GB1584421A - Process for the manufacture of tertiary optically active aliphatic compounds - Google Patents

Description

(54) PROCESS FOR THE MANUFACTURE OF TERTIARY, OPTICALLY ACTIVE ALIPHATIC COMPOUNDS (71) We, F. HOFFMANN-LA ROCHE & CO.

AKTIENGESELLSCHAFT, a Swiss Company, of 124--184, Grenzacherstrasse, Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The invention relates to a process for the manufacture of tertiary, optically active aliphatic compounds.

The process in accordance with tHe invention is characterised in that a compound of the general formula

is linked with the aid of Grignard or Wittig reaction with a compound of the general formula

in which one of the substituents X and Y represents a group Z-CH2-, wherein Z denotes a leaving group, and the other represents halogenomethyl or formyl, and wherein the dotted lines represent additional bonds which may be present, m and n each represent 0 or I and the sum of m and n is 1, and wherein R1 represents a hydroxymethyl group optionally substituted by a carbonyl-free group cleavable by hydrogenolysis or acid treatment, an acetalised formyl group or an optionally esterified carboxy group, or, where X represents a substituted sulphonyloxymethyl group and Y represents a halogenomethyl group, R1 can also signify a halogenomethyl group; whereby, where Y represents formyl, R1 signifies a hydroxymethyl group optionally substituted by a carbonyl-free group cleavable by acid treatment, an acetalised formyl group, or an optionally esterified carboxy group and where X represents formyl, m signifies zero and R1 signifies a halogenomethyl group, and, if desired, the obtained compound of the general formula

in which the dotted lines, m, n and R1 have the significance given above, is converted into optically active vitamin E, optically active vitamin E ester or optically active vitamin K1.

The process in accordance with the invention offers a novel advantageous route to natural, optically active vitamin E, vitamin E esters and vitamin K compounds which hitherto had to be produced from natural products or expensive synthetic methods in an uneconomic manner. In accordance with the invention there are obtained, by the use of partially novel, optically active starting compounds, intermediate products containing the chiral centres of the side-chain of vitamin E or Ki, which can subsequently be built up in a ready manner to the natural, optically active vitamins. The novel C5- and C10- building units, which are used for the process If the invention or for the manufacture of the starting compounds manufacturable in accordance with the invention, can be manufactured or further reacted in ready manner according to a novel process. In toto, therefore, the novel route to natural, optically active vitamin E, vitamin E esters and vitamin K1, including the process in accordance with the invention itself, represents a valuable addition to the state of the art.

In the formulae I and II one of the substituents X and Y represents a group Z-CM2-, wherein Z signifies a leaving group. Among these "leaving groups there are understood, in particular halogen atoms, especially chlorine, bromine and iodine; and substituted sulphonyloxy groups, such as lower alkanesulphonyloxy, e.g. methanesulphonyloxy (mesyloxy), or benzenesulphonyloxy optionally substituted by lower alkyl, e.g. benzenesulphonyloxy or p-tolyenesulphonyloxy (tosyloxy). "Halogenomethyl" signifies especially chloro-, bromo- or iodomethyl.

Where R1 signifies a substituted. hydroxymethyl group, the substituent is a carbonyl-free group cleavable by hydrogenolysis or by acid treatment. Among the hydrogenolytically cleavable groups the benzyl group may be particularly mentioned but functional groups, such as the triphenylmethyl group, also come into consideration. Groups cleavable by acid treatment are, in particular, hydrolytically cleavable groups. Such groups are, for example, groups of: the formula R2O-CHR3-, wherein R2 represents (1-C4 alkyl and R3 represents hydrogen or C1-C4 alkyl, or R3 together with R2 represent n-butylene, especially the 2-tetrahydropyranyl group; groups of the formula (R4)3-A-, wherein R4 signifies C1-C4 alkyl and A signifies carbon or silicon, e.g. t-butyl or trimethylsilyl or groups of the formula (R4)2C(OR4)-, for example dimethylethoxymethyl. Groups which are non-hydrolytically cleavable but cleavable by acid treatment with Lewis acids are, e.g. C1-C4 alkyl groups, such as methyl and ethyl. Among "esterified carboxy" there are preferably to be understood groups of the formula R4OOC-, wherein R4 represents C1-C4 alkyl, especially methyl or ethyl. The expression "C1-C4 alkyl" represents straight-chain or branched groups with up to 4 carbon atoms, i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

R, can also signify an acetalised formyl group, e.g. a group of the formula

wherein the substituent R5 represents C1-C4 alkyl, such as methyl or ethyl, or both substituents R5 together represent C2-C3 alkylene, e.g. ethylene.

In the starting compounds of the formulae I and II halogen atoms present have two different functions; thus, where R1 signifies halogenomethyl, the halogen atom represents a protecting group against the Grignard or Wittig reaction, hereinafter referred to as the magnesium- or phosphorus-organic reaction, and where X or Y represents the group Z-C112-, wherein Z signifies halogen, the halogen atom is a reactive (leaving) group which participates in the magnesium (i.e.

Grignard)- or phosphorus (i.e. Wittig)- organic reaction. For this reason R1 and X are defined so that they do not simultaneously represent halogenomethyl.

According to a preferred embodiment of the process in accordance with the invention, there are used a starting compound of the formula I wherein m represents zero, i.e. a C5-building unit, and a starting compound of the formula II wherein n represents one, i.e. a C10-building unit.

The process in accordance with the invention can be subdivided into two subgroups A and B: A) Where in the starting compounds of the formulae I and II one of the two substituents X and Y represents the group Z-CH2- and the other represents halogenomethyl, the reaction is carried out with the aid of a magnesium-organic reaction with the formation of a carbon-carbon single bond at the linkage position.

In this reaction the substituent R1 is a hydroxymethyl group substituted by a carbonyl-free group cleavable by hydrogenolysis or acid treatment, an acetalised formyl group or, where X represents a substituted sulphonyloxymethyl group, also a halogenomethyl group. Preferably, R1 represents benzyloxymethyl or 2tetrahydropyranyloxymethyl. For the conversion with magnesium there will preferably be used a reaction component (compound I or II) wherein the halogenomethyl group X or Y is bromomethyl. When X or Y signifies Z-C112-, the leaving group Z is preferably a halogen atom, especially bromine, or tosyloxy.

According to a preferred embodiment, X and Y are both halogenomethyl, especially bromomethyl. According to another preferred embodiment X is a substituted sulphonyloxymethyl group, e.g. tosyloxymethyl, and R1 is halogenomethyl, e.g. chloromethyl or bromomethyl. In the case of this embodiment the magnesium-organic reaction is effected selectively at the substituted sulphonyloxymethyl group X while the halogenomethyl group R1 serves as the protecting group.

A preferred starting compound of formula I is 2-[(S)-4-bromo-3methylbutoxyl]-tetrahydro-2H-pyran. Preferred starting compounds of formula II. are (R)-3,7-dimethyl- 1 -octanol p-toluenesulphonate and (R)-l-brcao-3,7- dimethyloctane. These starting compounds are manufacturable and convertible into the desired vitamin E, vitamin E esters and vitamin K1 in a particularly ready and productive manner.

For carrying out the magnesium-organic reaction one of the compounds of formulae I and II, wherein X and Y represents halogenomethyl, is reacted with metallic magnesium in an ethereal solvent, e.g., tetrahydrofuran, preferably at a temperature between about room temperature and 80"C, whereby the halogenomethyl group X or Y is transformed into a reactive magnesium halogenomethyl group. After addition of the second coupling component of the formula I or II, wherein X or Y represents Z-CH2-, as well as a catalytic amount of a di-(alkali metal)-tetrahalogenocuprate, preferably di-lithiumtetrachlorocuprate, there is obtained the desired product of the formula 111. As solvent there is used the mentioned ethereal solvent. The temperature lies in general between about -80"C and room temperature. The reaction is preferably initiated at a low temperature (-80 to OOC) and subsequently completed at a higher temperature, e.g. room temperature.

B) Where X signifies the group -CH2-Z and Y signifies formyl the reaction of the starting compunds of formulae I and II is carried out with the aid of a phosphorus-organic reaction. In this reaction the substituent R1 is a hydroxymethyl group optionally substituted by a carbonyl-free group cleavable by acid treatment, an acetalised formyl group or an optionally protected carboxy group; Rl is preferably lower alkoxycarbonyl, e.g., methoxy- or ethoxy-carbonyl.

In this case the starting compounds of formulae I and II are linked with the formation of a carbon-carbon double bond. For this purpose, the compound of formula I, wherein X represents the group CH2-Z, preferably halogenomethyl, such as, e.g., iodomethyl, is reacted with a tri-(aryl)-phosphine, e.g., triphenylphosphine, in an inert organic solvent, such as benzene, toluene, xylene, dimethylsulphoxide, dimethylformamide or hexamethylphosphoric acid triamide, at a temperature between about room temperature and 160"C, whereby the group -CH2-Z is transformed into the group CH2Pn(Ar)3Ze, wherein Z has the above significance and Ar represents aryl, e.g., phenyl.

The thus-obtained phosphonium salt is reacted with the coupling component of the formula II, i.e. wherein Y represents formyl. The reaction is effected in the presence of a base, such as a lower alkyl lithium, e.g. n-butyllithium, phenyllithium, or an alkali metal hydride or amide, if desired in an inert organic solvent, e.g. in a lower alkane, such as n-hexane, in a chlorinated hydrocarbon, such as methylene chloride, in an ether, such as diethyl ether, in an aprotic, polar solvent, such as dimethylsulphoxide, dimethylformamide or hexamethylphosphoric acid triamide or in mixtures of these solvents, and at a temperature between about -10"C and the boiling point of the reaction mixture. The reaction is suitably carried out at a temperature in the range -100C to room temperature.

The phosphorus-organic reaction can likewise be carried out on starting compounds of the formula

wherein Z and the dotted line have the significance given above and Hal represents a halogen atom, preferably chlorine.

Essentially the same reaction conditions as described above for the phosphorus-organic reaction are adhered to, although it should be observed that the temperature is preferably maintained lower in order that racemisation at the asymmetric carbon atom in the starting compound Ih is avoided. The reaction with the racemisation-sensitive sr-aldehyde of the formula Ia is conveniently carried out at about -100C to room temperature.

For the manufacture of natural, optically active vitamin E, which has the following structural formula:

it is necessary to exchange the group R, in the obtained product of the formula III with a halogenomethyl group, especially by bromo- or iodomethyl. This is effected at the substituted hydroxymethyl group by cleavage of the substituent and halogenation of the free hydroxymethyl group. The hydrogenolytic cleavage of the corresponding cleavable group (e.g. benzyl or trityl) is effected with the aid of hydrogen and a noble metal catalyst, such as palladium-carbon or platinum dioxide, e.g. in a lower alkanol, such as ethanol, or in ethyl acetate, at about 0 to 50"C. In the hydrogenolysis double bonds which may be present are saturated.

Double bonds remain intact where the cleavage of the benzyl group is carried out with boron tribromide or boron trichloride in methylene chloride or n-hexane at about -200C to OOC or when the cleavage of the trityl group is carried out with hydrogen chloride in chloroform at about 0 C. The acid hydrolytic cleavage of corresponding groups, e.g. groups of the formula R2O-CHR3-, such as, e.g., 2tetrahydropyranyl, or of the formula (R4)3-A-, such as t-butyl or trimethylsilyl, or a group of the formula (R4)2CX(OR4)-, for example dimethylethoxymethyl, is effected with aqueous mineral acids, such as hydrochloric acid, phosphoric acid or sulphuric acid. The cleavage generally proceeds at room temperature. For the cleavage of the trimethylsilyl group treatment with an aqueous lower alkanol, e.g. aqueous ethanol, at slightly elevated temperature is sufficient. the acid, nonhydrolytic cleavage of corresponding groups, e.g. lower alkyl groups, such as methyl and ethyl, can be effected by treatment with a Lewis acid, e.g. with boron tribromide, boron trichloride, or with an aluminium trihalide, such as the bromide or chloride. As the solvent for cleavage with a Lewis acid there can be used, e.g., methylene chloride or n-hexane. The temperature should be maintained low, e.g. in the range of about -20" to OOC.

The halogenation of the free hydroxymethyl group can be effected by treatment with the corresponding hydrogen halide or by treatment with N-chloroor N-bromosuccinimide and triphenylphosphine or phosphorus pentabromide or chloride, with triphenylphosphorus dibromide or chloride or with methyltriphenoxyphosphonium iodide. An obtained bromo derivative of formula III can be transformed into the corresponding iodo derivative by treatment with an alkali metal iodide in a ketonic solvent, e.g., methyl ethyl ketone or methyl isobutyl ketone, at elevated temperature.

When R1 represents an acetalised formyl group, this can be converted by treatment with dilute mineral acid into the free aldehyde, which can then be reduced with a complex metal hydride, such as sodium borohydride, to the corresponding alcohol. The alcohol can subsequently be halogenated in the above manner.

R1 in the significance "optionally esterified carboxy" can be converted by reduction, e.g. with a complex metal hydride, such as lithium aluminium hydride, into hydroxymethyl, which is subsequently halogenated. Chloromethyl is optionally transformed (by reaction with an alkali metal iodide or bromide) into iodomethyl or bromomethyl, which groups are more reactively for the further conversion.

Reaction of the above-mentioned halogenomethyl compound with the aid of a phosphorus-organic reaction with (S)-6-hydroxy-2-formyl-2,5 ,7 ,8-tetramethyl-2 chromane or the corresponding 6-ester in the manner described above yields natural, optically active vitamin E or optically active vitamin E-esters or corresponding compounds with 1 to 3 double bonds in the side chain. These double bonds can be saturated by catalytic hydrogenation. As the catalyst there is preferably used a noble metal catalyst which is customarily used for hydrogenations, such as, e.g., platinum dioxide or palladium-carbon; or Raneynickel or Raney-cobalt catalysts. The hydrogenation is preferably effected in a lower alkane-carboxylic acid ester, such as ethyl acetate, or in a lower alkanol, such as methanol or ethanol. It is preferably carried out under normal pressure and at a temperature between room temperature and about 80"C. A finally obtained product with a free hydroxy group in the 6-position of the chromane moiety can be esterified if desired, e.g. with acetic anhydride in pyridine.

The saturation of the double bonds in the side chain can, of course, also be carried out prior to coupling with the substituted chromane aldehyde, e.g. on an unsaturated product of formula III.

For the manufacture of natural, optically active vitamin K1, which has the following structural formula:

a compound of formula III, wherein R, represents hydroxymethyl and the dotted bonds are saturated, is halogenated, preferably, brominated, in the manner described above. The halogenomethyl group formed is then transformed by the action or an aceto-acetic acid-lower alkyl ester, e.g. the methyl or ethyl ester, into the group CII3COCH(COOnAlkyl)CH2-, which undergoes hydrolysis and decarboxylation with aqueous alkali with the formation of the group CH3COCH2CH2-. The thus-obtained, optically active hexahydrofarnesylacetone can be transformed into natural vitamin K, in a manner known per se, e.g. in accordance with the following reaction scheme:

In the above scheme R6 is the group

R7 is lower alkyl, e.g. methyl or ethyl, and R8 is hydrogen or lower acyl, e.g. acetyl, benzoyl.

According to one variant, the optically active hexahydrofarnesylacetone VI is transformed into optically active isophytol VIII by reaction with an alkali metal acetylide, followed by partial hydrogenation with Lindlar catalyst. Alternatively, the hexahydrofarnesylacetone VI is reacted with a compound of the formula

in a lower-alkanolic solvent and the corresponding lower alkali metal alkoxide, e.g. triethylphosphonoacetate in ethanolic sodium ethoxide, to give the compound IX, which is converted into optically active phytol X by reduction with a complex metal hydride, such as lithium aluminium hydride or diisobutylaluminium hydride.

The isophytol VIII or the phytol X can be condensed with menadiol or its 1acyl derivative (compound XI) with the aid of a Lewis acid, e.g. boron trifluoride, in an ethereal solvent, e.g. dibutyl ether. After saponification of the obtained l-acyl derivative XII, e.g. with methanolic alkali, there is obtained by oxidation with air the optically active vitamin K1 of the formula V. The proportion of the desired trans-product can be increased by separation of the cis- and trans-forms of compounds IX and/or XII, for example by chromatography or recrystallisation.

The conversion of optically active hexahydrofarnesylacetone into natural phytol and natural vitamin K1 is also described in J. Chem. Soc. (C), 1966, pages 2144-2176 (especially 2146, 2151 and 2152) as well as in Helv. Chim. Acta. 48, 1965, pages 1332-1347 (especially 1333 and 1346).

The invention also includes tertiary, optically aliphatic compounds of the general formula

in which the dotted line represents an additional bond which may be present; m represents zero or 1; Z represents a leaving group; and R, represents a hydroxymethyl group optionally substituted by a carbonyl-free group cleavable by hydrogenolysis or acid treatment, an acetalised formyl group, an optionally esterified carboxy group or, where Z represents a substituted sulphonyloxy group, a halogenomethyl group.

The starting compounds of formulae I and II employable in accordance with the invention, and which also form part of the present invention, can be manufactured as follows: Starting compounds of the formula I are obtained for example according to the following reaction scheme, whereby, for ease of reference, the various compounds falling within formula I have each been designated as "Ia", "Ib" and so forth up to "Iw":

In the above reaction schemes XA represents an optionally esterified carboxy group; YA represents an optionally acetalised formyl group;X represents an esterified carboxy group; YB represents carboxy; Xc represents an alkyl-etherified hydroxymethyl group; Yc represents an optionally acetalised formyl group; XD represents an optionally esterified hydroxymethyl group and YD represents an optionally acetalised formyl group. R10 is the residue of a carboxyl ester group; R is a carbonyl-free group which is hydrolytically non-cleavable, but cleavable by acid treatment with a Lewis acid; R,2 is a carbonyl-free group cleavable by acid hydrolysis; R,3 is an acetalised formyl group and R,4 is a carbonyl-free group cleavable by hydrogenolysis. R,5 represents the sum of the substituents R1, and R,2 and accordingly signifies in general a carbonyl-free group cleavable by acid treatment. Z is a leaving group, Z' is a substituted sulphonyloxy group and Hal is a halogen atom.

The reactions XIII~XIV, XXIIIoXXIV, XXVI~XXVII and XXX < XXXI are effected microbiologically with the aid of suitable aerobic or facultative aerobic microorganisms, which are allowed to act on the educts of the formulae XIII, XXIII, XXVI and XXX in aqueous medium. In the educts optionally present substituents such as carboxy, formyl and hydroxymethyl are of the same nature as the substituents explained above under R1, whereby, however, the hydroxymethyl group XD in the formula XXX can be esterified, e.g. lower-alkanoylated, preferably acetylated, in contrast to R,.

The microorganism used for the fermentation has aerobic or facultative aerobic character, i.e. it has the capability to grow not only under aerobic, but also under anaerobic conditions (facultative aerobic microorganism) or also only under aerobic conditions (aerobic microorganism). By testing out any aerobic or facultative aerobic yeasts, fungi or bacteria on the educt employed it is easy to find a suitable microorganism which is in the position the hydrogenate the double bond situated between CH and methylated C and which can therefore be employed in the process in accordance with the invention. Preferred usable known microorganisms are: -for the reactions XIII-XIV, XXVI < XXVIII and XXIIIeXXIV: Saccharomyces cerevisiae (pressed yeast; Bakers yeast); -for the reactions XXVIoXXVII and XXXeXXXI: Geotrichum candidum.

Saccharomyces cerevisiae is obtainable on the market as commercial pressed yeast. Also, Geotrichum candidum is a known microorganism which is generally available from recognised depositories. In order to safeguard the carrying out of the process with the use of Geotrichum candidum,, however, a culture of the strain used was deposited at the Centraalbureau voor Schimmelcultures in Baarn, Netherlands, under the number CBS 233.76.

It is understood that the microorganism should be cultivated prior to its use in the fermentation; which cultivation is effected as a rule in a manner known per se in an aqueous medium with the aid of the customary nutrient materials, i.e. in the presence of a carbon source, such as glucose, fructose, saccharose and/or maltose; a nitrogen source, such as urea, peptone, yeast extract, meat extract, amino acids and/or ammonium salts; inorganic salts, such as magnesium, sodium, potassium, calcium and/or iron salts; other growth-promoting substances, such as vitamins and the like. It is often convenient to use the cultivation medium also in the fermentation in accordance with the invention, although - as more precisely explained hereinafter - the composition of the fermentation medium used can be substantially simpler.

The fermentation can be carried out without additives, simply with the educt of the formula XIII, XXIII, XXVI or XXX and the microorganism to be used. It is, however, advantageous to add to the aqueous medium an assimilable carbon source as the microorganism nutrient material, preferably in an amount of about 10-100 g per litre, for example in the form of a sugar, such as glucose, fructose, saccharose, maltose and the like, in order that the viability of the microorganism and the metabolic activity associated therewith remains for as long as possible.

More than 100 g of carbon source per litre of nutrient medium does not influence the final result, but brings no advantage over the case in which the 10100 g of carbon source are added. The addition of a nitrogen source is not necessary; but, if desired, an assimilable nitrogen source can be added, preferably in an amount of about 1--50 g per litre, for example in the form of urea, peptone, yeast extract, meat extract, amino acids, ammonium salts and the like. The culture medium can additionally contain inorganic salts, such as magnesium, sodium, potassium, calcium and/or iron (II) salts, and other growth-promoting substances, such as vitamines and the like.

The pH-value of the fermentation should preferably lie within the range 2 to 10, especially 3-8, a range which, for the most part, is achievable without particular additives. If desired, the pH-value can be regulated by the use of buffers, e.g. phosphate, phthalate cr tris buffer [tris-(hydroxymethyl)-aminomethane]. The temperature can vary within a wide range, e.g. between 10 and 40"C, a temperature bf 20-350C being preferred. For optimal yields it is preferred that the educt of formula I be present in the fermentation broth in a concentration of 0.l-5.0V0, especially 1.0--2.5%.

The most suitable fermentation time is dependent on the microorganism used.

It varies in the case of a single educt addition for the most part between 4 and 250 hours, especially between I and 2 days.

The fermentation is preferably carried out aerobically, e.g. while stirring, shaking under an air supply or by means of an air through-put. For foam control there can be added the customary anti-foam agents, such as silicon oils, polyalkylene-glycol derivatives, soya bean oil and the like. There is preferably used a microorganism which exists in the non-growing (stationary) phase. The choice of a stationary microorganism has the advantage that the fermentation process need not proceed under sterile conditions if there is used a nutrient medium which permits no substantial reproduction of microorganisms for example a nutrient medium without nitrogen source.

With the use of educts of formula XIII the fermentation brings about the saturation of the double bond with the formation of an optically uniform compound, as well as the reduction of the formyl group or hydrolysis and reduction of the acetalised formyl group YA to hydroxymethyl. A substituent optionally present on the carboxy group is less readily hydrolysable and this substituent remains partially intact in the first instance after the saturation of the double bond.

Corresponding fermentation products which are still esterified at carboxy can be isolated as such from the fermentation broth, or they can be converted into the lactone of the formula XIV by lengthening the duration of the fermentation, e.g. up to 3-10 days. Fermentation products which are still esterified at the carboxy group can be converted into the lactone of formula XIV during the purification (e.g. by distillation, preferably under slightly acidic, e.g. p-toluenesulphonic acidic, conditions).

In accordance with an especially preferred process there is used, as, the starting compound of formula XIII, ethyl-trans-4,4-dimethoxy-3-methylcrotonate and, as the microorganism, Saccharomyces cerevisiae, whereby as the fermentation product there is obtained mainly (S)-3-methyl-4-hydroxy-butyric acid ethyl ester.

Acid hydrolysis of this compo emulsions, extraction in a continuous process or extraction by multiple distribution can be made use of. According to a preferred isolation method the fermented broth is filtered or centrifuged. The aqueous phase and the sediment are worked up separately. The crude product obtained can be purified in the customary manner, e.g. by fractional distillation. As already mentioned, open intermediate products obtained (with the exception of the alkyl ether) can be converted into the corresponding lactone of the formula XIV or XXXI during the working up stage.

The reactions XIV < Ia and XXXI < XXXII are effected by treatment with a hydrogen halide, preferably hydrogen chloride or hydrogen bromide, in an alcohol appropriate for the introduction of the ester group RXo, e.g. in a lower alkanol, such as methanol or ethanol. Chlorine or bromine in compounds Ia and XXXII can be exchanged fpr iodine if desired by treatment with an alkali metal iodide, e.g. sodium iodide. For the manufacture of the ester corresponding to formula Ia with leaving group other than halogen (substituted sulphonyloxy), i.e. the ester of formula Ig, the half ester of formula XXIV produced fermentatively is selectively reduced to the alcohol XXV, e.g. by treatment with a boron hydride/dimethylsulphide complex. The alcohol is reacted with the corresponding substituted sulphonyl halide, e.g. p-toluenesulphonyl chloride, to give the starting compound Ig. The reactions XVeId, XX-If and XXXIII < Ii are effected in the same manner. The alcohol XXV can be converted by acid hydrolysis into the lactone XXIV.

The ester group of compounds Ia and XXXII is transformed reductively into hydroxymethyl with the formation of compounds Ib and XXXIII respectively. The reduction is effected for example at -20 to OOC in an inert organic solvent with an aluminium-organic compound, e.g. apbranched aluminium-di-lower-alkyl hydride such as diisobutylaluminium hydride, or with lithium aluminium hydride. The reduction of the carboxy group of compounds XXVII to hydroxymethyl with the formation of the compounds XXVIII is effected in analogous manner.

By mild reduction of the ester group in compounds Ia and XXXII this is transformed into the aldehyde group with the formation of compounds XIX and Ih respectively, for example by treatment with a p-branched aluminium-di-lower-alkyl hydride, such as diisobutylaluminium hydride, at -80 to 400 C.

The hydroxy group of compounds Ib and XXXIII is protected with an acid hydrolytic ally cleavable group R,2 with the formation of compounds Ic and XXXIV. The introduction of this group is effected for example by treatment with the corresponding olefinic compound, such as 3,4-dihydro-2H-pyran, methyl vinyl either or 2-methoxy-propene, or with the corresponding halogenide, e.g. with chloromethyl-methyl ether or trimethylsilyl chloride.

The aldehyde group of compounds XIX can be acetalised with the formation of compounds Ie. The transformation is effected, for example, by treatment with an orthoformic acid lower alkyl ester, e.g. orthoformic acid triethyl ester in the corresponding lower alkanol, such as ethanol, at room temperature with ammonium nitrate as the catalyst. According to another method the formyl group is acetalised by treatment with a lower alkanol or alkanediol, e.g. ethanol or ethylene glycol, preferably in the presence of an acid catalyst, such as p-toluenesulphonic acid. The water formed can subsequently be distilled off azeotropically. As the entrainer there is used an inert organic solvent which is immiscible with water, e.g. benzene, xylene or methylene chloride.

Hydroxy compounds XV, XX and XXXV are obtained from halogeno compounds Ic, Ie and XXIV respectively by treatment with an alkali metal loweralkanoate, such as potassium acetate, in an aprotic organic solvent, such as dimethylformamide, and subsequent saponification and neutralisation.

The alcohols XVII can be manufactured from the alcohols XV, for example by benzylation (e.g. with an alkali metal hydride and benzyl bromide or triphenylmethyl chloride in pyridine) and cleavage of the protecting group R,2 from the obtained compound XVI by acid hydrolysis as given above for III.

Reactions XX-tXXIXXII and XXXVXXXVII take place in analogous manner.

Benzylated compounds XVI, XXI and XXXVI can likewise be obtained directly from the halogeno compounds Ic, Ie and XXXIV respectively by reaction with an alkali metal salt of benzyl alcohol at about room temperature in an aprotic organic solvent, such as, e.g., dimethylformamide or dimethylsulphoxide.

The alcohols XVII, XXVIII and XXXVII can be transformed into the compounds XVII I, XIX and Ij respectively by reaction with phosphorus pentachloride or phosphorus tribromide in pyridine, if necessary followed by treatment with an alkali metal iodide, or alternatively by reaction with the corresponding substituted sulphonyl halogenide, e.g. p-toluenesulphonyl chloride.

The starting compounds Ik are obtained from the compounds Ij by hydrogenolysis in the same manner as given above for the further processing of the products III.

The hydroxy group of compounds XXXV can be oxidised to the aldehyde group with the formation of compounds XXXVIII. There is preferably used as the oxidising agent finely divided manganese dioxide or a chromium trioxide/pyridine complex in W halogen-containing organic solvent, such as chloroform or methylene chloride, or in n-hexane. The aldehyde XXXVIII can, in turn, be transformed into the lactol XXXIX by cleavage of the group R,2. The cleavage is effected by acid hydrolysis as given above for the further processing of the product of formula III.

The reactions Ic, d + XVIII' o XL; Ie, f + XVIII' < XLI; Ij + + XXXIV < XLII and Ii + XXXIV < XLIII are effected with the aid of a magnesium-organic reaction in the same manner as described above for the reaction in accordance with the invention of corresponding starting compounds of formulae I and II, and yield products which are saturated at the linkage position. The reactions Ia,g + XXXIX XLIV; Ik + XXXVIII < XLVI; and Ih + XXXIV o XLVIII are effected with the aid of a phosphorus organic reaction in the same manner as described above for the reaction in accordance with the invention of corresponding starting compounds of formulae I and II, and yield products which are unsaturated at the linkage position.

The introduction of the protecting group R14 into the alcohols XLVI is effected in the same manner as given above for the reaction XV < XVI (e.g. with an alkali metal hydride and benzyl bromide or with triphenylmethyl chloride in pyridine).

The groupOR,4 in compounds XL and XLI as well as the group -OR12 in compounds XLII, XLIII, XLVII and XLVIII are exchanged for the leaving group Z or (for Iw) Z', with the formation of starting compounds I1 and Im or In, Ip, Iu and Iw, conveniently by cleavage of the protecting groups R,4 and R,2 and halogenation or sulphonylation of the free hydroxy group in the manner given above. By suitable choice of the protecting groups and cleavage conditions, only the protecting group at the right of the structural formula is cleaved off, the protecting group at the other end of the molecule remaining intact. Accordingly, the protecting groups R,4 in compounds XL and XLI are selectively cleavable by hydrogenolysis. The selective cleavage of the protecting groups R,2 in compounds XLII, XLIII, XLVII and XLVIII is effected by acid hydrolysis.

The reactions In < Io and XLIV XLV is effected hydrogenolytically in the manner described above. The alcohols XLIV and XLV are converted into starting compounds Iq or Is by halogenation or sulphonylation in the manner already described.

The saponification of the esters Iq and Is to the acids Ir and It respectively is effected in a manner known per se, e.g. by treatment with dilute acid or alkali.

The cleavage of the protecting group R,4 of the compounds Iu is effected, without the double bond in the molecule being saturated, by cleaving off the benzyl group with boron tribromide or boron trichloride in methylene chloride or n- hexane at about 0 C or by removing the trityl group with hydrogen chloride in chloroform at about 0 C. In this manner there are obtained starting compounds Iv.

The hydroxymethyl group of this compound can, if desired, be converted into groups R12OCH2- or R13-, whereby one proceeds in analogy to the above reactions Ib # Ic or XXXV # XXXVIII and XIX # Ie.

The starting compounds of the formula II, wherein n is zero, are known. The manufacture of the starting compounds of the formula II, wherein n represents one, can be effected according to the following reaction scheme, whereby for ease of reference, the various compounds falling within formula II have each been designated as "IIa", "IIb" and so on up to "IIf'.

The reaction of compounds Ia,g, Ic and Ie with compounds IIa is effected with the aid of a magnesium-organic reaction in the same manner as that described above for the reaction in accordance with the invention of corresponding starting compounds of formulae I and II, and yields compounds LII, XLIX and L respectively, which are saturated at the linkage position. The reactions Ih + IIa lle and la,g + IIb o LI are effected with the aid of a phosphorus-organic reaction in the same manner as that described above for the reaction in accordance with the invention of corresponding starting compounds of formulae I and II, and yields compounds IIe and LI which are saturated at the linkage position.

The reactions XLIX o IIc, L < IId, IIe IIe' and LI o IIf are effected in the same manner as the above-described reactions XVI < XVIII, XXI o XXII, Ic < Id and Ia < XIX respectively.

In place of the compound Ic there can also be employed a compound XXIX.

The obtained C,0-compound carries a group R11O- (e.g. lower alkoxy), which is converted by treatment with a Lewis acid, preferably boron tribromide or chloride in methylene chloride at about -20" to OOC, into the hydroxy group, which is subsequently halogenated or sulphonylated as described above with the formation of the compound IIc.

In the following Examples, which are given for the purpose of illustrating the invention, the following depositories are specified: ATCC = American Type Culture Collection, Rockville, Maryland, USA CBS = Centraalbureau voor Schimmelcultures, Baarn -- Netherlands NRRL = Northern Utilization Research and Development Division of U.S.D.A., Peoria, Illinois, USA NCIB = National Collection of Industrial Bacteria, Aberdeen Scotland ETH = Eidgenssische Technische Hochschule, Zurich - Switzerland PRL = Prairie Regional Laboratories, Sascatoon, Canada All temperatures are given in degrees Centigrade.

Example 1.

A Grignard solution prepared from 2.21 g (R)-l-bromo-3,7-dimethyloctane and 0.255 g magnesium in dry tetrahydrofuran under argon is treated at -700C with 0.4 ml of a 0.1M solution of dilithium tetrachlorocuprate in tetrahydrofuran. A solution of 1.74 g (S)-4-(benzyloxy)-2-methylbutyl-p-toluenesulphonate in 3 ml tetrahydrofuran is then added dropwise at the same temperature. The reaction mixture is brought to room temperature within 2-3 hours and subsequently stirred for 19 hours. 50 ml 3N aqueous hydrochloric acid are stirred in while cooling with ice, the phases are separated, and the organic phase is washed neutral, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by two-fold adsorption on silicagel (elution agent: n-hexane/ether 4:1 and n-hexane). There is obtained 0.86 g (54%) of (3R,7R)-3,7,l 1-trimethyldodecyl benzyl ether. After distillation under reduced pressure (0.3 mm, 1700 bath), there is obtained (3R,7R)-3,7,1 t-trimethyldodecyl benzyl ether as a colourless oil; [a]20= +3.60 (4.05% in n-octane).

The (S)-4-(benzyloxy)-2-methylbutyl-p-toluenesulphonate and (R)-l-bromo3,7-dimethyloctane used as the starting compounds can be manufactured as follows: Trans-3-(l,3-dioxolan-2-yl)-2-buten-l-ol (a) is transformed fermentatively by the microorganism Geotrichum candidum CBS 233.76 to the (S)-dihydro-3-methyl2(3H)-furanone (XXXI):

Cultivation of the microorganism The cultivation of the microorganism is effected in a medium of the following composition:

20 g D(+)-glucose (monohydrate) 10 g Yeast extract (Difco-trade mark) | in one litre t of deionised 16 g KH2PO4 | water (pH 6) 2.6 g Na2HPO4 This medium is sterilised for 30 minutes in the autoclave at 1350. The microorganism is inoculated using the customary microbiological procedures from an agar slant culture into 500 ml of etiltivation medium and incubated at 300 in a sterile Erlenmeyer flask with sterile stopper for 48 h on a rotary shaking machine.

This batch is then transferred into a sterile laboratory fermenter which contains 20 1 of nutrient medium of the composition named above. 10 ml polypropyleneglycol monobutyl ether are added for foam control. The fermenter is operated for 24 h at a thermostatically regulated temperature of 30 , a stirring frequency of 900 r/min and an air flow rate of 600 I/h. The biomass is subsequently filtered off. From such a 20 1 formulation there is produced 1 kg of biomass. The biomass is stored in the refrigerator until employed in the transformation experiment.

Transformation of trans-3-( 1 ,3-dioxolan-2-yl)-2-buten-1 -ol (a) 18 1 deionised water and 200 g saccharose are filled into a clean, but not sterilised, laboratory fermenter (total volume 31 1). 2 kg of biomass (Geotrichum candidum CBS 233.76) are suspended in this sugar solution and 350 g of substrate (a) are subsequently added. This batch is mixed for 24 h at a thermostatically regulated temperature of 30 with stirring (stirring speed of 900 r/min) and with an air flow rate of 600 I/h. After 2, 4, 6, 8 and 24 h samples each of 10 ml are withdrawn, extracted twice with methylene chloride, dried over Na2SO4 and concentrated under reduced pressure. The residue is taken up in dioxan and analysed gaschromatographically (glass column with 12% Carbowax) (trade mark) as the adsorbent, starting temperature 1000, temperature increase 4"/min, end temperature 220 , carrier gas: N2). The percentage transformation to the optically active fermentation product (S)-dihydro-3-methyl-2(3H)-furanone (XXXI) is shown in Table 1.

TABLE 1

Transformation to the Fermentation time lactone XXXI 2 h 11.6 % 4 h 23.9 % 6 h 35.7 % 8 h 44.0 % 24 h 61.1 VG The fermentation is interrupted after 24 hours and the desired fermentation product isolated as follows: The broth is filtered. Aqueous phase and sediment are worked up separately.

The aqueous phase is stirred out twice with 40 1 of methylene chloride each time, and the sediment is shaken out twice with 51 of methylene chloride each time. The separated solvent phase is de-watered over Na,SO, and concentrated under reduced pressure. It gives 248 g of crude extract. This crude extract is distilled at 8184 /1415 Torr (bath temperature 105-115 ). There are obtained 107.8 g of product which, in accordance with the gas chromatogram, consists of 95% (S)dihydro-3-methyl-2-(3H)-furanone and has an optical rotation &alpha;D=-20.7 (2% in ethanol). In the NMR spectrum of the product, recorded with the addition of chiral shift reagents, only the one enantiomer,(S-configuration) is perceptible.

100.8 g (S)-dihydro-3-methyl-2(3H)-furanone are added dropwise within 15 minutes to I litre of absolute ethyl alcohol which contain ca. 6.6-N hydrogen bromide, the reaction temperature being maintained at 200 by slight cooling. After I hour, the reaction mixture is stirred into 1.5 1 of water and extracted with methylene chloride. The combined organic phases are'neutralised with saturated, aqueous sodium bicarbonate solution, washed with water, dried over magnesium sulphate and concentrated at 15 Torr and 30 bath temperature. The dark, oily residue is subsequently fractionally distilled. At 16 Torr there pass over 187 g (88.8%) of (S)-4-bromo-2-methylbutyric acid ethyl ester, boiling point 84--86"; [a!]DO= = +26.70 (2.33% in ethanol). The optical purity of the product is established by NMR investigations with chiral shift reagents.

A well stirred suspension of 6.0 g lithium aluminium hydride in 300 ml absolute ether is cooled to 00. At this temperature there is added dropwise in about 40 minutes a solution of 41.8 g (S)-4-bromo-2-methylbutyric acid ethyl ester in 80 ml absolute ether. At 5--10" there are gradually added dropwise 7.0 ml methanol. The reaction mixture is then carefully stirred into ice/2N aqueous hydrochloric acid.

The mixture is extracted with ether, and the ether phase washed with saturated, aqueous sodium bicarbonate solution and water, dried over magnesium sulphate and concentrated under reduced pressure up to constant weight. There are obtained 27.7 g (82.9%) of (S)-4-bromo-2-methyl-butanol as a colourless oil.

According to the gas chromatogram the oil is more than 98% pure; [a]D =-16.1 (1.02% in ethanol).

27.7 g (S)-4-bromo-2-methyl-butanol are treated while stirring with 27 g 3,4dihydro-2H-pyran while cooling in a manner such that the reaction temperature is maintained at 50-60 . Thereafter, the mixture is stirred further for 16 hours more, the reaction mixture dissolved in ether, the solution washed with saturated, aqueous sodium bicarbonate solution and water, dried over magnesium sulphate and concentrated under reduced pressure. After distillation at 0.85 Torr, the residue yields 30.4 g (73.0%) of 2-[(S)-4-bromo-2-methylbutoxy]-tetrahydro-2H- pyran (diastereomeric mixture with reference to the asymmetric carbon atom of the tetrahydropyranyl ether) as a slightly beige coloured product; 1D2O=6.l0 (4.05% in ethanol).

A sodium benzylate solution is manufactured at 1100 from 25 ml benzyl alcohol and 2.0 g sodium metal. After cooling to room temperature, 20 ml dimethylformamide are added followed by a solution of 20.1 g 2-[(S)-4-bromo-2 methylbutoxy] -tetrahydro-2H-pyran in 10 ml dimethylformamide while cooling to 15 . The mixture is stirred for 3 hours at 150 and 2 hours at 250, then poured onto ice and extracted with ether. The ether phase is washed, dried over magnesium sulphate and concentrated under reduced pressure. The yellow, oily residue is purified by adsorption on silica gel (elution agent: n-hexane/ether4:l). Subsequent distillation at 0.05 Torr and 1700 bath temperature yields 10.7 g (48.0%) of 2-[(S)-4 (benzyloxy)-2-methylbutoxy] -tetrahydro-2H-pyran (diastereomeric mixture) as a colourless oil; [&alpha;]D20= +1.2 (2.08% in ethanol).

80 ml 6N aqueous hydrochloric acid are added dropwise in 2 minutes to a solution of 31.4 g 2-[(S)-4-(Benzyloxy)-2-methylbutoxy]-tetrahydro-2H-pyran in 200 ml ether and 50 ml water. The mixture is stirred for 15 minutes, the reaction mixture neutralised with sodium bicarbonate and extracted with ether. The organic phase, dried over magnesium sulphate, is concentrated under reduced pressure.

Distillation of the residue at 0.2 Torr gives 21.9 g (94.9%) of (S)-4-(benzyloxy)-2methyl-l-butanol as a colourless oil; [a120--9.l (3.92% in ethanol).

30 ml pyridine are added dropwise at 0 in 10 minutes to a solution of 21.7 g (S)-4-(benzyloxy)-2-methyl-1-butanol and 25.0 g p-toluenesulphonyl chloride in 100 ml of methylene chloride. The reaction mixture is stirred in an ice bath for 1 hour and left to stand for 36 hours at room temperature. The suspension is filtered, and the filtrate rinsed with methylene chloride. The combined organic phases are extracted successively with 3N aqueous hydrochloric acid and water. The organic phase is dried and concentrated under reduced pressure. The evaporation residue yields, after adsorption on silica gel (elution agent: n-hexane/ether 4:1) and drying the pure eluate, 34.5 g (88.9%) of (S)-4-(benzyloxy)-2-methylbutyl-p toluenesulphonate as a colourless, viscous oil, [&alpha;]D20=+8.2 (4.09%) in ethanol).

A Grignard solution prepared under argon from 18.2 g isoamyl bromide and 3.06 g magnesium in dry tetrahydrofuran is cooled to -700C and treated with 3.1 ml of a 0.1M solution of dilithium tetrachlorocuprate in tetrahydrofuran. A solution of 20.9 g (S)-4-(benzyloxy)-2-methylbutyl-p-toluenesulphonate in 20 ml dry tetrahydrofuran is then added dropwise at the same temperature. The reaction mixture is brought to room temperature within 2-3 hours and subsequently stirred for 17 hours. 100 ml aqueous 3N hydrochloric acid are stirred in while cooling with ice, the phases are separated, and the organic phase is washed neutral, dried over magnesium sulphate and concentrated under reduced pressure. The residue (23 g) is purified by adsorption on silica gel (elution agent: n-hexane/ether 4:1) and yields 12.1 g (81%) of (R)-3,7,dimethyloctyl benzyl ether as a colourless oil which boils at 0.1 Torr and 110 ; [&alpha;]D20=+2.3 (2.00% in CHCl3).

A solution of 12.1 g (R)-3,7-dimethyloctyl benzyl ether in 250 ml ethyl acetate is shaken in a hydrogen atmosphere with 1.0 g palladium catalyst (10% on active carbon). After 20 minutes, a further 2 g of catalyst are added. After 3 hours the hydrogenation comes to a standstill after uptake of 1540 ml hydrogen. The catalyst is filtered off, and the filtrate evaporated under reduced pressure and distilled at 0.15 Torr and 85 . There are obtained 6.3 g (81.7%) of (R)-3,7-dimethyl-1-octanol as a colourless oil; [&alpha;]D20=+3.9 (4.06% in CHCl3).

A weak stream of hydrogen bromide gas, which has previously been dried by passage through a thin layer of neutral aluminium oxide (activity 1), is conducted at 100 through 5.57 g (R)-3,7-dimethyl-1-octanol. The reaction is complete after 3 hours. The whole is extracted with ether, and the ether phase shaken with 1 ml sulphuric acid (96%), washed neutral, dried and concentrated under reduced pressure. The residue is distilled and yields 7.2 g (92.5%) of (R)-l-bromo-3,7dimethyloctane as a colourless oil; [al20 5.50 (3.5% in chloroform): Example 2.

A Grignard solution prepared under argon from 1.44 g isoamyl bromide and 0.24 g magnesium in dry tetrahydrofuran is treated at -70 with 0.4 ml of a 0.1M solution of dilithium tetrachlorocuprate in tetrahydrofuran; a solution of 2.0 g (2S,6R)-8-(benzyloxy)-2,6-dimethyloxyl-p-toluenesulphate in 3 ml tetrahydrofuran is then added dropwise at -70 . The reaction mixture is brought to room temperature within 2-3 hours and subsequently stirred for 18 hours. 50 ml of 3N aqueous hydrochloric acid are then stirred in while cooling with ice, the phases are spearated, and the organic phase is washed neutral, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by adsorption on silica gel (elution agent; n-hexane/ether 4:1) and distilled (0.3 mm, 180 bath).

Ther are obtained 1.05 g (69.0%) of (3R, 7R)-3,7,11-trimethyldodecyl benzyl ether as a colourless oil; [&alpha;]D=+3.6 (3.93% in n-octane).

The (2S,6 R)-8-(benzyloxy)-2,6-dimethyloctyl-p-toluenesulphon ate employed as starting material can be manufactured as follows: A Grignard solution prepared under argon from 5.03 g 2-[(S)-4-bremo-2- methylbutoxy]-tetrahydro-2H-pyran and 0.51 g magnesium in dry tetrahydrofuran is treated at 700 with 0.55 ml of a 0.1 M solution of dilithium tetrachlorocuprate in tetrahydrofuran, followed by a solution of 3.48 g (S)-4-(benzyloxy)-2-methylbutyl-ptoluenesulphonate in 5 ml tetrahydrofuran. The reaction mixture is brought to room temperature within 2-3 hours and subsequently stirred for 19 hours.

100 ml 3N aqueous hydrochloric acid are stirred in while cooling with ice. The phases are separated, and the organic phase is washed neutral, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by three-fold adsorption on silica gel (elution agent: n-hexane/ether 4: 1), and dried under strongly reduced pressure The yield is 1.5 g (43.1%) of 2-[[(2S,6R)- 8-(benzyloxy)-2,6-dimethyloctyl]-oxy]-tetrahydro-2H-pyran as a colourless oil; [&alpha;]D20=+2.1 (3.99% in chloroform).

A solution of 1.5 g 2-[[2S,6R)-8-(benzyloxy)-2,6-dimethyloctyl]-oxy]tetrahydro-2H-pyran in 10 ml ether is stirred for 30 minutes with 10 ml of 3N aqueous hydrochloric acid. The phases are separated, and the ether phase is washed neutral, dried and concentrated under reduced pressure. The residue is purified by adsorption on silica gel (elution agent: n-hexane/ether 4:1,). There is obtained 1.0 g (88.0%) of (2S,6R)-8-(benzyloxy)-2,6-dimethyl-1-octanol; [a]20=-4.80 (2.04% in chloroform).

A solution of 0.4 g (2S,6R)-8-(benzyloxy)-2,6-dimethyl-1-octanol and 0.31 gp- toluenesulphonyl chloride in 5 ml of methylene chloride is gradually treated at 0 with 0.6 ml of pyridine. The reaction mixture is left to stand for 2() hours without cooling, after which 1.5 ml of 3N aqueous hydrochloric acid are added dropwise, the phases are separated, and the organic phase is washed neutral, dried and concentrated under reduced pressure. The residue is purified by adsorption on silica gel (elution agent; n-hexane/ether 4:1). There is obtained 0.47 g (74%) of (2S,6R)-8-(benzyloxy)-2,6-dimethyloctyl-p-toluenesulphonate as a pale yellow oil; [CE]DO= +4.50 (0.96% in n-octane).

Example 3.

A solution of 6.1 g (S)-cis-l-iodo-3,7-dimethyl-4-octene and 7.2 g triphenylphosphine in 40 ml toluene is maintained under reflux for 24 hours, then concentrated under reduced pressure. The residue is treated with absolute ether until traces of triphenylphosphine are no longer observable in the thin-layer chromatogram. There are obtained 11.8 g (97.4%) of (S)-cis-3,7-dimethyl-4-octene I-triphenylphosphonium iodide. This is covered with 20 ml dry ether and treated dropwise in an argon atmosphere with stirring and slight cooling to room temperature with 22.2 ml of a 2M solution of n-butyllithium in n-hexane. The mixture is stirred at room temperature for 20 hours, cooled down to -100 and a solution of 2.8 g (S)-4-chloro-2-methylbutyraldehyde in 3 ml dry ether is added dropwise. The mixture is stirred for 1 hour without cooling, concentrated under reduced pressure to a small volume, the residue is treated with 80 ml dimethylformamide while cooling to room temperature and the solution is subsequently stirred at room temperature for 20 hours. The reaction mixture is poured on to ice, extracted with ether, freed from traces of dimethylformamide by washing with water, dried and concentrated under reduced pressure. The residue is purified by adsorption on silica gel (elution agent; n-hexane) and distilled at 100 /0.2 Torr. There is obtained (3S,7S)-l-chloro-3,7,l l-trimethyl-4-cis/trans-8-cis- dodecadiene in a yield of 1.7 g (30.1%); [tt]D =5.2 (2.11% in chloroform).

The (S)-4-chloro-2-methylbutyraldehyde and (S)-cis- I -iodo-3,7-dimethyl-4octene used as starting materials can be manufactured as follows.

250 ml of about I IN ethanolic hydrochloric acid are treated dropwise within 10 minutes with 25.8 g (S)-dihydro-3-methyl-2(3H)-furanone. The solution, which rapidly becomes dark, is stirred at room temperature for 10 hours and subsequently extracted with methylene chloride. The organic phase is washed successively with saturated, aqueous bicarbonate solution and water, dried and concentrated under reduced pressure. After distillation of the residue at 15 Torr, there are obtained 39.7 g (94%) of (S)-4-chloro-2-methyl-butyric acid ethyl ester as a colourless oil with boiling point 7778 ; [a]O = +26.9 (4.15% in ethanol).

A solution of 4.9 g (30.0 mmol) of(S)-4-chloro-2-methylbutyric acid ethyl ester in 50 ml n-hexane is treated dropwise at --700 under argon with 39 ml of a 20% solution of di-isobutylaluminium hydride in n-hexane. After complete reaction, the reaction mixture is treated with 5 ml methanol at 300, subsequently hydrolysed with ice-cooled IN hydrochloric acid, extracted with ether, washed neutral with water, dried and evaporated under reduced pressure (300 bath temperature). The residue is distilled at 55--580/15 Torr. There are obtained 2.3 g (64%) of (S)-4chloro-2-methylbutyraldehyde as a colourless liquid; [a]0=-33.4" (4.21% in CHCl3).

A solution of 72.0 g triphenylphosphine and 41.5 g isoamyl bromide in 250 ml dimethylformamide is heated under reflux conditions for 2 hours. The solvent is distilled off under reduced pressure, the residue crystallised twice from methanol/ether and finally dried for 48 hours at 1100 under strongly reduced pressure. There remain 70.3 g (61.9%) of 3-methylbutyl-triphenylphosphonium bromide, m.p. 153154 (uncorrected).

23.5 ml n-butyllithium (about 2M in n-hexane) are added dropwise under argon to a suspension of 20.4 g 3-methylbutyl-trimethylphosphonium bromide in 80 ml dry ether, a reaction temperature of about 20 C being maintained by slight cooling.

The mixture is then stirred for 2 hours at room temperature, after which it is cooled to -100 and a solution of 5.4 g (S)-4-chloro-2-methylbutyraldehyde in 5 ml dry ether is added dropwise. The separated precipitate is stirred for one hour without cooling bath, whereupon 100 ml dimethylformamide are added at room temperature. The mixture is stirred for 16 hours at room temperature, hydrolysed by the addition of ice and extracted with ether. The ether phase is washed with water, dried and concentrated under reduced pressure. The residue is purified by adsorption on silica gel as well as on neutral aluminium oxide of the activities III and II (elution agent: n-hexane). After distillation under reduced pressure (13 mm Torr/90 ), there are obtained 4.13 g (53%) of (S)-cis-1-chloro-3,7-dimethyl-4octene; [&alpha;]D20=+32.6 (2.15% in chloroform).

A solution of 4.4 g (S)-1-chloro-3,7-dimethyl-4-octene in 30 ml isobutyl methyl ketone is stirred at 130 for 37 hours with 7.55 g sodium iodide. A further 3.75 g sodium iodide is added thereto and the mixture is stirred further for 4 hours. After cooling to room temperature, the mixture is diluted with ether, washed with water, dried and concentrated under reduced pressure. The residue is pre-purified by adsorption on silica gel (elution agent: n-hexane). The pure fractions are combined and distilled at 1300/14 Torr. There are obtained 5.6 g (83.5%) of(S)-cis-l-iodo-3,7- dimethyl-4-octene as a colourless liquid; [a]D20= +14.3 (2.21% in CHCl3).

Example 4.

A Grignard solution manufactured as above from 2 g magnesium and 18.3 g (72.6 mmol) of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran in 50 ml absolute tetrahydrofuran, is treated at -78 with 11.4 g (36.3 mmol) of (R)-3,7 dimethyl-1-octanol-p-toluenesulphonate and 3 ml of a 0.1-molar solution of Li2CuCl4 in tetrahydrofuran. The working-up as well as the hydrolysis of the tetrahydro-2-1 [(3 R,7 R)-3,7,11 -trimethyldodecyl]-oxy)-2H-pyran to (3 R,7R)-3,7,11 trimethyl-l-dodecanol is effected in analogy to the following description for the working-up and hydrolysis of 2-[(R)-3,7-dimethyl-octanoxyl]-tetrahydro-2H-pyran.

The (3R,7R)-3,7,11-trimethyl-1-dodecanol distills at 114 /0.04 Torr in a yield of 7.0 g (84% based on (R)-3,7-dimethyl-1-octanol-p-toluenesulphonate); [&alpha;]D20=+3.7 (c=1.015, n-octane).

The mixture of tetrahydro-2-{[(3R,7R)-3,7,11-trimethyldodecyl]-oxy}-2Hpyran and (3R,7R)-3,7,11-trimethyl-1-dodecanol obtained in the course of the working-up can be separated chromatographically [(silica gel deactivated with 0.5% aqueous ammonia; (elution agent: toluene)]. The tetrahydro-2-{[(3R,7R) 3,7,11-trimethyldodecyl]-oxy}-2H-pyran has an optical rotation of [&alpha;]D20=+2.33 (c=4.0, chloroform).

The 2-[(S)-4-bromo-3-methylbutoxy-tetrahydro-2H-pyran and (R)-3,7 dimethyl-l-octanol-p-toluenesulphonate used as the starting materials can be manufactured as follows: Ethyl-trans-4,4-dimethoxy-3-methyl-crotonate (b) is transformed fermentatively by the action of pressed yeast:

A clean, but not sterilised, fermenter with 311 total volume is charged with the following ingredients: -deionised water 9.9 I -pressed yeast 1.1 kg -sugar 0.55 kg -ethyl-4,4-dimethoxy-3-methyl-crotonate 135 g -polypropyleneglycol monobutyl ether 10 ml The fermentation is carried out under the following conditions: Temperature 30 (thermostatically regulated) Stirring frequency 1000 r/min Air flow rate 600 I/h pH 3.4-3.8 (no pH regulation) Fermentation time 56 h After 16, 24, 40, 48 and 56 hours samples of 10 ml each are withdrawn and extracted twice with methylene chloride. The solvent phase is separated, dried over Na2SO4 and concentrated under reduced pressure. The residue is taken up in so much dioxan that there results a 1% solution based on the educt employed. This is subsequently analysed gas chromatographically. The results are shown in the following table:

Composition of the extract in % 0 Fermentation o SH3 "" OH H time zoo 0- 0H' H 16 h 23.8 40.6 34.3 0.3 24 h 11.9 43.4 42.7 0.3 40 h 3.7 43.3 49.1 0.3 48 h 1.8 44.4 50.1 0.7 56 h 0.5 46.9 49.2 LO The fermentation is interrupted after 56 hours and the desired fermentation product is isolated in accordance with the following: The broth is saturated with NaCI and extracted continuously with diethyl ether for 4 days. The extract is separated, dried over Na2SO4 and the solvent further removed under reduced pressure. There are obtained 122 g of crude extract which contains mainly (S)-3-methyl-4-hydroxy-butyric acid ethyl ester. This substance can be purified chromatographically (over silica gel which has been deactivated with 0.5% NH3).

The crude extract obtained above is treated with 100 mg p-toluenesulphonic acid and distilled under reduced pressure in a nitrogen atmosphere. The (S)dihydro-4-methyl-2(3H)-furanone formed during the distillation distils at 86--88"C/14 Torr (bath temperature 125--140"). There are obtained 26.2 g of product which, according to the gas chromatogram, contains 93% (S)-dihydro-4methyl-2(3H)-furanone and has an optical rotation of -21" (4% in methanol). The optical purity of the (S)-dihydro-4-methyl-2(3H)-furanone can be demonstrated after conversion of the lactone into the corresponding bromo ester

',;;;H3 OH3 H XIV IlBi/ethanol C2H500C H H Mc H2Br on the basis of the NMR spectrum recorded with the addition of a chiral shift reagent [Eu(HFC)3].

The yield of isolated, optically pure (S)-dihydro-4-methyl-2(3H)-furanone amounts to 34.4% of the theoretically possible amount of product.

11.0 g (0.11 mol) (S)-dihydro-4-methyl-2(3H)-furanone are added dropwise within 10 min. at 0 while stirring to 110 ml of a freshly manufactured ethanolic hydrogen bromide solution (about 8N). The reaction mixture is subsequently stirred for three hours at room temperature. For the working-up, the reaction mixture is poured onto ice, diluted with water to about 1 litre and shaken out twice with chloroform. The combined organic phases are washed neutral, first with water, then with saturated sodium bicarbonate solution, and dried over sodium sulphate. After removal of the chloroform on the rotary evaporator the colourless ethyl-(S)-4-bromo-3-methyl-butyrate distils in the water-jet vacuum at 90-92 .

Yield: 18.5 g (80%); [&alpha;]D20=-2.3 (c=4.0, CHCl3).

204 ml (0.204 mol) of a 1M solution of diisobutyl-aluminium hydride are added dropwise in an argon atmosphere at 0 to 17.8 g (0.085 mol) of ethyl-(S)-4-bromo-3methyl-butyrate while stirring within 15 min. The excess of the reduction agent is decomposed by dropwise addition of methanol at 00. Subsequently, the reaction mixture is poured onto ice and acidified by addition of 2N aqueous sulphuric acid, the separated aluminium hydroxide partially going into solution. The (S)-4-bromo3-methyl-l-butanol formed is taken up in ether by shaking out several times. The combined ether phases are washed neutral, first with saturated sodium bicarbonate solution, then with saturated- common salt solution, and dried over sodium sulphate. After removal of the solvent on the rotary evaporator, the yield amounts to 14.0 g (98%); the product can be used further without distillation. For analytical purposes a sample is distilled in the bulb tube at 60 /0.04 Torr; [&alpha;]D20=-2.0 (c=3.3, CHCl3).

The above-described reduction of ethyl-(S)-4-bromo-3-methylbutyrate with the aid of diisobutylaluminium hydride is carried out at a temperature below OOC, especially at -70 C. There is obtained (S)-4-bromo-3-methylbutyraldehyde, boiling point 85 /15 Torr. [&alpha;]D20=-7.53 (c=3.92 in n-hexane).

The obtained aldehyde can be used as condensation component XIX in the condensation, outlined on page 9 herein, with the compound Ia to form the compound Iq.

14 g (0.084 mol) of (S)-4-bromo-3-methyl-l-butanol are treated dropwise at 0 with 50 ml of freshly distilled 3,4-dihydro-2H-pyran. The reaction mixture is subsequently stirred at 0 for 1 hour. Excess 3,4-dihydro-2H-pyran is removed on the rotary evaporator at 350. In order to remove last traces of the 3,4-dihydro-2Hpyran chloroform is repeatedly added and removed again on the rotary evaporator.

The crude product, 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran, is distilled at 75 /0.03 Torr. Yield 17.5 g (83%); [&alpha;]D20=+3.4 (c=4.0, CHCl3).

4.7 g (0.202 mol) of magnesium shavings are activated by addition of 2.0 ml methyl iodide in a 3-necked flask provided with a calcium chloride tube in the presence of argon. After 5 minutes, the methyl iodide is sucked off and the magnesium washed several times with absolute tetrahydrofuran. To the activated magnesium is added dropwise a solution of 44 g (0.175 mol) of 2-[(S)-4-bromo-3methylbutoxy]-tetrahydro-2H-pyran in 50 ml absolute tetrahydrofuran with such a velocity that the solvent just boils. If the Grignard reaction does not start by itself, the mixture is warmed to 85 using an oil bath. After completion of the addition of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran, the mixture is stirred at 85 for such a time (0-15 min.) that only traces of 2-[(S)-4-bromo-3-methylbutoxy]tetrahydro-2H-pyran are present in accordance with gas-chromatographic analysis. The solution obtained is cooled to 780 and treated dropwise with 21.2 g (0.0875 mol) of 3-methyl-l-butanol-p-toluene-sulphonate, followed by 3.6 ml of a 0.1 molar solution of Li2CuCl4 in absolute tetrahydrofuran. The reaction mixture is stirred for 10 min. at 780, then for 2 hours at 0 and subsequently for a further 14 hours at room temperature. For the working up of the 2-[(R)-3,7dimethyloctanoxy]-tetrahydro-2H-pyran obtained, the mixture is poured onto ice and brought to pH 5-6 with 2N sulphuric acid. By three-fold extraction with ether and removal of the solvent on the rotary evaporator there is obtained a mixture of (R)-3,7-dimethyl-l-octanol and 2- [(R)-3 ,7-dimethyloctanoxy]-tetrahydro-2H- pyran. This mixture is treated portionwise in 100 ml methanol at 0 with a total of 100 ml of 7N aqueous hydrochloric acid. After 2 hours stirring at room temperature, the mixture is neutralised with dilute aqueous caustic soda and extracted with ether. After chromatography on silica gel deactivated with 0.5% ammonia with pentane/ether (4:1), there are obtained 10.6 g (76% based on 3methyl-1-butanol-p-toluenesulphonate employed) of pure (R)-3,7-dimethyl-1octanol. B.p. 58-59 /0.05 Torr; [&alpha;]D20 = +4.0 (c=1.03, CHCl3).

The (R)-3,7-dimethyl-1-octanol can also be obtained as follows: To a Grignard solution (manufactured in analogy to the above-described magnesium derivative of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran) from 0.3 g (12.4 mmol) of magnesium and 1.51 g (10 mmol) of l-bromo-3- methylbutane in 25 ml tetrahydrofuran are added dropwise, within one minute at 0 C under argon and while stirring, 1.26 g (5 mmol) of 2-[(S)-4-bromo-3 methylbutoxy]-tetrahydro-2H-pyran. Subsequently, 0.3 ml of a 0.1M solution of Li2CuCl4 in tetrahydrofuran is added. The reaction mixture is stirred further at 0 for 3 hours. The working-up as well as the hydrolysis of 2-[(R)-3,7dimethyloctanoxy]-tetrahydro-2H-pyran to (R)-3,7-dimethyl-1-octanol is effected in the manner given above. The yield of (R)-3,7-dimethyl-1-octanol after bulb-tube distillation at 95 /14 Torr amounts to 0.56 g (71%); [&alpha;]D20=+4.0 (c=1.03 CHCl3).

The (R)-3,7-dimethyl-1-octanol can further be obtained as follows: A Grignard solution manufactured as above from 528 mg (3.4 mmol) 1-bromo3-methylbutane and 90 mg (3.75 mmol) magnesium is cooled to -78 under argon and treated dropwise with 600 mg (2.92 mmol) ethyl-(S)-4-bromo-3-methylbutyrate, followed by 0.1 ml of a 0.1M solution of Li2CuC14 in tetrahydrofuran. The reaction mixture is stirred for 10 minutes at 780, then for 2 hours at 0 , and finally for 14 hours at room temperature. The reaction product is purified by adsorption on silica gel (elution agent: n-hexane/ether 9:1). There is obtained, in addition to unreacted ethyl-(S)-4-bromo-3-methylbutyrate, pure ethyl-(R)-3,7-dimethyl-octanoate; boiling point 105 /11 Torr; [&alpha;]D20=+3.32 (c=1.42, chloroform).

The obtained ethyl-(R)-3,7-dimethyl-octanoate is reduced with the aid of diisobutylaluminium hydride to (R)-3,7-dimethyl-l-octanol, in analogous manner to that described above for the reduction of ethyl-(S)-4-bromo-3-methylbutyrate to (S)-4-bromo-3-methyl- 1 -butanol.

A solution of 6.5 g (41 mmol) of (R)-3,7-dimethyl-l-octanol and 7.8 g (41 mmol) of p-toluenesulphonyl chloride in 50 ml absolute chloroform is treated at 0 with 7.9 g (0.1 mol) of absolute pyridine. The mixture is subsequently stirred at 40 for 20 hours. For the working-up, the mixture is poured on to 500 g of ice and extracted three times with chloroform. The combined organic phases are washed first with cold IN hydrochloric acid, then with saturated aqueous sodium bicarbonate solution and subsequently with saturated aqueous common salt solution. After drying over potassium carbonate and removal of the solvent under reduced pressure, the crude product is chromatographed on 300 g of silica gel with benzene. There are obtained 11.4 g (89%) of (R)-3,7-dimethyl-l-octanol ptoluenesulphonate; lal20= +2.0 (c=4.0, benzene).

Example 5.

A Grignard solution is manufactured in analogy to Example 4 from 0.3 g (12.4 mmol) of magnesium and 2.54 g (11.5 mmol) of(R)-l -bromo-3,7-dimethyloctane in 10 ml absolute tetrahydrofuran. To this solution are added dropwise at 0 1.45 g (5.57 mmol) of 2-[(S)-4-bromo-3-methyl-butoxy]-tetrahydro-2H-pyran followed by 0.3 ml of a 0.1 molar solution of Li2CuCl4 in tetrahydrofuran. This reaction mixture is stirred at 0 for 3 hours. The working-up as well as the hydrolysis of the tetrahydro-2-{[(3R,7R)-3,7,11-trimethyldodecyl]-oxy}-2H-pyran obtained to (3R,7R)-3,7,11-trimethyl-1-dodecanol is effected in a manner analogous to that of Example 4. The yield of (3R,7R)-3,7,11-trimethyl-1-dodecanol amounts, after bulb tube distillation at 90-95 /0.05 Torr, to 0.5 g (43% based on 2-[(S)-4-bromo-3methylbutoxy]-tetrahydro-2H-pyran); [&alpha;]D20=+3.9 (c=1.05, n-octane).

The (R)-1-bromo-3,7-dimethyloctane used as the starting material can be manufactured as follows: 5.65 -g (31.8 mmol) of N-bromosuccinimide are added portionwise while stirring to a solution of 5 g (31.6 mmol) of (R)-3,7-dimethyl-l-octanol and 9.05 g (34.5 mmol) of triphenylphosphine in 20 ml methylene chloride. By occasional cooling of the reaction vessel the temperature is maintained below 25 . After 30 minutes stirring at room temperature, the solvent is removed on the rotary evaporator. The residue is washed out several times with n-hexane, then filtered and again washed with n-hexane. The combined n-hexane phases are concentrated on the rotary evaporator. The crude product is chromatographed on 200 g of silica gel with n-hexane. Distillation in the bulb-tube at 1050/15 Torr gives 6.1 g (87%) of (R)-l-bromo-3,7-dimethyloctane; [a]O = -5.0 (c = 0.82, CHCI3).

Example 6.

A Grignard solution prepared in the customary manner from 1.52 g (R)-l- chloro-3,7-dimethyloctane and 0.22 g magnesium in dry tetrahydrofuran under argon is cooled to -70 and treated gradually with 0.3 ml of a 0.1M solution of dilithium tetrachlorocuprate in dry tetrahydrofuran. A solution of 1.19 g (S)-4chloro-2-methylbutyl-p-toluenesulphonate in 5 ml dry tetrahydrofuran is then slowly added dropwise at -70". The mixture is left to come to room temperature in 2-3 hours and afterwards stirred for a further 19 hours. The mixture is treated while cooling with 3N aqueous hydrochloric acid, extracted with ether, washed neutral, dried and concentrated under reduced pressure. The residue (1.7 g) contains, according to the gas chromatogram, 14.2% of (3R,7R)-1-chloro-3,7,1 1- trimethyldodecane, 33.3% of (R)-3,7-dimethyl-l-octanol and 26.5% of (R)-l chloro-3 ,7-dimethyloctane.

The (R)-l-chloro-3,7-dimethyloctane and (S)-4-chloro-2-methylbutyl-ptoluenesulphonate used as the starting materials can be manufactured as follows: A solution of 6.3 g (S)-4-chloro-2-methyl-butyric acid ethyl ester in 20 ml dry ether is added dropwise, while cooling to 00, to a suspension of 1,15 of lithium aluminium hydride in 100 ml of dry ether. After termination the reaction the excess of lithium aluminium hydride is destroyed by adding methanol and the mixture, after cooling with ice is treated with 3N aqueous hydrochloric acid. The mixture is extracted with ether, washed neutral with water, dried and concentrated under reduced pressure. The residue is distilled under reduced pressure. There are obtained 3.9 g (S)-4-chloro-2-methyl-1-butanol as a colourless liquid. Yield 83.1%; boiling point 86 /16 Torr; lai20=2l.30 (2.03% in chloroform).

A solution of 3.75 g (S)-4-chloro-2-methyl-l-butano and 6.8 g ptoluenesulphonyl chloride in 30 ml methylene chloride is treated dropwise at b"C with 8ml pyridine, and the mixture is afterwards stirred for 1 hour at 00. After 12 hours the mixture is hydrolysed with ice, shaken successively with 6N hydrochloric acid, water and aqueous sodium bicarbonate solution, dried and evaporated under reduced pressure. The residue is purified by adsorption on silica gel (elution agent: n-hexane/ether 4:1). The dried residue, (S)-4-chloro-2-methylbutyl-p toluenesulphonate, weighs 8.1 g (95% yield); [a!]20=0.3 (4.07% in CHCl3).

A Grignard solution prepared in the usual manner from 18.13 g isoamyl bromide and 3.06 g magnesium in dry tetrahydrofuran under argon is cooled to -70" and treated gradually with 4 ml of a 0. I M solution of dilithium tetrachlorocuprate in dry tetrahydrofuran. A solution of 16.61 g (3)-4-chloro-2methylbutyl-p-toluenesulphonate in 20 ml dry tetrahydrofuran is then added dropwise slowly at --700. The reaction mixture is brought to room temperature within 2-3 hours and stirred for a further 16 hours. The mixture is stirred into icecold 3N hydrochloric acid, the phases are separated, dried and concentrated under reduced pressure. The residue is distilled (16 Torr, 1150 bath) and yields 8.8 g (83% yield) of (R)-1-chloro-3,7-dimethyloctane; [&alpha;]D20=-2.1 (1.99% in CHCl3).

The (R)-1-chloro-3,7-dimethyloctane obtained can be converted into (R)-3,7dimethyl-l-octanol which can be used in accordance with Example 1, 4 or 5. The transformation can be effected, for example, as follows: A mixture of 1.76 g (R)-l-chloro-3,7-dimethyloctane, 1.48 g dry potassium acetate and 10 ml dry dimethylformamide is heated under reflux conditions for 6 hours. The reaction mixture is cooled to room temperature, treated with water and extracted with ether. The ether extract is washed with water, dried and concentrated under reduced pressure. The residue (2.0 g) is purified by adsorption on silica gel (elution agent: n-hexane/ether 4:1) and then dissolved in methanol. The solution is stirred for 1/2 hour with 3 ml of 4N aqueous caustic soda, extracted with ether, washed neutral with water, dried and evaporated under reduced pressure.

The residue is distilled in the bulb-tube (75 0.1 Torr). There is obtained 1.36 g (86.0%) of(R)-3,7-dimethyl-1-octanol as a colourless liquid; [a]020 = +3.9 (4.08% in chloroform).

Example 7.

A Grignard solution prepared in the customary manner from 2.36 g (R)-lbromo-3,7-dimethyloctane and 0.27 g magnesium in dry tetrahydrofuran under argon is treated gradually at --700 with 0.35 ml of a 0.1M solution of dilithium tetrachlorocuprate in dry tetrahydrofuran, followed by 1.71 g (S)-4-bromo-2methylbutyl-p-toluenesulphonate in 5 ml dry tetrahydrofuran. The reaction mixture is brought to room temperature within 2-3 hours, stirred for two and a half days, then hydrolysed with dilute aqueous hydrochloric acid while cooling, extracted with ether, washed neutral, dried and evaporated under reduced pressure. In the-gas chromatogram the residue shows (3R,7R)-l-bromo-3,7,l 1- trimethyldodecane. The yield amounts to about 5%.

The (S)-4-bromo-2-methylbutyl-p-toluenesulphonate and (R)-l-bromo-3,7dimethyloctane used as the starting materials can be manufactured as follows: A solution of 10.0 g (S)-4-bromo-2-methyl-butanol and 14.0 g tosyl chloride in 100 ml methylene chloride is treated dropwise at e20 with 16 ml pyridine and is stirred at room temperature for 16 hours. The mixture is hydrolysed with ice, shaken with 3N aqueous sodium bicarbonate solution, dried and evaporated under reduced pressure. The residue is purified by adsorption on silica gel (elution agent: n-hexane/Ether 4:1). The dried residue weighs 13.0 g (68%) and consists of (S)-4bromo-2-methylbutyl-p-toluenesulphonate; [&alpha;]D20=-1.0 (4.14% in CHCl3).

A Grignard solution prepared from 6.04 g isoamyl bromide and 0.51 g magnesium in dry tetrahydrofuran under argon is cooled to 700 and treated gradually with 1.3 ml of a 0.1M solution of dilithium tetrachlorocuprate in dry tetrahydrofuran. A solution of 6.42 g (S)-4-bromo-2-methylbutyl-ptoluenesulphonate in 5 ml dry tetrahydrofuran is then slowly added dropwise at -70". The reaction mixture is brought to room temperature within 2-3 hours, stirred for two and a half days, and then hydrolysed

3.63 g [(S) 2-methyl-3-carbethoxypropyl]-1-triphenylphosphonium iodide (7.0 mmol) are treated with sodium hydride in dimethylformamide and reacted with 505 mg (3.25 mmol) of (S)-cis-3,7-dimethyl-4-octenal. The reaction and working-up is effected in analogy to the reaction of the same phosphonium salt with isovaleric aldehyde described hereinafter. There are obtained 500 mg (57%) of ethyl-(3S,7S)3,7,11 -trimethyl-4-cis-8-cis-dodecadienoate which boils at about 85 /0.01 Torr. The configuration of the double bonds is confirmed by NMR spectroscopy. Small amounts of the trans-compound(s) (about 35%) are recognisable in the gas chromatogram.

Analysis: C,7H3002 (266.42) Calculated: C 76.64% H 11.35% Found: C 76.70% H 11.21% [&alpha;]D20=-45.8 (c=2.86% in CHCl3) The ethyl-(S)-4-iodo-3-methylbutyrate and (S)-cis-3,7-dimethyl-4-octenal used as the starting materials can be manufactured as follows: A solution of 4.58 g sodium iodide in 40 ml methyl ethyl ketone is treated dropwise at room temperature while stirring with 4.21 g ethyl-(S)-4-bromo-3methylbutyrate in 5 ml methyl ethyl ketone. Subsequently, the mixture is heated under reflux conditions for 18 hours. The precipitated sodium bromide is filtered off, and the filtrate concentrated to about 5 ml and treated with 80 ml benzene.

After filtration, the benzolic solution is washed with dilute aqueous sodium thiosulphate solution and subsequently with water, dried over sodium sulphate and concentrated to 20 ml. This solution of ethyl-(S)-4-iodo-3-methylbutyrate in benzene can be used directly for the above reaction with trimphenylphosphine.

A solution in benzene of ethyl-(S)-4-iodo-3-methylbutyrate manufactured as above is reacted with triphenylphosphine in the above manner. 7.77 g (15 mmol) of the [(S)-2-methyl-3-carbethoxypropyl]-1-triphenylphosphonium iodide obtained are dissolved in 7.5 ml dry dimethylformamide. 326 mg (13.5 mmol) of sodium hydride (manufactured from 589 mg of a 55% suspension of sodium hydride in mineral oil by repeated washing with n-hexane under nitrogen) suspended in I ml dimethylformamide are added portionwise at 100 within 5 minutes under nitrogen.

A dark orange solution of the corresponding ylid forms with the evolution of hydrogen; for the complete reaction the hydride is stirred for a further 1 hour at room temperature. Then 968 mg (11.25 mmol) of freshly distilled isovaleric aldehyde are added dropwise while stirring at 100 within 5 min. (disappearance of the colour); subsequently the mixture is stirred further overnight at room temperature;, and thereafter is shaken with 25 ml of ice-cold 0;2N aqueous sulphuric acid and 25 ml methylene chloride. The organic phase is separated and the aqueous phase extracted three times with 25 ml methylene chloride each time.

The combined organic extracts are dried over sodium sulphate and concentrated.

In accordance with thin-layer chromatogram the crude product contains, besides triphenylphosphine oxide, only traces of impurities. The separation of the triphenylphosphine oxide is effected by chromatography on a silica gel column with methylene chloride as the elution agent. After subsequent distillation at 110 /11 Torr, there are obtained 1.5 g ethyl-(S)-cis-3,7-dimethyl-4-octenoate..

Analysis: C12H22O2(198.31) Calculated: C 72.68% H 11.18% Found: 72.63% 11.06% Optical rotation: [lD3O = 8.60 (c = 1.87% in CHCI3) The cis-configuration follows from the NMR spectrum. About 3% of the transcompound are recognisable in the gas chromatograph. The compound can be reduced with hydrogen and Raney-nickel in ethyl acetate to ethyl-(S)-3,7dimethyloctanoate which has the following optical rotation: [&alpha;]D20=+3.3 (c=1.42% in CHCl3).

A solution of 1.6(8.1 mmol) of ethyl-(S)-cis-3,7-dimethyl-4-octenoate in 60 ml n-hexane is treated dropwise within 5 min. while stirring at -70 with 12.8 ml of a 0.7M solution of diisobutylaluminium hydride (8.9 mmol) in n-hexane. The reaction mixture is stirred at -70 for 20 min. and subsequently treated slowly (dropwise) at 700 with 6 ml methanol followed by 6 ml water (rapidly).

The reaction mixture is then warmed to 0 while stirring (sepration of aluminium hydroxide) and worked-up with n-hexane/lN aqueous sulphuric acid.

The n-hexane phase is washed neutral, dried over sodium sulphate and evaporated.

Traces of a side-product are separated by chromatography on a silica gel column with methylene chloride. The (S)-cis-3,7-dimethyl-4-octenal obtained is distilled (about 95 /11 Torr).

Analysis: CioMisO (154.24) Calculated: 077.87% H 11.76% Found 77.52% 12.17% L]D0 = +8.6 (c = 2.30% in CHCI3).

Example 10.

A mixture of 2.09 g (10 mmol) of ethyl-(S)-4-bromo-3-methylbutyrate and 2.63 g triphenylphosphine (10 mmol) is heated to 130--1350 for 3 hours under nitrogen.

The cooled glass-like melt is washed with ether and dried in a desiccator over phosphorus pentoxide. The obtained (S)-2-methyl-3-carbethoxypropyl]- 1 triphenylphosphonium bromide can be employed in place of the corresponding iodide in a procedure identical with that of Example 9. There is obtained ethyl (3S,7S)-3,7,11 -trimethyl-4-cis-8-cis-dodecadienoate which is identical with the product obtained according to Example 9.

Example 11.

A solution of 1.6 g (3S,7S)-I-chloro-3,7,11-dimethyl-4-cis/trans-8- cis-dodecadiene in 20 ml isobutyl methyl ketone is stirred at 1300 (bath temperature) for 48 hours with 3.0 g sodium iodide. The reaction mixture is cooled to room temperature, taken up in ether, washed with water and evaporated under reduced pressure. The residue is purified by adsorption on silica gel (elution agent: n-hexane). After distillation at 100 /0.07 Torr there are obtained 1.98 g (90%) of (3S,7S)-1-iodo-3,7,11-trimethyl-4-cis/trans-8-cis-dodecadiene as a colourless product; [lD2O=7.3O (4.11% in chloroform).

The product is a cis/trans isomer mixture. The cis/trans ratio differs from batch to batch and therefore different rotation values are observed.

The optical purity of the product obtained is proved as follows: It is hydrogenated on pre-hydrogenated platinum oxide, and the iodine atom is exchanged by the hydroxy group by heating with potassium acetate in dimethylformamide and saponification with 4N aqueous caustic soda. The resulting product, (3R,7R)-3,7,11-trimethyl-1-dodecanol, has a rotation of [&alpha;]D20=+4 (4.14% in n-octane) and is accordingly identical with authentic, optically pure material.

A solution of 1.1 g (3S,7S)-l-iodo-3,7,l 1-trimethyl-4-cis/trans-8-cis- dodecadiene, 1.0 g triphenylphosphine and 10 ml xylene is heated under reflux conditions for 24 hours, then concentrated under reduced pressure. The residue is digested with dry ether until only traces of triphenylphosphine are detectable in the thin-layer chromatogram. The dried residue consists of (3S,7S)-3,7,11 -trimethyl-4 cis/trans-8-cis-dodecadiene-l-triphenylphosphonium iodide and weighs 1.9 g (97%).

The phosphonium salt is covered with 10 ml dry ether and treated dropwise with 1.6 ml 2M n-butyllithium in n-hexane, whereupon the mixture is stirred at room temperature for 2 hours. A solution of 880 ml (S)-7-acetoxy-2-formyl-2,5,7,8 tetramethyl-chromane in 10 ml dry ether is added dropwise at -150 in 15 minutes, and the mixture is then stirred for 1 hour without cooling and then treated with 30 ml dry dimethylformamide. The mixture is stirred at room temperature for 20 hours, hydrolysed by the addition of ice and extracted with ether after saturation with common salt. The ether extract is washed with water, dried and concentrated under reduced pressure. The residue is purified by adsorption on silica gel (elution agent: chloroform) and concentrated, and the residue re-acetylated in 2 ml dry pyridine with 2 ml acetic anhydride (17 hours at room temperature). The resulting product is hydrolysed by the addition of ice, extracted with ether and the ether phase washed with 3N hydrochloric acid, water and aqueous sodium bicarbonate solution. After drying and concentration under reduced pressure, the residue is again purified by adsorption on silica gel (elution agent: chloroform), concentrated under reduced pressure and then dried under strongly reduced pressure to constant weight. There are obtained 459 mg (31%) of (2S)-2,5,7,8-tetramethyl-2-[(4S,8S) 4,8,12-trimethyl-1-cis/trans-5-cis/trans-9-cis-tridecatrienyl]-6-chromanyl acetate as a pale yellowish oil; [al020---4l.30 (0.75% in CHCI3).

The product is a cis/trans isomer mixture. The cis/trans ratio differs from batch to batch and therefore different rotation values are observed.

A solution of 400 mg (2S)-2,5,7,8-tetramethyl-2- [4S,8S)-4,8, I 2-trimethyl- I - cis/trans-5-cis/trans-9-cis-tridecatrienyl]-6-chromanyl acetate in 5 ml pure ethyl acetate is hydrogenated with the aid of 50 mg pre-hydrogenated platinum dioxide.

68 ml hydrogen are taken up after 40 minutes. The catalyst is filtered off the filtrate is concentrated under reduced pressure and the residue is then dried under strongly reduced pressure. There are obtained 396 mg (97.7%) of (2R,4'R,8'R)-a-tocopheryl acetate in 99.7% purity; [&alpha;]D20=+2.2 #0.5 (1.07% in cyclohexane), identical with authentic (2R,4'R,8'R)-&alpha;-tocopheryl acetate.

Example 12.

2.0 g (3S,7S)-1-chloro-3,7,11-trimethyl-4-cis/trans-8-cis-dodecadiene are heated under reflux conditions for 24 hours with 2.5 g triphenylphosphine in 20 ml dry dimethylformamide. The solvent is drawn off under reduced pressure and the residue digested with dry ether until only traces of triphenylphosphine are observable in the thin-layer chromatogram. The residue, dried under a slight vacuum, weighs 1.85 g (44.5% yield) and consists of (3S,7S)-3,7,l l-trimethyl-4- cis/trans-8-cis-dodecadiene-1-triphenylphosphonium chloride. Under argon there are now added 10 ml dry ether, followed by 1,8 ml 2M n-butyllithium in n-hexane.

A brown-red suspension results after 5 hours. A solution of 900 mg (S)-6-acetoxy-2formyl-2,5,7,8-tetramethyl chromane in 5 ml dry ether is added dropwise at 100 in 15 minutes, and the mixture is stirred for I hour without cooling and then treated with 30 ml dry dimethylformamide. The mixture is stirred further at room temperature for 18 hours, hydrolysed with ice, extracted with ether after saturation with common salt, washed free from dimethylformamide, dried and concentrated under reduced pressure. The residue is purified by adsorption on silica gel, concentrated and the residue reacetylated in 2 ml dry pyridine with 2 ml acetic anhydride (17 hours at room temperature). The reaction product is hydrolysed with ice, extracted with ether and the ether phase washed with 3N hydrochloric acid, water and aqueous sodium bicarbonate solution. After drying and concentration under reduced pressure, the residue is purified by adsorption on silica gel (elution agent: chloroform), concentrated under reduced pressure and dried under strongly reduced pressure to constant weight. There are obtained 1.29 g (75%) of (2S)2,5,7,8 - tetramethyl - 2 - [(4S,8S) - 4,8,12 - trimethyl - 1 - cis/trans - 5 - cis/trans - 9 - cis tridecatrienyl]-6-chromanyl acetate as a pale yellow, viscous oil; [&alpha;]D20 = -60.7 (2.11% in CHCl3).

The product is a cis/trans isomer mixture. The cis/trans ration differs from batch to batch and therefore different rotation values are observed.

A solution of 321 mg (2S)-2,5,7,8-tetramethyl-2-[(4S,8S)-4,8, 1 2-trimethyl- I-' cis/trans-5-cis/trans-9-cis-tridecatrienyl]-6-chromanyl acetate in 5 ml pure ethyl acetate is hydrogenated with the aid of 35 mg pre-hydrogenated platinum dioxide.

60.0 ml hydrogen are taken up after 25 minutes. The catalyst is filtered off, the solution concentrated under reduced pressure and the residue then dried under strongly reduced pressure. There are obtained 319 mg (98.1%) of (2R,4'R,8'R)-a- tocopheryl acetate as a colourless, viscous oil; [a]20= +2.2 (2.09% in cyclohexane), identical with authentic material.

Example 13.

A solution of 0.570 mg (3R,7R)-3,7,11-trimethyldodecyl benzyl ether in 5 ml ethyl acetate is shaken in a hydrogen atmosphere with 70 mg 10% palladiumcarbon. After 30 minutes, a further 70 mg 10% palladium-carbon are added, and likewise after 1 hour. The hydrogenation lasts about I hour during which 51 ml hydrogen gas are taken up. The reaction mixture is filtered, evaporated under reduced pressure and dried under strongly reduced pressure. The residue 295 mg (3R,7R)-3,7,11-trimethyl-1-dodecanol is an oil; [&alpha;]D20=+4.1 (4.09% in n-octane).

3.1 g (13.6 mmol) of (3R,7R)-3,7,11-trimethyl-1-dodecanol are treated according to the method described in Example 5 with 4.02 g (15.3 mmol) of Nbromosuccinimide and 2.62 g (14.7 mmol) of triphenylphosphine in 13 ml methylene chloride. After chromatography and distillation, there are obtained 3.54 g (90%) of (3R,7R)-1-bromo-3,7,11-trimethyldodecane. B.p. 90 /0.05 Torr; [&alpha;]D20=-3.6(c - 1.005, n-octane).

The (3R,7R)-1-bromo-3,7,1 I-trimethyldodecane obtained can be transformed, in accordance with Helv. Chem. Acta, Volume 46 (1963), page 650-675, into (2R,4'R,8'R)- -tocopherol or (2R,4'R,8'R)-&alpha;-tocopheryl acetate.

Example 14.

356 mg (1,34 mmol) of ethyl-(3S,7S)-3,7,1 1-trimethyl-4-cis-8-cis- dodecadienoate in 10 ml hexane are treated dropwise in 10 ml hexane in a nitrogen atmosphere while stirring at 0 with 4.2 ml of a 0.7M solution of diisobutylaluminium hydride in n-hexane. The reaction mixture is subsequently stirred at 0 for 3 hours. There are now added slowly, while stirring, 2 ml water, followed by 3 ml 0.4N aqueous sulphuric acid. The n-hexane phase is separated and the aqueous phase shaken out three times with n-hexane.

The combined n-hexane phases are dried over sodium sulphate, and evaporated and the residual colourless oil distilled at about 85 /0.08 Torr. There are obtained 279 mg (89%) of (3S,7S)-3,7,11-trimethyl-4-cis-8-cis-dodecadienol. The NMR spectrum confirms the given structure. The gas chromatogram shows a small portion (about 3%) of trans product(s).

Analysis: C15H28O Calculated: C 80.29% H 12.58% Found: 80.01% 12.32% [a]420 = - 33.30 (c = 3.16% in 011013) The product can be transformed into the corresponding chloride or bromide (see Example 13) which can be transformed, for example according to Example 11 into (2R,4'R,8'R)-a-tocopheryl acetate.

Example 15.

(3S,7S)-3,7,11-trimethyl-4-cis-8-cis-dodecadienol is hydrogenated in ethyl acetate with Raney-nickel as the catalyst. There is obtained (3R,7R)-3,7,11 trimethyl-1-dodecanol which is identical with the authentic material.

Example 16.

* 300 mg (2.3 mmol) of ethyl acetate and then 671 mg (2.3 mmol) of (3R,7R)-1bromo-3,7,11-trimethyldodecane in 2 ml ethanol are added dropwise to 2.3 mol of a solution of 1.01N sodium ethylate in ethanol in a flask provided with a reflux condensor and calcium chloride tube. The mixture is boiled under reflux for 15 hours while stirring. After cooling, so much ice-water is added that the separated salt is just dissolved, and the organic phase is separated in a separating funnel and shaken out four times with methylene chloride. After drying the combined organic phases over magnesium sulphate and distillation of the solvent, there are obtained 755 mg of crude (5R,9R)-2-acetyl-5,9,13-trimethyl-tetradecanoic acid ethyl ester.

For analytical purposes a sample of the crude (5R,9R)-2-acetyl-5,9,13-trimethyltetradecanoic acid ethyl ester is chromatographed on a preparative silica gel plate with toluene/hexane/acetic acid ethyl ester (= 30:10:3) and the thus-obtained pure (5R,9R)-2-acetyl-5,9,13-trimethyl-tetradecanoic acid ethyl ester is distilled at 150 /0.03 Torr; [&alpha;]D20=-4.0 (c=1.04; CHCl3).

A solution of 154 mg (5R,9R)-2-acetyl-5,9,13-trimethyl-tetradecanoic acid ethyl ester in 5 ml ethanol is treated dropwise at a temperature of 80 with 1 ml 10% caustic soda. The reaction mixture is subsequently boiled under reflux for 3.5 hours. The cold reaction mixture is neutralised with 1N aqueous hydrochloric acid and extracted four times with methylene chloride. The combined organic phases are first washed with saturated common salt solution and then dried over magnesium sulphate. After removal of the solvent under reduced pressure and distillation at 1500/0.03 Torr, there are obtained 118 mg (95%) of (6R,10R)-14trimethyl-pentadecanone-2 (hexahydrofarnesylacetone) [&alpha;]33020=+7.55 (c=1.57; n-octane). The ORD spectrum is identical with that of (6R,10R)-14trimethylpentadecanone-2 prepared from natural phytol (Helv. Chem. Acta, 47, 1964, pages 221 et seq).

The (6R,10R)-14-trimethylpentadecanone-2 obtained can be converted into natural vitamin K1, e.g. in accordance with J. Chem. Soc. (C), 1966, Pages 2144-2176 or Helv. Chim. Acta, 48, 1965, pages 1332-1347.

Example 17.

Manufacture of the optically active half-ester 2-methyl-3-ethoxyearbonyl-propionic acid Geotrichum candidum CBS 233.76 is cultivated as in Example 1. The transformation experiments are established as follows: 5 g of biomass (Geotrichum candidum) are suspended in 45 ml of sterile transformation medium which has the following composition: D(+)-glucose (monohydrate) 50 g KH2PO4 8 g in 11 of de-ionised Na2HPO4 1.3 g water (pH 6) The educt is now added in a concentration of 1 or 2 g/l (see following Table) and the batch is incubated at 30 in a thermostatically-controlled room for 7 days on a rotary shaking machine (260 r/min). After 1,3 and 7 days respectively, a sample of 10 ml is withdrawn and extracted twice with methylene chloride. The solvent phase is separated, dried over Ha2SO4 and concentrated under reduced pressure.

The residue is taken up in so much dioxan that there results a 1% solution based on the educt employed, which is subsequently analysed gas-chromatographically. The results are contained in the following Table.

o CH3 Educt,IC,OH in O/o concentration Micro- H Educt in gil organism 1 day 3 days 7 days I 0H I Pressed 70 92 76 yeast 0 XH l 72 82 78 0 1 1 xs 1 14 38 o o Q ' 7 C 2 66 84 7 66 84 .jte 1 U 8U 75 75 ~ 0 of 0 819 mg of the optically active half ester obtained above is dissolved in 6 ml absolute tetrahydrofuran in an argon atmosphere and cooled to 0 to 100. After addition of 3 ml trimethyl borate and 10.3 ml BH3S(CH4)2 in tetrahydrofuran (dropwise), the reaction mixture is stirred at -10 to 0 for 50 minutes in an argon atmosphere. After cautious addition of 20 ml methanol, the mixture is evaporated at 40 under reduced pressure. The residue is dissolved in dichloromethane and shaken successively with 30 ml saturated aqueous sodium bicarbonate solution and twice with 20 ml aqueous common salt solution. The aqueous phase is extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. There are obtained 586 mg ethyl-(S)-3-methyl-4-hydroxybutyrate as a colourless oil.

The ethyl-(S)-3-methyl-4-hydroxybutyrate obtained is heated under reflux conditions for 3 hours in methanol with a trace ofp-toluenesulphonic acid. There is obtained (S)-dihydro-4-methyl-2(3H)-furanone which boils at about 50 /0.1 Torr.

Example 18.

Transformation of trans-1,1,4-trimethoxy-2-methyl-2-butene and trans-4-methoxy-2-methyl-2-buten-1-ol or bI-ol-acetate by pressed yeast or Geotrichum candidum As the microorganism there are used commercial pressed yeast or Geotrichum candidum CBS 233.76 (cultivated as in Example 1). As the substrate there are employed 0.2% of the following educts a, b and c. The transformation experiments are carried out as in Example 2. Depending on the choice of the microorganism the following main products result:

a) Xo ~ ,OH ) CH3 OH w o09 b) y yeast H yeast CH3 O Geotrichum OH O \0 candidum c) or , CBS 233.76 0 0 The conversions to these products (according to GO = gas chromatogram) are tabulated hereinafter for fermentation times of 1,3 and 7 days:

CH CH3 OH Micro- Fermentation ȮMYOH OMwiwo Educt organism time in I acc. to tiC in % acc. to tiC I 1 17 0 yeast 3 36 7 c: H '" 1 1 42 candidum I U candidum CBS 233.76 7 0 45 oM% 6 Geotrichum I 7 O > m e c) a =

Claims (46)

WHAT WE CLAIM IS:

1. A process for the manufacture of tertiary, optically active aliphatic compounds, which comprises linking a compound of the general formula

with the aid of a Grignard or Wittig reaction with a compound of the general formula

in which one of the substituents X and Y represents a group Z-C113-, wherein Z denotes a leaving group, and the other represents halogenomethyl or formyl, and wherein the dotted lines represent additional bonds which may be present, m and n each represent zero or I and the sum of m and n is 1, and wherein R1 represents a hydroxymethyl group optionally substituted by a carbonyl-free group cleavable by hydrogenolysis or acid treatment, an acetalised formyl group, or an optionally esterified carboxyl group, or, where X represents a substituted sulphonyloxymethyl group and that represents a halogenomethyl group, R1 can also signify a halogenomethyl group; whereby, where Y represents formyl, R1 signifies a hydroxymethyl group optionally substituted by a carbonyl-free group cleavable by acid treatment, an acetalised formyl group, or an optionally esterified carboxy group, and where X represents formyl, m signifies zero and R1 signifies a halogenomethyl group, and, if desired, converting the obtained compound of the general formula

in which the dotted lines, m, n and R, have the significance given above. into optically active vitamin E, optically active vitamin E ester or optically active vitamin K,.

2. A process according to claim I, wherein there is used a starting compound of the formula I wherein m represents 0 and a starting compound of the formula II wherein n represents 1.

3. A process according to claim I or 2, wherein starting compounds of formulae I and II, wherein one of the substituents X and Y represents the group Z-C113- and the other represents halogenomethyl and R, represents a hydroxymethyl group substituted by a carbonyl-free protecting group cleavable by hydrogenolysis or acid treatment, an acetalised formyl group, an optionally esterified carboxyl group, or, where X represents a substituted sulphonyloxymethyl group, can also signify a halogenomethyl group, are reacted with one another with the aid of metallic magnesium and a catalytic amount of a di-(alkali metal)tetrahalogenocuprate in an etheral solvent.

4. A process according to claim 3 wherein there are employed starting compounds of formulae I and 11, wherein one of the substituents X and Y represents bromomethyl and the other represents tosyloxymethyl.

5. Process according to claim 3, wherein there are employed starting compounds of the formulae I and II, wherein both substituents X and Y represent halogenomethyl.

6. Process according to claim 5, wherein there are employed starting compounds of the formulae I and II, wherein both substituents X and Y represent bromomethyl.

7. Process according to one of the claims 3-6, wherein there is employed a starting compound of the formula I, wherein R, represents benzyloxymethyl, triphenylmethoxymethyl or a group of the formula R2-C11R3-OC112-, (R4)-A-OCM3-, (R4)3C(OR4)OCM3-, R4OC112- or

wherein R2 represents C1-C4 alkyl and R3 represents hydrogen or C,C4 alkyl or together with R2 n-butylene, R4 signifies C1-C4 alkyl, A signifies carbon or silicon and R5 signifies C1-C4 alkyl or both substituents R5 together signify C2-C3 alkylene.

8. Process according to claim 7, wherein R, represents benzyloxymethyl or 2 tetrahydropyranyloxymethyl.

9. Process according to one of the claims 34, wherein there is employed a starting compound of the formula I, wherein X represents a substituted sulphonyloxymethyl group and R, represents halogenomethyl.

10. Process according to claim 9, wherein X represents tosyloxymethyl and R, represents chloromethyl or bromomethyl.

I I. Process according to one of the claims 3-10, wherein di-lithium tetrachlorocuprate is used as the di-(alkali metal)-tetrahalogenocuprate.

12. Process according to one of the claims 2-10, characterised in that it is carried out within about -80 C to room temperature.

13. A process according to any of claims 1-12, wherein 2-[(S)-4-bromo-3methyl-butoxyl]-tetrahydro-2H-pyran is used as the starting compound of formula I and (R)-l-bromo-3,7-dimethyl-l-octanol-p-toluene-sulphonate is used as the starting compound of formula II.

14. A process according to any of claims 1--12, wherein 2-[(S)-4-bromo-3methyl-butoxyl]-tetrahydro-2H-pyran is used as the starting compound of formula I and (R)-l-bromo-3,7-dimethyloctane is used as the starting compound of formula II.

15. A process according to claim 1 or 2, wherein a starting compound of formula I, wherein X represents halogenomethyl and R, represents a hydroxymethyl group optionally substituted by a carbonyl-free protecting group cleavable by acid treatment, an acetalised formyl group or an optionally esterified carboxy group, is reacted with a tri-(lower-aryl)-phosphine in an inert organic solvent and the phosphonium salt obtained is allowed to react with a starting compound of formula II, wherein Y represents formyl, in an inert organic solvent in the presence of a base.

16. A process according to claim 15 wherein there is employed a starting compound of formula I, wherein X represents iodomethyl.

17. A process according to claim 15 or 16 wherein there is employed a starting compound of formula I wherein R, represents hydroxymethyl, carboxy, or a group of the general formula R2-CHR3OCH2-, (R4)3-A-OCH2-, (R4)2C(OR4)OC112-, R4OC112-, R4OOC- or

wherein R2 represents lower alkyl, R3 represents hydrogen or lower alkyl or R3 together with R3 represent lower alkylene, R4 represents lower alkyl, A represents carbon or silicon and both substituents R5 together signify lower alkylene.

18. A process according to claim 17 wherein R, represents methoxycarbonyl or ethoxycarbonyl.

19. A process according to claim 2, wherein a starting compound of the formula

wherein Hal' represents a halogen atom and the dotted line represents an additional double bond which may be present, is reacted with a tri-(aryl)-phosphine in an inert organic solvent and the phosphonium salt obtained is allowed to react with a compound of the formula

wherein Hal2 represents a halogen atom, at a low temperature in an inert organic solvent in the presence of a base.

20. A process according to any of claims 15-19, wherein triphenylphosphine is used as the tri-(lower-aryl)-phosphine.

21. A process according to any of claims 15-19, wherein a lower alkyl lithium, phenyl lithium, an alkali metal hydride or alkali metal amide is used as the base.

22. A process according to claim 21 wherein n-butyllithium or sodium hydride is used as the base.

23. A process according to claim 19 wherein the said low temperature reaction is carried out at a temperature in the range -10 C to room temperature.

24. A process according to claim 1, substantially as hereinbefore described with reference to the Examples.

25. Tertiary, optically active aliphatic compounds of general formula III given in claim 1, whenever manufactured by a process as claimed in any preceding claim.

26. Tertiary, optically active aliphatic compounds of the general formula

in which the dotted line represents an additional bond which may be present; m represents zero or 1; Z represents a leaving group; and R, represents a hydroxymethyl group optionally substituted by a carbonyl-free group cleavable by hydrogenolysis or acid treatment, an acetalised formyl group, an optionally esterified carboxy group or, where Z represents a substituted sulphonyloxy group, a halogenomethyl group.

27. Compounds in accordance with claim 26 wherein Z represents halogen or substituted sulphonyloxy.

28. Compounds in accordance with claim 26 wherein Z represents bromine, iodine or tosyloxy.

29. Compounds in accordance with any of claims 26-28, wherein R, repreents benzyloxymethyl, triphenylmethoxymethyl, hydroxymethyl, carboxy, or a group of the general formula R4OOC-, R3O-C HR3OC112-, (R4)3-A-OC113-, (R4)2 C(OR4)OC113-, R4OC113- or

wherein R3 represents C14 alkyl, R3 represents hydrogen or C14 alkyl or R3 together with R3 represent butylene, A represents carbon or silicon and R5 represents C14 alkyl or both substituents R5 together represent C33 alkylene.

30. Compounds in accordance with claim 29 wherein Rj represents benzyloxymethyl, 2-tetrahydropyranyloxymethyl, methoxycarbonyl or ethoxycarbonyl.

31. 2-[(S)-4-B romo-3-methylbutoxy]-tetrahydro-2H-pyran .

32. Compounds in accordance with any of claims 26-28, wherein Z represents substituted sulphonyloxy and R, represents halogenomethyl.

33. Compounds in accordance with claim 32 wherein Z represents tosyloxy and R1 represents chloromethyl or bromomethyl.

34. Tertiary, optically active aliphatic compounds of the general formula

wherein Hal represents a halogen atom.

35. (S)-4-Chloro-2-methylbutyraldehyde.

36. Tertiary, optically active aliphatic compounds of the general formula

in which R, represents a hydroxymethyl group substituted by a carbonyl-free group cleavable by acid hydrolysis, or an acetalised formyl group and R,7 represents hydrogen or a carbonyl-free group cleavable by hydrogenolysis.

37. Tertiary, optically active aliphatic compounds of the general formula

in which Z" represents hydroxy or a leaving group and R,4 represents a carbonylfree group cleavable by hydrogenolysis.

38. Tertiary, optically active aliphatic compounds of the general formula

in which R18 represents a halogen atom or the group -OR14, where R14 represents a carbonyl-free group cleavable by hydrogenolysis.

39. (S)-4-Bromo-3-methyl-butyraldehyde.

40. Tertiary, optically active aliphatic compounds of the general formula

in which Hal represents a halogen atom and R19 represents a group of the formula -COOR10, -CH2OH or -CH2OR12, wherein R10 represents the residue or a carboxyl ester group and R12 represents a carbonyl-free group cleavable by acid hydrolysis.

41. Tertiary, optically active aliphatic compounds of the general formula

in which R100 represents a group of the formula HOCH2-, R14OCH2- or OHC-, wherein R14 represents a carbonyl-free group cleavable by hydrogenolysis and R12 represents a carbonyl-free group cleavable by acid hydrolysis.

42. Tertiary, optically active aliphatic compounds of the general formula

in which R,4 represents a carbonyl-free group cleavable by hydrogenolysis.

43. Tertiary, optically active aliphatic compound of the formula

44. Tertiary, optically active aliphatic compounds of the general formula

in which R101 represents an acetalised formyl group or a group of the formula R15OCH2-, wherein R,5 denotes a carbonyl-free group cleavable by acid treatment, and R,4 represents a carbonyl-free group cleavable by hydrogenolysis.

45. Tertiary, optically active aliphatic compounds of the general formula

in which R102 represents a group of the formula R14OCH2-, HalCH2-, or HOCH2-, wherein Hal represents a halogen atom and R14 respresents a carbonylfree group cleavable by hydrogenolysis, R12 represents a carbonyl-free group cleavable by acid hydrolysis, and the dotted line represents an additional bond which may be present; whereby, where R102 represents the group HOCH2-, an additional bond is present at the dotted line.

46. Tertiary, optically active aliphatic compounds of the general formula

in which R10 represents the residue of a carboxy ester group, and wherein the dotted line represents an additional bond which may be present.