FORMATION OF CHROMANES BASED ON INTERMOLECULAR REACTION OF ALKYNES WITH DIMETHYLFURAN IN THE PRESENCE OF GOLD(I) COMPLEXES Technical Field

The present invention relates to the field of the formation phenol derivatives and particularly to the field of synthesis of tocopherol and tocotrienol.

Background of the invention

An important class of the chromane compounds are vitamin E and its esters. Due to the high relevance of this substance class in food and feed industry, new synthetic pathways of tocopherols and tocotrienols are of high interest.

J. Am. Chem. Soc. 2000, 122, 1 1553-1 1554 discloses that the gold(lll) salt AuCb catalysis an intramolecular ring closure reaction of ω-alkynylfuran.

A. S. K. Hashmi et al., Adv. Synth. Catal. 2006, 348, 709-713 disclosed the first intermolecular reaction of an alkyne with furan using binuclear gold(l) complexes. However, said reaction formed next to a substituted phenol an almost equimolar amount of an alkenylfuran as side product.

N. Huguet et al. disclosed in Chem. Eur. J. 2013, 19, 6581 -6585 an intermolecular gold(l) catalysed cyclization of furans with alkynes. Next to aromatic substituted alkynes such as phenylacetylene only very short chain alkyl acetylenes have been used.

Y. Roman-Leshkov et al., Nature 2007, 447, 982-985, discloses that 2,5- dimethylfuran can be obtained from biomass. Summary of the invention

The present invention offers a new synthetic pathway for chromane synthesis, particularly for tocopherols and tocotrienols.

In a first aspect the present invention relates to a process according to claim 1 to the formation of specific phenols (formula I) being substituted in the ortho position to the phenolic OH groups with a long hydrocarbonyl chain having a double bond in a specific position allowing to be used of said product as intermediate for the synthesis of chromanes.

This pathway offers a possibility for the synthesis of chromanes in a high yield and selectivity. Using 2,5-dimethylfuran enables the synthesis of chromanes from biomass. Hence, a synthesis of chromanes with a good ecological food print is possible. Particularly important is the synthesis of β-tocophenol and β- tocotrienol by this advantageous process. As a-tocopherol, resp. a-tocotrienol, can be prepared by methylation from β-tocophenol, resp. β-tocotrienol. This process offers also a very interesting synthetic route for a-tocopherol and a- tocotrienol.

This process is very advantageous as any Friedel-Crafts alkylation using substoichiometric Lewis-acidic salts becomes redundant and corrosive conditions can be avoided.

Further aspects of the invention are subject of further independent claims. Particularly preferred embodiments are subject of dependent claims.

Detailed description of the invention

In a first aspect the present invention relates to a process of preparing a compound of formula (I)

comprising the step of reacting compound of formula (II) with formula (III)

wherein R ⁵ represents either a completely saturated C _5- 25-alkyl group or a

C _5- 25-alkyl group comprising at least one carbon-carbon double bond;

wherein the dotted line indicates a double bond which is localized in one of the three indicated positions;

and wherein the wavy line represents a carbon-carbon bond which when linked to the carbon-carbon double bond is either in the Z or in the E-configuration;

in the presence of a gold(l) complex.

The term "independently from each other" in this document means, in the context of substituents, moieties, or groups, that identically designated

substituents, moieties, or groups can occur simultaneously with a different meaning in the same molecule.

The term "vitamin E" is used in the present document as a generic descriptor for all tocol and tocotrienol derivatives exhibiting qualitatively the biological activity of a-tocopherol (lUPAC-IUB Recommendation 1981 , Eur. J. Biochem. 123, 473-475 (1982)). A "Cx- _y -alkyl" group is an alkyl group comprising x to y carbon atoms, i.e., for example, a Ci-3-alkyl group is an alkyl group comprising 1 to 3 carbon atoms. The alkyl group can be linear or branched. For example -CH(CH ₃ )-CH ₂ -CH3 is considered as a C ₄ -alkyl group.

The term "hydrogen" means in the present document H and not H ₂ .

In the present document any single dotted line represents the bond by which a substituent is bound to the rest of a molecule.

The chirality of an individual chiral carbon centre is indicated by the label R or S according to the rules defined by R. S. Cahn, C. K. Ingold and V. Prelog. This R/S-concept and rules for the determination of the absolute configuration in stereochemistry is known to the person skilled in the art.

In case identical labels for symbols or groups are present in several formulae, in the present document, the definition of said group or symbol made in the context of one specific formula applies also to other formulae which comprises said same label.

The expression "process of preparation" is a synonym for "method of preparation" and can be used interchangeable to each other.

The anion tetra(3,5-bis(trifluoromethyl)phenyl)borate is abbreviated in the present document as "BAr _F " being known to the person skilled in the art also by the abbreviation "[BAr ^F ₄ ] ^~ ".

In the present document a specific structural element is used in some formulae. The use of said specific structural element is clarified by the following generic formula (X).

In formula (X) the dotted line indicates a double bond which is localized in one of the three indicated positions and the wavy line represents a carbon-carbon bond which when linked to the carbon-carbon double bond is either in the Z or in the E-configuration. A and B are residues attached to said structural element of the molecule.

Thus formula (X) actually represents the 5 different possibilities, i.e. (X-a), (X-b), (X-c), (X-d) or (X-e), by one formula.

Hence, a fornnula of compound of formula (III) represents the formul a), (lll-b), (lll-c), (lll-d) or (lll-e) by one formula.

The same concept is to be applied for compounds which comprise said structural element, such as for compounds of formula (I), (l-A), (III), (ΙΙΓ), (lll-A), (lll-B), (VI) and (VII). Said process of preparing compound of formula (I) comprises the step of reacting compound of formula (II) with formula (III).

Compound of formula (II) is 2,5-dimethylfuran which is commercially available.

Compound of formula (II) can be obtained from biomass such as cellulose. As biomass is a renewable raw material, the use of 2,5-dimethylfuran is very interesting from an ecological and sustainability point of view. The process of obtaining 2,5-dimethylfuran from biomass, respectively from fructose, is described in detail by Y. Roman-Leshkov et al., Nature 2007, 447, 982-985, the entire content of which is hereby incorporated by reference. Fructose is obtainable from glucose, a building block in cellulose.

The compounds of formula (III) can be produced by the reaction of mpound of formula (Xlll-a) and from compound of formula(XIII-b)

wherein X represents a halogen atom, particularly Br, and wherein R represents either H or SiR'3 wherein R' represents independently from each other a linear or branched C2-8-alkyl group or a C6-i2-aryl group. Particularly, R° is Si(CH ₃ ) ₃ or Si(CH ₂ CH ₃ ) ₃ (=Si(Et) ₃ ) or Si(CH(CH ₃ ) ₂ ) ₃ (=Si(iPr) ₃ ) or Si(C ₆ H ₅ ) ₃ (=Si(ph) ₃ ) or SiCH ₃ (C ₆ H ₅ ) ₂ or Si(CH ₃ ) ₂ C ₆ H ₅ or Si(CH ₃ ) ₂ (C(CH ₃ ) ₃ ).

More particularly, compounds of formula (III) can be obtained from the compounds of formula (Xlll-a) and from compound of formula (Xlll-b) by the following reaction scheme:

Furthermore, compound of formula (III) can be obtained from the compounds of formula (Xlll-c) and from compound of formula (Xlll-d) by the following reaction scheme:

(XIII-c)

wherein X' represents OH, CI or Br.

Furthermore, compound of formula (III) can be prepared from compound of formula (Xlll-e) by elimination of water.

(XIII-e) (III)

The group R ⁵ in the precedent formulae is particularly either a completely saturated C _5- 25-alkyl group (=R ⁵ ) or a C _5- 25-alkyl group comprising at least one carbon-carbon double bond.

wherein m represents an integer being 0 or 1 or 2 or 3 or 4;

and the dotted line represents the bond by which the substituent of formula (IV) is bound to the rest of the molecule such as of compound of formula (I) or formula (III);

and wherein the double bonds having dotted lines ( ) represent independently from each other either a single carbon-carbon bond or a double carbon-carbon bond;

and wherein ^* indicates a chiral centre in case the respective double bond having dotted line ( ) represents a single carbon-carbon bond.

Any carbon-carbon double bonds being eventually present in R ⁵ can be in the Z or in the E-configuration. Preferably, they are in the E-configuration, more preferably they are all in the E-configuration in case more than one carbon-carbon double bonds are present in R ⁵ . The chiral centre indicated by ^* has preferably the R configuration.

In one embodiment, R ⁵ is preferably of formula (IV-A), particularly (IV- -B).

R ⁵ , preferably R ^5' , is most preferably of formula (IV-A) or (IV-ARR).

Said process of preparing a compound of formula (I) comprises the step of reacting compound of formula (II) with formula (III) in the presence of a gold(l) complex.

The gold(l) complex has preferably the formula [Au(l)OL]AN wherein OL represents an organic ligand and AN represents a single charged anion.

The gold(l) complex has preferably a single charged anion (AN) which is selected from the group consisting of [BX ₄ ] ^" , [PX ₆ ] ^" , [SbF ₆ ] ^" , [CIO ₄ ] ^~ , CF ₃ COO ^" , sulfonates, particularly a sulfonate of formula (AN-I I), tetra(3,5-bis(trifluoromethyl)- phenyl)borate (BAr _F ), tetraphenylborate, and anions of formula (AN-1 )

wherein X represents a halogen atom, particularly F or CI; and Y ¹ represents a phenyl or a Ci-s-alkyl group which preferably is substituted by at least one halogen atom.

Preferably Y ¹ represents a CF ₃ group. So, preferably, the anions of formula (AN-I) is the anion of formula (AN-la), i.e. the anion of

bis(trifluoromethane)sulfonimide, which is also known as triflimidic acid.

Preferred sulfonates are halogenated anions of organic sulfonic acids, particularly of trifluoromethanesulfonic acid, which is also known as triflic acid, Therefore, the preferred sulfonates are trifluoromethanesulfonates, which are also known as triflates.

In a more preferred embodiment the anion (AN) in step b) is an anion which is selected from the group consisting of [BX ₄ ] ^" , triflate, and anions of formula

It is preferred that the gold(l) complex has an organic ligand (OL) which is either

- at least one phosphorous containing ligand, particularly a phosphorous containing ligand which is selected from the group consisting of formula (P1 ), (P2), (P3), (P4), (P5), (P6), (P7) and (P8);

or

- at least an imidazole-2-ylidene ligand, particularly 1 ,3-bis(2,6- diisopropylphenyl)-1 ,3-dihydro-2H-imidazol-2-ylidene (=compound of formula (IM));

or

- at least an 1 H-1 ,2,3-triazol ligand, particularly of formula (TR-1 ) or (TR-2) or (TR-3), more particularly of formula (TR-3);

P3) P4)

(P5)

(P7) (P8)

wherein R ¹⁰ and R >1"1 represent independently from each other either H or a linear or branched Ci-io-alkyl or C _4- io-cycloalkyl group;

and

wherein R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ represent independently from each other H or a linear or branched Ci-6-alkyl group;

n stands for an integer of 1 -6 and n' stands for 0 or 1 or 2.

The organic ligand (OL) of formula (P4) is also known as CyJohnPhos. The Au(l) complex can be added to one or a mixture of the starting material of compound of formula (II) and/or formula (III) as such, i.e. particularly in the form of a gold(l) complex of formula [Au(l)OL]AN, or the Au(l)-complex is formed in situ in one of the starting material or the reaction mixture (before or after the reaction has started).

The gold(l) complex is preferably formed in situ in the reaction mixture.

Particularly, the gold(l) complex is prepared from a gold(l) chloro complex and a silver(l) salt. The silver(l) salt is preferably Ag(l)AN. The organic ligand is in this case either present in the reaction of the gold(l) chloro complex with the silver(l) salt or is part of the gold(l) complex. By this reaction the desired gold(l), i.e. preferably [Au(l)OL]AN, is prepared. AgCI formed by this reaction as precipitate does not interfere negatively with the reaction of preparing the compound of formula (I).

Hence, the gold (I) complex is preferably of formula [Au(l)OL]AN wherein OL represents an organic ligand and AN represents a single charged anion and the gold (I) complex is prepared by the reaction of Au(l)OLCI and AgAN.

Preferred Au(l) complexes of the formula [Au(l)OL]AN are selected from the group consisting of

and [Au(l)P6]AN-la, wherein P6 is the organic ligand of formula (P6) and AN-la the anion of formula (AN-la). The gold(l) complex is used typically in a molar ratio of gold(l) complex to compound of formula (II) of 1 : 2 to 1 : 10Ό00, particularly 1 : 10 to 1 : 3Ό00, preferably 1 : 25 to 1 : 3Ό00. The molar ratio of compound of formula (II) to compound of formula (III) is preferably between 0.8 and 1 .2, preferably between 0.9 and 1 .1 , more preferably 1 .

The reaction is preferably carried out under normal pressure (i.e. 1013 mbar). The reaction temperature is particularly between 10 - 50 °C, preferably between 15 - 30 °C.

The reaction is usually carried out in an inert solvent (or mixture of inertsolvents). Preferably the solvent (or the mixture of solvents) has a pH of 7 or less than 7. Preferred solvents are halogenated solvents, particularly

dichloromethane, 1 ,2-dichloroethane, chloroform or 2,2,2-trifluoroethanol; or toluene, ethyl acetate, cyclohexanone or acetone. More preferred, the solvents are dichloromethane and 1 ,2-dichloroethane as well as a mixture of

dichloromethane with 5 % by volume of 2,2,2-trifluoroethanol.

The reaction of compound of formula (II) with formula (III) yields

compound of formula (I).

The substituent R ⁵ corresponds to the one used in its starting products, i.e. in formula (II) and (III).

It may be needed that undesired by-products are to be separated. Such separation can be easily performed by standard separation techniques such as distillation or chromatography.

The desired product of formula (I) is formed in very high yield. Most preferably connpound of formula (I) is compound of formula (l-A)

wherein ^* indicates a chiral centre.

Compound of formula(l) can be further reacted to compound of formula (V). Hence, in a further aspect, the invention relates to a process of preparing a compound of formul

comprising the steps of

a) oxidizing compound of formula (I) to compound of formula (VI)

followed by

b) reducing compound of formula (VI) to compound of formula (VII) c) acid ring closure of compound of formula (VII) to yield compound of formula (V).

The residue R ⁵ is the same as already discussed for compound of formula

(l) resp. (II) and (III).

In step a) compound of formula (I) is oxidized to compound of formula (VI). The oxidation is preferably carried out with air using salcomine as catalyst in ethanol according to the procedure published by A. Stocker, W.-D. Woggon, A. Ruttimann, Helv. Chim. Acta 1993, 76, 1729-1738, the entire content of which is hereby incorporated by reference. In step b) compound of formula (VI) is reduced to compound of formula

(VII). The reduction is preferably achieved with sodium dithionite in water according to the method as disclosed by K. Sato, Y. Fujima, A. Yamada Bull.

Chem. Soc. Jap. 1968, 41, 442-444, the entire content of which is hereby incorporated by reference.

Finally, in step c) compound of formula (V) is formed from compound of formula (VII) by acid ring closure.

Details for step c) are disclosed in WO 2004/046126 A1 , the entire content of which is hereby incorporated by reference. Preferred as acids for the ring closure are sulfonic acids, particularly fluorosulphonic acid, methanesulfonic acid, ethanesulphonic acid, trifluoromethanesulphonic acid or benzene-or p- toluenesulphonic acid, respectively. Trifluoromethanesulphonic acid and p- toluenesulphonic acid are the most preferred acid. The amount of acid used for the acid ring closure is preferably 0.01 - 10 mol-% in relation to compound of formula (VII). The temperature of the ring closure reaction is typically between 20 and 160 °C, preferably between 80 and 140 °C.

For the present invention, it is important to realize, that all compounds of formula (Vll-a), (Vll-b), (Vll-c), (Vll-d) or (Vll-e), respectively (covered all by formula (VII)) all yield only one product, i.e. compound of formula (V).

Hence, a separation of these isomers, or the separation of the isomers of their precursors of formula (I) resp. (VI) resp. (Ill) is not necessary. This leads to that the overall yield for the complete synthesis of compound of formula (V) from the starting compounds of formula (II) and (III) is very high.

When compound of formula (III) having the formula (IV-B) as substituent R ⁵ is used β-tocotrienol is obtained as compound of formula (V).

When compound of formula (III) having the formula (IV-A) as substituent R ⁵ is used β-tocopherol is obtained as compound of formula (V);

It is preferred that by this process compound of formula (V-A) is formed.

wherein ^* indicates a chiral centre.

It is preferred that the configuration of the chiral centres indicated by ^* is R. Particularly, it is preferred that all chiral centres are in the R configuration.

Compound of formula (VII) or (V-A) can be further methylated. Hence, in a further aspect, the invention relates to a process of preparing a compound of formula (V) comprising the steps

- preparing compound of formula (V) by a process as described above in details;

- methylating compound (V) to yield compound of formula (V)

wherein R ⁵ represents either a completely saturated C _5- 25-alkyl group or a C _5- 25-alkyl group comprising at least one carbon-carbon double bond;

and ^* represents the chiral centre of the chiral isomer.

Said alkylation, by which an H attached to an aromatic ring is replaced by a methyl group attached to an aromatic ring, is known to the person skilled in the art for example from EP 0 769 497 A1 or EP 0 735 033 A1 or Eur. J. Org. Chem., 2007, 1 176-1 183, the entire content of which is hereby incorporated by reference. Hence, compound of formula (V) is preferably hydroxymethylated or amino- methylated or chloromethylated. The hydroxymethylation or aminomethylation or chloromethylation, respectively, of formula (V) introduces by the use of a formaldehyde or source of formaldehyde such as para-formaldehyde, and HCI, water or methanol or a secondary amine (HNR" ₂ ), respectively, CH ₂ OH or CH ₂ CI or CH ₂ NR" ₂ (R" represents a Ci-s-alkyl group or the two R" groups form together a divalent group such as a C _4- i2-alkylene group or CH2CH2-O-CH2CH2) group(s), respectively, attached to the aromatic rings. After catalytic hydrogenation said CH ₂ OH or CH ₂ CI or CH ₂ NR" ₂ group(s), are transformed to methyl groups, by which compound of formula (V) is obtained.

A further method of methylation is disclosed in US 5,932,748, the entire content of which is hereby incorporated by reference. By this method using a mixed oxide hydrotalcite catalyst a permethylation (all protons attached directly to the aromatic rings are transformed to methyl groups) is obtained.

Therefore, in a preferred embodiment β-tocopherol is transformed to a- tocopherol.

Furthermore, the phenolic group of compound of formula (V) or (V) can be protected by reaction with a protecting agent to form compound of formula (V-P) or (V'-P)

Wherein R represents a phenol protecting group which is linked to the oxygen atom which is directly linked to the aromatic ring.

A phenol protection group is a group which protects the phenolic group and can be deprotected easily, i.e. by state-of-the-art methods, to the phenolic group again.

The phenol protection group forms with the rest of the molecule a chemical functionality which is particularly selected from the group consisting of ester, ether or acetal. The protection group can be easily removed by standard methods known to the person skilled in the art. In case where the phenol protection group forms with the rest of the molecule an ether, the substituent R ² is particularly a linear or branched CMO- alkyl or cycloalkyi or aralkyi group. Preferably the substituent R ² is a benzyl group or a substituted benzyl group, particularly preferred a benzyl group.

In case where the phenol protection group forms with the rest of the molecule an ester, the ester is an ester of an organic or inorganic acid.

If the ester is an ester of an organic acid, the organic acid can be a monocarboxylic acid or a polycarboxylic acid, i.e. an acid having two or more COOH-groups. Polycarboxylic acid are preferably malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid or fumaric acid.

Preferably the organic acid is a monocarboxylic acid.

Hence, the substituent R ² is preferably an acyl group. The acyl group is particularly a Ci _-7 -acyl, preferably acetyl, trifluoroacetyl, propionyl or benzoyl group, or a substituted benzoyl group.

If the ester is an ester of an inorganic acid, the inorganic acid is preferably nitric acid or a polyprotic acid, i.e. an acid able to donate more than one proton per acid molecule, particularly selected from the group consisting of phosphoric acid, pyrophosphoric acid, phosphorous acid, sulphuric acid and sulphurous acid.

In case where the phenol protection group forms with the rest of the molecule an acetal, the substituent R ² is preferably

with n=0 or 1 .

Hence, the acetals formed so are preferably methoxymethyl ether (MOM- ether), β-methoxyethoxymethyl ether (MEM-ether) or tetrahydropyranyl ether (THP-ether). The protection group can easily be removed by acid.

The protecting group is introduced by reaction of the compound of formula (V) or (V) with a protecting agent.

The protecting agents leading to the corresponding phenol protection groups are known to the person skilled in the art, as well as the chemical process and conditions for this reaction. If, for example, the phenol protection group forms with the rest of the molecule an ester, the suitable protecting agent is for example an acid, an anhydride or an acyl halide.

In the case that an ester is formed by the above reaction with the protecting agent, and that said ester is an ester of an organic polycarboxylic acid or an inorganic polyprotic acid, not necessarily all acid groups are esterified to qualify as protected in the sense of this document. Preferable esters of inorganic polyprotic acids are phosphates.

It is preferred that the protection group R ² is a benzoyl group or a Ci _-4 -acyl group, particularly acetyl group or trifluoroacetyl. The molecules in which R ² represents an acyl group, particularly an acetyl group, can be easily prepared from the corresponding unprotected molecule by esterification, respectively the phenolic compound can be obtained from the corresponding ester by ester hydrolysis. The phenol protecting group is preferably selected such that it is cleaved inside the human or animal body, particularly in the stomach.

As compound of formulae (III), (ΙΙΓ) and (lll-A) are important intermediates in the preparation of compound of formula (I) or (V) or (V), respectively, as described above in detail, further aspects of the present invention are compound of formula (ΙΙΓ) or of formula (lll-A), respectively.

wherein ^* represents a chiral centre; R° represents either H or SiR'3 wherein R' represents independently from each other a linear or branched C2-8-alkyl group or a C6-i2-aryl group ;

R ^5' represents a completely saturated C _5- 25-alkyl group;

and wherein the dotted line indicates a double bond which is localized in one of the three indicated positions;

and wherein the wavy line represents a carbon-carbon bond which when linked to the carbon-carbon double bond is either in the Z or in the E- configuration.

Particularly, R° represents Si(CH ₃ ) ₃ or Si(CH(CH ₃ ) ₂ )3 (=Si(iPr) ₃ or

Si(C ₆ H ₅ ) ₃ (=Si(ph) ₃ ) or SiCH ₃ (C ₆ H ₅ ) ₂ or Si(CH ₃ ) ₂ C ₆ H ₅ .

Particularly, R° is Si(CH ₃ ) ₃ or Si(CH ₂ CH ₃ ) ₃ (=SiEt ₃ ) or Si(CH(CH ₃ ) ₂ ) ₃ (=Si(iPr) ₃ ) or Si(C ₆ H ₅ ) ₃ (=Si(ph) ₃ ) or SiCH ₃ (C ₆ H ₅ ) ₂ or Si(CH ₃ ) ₂ C ₆ H ₅ or

Si(CH ₃ ) ₂ (C(CH ₃ ) ₃ ).

It is preferred that R° represents H.

In a further embodiment the invention relates to specific compounds compounds of above mentioned formula (III)

wherei ⁵ is of formula (IV)

with the proviso that at least one of said double bonds having dotted lines ( ) represents a single carbon-carbon bond.

Particularly such compounds are selected from the group consisting of 5,9,13,17-tetramethyloctadeca-4,16-dien-1 -yne, 5,9,13,17-tetramethyloctadeca- 4,12,16-trien-1 -yne, 5,9,13,17-tetramethyloctadeca-4, 8,16-trien-1 -yne, 5,9,13,17- tetramethyloctadeca-4,12-dien-1 -yne, 5,9,13,17-tetramethyloctadeca-4, 8,12-trien- 1 -yne, 5,9,13,17-tetramethyloctadeca-4,8-dien-1 -yne, 5,9,13,17-tetramethylocta- deca-4,8,16-then-1 -yne and 5,9,13,17-tetramethyloctadeca-4, 8,12-then-1 -yne.

More particularly, such specific compound of formula (III) are selected from the group consisting of (E)-5,9,13,17-tetramethyloctadeca-4,16-dien-1 -yne, (4E,12E)-5,9,13,17-tetramethyloctadeca-4,12,16-trien-1 -yne, (4E,8E)-5,9,13,17- tetramethyloctadeca-4,8,16-trien-1 -yne, (4E,12E)-5,9,13,17-tetramethyloctadeca- 4,12-dien-1 -yne, (4E,8E,12E)-5,9,13,17-tetramethyloctadeca-4,8,12-trien-1 -yne, (4E,8E)-5,9,13,17-tetramethyloctadeca-4,8-dien-1 -yne, (4E,8E)-5,9,13,17- tetramethyloctadeca-4,8,16-trien-1 -yne and (4E,8E,12E)-5,9,13,17- tetramethyloctadeca-4,8,12-trien-1 -yne.

Examples

General

The solvents were purchased from Fluka. All solvents and other chemicals were used without further purification. All reactions were carried out under argon. The reactions were monitored using GC. The crude products were analyzed by GC (area%), HPLC with external standard and quantitative NMR.

Gas chromatography

The GC analyses have been performed on an Agilent HP-6850 series system. The separation is achieved on an HP-1 Methyl Siloxane (30m x 0.32mm, 0.25 μηη) column with the following temperature program 50°C (0 min) -> 10 min -> 300°C (5 min). The samples were dissolved in ethyl acetate (5 mg in 1 ml_) and 1 μΙ_ was injected with a split ratio of 50:1 . GC-MS

GC-MS analysis was carried out on a Hewlett-Packard HP-6890, MSD-5973 series system. The separation is achieved on an HP-5MS (30 m x 250 μητι, 0.25 μΐη) column with the following temperature program:

70°C(0min)→(10°C/min)→315°C(15min).

The mass spectra have been generated by electron ionization.

IR

IR spectra have been generated on a Perkin Elmer Spectrum One FT-IR spectrometer in the range of 4000 - 600 cm ^"1 with a resolution of 4 cm ^"1 using 16 accumulations.

NMR

The NMR spectra were recorded on a Bruker Avance 300 spectrometer equipped with a 5 mm BBO BB-1 H probe head operating at 300 MHz for ¹ H and 75.5 MHz for ¹³ C. Spectra were recorded in CDCI3 and were referenced to residual chloroform (7.26 ppm CHCI ₃ ; 77.0 ppm CHCI ₃ ).

Equipment: 200-mL 4-necked flask, solid CO ₂ (-75°C), lcebath (0°C), 50mL dropping funnel, argon bubbler, thermometer, magnetic stirring bar.

The equipment was carefully dried and flushed with argon. Under argon 2.0 g 4-bromobut-1 -yne (14.6 mmol) was dissolved in 45 mL dry THF. The solution was cooled to -75°C using solid CO2. N-Butyl lithium in hexane was added dropwise (10.9 mL of 1 .6 M solution in hexane, corresponding to 17.5 mmol, 1 .2 equiv) over five minutes. The temperature of the solution rose to -30°C. The mixture was stirred for 15 minutes. Then 3.2 g chlorotriisopropylsilane (16.1 mmol, 1 .1 equiv.) in 6mL dry THF was added drop-wise. The mixture was allowed to warm to 0°C. The conversion was monitored by TLC (heptane/ methyl-tert.- Butylether (MTBE) = 20/1 v/v). After 1 h the silylation reaction was complete and the reaction mixture was carefully quenched with 50 mL 10% aqueous NH CI solution. The aqueous phase showed pH 4. The organic layer was washed twice with 50 mL each desalted water. The aqueous layer was extracted twice with 50 mL each diethyl ether. The combined organic phases were dried over Na2SO ₄ , filtered and concentrated at 20 °C bath temperature and 15 mbar during 1 h.

4.02 g of crude (4-bromobut-1 -yn-1 -yl)triisopropylsilane were obtained as a yellow oil with a purity of 86% (GC-MS).

Characterization:

¹ H NMR (300MHz, CDCI ₃ ) δ = 3.45 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.3 Hz, 2H), 1 .12 - 1 .00 (m, 21 H).

¹³ C NMR (75MHz, CDCI3) δ = 104.87, 83.08, 29.73, 24.37, 18.59, 1 1 .22.

Equipment: 100ml 4-necked round bottom flask, septum, reflux condenser, syringe pump, magnetic stirring bar, argon supply.

The glassware was dried under argon using a heat gun, then cooled to 23°C under vacuum and flushed with argon. The flask was then charged with 12.23g triphenylphosphane (46.6 mmol) and diluted in 25ml_ toluene leading to a colourless solution. Using a syringe pump 16.58g (4-bromobut-1 -yn-1 - yl)triisopropylsilane (42.4 mmol) were added over two hours. The addition was slightly exothermic, the colour of the solution turned to yellow. The solution was then heated with an oil-bath (135°C) to reflux overnight. After 15 hours the phosphonium salt had precipitated. The reaction mixture was allowed to cool to 23°C. The suspension was then filtered over a G3 filter. Toluene was replaced with n-pentane. The remainder was rinsed with pentane. After drying at 40°C and 20mbar, 20.13g crude bromotriphenyl(4-(triisopropylsilyl)but-3-yn-1 -yl)phos- phorane (white crystals) was obtained in a purity of 77% (yield 66%).

Equipment: 350ml 4-necked round bottom flask, 25ml dropping funnel, magnetic stirring bar, argon supply, thermometer, ice-bath

The glassware was dried as described above. The flask was then charged with 20g bromotriphenyl-(4-(triisopropylsilyl)but-3-yn-1 -yl)phosphorane (27.9 mmol) and 200ml_ dry THF leading to a white suspension. The suspension was cooled to 5°C.

n-Butyl lithium in hexane (17.45ml_, 1 .6 molar, 27.9 mmol) was added using a dropping funnel over a period of 35 minutes. The solution turned immediately to orange and finally to dark red at the end of the addition. The solution was stirred for five minutes.

6,10,14-trimethylpentadecan-2-one (7.50g, 27.9 mmol) was added over five minutes. The inner temperature rose to 1 1 °C. Stirring was continued for 4h at 5°C. Finally the reddish-brown suspension was allowed to warm to RT and then stirred for another 1 h. The reaction mixture was then quenched with 250ml_ ice- water. The aqueous layer was subsequently extracted with three times each 250ml_ heptane and the combined organic layers were washed with 250ml_ aqueous 10% NaCI-solution. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated at 40°C and 20mbar. The crude product was obtained in 20.61 g as a mixture of brown oil and white crystals. This mixture was then suspended in 200ml_ n-hexane, cooled overnight in a freezer to -20°C. The white crystals were filtered over a G3 filter, the filtrate was concentrated at 40°C and 20mbar. The crude triisopropyl(5,9,13,17-tetramethyloctadec-4-en-1 -yn-1 -yl)silane was obtained in 20.06g as brown oil in a purity of 47% (yield 76%).

Characterization:

¹ H NMR (300 MHz): δ = 0.83 (s, 3H, CH ₃ ); 0.86 (s, 6H, CH ₃ ); 0.88 (s, 3H, CH ₃ ); 1 .05 (s, 18H, TIPS-CHs) 1 .07 (s, 3H, CH ₃ ); 1 .08 (s, 3H, CH-Si); ); 0.99- 1 .15 (m, 16H, CH ₂ ), 1 .20- 1 .41 (m, 3H, CH), 1 .69 (d, 2H, J=1 .3 Hz, CH); 2.95 (dd, 2H, J=6.8, 1 .1 Hz, CH ₂ ); 5.20 (t, J=6.78 Hz, 1 H, CH).

¹³ C NMR (75 MHz) δ in ppm: δ = 1 1 .3; 1 1 .4; 18.5; 18.7; 18.8; ; 22.7; 22.74; 24.5; 24.8; 28.0; 32.8; 32.81 ; 37.3; 37.4; 39.4; 39.7; 79.4; 107.9; 1 18.9; 1 19.5; 137.7.

Equipment: 250ml round-bottom flask, magnetic stirrer, dropping funnel. The flask was charged with 9.9g triisopropyl(5,9,13,17- tetramethyloctadec-4-en-1 -yn-1 -yl)silane (21 .5 mmol), 100ml_ THF and 0.8ml_ desalted water leading to a colourless solution. Cooling the solution to 2°C. During 25 minutes a solution of 9.2g tetrabutylammonium fluoride hydrate in 36 ml_ THF was added. The mixture was stirred overnight. The reaction mixture was quenched with 200ml_ 10% NaHCO ₃ and the aqueous phase extracted three times with 200ml_ MTBE each. The combined organic layers were washed with 200ml_ aqueous 10% NaCI. The combined organic layers were dried over Na ₂ SO ₄ , filtred and dried at 40°C and 20mbara.

The crude product was obtained in 9.72g as light brown oil in a purity of 60% (GC-MS total ion count). The product was purified by column chromatography using pentane as eluent furnishing 4.31 g 5,9,13,17- tetramethyloctadec-4-en-1 -yne (61 % yield, purity of 93% q-NMR).

Characterization:

1H NMR (300 MHz): δ = 0.84 (d, 3H, J=2.3 Hz, CH ₃ ), 0.85- 0.87 (m, 6H,), 0.88 (s, 3H, CH ₃ ), 1 .04- 1 .42 (m, 18H, CH, CH ₂ ), 1 .48- 1 .55 (m, 1 H, CH ₂ ), 1 .62 (s, 1 H, CH ₂ ), 1 .71 (d, 2H, J=1 .1 Hz, M05), 1 .91 - 2.05 (m, 2H, CH ₂ ), 2.85- 2.94 (m, 2H, CH ₂ ), 5.16- 5.24 (m, 1 H, CH).

¹³ C NMR (CDCIs, 75MHz): δ = 138.5, 138.3 (E+Z), 1 18.6, 1 18.0 (E+Z), 83.6, 67.6, 67.6, 39.7, 39.4, 37.4, 37.3, 37.0, 36.9, 36.8, 36.7, 32.8, 32.7, 32.7, 32.1 , 28.0, 25.2, 24.8, 24.5, 23.3, 22.8, 22.7, 19.8, 19.7, 19.7, 17.5, 17.4, 16.0 ppm. GC-MS: M+ 454.4; 41 1 .3; 205.1 ; 157.1 ; 135.0; 109.1 ; 69.0; 41 .0.

IR (cm ^"1 ): 3314, 2952; 2925; 2120; 1667. Synthesis of 3,6-dimethyl-2-(3,7,1 1 ,15-tetramethylhexadec-2-en-1 -yl)phenol

OH

Equipment: Glovebox, 10ml vial, magnetic stirring bar, heating device.

In the vial are placed 0.027g AgSbF ₆ (0.08 mmol), 0.047 g CyJohnPhosAuCI (0.08 mmol), 0.429 mL 2,5-dimethylfuran (4 mmol) and 1 .218g 5,9,13,17-tetramethyloctadec-4-en-1 -yne (4 mmol). Dichloromethane (4 mL) is added leading to a dark purple mixture. The mixture was stirred for 94h at 60°C.

The suspension were filtered over celite, the filter washed with CH ₂ CI ₂ . The filtrate was concentrated at 40°C giving 1 .6g brownish dark oil. The purification was achieved with column chromatography (pentane/ MTBE) leading to 0.69g of the desired a.e-dimethyl^-ia .H.IS-tetramethylhexadec^-en-l- yl)phenol (sum of all 8 stereoisomers, 20% yield).

Characterization:

¹ H NMR (CDCI3, 300MHz): δ = 6.88 (d, J=7.3 Hz, 1 H), 6.66 (d, J=7.5 Hz, 1 H), 5.33 + 5.16 (2t, J=6.78 Hz, J=7.16 Hz, E+Z 1 H), 5.1 1 (d, J=3.8 Hz, 1 H), 3.37 +3.12 (2d, J=7.16 + 6.78 Hz, E+Z, 2H), 2.27 (s, 3H), 2.14 (s, 3H), 1 .99 (t, J=7.5 Hz, 2H), 1 .74 + 1 .73 (2t, J=4.14Hz, E+Z, 2H), 1 .48-1 .57 (m, 4H), 1 .03-1 .41 (m, 16H), 0.88 (d, J= 6.22 Hz, 6H), 0.86 (d, J=6.22Hz, 6H).

¹³ C NMR (75MHz, CDCI ₃ ) δ = 139.99 + 138.91 (E+Z), 128.12, 122.01 , 121 .9; 1 16.1 1 , 43.23, 39.41 , 37.42, 37.33, 36.95, 32.82, 32.75, 32.34, 29.47, 28.01 , 25.75, 25.24, 24.84, 24.49, 23.46, 22.75, 22.65, 19.90, 19.78, 19.71 , 15.83.

IR (cm ^"1 ): 3481 ; 2951 , 2924, 2866, 1582, 1492, 1462.

HRMS: found M ⁼ 400.3693, C28H28O. Calc. 400.37.

Equipment: 10ml 2-necked-roundbottomflask, magnetic stirring bar, thermometer

The starting material 3,6-dimethyl-2-(3,7,1 1 ,15-tetramethylhexadec-2-en- 1 -yl)phenol (0.2 g, 0.299 mmol) was dissolved in ethanol (3 ml_) and the the solution cooled to 10°C. The catalyst salcomine (19.6 mg, 0.12 mmol, 0.24 eq.) and another 3 ml_ ethanol was added. An air stream was flowing over the solution for 20 hours at 23°C leading to a dark-brown reaction mixture.

The solvent was evaporated at 40°C and 20 mbar, leading to 0.14g of brown oil that contained some small dark particles. For purification the crude product was diluted in pentane and chromatographed (eluent 100% pentane). The 2,5- dimethyl-3-(3,7,1 1 ,15-tetramethylhexadec-2-en-1 -yl)quinone was obtained in 33 mg as yellow oil. Characterization:

¹ H NMR (CDCI ₃ , 300MHz): δ = 6.55 (d, J=1 .5 Hz, 1 H); 4.94 (2t, J=6.9, 8.1 ; E+Z, 1 H); 3.21 (d, J=7Hz, 2H); 2.04 (d, J=1 .5Hz, 3H); 2.02 (s, 3H); 2.0-1 .84 (m, 3H); 1 .71 -1 .75 (m; 2H); 1 .65-1 .68 (m, 2H); 1 .46-1 .55 (m, 4H); 1 .4-1 .0 (m); 0.88 (d, J=6.6Hz, 6H); 0.85 (d, J=8.1 Hz, 6H).

¹³ C NMR (75MHz, CDCI ₃ ) δ = 145.37, 140.58, 138.21 , 133.03, 1 19.45, 40.04,

39.41 , 37.42, 37.33, 37.16, 37.07, 32.81 , 32.31 , 29.73, 28.01 , 25.42, 24.84, 24.50,

23.42, 22.75, 22.66, 19.72, 16.25, 15.96, 1 1 .92. Synthesis of 2,5-dimethyl-3-(3,7,1 1 ,15-tetramethylhexadec-2-en-1 -vDhvdro- quinone

Equipment: 10ml 2-necked-roundbottom flask, magnetic stirring bar, septum, syringe, light shield.

Under argon atmosphere the starting material 2,5-dimethyl-3-(3,7,1 1 ,15- tetramethylhexadec-2-en-1 -yl)hydroquinone (0.033 g, 0.08 mmol) was taken up in THF (0.4 mL) and shielded from light under a black towel. Into the resulting yellow solution was added a solution of sodium dithionate (0.039 g) in water (0.2ml_) over 30 minutes (dropwise addition via syringe). The reaction mixture was stirred for 30 min. and afterwards the THF was removed. According to TLC the reaction was still not complete. Another solution of sodium dithionate ( 0.039g in 0.2 mL water) was added and stirred overnight. For work-up the reaction was extracted three times with 1 mL each dichloromethane. The combined organic phases were washed three times with 1 mL each water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure (40°C, 10mbar). The 2,5-dimethyl-3-(3,7,1 1 ,15-tetramethylhexadec-2-en-1 -yl)hydroquinone was obtained in 27 mg as a light yellow solid. It was immediately transformed in the following reaction step. ynthesis of β-tocopherol

Equipment: 10ml round-bottom flask, magnetic stirring bar, reflux condenser, argon supply.

Under argon at 23°C the flask was charged with 27mg 2,5-dimethyl-3- (3,7,1 1 ,15-tetramethylhexadec-2-en-1 -yl)hydroquinone (0.065 mmol), 1 mL ethylene carbonate, and 1 mL n-heptane leading to a light yellow biphasic mixture. Under vigorous stirring one drop of sulfuric acid was added. The mixture was heated to 120°C and refluxed for three hours.

After three hours, the reaction mixture was cooled to room temperature. Three phases were obtained, one solid phase and two liquid phases. The reaction mixture was diluted with heptane (4 mL). The layers were separated and the ethylene carbonate layer was washed with 4 mL heptane. The combined heptane layers were concentrated under reduced pressure at 20 mbar giving 29 mg of a brown oil. The crude product was analyzed by NMR, GC-MS and LC-MS. The spectra and chromatograms were shown to be identical to analyses of commercially available β-tocopherol.