a mixture of diastereoisomers, called (Iq), when the alcohol or the phenol is a well-defined optical isomer and the chiral atoms of the lactone are not all of unequivocal configuration, and which consists in 15 separating by a physical method the disstereoisomeric ethers contained either in the mixtures of the type (Ιβ) or in the mixtures of the type (Iq) and especially the ethei’ called (IA), of which the chiral centres arc nil of unequivocal configuration and characterised in that each of the diastereo-20 isomeric ethers thus separated is subjected to hydrolysis or alcoholysis,,in acidic medium, to obtain either a compound of type II and the other diastereoisomers arising possibly from the existence of several asymmetric, centres, or a compound of type III and the other diastereoisomers arising possibly 25 from the existence of several asymmetric centres, these compounds II and III and the various corresponding diastereoisomers containing chiral centres of unequivocal configuration, in other words chiral centres resolved with respect to the 15 48736 corresponding chiral centres of the starting alcohols or phenols, or with respect to the chiral centres ot starting 1 lactone compounds.

The acid solvolysis of the compounds of the type 5 (diastereoisomers of unequivocal configuration) whether they be derived from the mixtures of diastereoisomers (Ig) or (1^,) enables the alcohol or the phenol ZOH (III) as well as the lactone (II) to be obtained, each in the form of an optical isomerv that is to say of which all the configurations of the 10 chiral centres are perfectly defined, either (R) or (S).

By using the method as described in diagram. (Ill) in which, at the beginning, the alcohol containing only, a single chiral centre is a racemate formed from 2 antipodes (R) and (S), it is possible, contacting with it-.a well-defined. optical isomer of the lactone (II), to obtain-two ethers of ’ the type (IA) called respectively (1^) and (Ig) which can be separated by physical treatment especially by crystallisation or chromatography. In these two compounds (1^) and (Ig) the alcoholic residue has an antipodal configuration. By 20 acid solvolysis either of (1^) or of (Ip) the alcohol ZOH (III) is thus recovered, resolved into its antipodes (R) and (S) respectively (cf. diagram III).

By using the method described in diagram (IV), using at the beginning a lactone of which the chiral centre(s) has/have 25 configuration, corresponding to a racemate and contacting with it a perfectly-defined optical isomer of an alcohol or of a phenol (III) it is also possible to obtain 2 ethers of type (1.^), called respectively (Ip) and (I&) which can 16 48736 be separated by a physical method, especially by chromatography or crystallisation.

In these two compounds (Ip) and (Ifi) the lactone residue has an antipodal configuration. By acid solvolysie 5 either of (Iy) or of (I&) the lactone (II) is thus recovered, resolved into its antipodes (cf. diagram 17).

The subject of the invention is more particularly the application as defined above which consists in reacting the lactone of cis 2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-10 -lH-carboxylic acid, in the presence of an acid agent, with 1(RS)-hydroxy-2-methyl-3-(2-propen-l-yl)-cyclopent-2-en-4-one and in separating by crystallisation from isopropanol (1R,5S) 6,6-dimethyl" 4(R)-Cl(R)-2-methyl- ft-oxo-3-(2-propen-l-yl)— cyclopent-2?enyloxy)3~3-oxa bicyclo-(3.1.0)hexan-2-one from 15 (1R,5S) 6,6-dimethyl-h(R)-Cl(S)-2-methy]r4-oxo-3-(2-propen- -l-yl)cyclopent-2-enyloxy)]~3-oxa-bicyclo-(3.1.0)hexan-2-one and is characterised in that the latter isomer "IS" is subjected to solvolysis in acid medium to obtain 1(S)--hydroxy-2-methyl-3-(2-propen-l-yl)cyclopent-2-en-h-one.

Of course the solvolysis of the isomer "1R" enables 1(R)--hydroxy-2-methy1-3-(2-propen-l-yl)cyclopent-2-en-h-one to be obtained.

In this application the solvolysis is carried out advantageously in aqueous medium, in the presence of 25 hydrochloric acid, or else in methanol, in the presence of paratoluene sulphonic acid.

The subject of the invention is also the application as defined above which consists in reacting the lactone of 17 , 48736 dl cis-2,2-dimethyl-3-(dihydroxy methyl) cyclopropane 1-carboxylic acid, in the presence of an acid agent, with l(S)-hydroxy 2-metljyl 3-(2-propen-l-yl)cyclopent-2-en 4—one and in separating by crystallisation from isopropyl ether 5 (1R,5S) 6,6-dimethyl-4(S)-Cl(S) 2-methyl-h-oxo-3-(2-propen-l- -yl)cyclopent-2-enyloxy)-3-oxo bicyclo (3.1.0) hexan-2-one from (1R,5S) 6,6-dimethyl-4(R)-Cl(S) 2-methyl-4-oxo-3-(2--propen-l-yl)cyclopent-2-enyloxy]-3-oxa bicyclo (3.1.0) hexan-2-one, being characterised in that the latter isomer 10 (hS) is subjected to solvolysis in acid medium to obtain the lactone of cis 2,2-dimethyl _3S-(dihydroxymethyl)cyclo-propane-lR-carboxylic acid.

In this application the acid agent used is especially hydrochloric acid.

The subject of the invention is also the application ' as defined above which consists in reacting the lactone of cis 2,2-dimethyl-3~S(dihydroxymethyl)cyclopropane-lB-carboxylic acid, in the presence of an acid agent, with 2(R,S)“hydroxy-3, 3-dimethyl butyrolactone and in separating by chromato-2o graphy (1R.SS) 6,6-dimethyl-4(R)~(3',31-dimethylbutyrolactone 2'-(d)-oxj] -3-oxa bicyclo [3.1.0] hexan-2-one from (1R,3S) 6,6-dimethyl-4-(R)-C3',3'"dimethyl butyrolactone 2’(R')-0Xy]- 3-oxa bicyclo [3.1.0) hexan-2-ono and is characterised in that one or other of these isomers is subjected to solvolysis, 25 in acid medium, to obtain 2(S)-hydroxy-3,3-dimethyl butyrolactone or 2(R)-hydroxy-3,3-dimothyl butyrolactone according to the isomer selected.

Of course the isomer "2‘R" of the ether leads to the 2(R)-hydroxy-3,3”dimethyl butyrolactone and the isomer "2'S" j 18 A 48736 to the 2(S)-hydroxy-3,5-dimethyl-butyrolactone.

In this application the solvolysis can he carried out, for example, with paratoluene sulphonic acid in aqueous medium or in methanol.

The subject of the invention is also the application as defined above which consists in reacting (3R) (3aR) (as) (7R) (7aS) 3-hydroxy-tetrahydro-4,7-methano-isobenzofuran-1- -one with (R,S) menthol, in the presence of an acid agent, and in separating by chromatography (3R) (3aR) (hS) (7R) 10 (7aS) 3"C(1'R) (2'S) (3'R)-2'-isopropyl-5'-aethylcyclo- hexyloxy j] ~t etrahydro ^, 7-methano-isObenzofuran-l-one from (3B) (3aH) (*S) (7H) (7aS) 3-C(l’S) (2Ή) (5'S) 2'-isopropyl- 5'-methyl-cyclohexyloxf]-t etrahydro-4,7-methanoisobenzofuran- -1-one and is characterised in that one or other of these * 15 isomers is subjected to solvolysis in acid medium to obtain (R) or (S)-menthol.

The subject of the invention is also the application as defined above which consists in reacting the lactone of cis 2,2-dimethyl-3S-(dihydroxyaethyl)cyclopropane-lR-carboxylic 20 acid, in the presence of an acid agent, with (R,S)menthol and in separating by chromatography (1R,5S) 6,6-dimethyl-(/|R)-C(l'R) (2'S) (5'R) 2'-isopropyl-5'-methylcyclohexyloxy]-3-oxa bicyclo-C3.1.G]-hexan-2-one from (1R,5S) 6,6-dimethyl-JiR -[(1 *S) (2'R) (5'S)2'-isopropyl-5'-n;ethyl-cyclohexyloxy3r3-oxa 25 bicyclo-C3-1.0Dhexan-2-one and is characterised in that one or other of these isomers is subjected to solvolysis in acid medium to obtain (R) or (:0-menthol.

In this application and the previous one the solvolysis 19 48 7 3 6 can tie carried out, for example, with paratoluene sulphonic acid in aqueous medium.

A few general processes for resolving alcohols containing asymmetric carbon atoms were already known. For 5 example, it was known how to resolve certain racemic alcohols (R,o) by combining them with an optically-active organic acid, by separating, by suitable physical treatment, the resultant ester of alcohol (S) and ester of alcohol (R) then by hydrolysing, separately, these two esters to obtain the 10 alcohols of structure (R) or of structure (S).

A more complicated process was also known consisting in resolving racemic alcohols (RS) by combining them with an organic diacid, reacting the resultant hemiester with an optically-active base to obtain the corresponding 15 diastereoisomeric salts, in acidifying to release the hemiesters of alcohol (S) and of alcohol (R) then in hydrolysing, separately, these hemiesters to obtain the alcohol of structure (S) and the alcohol of structure (R).

In fact, this type of resolution only applies without 20 difficulty to the sufficiently stable alcohols insensitive or not very sensitive to the conditions of formation and of hydrolysis of the intermediate esters or hemiesters.

The Applicant Company has now, according to the present invention, perfected a new, very general, method 25 enabling alcohols or substituted phenols 20H (III),, containing one or more asymmetric carbon atoms, to be resolved, a method which does not include the disadvantages of the methods already mentioned. 48736 This new method, of which the various stages have been described above, consist in reacting, in the presence of an acid agent, the alcohol or the substituted phenol ZQH of formula (III), containing at least one asymmetric 5 carbon atom of racemic configuration (H,S) with an optical isomer of a lactone (II) possessing one or more chiral atoms of perfectly-defined steric configuration, either (R) or (S), to obtain an equimolecular mixture of diastereo-isomers of the type (1^), in each of which the residue (Z) 10 possesses an unequivocal stereochemistry with respect to each chiral centre. The diastereoisomcrs of the type (IA) are then separated by physical means such as chromatography or crystallisation from a solvent and these diastereoisomeric compounds of type (1^) are subjected individually to 15 solvolysis in acid medium to obtain respectively the alcohol or the substituted phenol ZOH (III) of unequivocal stereochemistry.

This method has, in particular, the advantage over the already-existing methods of resolution of being very simple 20 since it includes only the following stages: combination of the alcohols or the phenols SOII (III) with the compound (II), the latter being taken in the form of an optical isomer of fixed stereochemistry, to obtain the corresponding diastereoisomeric ethers (Ig), separation by 25 physical means of the diastereoisomcrs contained into compounds of the type IA having a well-defined stereochemistry, then solvolysis of each compound of the type (1^) to obtain the resolved compounds ZOH (III).' 21 . 48736 The method of resolution according to the invention has, in addition, a wide range of uses. The combination of the compound ZOH (111) and of an optical isomer (11) is carried out with a good yield. The ethers resulting from 5 this possess, in^neral, a structure such that separation by physical means of stereoisomers of the type is easy.

This separation can often be carried out by crystallisation from a suitable solvent. Solvolysis of the diastereoisomers of the type (1^), in acid medium, leadswithout difficulty 10 and with good yields to the resolved alcohols or phenols expected.

During this final solvolysis no notable deterioration of the compounds ZOH (III) is detected. The stereochemistry of the compounds (II) is maintained, during the solvolysis, 15 the structure of the molecule (II) imposes on the hydroxyl an unequivocal disposition.

Thus the method of resolution accordihg to the invention applies especially to those especially unstable alcohols which the cyanhydrins are.

Such a method of resolving alcohols or substituted phenols, of general importance, is very useful since it enables there to be obtained in the majority of cases and under advantageous conditions, starting with racemic compounds obtained by chemical synthesis, resolved optical isomers of 25 which one of them retains, in general, almost all of the activity of the molecule concerned, (case of the natural compounds which are optically-active).

From the above data it follows that the Applicant Company 22 <»8736 .. has also perfedted a new method of resolving lactone compounds (II) which contain one or more chiral atoms. This new method consists in reacting, in the presence of an acid agent, the lactone compound (II) containing at least one chiral atom 5 of racemic configuration (RS) with an optical isomer of an alcohol or of a substituted phenol of formula (III) of fixed steroid configuration (R^ or (S), to obtain a mixture of diastereoisomeric ethers called (Iq), in subjecting this mixture to physical treatment such os chromatography or 10 crystallisation to separate the diastereoisomeric compounds of the type (1^) contained in this mixture, each diastereo-isomer having in its lactone part a well-defined stereochemistry, then in hydrolysing these compounds in acid medium to obtain the compound (II) in resolved form.

Such a method had never, until now, been described in the literature.

It has, generally speaking, the same advantages and the same simplicity as the method of resolving alcohols and phenols previously described.

The following examples illustrate the invention without limiting it. t 23 4 - 48736 Example 1; Mixture of (1R.5S) 6,6-dimethyl-4(R)-Cl(S)-2--methyl-4-oxo ~3-(2-propen-1-?1)-cyclopent-2-enyloxy3-5-oxa— bicycIo-(3.1.0)-hexan-2-one and (1R.5S) 6.6-dimethyl-4(R)~ Cl(R)-2-methyl~4-oxo-5-(2-propen-l-yl)-cyclopent-2-enyloxy]-5 5-oxa-bicyclo-(3.1.0)-hexan-2-one starting with 1 (RS)- -hydroxy-2-methyl-3-(2'-propen-l-yl)-cyclopent-2-en —4-one.

Into 1000 cm^ of benzene one introduces 152 g of 1(RS)-hydroxy-2-methyl-3-(2-propen-l-yl)-cyclopent-2-en- 4-one, 152 g of lactone of cis 2,2-dimethyl-3S-(dihydroxy -10 methyl)_cyclopropane-lR-carboxylic acid, and 3·3 g of paratoluene sulphonic acid, one takes the reaction mixture to reflux, maintains the refluxing for 4 hours separating, by azeotropic decantation, the water formed, allows to cool to 20°C, brings pH to 7-8 by the addition of triethylamine, 15 concentrates to dryness by distillation under reduced pressure and obtains a mixture of (1R,5S) 6,6-dimethyl"4(R)-[1(S)-2-methyl~4-oxo-3-(2-propen-l-yl-cyclopent-2-enyloxy3- 3-oxa-bicyclo~(3*l»0)-hexan-2-one and (1R,5S) 6,6-dimethyl-4(R)“[l(R)-2*-methyl-4-oxo-3-(2-propen-l-yl)-cyclopent-2-20 -eny1oxy]-3-oxa-bicyclo-(3·1.0)-hexan-2-one.

Example 2: (1R,5S) 6,6-dimethyl-a(R)-Cl(S)-g-methyl-4-oxo - 3-(2-propen-l-yl)-cyclopent-2-enyloxy3-3-oxa-bicyclo-(3.1-0)-hexan-2-one, starting with a mixture of (1R,5S) 6,6-dimethyl-4( R)-[1 (s)-2-methyl- 4-oxo-3-(2-propen-l-yl)cyclopent-2-25 -enyloxy3-3-oxa-bicyclo-(3.1.0)~hexan-2-one and (1R,5S) 6,6-d imethyl-4(R)~[1(R)-2-methyl-4-0x0-3-(2-propen-l-yl)-cyclopent-2-enyloxy3-3-oxa—bicyclo-(3.1.0)-bexan-2-one.

One crystallises the mixture of (1R,5S) 6,6-dimethyIv , 24 i / 48736 4(R)-Cl(S)-2-methyl-4-oxo-3_(2-propen-l-yl) cyclopent-2--enyloxy)"3-oxa bicyolo (3.1.0) hexan-2-oae and (1R,5S) 6,6~dimethyl-4(R)-Cl(R)-2-methyl-4-oxo-3-(2-propen-l-yl) cyclopent-2-enyloxy]-3-oxablcyolo <3.1.0) hexan-2-ono, obtained in Example 1, from 300 car of isopropanol, cools 5 to 0°C, agitates, isolates by vacuum-filtration the precipitate formed, washes it, dries it and obtains 82.6 g of (1R.5S) 6,6-dimethyl-4(R)-Cl(S)-2-methyl-4-oxo-3-(2--propen-l-yl) cyclopent-2-enyloxy]-3-oxa bicyolo (3.1.0) hexan-2-one, M.Pt. « 104°C. (a)jp« -66.5° (c = 1.1%, benzene) ANALYSIS; (276) Cfo Calculated:69.54 7·3 Found :69.3 7·4 15 Circular dichtoisin. : (dioxan) Δε * -26.4 at 222 nm (max.); Δε * +2.80 at 321 nm (max.) ; Δε » +2.50 at 332 nm (max.) N.M.R. Spectrum (deuterochloroform) Peak at 1.22 p.p.m. characteristic of the hydrogens of the 20 geminal methyls; peaks from 1.97 to 2.33 p.p.m. characteristic of the hydrogens of the cyclopropane ring; peak at 2.1 p.p.m. characteristic of the hydrogens of the methyl at position 2 of the allethrolone; peaks at 2.92-3.02 p.p.m. characteristic Of the methylene at position 1 of the allyl chain of the 25 allethrolone; peak at 4.63 p.p.m. characteristic of the hydrogen at position 1 of the allethrolone; peaks at 4.75-5.17 p.p.m. characteristic of the hydrogens of the terminal 25 - 4 8 7 3 6 methylene at position 3 of the allyl chain of the allethrolone; peak at 5*33 p.p.m. characteristic of the hydrogen home by the carbon at a of the endocyclic oxygen; peaks at 5*47-6.16 p.p.m. characteristic of the hydrogen at position 2 of the 5 allyl chain of the allethrolone.

Example 5: (1R.5S) 6.6-dlmeth7l-4(R)-Cl(R)-2-niethyl-4-oxo- 3-(2-propen-l-vl)-cyclopent-2-enYloxy]-5-oxa-bicyclo-(5.1,φ-hexan-2-one starting with 1(R)-hydroxy-2-methyl-3-(5-propen-l--yl)-cyclopent-2-en-4-one Cor (R) allethrolone].

Into 75 cm^ of benzene one introduced 7*5 g of lactone of cis 2,2-dimethyl-3S-(dihydroxy methyl)-cyclopropane-lB-carboxylic acid, 7*5 g of l(R)-hydroxy-2-methyl-3-(2-propen--l-yl)-cyclopent-2-en-\4-one and 0.100 g of paratoluene sulphonic acid, one takes the reaction mixture to reflux, 15 maintains the* refluxing for a hours separating, by azeotropic decantation, the water formed, concentrates to dryness by distillation under reduced pressure and obtains 15 g of (1R,5S) 6,6-dimethyl-4(R)"[l(R)-2-methyl-4-oxo-3-(2-propen-l--yl)-cyclopent-2-enyloxy]-3-oxa-bicyclo-(3*1.0)-hexan 2-one.

Circular dichroism (dioxan) Δε = -2.56 at 33Q nm (max.) ; Δε = -2.8 at 316 nm (max.); Δε = +14.6 at 225 nm (max.) N.M.R, Spectrum (deuterochloroform) Peaks at 1.22-1.23 p.p.m. characteristic of the hydrogens of 25 the geminal methyls; peaks at 2.07 p.p.m. characteristic of the hydrogens of the methyl at position 2 of the allethrolone; peaks at 2.92-3.02 p.p.m. characteristic of the hydrogens of the methylene at position 1 of the allyl chain of the allethrolone; peaks at 4.83-5.08 p.p.m. characteristic 26 48736 Of the hydrogens of the methylene at position 3 of the allyl chain of the allethrolone; peak: at ft.87 p.p.m. characteristic of the hydrogen at position 1 of the allethrolone; peak at 5.26 p.p.m. characteristic of the hydrogen home hy 5 the carbon at a of the endocyclic oxygen; peaks at 5.47-6.33 p.p.m. characteristic of the hydrogen at position 2 of the allyl chain of the alletttrolone.

, , Example ft; (1R.5S) 6.6-dime thy l-ft(R)- [l(a)-2-methvl- ft-oxo i 5-C2-nropen-l-vl) cvclopent-2-enyloxy]-3-oxa bicYclo (3.1.0) 10 > hexan 2-one. starting with 1(6)-hydroxy-2-methyl-3.-(propen-1--Yl) cvclopent-2-cn-ft-oneCor (6)-allethrolone].

Into a mixture of 30 cm^ of petroleum ether (B.Pt. = 35**75°C) and 3 c»^ of benzene one introduces 5 g of lactone of cis 2,2-dimethyl -3§-(dihydroxymethyl) cyclopropane-JR-15 -carboxylic acid, 5 g of l(s)hydroxy-2-methyl-3-(2-propon-l--yl) cyclopent-2-en -ft-one and 0.05 g of paratoluene sulphonic acid, one takes the reaction.mixture to reflux, under agitation, agitates for Λ hours at reflux separating, by azeotropic decantation, the water formed, cools to 0°C, agitates, 20 isolates by vacuum-filtration the precipitate formed, washes ' it, dries it and obtains 8.7 g of (1H,53) 6,6-dimethyl’-ft(R)- i Cl(y)-2-methyl-ft-oxo-3-(2-propcn-l-yl) cyclopent-2-enyloxy]-3~oxa bicyclo (3·1·θ) hexan-2-one, M.I’t. - 10ft°0.

The mother liquors are concentrated to dryness, one crystallises 25 the residue from isopropanol and obtains 0.12 g of second yield. 27 48736 Example -5: (1R.5S) 6.e-dimethvl-4(Ry-Cl(s3-2-methvl-4-0x0- 3-(2-propen-l-Tl)-CTclopent-2-envloxy3-5-oxa bievclo-(3.1,Pl- hexan-2-one starting with the lactone of dl cis 2.2-dimethvl- 3-(dihydroxymethvl)-cvclopropane-l-carboxvlic acid.

Into a container topped by an azeotropic decantation system one introduces 25.2 g of 1(S)-hydroxy-2-methy1-3-(2- -propen-l-yl)-cyclopent-2-enT4-one Cor (S) allethrolonel, 250 cm^ of benzene, 25.5 g of lactone of dl cis 2,2-dimetbyl- 3-(dihydroxymethyl)-cyclopropan-1-carboxylic acid and 0.25 g ' 10 of paratoluene sulphonic acid, one takes the reaction mixture to reflux under agitation, removing, by azeotropic decantation, the water formed, agitates thus for 4 hours, cools, neutralises by the addition of triethylamine, concentrates to dryness 7. under vacuum, adds to the residue 5 cnr of isopropyl ether, 15 agitates at 0°0 for one hour, isolates by vacuum-filtration the precipitate formed, washes it, dries it and obtains 15-1 g of (IE,5S) 6,6-dimethyl-4(R)-tl(S)-2-methyl·-4-0x0-3-(2-propen--l-yl)-cyclopent-2-enyloxy]-5-oxa bicyclo-(5,1.0)-hexan-2-one, M.Pt. = 104°C. ; 20 Example 6: 1(S)-hydroxy-2-methyl-5-(2-propen-l-yl)-cyclopent--2-en - 4-one [or (S) allethrolonel starting with (1R.5S) 6,6-dimethyl-4(R)-.Cl(S) -2-methyl-4-oxo-3-(2-prouen-l-yl)-cyclopent-2-enyloxy3-5-oxa bioyclo-(5.1.0)-hexan-2-one.

One mixes 82.6 g of (1R,5S) 6,6-dimethyl-4(R)-Cl(S)-25 -2-methyl-a-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy3 - 3-oxa-hicyclo-(3.1.0)--hexan-2-one, obtained in Example 4, 826 cm^ of water and 8.2 cm^ of 22°Bd aqueous solution of hydrochloric acid, agitates for 72 hours at 20°C, brings 28 48736 the solution obtained to pH 10.3 by the addition of normal aqueous solution of sodium hydroxide, extracts with methylene chloride, dries, concentrates to dryness by distillation under reduced pressure and obtains λ2.9 g of 1(S)-hydroxy-5 2-methyl-3-(2-propen-l-yl)-cyclopent-2-en- 4-one Cor (S) allethrolone], (a) » +14° (c. = 1.2%, chloroform) Circular dichroism (dioxan) Δε * -20 at 230 mm (max.); Δε = +3.36 at 321 nm (max.); Δε <* +3.0 at 331 nm (max.) 10 Example 7: 1 (R)-hydroxy-2-methyl -3-(2-propen-l-yl)-cyclopent--2-en-fr-one [or (R) allethrolone) starting with (1R.5S) 6.6-dimethyl- n(R)~ C1(R)-2-methyl- a-oxo~5-(2-propen-l-yl)-cyclopent-2-enyloxy3-3-oxa-bicyclo-(3.1.0)-hexan-2-one.

One mixes 82.4 g of (1R,5S) 6,6-dimethyl-4(R)H(R)-2-15 -methyl-4-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy3-3-oxa - bicyclo-(3.1.0)-hexan-2-one, obtained in Example 3, 824 cm^ of water and 8.2 cm^ of 22°%έ aqueous solution of hydrochloric acid, agitates for 72 hours at 20°C, brings the solution obtained to pH 10.5 by the addition of normal 20 aqueous solution of sodium hydroxide, extracts with methylene chloride, dries, concentrates to dryness by distillation under reduced pressure and obtainsj ¢2.7 g of l-(R)-hydroxy- 2-methyl-3-(2-propen-l-yl)-cyclopent-2-en—4-one Cor (R) allethrolone], 25 (»)p = -1Λ.30 (c - 1.2%, chloroform) Circular dichroism (dioxan) Δε = +20 at ?30 nm (max .) ; Δε = -3.36 at 321 nm (max.) Δε- -3.0 at 331 nm (max.). 29 48736 Example 8: 1( S)-hydroxy-2-methyl-3-(2-propen-l-Tl)-c:rclopent--2-en- a-one Cor (S) allethroloae) starting with (1R.9S) . 6,e-dimethyl-4(R)~ Cl(S)-2-methyl-4-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy]-3-oxa-bicyclo -C3.1.0)-hexan-2-one.

Into 42 cm^ of methanol one introduces 0.85 £ of- . paratoluene sulphonic acid and 8.3 g of (1R,5S) 6,6-dimethyl -4(E)[l(S)-2-methyl-4-oxo-3-(2-propen-l-yl)-cyclopent-2-eny-loxy]-3-oxa-bicyclo-(3»1.0)-hexan-2-one obtained in Example 2,, one agitates for 2 hours at 20°C, brings the reaction 10 mixture to pH 7 by the addition of sodium carbonate, filters, concentrates the filtrate under reduced pressure, chromatographs the residue (10 g) on silica gel eluting with a mixture of benzene and ethyl acetate (7*3) and obtains 4.4 g of l(S)-hydroxy-2-methyl-2-(2-propen-l-jyi)-cyclopent·!- : . . -2-en- 4-one Cor (S) allethrolonel ? (ct)j0 = +14-5° (c = 1.254 chloroform).

Circular dichroism (dioxan) Δε = -20.4 at 229 nm (max.) ; Δε = +3.36 at 321 nm (max.); Δε = +3-08 at 331 nm (max.).

Example 9* Lactone of cis 2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-l-R carboxylic acid starting with (1R.5S) - 6,6-dimethyl-4(R) -Cl(S)-2-methyl-n-oxo-3-(2-propen-l-yl) -cyclopent-2-enyloxy]~3-oxa bicyclo-(3.1.0)~hexan-2-one.

X X Into a mixture of 100 cur of water and 1 cm of 25 22°Baume aqueous solution of hydrochloric acid one introduces 2.76 g of (1R,5S) 6,6-dimethyl-4(R)“Cl(S)-2-methyl·· 4-oxo - 3-(2-propen-l-yl)-cyclopent-2-enyloxyl-3-oxa-bicyclo-(3.1.0) — hexan-2-one, K.Pt. = 104°C, obtained in Example 5» one 30 f 48736 agitates the reaction suspension for 72 hours, brings the reaction mixture to pH 10 by the addition of normal aqueous solution of sodium hydroxide, extracts the basic aqueous solution with methylene chloride, washes the organic phase 5 with water, dries it, concentrates it to dryness under reduced pressure and obtains 1.39 g of (S) allethrolone.

One saturates the aqueous phase with ammonium sulphate, acidifies it with an aqueous solution of hydrochloric acid, agitates for one hour, separates by vacuum-filtration the 10 gummy product rendered insoluble, dissolves it in ethyl acetate, filters, concentrates the filtrate to dryness and obtains 1.32 g of lactone of cis 2,2-dimethyl~3S-(dihydroxymethyl )-cyclopropane-lR-carboxylic acid.

Example 10; pR. 5a5« 45. 7R. 7aS) 3-((15)-2-«eth.Tl-4-oX0“ 15 3-(2-propen-l-yl)-cvclopent-2-enyloxy3-tetrahrdro-4.7-methano-isohenzofuran-l-one.

Into 50 cm^ of anhydrous benzene one introduces 4.3 g of'(3R, 3aR, 4S, 7R, 7aS)-3-hydroxy-tetrahydro-^,7-methano-isobenzofuran-l-one described - in Example 24, 3·9 g of 20 1 (R,G)-hydroxy-2-methyl"3-(2-propen-l-yl) cyclopent-2-en- 4-one and 40 mg of paratoluene sulphonic acid. One takes the reaction mixture to reflux, maintains the refluxing for 18 hours then concentrates to dryness by distillation under reduced pressure. One chromatographs the residue on silica 25 gel eluting with a mixture of chloroform and acetone (100:2.5).

One obtains 2.4 g of expected product in the form of a thick oil. 31 . 48736 Example 11; (3R. 3aR. 4S. 7R. 7aS) 5-C(IS)-2-methyl-4-oxo ~ 3-( 2-propen 1-yl)-cyclopent-2-enyloxy]-tetrahydro-A«7-methano - isobenzofuran-l-one.

By carrying out the chromatography described in Example 5 10 one recovers 2.7 g of expected product in the form of white crystals. M.Pt. = 148°C.

Example 12: (5R. 3aR, aS. 7R. 7aS)-3-[(lS)-2-methyl-A-oxo - 3-(2-propen 1-yl)-cyclopent~2-enyloxy]-t8trahydro-4.7-methano-isobenzofuran-l-one (isomer A) and (3S. 3aS, aR, 7S. 7aR) -10 3-C(IS)-2-methyl~h-oxo-3-(2-propen~l-yl)-cyclopent~2-envloxy3- tetrahydro-h,7-methano~isohenzofuran~i-one (isomer B). 3 Into 200 cm of benzene one introduces 33 g of racemic 3-hydroxy-1 etrahydro-4,7-methano-isobenzofuran-l-one, 30 g of 1 (S)- hydroxy-2-methyl- 3-( 2-propen-l-yl)-cyclopent- ... :, 15 2-en-4-one [or (S) allethrolone] and 0.18 g of paratoluene > sulphonic acid. One heats to reflux for 4 hours then concentrates to dryness by distillation under reduced pressure. The 60.3 g of residue obtained are chromatographed on silica and eluted with a mixture of chloroform and 20 acetone (100:3). One obtains 17«4 g of (3R, 3«®, 4S, 7R, 7aS)-$-[(lS)-2-methyl-4-oxo-3-(2-propen-l-yl)-cyclopent - 2-enyloxy]-tetrahydro-4,7-methano-isobenzofuran-l-one (isomer A) and 13.6 g of (3S, 5aS, AR, 78, 7aR) 3“C(18)—2--methyl-4-oxo-3~(2-propen-l-yl)-cyclopent-2-enyloxy]-tetra- ! 35 hydro-a,7 methano-isobenzofuran-l-one (isomer B).

The isomer A has the following characteristics: Μ.Γ-t. =- 148°C [tt]2° = -3° (C = 1.5¾ benzene) 32 - 48736 ΛΝΛΙ/Χΰΐΰ ; 018 Hgg : 300.36 % calculated : Cft 71.98 Η& 6.71 % found : 72.0 6.8 l.R. S1ECTRUH (chloroform) 5 Absorption at 1775 cm"·*" characteristic of the lactone.

Absorption at 1700 cm-1, characteristic of the carbonyl. -1 -1 Absorption at 1657 cm , 1640 cm characteristic of the conjugated ethylenic double bond.

Absorption at 981-918 cm-'1' characteristic of the vinyl.

Circular diohroism (dioxan).

As - -18.3 at 225 nm (max.) Ac* +2.29 at 321 nm (max.) Ae » +2.59 at 332 nm (max.) N.I1.R. SPECTRUM (CDC15) 15 Peaks at 6.25-6.28 p.p.m. characteristic of the ethylonic hydrogens of the lactone (at 5,6).

Peak at 5.1 p.p.m. characteristic of the hydrogen at position 3 of the lactone.

Peaks from I..33 to 1.75 p.p.m. characteristic of the hydrogens 20 of the CH2 of the lactone (at 8).

Peak at 4.58 p.p.m. characteristic of the hydrogen at 1 of the allethrolonc ring.

Peak at 2.07 p.p.m. characteristic of the hydrogens of the methyl at 2 of the allethrolone ring.

Peaks from 5.17 to 6.33 p.p.m. characteristic of the hydrogens at 2' of the propenyl.

Peaks from λ.83 to 5.13 p.p.m. characteristic of the hydrogens at 3' of the propenyl. 33 48736 The isomer B has the following characteristics: [ctlp0 = +42.5° (C = 1%, benzene) ANAhYlUS : C1Q H2Q : 300.36 % calculated: C'/ί 71.98 6.71 5 °/o found : 71.8 6.7 I. K. S1ECTRUH (chloroform) Absorption at 1770 cm-·*· characteristic of the carbonyl. Absorption at 1706 cm-'*' characteristic of the conjugated carbonyl.

Absorption at 1656-1640 cm-·*· characteristic of the conjugated ethylenic double bond.

Absorption at 982-918 cm-1 characteristic of the vinyl group. Circular dichroism (dioxan) Ac = -18.4 at 226 nm (max.) 15 = +2.9 at 319 am (max.) = +2.63 at 331 nm (max.) II. M.R. ϋΡΞΟΤΚΜ (CDClj) Peaks at 6.25-6.28 p.p.m. characteristic of the pthy1enic hydrogens of the lactone (at 5-6).

Peak at 5.0 p.p.m. characteristic of the hydrogen at position 3 of the lactone.

Peaks from 1.33 to 1.75 p.p.m. characteristic of the hydrogens of the CHg of the lactone (at 8).

Peak at 4.73 p.p.m. characteristic of the hydrogen at 25 position 1 of the allethrolone ring.

Peak at 2.03 p.p.m. characteristic of the hydrogens of the methyl at 2 on the allethrolone.

Peaks at 5.33-6.33 p.p.m. characteristic of' the hydrogen at 2' 1 48736 of the propenyl.

Peaks from 4.85 to 5.13 p.p.m. characteristic of the hydrogens at 3' of the propenyl.

The 3-hydroxy-tetrahydro-4,7-methano“isobenzofuraft‘ 5 1-one, used at the start of the example was prepared as follows: One agitates at 20°C under inert atmosphere 30 g of 5-hydroxy-2(5H)-furanone, 150 em^ of chloroform, 50 mg of hydroquinone and 35 cm^ of freshly distilled cyclopentadiene.

One leaves for 17 hours under agitation maintaining the temperature between 20 and 45°C then concentrates to dryness under reduced pressure. The residue is crystallised from a mixture of isopropyl ether and petroleum ether.

One obtains 46.6 g of product, M.Pt. * 1Q3°C * 15 ANALYSIS : 0? : 166.17 Calculated : (FA 65.05 6.06 Pound : 65-3 6.2 I.R. SPECTRUM (CHClj) OH : 3580 cm"1 20 C=0 1770 cm"1 H.M.R. oPSCTHUM (CDClj) Peaks at 6.2-6.22 p.p.m. characteristic of the ethylenic hydrogens.

Peaks at 5.13-5.27 p.p.m. characteristic of the hydrogen at 1.

Peaks at 4.87-4.95 p.p.m. characteristic of the hydrogen of the hydroxyl at 1.

Peaks from 1.33 to 1-75 p.p.m. characteristic of the hydrogens of the methylenes. 48736 Sample 13: (3^. 3aS, 4B, 7S, 7aR) 3-[(IS)-2-methyl-ft-oxo- 3-(2-propen-l-yl)-cvclopent-2-envloxy3-tetrahvdro-4-.7-methano- iaobenzofuran-1-one (isomer D) and (3R. 3aB, 4-S, 7R. 7aS)~ 3-[(1R)-2-methyl-4-oxo -3-(2-pronen -1-yl)-cyclonent-2-en?loXy3- 5 tetrahyaro-4-.7-methano-lBobenzofuran-l-one (isomer Cl. x Into 100 cur of anhydrous benzene one introduces 18.4- g of racemic 3-hydroxy-tetrahydro~4,7-methano-isobenzofuran-1-one prepared as in Example 12, 16 g of 1(R) hydroxy-2-methyl~ 3-(2-propen-1-yl)-cyclopent-2-en- 4-one (or R allethrolone) 10 and 0.10 g of monohydrated paratoluene sulphonic acid. One takes to reflux for 18 hours then one drives off the solvent under reduced pressure. One obtains 31-4- g of crude product which one chromatographs on silica eluting with a mixture of chloroform and acetone (100:5). One recovers 9*4- g of 15 (3S, 3aS, aR* 7S, 7aR)-3-[(lR)"2-methyl-4--oxo-3-(2-propen- 1- yl) -cyclopent-2-enyloxyl· tetrahydro-4-,7- methano-isobenzo-. furan-l-one (isomer D) in the form of white crystals, M. Pt. = +U8°C, and 11.7 g of (3R, 3aR, 4S, 7R, 7aS)-3-C(lR)“ 2- methyl-4-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy3-tetra- 20 hydro-4,7-aiethano-isobenzofuran-1-one (isomer C) in the form of gummy crystals'.

The isomer D has the following characteristics: Ca)p° = +11.5° - 1° (C = 1% benzene) N. H.R. iiPiCTRUH (CDC1,) - 3 25 Peak at 6.23 p.p.m. characteristic of the ethylenic hydrogens of the lactone (at 5-6).

Peaks it 1.33-1.75 p.p.m. characteristic of the hydrogens of the 0::-, of the lactone at 8.

Peak at 5.0 p.p.m. characteristic of the hydrogen at position 3 36 ! 48736 of the lactone «oiety.

Peaks at 4-.5~4.5S p.p.m. characteristic of the hydrogen at position 1 of the allethrolone ring.

Peak at 2.06 p.p.m. characteristic of the hydrogens of the 5 CHj of the allethrolone.

I.R. SPECTRUM (CHOlj) C » 0 lactone 1775 ca~^ C * 0 conjugated 1700 cm-1 C * 0 + conj. 1657-1640 cm-1.

CIRCULAR DICHKOISM (dioxan) Agreement with the ether of R allethrolone, curve practically antipodal to that of the isomer A obtained in Example 16. max. 225 nm Δε +25.0 ]5 max. 520 nm Δε -5.0 max. 552 nm Δε -2.69.

The isomer C has the following characteristics: Ca]^° = -51° - 1° (C - 1% benzene) CIRCULAR UICHUQItSH (dioxan) 20 In agreement with the ether of H nllfthrolone, curve antipodal to that of the isomer B obtained in Example 12. max. 22/i nm Δ e * +19.1 max. 518 nm fle = -2.88 max. 550 nm Δε = -2.59 25 M.ii.R. orECIRUM (CDClj) Peak at 6.26 p.p.m. characteristic of the ethylenic hydrogens of the lactone moiety.

Peaks at 1.55-1-75 p.p.m. characteristic of* the hydrogens of 37 48^36 the CH2 of the lactonic moiety.

Peak at 5.0 p.p.m. characteristic of the hydrogen at position 1 of the lactonic moiety.

Peak at a.7 p.p.m. characteristic of the hydrogen at position 5 1 of the allethrolone ring.

Peak at 2.0 p.p.m. characteristic of the hydrogen -of the CHj of the allethrolone.

Peaks at 5.33-6.33 p.p.m. characteristic of the hydrogen at position 2' of the propenyl.

Peaks at a.83-3.1 p.p.m. characteristic of the hydrogen at position 3' of the propenyl.

I.R. nl'EC'l'RUM (CHC1,) - 3 C = 0 lactone 1770 cm-'*' C = 0 conjugated 1706 cm-^ * i 15 0 = C + conjugated 1656-1640 cm_ Example la.; (1H,5S) 6.6-dimethyl-n(R) -C31.3'-dimethyl--butyrolactone-2'-(S)-ox?]-3-oxabicyclo-C3.1.0]-hexan-2-one (compound A) and (1R,58) 6,6-dimethyl-h(R) —C31.31-dimethyl-butyrolactone-2'(R)-oxyl -5-oxabicyclo -[3.1.03~hexan-2-one 20 (compound B).

Under inert atmosphere one agitates 7 g of pantolactone, 7.1 g of the lactone of 2,2-dimethy1-3-3(dihydroxymethyl)- cyclopropane-lR-carboxylic acid, 1λ0 mg of paratoluene x sulphonic acid and 50 cnr of benzene. One heats for 7 hours 25 15 minutes to reflux. The benzene is distilled at 40°C under reduced pressure. The residue is chromatographed on silica and eluted with a mixture of benzene and ethyl acetate (85:15).

One obtains 2.956 g of (lR,5b) 6,6-dimothyl-4-(R)-H3'»3'“ 38 48736 -dimethylbutyrolact one-2'(S)-oxy]~3-oxabicyclo -C 3.1.0]-hexan-2-one M.Pt. «102-104°C (compound A) then 547 mg of (1R,5S) 6,6-dimethyl-4-(S)-C3',31-dimethylbutyrolactone -2'-(R) oxy3-3-oxahicyclo-C3.1.03-hexan-2-one M.Pt. 134°C 5 and finally 1.654 g of (1R,5S) 6,6-dimethyl_4(R)~ [3',3'“dimethyl-hutyrolactone-21(R)-oxy]-3-oxahicyclo-t3.1.0]-hexan-2-one, M. Pt. ·= 120°C (compound Bi N. M.R. SPECTRUM (CDClj) Compound A Peak at 4.0 p.p.m. characteristic of the hydrogens at position 4' of the pantolactone.

Peak at 4.2 p.p.m. characteristic of the hydrogen at position 2' of the pantolactone.

Peak at — 5.7 p.p.m. characteristic of the hydrogen at ♦ 15 position 4 of the bicyclo (3.1.0] hexanone.

Peaks at 2-2.1 and 2.22-2.31 p.p.m. characteristic of the hydrogens at positions 1 and 3 of the cyclopropyl.

Peaks at 1.1-1.22 p.p.m. characteristic of the hydrogens of the methyls.

Compound B Peak at 4.0 p.p.m. characteristic of the hydrogens at position 4' of the pantolactone.

Peak at 4.23 p.p.m. characteristic of the hydrogen at position 2' of the pantolactone.

Peak at 5.47 p.p.m. characteristic of the hydrogen at position 4 of the bicyclo (3.1.0] hexanone.

Peaks at 2.06-2.15 and 2.36-2.^5 p.p.m. characteristic of the hydrorenr. at 1 and 3 °f tho cyclopropyl. 39 48736 Peaks at 1.12-1.2-1.24 p.p.m. characteristic of the hydrogens of the methyls.

Example 15: (3S. 3aR. 4S, 7R, 7aS) 3-[(lS)-2-methyl-4-oxo- 3-(2-propen-l-yl)-cyclopent-2-enyloxy]-tetrahydro-a.7 -5 methano-isobeny.ofuran-l-one and (3H, 3aS, 4R, 7S, 7aR) 3-[(lS) 2-methyl-4-oxo-3-(2-propen- 1- yl)- cyclopent-2-enyloxy]-tetrahydro-4.7- methano-isobenzo-furan-l-one, in the form of a racemic mixture.

One heats to reflux for 3 hours 66 g of racemic 3~hydroxy -1q tetrahydro-4,7-methano-isohenaofuran~l-one prepared as in Example 12, 60 g of 1(S) hydroxy-2-methyl~3-(2-propen-l-yl)- X l cyclopent-2-en 4-one, 600 cnr of benzene and 300 mg of paratoluene sulphonic acid. One neutralises with 4 cm·'’ of triethylamine then concentrates to dryness. One takes 15 up with ethyl ether and vacuum-filters 23 g of a crystalline product, M.Pt. = 148°G, corresponding to (3R, 3aR, 4S, 7H* 7aS) 3-C( IS)-2-methyl-h-oxo^'i2-propen-l-yl)-cyclopent- 2- e ny 10 xy ] -1 et r ahydr o- 4,7-methano -i s obenz 0 fur an -1 -one (compound A obtained in Example 12). The mother liquors 20 are chromatographed on silica and eluted with a mixture of chloroform and acetone (100:3). One isolates in succession 28.8 g of (3S, 3aS> 4E, 7S, 7aK) 3-C(l8)"'2-methyl-4-oxo-T 3- (2-propen-l-yl)-cyclopent—2-enyloxy]-tetrahydro-4,7-methano -isobcnzofuran-l-one (compound B obtained in Example 12) then 25 26 g of compound A and finally 16 g of a mixture of endo diastereoisomers sought.

I.K. -->] ;-.CTHUH (CHClj) Y lactone = absorption at 17b'i cm ^ 40 48736 allethrolone » absorptions at 1708 cm-·*· 1655 cm-1 1639 cm-1 skeletal region very different from the products A and B.

H.M.B. SPECTRUM (CDClj) 5 Peak at 6.1? p.p.m. characteristic of the ethylenic hydrogens at positions 5 and 6.

Peaks from 2.92 to 3*42 p.p.m. characteristic of the hydrogens at positions 3a, 4,7 and 7a.

Peaks at 1.33-1»48 and 1.55-1.7 p.p.m. characteristic of 10 the hydrogens at position 8.

Peaks from 5.58 to 5*75 p.p.m. characteristic of the hydrogen at position 3.

Peaks from a.5 to 4.83 p.p.m. characteristic of the hydrogen <» at 1' in the allethrolone.

Peak at 2.07 p.p.m. characteristic of the hydrogens of the methyl at 2' of the allethrolone.

Peaks from 5.52 to 6.17 p.p.m. characteristic of the hydrogen at 2 of the propenyl.

Peaks from 4.83 to 5.17 p.p.m. characteristic of the 20 hydrogens at 3 of the propenyl.

Compounds different from the products A and B.

Example 16: (lR.US) 6,6-dimethyl-4-(R)-C(R)ethynyl-(5'-phenoxy-phenyl)-methoxy3-5-oxabicyclo-[3.1.0)-hexan-2-one (isomer R).

For 1 hour, under agitation, one heats to reflux, 25 removing the water formed by azeotropy, 20 g of lactone of cis 2,2-dimethyl-~33-(dihydroxy-methyl)-cyclopropane-1R--•carboxylic acid, 200 cm^ of benzene, 30 E of racemic ethynyl 41 . 48736 (31-phenoxyphenyl)-methanol and 200 mg of paratoluene j sulphonic acid. One allows to cool to 20°C then neutralises by the addition of triethylamine. One concentrates to dryness under reduced pressure and obtains 51 g of a brown oil. By 5 chromatography under pressure and j elution with a mixture of benzene and ethyl acetate (95s5) one isolates 10.7 g of isomer R in the form of an oil.

Characteristic of the isomer Rs H.tt.H. SPECTRUM (CDClj) 10 Peaks at 1.16-1.25 p.p.m. characteristic of the hydrogens of the geminal methyls.

Peak at 5.65' p.p.m. characteristic of the hydrogen at 4.

Peaks at 2.68-2.7 p.p.m. characteristic of the hydrogen of the ethynyl. s * 15 Peaks at 5.50-5.52 p.p.m. characteristic of the hydrogen borne by the same carbon as the ethynyl.

Peaks from 6.85 to 7*50 p.p.m. characteristic of the hydrogens of the aromatic nuclei.

Peaks at 1.95-2.03 and 2.1-2.18 p.p.m. characteristic of the 20 hydrogens of the cyclopropyl.

Example 17: (1R.50) 6.6-dimethyl-h-(R)-C(t>)-ethymrl-(5'--phenoxyph eny1)-methoxy]-3-oxabicyolo-[3.1.0]-hexan~2-one (isomer S).

By carrying out chromatography under pressure, described 25 in Example 16, one isolates 10.a g of isomer S in the form of an oil, then 8.a g of a mixture of isomers R and S.

Characteristics of the isomer S: J-Cl'RUH (CDClj) Peak at 1.11 p.p.m. characteristic of the hydrogens of the 42 48736 geminal methyls.

Peak at 5.05 p.p.m. characteristic of the hydrogen at 4.

Peaks at 2.65-2.68 p.p.m. characteristic of the hydrogen of the ethynyl.

Peaks at 5.4-1-5.45 p.p.m. characteristic of the hydrogen borne by the same carbon as the ethynyl.

Peak at 2.05 p.p.m. characteristic of the hydrogens of the cyclopropyl.

Example 18: (IB.53) 6.6-dimethvl-4(R)-C 31 -methyl -21 ( R)-butoxy3- 10 3-oxabicyclo-C3.1.03-hexan-2-one.

For two hours one heats to reflux, under agitation, 28 g of lactone of cis 2,2-dimethyl-3S-(.ddi^fcoxymethyl) - x cyclopropane-lH-carboxylic acid, 100 car of benzene, 100 mg x of paratoluene sulphonic acid and 25 car of racemic 3-methy1-15 -2-butanol.* The water formed during the reaction is removed, by azeotropy. One allows to cool to 20°C then neutralises with triefchylamine. One concentrates to dryness under reduced pressure and obtains 44 g of oil. By chromatography of this oil on silica one obtains 33 g of a mixture of the two 20 diastereoisomers. One chromatographs under pressure, on silica, 360 aig of the latter, elutes with methylene chloride containing 2$ of acetonitrile and recovers 160 mg of the diastereoisomer R. M.Pt. — 19-21°C. [cdjj0 = -143° -3.5° (C = 0.55.' benzene) 25 N.H.R. SPECTRUM (CDCl^) Peaks at 1.15-1.17 p.p.m. characteristic of the hydrogens of the geminal methyls. leak at 5.25 p.p.m. characteristic of the hydrogen at 4. 43 .48736 Peaks at 1.07-1=17 p.p.m. characteristic of the hydrogens of the methyl at 1' of the propyloxy.

Peaks from 3.45 to 3»8? p.p.m. characteristic of the hydrogen at 1' of the propyloxy» 5 Peaks from 0.83 to 0.93 p.p.m. characteristic of the hydrogens of the methyls at 2', 3' of the propyloxy.

Example 19; (1R. 5S) 6,6-dimethyi--a(R)-[51-methyl-2'(S)-hutoxy3- 3-oxabicyclo [5.1.03 hexan-2-one.

After having recovered the isomer A in Example 18 one 10 continues the elution to obtain 57 mg of isomer S.

M.Ft. 35°C. [α]β° = -121° - 3.5° (C = 0.5^ benzene) tUi.R. olKCTRUM (CDClj) Peak3 at 1.17-1.19 p.p.m. characteristic of the hydrogens of 15 the geminal methyls.

Peak at 5.2 p.p.m. characteristic of the hydrogen at 4.

Peaks from 3·38 to 3»46 p.p.m. characteristic of the hydrogen at 1' of the propyloxy.

Peaks at 0.83-0.95 p.p.m. characteristic of the hydrogens 20 of the methyls at 2' and 3' of the propyloxy.

Peaks at 1.15-1.25 p.p.m. characteristic of the hydrogens of the methyl at 11.

Example 20: (3S, 5aS.

One heats to reflux for one and a half hours 300 mg of (3s, 3aO, 4R, 7S, 7aR) 3-hydroxy-tetrahydro 4,7-methano isobenzofuran-l-one obtained hereinafter in Example 25, 30 cm^ of benzene, 400 mg of l(R)-(3'-phen0xyphenyl)-a-methyl 44 48736 methanol and 30 mg of paratoluene sulpbonic acid. After cooling to 20°C one neutralises with triethylamine and concentrates to dryness under reduced pressure. The oil obtained is chromatographed on silica then eluted with a 5 mixture of benzene and ethyl acetate (9:1)* One obtains 400 mg of product, M.Pt. * 146°C.

N.M.R. SPECTRUM (CDClj) Peaks at 1.5-1.65 p.p.m. characteristic of the hydrogens of the CHg at 8.

Peaks at 5.83-6.25 p.p.m. characteristic of the ethylenic hydrogens.

Peak at 4.7 p.p.m. characteristic of the hydrogen at position 3* Peaks at 1.37-1·Λ8 p.p.m. characteristic of the hydrogens I5 of the methyl at a.

Peaks at 4.58-4.7-4.82-4.95 p.p.m. characteristic of the hydrogen at 1' of the alcoholic moiety.

Feaks at 6.83-7.5 p.p.m. characteristic of the hydrogens of the aromatic nuclei.

CIRCULAR DICHKOISH (dioxan) max. 235 nm Ae = +1.9 inf1.257 n 4ε= +0.58 max. 263 nm Δε = +0.77 max. 276 nm Δε ** -1.67 max. 281 nm Δε « -2.00 structure R at -O-CII-0- Oil, 45 * 48736 Example 21; (3S, 3aS, 4R, 7S, 7aH) 3[1(6)-(31-phenoyyphenyl)-g-methyl-methoxy3-tetrahvdro-4.7-methano-jsobenzofuran-l-one.

One heats to reflux, for 1 hour 30 minutes under agitation, 300 mg of (3S, 3aS, 4R, ?S, 7aR)-3-hydroxy-5 tetrahydro-a,7-methano-isobenzofuran-l-one obtained hereinafter in Example 25, 15 cm? of benzene and 400 mg of l(S)-(3'--phenoxyphenyl)~ a-methyl-methanol and 30 mg of paratoluene aulphonic acid. After cooling one concentrates to dryness under reduced pressure and obtains 900 mg of a thick oil.

One chromatographs this,eluting with a mixture of benzene and ethyl acetate (95s5). One recovers 400 mg of product which crystallises, M.Pt. = 78-79°C.

I.B. SPECTRUM (CHClj) Absorption C = 0 V-lactone at 1769 cm-·*·, 15 absorption of the aromatic nuclei at 1587-1490 cm-·*·, absorption C-O-C at 1250 cm \ absorption ^ ^ 694 cm CIRCULAR DICHROISM (dioxan) max. 281 ran Δε +0.8 20 max. 275 am Δε +0.6 max. - 225 am Δεν-2.5 to -3 compatible with the configuration S for the alcohol part.

N.M.R. JPECTKUM (CDClj) Peak at 6.2 p.p.m. characteristic of the ethylenic hydrogens.

Peaks at 1.33-1.75 p.p.m. characteristic of the hydrogens of the Clip at 8.

Peak at 5.07 p.p.m. characteristic of the hydrogen at position 3· 46 48736 Peaks at 1.4-1.5 p.p.m. characteristic of the hydrogens of α-methyl.

Peaks at 4.6-4.7-4.8 p.p.m. characteristic of the hydrogen borne by the same carbon as a-methyl.

Peaks at 6.7-7-5 p.p.m. characteristic of the hydrogens of the aromatic nuclei.

Peaks from 2.67 to 3.5 p.p.m. characteristic of the other protons.

Example 22; 1(8) hydroxy-2-methyi~3-(2-propen-1-yl) cyclopent-10 2-en - 4-one (or S allethrolone).

Into 20 cm^ of dioxan one introduces 2.7 g of (3R> JaR, 4S, 7R, 7a8) 3-C(lS) 2-methyl-4-oxo-3~(2-propen-l-yl)-cyclopent 2-enyloxy] tetrahydro 4,7-methano isobenzofuran-l-one obtained in Example 12, 30 cm^ of water and 0.25 g of monohydrated 15 paratoluene sulphonic acid and one heats to reflux for 24 hours. After removing the solvent under reduced pressure one neutralises with triethylamine until pH 7* then concentrates to dryness under reduced pressure. One obtains 2.8 g of crude product. This is chromatographed on silica 20 ahd eluted with a mixture of benzene and ethyl acetate (1:1) containing 1 ml per litre of triethylamin·. One recovers 1 g of allethrolone of configuration 3, 0.4 g of lactone and 0.7 g of a mixture of lactone and allethrolone. [ajjp = +6.5° ^ 1°(0 » 1.5( benzene).

CIRCULAR DICHROISM (dioxan) max. 228 nm Δε : -15.7 max. 318-319 nm Δε: +2.46 max. 350 nm Δε.: +2.26. 47 „ 48738 Example 25; l(R)-hydroxy-2~methyl-2-(2-propen-1-yl)-cyclopent- 2-en - 4-one (or B allethrolone).

Operating in the same manner as in the previous example, hut starting with (JR, JaS, 4S, 73., 7aS) 3“C(IE)-2-methyl-5 4-0x0-3-(2-propen-l-yl)-cyclopent-2-enyloxyil-tetrahydro - 4,7-methano'isobenzofuran-l-one obtained in Example 13, one obtains some H allethrolone with the same yield.

[ CIRCULAR DICHROISH (dioxan) 10 max. 228 nm Δε +17·3 max. 318 nm &ε -2.92 max. 330 nm Δε -2.68 Example 24: (3K. 3aR. 4S. 7R. 7aS)-3-hydroxy-tetrahydro-4.7- methano -dsobenzofuran-lrone. ♦ 2 15 Into 60 cmy of dioxan one introduces 12.8 g of (3R, 3aR, 4S, 7R, 7aS)-3-C(lS)-2-methyl-4-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy)-tetrahydro-4,7-methano-isobenzofuran- 1-one obtained in Example 12, 120 cm^ of water and 1.2 g Of monohydrated paratoluene sulphonic acid. One heats to reflux 20 for 2 hours. One neutralises to pH 7 with triethylamine and concentrates to dryness under reduced pressure. The crude product is chromatographed on silica eluting with a mixture of benzene and ethyl acetate (1:1) containing lml/1 of triethylamine. One obtains 5.3 g of the product expected 25 in the form of white crystals melting at 120°C.

ANALYSIS : Cg H1Q 0^ M.W.: 166.17 Calculated: Ci'; 65.03 H5‘ 6.07 Round : 65-0 6.1 : 48 i 48736 CIRCULAR DICHHOISM (dioxan) max. 218 run Δε * +2.57 max. 292 nm Δε » -0.015 max. 553 nm Δε * +0.011 5 max. 545 nm Δε * +0.006 Ca3p° = +49.5° (C - 1%, chloroform) I.R. SPECTRUM (CEClj) Absorption at 5580 cm-^· characteristic of the hydroxyl, absorption at 1769-1740 cm-1 characteristic of the carbonyl.

N.M.R. SPECTRUM Peak at 6.2 p.p.m. characteristic of the ethylenic hydrogens. Feaks at 5.22-5.25 p.p.m. characteristic of the hydrogen at position 5· Peak at 4.75 p.p.m. characteristic of the hydrogen of the % 15 hydroxyl.

Peaks at 1.53-1.73 p.p.m. characteristic of the hydrogen of the CRL, at 8.

Peaks at 2.75-5.52 p.p.m. characteristic of the other protons. Example 25: (5S. 5aS. aR, 7S. 7aR) 5-hydroxy-tetrahydro-20 a.7-methano-isobenzofuran -1-one.

Into 20 car* of dioxan one introduces 1.9 g of (5S, 3aS, 4R, ?S, 74R) 5C(lR)-2-methyl-a-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy3»tetrahydro-4,7-methano-isobenzofuran- 1-one obtained in Example 13, 20 cm^ of water and 0,2 g of 25 monohydrated paratoluene sulphonic acid. One heats to reflux for 6 hours. One neutralises to pH 7 with triethyl-amine and concentrates to dryness under reduced pressure.

The residue is chromatographed on silica and eluted with a 49 - 4ST36 mixture of benzene and ethyl acetate (1:1) containing 1 ml/1 of triethylamine. One obtains 650 mg of product melting at 120°C having the following characteristics: Ca]p° = -47-5° - 2.5° (C = 1%, chloroform).

Il.M.R. SPECTRUM (CDCl^) Peak at 6.23 p.p.m. characteristic of the ethylenic hydrogens.

Peak at 5-25 p.p.m. characteristic of the hydrogen at position 3.

Peak at 4.9 p.p.m. characteristic of the hydrogen of the OH.

Peaks at 1.-55-1.5 and 1.6-1.75 p.p.m. characteristic of the hydrogens of the CH2 at position 8.

Peaks from 2.83 to 3-58 p.p.m. characteristic of the other protons.

Example 26: (|3S. 3aB. 4S, 7H. 7aS)-3-hydroxy-tetrahydro-4.7-15 methano—isobsnzofuran-l-one and (3R. 5aS. 4R. 7S. 9aR) 3-hvdroxv-tetrahydro-4.7-methano-isobenzofurap-l-one. in the form of a racemic mixture.

One heats to reflux, for 2 hours, 15 g of the mixture obtained in Example 15 C(3S, 3aR, 4S, 7R, 7aS) 3-C(lS)~ 20 2-methyl-4-oxo-3-(2-propen~l-yl)-cyclopent-2-enyloxy3 - tetrahydro-4,7-methano-isobenzofuran-l-one and (3H, 3aS> 4P, 7S, 7aR)~3-C(IS)-2-methyl-4-0x0-3-(2-propen-1-yl) -cyclopent'2-enyloxy)-tetrahydro-4,7-methano-isobenzofuran— 1-one], 75 cm'* of dioxan, 150 cm^ of water and 1.5 g of 25 paratoluene sulphonic acid. One cools, adjusts the pH to 7-8 with triethylamine and concentrates to dryness under reduced pressure. The oil obtained is chromatographed under pressure on silica and eluted with a mixture of benzene and 50 ί 48736 ethyl acetate (1:1) containing 1 ml/1 ,of triethylamine.

One obtains 4.85 g of product , M.Pt. n 103°C.

H.M.K. oPECl'RUH (CDClj) Peak at 6.2 p.p.m. characteristic of the ethylenic hydrogens.

Peak at 5.22 p.p.m. characteristic of the hydrogen at position 3.

Peaks at 1.33-1.48 and 1.55-1.7 p.p.m. characteristic of the hydrogens of the CE^ at 8.

Peak at 4.67 p.p.m. characteristic of the hydrogen of the OH.

Peaks from 2.75 to 3-5 p.p.m. characteristic of the other protons.

No dichroism at 218 nm for the lactone chromophore, therefore racemic product.

Example 27: (S) 1-(5-phenoxy-nhenyl)-prop-2-ro-l-ol). 7. 7 15 Into a mixture of 80 cur of dioxan and 80 cur of water one introduces 10.4 g of (lR,5S)-6,6-dimethirl"4(E)-[(S)--ethyny1-(3'-phenoxy-phenyl-methoxy)-3-oxabicyclo-[3.1.0)-hexan-2-one obtained in Example 17 and 1 g of paratoluene sulphonic acid, one takes the reaction mixture to reflux, 20 maintains the refluxing for 2 hours, concentrates almost to dryness by distillation under reduced pressure, adds water, agitates, extracts with isopropyl ether, carries out the usual treatments, concentrates to dryness by distillation under reduced pressure, chromatographs the residue (6 g) 25 on silica gel eluting with a mixture of benzene and ethyl acetate (7:3) and obtains 5.1 g of (3) l-(3-phenoxy~phenyl)-prop-l'-yn-l-ol. [α]^° == +10.5° (C = 0.631-, benzene). 51 - 48736 Μ.Μ.R. SPECTRUM (deuterochloroform) Peak at 2.JO p.p.m. characteristic of the hydrogen of the hydroxyl.

Peaks at 2.61-2.66 p.p.m. characteristic of the ethylenic 5 hydrogen.

Peaks at 5.44.-5.50 p.p.m; characteristic of the hydrogen borne by the same carbon as the ethynyl group.

Peaks at 6.91-7.0 p.p.m. characteristic of the hydrogens of the aromatic nuclei.

CIRCULAR DICHBOISM ; (dioxan) ε = +1.9 at 215 nm (max.) ε = +0.02 at 272 nm (max.) ε = -0.01 at 276 nm (max.) e = +O.O4 at 278 nm (max.) % IS ε = -O.OJ at 285 nm (max.) Example 28: (R) 1-(5-phenoxy-phenyl)-prop-2-yn-l-ol.

Operating in a manner similar to that of Example 27, but starting with 10.6 g of (1R, 5S) 6,6-dimethyl~k(R)-[(R)-ethynyl-(31-phenoxy-phenyl)-methoxy]-3-oxabicyclo-20 [3.1.0]-hexan-2-one obtained in Example 16, one obtains 5.6 g of (R) 1-(3-phenoxy-phenyl)-prop-2-yn-l-ol. ta]j° = -16° (C = 1%, benzene).

N.M.R. oI-ECTRUM (deuterochloroform) Feaks at 2.58-2.62 p.p.m. characteristic of the acetylenic 25 hydrogen.

Peak at 2.66 p.p.m. characteristic of the hydrogen of the hydroxyl. leaks it 5-36-5.AO p.p.m. characteristic of the hydrogen 52 48736 borne by the same carbon as the ethynyl group.

Peaks at 6.83-7.50 p.p.m. characteristic of the hydrogens of the aromatic nuclei.

Example 29: 3-methTl-2-(S) butanol.

One heats to 50°C, for 16 hours, 16.9 g of (1H, 5S) 6,6-dime thy 1-4.(R)-[3-methyl-2(S)-butoxy]-3-oxabicyclo-[3.1.0] - hexan-2-one, obtained in Example 19, 70 cm^ of 2N hydrochloric 3 o acid and 8.5 cur of acetone. One allows to cool to 20 C then extracts with ether. The combined organic extracts are 10 washed with~2K ammonia then with water until neutral, dried, then concentrated todryness under reduced pressure. One obtains an oil which one purifies by distillation, that is 1.7 g of product, B.Pt/rjgQ = 108°C.

Ca]p° = +3° i 1° (C * 1% -ethanol).

N.M.R. SPECTRUM (CDOlj) Peak at 1.5 p.p.m. characteristic of the hydrogen of the hydroxyl.

Peaks at 1.08-1.2 p.p.m. characteristic of the hydrogens of the methyl at 1.

Pecik at 3.58 p.p.m. characteristic of the hydrogen at 2.

Peak at 1.58 p.p.m. characteristic of the hydrogen at 3· Peaks at 0.85-0.95 p.p.m. characteristic of the hydrogens of the methyls at 3 and 4-.

Example 30: 3-methyl-2-(R) butanol.

One heats to 50°C, under agitation for 16 hours, 16 g of (1R, 58) 6,6-dimethyl-4-(R)-C3'-methyl'-2,(R) butoxy)— 3-oxabicyclo-[3.1.0]-hexan-2-one obtained in Example 18, 70 cm of 2N hydrochloric acid and 10 cur of acetone. One 53 »48736 allows: to cool to 20°C and one extracts with ether. The combined organic extracts are washed with «v2N ammonia and f with water until neutral, dried and concentrated to dryness ' under reduced pressure. One obtains 7 g of crude product ! 5 which one distils to obtain 1.5 g of oil, B.Pt./^gQ = 110°G. [a3^° = -4.5° 1 1° (C = 1.3% ethanol) H.M.K. oPECTRUM (CDCl^ Peaks at 1.1-1.2 p.p.m. characteristic of the hydrogens of the methyl at 1.

Peak at 1.67 p.p.m. characteristic of the hydrogen of the OH.

Peak at 3.58 p.p.m. characteristic of the hydrogen at 2.

Peak at 1.6? p.p.m. characteristic of the hydrogen at 3· Peaks at 0.85-0.97 p.p.m. characteristic of the hydrogens of the methyls at 3 and 4.

Example 31: 2-(S)-hydroxy-3,3-dimethyl-butyrolactone or (S) pantolactone.

One heats to reflux for 2 hours and under agitation 20 g of (IK, 5S) 6,6-dimethyl-4 •(R)-C3‘,31-dimethylbutyrol- actone-21-(6)-oxy]-3-oxa-bicyclo-(3.1.03-hexan 2-one, 5 z 20 obtained in Example 14, 100 cm of water, 100 cm of dioxan and 1 g of monohydrated paratoluene sulphonic acid. One cools to ambient temperature, adds 100 cm^ of water and concentrates by distillation under reduced pressure to about 60 cm'’. One saturates with sodium chloride and extracts 25 with methylene chloride. The dried organic phases are concentrated at k0°C under reduced pressure. One recovers a white product which is a mixture of (IE, 5S) 6,6-dimethyl-4 (H)-hydroxy- y-oxabicyclo- 1'3· 1.0]—hexan—2-one (or product A) 54 48736 and of expected product. One dissolves it at reflux in 40 cm of water. After cooling to ambient temperature one initiates crystallisation of the product A with a few crystals and agitates for 16 hours. One vacuum-filters, 5 washes with water, concentrates the filtrate to dryness and treats as before by cooling to 0° + 5° for 2 hours to recover some more product A. The last filtrate concentrated to dryness is chromatographed on silica and eluted with a mixture of toluene and ethyl acetate (6:4).

One recovers 7 g of white crystals containing more product A. One takes up 6 g thereof which one dissolves in 50 cm^ of water and 2 cm^ of ethanol, one adds 25 cm^ of sodium bisulphite solution and agitates vigorously for 2 hours at ambient temperature. One saturates with sodium 15 chloride and extracts with ethyl acetate. The dried organic phases are concentrated to dryness under reduced pressure at 40°C. The a.5 g of product obtained are sublimed at 90°0 under 0.1 nun of mercury. One obtains 2.7 g of expected product. M.Pt. *90°C, 20 20 = +/1.7.50 t 1° (C = 250 - water) H.K.R. Ql^OTRUH (CDClj) Peaks at 1.08-1.22 p.p.m. characteristic of the hydrogens of the geminal methyls.

Peak at^3.77 p.p.m. characteristic of the hydrogen of the 25 hydroxyl.

Peak at 3·98 p.p.m. characteristic of the hydrogens of the methylene at 4 of the cyclopentyl. 55 48736 ' Peak at 4.18 p.p.m. characteristic of the hydrogen at position 2 of the cyclopentyl.

Example 32: 2-(B) hydroxy·»?,3-dimethyl-butyrolactone or (R) pantolactone. : 5 One heats to reflux for 2 hours and under agitation 9 g of (1R, 5S)-6,6-dimethyl-4(R)-[3',5'-dimethyl-hutyrolaotone— 2' (R)-oxy]-J-oxabicyclo-Cj.l.O]—hexan-^S-one obtained in Example In, 90 cm of methanol and 85 mg of monohydrated / paratoluene sulphonic acid. The reaction mixture is con-10 centrated to dryness under reduced pressure then chromatographed on silica eluting with a mixture of toluene and ethyl acetate (6:4). One recovers 1.5 g of yellow crystals which are sublimed at 90-°-100°C under 0.1 mm of mercury. One obtains 1 g ^of hygroscopic white crystals of the product 15 expected. M.Pt. = 89°C.

CaJp0 = -50° - 1° (C = 1.96%, water) Example 35: (5R) (3aB) (4S) (7R) (?a3) 3-C(l,5) 2'S) (5'R)- 21-isopropyl -51-methylcyclohexyloxyl-tetrahydro-4.7-methano - isobenzofur-iir-l-one.

For one and a half hours one heats to reflux under agitation l.(i6g of (3R) (3aR) (4S) (7R) (7aS)-3-hydroxy-tetrahydro-4,7-methano-isobenzofuran~l-one, 2.34- g of 1-menthol, 50 mg of paratoluene sulphonic acid and 42 cnr of benzene. After returning to ambient temperature the reaction 25 mixture is concentrated to dryness under reduced pressure.

One obtiins 4.41 g of oil which is chromatographed on silica eluting with a mixture of benzene and ethyl acetate (95s3)-One obtains 2.76 g of expected product (M.Pt. = 54°C) and 56 · 48736 92 mg of the diastereoisomer 8 (M.Pt. * 100°C).

I.B. SPECTRUM (CHClj) C = 0 Y-lactone absorption 1769 cm-1 max. 1760 cm""1 infl. geminal methyls 1390 cm"1 - C - 0 - C (ether) 1117 cm"1 N.M.R. SPECTRUM (CDClj) Peak at 0.66-0.8-0.92 p.p.m. characteristic of the hydrogens of the methyls of the isopropyl.

Peaks at 0.88-0.97 p.p.m. characteristic of the hydrogens of the methyl of the menthol.

Peaks at 2.67-3*67 p.p.m. characteristic of the hydrogen at 1' of the menthol and of the hydrogens at 3a, 4, 7 and 7a of the lactone.

Peaks at 5.03-5.06 p.p.m. characteristic of the hydrogen at 3 of the lactone.

Peak at 6.22 p.p.m. characteristic of the ethylenic hydrogens. CIKOULaR DIOHKOIbM (dioxan) I.ax. at 217 nm Δε = +2.3 20 [alp0 - -120.5° -2° (0*1% benzene) Example 3ft: (5R).(5aR). (hQ). (7R)(7a3) 5-C(l'R). (2'S)- (5'R) ~2'-isopropyl-51-methylcyclohexyloxyl-tetrahydro - 4.7-methano-isobenzofuran-l-one (product R) and (3H) (5aR) 0-S) (7R) (7aS) 3-[(l'S)(2,R)(5,S)-2l-isopropyl-25 5l-methylcyclohexvloxy3-tetrahydro-4-,7-methano-i3obenzofuran~ 1-one (product a).

One heats to reflux for 2 hour;; 6.65 g of (3R)( 3aR)(^6)-('/R) ( 7ao) -J-hydroxy -tetrahydr0-4, ‘/-mo ihano -isobenzofuran - 57 '48736 1-one, 9·37 s of racemic menthol, 200 mg of monohydrated x paratoluene sulphonic acid and 170 cnr of benzene. The reaction mixture is concentrated to dryness under reduced pressure at 40°C and one obtains 16.17 E °f brown oil.

To separate the constituents ol' this crude product one carries out one chromatography under pressure and one chromatography at atmospheric pressure. One elutes with a mixture of benzene and ethyl acetate (96:5) for the first and (98:2) for the second. One recovers 3.58 g of white 10 product, M.Pt. = 53°C, corresponding to the product R, 4.25 g of a thick oil corresponding to the product O and 0.57 E of a white wax constituted by a mixture of the products K and 8.

Diastereoisomer R: 15 H.I-l.R. JlhCTRUM (CDClj) Peaks at 0.7-0.82-0.93 p.p.m. characteristic of the hydrogens of the methyls of the isopropyl.

Peaks at 0.88-0.97 p.p.m· characteristic of the hydrogens of the methyl.

Peaks at 5.05-5.07 p.p.m. characteristic of the hydrogen at 3 of the lactone.

Peak at 6.23 p.p.m. characteristic of the ethylenic hydrogens. Feaks at 2.67-3.67 p.p.m. characteristic of the hydrogen at 1 of the menthol and of the hydrogens at 4, 3a, 7 and 7a 25 of the lactone. [«]p° = -113.5° - 3° (C = 0.66/0 benzene). 58 48736 Diastereoisomer S: H.M.R. SPECTRUIt (CDClj) Peaks at 0.75-0.87-0.98 p.p.m. characteristic of the hydrogens of the methyls of the isopropyl.

Peaks at 0.92-0.87 p.p.m. characteristic of the hydrogens of the methyl.

Peaks at 4.92-4.95 p.p.m. characteristic of the hydrogen at 3 of the lactone.

Peak at 6.23 p.p.m. characteristic of the ethylenic hydrogens.

Ca3p° = -74° - 5° (C = 0.3¾ benzene).

Example 35: ClR) (2S) (5R) 2-isopropyl-5-methyl-cyclohexanol.

One heats to reflux for 1 hour under agitation 1.78 g of (JR) (3aR) (4S) (7R) (7aS)-3-C(l,R)(2'S)(5'R)-2,-isopropyl- 51-methylcyclohexyloxy]-tetrahydro-4,7-methano-isobenzofuran -15 1-one, 25 cv? of water, 300 mg of monohydrated paratoluene z z sulphonic acid and 40 cm of dioxan. One adds 100 cm of water and distils off, at 40°G under reduced pressure, most of the dioxan. One extracts with ethyl ether, washes with water, dries and concentrates to dryness under reduced 20 pressure to obtain 1.12 g of oil. The crude product is chromatographed on silica and eluted with a mixture of benzene and ethyl acetate (95:3). One isolates 750 mg of expected product, H.Pt. <50°G. l.R. bPECTRUri (CHOI,) - 3 25 Geminal methyls: absorption at 1370 cm ^ -1 alcohol function : absorption at 3^9*5 cm t 3610 cm ^ [α3£ϋ = -ί9° - 2.5° (C = 0.7,V ethanol) 59 i 48736 Example 36: (IB. 5S) e.e-dimethyl-qaO-CCl’RXR'SXq'R:)-21-isopropyl-51-methylcyclohexvloxy]-5-oxabicyclo-C3.1.03 -hexan-2-one (diastereoisomer R) and (1R. 5S) 6,6-dimethyl-4R-[(l's)(2'R)(5'S)-2,--isopropyl-· 5 5l-methyl-cyclohexvloxy3-'3-oxabicyclo-C3.1.03~hexan-2-one (diastereoisomer S).

One heats to reflux, for 1 hour 30 minutes, under agitation, 7°3 g of (1R,5S) 6,6-dimethyl-A-(R)-hydroxy- 3-oxabicyclo-[3.1.03-hexan-2-one, 100 cm^ of benzene, 7.8 g 10 of racemic menthol and 100 mg of paratoluene sulphonic acid.

The reaction mixture is cooled to ambient temperature, x neutralised by the addition of 2 cm of triethylanane then concentrated to dryness under reduced pressure. One obtains 15.7 g of colourless oil. This is chromatographed under 15 pressure on silica eluting with a mixture of methylene chloride and acetonitrile (98;2).

One recovers 5»74 g of a crystalline product, M.Pt.=83°C, corresponding to the diastereoisomer R and 5·87 g of an oil corresponding to the diastereoisomer S.

The diastereoisomer R has the following characteristics: I.R. blEC'TRUM (CHClj) Absence of OH.

C = 0 Y-lactone 1795 cm-·*· max. 1748 cm-'L infl. geminal methyls 1385 cm M.M.R. oPJOTRUM (CDClj) Peak at 2.u p.p.m. characteristic of the hydrogens at 1 and 5 of the 1-ictonic part. 60 48736 Peaks at 1.15-1.18 p.p.m. characteristic*of the hydrogens of the methyls of the lactonic part; .

Peak at 5.35 p.p.m. characteristic of the hydrogen at 4 of the lactonic part.

Peak at 3.58 p.p.m. characteristic of the hydrogen at 1 of the menthol.

Peaks at 0.82-0.99 p.p.m. characteristic of the hydrogens of the methyl at 5 of the menthol.

Peaks at 0.75-0.99 p.p.m. characteristic of the hydrogens of 10 the methyls of the isopropyl.

CIRCULAR PICHHOISM Max. 224 nm Δε « -3-65 [<χ]ρ° = -180° - 2.5° (C = 1.1?: benzene).

The diastereoisomer S has the following characteristics: % 15 I.R. SPECTRUM (CHClj) Absence of OH C = 0 Y-lactone 1795 cm-·1· 1748 cm-1 geminal methyls 1385 cm 20 N.M.R. SPECTRUM (CDCl^) Peak at 2.0 p.p.m. characteristic of the hydrogens at 1 and 5 of the lactonic part.

Peaks at 1.17-1.18 p.p.m. characteristic of the hydrogens of the methyls of the lactonic part. , 25 Peak at 5.18 p.p.m. characteristic of the hydrogen at 4 of the lactonic part.

Peak at 3·'·'3 p.p.m. characteristic of the hydrogen at 1 of the menthol. 61 - 48736 Peaks at 0.75-0.98 p.p.m. characteristic of the hydrogens of the methyl at 5 of the menthol.

Peaks at 0.75-0.82 p.p.m. characteristic of the hydrogens of the methyls of the isopropyl.

CIRCULAR DICHROISH max. at 224-225 nm de = -3*20 Ca]j° * -33° 1 2.5° (0 = 0.4254 benzene).

Example 37; (1R)(2S)(5R) 2-isopropyl-5-methyl- cyclohexanol.

For two hours one heats to reflux under agitation 10 1 g of (1R,5S) 6,6-dimethyl-(4R)-C(l,R)(2,S)(5,R)-2,-isopropyl- 3'-methylcyclohexyLoxy]-3-oxahicyclo-[3.1.0]-hexan-2-one, x z 10 cm^ of water, 10 cm of dioxan and 100 mg of paratoluene sulphonic acid. One concentrates, dilutes with water and drives off mgst of the dioxan by distillation under reduced 15 pressure. One extracts with isopropyl ether, dries and concentrates to dryness under reduced pressure.

One obtains 430 mg of oil. One chromatographs on silica and elutes with a mixture of cyclohexane and ethyl acetate (7:3).

One isolates 350 mg of product identical to natural menthol, M.Pt. <50°C. [a]2° = -54.5° - 1° (C = 2% ethanol).

Example 38: (1S)(2R)(5S) 2-isopropyl-9-methylcyclohexanol.

For 2 hours one heats to reflux under agitation 5 g 25 of (1R, 5E) 6,6-dimethyl-4R-[(llb)(2'Ii)(5'8)-2,-isopropyl- 5,-methylcyclohexyloxy]-3~oxabicyclo-[3.1.0]-hexan-2-one, . a z 25 cur of dioxan, 25 car of water and 100 mg of paratoluene sulphonic acid. One distils off under reduced pressure most 62 48736 of the dioxan, dilutes with water and extracts with isopropyl ether. The organic phase is dried and concentrated to dryness under reduced pressure to give ¢.8 g of oil.

After chromatrography on silica one obtains 1.7 g of expected 5 product, H.Pt. 450°C.

CcJp0 = +4G.50 * 2.5° (C - 0.35% ethanol). 63 p Sheets IV-1 .* 4873 6 DIAGRAM 1 "V HI) Optical isomer of a lactone containing one or more chiral centres of unequivocal configuration (R) or (S) Optical isomer of / \ an alcohol or phenol / \ Racemate of an alcohol ZOH (III) containing / \ or phenol ZOH (III) one or more chiral / \ containing one or more centres of unequivo- / \ unresolved chiral centres, cal configuration / \ (R) or (S) / \ m-f > ^ X0>° I. JB Ji.

Mixture of "n" dinstereo- with retention of con- isomers including (1^) figuration of the p% n = 21 for an unresolved and of the molecule ZOH chiral centre in ZOH O n = 2 for 2 unresolved chiral centres in ZOH n = 2X for "x" unresolved chiral centres in ZOH Physical treatment such as chromatography or crystallisation IA and n-1 other diastereoisomers 64 .· ' Sheets IV-2 DIAGRAM II 48736 ZOH (III) Optical isomer of an alcohol or a phenol containing one or more chiral centres of unequivocal configuration (R) or (S) ,N< >° / \ x. > Optical isomer of a / \ Racemate of a lactone II lactone II containing / \ containing one or more one or more chiral \ unresolved chiral centres centres of unequivocal \ configuration (r) or (s) ZO / 20v /Γ'λ .

C*° JA *C with retention of con- Mixture of n diastereo- figuration of the isomers including (I.) residues of the lactone and of the molecule ZOH _ -1 -n_ __ , . n * 2 for an unresolved chiral centre in the • lactone 2 n = 2 for 2 unresolved chiral centres in the lactone n = 2X for "x" unresolved chiral centres in the lactone Physical treatment such as chromatography or crystallisation V IA and n-1 other diastereo-iiioraers. 65 - . Sheets IV-3 ^ 487 36 Ο DIAGRAM III ZOH possessing an unresolved asymjetric centre XO A"\ > (II) Optical isomer of lactone (II) possessing one or more chiral ' centres of well-defined con- \/ figuration, either (R) or (S).

Z°\ ""V0 ' Gy Mixture of 2 diastereo-n / isomeric ethers (Ιπ + IF) of the type IA Separation by physical treatment such as chromato-v graphy or crystallisation. v\ I„ (containing one IF (containing the other or the two enantiomers enantiomer of the residue of the residue ZO ZO Acid solvolysis Acid solvolysis enantiomer of ZOH the other enantiomer of (for example (S) ) ZOH (for example (R) ) 66 K . X Sheets IV-4 DIAGRAM IV 48736 ”°x<\ y* Lactone containing one or more chiral centres and which, bearing in mind the configuration of these centres, is presented in racemic form ZOH (III) Optical isomer of a structure III containing one or more chiral centres of unequivocal \1/ configuration (R) or (S) /f 'y 0 C. C Mixture of 2 diastereoisomeric ethers (I™ and Ir) of the ° type IA F G Separation by physical treat-v 1 ment (such as chromatography ^ or crystallisation) L·: ^ Ij, containing one of Ip containing the other tne two enantiomers enantiomer of the of the lactone residue lactone residue Acid Acid ν' solvolysis solvolysis enantiomer of the lactone the other enantiomer of the lactone. 67

Claims (5)

1. Optically active compounds of the general formula X: ζονΓA Ό-Η C=0 (I) in which formula the symbol A represents a hydrocarbon chain 5 containing from 1 to 10 links, this chain being capable of containing one or more heteroatoms, or one or more unsaturations, all of the links constituting the chain being capable of representing a mono or polycyclic system, including a system of the spiro or endo type, the chain A being capable of 10 containing one or more chiral atoms or else the lactone component being''capable of displaying a chirality due to the dissymmetric spacial configuration of the whole of the molecule and the symbol Z represents either a primary, secondary or residue/ tertiary alcohol/containing at least one asyiimefcric carbon 15 atom or a substituted phenolic residue containing at least one asymmetric carbon atom, or an alcoholic or substituted phenolic residue of which the chirality is due to the dissymmetric spacial configuration of the whole of the molecule, it being understood that Z cannot represent a (R) or (S) 20 a-cyano-3-phenoxy benzyl radical when A represents a hydrocarbon chain of structure H,C CH, 3\ / 5 B\0A0^a (d) | | (iO 68 48736

2. Compounds according to the formula I of Claim 1 in which the chain A contains at least one asymmetric carbon atom and in which the two different atoms or radicals which form the substituents on the asymnetric carbon atom or atone are selected 5 indiscriminately from one or other of the following groups: a) the group constituted by hydrogen, the halogen atoms, the nitro group, the alkyl radicals containing from 1 to 10 carbon atoms, the cycloalkyl radicals containing from 3 to 6 carbon atoms, the phenyl radical, the phenyl radicals 10 substituted by at least one of the members, of the group constituted by the halogen atoms, the alkyl radicals containing from 1 to 6 carbon atoms, the carboxyl group, the nitrile group, the group -CHO, the acyl groups, the group -C-CF,, W 9 0 the groups S-alk and O-alk in which alk represents an alkyl 15 group containing from 1 to 6 carbon atoms, b) the group constituted by the radicals : s '''"I s in which represents hydrogen, an alkyl radical containing from 1 to 6 carbon atoms, 20 the radical : n—λ i 5 -N^ ^ H3 in which S2 and Rj, being the same or different, panh an alkyl radical containing from 1 to 6 carbon atoms, or in which R2 and R^ represent together with the nitrogen atom to which they are bonded, a heterocycle containing 6 atoms, 10 or else R2 represents a carboxyl group and R^ represents a benzyl radical.

3. · Compounds according to one of Claims 1 or 2, characterised in that the chain A is an aliphatic hydrocarbon chain containing 2 or 3 carbon atoms. i 4. -Q ^ •-Q R" representing an alkyl radical containing from 1 to 6 carbon atoms, an alkenyl radical containing from 2 to 6 carbon atoms, an alkynyl radical containing from 2 to 6 carbon atoms or a cyano radical. 15 14.. The compounds or mixtures of compounds of general formula I of which the names are as follows: - mixture of'(lR,5S) 6,6-dimethyl-4(R)- Cl (S)-2-methyl— 4-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy3-3-oxa-bicyclo — (3-1-C)-hex;m-2-one and (1R,5S) 6,6-dimethyl-4(R)-Cl(R)- 20 -2-mothyl“4-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy]- 3-oxa"bicyclo-(3.1.0)-hexan-2-one, - mixture of (1C,SR) 6£-dimethyl-4(K)_Cl(S)-2-methyl-4-oxo- 3-( 2-:;ropen-l-yl)-cyclopent-2-enyloxy]-3~oxa-hicyclo-(3.1-0)^ hexan-2-one and (IS,SR) 6,6-dimethyl-h(R)-[l(R)-2-methyl— 72 4873 β 4-οχο-3-(2-propen-l-yl)-cyclopent-2-enyloxy]-3-oxa-bicyclo- (3.1.0)-faexan-2-one, - (1R,3S) 6,6-dimethyl-4(R)-Cl(S)-2-methyl-4-oxo-3-(2-propen--1-yl)-cyclopent-2-enyloxyD-3-oxa-bicyclo-(3.1.0)-hexan-2-one, 5 - (1S,5R) 6,6-dimethyl-4(R)-[l(R)-2-methyl-4-oxo-3-(2-propen- -1-yl)-cyclopent-2-enyloxy3-3-oxa-bicyclo-(3.1.0)-hexan-2-onee 15. CLR,5S) 6,6-dimethyl-4(R)“t31,31-dimethyl-butyrolactone -2'-(S)-oxy]-3-oxa-bicyclo-[3.1.0]-hexan-2-one, - (1R,5S) 6,6-dimethyl-4(R)-[3',3'-dimethyI-butyro1actone- 10 2'-(R)-oxy]-3-oxa bicyclo-C3.1.0]-hexan-2-one, as well asthe mixture of the two latter compounds. 16. (38) (3aR) (4S) (7R) (7aS) 3-CCl'H) (2'S) (5'R) 2'-iso-propyl-3'-raethyl-cyclohexyloxy]-t etrahydro-4,7-methano-iso-benzofuran-1-one. 15 (3R)(3aR) (4S) (7R) (7aS) 3-C(l'S) (2Ή) (5'S) 2’-iso- propyl-5'-methyl-cyclohex ylbxy3-tetrnhydro-4,7-methano-iso-benzofuran-l-one, as well as the mixture of the two latter compounds, - (1R,5S) 6,6-dimethyl-lf(R)-[(l'R) (2'S) (5'R)-2'-isopropyl- 20 <31-methyl-cyclohexylDxyl·-3-oxa-bicyclo-C 3.1.Q3-hexan-2-one, and - (1R,5S) 6,6-dimethyl-4(R)-C(l'ii)(2,R)(5,B)-2,-isopropyl-51-methyl--cyclohexyloxy]-3-oxa-bicyclo-C 3.1.0J-hexan-2-one, as well as the mixture of the two latter compounds. 17. Process for preparing the compounds of general formula I, as defined in Claim 1, characterised in that a lactone compound of general formula II ·' 73 - 48736 θ' C* (II) in which formula X represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms and A keeps the meanings of Claim 1, is reacted in the presence of an adid, 5 with an alcohol or a substituted phenol of general formula III: . ZOH (III) in which formula Z keeps the meanings of Claim 1, to obtain - either a compound of formula (I), called (1^) in which all the chiral atoms have well defined configurations 10 . ZO \ λη ) >o < (½) XcT when the lactone and the alcohol or the phenol have one or more chiral atoms of well-defined configurations - or a mixture of diastereoisomers, called (Ig), when the 15 lactone is a well-defined optical isomer and the chiral centres of the alcohol or of the phenol are not all of unequivocal configuration, - or a mixture of diastereoisomers, called (Iq), when the alcohol or the phenol is a well-defined optical isomer and 20 the chiral atoms of the lactone are not all of unequivocal configuration, then there are separated’ by a physical method the diastereo-isomeric ethers contained either in the mixtures of the type (Ig) 74 48736 or in the mixtures of the type (Ig) and, especially, the ether called (IA), of which the chiral centres are all of unequivocal configuration. 18. Process for preparing the compounds of general formula I 5 according to Claim 17, characterised in that the acid agent is selected from the group constituted by sulphonic acids, perchloric acid and 5~sulphosalicylic acid. 19. Process for preparing the compounds of general formula I according to one of Claims 17 or 18, characterised in that 10 the water formed during the condensation of the alcohol or of the phenol and of the lactone compound is removed by azeotropic decantation at reflux of a solvent aiected from the group constituted by the chlorinated solvents, aromatic or aliphatic hydrocarbons and ethers. 20. Process for preparing the compounds of general formula I according to Claims 17 or 18, characterised in that the condensation of the alcohol or of the phenol and of the lactone compound is carried out under reduced pressure and without solvent. 21. Process for preparing the compounds of general formula I according to one.of Claims 17 to 20, characterised in that the separation of the diastereoisomeric compounds I is carried out by crystallisation or chromatography. 22. Preparation process according to any one of Claims 17 25 to 21, characterised in that the compound of formula II is the racemic or optically-active lactone of a cis 2,2-dimethyl" 5-(dihydroxy-methyl)cyclopropane-l-carboxylic acid, the compound of formula III is racemic or optically-active 75 -48736 1-hydroxy-2-methyl-3-(2-propen-l-yl)-cyclopent-2-en- 4-one and in that the possible separation of the diastereoisomeric compounds I is carried out by crystallisation from an organic solvent. 23. Preparation process according to any one of Claims 17 to 2i, characterised in that the compound of formula II is the racemic or optically-active lactone of a cis 2,2-dimethyl- 3-(dihydroxymethyl)-cyclopropane-1-carboxylic acid, the compound of formula III is racemic or optically-active 10 2-hydroxy-3,3-dimethyl-butyrolactone (or pantolactone) and the possible separation of the diastereoisomeric compounds is carried out by chromatography. 24. Preparation process according to any one of Claims 13 to 21, characterised in that the compound of formula II is i 15 racemic or optically-active 3-hydroxy-tetrahydro-4.,7~methano — isobenzofuran-l-one, the compound of formula III is racemic or optically-active menthol and the possible separation of the diastereoisomeric compounds is carried out by chromatography. 2o 25. Preparation process according to any one of Claims 17 to 21, characterised in that the compound of formula II is the racemic or optically-active lactone of a cis 2,2-dimethyl - 3-(dihydroxymethyl)-cyclopropane-l-carboxylic acid, the c impound of formula III is racemic or optically-active menthol 25 and the possible separation of the diastereoisomeric compounds is carried out by chromatography. 26. Use of the compounds of general formula (I), as defined in Claim 1, in resolving the compounds of formula (II) 76 48736 or (III), which use consists in reacting a lactone compound of general formula (II) XO \P V (H) in which formula X represents a hydrogen atom or an alkyl 5 radical containing from 1 to 4 carbon atoms and A keeps the meanings of Claim 1, in the presence of an acid, with an alcohol or a substituted phenol of general formula (IIl)s ZOH (III) 10 in which formula Z keeps the meanings of Claim 1, to obtain either a mixture of diastereoisomers, called (Ig), when the lactone is a well-defined optical isomer and the chiral centres of the alcohol or of the phenol are not all of fixed configuration, or a mixture of diastereoisomers, called 15 (Ιβ), when the alcohol or the phenol is a well-defined optical isomer and the chiral atoms of the lactone are not all of unequivocal configurations, and consists in separating by a physical method the diastereoisomeric ethers contained either in the mixtures of the type (Ig) or in the 20 mixtures of the type (Iq) and especially the ether called (IA) of which the chiral centres are all of unequivocal configuration and characterised in that each of the diastereoisomeric ethers thus separated is subjected to hydrolysis or alcoholysis in acidic medium, to obtain either 25 a compound of the type II and the other diastereoisomers 77 48736 arising possibly from the existence of several asymetric centres, or a compound of the type III and the other diastereoisomers arising possibly from the existence of several asymetric centres, these compounds II and III and 5 the various corresponding diastereoisomers containing chiral centres of unequivocal configuration, in other words chiral centres resolved with respect to the corresponding chiral centres of the starting alcohols or phenols, or with respect to the chiral centres of the starting lactone compounds. 27. Use according to Claim 26 which consists in reacting the lactone of cis 2,2-dimethyl-3S-(dihydroxymethyl)-cyclo-propane-lR-carboxylic acid, in the presence of an acid agent, with l(RS)-hydroxy-2-methy1-3-(2-propen-l-yl)-cyclopent--2-en-*-one and in separating by crystallisation from iso- ς. 15 propanol (1R,5S) 6,6-dimethyl-4(R)-[l(R)-2-methyl-4-oxo- 3- (2-propen-l-yl)-cyclopent-2-enyloxy]-3-oxa-bicyclo-(3.1.0)-hexan-2-one from (1R,SS) 6,6-dimethyl-4(H)-[l(S)-2-methyl— 4- oxo-5-(2-propen-l-yl)cyclopent-2-enyloxy]- 3-oxa-bicyclo-(3-1.0)-hexan-2-one and is characterised in that the latter 20 isomer "IS" is subjected to solvolysis in acidic medium to obtain 1(d)-hydroxy-2-methy1-3-(2-propen-l-yl)-cyclopent--2-en-4-one. 28. Use according to Claim 27 t characterised in that the solvolysis is carried out in aqueous medium in the presence 25 of hydrochloric acid. 29. Use according to Claim 27, characterised in that the solvolysis is carried out in methanol in the presence of paratoluene sulphonic acid. 78 48736 30. Use according to Claim 26, which consists in reacting the lactone of dl-cis-2,2-dimethyl-3S-(dihydroxymethyl)-cyclopropane-l-carhoxylic acid, in the presence of an acid agent, with l(S)-hydroxy-2-methy1-5-(2-propen-l-yl)-cyclo- 5 pent-2-en-^-one and in separating by crystallisation from isopropyl ether (1H,5S) 6,6-dimethyl-h(S)-[l(S)-2-methyl- 4-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy]-J-oxa-bicyclo- (3.1.0)-hexan-2-one from (1R,5S) 6,6-dimethyl-4(R)-Cl(S)--2-methyl-4-oxo-3-(2-propen-l-yl)-cyclopent-2-enyloxy]-3-Oxa -10 bicyclo^3-1-0)-hexan-2-one and is characterised in that the "4SM isomer is subjected to solvolysis in acidic medium to obtain the lactone of cis 2,2-dimethyl-3S-(dihydroxy-methyl)-cyclopropane-lR-carboxylic acid. 31. Use according to Claim 30, characterised in that the 15 acid agent used is hydrochloric acid. 32. Use according to Claim 26 which consists in reacting the lactone of cis 2,2-dimethyl-3S-(dihydroxymethyl)-cyclo-propane-lR-carboxylic acid, in the presence of an acid agent, with 2(R,S)-hydroxy-3,3-diraethylbutyrolactone and in 20 separating hy chromatography (1R,S3) 6,6-dimethyl'h(R)-[3',3'-dimethylbutyrolactone-2'-(3)-oxy]-3-oxa-bicyclo-C3.1.0]-hexan-2-one from (1R,5S) 6,6-dimethyl-4(R)-C5,>5,“ -dimethylbutyrolactone-2'(R)oxy] -3-oxa-bicyclo -E3.1.0]-hexan--2-one and is characterised in that one or other of these 25 isomers is subjected to solvolysis, in acidic medium, to obtain 2(S)-hydroxy -3,3-dimethylbutyrolactone or 2(R)--hydroxy-3,3-dimethylbutyrolactone according to the isomer selected. 79 48736 33. Use according to Claim 32, characterised in that the solvolysis is carried out in aqueous or methanolic medium, in the presence of paratoluene sulphonic acid. 34. Use according to Claim 26, which consists in reacting 5 (3R) (3aH) (as) (7B) (7aS) 3-hydroxytetrahydro-a,7~methano- isobenzofuran-l-one with (R,S)menthol, in the presence of an acid agent and in separating by chromatography (3R) (3aR)- (43) (7R) (7aS) 3~ ((11R) ( 2' S) (5' R)~ 2'-isopropyl-5’-methyl- · 4 cyclohexyloxyl-tetrahydro—^,7-methano -isobenzofuran-l-one 10 from (3R) (3aR) (4S) (7R) (7aS) $-C(l'S)(2*R) (5'S)-2'- ^ -isopropyl-5'-methylcyclohexyloxyl·-t etrahydro-K,7-methano -isobenzofuran-l-one and is characterised in that one or other 1 of these isomers is subjected to solvolysis in acidic medium to obtain (R) or (s) menthol. 35. Use according to Claim which consists in reacting the lactone of cis 2,2-dimethyl-30-(dihydroxymethyl)-cyclo-propane-lR-carboxylic acid, in the presence of an acid agent, with (R,o) menthol and in separating by chromatography (1R,53) 6,6-dimethyl-(4R)-C(11R)(2'3)(5'R)“2'-isopropyl-20 51-methylcyclohexyloxyD-3-oxa-bicyclo-(3.1.03-hexan-2-one from (1R,5S) 6,6-dimethyl-4R-[(l'S)(2'R)(5,S)-2'-isopropyl-5'-methyl-cyclohex yloxy]-3-oxa-bicyclo-C3.1.0]-hexan-2-one and is characterised in that one or other of these isomers is subjected to solvolysis in acidic medium to obtain (R) 25 or (S) menthol. 36. Use according to Claim 34 or 35, characterised in that the solvolysis is carried out in aqueous medium, in the presence of paratoluene sulphonic acid. 80 48736 1 37. Compounds as claimed in claim 1, other than those claimed in any one of claims 14 to 16 as herein specifically disclosed in any one of Examples 1 to 38. 38. A process for the preparation of compounds as claimed < 5 in claim 1 substantially as herein described. 39. A process for the preparation of compounds as claimed in claim 1 substantially as herein described with reference to the Examples. 40. Compounds as claimed in claim 1 whenever prepared by 10 a process as claimed in any one of claims 17 to 25 , 38 and 39. 41. A process for the preparation of a well defined optical isomer of a compound of formula II or III as defined in claim 17 which comprises subjecting a compound as claimed in claim 15. to hydrolysis or alcoholysis in acidic medium. 42. A process as claimed in claim 41 substantially as herein described. 43. A process as claimed in claim 41 substantially as herein described with reference to the Examples. 20 44. A process as defined in claim 26 for resolving into optical isomers a compound of formula II or III substantially as herein described. 45. A process as defined in claim 26 for resolving into optical isomers a compound of formula II or III substantially 25 as herein described with reference to the Examples. Dated this 8th day of August 1979, »£^ents, (signed)

4. Compounds according to one of Claims 1 or 2, characterised in that the chain A is an aliphatic hydrocarbon chain interrupted by a heteroatom. 5. Compounds according to Claims 1 or 2, characterised in : that the chain A is an aliphatic hydrocarbon chain containing 20 one double bond. 6. Compounds according to one of Claims 1 or 2, characterised in that the chain A is a monocyclic hydrocarbon chain containing from 3 to 6 carbon atoms, possessing, possibly, one unsaturation. 25 7· Compounds according to one of Claims 1 or 2, 70 48736 characterised in that the chain A is a bicyclic hydrocarbon chain containing iron 5 to 10 carbon atoms, possessing, possibly, one unsaturation. 8. Compounds according to Claim 2, characterised in that 5 the chain A has as its structure: H3\ /\ 9. Compounds according to Claim 2, characterised in that the chain A has as its structure: I I 10. and Y', being the same or different, representing hydrogen, fluorine,. chlorine or bromine atoms or an alkyl radical containing from 2 to 6 carbon atoms or else Y and Y' being capable of forming together with the carbon atom to which they are bonded a carbon homocycle containing from 3 to 7 carbon 15 atoms. 10. Compounds according to Claim 2, characterised in that the chain A has as its structure: R C- I I R representing an oxygen or sulphur atom, or a group -HH or 20 -NR', R' being an alkyl radical containing from 1 to 6 carbon 71 - 48736 atoms. 11. Compounds according to one of Claims 1 or 2, characterised in that the symbol Z has as its structure: C!3X Xk 12. Compounds according to any one of claims 1 or 2, characterised in that the symbol Z represents the residue of a cyanhydrin. 13. Compounds according to any one of Claims 1 or 2, characterised in that the symbol Z has as its structure:

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