CA1306999C - Vitamin e intermediates and methods for the preparation of (2r,4'rs,8'rs)-o-tocopherol and (all-rac)-o-tocopherol via the new intermediate products - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:

The present invention relates to compounds having the general formula I

Description

~ '6~9~

lhis is a division of Canadian Patent application n. 431.302 filed on June 28, 1983.

Background of the Invention 1. Field of the Invention This invention rel~tes to new vitamin E inter-mediates and methods for their prepara~ion~
2. Prior Art During the past years, vitamin ~ tocopherol) has gained importance as antioxidant a5 well as in ~he field of human and animal nutrition. Th~ most diverse methods are known for synthesizing all-rac-~-tocopherol. A survey by Siebrell and Harris on this subject is found in Vitamins, vol. V, pages 165 seq, (1972). The more recent literature also contains methods for the preparation of natural, optically active vitamin E ~2R,4'~,B'R~-tocopherol)(compare also N. Cohen et al, Journal of the Americal Chemical Society, 101 (1979), pages 6710-16). The preparation of stereoisomers of ~-tocopherol is of interest since the various stereoisomers have a varying biological effect~
. Among the three asymmetry centers of the natural vitamin E
having formula , ..

, i .

~3~)6~

the center at the carbon atom in the 2-poSition iS ~f particular import~nce for the biological effect (compare S. Ames, Lipids No. 6 (1971), pages 281-290, particularly page 2%5). Thus, for example, the (2R,4'RS,B'RS3, compared with the (2S,4'RS,8'RS) epimer is five times more effec-tive. Because of the multi-stage and ~omplicated nature of the known processes, the synthe5is of RRR-~-tocopherol appears cumbersome and technically hardly implementable.
However, since centers C~4' and C-8' înfluence the effec-tiveness of the molecule on a subordinate scale only, asynthesis of (2R,4'RS,8'RS)-~-tocopherol i~ already suf-ficient to achieve increased biological activity.
In Helv. Chim. Acta, vol. 64; Fasc. 4 (1981), pages 1158-73, Cohen et ~1 describe the preparation of all eight possible stereoisomers of ~-tocopheryl acetate in high chemical and stereoisomeric purity The (2R,4'RS,8'RS)-isomer was obtained, for example, by reacting racemic tetrahydronerolidol with triphenylphosphonium bromide in CH2C12 and Wittig reaction of the resultant triphenyl-phosphonium salt with (+)-(s)-6-benzyloxy-2~s~7-tetrameth chroman-2-carbaldehyde in the presence of sodium methylate and subsequent hydrogenation of the resultan ~-tocopherol on Pd/Charcoal.

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Summary of the Invention Canadian Patent Application n 431.302 provides a compound having the general formula (II) Z ~ ~ (II) in all its isomeric forms, in ~which Z is selected from the group consisting of ClMg- ; BrMg-Cl (C6~ 3P ; Br(C6 5)3 and ~R )2~- ' wherein R is alkyl of 1 to 4 carbon atoms, and the dotted line indicates that the compound may have an additional double bond.
In another aspect Canadian Patent Application : n 431.302 provides a process for the preparation of a ~o compound having the general formula (II) : z ~ ~II) in all its isomeric forms~ in which Z is selected from the group consisting of ClMg- ; BrMg-Cl (C6Hs)3P-; Br(C6H5)3 and (R20)2~- , wherein R is alkyl of 1 to 4 carbon atoms, and the dotted line indicated that the compound may have an additional double bond, characterized in that . ..

.

. . ~

~3~6~9~

(a) when ~ is ClMg- or BrMg-, an isomer of a compound ~f formula hal ~
; 5 wherein hal is a chlorine or bromine atom and the dotted l~ne indicates that the com-pound may have an adaitional double bond, is reacted with~ g, ~ ~ ~
(b) when .Z is C C6~5)3P or Br~C6H5~3P- an isomer of a compound of formula ha ~
wherein hal is a chlvxine or bromine atom and the dotted line indicates that the compound 1~ may have an additional double bond, is reacted with triphenylphosphine, and (c~ when Z is a group of formula : O
20) wherein R' is as defined above, an isomer of a compound of formula hal ~
wherein hal is a chlorine or bromine atom and the dotted line indicates that the compound may have an additional double bond, is reacted ~ with a trialkylphosphate of formula ; P(oR2~3 wherein R2 is as defined above.
The present invention provides a compound of general formula (I) . :,.
- 3a - .

"

" ~3(,'6999 in all its i~omeric forms, wherein Rl is H ox an alkyl, arylalkyl or an aliphatic acyl radical: Y is OH and X is H
or Y and X together represent an additional bond; and the dotted line indicates that the compound may have a further double bond.
In another a~pect the present invention provides a process f~r the preparation of a compound of general formula ~I) Rl ~ (I) in all its isomeric forms, wherein ~ i5 H or an alkyl, arylalkyl or an aliphatic ac~l radical; Y is OH and X is H
or Y and X together represent an additional bond; and the dotted line indicates that the compound may have a further double bond, characterized in that (a) when Y is OH and X is H, an isomer of a : compound of general formula (III') ; 20 RlO ~ (III') ~ HO
wherein Rl is as defined above is reacted with an isomer of a compound of formula (IIa) I
Z ~ ~IIa) wherein Z is ClMg- or BrMg- and the dotted line indicates that the compound may have a further double bond to obtain a compound of formula I as defined above wherein Y is OH
and H,is (b) when Y and X together represent an additional bond, an isomer of a compound of general formula I as defined above wherein Y is OH
and X is H, is subjected to a dehydration - 3b -, . . , ~ .

, - . ~ . .

~3~699~

treatment to obtain a compound of formula (I) as defined above wherein Y and X together represent an additional bond, or ~c1 when Y and X together represent an additional bond an isomer of a compound of general formula (III') Rl HO (III') wherein Rl is as defined above, is reacted with an isomer of a compound selected from the group consisting of ~a) a compound of formula (IIb) Z ~ (IIb) wherein Z is Cl (C~H5)3P- or Br(C6H5)3P-: and the dotted line indicates that the com-position may have a further double bond;
and ~b) a compound of formula (IIc) (IIc) wherein Z is a group of formula ' (R2O)P-wherein R is alkyl of l to 4 carbon atoms and the dotted line indicates that the com-pound may have a further double bond, to obtain a compound of formula (I) as defined above, wherein Y and X together reprèsent said additional bond.
In a further ~spect the present invention pro-vides a process for the preparation of ~-tocopherol or a 6-O-derivative thereof, said derivative having at the six position the group RlO- wherein R is an alkyl, axalkyl or :. ~
- 3c -' ~3~ 9 an aliphatic acyl residue characterized in that an isomer of a compound of formula r~ ~
wherein R" is H or an alkyl, aralkyl or aliphatic acyl radical; Y is O~ and X ls H or Y and H together represent an adaitional bond; and the dotted line indicates that the compound may have as further double bond, is converted into a-tocopherol or said 6-O-derivative thPreof~
In particular, it has now been found that biologically very effective (2R,4'RS,8'RS)-a-tocopherol can be obtained in a rather advantageous manner via the new compounds having general formula (I~ when starting with the new multiple unsaturated compounds having the general formula (II) and one ~+) (S)-2,5,7-tetramethylchroman-2-carbaldehyde having formula (III) : 20 ~1 ~ CHO (III) in which R is an alkyl, aralkyl or an aliphatic acyl radical.
The subject of this invention also relates to methods for the preparation of (2R,4'~S,8'RS)--tocophero or ~all-r )--tocopherol wherein a compound having the general formula ~IIl and a compound having general formula (III~ and/or the racemic compound (IIIa) Rll~ p~lo_~
HO ~ ~ HO
(III) (IIIa) .
': ' - 3d -~3(~6~9 in which Rl is an alkyl, arylalkyl or an aliphatic acyl radical which is reacted with the ai~ of a phosphorous or magnesium organic reactant in a basically known manner to result in the correspondin9 new compound having general formula I and wherein this is transformed in a basically known fashion in (2R,4'RS,8'RS)-~-tocopherol and/or (all rac)-~-tocopherol.
Detailed Description of the Invention For the practical implementation of the methods according to this invention, the compounds of ~ormula IIb in which Z is Cl(c~H5)3P or Br(C6 5)3 under conditions of a Wittig reaction or compounds of formula IIc in which Z is : (R O)2P
under conditions of the variation of the Wittig reaction of Fouquet and Schlosser (compare An~ew. Chem,, International Edition, 13, (1974~ page 82 sey.) are reacted in a basically known manner with a chroman-2-carbaldehyde having formula III to result in the corresponding compound of formula Ib in which X and Y together span an additional bond between the X and Y carrying carbon atoms and wherein this ~;compound is hydrogenated in a basically known fashion using noble metal catalysts such as Pd and activated charcoal to 13`~

result in (2R,4'RS,8'RS~ tocopherol or a 6-O-derivative thereof; or wherein compounds having general formula IIa in which Z stands for Cl-Mg or ~r-Mg are reacted under condi-tions of a Grignard reaction in a basically known manner with a chroman-2-carbaldehyde having formula III to result in the new compounds having formula I in which Y is OH and X
is H wherein the correspond:ing compound of formula I, in which X and Y together span an additional bond, is prepared by dehydration and which compound can ~hen be hydrogenated as described above to result in l2R,4'RS,8'RS)-~-tocopherol or a 6-O-derivative thereof.
~ y the corresponding reaction of the new compounds of formula II with a 6-O-substituted derivative of the racemic 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carbaldehyde and subsequent hydrogenation, the corresponding 6-O-deriva-tive of (all rac)-~-tocopherol can be obtained.
The new compounds having the general formula II
can be produced in a basically known fashion from the corresponding halides by reactlon with magnesium, triphenyl-phosphine or trialkylphosphite P~OR2~3.
The reaction of the chroman-~2)-carbaldehydes III
and/or IIIa with the organic magnesium halides IIa generally takes place in etheric solvents such as diethyle~her, tetrahydrofuran (THF), methyl-tertiary-butylether (MTB), dioxane or similar substances.

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The water can be ~eparated from the resultant compounds of formula Ia using known substances for dehydra~
tion of secondary alcohols such as distillation in the presence of small amounts of an acid,heating with acetic anhydride, or similar substances.
The chroman-~2)-carbaldehYdes III and/or IIIa are reacted with the phosphonium salts having formula IIb and/or the phosphonate anions of formula IIc in such a manner that these substances are transformed into the corresponding anions using the bases normally used for this purpose such as alkali hydroxides; metal hydrides, particularly NaH;
alkali metal organic compounds, particularly butyl lithium;
or ammonium and by reacting these in suitable solvents such as alkanols; ethers, particularly dimethoxyethane, and THF;
dimethylformamide, N-methyl-pyrrolidone, dimethylsulfoxide or similar substances at a temperature of -40C to lOODC, preferably -10C to ~80C with III and/or IIIa. Compared with the familiar analogous Wittig reaction with a saturated halide, this reaction is more advantageous by the fact that the formation of the phosphonium salt and particularly the anion production is more easily facilitated as a result of the allyl position of the halide radical.
Depending upon the starting materials used, the compounds of formula I resulting from this reaction are obtained in various isomeric forms. When using optically . . -- 6 --.

~3~6999 active III, one obtains optially active I. Depending upon ~the adduct used, the double bonds may be present as E/Z
mixtures or in sterically uniform form. Thus, for example, the reaction of III with compounds of IIb in all-E-form results predominantly in the l'Z,3'E,7'E,ll'E-isomers of Ib.
The compounds of formula I are hydrogenated with the use of catalysts normally applied for ~lefin hydro~ena-tions such as nobel metals, particularly Pd and Pt or Raney nickel in inert solvents such as alkanols, estPrs, particu-larly ethylacetate, under a hydrogen pressure of 1 to 100bars at a temperatures of -10C to +150C, preferably of +10C to 100C.
When using compounds of formula I in which R is 3 hydrogenolytically cleavable group such as the benzyl group, the ~-tocopherol is obtained directly.
The new compounds having the general formulas I
~nd II facilitate advantageous methods for the preparation of (2Rl4~RS~8~RS)-~-tocopherol and (all-rac)-~-tocopherol.
Furthermore, the compounds of formula I are usable as antioxidants.
The following examples illustrate the various aspects of the invention but are not intended to limit its scope. Where not otherwise specified throughout this specification and claims, temperatures are given in degrees centigrade and parts, percentages and proportions are by weight.
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;L3(~6999 Example 1 Preparation of (2R,4' RS, 8 ' RS ) - ~-tocopherol (a~ (2E,6E)-l-chloro-3,7,11-trimethyl-dodeca-2,6-diene:

An amount of 7~70 grams (34.4 mmol)(2E,6~)-3,7,11-trimethyl-dodeca-2.6-di~en-1-ol in 54 ml of CH2Cl~ were mixed at room temperature (RT) with 7018 grams (35 mmol) PC15 and the reaction mixture was refluxed for one hour. Subsequently, the mixture was mixed with H2O, was extracted with CH2C12, was washed with saturated NaHCO3 solution and water and the extract was dried and concentrated~ The resulting crude product was distilled in a ball tube (Kugel rohr) over 0.3 gram of solid K2CO3 at 100C and a pressure of 0.2 mbar. The result was 5.40 grams (~E, 6E) of 1 chloro-3,7.11-trimethyl-dodeca 2,6-diene in the form of an oil. The yield was 65 percent of theory.
.
~b) Five grams of the chloride obtained according to (a) and 5.5 grams (21 mmol) of triphenylphosphine were heated to boiling in 15 ml of toluene for five hours.
The resultant suspension was stirred with 100 ml of hexane and was decanted therefrom after the white solid substance had settled out. This stirring with hexane ;' - 8 -~3~6~99 was repeated ive times. and the remaining tacky solid material was dried under reduced pressure. An amount of 7.2 grams of 2E,6E-~3,7,11-trimethyl-dodeca-2,6-dien-1-yl)triphenylphosphonium chloride was obtained.

(c) Added to a suspension of 4.4 gr,~ms (803 mmol) of a phosphonium salt produced according to (b) in 35 ml of diethylether were 6.27 ml (1.28 mmol3 of butyl lithium in hexane in a dropwise fashion at -10C, and the reaction mixture was agitated for 10 minutes. Subse-quently, 20 ml of dimethylformamide ~DMF) were added and 0.92 gram (2,8 mmol~ of 2S-6-benzyloxy-2~5~7~8-tetramethyl-chroman-2-carbaldehyde dissolved in 35 ml of diethylether was added dropwise at -10C. The mixture was then agitated at -lO~C for two hours, was mixed with H2OI extracted with hexane, dried and concentrated. The crude product was chromatographed on 200 grams of silica gel with hexane-ethylacetate (9:1). An amount of 0.86 grams (60 percent of theory) [2S]-6-benzyloxy-2,5~7,8-tetramethyl-2-(4',8',12'-trimethyl-trideca-l' 9 3',7' trien~ yl)chroman was obtained in the form of a colorless oil as a diastereo-isomeric mixture. A sample thereof was purified by HPLC in a silica column (Merck Si 60) with i-octane/ethylacetate (99.5:0.5):

_ g _ ' l~] 25 = 43.4 (c ~ 1.5/CH2C12)-(d) Hydrogenation to (2R,4'RS,8'RS3-u-tocopherol.

Sixty-one ~rams of a product obtained in accordance with (c) were hydrogenated with 54 mg Pd/Charcoal (5 percent) in lS ml of ethylacetate under normal pressure and at room temperature.

After completing the hydrogen absorption, the reaction mixture was filtered, concentrated and distilled in a ball tube (Kugel rohr~ at 200C and under a pressure of 1o~2 mbar. An amount of 0~32 gram ~2R,4'RS,8'RS)-Q-tocopherol was obtained as colorless oil. (Yield 52 percent of theory.) Example 2 Preparation of (all-rac)-~-tocopherylacetate ~a) (3,7,11-trimethyl-dodeca-2,6,10-trien-1-yl)triphenyl-phosphonium chloride (E/Z isomer mixture3~

An amount of 10.0 grams (41.6 mmol) of Farnesyl chloride and 10.9 grams (41.6 mmol) triphenylphosphine were heated ln 30 ml toluene for five hours under : L3~ 39 reflux. The resultant suspension was stirred with approximately 200 ml hexane and after precipitation of the white solid material was decanted; this stirrin~
process with hexane was repeated five times and the remaining tacky solid substance was dried under reduced pressure.

An amount of 18.2 grams (3,7,11)-trimethyl-dodeca-2,S,10-trien-1-yl)triph~enylphosphonium chloride iE/Z
isomer mixture3 was obtained corresponding with a yield of 87 percent of theory.

(b) Added dropwise to 1.00 gram (1.96 mmol) of the phos-phonium salt produced in accordance with (a) in 10 ml of diethyl ether were 1.5 ml ~2 mmol) of butyl lithium ?
in hexane at room temperature and the mixture was stirred at room temperature under an argon gas blanket for five minutesO Subsequently a solution of 0.43 grams (1.33 mmol) of rac-6-benzyloxy-2,5,7,8-tetra-me~hylchroman-2-carbaldehyde ~produced in accordance with N. Cohen et al, Journal of American Chemical Society, 101, (1979), pages 6710 seq., particularly page 6715) in 10 ml of diethylether was added to the above-described mixture at -10C. After standing at room temperature for 30 minutes, the mixture was mixed .. . ' ' " .

: . :
~ ~ .

, . . , .

:~3Q69~39 with 20 ml of absolute dimethylformamide and was stirred for an additional 30 minutes. After adding 10 ml of H2O, the mixture was extracted with diethyl-ether, the extract was washed, dried and concen-trated~ The substance was chromatographed on 150 grams of silica gel with toluene/ethylacetate (7:3). An amount of 0.66 gram (97 percent of theory) of 6-benzyloxy-2~5,7,8-tetramethyl-~4'~8',12'-trimethyl-trideca-1',3'~7'11'-tetraen-l'~yl)chroman was obtained~

(c) The crude product obtained according to (b) was hydrogenated in 15 ml of ethylacetate on 0.10 gram of Pd/charcoal (5 percent~ under normal pressure and at room temperature for 16 hours. Subsequently the substance was filtered, concentrated and was mixed with 5 ml acetic anhydride and 5 ml of pyridine at 0 to +10C. After 16 hours at room temperature the mixture was poured into water, extracted with petroleum ether, and washed with dilute hydrochloric acid, saturated NaHCO3 solution and water; dried and concentrated. An amount of 0.35 gram of (all-rac)-~-tocopherol acetate was obtained as a colorless oil ~yield 56 percent of theory).

~31;~

Example 3 (3,7,11-trimethyl-clodeca-2,6-dien-1-y~)triphenyl-phosphonium chloride ~E/Z isomer mixture).
An amount of 9.1 grams (37 mmol) of l-chloro 3,7,11-trimethyl-dodeca-2,6-diene and 9.8 ~rams (37 ~mol) of triphenyl phosphine were heated to boiling in 30 ml of toluene for a period of f ive hours . The resultant suspen-sion wa~ mixed with 200 ml oE hexane and after precipitation of ~he white solid material, the liquid was decanted. This mixing with hexane was repeated five times and the remaining tacky solid substan~e was dried under reduced pressure ~ An amount of 18.2 grams (3,7,11)-trimethyl-dodeca-2,6,10-trien-l-yl)triphenylphosphonium chloride (E/2 isomer mixture) was obtained. The yield was 87 percent of theory.
Example 4 (a) (3,7,11-trimethy'-dodeca-2,~~dien-1-y'~-magnesium chloride (E/Z isomer mixture)~

An amount of 1.38 grams ~57~5 mmol) of Mg shavings in 120 ml of tetrahydrofuran (THF? were mixed with 5~7 ml of dibromoethane while being stirred and ~ere heated to boi ing for 30 minutes. The solvent was removed by distillation and the residue was heated to 150C in an argon stream for one hour. After cooling, the mixture , ~l3~

was mixed with 80 ml of THF, 3.32 grams ~20 mmol~ ~I
and 1.48 gram~ ~37.9 mmo ) of pota~sium pieces and was heated to boiling while being vigorous~y stirred for three hours. The resultant suspension was agitated at O ~o -5C with 14~5 grams t5709 mmol, approximately 90 percent content~ of l-chloro-3,7,11-trimethyl-dodeca-2,6-diene and was stirrled at 0C for 15 minutes. The resultant ~uspension wa~s filtered under argon. The result was 260 m~ of a grey solution which had a content of 0.2 mol/l of the Grignard compound (90 percent of theory~ after filtration with n-butanol.

(b) To 0.49 gram (1.51 mmo' )(rac)-S-benzyloxy-2,5,7,8-tetramethyl-chroman-2-carba~dehyde in 12 ml of THF
there were added dropwise, 11.8 ml of a 1.44 molar Grignard solution prepared in accordance with Example 4(a) and the reaction mixture was stirred at room temperature for 14 hours. Subsequently the product was mixed with 20;ml of concentrated N~4Cl solution, extracted with hexane, washed with ~2~ dried and concentrated. The crude product was chromatographed on 160 grams silica ge~ with hexane/ethyl acetate (9:1). The result was 0.64 grams of 6-benzyloxy-2,5,7,8-tetramethyl-2-(1'-hydroxy-4',8',12'-trimethyl-trideca-3',7'-dien-1-yl)chroman . , :

~3~

(diastereoisomer mixture~ as a light yellow oil~ The yield was 80 percent of theory.

Exam~'e 5 (a) ~3,7,11-trimethyl-dodeca-2,6-dien-1-yl~phosphorous dimethylester.

An amount of 30 grams (125 mmol) E/Z-Farnesy~ chloride and 15.5 grams (125 mmol) phosphorous trimethylester were heated to boiling under ref~ux for five hour~, Subsequently the mixture was distilled at a pressure of 0.2 mbar and 150~C to 170C. The result was 15.6 grams (3,7,11-trimethy -dodeca-l,b-dien-l-yl)phosphorous dimethy~ester as a pa'e yellow oil. The yield was 40 percent lnot optimized).

(b) An amount of 0.60 gram ~1.9 mmol~ of a phosphorous ester obtained in accordance with Example 5(a) was dissolved in 5 m dimethylsulfoxide (DMS0) and mixed with 50 mg of 80 percent NaH in mineral oil, and the mixture was stirred at room temperature for one hour.
Subsequently, 0.50 ~ram ~l.S ~mo') of ~rac)-S-benzy~-oxy-2~5~7~8-tetramethy~-chroman-2-carba'dehyde in 3 ml of DMSO were added and the reaction mixture was allowed to stand for 16 hours~ After this period, the sub-~, ., ,~, , . . . .
., ' ~ , ~ - ~ - ' ' ' .

~3(~

stance was diluted with approximately 100 ml of diethylether, was was~ed with water four times, dried and concentrated~ The result was 0.51 gram of crude product which was chromatographed on 30 grams of silica gel with diethylether/hexane (1:8). An amount of 0~27 gram of 6-benzyloxy-2,5,7,8-tetramethyl-2-(4',8',12'-trimethyl-trideca~ 2',6',10'-tetra-en~ yl)chroman was obtained as colorless oil ~diastereo isomer mixtures).

~xample 6 Analogous with Example 4(a), 200 ml of a Grignard solution were obtained from 1.0 gram (41.7 mmol) of M~
shavings and 12.0 grams (42 mmol~ of 1-bromo-3,7,11-tri-methyl-dodeca-2,6,10-triene which contained 1O67 moles per liter of 3,7,11~trimethyl-dodeca-2,6,10-triene-1-yl)-magnesium bromide (E/Z isomer mixture)~ The yield thus is approximately 80 percent of theory.
While this invention has been described with reference to certain specific embodiments, it will be recognized by those skilled in the art that many variations are possible without departing from the scope and spirit of the invention and it will be understood that it is intended to cover all changes and modifications of the invention disclosed herein for the purposes of illustration which do ~V69~1 not constitute departures from the ~spirit and ~ope of the invention 1 ,

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A process for the preparation of a compound of general formula (I) (I) in all its isomeric forms, wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical; Y is OH and X is H
or Y and X together represent an additional bond; and the dotted line indicates that the compound may have a further double bond, characterized in that (a) when Y is OH and X is H, an isomer of a com-pound of general formula (III') (III') wherein R1 is as defined above is reacted with an isomer of a compound of formula (IIa) (IIa) wherein Z is ClMg- or BrMg- and the dotted line indicates that the compound may have a further double bond to obtain a compound of formula (I) as defined above wherein Y is OH
and H, (b) when Y and X together represent an additional bond, an isomer of a compound of general formula (I) as defined above wherein Y is OH
and X is H is subjected to a dehydration treatment to obtain a compound of formula (I) as defined above wherein Y and X together represent an additional bond, and (c) when Y and X together represent an additional bond, an isomer of a compound of general formula (III') (III') wherein R1 is as defined above, is reacted with an isomer of a compound selected from the group consisting of (a) a compound of formula (IIb) (IIb) wherein Z is or and the dotted line indicates that the composition may have a further double bond;
and (b) a compound of formula (IIc) (IIc) wherein Z is a group of formula (R2O)?-wherein R2 is alkyl of 1 to 4 carbon atoms and the dotted line indicates that the com-pound may have a further double bond, to obtain a compound of formula (I) as defined above, wherein Y and X together represent said additional bond.
2. A compound of general formula (I) (I) in all its isomeric forms, wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical; Y is OH and X is H

or Y and X together represent an additional bond; and the dotted line indicates that the compound may have a further double bond, 3. A process for the preparation of a compound of general formula (I) (I) in all its isomeric forms, wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical; Y is OH and X is H;
and the dotted line indicates that the compound may have a further double bond, characterized in that an isomer of a compound of general formula (III') (III') wherein R1 is as defined above is reacted with an isomer of a compound of formula (IIa) (IIa) wherein Z is ClMg- or BrMg- and the dotted line indicates that the compound may have a further double bond to obtain a compound of formula (I) as defined above.

4 A compound of general formula (I) (I) in all its isomeric forms, wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical; Y is OH and X is H;
and the dotted line indicates that the compound may have a further double bond.

5. A process as defined in claim 3 wherein R1 is alkyl, arylalkyl or an aliphatic acyl radical.

6. A compound of general formula (I) (I) in all its isomeric forms, wherein R1 is an alkyl, arylalkyl or an aliphatic acyl radical; Y is OH and X is H; and the dotted line indicates that the compound may have a further double bond, 7. A process as defined in claim 3 wherein R1 is benzyl.

8. A compound of general formula (I) (I) in all its isomeric forms, wherein R1 is benzyl; Y is OH
and X is H; and the dotted line indicates that the compound may have a further double bond.

9. A process as defined in claim 3 wherein R1 is acetyl.

10. A compound of general formula (I) (I) in all its isomeric forms, wherein R1 is acetyl; Y is OH
and X is H; and the dotted line indicates that the compound may have a further double bond 11. A process for the preparation of a compound of general formula (I) (I) in all its isomeric forms, wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical; Y and X together represent an additional bond; and the dotted line indicates that the compound may have a further double bond, character-ized in that (a) an isomer of a compound of general formula (I') (I') wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical; Y is OH and X is H, and the dotted line indicates that the compound may have a further double bond, is subjected to a dehydration treatment to obtain a compound of formula (I) as defined above wherein Y and X together represent an additional bond, or (b) an isomer of a compound of general formula (III') (III') wherein R1 is as defined above, is reacted with an isomer of a compound selected from the group consisting of (a) a compound of formula (IIb) (IIb) wherein Z is C?(C6H5)3?- or B?(C6H5)3?- and the dotted line indicates that the composition may have a further double bond, and (b) a compound of formula (IIc) (IIc) wherein Z is a group of formula wherein R2 is alkyl of 1 to 4 carbon atoms and the dotted line indicates that the com-pound may have a further double bond, to obtain a compound of formula (I) as defined above, wherein Y and X together represent said additional bond.
12. A compound of general formula (I) (I) in all its isomeric forms, wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical; Y and X together represent an additional bond; and the dotted line indicates that the compound may have a further double bond.

13. A process for the preparation of a compound of general formula (I) (I) in all its isomeric forms, wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical; Y and X together represent an additional bond; and the dotted line indicates that the compound may have a further double bond, character-ized in that an isomer of a compound of general formula (I') (I') wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical, wherein Y is OH and X is H, and the dotted line indicates that the compound may have a further double bond, is subjected to a dehydration treatment to obtain a compound of formula (I) as defined above wherein Y and X together represent an additional bond.

14. A compound of general formula (I) (I) in all its isomeric forms, wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical; Y and X together represent an additional bond; and the dotted line indicates that the compound may have a further double bond, whenever obtained by the process of claim 13 or an obvious chemical equivalent thereof.

15. A process for the preparation of a compound of general formula (I) (I) in all its isomeric forms, wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical; and the dotted line indicates that the compound may have a further double bond, characterized in that an isomer of a compound of general formula (III') (III') wherein R1 is as defined above, is reacted with an isomer of a compound selected from the group consisting of (a) a compound of formula (IIb) (IIb) wherein Z is or and the dotted line indicates that the composi-tion may have a further double bond, and (b) a compound of formula (IIc) (IIC) wherein Z is a group of formula (R2O)?-wherein R2 is alkyl of 1 to 4 carbon atoms and the dotted line indicates that the com-pound may have a further double bond, to obtain a compound of formula (I) as defined above.

16. A compound of general formula (I) (I) in all its isomeric forms, wherein R1 is H or an alkyl, arylalkyl or an aliphatic acyl radical; and the dotted line indicates that the compound may have a further double bond, whenever obtained by the process of claim 15 or an obvious chemical equivalant thereof.

17. A process for the preparation of .alpha.-tocopherol or a 6-O-derivative thereof, said derivative having at the six position the group R1O- wherein R1 is an alkyl, aralkyl or an aliphatic acyl residue characterized in that an isomer of a compound of formula wherein R" is H or an alkyl, aralalkyl, or aliphatic acyl radical; Y is OH and X is H or Y and H together represent an additional bond; and the dotted line indicates that the compound may have a further double bond, is converted into .alpha.-tocopherol or said 6-O-derivative thereof.

18. A process for the preparation of .alpha.-tocopherol characterized in that an isomer of a compound of formula wherein R" is benzyl and the dotted line indicates that the compound may have a further double bond is subjected to a hydrogenation treatment to obtain .alpha.-tocopherol.

19. A process for the preparation of .alpha.-tocopherol acetate characterized in that an isomer of a compound of formula wherein R" is acetyl and the dotted line indicates that the compound may have a further double bond is subjected to a hydrogenation treatment to obtain .alpha.-tocopherol acetate.