WO2018050792A1 - Process for preparing esters of 12'-apocarotenals as building blocks for carotenoids - Google Patents

Abstract

The present invention relates to a process for preparing a 12'-apocarotenal ester of the formula (I), R¹ is e.g. hydrogen, C₁-C₂₀-alkyl, C2-C2o-alkenyl, C₄-C₂₀-alkdienyl, C₆-C₂₀-alktrienyl or C₈-C₂₀-alktetraenyl, R² is e.g. hydrogen or -NRaRb, wherein R^a is e.g. hydrogen, C₁-C₄-alkyl, -C(0)-C₁-C₃-alkyl, -Boc or -Cbz, R^b is e.g. hydrogen or C₁-C₄-alkyl, R³ is e.g. hydrogen, and X is CH₂ or C=0, the process being characterized in that an alcohol of the formula (IV), is reacted with a carboxylic acid or one of its derivatives of the formula (V), wherein the variables R¹, R² and R³ are as defined above, and for n = 1 the variable Z is halogen, -OH or -0-C(0)-C₁-C₄-alkyl, and for n = 2 the variable Z is O or S, wherein the reaction is carried out in the presence of a tertiary amine and in case a compound of the formula (IV) with Z = -OH is used also in the presence of an activator. The invention further relates to certain 12'-apocarotenal esters of the formula (I).

Description

Process for preparing esters of 12'-apocarotenals as building blocks for carotenoids

The present invention relates to a new process for preparing an 12'-apocarotenal ester of the formula (I),

wherein R¹, R², R³ and X are as defined herein. BACKGROUND OF THE INVENTION

Apocarotenals are naturally occurring degradation products of the corresponding carotenoid-type tetraterpenes, e.g. β-carotene, astaxanthin, zeaxanthin or lutein, and, thus, are present in many carotenoid-containing foods (see e.g. H. Etoh et al. 2012, J. Oleo Sci. 61 ,17; N. Akimoto et al. 2000, J. Mass Spectrom. Soc. 48, 32). Since zeaxanthin and astaxanthin stemming from natural sources are usually mono- or diesterified, the respective esterified apocarotenals have also to be expected in food products (see Y. Weesepoel et al. 2014, J. Agricult. Food Chem. 62, 10254). In addition, apocarotenals are known to be valuable building blocks for the synthesis of asymmetric carotenoids. 12'-Apocarotenals are particularly useful for this purpose, because they can be converted to asymmetric tetraterpenes, such as lutein, via a Wittig reaction or a Julia olefination with the corresponding Ci5-phosphonium salts and Ci5-sulfones, respectively, which are well established starting compounds for carotenoid syntheses.

12'-Apozeaxanthinal as well as 12'-apoastaxanthinal of the formula (IV) are typically prepared by the Wittig reaction of the appropriate Ci5-phosphonium salt with the respective Cio-dial, as described e.g. by J. A. Haugan et al. 1994, Acta Chem. Scand. 48, 899; and K. Bernhard et al. 1981 , Helv. Chim. Acta 64, 2469.

X = CO: 12 '-Apoastaxanthinal,

X = CH₂: 12'-Apozeaxanthinal.

In contrast, so far preparations of esters of 12'-apozeaxanthinal or

12'-apoastaxanthinal are practically unknown, with the only exception of the esterification of 12'-apoastaxanthinal using phenoxyacetyl chloride (see K. Bernhard et al. 1980, Helv. Chim. Acta 63, 1473). In this case, however, the phenoxyacetyl group functions as a transient protection group, only, which does not even survive

conventional conditions of a Wittig reaction.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a process for preparing a broad spectrum of esters according to formula (I), with the esters being derived from a variety of different acids, including in particular fatty acids and optionally N-protected amino acids. The process should, in addition, be simple to perform and should enable good yields of the desired esters.

It has been found that this object can indeed be achieved by acylating the unesterified 12'-apocarotenal of the formula (IV) as defined herein, with a carboxylic acid or an activated carboxylic acid in the presence of a tertiary amine. This finding is surprising because the prior art does not provide any indication that such an introduction of an permanent ester group in position 3 of 12'-apozeaxanthinal or 12'-apoastaxanthinal is possible.

Accordingly, the invention firstly relates to a process for the preparation of an ester of the formula (I), which comprises reacting an alcohol of the formula (IV) with a carboxylic acid or one of its derivatives of the formula (V), wherein the reaction is carried out in the presence of a tertiary amine and, in case a compound of the formula (V) with Z = -OH is used, also in the presence of an activator.

In formula (I) the variables X, R¹, R² and R³ have the following meanings: R¹ is selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl, Ci-C4-alkoxy, where the alkyl, alkenyl, alkdienyl, alktrienyl, alktetraenyl and alkpentaenyl moieties of the seven aforementioned residues are unsubstituted or carry 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH and Ci-C4-alkoxy,

C6-Cio-aryl, benzyl, where the aryl moieties of the two aforementioned residues are unsubstituted or may carry 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH, Ci-C4-alkyl and Ci-C4-alkoxy,

A-COOH, A-CONH2, A-COO-(Ci-C₄-alkyl), and

A-NR^aR^b,

R² and R³ are each independently from one another selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, Cs-C2o-alktetraenyl and Cio-C2o-alkpentaenyl, where the alkyl, alkenyl, alkdienyl, alktrienyl, alktetraenyl and alkpentaenyl moieties of the six aforementioned residues are unsubstituted or carry 1 , 2 or 3 substituents selected from the group consisting of halogen and Ci-C4-alkoxy,

R² may also be selected from the group consisting of

-COOH, -COO-(Ci-C₄-alkyl), and

-NR^aR^b, or

R¹ and R² together form a grou of the formula (II),

wherein

_* is the attachment point to the remainder of the molecule,

R^c is selected from the group consisting of hydrogen, Ci-Cig-alkyl,

C2-Ci9-alkenyl, C4-Cig-alkdienyl, C6-Ci9-alktrienyl, Cs-dg-alktetraenyl, Ci-C₄-alkandiyl-COOH, C₂-C₄-alkendiyl-COOH, C₂-C₄-alkyndiyl-COOH, and R^d is hydrogen or Ci-C4-alkyl, or

R¹, R² and R³ together form a group of the formula

^■R wherein * and R^c have the meanings defined above, or

if R² is -NR^aR^b, R¹ together with R^a may form a C3-C4-alkandiyl group,

X is CH₂ or C=0, R^a is selected from the group consisting of hydrogen, Ci-C4-alkyl, -C(0)H,

-C(0)-Ci-C3-alkyl, C4-C7-cycloalkyl, and N-protecting groups such as tert- butyloxycarbonyl (-Boc) and carboxybenzyl (-Cbz),

R^b is selected from the group consisting of hydrogen, Ci-C4-alkyl,

-C(0)-Ci-C3-alkyl, and N-protecting groups such as -Boc and -Cbz, and

A is selected from the group consisting of d-Cs-alkandiyl, C2-Cs-alkendiyl and C2-C5-alkyndiyl.

In formula (IV) X is CH₂ or C=0.

In formula (V) the variables R¹, R² and R³ have the meanings defined for formula (I), and

for n = 1 the variable Z is selected from the group consisting of halogen, -OH,

-0-C(0)-Ci-C₄-alkyl, and

for n = 2 the variable Z is O or S.

The invention further relates to 12'-apocarotenal esters of the formula (I) as defined herein, provided that the group -C(0)CR¹R²R³ is not acetyl, i.e. R¹, R² and R³ are not simultaneously hydrogen.

The inventive process affords an easy and efficient access to the 12'-apocarotenal ester of the formula (I) in sufficient yield and good specificity by starting from the corresponding alcohol of the formula (IV), which itself is generally readily obtainable in good quality and high yield.

The 12'-apocarotenal esters of the formula (I) may serve as a starting material for monoesters of symmetric tetraterpenes, such as astaxanthin or zeaxanthin via Wittig reaction or a Julia olefination with the corresponding Ci5-phosphonium salts and

Ci5-sulfones, respectively.

DETAILED DESCRIPTIOM OF THE INVENTION

In the context of the present invention the terms used generically are defined as follows:

The prefix C_x-C_y denotes the number of possible carbon atoms in the particular case.

The term "halogen" in each case denotes fluorine, bromine, chlorine or iodine, preferably fluorine, chlorine or bromine, and specifically chlorine. The term "Ci-C2o-alkyl" as used herein and in the alkyl moieties of alkoxy and the like refers to saturated straight-chain or branched hydrocarbon radicals having 1 to 3

("Ci-C₃-alkyl"), 1 to 4 ("Ci-C₄-alkyl") or 1 to 20 ("Ci-C₂₀-alkyl") carbon atoms.

Ci-C3-Alkyl is methyl, ethyl, propyl or isopropyl. Ci-C₄-Alkyl is additionally butyl,

1 -methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) or 1 ,1 -dimethylethyl (tert-butyl). Ci-C2o-Alkyl is additionally also, for example, pentyl, 1 -methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, hexyl, 1 -methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethylpropyl,

1 - ethyl-1 -methylpropyl, 1 -ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl and positional isomers thereof. The term "C2-C2o-alkenyl" as used herein refers to monounsaturated straight-chain or branched hydrocarbon radicals having 2 to 20 carbon atoms and a double bond in any position, for example ethenyl 1 -propenyl, 2-propenyl, 1 -methylethenyl, 1 -butenyl,

2- butenyl, 3-butenyl, 1 -methyl-1 -propenyl, 2-methyl-1 -propenyl, 1 -methyl-2-propenyl,

2- methyl-2-propenyl, 1 -pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl-1 -butenyl,

3-methyl-1 -butenyl, 1 -methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl,

3- methyl-3-butenyl, 1 , 1 -dimethyl-2-propenyl, 1 ,2-dimethyl-1 -propenyl,

1 ,2-dimethyl-2-propenyl, 1 -ethyl-1 -propenyl, 1 -ethyl-2-propenyl, 1 -hexenyl, 3-hexenyl, 5-hexenyl, 1 -methyl-1 -pentenyl, 3-methyl-1 -pentenyl, 2-methyl-2-pentenyl,

4- methyl-2-pentenyl, 1 -methyl-3-pentenyl, 4-methyl-3-pentenyl, 2-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1 ,1 -dimethyl-2-butenyl, 1 ,1 -dimethyl-3-butenyl,

1 .2- dimethyl-1 -butenyl, 1 ,2-dimethyl-2-butenyl, 1 ,2-dimethyl-3-butenyl,

1 .3- dimethyl-1 -butenyl, 1 ,3-dimethyl-2-butenyl, 1 ,3-dimethyl-3-butenyl,

2.2- dimethyl-3-butenyl, 2,3-dimethyl-1 -butenyl, 2,3-dimethyl-2-butenyl,

2.3- dimethyl-3-butenyl, 3,3-dimethyl-1 -butenyl, 3,3-dimethyl-2-butenyl,

1 -ethyl-1 -butenyl, 1 -ethyl-2-butenyl, 1 -ethyl-3-butenyl, 2-ethyl-1 -butenyl,

2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1 ,1 ,2-trimethyl-2-propenyl,

1 -ethyl-1 -methyl-2-propenyl, 1 -ethyl-2-methyl-1 -propenyl, 1 -ethyl-2-methyl-2-propenyl,

1 - hexenyl, 2-hexenyl, 3-hexenyl, 1 -heptenyl, 2-heptenyl, 3-heptenyl, 1 -octenyl,

2- octenyl, 3-octenyl, 4-octenyl, as well as linear and branched isomers of nonenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, such as (8Z)-nonenyl, and mixtures thereof, linear and branched isomers of decenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, and mixtures thereof, linear and branched isomers of undecenyl which may differ in the position and configuration of the double bond and the type of the possible branching, and mixtures thereof, linear and branched isomers of dodecenyl which may differ in the position and the

configuration of the double bond and the type of the possible branching, such as (7Z)- dodecenyl, and mixtures thereof, linear and branched isomers of tridecenyl which may differ in the position and configuration of the double bond and the type of the possible branching, and mixtures thereof, linear and branched isomers of tetradecenyl which may differ in the position and configuration of the double bond and the type of the possible branching, such as (7Z)-tetradecenyl and (4Z)-tetradecenyl, and mixtures thereof, linear and branched isomers of pentadecenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, and mixtures thereof, linear and branched isomers of hexadecenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, such as (7Z)-hexadecenyl, (7E)-hexadecenyl and (9E)-hexadecenyl, and mixtures thereof, linear and branched isomers of heptadecenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, and mixtures thereof, linear and branched isomers of octadecenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, such as (7Z)-octadecenyl and (9Z)-octadecenyl, and mixtures thereof, linear and branched isomers of nonadecenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, and mixtures thereof, and linear and branched isomers of eicosenyl which may differ in the position and the configuration of the double bond and the type of the possible branching, such as (9Z)-eicosenyl and (1 1 Z)-eicosenyl, and mixtures thereof. The term "C4-C2o-alkdienyl" as used herein refers to diunsaturated straight-chain or branched hydrocarbon radicals having 4 to 20 carbon atoms and two double bonds in any positions, provided that the two double bounds are either conjugated or isolated, for example 1 ,3-butadienyl, 1 ,3-pentadienyl, 2,4-pentadienyl, 1 ,4-pentadienyl,

1 .3- hexadienyl, 1 ,4-hexadienyl, 1 ,5-hexadienyl, 2,4-hexadienyl, 2,5-hexadienyl, 1 ,3-heptadienyl, 1 ,4-heptadienyl, 1 ,5-heptadienyl, 1 ,6-heptadienyl, 2,4-heptadienyl, 2,5-heptadienyl, 2,6-heptadienyl, 3,5-heptadienyl, 3,6-heptadienyl, 1 ,3-octadienyl,

1 .5- octadienyl, 1 ,7-octadienyl, 2,4-octadienyl, 2,6-octadienyl, 3,5-octadienyl,

3.7- octadienyl, 4,6-octadienyl, 5,7-octadienyl, 1 ,3-nonadienyl, 1 ,4-nonadienyl,

1 .6- nonadienyl, 1 ,8-nonadienyl, 2,4-nonadienyl, 2,7-nonadienyl, 3,5-nonadienyl, 4,6-nonadienyl, 5,7-nonadienyl, 6,8-nonadienyl, 1 ,3-decadienyl, 1 ,6-decadienyl,

2.4- decadienyl, 2,8-decadienyl, 3,5-decadienyl, 4,6-decadienyl, 5,7-decadienyl,

6.8- decadienyl, 7,9-decadienyl, 1 ,3-undecadienyl, 1 ,8-undecadienyl, 2,4-undecadienyl,

2.9- undecadienyl, 3,5-undecadienyl, 4,6-undecadienyl, 5,7-undecadienyl,

5.10- undecadienyl, 6,8-undecadienyl, 7,9-undecadienyl, 8,10-undecadienyl, 1 ,3-dodecadienyl, 1 ,8-dodecadienyl, 2,4-dodecadienyl, 2,7-dodecadienyl,

3.5- dodecadienyl, 4,6-dodecadienyl, 5,7-dodecadienyl, 5,1 1 -dodecadienyl,

6.8- dodecadienyl, 7,9-dodecadienyl, 8,10-dodecadienyl, 9,1 1 -dodecadienyl,

1 ,3-tridecadienyl, 1 ,8-tridecadienyl, 2,4-tridecadienyl, 3,5-tridecadienyl,

4,6-tridecadienyl, 5,7-tridecadienyl, 5,1 1 -tridecadienyl, 6,8-tridecadienyl,

7.9- tridecadienyl, 8,10-tridecadienyl, 9,1 1 -tridecadienyl, 10,12-tridecadienyl,

1 ,3-tetradecadienyl, 1 ,9-tetradecadienyl, 2,4-tetradecadienyl, 3,5-tetradecadienyl,

4.6- tetradecadienyl, 5,7-tetradecadienyl, 5,1 1 -tetradecadienyl, 6,8-tetradecadienyl, 7,9-tetradecadienyl, 8,10-tetradecadienyl, 9,1 1 -tetradecadienyl, 10,12-tetradecadienyl, 1 1 ,13-tetradecadienyl, 1 ,3-pentadecadienyl, 1 ,9-pentadecadienyl, 2,4-pentadecadienyl, 3,5-pentadecadienyl, 4,6-pentadecadienyl, 5,7-pentadecadienyl, 5,12-pentadecadienyl, 6,8-pentadecadienyl, 7,9-pentadecadienyl, 8,10-pentadecadienyl,

9,1 1 -pentadecadienyl, 10,12-pentadecadienyl, 1 1 ,13-pentadecadienyl,

12,14-pentadecadienyl, as well as linear and branched isomers of hexadecadienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, such as (7Z,10Z)-hexadecadienyl and

(7E,10E)-hexadecadienyl, and mixtures thereof, linear and branched isomers of heptadecadienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, linear and branched isomers of octadecadienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, linear and branched isomers of nonadecadienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, and linear and branched isomers of eicosadienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof.

The term "C6-C2o-alktrienyl" as used herein refers to triunsaturated straight-chain or branched hydrocarbon radicals having 6 to 20 carbon atoms and three double bonds in any positions, provided that the each pair out of the three double bounds is either conjugated or isolated, for example 1 ,3,5-hexatrienyl, 1 ,3,5-heptatrienyl,

1 ,4,6-heptatrienyl, 1 ,3,6-heptatrienyl, 2,4,6-heptatrienyl, 1 ,3,5-octatrienyl,

1 ,3,6-octatrienyl, 1 ,3,7-octatrienyl, 1 ,4,6-octatrienyl, 1 ,4,7-octatrienyl, 1 ,5,7-octatrienyl, 2,4,6-octatrienyl, 2,4,7-octatrienyl, 2,5,7-octatrienyl, 3,5,7-octatrienyl, 1 ,3,5-nonatrienyl, 1 ,3,8-nonatrienyl, 2,4,6-nonatrienyl, 2,4,7-nonatrienyl, 3,5,7-nonatrienyl,

4.6.8- nonatrienyl, 1 ,4,7-nonatrienyl, 1 ,3,5-decatrienyl, 1 ,3,8-decatrienyl,

2.4.6- decatrienyl, 2,4,9-decatrienyl, 3,5,7-decatrienyl, 4,6,8-decatrienyl,

5.7.9- decatrienyl, 2,5,7-decatrienyl, 1 ,6,8-decatrienyl, 2,7,9-decatrienyl,

1 .4.7- decatrienyl, 2,5,9-decatrienyl, 1 ,3,5-undecatrienyl, 1 ,3,8-undecatrienyl, 1 .6.8- undecatrienyl, 2,4,6-undecatrienyl, 2,4,10-undecatrienyl, 2,6,9-undecatrienyl,

2.7.9- undecatrienyl, 3,5,7-undecatrienyl, 4,6,8-undecatrienyl, 4,7,10-undecatrienyl,

5.7.9- undecatrienyl, 6,8,10-undecatrienyl, 1 ,3,5-dodecatrienyl, 1 ,3,8-dodecatrienyl,

1 .6.8- dodecatrienyl, 2,4,6-dodecatrienyl, 2,4,10-dodecatrienyl, 2,6,9-dodecatrienyl, 3,5,7-dodecatrienyl, 4,6,8-dodecatrienyl, 4,7,1 1 -dodecatrienyl, 5,7,9-dodecatrienyl,

6.8.10- dodecatrienyl, 7,9,1 1 -dodecatrienyl, 1 ,3,5-tridecatrienyl, 1 ,3,7-tridecatrienyl, 1 ,8,10-tridecatrienyl, 2,4,6-tridecatrienyl, 2,4,10-tridecatrienyl, 2,7,10-tridecatrienyl, 3,5,7-tridecatrienyl, 4,6,8-tridecatrienyl, 4,7,1 1 -tridecatrienyl, 5,7,9-tridecatrienyl, 6,8,10-tridecatrienyl, 7,9,1 1 -tridecatrienyl, 8,10,12-tridecatrienyl, 1 ,3,5-tetradecatrienyl, 1 ,3,9-tetradecatrienyl, 2,4,6-tetradecatrienyl, 2,4,10-tetradecatrienyl,

2.7.10- tetradecatrienyl, 3,5,7-tetradecatrienyl, 4,6,8-tetradecatrienyl,

4.7.1 1 - tetradecatrienyl, 5,7,9-tetradecatrienyl, 6,8,10-tetradecatrienyl,

7,9,1 1 -tetradecatrienyl, 7,10,12-tetradecatrienyl, 8,10,12-tetradecatrienyl,

9,1 1 ,13-tetradecatrienyl, 1 ,3,5-pentadecatrienyl, 1 ,3,1 1 -pentadecatrienyl,

2,4,6-pentadecatrienyl, 2,4,9-pentadecatrienyl, 2,9,12-pentadecatrienyl,

3,5,7-pentadecatrienyl, 4,6,8-pentadecatrienyl, 4,7,10-pentadecatrienyl,

5.7.9- pentadecatrienyl, 6,8,10-pentadecatrienyl, 7,9,1 1 -pentadecatrienyl,

7,10,12-pentadecatrienyl, 8,10,12-pentadecatrienyl, 9,1 1 ,13-pentadecatrienyl, 10,12,14-pentadecatrienyl, as well as linear and branched isomers of hexadecatrienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, such as (7Z,10Z,13Z)-hexadecatrienyl,

(4Z,7Z,10Z)-hexadecatrienyl, (6E,8E,10Z)-hexadecatrienyl,

(7Z,9E,1 1 Z)-hexadecatrienyl, (7Z,9E,1 1 E)-hexadecatrienyl and

(7E,9E,1 1 E)-hexadecatrienyl, and mixtures thereof, linear and branched isomers of heptadecatrienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, linear and branched isomers of octadecatrienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, linear and branched isomers of nonadecatrienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, and linear and branched isomers of eicosatrienyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof. The term "C8-C2o-alktetraenyl" as used herein refers to tetraunsaturated straight-chain or branched hydrocarbon radicals having 8 to 20 carbon atoms and four double bonds in any positions, provided that the each pair out of the four double bounds is either conjugated or isolated, for example 1 ,3,5,7-octatetraenyl, 1 ,3,5,7-nonatetraenyl, 1 ,3,5,8-nonatetraenyl, 2,4,6,8-nonatetraenyl, 1 ,4,6,8-nonatetraenyl, 1 ,3,6,8-nonatetraenyl, 1 ,3,5,7-decatetraenyl, 1 ,3,5,9-decatetraenyl,

2.4.6.8- decatetraenyl, 2,4,7,9-decatetraenyl, 3,5,7,9-decatetraenyl,

1 ,3,5,7-undecatetraenyl, 1 ,3,8,10-undecatetraenyl, 2,4,6,8-undecatetraenyl,

2,4,7,10-undecatetraenyl, 3,5,7,9-undecatetraenyl, 4,6,8, 10-undecatetraenyl,

1 ,3,5,7-dodecatetraenyl, 1 ,3,6,8-dodecatetraenyl, 2,4,6,8-dodecatetraenyl,

2.5.8.10- dodecatetraenyl, 3,5,7,9-dodecatetraenyl, 4,6,8, 10-dodecatetraenyl,

4.6.9.1 1 - dodecatetraenyl, 5,7,9,1 1 -dodecatetraenyl, 1 ,3,5,7-tridecatetraenyl,

1 .3.8.10- tridecatetraenyl, 2,4,6,8-tridecatetraenyl, 2,5,8,1 1 -tridecatetraenyl,

3.5.7.9- tridecatetraenyl, 3,5,8,1 1 -tridecatetraenyl, 4,6,8,10-tridecatetraenyl,

5,7,9,1 1 -tridecatetraenyl, 6,8,10,12-tridecatetraenyl, 1 ,3,5,7-tetradecatetraenyl,

1 .3.9.1 1 - tetradecatetraenyl, 2,4,6,8-tetradecatetraenyl, 2,5,8,1 1 -tetradecatetraenyl,

3.5.7.9- tetradecatetraenyl, 3,5,9,12-tetradecatetraenyl, 4,6,8, 10-tetradecatetraenyl, 5,7,9,1 1 -tetradecatetraenyl, 6,8,10,12-tetradecatetraenyl, 7,9,1 1 ,13-tetradecatetraenyl, 1 ,3,5,7-pentadecatetraenyl, 1 ,4,10,13-pentadecatetraenyl, 2,4,6,8-pentadecatetraenyl, 2,4,9,1 1 -pentadecatetraenyl, 3,5,7,9-pentadecatetraenyl, 3,5,8,1 1 -pentadecatetraenyl,

4.6.8.10- pentadecatetraenyl, 5,7,9,1 1 -pentadecatetraenyl,

6,8,10,12-pentadecatetraenyl, 7,9,1 1 ,13-pentadecatetraenyl,

8,10,12,14-pentadecatetraenyl, 1 ,3,5,7-hexadecatetraenyl, 2,4,6,8-hexadecatetraenyl,

2.6.9.12- hexadecatetraenyl, 3,5,7,9-hexadecatetraenyl, 4,6,8, 10-hexadecatetraenyl, 5,7,9,1 1 -hexadecatetraenyl, 6,8, 10,12-hexadecatetraenyl,

6,8,1 1 ,14-hexadecatetraenyl, 7,9,1 1 ,13-hexadecatetraenyl,

8.10.12.14- hexadecatetraenyl, 8,10,13,15-hexadecatetraenyl,

9.1 1 .13.15- hexadecatetraenyl, 1 ,3,5,7-heptadecatetraenyl, 2,4,6,8-heptadecatetraenyl, 3,5,7,9-heptadecatetraenyl, 4,6,8, 10-heptadecatetraenyl,

4,7,10,13-heptadecatetraenyl, 5,7,9,1 1 -heptadecatetraenyl,

6.8.10.12- heptadecatetraenyl, 6,8,1 1 ,14-heptadecatetraenyl,

7.9.1 1 .13- heptadecatetraenyl, 7,9,12,14-heptadecatetraenyl,

8,10,12,14-heptadecatetraenyl, 9,1 1 ,13, 15-heptadecatetraenyl,

10,12,14,16-heptadecatetraenyl, as well as linear and branched isomers of

octadecatetraenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, such as

(3Z,6Z,9Z,12Z)-octadecatetraenyl, and mixtures thereof, linear and branched isomers of nonadecatetraenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, and linear and branched isomers of eicosatetraenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof. The term "Cio-C2o-alkpentaenyl" as used herein refers to pentaunsaturated straight- chain or branched hydrocarbon radicals having 10 to 20 carbon atoms and five double bonds in any positions, provided that the each pair out of the five double bounds is either conjugated or isolated, for example 1 ,3,5,7,9-decapentaenyl,

1 ,3,5,7, 9-undecapentaenyl, 1 ,3,6,8,10-undecapentaenyl, 1 ,4,6,8,10-undecapentaenyl,

2.4.6.8.10- undecapentaenyl, 1 ,3,5,7,9-dodecapentaenyl, 1 ,3,6,8,10-dodecapentaenyl,

1 .4.6.9.1 1 - dodecapentaenyl, 2,4,6,8,10-dodecapentaenyl, 3,5,7,9,1 1 -dodecapentaenyl,

1 .3.5.7.9- tridecapentaenyl, 1 ,4,7,10,12-tridecapentaenyl, 2,4,6,8, 10-tridecapentaenyl, 2,5,7,9,1 1 -tridecapentaenyl, 3,5,7,9,1 1 -tridecapentaenyl, 4,6,8, 10,12-tridecapentaenyl, 1 ,3,5,7,9-tetradecapentaenyl, 1 ,4,7,10,13-tetradecapentaenyl,

2.4.6.8.10- tetradecapentaenyl, 2,5,8,1 1 ,13-tetradecapentaenyl,

3.5.7.9.1 1 - tetradecapentaenyl, 3,5,8, 10,12-tetradecapentaenyl,

4.6.8.10.12- tetradecapentaenyl, 4,6,8, 10,13-tetradecapentaenyl,

5.7.9.1 1 .13- tetradecapentaenyl, 1 ,3,5,7,9-pentadecapentaenyl,

2,4,6,8, 10-pentadecapentaenyl, 2,5,8,1 1 ,14-pentadecapentaenyl,

3,5,7,9,1 1 -pentadecapentaenyl, 3,5,8,1 1 ,14-pentadecapentaenyl,

4,6,8,10,12-pentadecapentaenyl, 4,6,8,1 1 ,14-pentadecapentaenyl,

5.7.9.1 1.14- pentadecapentaenyl, 5,7,9,12, 14-pentadecapentaenyl,

6,8,10,12,14-pentadecapentaenyl, 1 ,3,5,7,9-hexadecapentaenyl,

2,4,6,8, 10-hexadecapentaenyl, 2,5,8,1 1 ,14-hexadecapentaenyl,

3,5,7,9,1 1 -hexadecapentaenyl, 3,5,8,10,12-hexadecapentaenyl,

4.6.8.10.12- hexadecapentaenyl, 5,7,9,1 1 ,13-hexadecapentaenyl,

6.8.10.12.14- hexadecapentaenyl, 7,9,1 1 ,13,15-hexadecapentaenyl,

1 ,3,5,7,9-heptadecapentaenyl, 1 ,3,6,9,1 1 -heptadecapentaenyl,

2,4,6,8, 10-heptadecapentaenyl, 2,4,7, 10,14-heptadecapentaenyl,

3,5,7,9,1 1 -heptadecapentaenyl, 4,6,8, 10,12-heptadecapentaenyl,

5.7.9.1 1.13- heptadecapentaenyl, 6,8,10,12,14-heptadecapentaenyl,

6.8.1 1 .13.15- heptadecapentaenyl, 7,9,1 1 ,13,15-heptadecapentaenyl,

8,10,12,14,16-heptadecapentaenyl, as well as linear and branched isomers of octadecapentaenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, such as

(3Z,6Z,9Z,12Z,15Z)-octadecapentaenyl, and mixtures thereof, linear and branched isomers of nonadecapentaenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, and mixtures thereof, and linear and branched isomers of eicosapentaenyl which may differ in the positions and the configurations of the double bonds and the type of the possible branching, such as (5Z,8Z,1 1 Z,14Z,17Z)-eicosapentaenyl and mixtures thereof.

The term "Ci-C4-alkoxy" denotes straight-chain or branched saturated alkyl groups comprising 1 to 4 carbon atoms which are bonded via an oxygen atom. Examples of Ci-C4-alkoxy are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy,

1 - methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) and 1 ,1 -dimethylethoxy (tert-butoxy).

The term "C6-Cio-aryl" is understood as an unsaturated mono- or dicyclic hydrocarbon group having at least one benzene ring; examples include phenyl, indanyl and naphthyl. The term "-COO-(Ci-C4-alkyl)" refers to a Ci-C4-alkoxy group, as defined above, which is bound to the remainder of the molecule via a carbonyl group. Examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,

butoxycarbonyl, sec-butoxycarbonyl, isobutoxycarbonyl and tert-butoxycarbonyl. The term "-C(0)-Ci-C3-alkyl" refers to a Ci-C3-alkyl group, as defined above, which is bound to the remainder of the molecule via a carbonyl group. Examples are

methylcarbonyl (acetyl), ethylcarbonyl (propionyl), propylcarbonyl and

isopropyl carbonyl. The term "C4-C7-cycloalkyl" denotes a cyclic, saturated hydrocarbyl radical comprising 4 to 7 carbon atoms. Examples are cyclobutyl, cyclopentyl, cyclohexyl,

bicyclo[2.1 .1]hexyl, cycloheptyl, bicyclo[2.2.1 ]heptyl, bicyclo[3.1 .1]heptyl and bicyclo[2.2.1 ]heptyl. The term "d-Cs-alkandiyl" denotes a straight-chain or branched hydrocarbon diradical having 1 to 5 carbon atoms, such as methylene, ethan-1 ,2-diyl, propan-1 ,3-diyl,

2- methylpropan-1 ,3-diyl, butan-1 ,3-diyl, butan-1 ,4-diyl, 2-methylbutan-1 ,4-diyl and pentan-1 ,5-diyl. The term "C2-C5-alkendiyl" denotes a straight-chain or branched unsaturated hydrocarbon diradical having 2 to 5 carbon atoms, such as ethen-1 ,2-diyl, prop-1 -en- 1 ,3-diyl, but-2-en-1 ,4-diyl but-1 -en-1 ,3-diyl and pent-2-en-1 ,5-diyl.

The term "C2-C5-alkyndiyl" denotes a straight-chain or branched hydrocarbon diradical which has 2 to 5 carbon atoms and includes a triple bond, such as ethyn-1 ,2-diyl, prop- 1 -yn-1 ,3-diyl, but-2-yn-1 ,4-diyl and pent-2-yn-1 ,5-diyl.

The term "N-protecting group" denotes a protective group suitable for protecting or blocking amino groups. With regard to N-protective groups reference is made to P.G.M. Wuts, "Greene's Protective Groups in Organic Synthesis", 5^th ed. John Wiley and Sons, 2014, Chapter 7, pages 895 - 1 194 and the references cited therein. N-protecting groups are in particular protecting groups, which together with the nitrogen atom form carbamate type group, such as 9-fluorenylmethyl carbamate (Fmoc), substituted 9-fluorenylmethyl carbamates such as Bts-Fmoc, Dtb-Fmoc, Mio-Fmoc, Dio-Fmoc, and 9-(2,7-dibromo)fluorenylmethyl carbamate, 3-idenylmethyl carbamates such as

2-chloro-3-indenylmethyl carbamate (Climoc) and Benz[f]inden-3-ylmethyl (Bimoc), 1 ,1 -dioxobenzo[b]thiophene-2-ylmethyl carbamate (Bsmoc), substituted ethyl carbamates such as 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate, (Teoc), (2-phenyl-2-trimethylsilyl)ethyl carbamate (Psoc), 2-chloroethyl carbamate, 2-phenylethyl carbamate (hZ), 1 ,1 -dimethyl-2,2-dibromoethyl carbamate (DB-t-Boc), 1 ,1 -dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 2-pyridylethyl carbamate (Pyoc), t-butyl carbamate (BOC), fluorous BOC (^FBOC), 1 - and 2-adamantyl carbamate (Adoc and 2-Adoc), 1 -(1 -adamantyl)-1 -methylethyl carbamate (Adpoc), 1 -(3,5-di-t-butylphenyl)-1 -methylethyl carbamate (t-Bumeoc), N-(2-pivaloylamino)-

1 ,1 -dimethylethyl carbamate, allyl carbamate (Alloc), benzyl carbamate (Cbz or Z), and substituted benzyl carbamates, such as 4-methoxybenzyl carbamate (Moz),

4-nitrobenzyl carbamate (PNZ), 4-methylsulfinylbenzyl carbamate (Msz),

4-trifluoromethylbenzyl carbamate (CTFB), and 2-naphtylmethyl carbamate (CNAP). Preference is given to Cbz and BOC.

The remarks made below concerning preferred embodiments of the process of the invention, the reaction conditions and also of compounds of formulae (I), (la), (II), (III), (IV), (IVa) and (V) involved in the process, especially with respect to their substituents R¹, R², R³, X, Z, A, R^a, R^b, R^c and R^d, are valid both on their own and, in particular, in every possible combination with each other.

The six C-C double bonds in the exocyclic chain of the compounds of formulae (I) and (IV) may independently from each other have E or Z configuration. According to preferred groups of embodiments of the present invention the compounds of formulae (I) and (IV) predominately have E configuration, i.e. the compounds of formulae (I) and (IV) contain a high proportion of formulae (la) and (IVa), respectively:

In the process of the invention, the compound of formula (IV) used for the reaction with the compound of formula (V) contains a high proportion of the all-E isomer (IVa), i.e. the amount of the all-E isomer IVa is frequently at least 80 mol-%, in particular at least 90 mol-% more particularly at least 95 mol-% and specifically at least 98 mol-% of the total amount of the compound of formula (IV). In the process of the invention, the configurations of all six exocyclic C-C double bonds usually remain essentially unchanged during the process of the invention, i.e. their configurations in the product of the formula (I) is essentially the same as in the educt of the formula (IV). Thus, the configurations of the exocyclic C-C double bonds of the educt of formula (IV) correspond to the configurations of the exocyclic C-C double bonds of the product of formula (I) to a degree of at least 80%, in particular to a degree of at least 90%. In particular an educt of formula (IV) with essentially all six exocyclic C-C double bonds being E configurated, i.e. at least 90 mol-%, preferably at least 95 mol-% and in particular at least 98 mol-% of the educt have an all-E configuration as depicted in formula (IVa), is converted to a product of formula (I) with essentially all six exocyclic C-C double bonds being E configurated, i.e. at least 80 mol-%, preferably at least 90 mol-% and in particular at least 95 mol-% of the product of formula (I) have an all-E configuration as depicted in formula (la).

The compounds of the formulae (I), (la), (IV), (IVa) each have an asymmetric center in position 3 of the 6-membered cycle and can therefore exist as an enantiomeric mixture of the 3R and 3S isomers, e.g. as a racemate, or in the form of the pure isomers having the formulae (1-1 ), (IV-1 ), (I-2) and (IV-2), respectively:

According to a preferred embodiment the compounds of formulae (I) and (IV) with X being C=0 are predominately, i.e. to an extent of at least 80 mol-%, preferably at least 90 mol-% and in particular at least 95 mol-%, present as their S isomers (1-1 ) or (IV-1 ). Likewise, according to a further preferred embodiment the compounds of formulae (I) and (IV) with X being Chb are predominately, i.e. to an extent of at least 80 mol-%, preferably at least 90 mol-% and in particular at least 95 mol-%, present as their R isomers (1-1 ) or (IV-1 ).

Preferably, the variables R¹, R², R³ in the compounds of formulae (I), (la) and (V) have the following meanings:

R¹ is selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl,

A-COOH, A-CON H2, A-COO-(Ci-C₄-alkyl) and Ci-C₄-alkoxy, in particular hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C₄-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C20- alktetraenyl, Cio-C₂₀-alkpentaenyl, A-COOH , A-CON H2 and A-COO-(Ci-C₄-alkyl), and specifically Ci-C2o-alkyl, C2-C2o-alkenyl, C₄-C2o-alkdienyl, C6-C2o-alktrienyl, C₈-C₂₀-alktetraenyl, A-COOH , A-CON H2 and A-COO-(Ci-C₄-alkyl),

where A, at each occurrence, is as defined above and in particular C1-C4- alkandiyl and especially CH2 or CH2CH2,

R² is selected from the group consisting of hydrogen, -COOH , -COO-(Ci-C₄-alkyl), and -NR^aR^b, where R^a and R^b have the meanings defined above, in particular R² is hydrogen or -NR^aR^b, where R^a and R^b have the meanings defined above and specifically have the following meanings:

R^a is selected from the group consisting of hydrogen, Ci-C4-alkyl,

-C(0)-Ci-C3-alkyl, and N-protecting groups, in particular -Boc or -Cbz, and R^b is hydrogen or Ci-C4-alkyl, or, alternatively,

R¹ and R² together may form a group of formulae (I I) or (I II), in particular may form a group of formula (II) only, and specifically do not form a group of formulae (I I) or (I I I). In this context the variables in R^c and R^d are as defined above and in particular have the following meanings:

R^c is selected from the group consisting of hydrogen, Ci-Cig-alkyl, C2-C19- alkenyl, C4-Cig-alkdienyl, C6-Ci9-alktrienyl and Cs-dg-alktetraenyl, in particular hydrogen, Ci-Cig-alkyl, C2-Cig-alkenyl, C4-Cig-alkdienyl and C6-Ci9-alktrienyl and specifically hydrogen, Ci-Ci7-alkyl, C2-Ci7-alkenyl and C4-Ci7-alkdienyl, and

R^d is hydrogen or Ci-C4-alkyl and in particular hydrogen,

R³ is selected from the group consisting of hydrogen, Ci-C2o-alkyl and C2-C20- alkenyl, and in particular is hydrogen.

More preferably, the variables R¹ , R², R³ in the compounds of formulae (I), (la) and (V) have the following meanings:

R¹ is selected from the group consisting of hydrogen, Ci-Cis-alkyl, C2-Ci8-alkenyl, C₄-Ci8-alkdienyl, C₆-Ci₈-alktrienyl, C₈-Ci₈-alktetraenyl, A-COOH, A-CONH2 and A-COO-(Ci-C4-alkyl), and in particular hydrogen, Ci-Cis-alkyl, C2-Ci8-alkenyl, C₄-Ci8-alkdienyl, C₆-Ci₈-alktrienyl, A-COOH, A-CONH2 and A-COO-(Ci-C₄-alkyl), where A, at each occurrence, is as defined above and in particular C1-C4- alkandiyl and especially CH2 or CH2CH2,

R² is hydrogen or -NR^aR^b, where R^a and R^b have the meanings defined above and in particular have the following meanings:

R^a is selected from the group consisting of hydrogen, Ci-C4-alkyl,

-C(0)-Ci-C3-alkyl, and N-protecting groups such as -Boc and -Cbz, specifically hydrogen, -Boc and -Cbz, and

R^b is hydrogen or Ci-C4-alkyl, specifically hydrogen, and

R³ is hydrogen or Ci-C2o-alkyl, in particular hydrogen.

Preferably, the variable X in the compounds of formulae (I), (la), (IV) and (IVa) has the following meaning:

X is CH2 or C=0 and in particular C=0. Preferably, the variable Z in the compound of formula (V) is, in case n = 1 , chlorine, -OH or -0-C(0)-CH3, in particular chlorine or -OH, and, in case n = 2, is O.

According to one group of embodiments of the invention the variable X in in formulae (I), (la), (IV) and (IVa) is CH₂.

According to a preferred group of embodiments of the invention the variable X in formulae (I), (la), (IV) and (IVa) is C=0. Preferably, in the process of the invention, any group NR^aR^b in the compound of formula (V), is a tertiary amino group or at least one radical R^a or R^b is an N-protecting group, which can be cleaved after the reaction of the compound of formula (IV) with the compound of formula (V).

According to a first preferred group of embodiments of the invention the group

-C(0)CR¹R²R³ in formulae (I), (la) and (V) is derived from a saturated or unsaturated fatty acid, having 2 to 22 carbon atoms, in particular 10 to 20 carbon atoms i.e. R² and R³ are H and R¹ is selected from hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C20- alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl, in particular from Ci-Ci8-alkyl, C2-Ci8-alkenyl, C4-Ci8-alkdienyl, C6-Ci8-alktrienyl and Cs-ds-alktetraenyl and especially from hydrogen, C6-Ci8-alkyl, C6-Ci8-alkenyl, C6-Cis-alkdienyl and C6-C18- alktrienyl. Examples of such groups -C(0)CR¹R²R³ include but are not limited to acetyl, caproyl, lauroyl, myristoyl, palmitoyl, stearoyl, myristoleoyl, palmitoleoyl, oleoyl, linoleoyl, a-linolenoyl, γ-linolenoyl, and arachidonoyl, in particular acetyl, lauroyl, myristoyl, palmitoyl, oleoyl, linoleoyl, a-linolenoyl, γ-linolenoyl, arachidonoyl, and specifically acetyl, lauroyl, myristoyl, palmitoyl, oleoyl, linoleoyl, a-linolenoyl, γ-linolenoyl. In this particular group of embodiments, the variable X in in formulae (I), and (la) is especially C=0. According to a second group of embodiments of the invention the group -C(0)CR¹R²R³ in formulae (I), (la) and (V) is derived from an a-amino acid or an N-protected a-amino acid, i.e. R² is a radical NR^aR^b, where R^a and R^b are as defined above and where in particular one or both of R^a and R^b are an N-protecting groups such as BOC or Cbz, respectively, while the other group R^a and R^b is hydrogen, Ci-C4-alkyl,

-C(0)H, -C(0)-Ci-C3-alkyl or C4-C7-cycloalkyl, in particular hydrogen or Ci-C4-alkyl, or R^a together with R¹ may form a C3-C4-alkandiyl group. In this group of embodiments, R³ is in particular hydrogen. R¹ is as defined above and in particular selected from hydrogen, Ci-C4-alkyl, which is unsubstituted or carries one OH group, A-CO2H , A-CON H2, where A is as defined above and in particular CH2 or CH2CH2, and benzyl, which is unsubstituted or carries OH. Examples of such groups -C(0)CR¹R²R³ include but are not limited to N-Boc-glycyl, N-Cbz-glycyl, sarconsinyl, N-Boc-sarcosinyl, N-Cbz-sarcosinyl, prolinyl, N-Boc-prolinyl, N-Cbz-prolinyl, N-Boc-alaninyl,

N-Cbz-alaninyl, N-Boc-valinyl, N-Cbz-valinyl, N-Boc-leucinyl, N-Cbz-leucinyl,

N-Boc-isoleucinyl, N-Cbz-isoleucinyl, N-Boc-phenylalaninyl, N-Cbz-phenylalaninyl, N-Boc-tyrosinyl, N-Cbz-tyrosinyl, N-Boc-serinyl, N-Cbz-serinyl, N-Boc-threoninyl, N-Cbz-threoninyl, N-Boc-asparaginyl, N-Cbz-asparaginyl, N-Boc-glutaminyl,

N-Cbz-glutaminyl, in particular N-Boc-glycyl, N-Cbz-glycyl, N-Boc-alaninyl,

N-Cbz-alaninyl, N-Boc-valinyl, N-Cbz-valinyl, N-Boc-leucinyl, N-Cbz-leucinyl,

N-Boc-isoleucinyl, N-Cbz-isoleucinyl, N-Boc-sarcosinyl, N-Cbz-sarcosinyl,

N-Boc-prolinyl, N-Cbz-prolinyl, and specifically N-Boc-glycyl and N-Boc-sarcosinyl and also the corresponding deprotected radicals. In this particular group of embodiments, the variable X in in formulae (I), and (la) is especially C=0. According to a third preferred group of embodiments of the invention the group

-C(0)CR¹R²R³ in formulae (I), (la) and (V) is derived from a saturated or unsaturated dicarboxylic acid or a semi-ester thereof. In this group of embodiments, R² and R³ are H and R¹ is a group A-COOH or A-COO-Ci-C4-alkyl, where A is as defined above and in particular Chb or CH2CH2. Examples of such groups -C(0)CR¹R²R³ include, but are not limited to, succinoyl, i.e. -C(=0)-CH2CH2COOH, and the corresponding Ci-C4-alkyl esters -C(=0)-CH2CH2COO-Ci-C4-alkyl. In this particular group of embodiments, the variable X in in formulae (I), and (la) is especially C=0.

Accordingly, the carboxylic acid or one of its derivatives of the formula (V) is preferably selected from the group consisting of:

- saturated and unsaturated fatty acids having 3 to 20 C-atoms, in particular having 8 to 20 C-atoms, and the acid halides, such as in particular the acid chlorides, derived therefrom,

- acetyl chloride, acetic anhydride,

- succinic acid, succinic acid anhydride, and

- N-protected a-amino acids, in particular N-Boc or N-Cbz protected a-amino acids preferably selected from glycine, alanine, valine, leucine, isoleucine, sarcosine and proline. The reactions of the invention as described hereinafter are performed in reaction vessels customary for such reactions, the reaction being carried out in a continuous, semicontinuous or batchwise manner. In general, the particular reactions will be carried out under atmospheric pressure. The reactions may, however, also be carried out under reduced or elevated pressure. The reaction of the process according to the invention for preparing an ester of the formula (I) may be regarded as an esterification or acylation reaction. The conversion is effected by reacting an alcohol of the formula (IV) with a carboxylic acid or one of its derivatives of the formula (V) in the presence of a tertiary amine and, in case a free carboxylic acid is used as the compound of formula (V), also in the presence of an activator.

Suitable tertiary amines are amines of the formula (A)

NR^eR^fR9 (A) where R^e, R^f and Rs, each independently are selected from the group consisting of Ci-C6-alkyl, Cs-Cs-cycloalkyl, phenyl and phenyl which is substituted by 1 , 2, or 3 Ci-C4-alkyl radicals, or R^e and R^f together with the N-atom form a saturated N- heterocycle, which in addition to the tertiary nitrogen atom may have a further heteroatom or heteroatom group selected from O, S and N-R^x, where R^x is Ci-C6-alkyl, as a ring member, or R^e, R^f and Rs together with the nitrogen atom form a 8 to 12 membered N-heterobicycle, in particular a 8 to 12 membered N-heterobicycle where the tertiary heteroatom is part of an endocyclic amidine group. Further suitable tertiary amines are N-heteroaromatic compounds, where the N-atom is a ring-atom of the aromatic moiety. The N-heteroaromatic compounds are optionally substituted by 1 , 2, or 3 radicals selected from Ci-C4-alkyl, halogen, 1-pyrrolidinyl and di(Ci-C3-alkyl)- amino. Suitable N-heteroaromatic compounds are pyridine, N-(Ci-C4)-alkylimidazoles and quinolines, wherein the carbon atoms are unsubstituted or carry 1 , 2, or 3 radicals selected from Ci-C4-alkyl, halogen, 1-pyrrolidinyl and di(Ci-C3-alkyl)amino.

Examples of tertiary amines include, but are not limited to tri-Ci-C6-alkyl amines (or (Ci-C6-alkyl)sN), such as trimethylamine, methyldiethylamine, methyldiisopropylamine and ethyldiisopropylamine, cyclohexyldimethylamine, cyclohexyldiethylamine,

N-methylpiperidine, N-methylmorpholine, N,N-dimethylpiperazine,

1 ,4-diazabicyclo[2.2.2]octane (DABCO, 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1 ,8-diazabicyol[5.4.0]undec-7-ene (DBU), N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 substituents selected from methyl and ethyl,

4-(dimethylamino)pyridine and 4-(1-pyrrolidinyl)pyridine.

Preferred tertiary amines for the transformation of the inventive process are

Ci-C6-alkyl)3N , DBU, DABCO, N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 substituents selected from methyl and ethyl, 4-(dimethylamino)pyridine and 4-(1 -pyrrolidinyl)pyridine, in particular trimethylamine, N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 methyl groups, 4-(dimethylamino)pyridine and

4-(1 -pyrrolidinyl)pyridine, and specifically N-methylimidazole and pyridine. In one embodiment of the invention the tertiary amine is selected from trimethylamine, N-methylimidazole, 4-(dimethylamino)pyridine and 4-(1 -pyrrolidinyl)pyridine, and in particular is N-methylimidazole.

In another embodiment of the invention the tertiary amine is pyridine optionally carrying 1 , 2 or 3 methyl groups, and in particular is pyridine.

Suitable activators for the transformation of the inventive process are in principle all compounds capable of converting a carboxylic acid of the formula (V), i.e. the variable Z in formula (V) is -OH, into an corresponding activated ester or a mixed anhydride, which is able to convert an alcohol of formula (IV) in the presence of a tertiary amine into the desired ester of formula (I). Preferred activators are

Ν,Ν'-dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), Ν,Ν'-diisopropylcarbodiimide (DIC), 1 ,1 '-carbonyldiimidazole (CDI), pivaloyl chloride, Ci-C3-alkyl ester of chloroformic acid, phosgene, thionyl chloride and phosphoryl chloride, in particular DCC, EDC and DIC.

In the reaction of the inventive process the alcohol of formula (IV) and the carboxylic acid or one of its derivatives of formula (V) are reacted in a molar ratio within the range of typically 1 :1 to 1 :5, preferably 1 : 1 to 1 :4, more preferably 1 : 1 to 1 :3 and specifically 1 :1 .1 to 1 :2. In particular, in case a carboxylic acid of formula (V) is used, i.e. Z in formula (V) is -OH, the molar ratio of the compounds (IV) and (V) is within the range of typically 1 :1 to 1 :2 and preferably 1 : 1 to 1 :1 .5, while in case a carboxylic acid derivative of formula (V) is used, i.e. Z in formula (V) is not -OH, the molar ratio of the

compounds (IV) and (V) is within the range of typically 1 : 1 to 1 :5 and preferably 1 : 1 to 1 :4.

In the reaction of the inventive process the tertiary amine is used in an amount of typically 1 .0 to 4.0 mol, preferably 1 .0 to 3.0 mol, in particular 1 .0 to 1 .5 mol, and specifically 1 .0 to 1 .3 mol, based in each case on 1 mol of the carboxylic acid or one of its derivatives of formula (V). In case pyridine is employed as tertiary amine, it is used in an amount of typically 1 .0 to 1 .5 mol, preferably 1 .0 to 1 .3 mol and in particular 1 .0 to 1 .1 mol, based in each case on 1 mol of the carboxylic acid or one of its derivatives of formula (V). In the reaction of the inventive process, if a carboxylic acid of formula (V) is used, i.e. Z in formula (V) is -OH, the activator is used in an amount of typically 1.0 to 2.0 mol, in particular 1.0 to 1 .5 mol, and specifically 1 .1 to 1.3 mol, based in each case on 1 mol of the carboxylic acid of formula (V).

In one embodiment of the present invention the inventive process is performed with X in formulae (I) and (IV) being C=0, i.e. the process is an esterification of

12'-apoastaxanthinal or of a configurational isomer thereof, and the tertiary amine used in the process is pyridine which is used in an amount of 1 .0 to 1 .1 mol, based on 1 mol of the carboxylic acid or one of its derivatives of formula (V).

In another embodiment of the present invention the inventive process is performed with X in formulae (I) and (IV) being C=0, i.e. the process is an esterification of

12'-apoastaxanthinal or of a configurational isomer thereof, and the tertiary amine used in the process is selected from trimethylamine, N-methylimidazole,

4-(dimethylamino)pyridine and 4-(1 -pyrrolidinyl)pyridine, and in particular is

N-methylimidazole.

The reaction of the inventive process is preferably carried out in an organic solvent.

It has generally been found to be advantageous to use an aprotic organic solvent, in particular a polar aprotic organic solvent, for the reaction of the inventive process. Useful aprotic organic solvents here include halogenated Ci-C4-alkanes, such as dichloromethane and trichloromethane, Ci-C4-alkyl nitrile, such as acetonitrile, ethers, for example, aliphatic C2-Cio-ethers having 1 , 2, 3, or 4 oxygen atoms, such as C1-C4- alkoxy-Ci-C4-alkanes, e.g. diethyl ether, dipropyl ether, methyl isobutyl ether, methyl tert-butyl ether or ethyl tert-butyl ether, ethylene glycol dimethyl ether (glyme), diethylene glycol dimethyl ether (diglyme) and triethylene glycol dimethyl ether

(triglyme), alicyclic C4-C6-ethers, such as tetrahydrofuran (THF), tetrahydropyran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran and 1 ,4-dioxane, aliphatic esters, such as C1-C4-alkyl-C1-C4-alkanoat.es, e.g. ethyl acetate or isopropyl acetate, aromatic hydrocarbons, such as benzene optionally carrying 1 to 4 substituents selected from Ci-C4-alkyl and chlorine, such as chlorobenzene, toluene, the xylenes and mesitylene, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), or mixtures of these solvents with one another.

The solvent for the reaction of the inventive process is preferably selected from halogenated Ci-C4-alkane, Ci-C4-alkyl nitrile, Ci-C4-alkoxy-Ci-C4-alkane, THF, 1 ,4-dioxane, Ci-C4-alkyl-Ci-C4-alkanoate, benzene optionally carrying 1 to 4 substituents selected from Ci-C4-alkyl and chlorine, DMF and NMP, and in particular from dichloromethane, acetonitrile, methyl tert-butyl ether, THF, 1 ,4-dioxane, ethyl acetate, isopropyl acetate and toluene. The total amount of the solvent used in the reaction of the process according to the invention is typically in the range from 500 to 15000 g, preferably in the range from 1000 to 12000 g and in particular in the range from 1000 to 4000 g, based on 1 mol of the alcohol of formula (IV). Preference is given to using solvents which are essentially anhydrous, i.e. have a water content of less than 1000 ppm and especially not more than 200 ppm.

The reactants can in principle be contacted with one another in any desired sequence. For example, the alcohol of formula (IV) and the tertiary amine, if appropriate in dissolved or dispersed form, can be initially charged and mixed with each other. The obtained mixture can then be admixed with the carboxylic acid or its derivative of the formula (V). Conversely, the carboxylic acid or its derivative of formula (V), if appropriate in dissolved or dispersed form, can be initially charged and admixed with a mixture of the alcohol of formula (IV) and the tertiary amine. Alternatively, all reactants can also be added simultaneously to the reaction vessel. As an alternative to the joint addition of the alcohol of formula (IV) and the tertiary amine they can also be added separately to the reaction vessel. Both of them can independently of one another be added, either in a solvent or in bulk, before or after the addition of the carboxylic acid or its derivative of formula (V). In case a carboxylic of formula (V) is used (Z = -OH) the activator may be added before or after the addition of the carboxylic acid.

It has been found to be beneficial to initially charge the reaction vessel with the alcohol of formula (IV) or its mixture with the tertiary amine, e.g. in dispersed form or preferably in dissolved form, and then to add the tertiary amine, if applicable, followed by the addition of the carboxylic acid or its derivative of formula (V) in a gradual manner or at once. The carboxylic acid or its derivative of formula (V) is employed as such or in dissolved form. In case an activator is used it is preferably charged to the reaction vessel before, after or together with the alcohol of formula (IV) and only thereafter the tertiary amine and the carboxylic acid of formula (V) with Z = -OH are successively added.

In general, the reaction of the inventive process is performed under temperature control. The reaction is typically effected in a closed or preferably in an open reaction vessel with stirring apparatus. The reaction temperature of the inventive process depends on different factors, in particular on the reactivity of either the carboxylic acid derivative of formula (V) used or of the active ester formed from the carboxylic acid of formula (V), and can be determined by the person skilled in the art in the individual case, for example by simple preliminary tests. In general, the conversion of the inventive process is performed at a temperature in the range from -78 to 100°C, preferably in the range from -20 to 50°C, more preferably in the range from -10 to 35°C and specifically in the range from -5 to 25°C.

According to one embodiment of the invention the reaction of the inventive process is initiated at a lower temperature, for instance at a temperature in the range of -10 to 40°C and preferably -5 to 20°C, and the temperature is then increased stepwise or continuously to an upper temperature, for instance to an temperature in the range of 0 to 80°C and preferably 10 to 50°C. Depending on the solvent used, the reaction temperature and on whether the reaction vessel possesses a vent, a pressure of generally 1 to 5 bar and preferably of 1 to 3 bar is established during the reaction.

The work-up of the reaction mixtures obtained in the reaction of the inventive process and the isolation of the ester of formula (I) are effected in a customary manner, for example by a quenching step followed by an aqueous extractive work-up or removal of the solvent, for example under reduced pressure. Instead of removing the solvent it may alternatively be replaced in an isochoric distillation process with another solvent from which the ester of formula (I) crystallizes. Frequently, the esters of formula (I) are obtained in sufficient purity by applying such measures or a combination thereof. Thus, additional purification steps, in particular elaborated ones such as chromatography or distillation are often not necessary. If desired, however, further purification can be effected by methods commonly used in the art. Preferably, as the initial step of the work-up, the reaction of the inventive process is quenched by adding to the reaction mixture obtained in the reaction a nucleophilic compound, such as an alcohol, e.g. methanol, water or a diluted acid such as an aqueous solution of acetic acid or hydrochloric acid. The aqueous phase is then removed, if applicable, and the organic phase is extracted with water or a diluted acid, such as an aqueous solution of acetic acid or of hydrochloric acid, usually followed by washing steps with a diluted base, such as an aqueous solution of sodium hydrogen carbonate, and/or water. The organic phase containing the ester of formula (I) can afterwards be introduced into a further reaction step, either directly or after partial or complete removal of the solvent and optional further purification steps. Alternatively, the organic phase is subjected to crystallisation conditions and after completion of the crystallisation the formed crystals are isolated, washed and dried. It is often

advantageous to perform the crystallization in a solvent other than that used for the reaction. In that case the original solvent is replaced with one that is more appropriate for crystallization, for example by simply removing the original solvent, e.g. under reduced pressure, and re-dissolving the obtained residue in the new solvent, or, alternatively, by using an isochoric distillation process.

The alcohols of the formula (IV) used as starting materials in the inventive process can be prepared e.g. analogous to the process disclosed in J. A. Haugan et al. 1994, Acta Chem. Scand. 48, 899, or in K. Bernhard et al. 1981 , Helv. Chim. Acta 64, 2469, by a Wittig reaction of (S)-3-methyl-5-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)- 2,4-pentadienyl-triphenylphosphonium bromide or its 3-deoxo derivative

(Ci5-phosphonium salts) with 2,7-dimethyl-2,4,6-octatrien-1 ,8-dial (Cio-dial). The

Ci5-phosphonium salts, in turn, can be prepared e.g. by analogy to the process disclosed in J. A. Haugan 1994, Acta Chem. Scand. 48, 657, via a Grignard reaction of 3-hydroxy-p-ionone or 3-oxo-4-hydroxy-p-ionone with vinylmagnesium bromide to obtain the corresponding tertiary Cis-alcohol, which is then reacted with suitable phosphine reagent, such as triphenylphosphine hydrobromide.

As mentioned before, the present invention also relates to the esters of formula (I) as such, wherein the aforementioned statements regarding their preferred characteristics, such as the enantiomeric configuration in position 3 of the 6-membered cycle, the configuration of the exocyclic chain and the meanings of the variables R¹, R², R³ and X, fully apply here, too, with the only exception that the group -C(0)CR¹R²R³ in formula (I) is not acetyl.

Preferred esters of the formula (I) are those which include the group -C(0)CR¹R²R³ selected from the group consisting of lauroyl, myristoyl, oleoyl, linoleoyl, a-linolenoyl, γ-linolenoyl, arachidonoyl, succinoyl, glycyl, sarcosinyl, N-Boc-glycyl, N-Cbz-glycyl, N-Boc-sarcosinyl and N-Cbz-sarcosinyl, and in particular lauroyl, linoleoyl, oleoyl and N-Boc-sarcosinyl.

The 12'-apocarotenal esters of the formula (I) may serve as a starting material for the preparation of asymmetric diesters of carotenoid-type tetraterpenes but also of monoesters of symmetric carotenoid-type tetraterpenes, such as monoesters of astaxanthin or zeaxanthin. The monoesters as well as the asymmetric diesters can be prepared from 12'-apocarotenal esters of the formula (I) via Wittig reaction or a Julia olefination with the corresponding Cis-phosphonium salts and Cis-sulfones,

respectively.

The following examples are intended to serve as further illustration of the invention.

EXAMPLES

Hereinafter the following abbreviations are used:

aq. = aqueous

wt-% = % by weight

DCM = dichloromethane

MeOH = methanol

EtOAc = ethyl acetate

DIPE = diisopropyl ether

EDC = 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

NMI = 1 -methylimidazole

Example 1 : (S)-2,7,1 1 -Trimethyl-13-(4-acetyloxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen- 1 -yl)-2,4, 6,8,10,12-tridecahexaen-1 -al (Acetyl-12'-apo-(S)-astaxanthinal)

DCM (100 mL), (S)-2,7,1 1 -trimethyl-13-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen- 1 -yl)-2,4,6,8,10,12-tridecahexaen-1 -al (38.0 g, 100 mol), pyridine (34.8 g, 440 mmol) and acetic anhydride (40.8 g, 400 mmol) were charged to a 500 mL three-necked flask and the mixture was stirred over night at a temperature in the range of 20 to 25°C. After adding water (10 mL) and DCM (100 mL) the phases were separated and the organic phase was washed with water (2 x 50 mL), dried over sodium sulfate and concentrated to dryness yielding a pasty, black residue (57.3 g), which was subjected to column chromatography on silica gel using cyclohexane/EtOAc with a gradient of 10:1 to 4:1 (v/v) as eluent. The main fraction was concentrated to dryness and then crystallized from a mixture of DIPE (400 mL) and EtOAc (75 mL). After completion of the precipitation the formed solids were isolated and washed with DIPE (3 x 50 mL) and dried at a temperature of 60°C and a pressure of 20 mbar. The title compound was obtained in an amount of 27.1 g. Example 2: (S)-2,7,1 1 -Trimethyl-13-(4-(N-Boc-sarcosinyloxy)-2,6,6-trimethyl-3-oxo- 1 -cyclohexen-1 -yl)-2,4,6,8, 10,12-tridecahexaen-1 -al (N-Boc-sarcosinyl-12'-apo-(S)- astaxanthinal) (S)-2,7,1 1 -Trimethyl-13-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)- 2,4,6,8,10,12-tridecahexaen-1 -al (25.0 g, 60.5 mmol), EDC (17.4 g, 90.7 mmol) and DCM (200 mL) were charged at a temperature of 0°C to a 750 mL reactor and then NMI (7.45 g, 90.7 mmol) and a solution of N-Boc-sarcosine (13.7 g, 72.6 mmol) in DCM (100 mL) were successively metered into the reactor. The mixture was stirred for 21 hours at a temperature of 0°C. After adding an aq. solution of hydrochloric acid (10 wt- %, 150 mL) the mixture was warmed to 25°C, the phases were then separated and the organic phase was washed initially with a saturated aq. solution of sodium hydrogen carbonate (50 mL) and subsequently with water (2 x 100 mL). Finally the organic phase was reduced to dryness, affording 47.35 g of the title compound.

Example 3: (S)-2,7,1 1 -Trimethyl-13-(4-palmitoyloxy-2,6,6-trimethyl-3-oxo-1 - cyclohexen-1 -yl)-2,4,6,8,10,12-tridecahexaen-1 -al (Palmitoyl-12'-apo-(S)-astaxanthinal) (S)-2,7, 1 1 -Trimethyl-13-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen-1 -yl)-

2,4,6,8,10,12-tridecahexaen-1 -al (20.0 g, 48.35 mmol), NMI (1 1.9 g, 145.1 mmol) and DCM (400 mL) were charged to a 750 mL reactor at a temperature of 23°C, followed by the dropwise addition of a solution of palmitoyl chloride (15.95 g, 58.0 mmol) in DCM (35 g). After continued stirring overnight, water (100 mL) and an aq. solution of acetic acid (10 wt-%, 60.9 g) were added. The phases were separated and the organic phase was washed with water (100 mL). Then the solvent of the organic phase was replaced with isopropanol by means of an isochoric distillation at a pressure of 500 to 350 mbar and an inner temperature of up to 60°C. During the subsequent process of cooling the solution to 0°C seed crystals were added at a temperature of 32°C. The suspension was then stirred overnight at 0°C and then filtered. The obtained filter cake was washed with isopropanol (2 x 50 mL) and dried under vacuum at 30°C affording 27.3 g of the title compound.

Example 4: (S)-2,7,1 1 -Trimethyl-13-(4-oleoyloxy-2, 6, 6-trimethyl-3-oxo-1 -cyclohexen- 1 -yl)-2,4,6,8,10,12-tridecahexaen-1 -al (Oleoyl-12'-apo-(S)-astaxanthinal)

DCM (250 mL), (S)-2,7,1 1 -trimethyl-13-(4-hydroxy-2,6,6-trimethyl-3-oxo-1 -cyclohexen- 1 -yl)-2,4, 6,8,10,12-tridecahexaen-1 -al (1 14.2 g, 300 mmol) and pyridine (39.15 g, 495 mmol) were charged at a temperature of 0°C to a 1 .6 L reactor, followed by the dropwise addition of oleoyl chloride (150.45 g, 450 mmol). After adding MeOH

(150 mL) and warming the mixture to 20°C, water (300 mL) was added and the phases were separated. The organic phase was then washed with water (300 mL), diluted with DCM (500 mL) and cyclohexane (500 mL), filtered through a celite pad, dried over sodium sulfate and reduced to dryness at a temperature of 60°C and a pressure of 20 mbar. The obtained residue (262.6 g) was subjected to column chromatography on silica gel using cyclohexane/EtOAc with a gradient of 20:1 to 5:1 (v/v) as eluent, yielding 104.9 g of the title compound.

Claims

Claims

1 . A process for the preparation of an ester of the formula (I),

wherein,

R¹ is selected the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, C10-C20- alkpentaenyl, Ci-C4-alkoxy, where the alkyl, alkenyl, alkdienyl, alktrienyl, alktetraenyl and alkpentaenyl moieties of the seven aforementioned residues are unsubstituted or may carry 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH and Ci-C4-alkoxy,

C6-Cio-aryl, benzyl, where the aryl moieties of the two residues aforementioned are unsubstituted or may carry 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH, Ci-C4-alkyl and C1-C4- alkoxy,

A-COOH, A-CONH2, A-COO-(Ci-C₄-alkyl), and

A-NR^aR^b,

R² and R³ are each independently from one another selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, Cs-C2o-alktetraenyl and Cio-C2o-alkpentaenyl, where the alkyl, alkenyl, alkdienyl, alktrienyl, alktetraenyl and alkpentaenyl moieties of the six aforementioned residues are unsubstituted or may carry 1 , 2 or 3 substituents selected from the group consisting of halogen and C1-C4- alkoxy,

R² may also be selected from the group consisting of

-COOH, -COO-(Ci-C₄-alkyl), and

-NR^aR^b, or

R¹ and R² together form a roup of the formula (II),

wherein

_* is the attachment point to the remainder of the molecule, R^c is selected from the group consisting of hydrogen, Ci-Cig-alkyl,

C2-Ci9-alkenyl, C4-Cig-alkdienyl, C6-Ci9-alktrienyl, Cs-dg-alktetraenyl, Ci-C₄-alkandiyl-COOH, C₂-C₄-alkendiyl-COOH, C₂-C₄-alkyndiyl- COOH, and

R^d is hydrogen or Ci-C₄-alkyl, or

R¹, R² and R³ together form a group of the formula (III),

*≡=— R^C (III) wherein * and R^c have the meanings defined above, or

if R² is -NR^aR^b, R¹ together with R^a may form a C3-C₄-alkandiyl group,

X is CH₂ or C=0,

R^a is selected from the group consisting of hydrogen, Ci-C₄-alkyl,

-C(0)H, -C(0)-Ci-C3-alkyl, C₄-C7-cycloalkyl, and N-protecting groups such as tert-butyloxycarbonyl (-Boc) and carboxybenzyl (-Cbz);

R^b is selected from the group consisting of hydrogen, Ci-C₄-alkyl,

-C(0)-Ci-C3-alkyl, and N-protecting groups such as -Boc and -Cbz, and

A is selected from the group consisting of Ci-Cs-alkandiyl, C2-Cs-alkendiyl and C2-C5-alkyndiyl; the process being characterized in that an alcohol of the formula (IV),

is reacted with a carboxylic acid or one of its derivatives of the formula (V),

wherein

the variables R¹, R² and R³ have the meanings defined above, and

for n = 1 the variable Z is selected from the group consisting of halogen, -OH,

-0-C(0)-Ci-C₄-alkyl, and

for n = 2 the variable Z is O or S, wherein the reaction is carried out in the presence of a tertiary amine and in case a compound of the formula (V) with Z = -OH is used also in the presence of an activator.

The process according to claim 1 , wherein the alcohol of the formula (IV) comprises at least 80 mol-%, in particular at least 90 mol-% of the all-E isomer of the formula (IVa),

The process according to claim 1 or 2, wherein in formulae (I) and (V):

R¹ is selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C4-C2o-alkdienyl, C6-C2o-alktrienyl, C8-C2o-alktetraenyl, Cio-C2o-alkpentaenyl, A-COOH, A-CON H2 and A-COO-(Ci-C₄-alkyl), wherein A has the meaning defined in claim 1 ,

R² is hydrogen or -NR^aR^b, wherein R^a and R^b have the meanings defined in claim 1 , or

R¹ and R² together form a group of the formula (II), wherein

R^c is selected from the group consisting of hydrogen, Ci-Cig-alkyl,

C2-Ci9-alkenyl, C₄-Ci9-alkdienyl, C6-Ci9-alktrienyl and Cs-dg- alktetraenyl, and

R^d is hydrogen, and

R³ is hydrogen.

The process according to any one of the preceding claims, wherein in formulae (I) and (V):

R¹ is selected from the group consisting of hydrogen, Ci-C2o-alkyl, C2-C2o-alkenyl, C₄-C₂o-alkdienyl, C₆-C₂o-alktrienyl, C₈-C₂o-alktetraenyl, A-COOH, A-CON H2 and A-COO-(Ci-C₄-alkyl), where A is CH₂ or CH₂CH₂;

R² is hydrogen or -NR^aR^b, wherein

R^a is selected from the group consisting of hydrogen, Ci-C₄-alkyl,

-C(0)-Ci-C₃-alkyl, -Boc and -Cbz,

R^b is selected from the group consisting of hydrogen and Ci-C₄-alkyl, and

R³ is hydrogen.

5. The process according to any one of the preceding claims, wherein in formulae (I) and (IV) the variable X is C=0.

The process according to any one of the preceding claims, wherein the carboxylic acid or one of its derivatives of the formula (V) are selected from the group consisting of acetic anhydride, succinic anhydride, saturated and unsaturated fatty acids having 8 to 20 C-atoms, the chlorides of saturated and unsaturated fatty acids having 8 to 20 C-atoms, and N-Boc or N-Cbz protected a- amino acids selected from glycine, sarcosine, proline, alanine, valine, leucine and isoleucine.

The process according to any one of the preceding claims, wherein the tertiary amine is selected from the group consisting of (Ci-C6-alkyl)3N ,

1 ,8-diazabicycloundec-7-ene (DBU), 1 ,4-diazabicyclo[2.2.2]octane (DABCO), N-methylimidazole, pyridine optionally carrying 1 , 2 or 3 substituents selected from methyl and ethyl, 4-(dimethylamino)pyridine and 4-(1 -pyrrolidinyl)pyridine.

The process according to any one of the preceding claims, wherein the activator is selected from the group consisting of Ν,Ν'-dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),

Ν,Ν'-diisopropylcarbodiimide (DIC), 1 ,1 '-carbonyldiimidazole (CDI), pivaloyl chloride, Ci-C3-alkyl ester of chloroformic acid, phosgene, thionyl chloride and phosphoryl chloride.

The process according to any one of the preceding claims, wherein the reaction between the compounds of formulae (IV) and (V) is carried out in a polar, aprotic organic solvent, which is preferably selected from the group consisting of benzene optionally carrying 1 to 4 substituents selected from Ci-C4-alkyl and chlorine, Ci-C4-alkoxy-Ci-C4-alkane, halogenated Ci-C4-alkane, Ci-C4-alkyl nitrile, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP),

tetrahydrofurane (THF), 1 ,4-dioxane and Ci-C4-alkyl-Ci-C4-alkanoate.

The process according to any one of the preceding claims, wherein the reaction between the compounds of formulae (IV) and (V) is carried out at a temperature in the range of -78°C to 100°C, and preferably in the range of -20°C to 50°C.

1 1 . The process according to any one of the preceding claims, wherein the

compounds of formulae (IV) and (V) are reacted in a molar ratio within the range of 1 :1 to 1 :5 and preferably 1 :1.1 to 1 :2.

12. An ester of the formula (I),

wherein X, R¹, R², and R³ are as defined in one of claims 1 , 3, 4 or 5, except for the compound of the formula (I), wherein -C(0)CR¹R²R³ is acetyl.

The ester according to claim 12, which is or comprises at least 80 mol-%, in particular at least 90 mol-% of the all-E isomer of the formula (la),

14. The ester according to any one of claims 12 or 13, wherein the group

-C(0)CR¹R²R³ in formulae (I) or (la) is selected from the group consisting of lauroyi, myristoyl, oleoyi, linoleoyi, a-linolenoyl, γ-linolenoyl, arachidonoyi and succinoyl.

The ester according to any one of claims 12 or 13, wherein the group

-C(0)CR¹R²R³ in formulae (I) or (la) is selected from the group consisting of N-Boc-glycyl, N-Cbz-glycyl, N-Boc-sarcosinyl, N-Cbz-sarcosinyl, glycyl and sarcosinyl.