SYNTHESIS OF E,E-FARNESOL, FARNESYL ACETATE AND SQUALENE FROM FARNESENE VIA FARNESYL CHLORIDE
The present disclosure provides methods for preparing polyunsaturated hydrocarbons, such as E,E-farnesol, farnesyl acetate and squalene, by base catalyzed addition of a dialkylamine to a 3-methylene-1-alkene, such as farnesene. The present disclosure also provides compositions including one more farnesene derivatives prepared using the disclosed methods.
1 . A method for preparing a compound of formula (I) having the structure:
the method comprising:
forming a first reaction mixture comprising a compound of formula NHR 3 R 4 , a reagent comprising an alkali metal, and a compound of formula (II):
under conditions sufficient to form an amine compound of formula (I) having the structure:
and
forming a second reaction mixture comprising a chloroformate and the amine compound of formula (I), under conditions sufficient to form a chloride compound of formula (I) having the structure:
wherein R 1 is selected from the group consisting of C 2-18 alkyl and C 2-18 alkenyl; wherein R 2 is selected from the group consisting of NR 3 R 4 , halogen, OH, —OC(O)R 5 , and —SO 2 —R 5 ; wherein R 3 and R 4 are each independently C 1-6 alkyl; and wherein R 5 is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, C 3-8 heterocycloalkyl, C 6-12 aryl, and C 5-12 heteroaryl.
2 . The method of claim 1 , wherein R 3 and R 4 are each ethyl.
3 . The method of claim 1 , wherein the alkali metal is sodium or lithium.
4 . The method of claim 3 , wherein the reagent comprises an alkyllithium compound or an aryllithium compound.
5 . The method of claim 3 wherein the reagent comprises n-butyllithium.
6 . The method of claim 1 , wherein the first reaction mixture further comprises isopropyl alcohol or styrene.
7 . The method of claim 1 , wherein the chloroformate is isobutyl chloroformate.
8 . The method of claim 1 , further comprising:
forming a third reaction mixture comprising the chloride compound of formula (I) and a compound of formula (III):
under conditions sufficient to form an ester compound of formula (I) having the structure:
wherein X is an alkali metal.
9 . The method of claim 8 , wherein the third reaction further comprises a crown ether.
10 . The method of claim 8 , further comprising:
forming a fourth reaction mixture comprising a strong base and the ester compound of formula (I) under conditions sufficient to form an alcohol compound of formula (I) having the structure:
11 . The method of claim 10 , wherein the strong base comprises sodium hydroxide or potassium hydroxide.
12 . The method of claim 1 , further comprising:
forming a third reaction mixture comprising a benzenesulfonate, a quaternary ammonium salt, and the chloride compound of formula (I), under conditions sufficient to form a sulfone compound of formula (I) having the structure:
13 . The method of claim 12 , wherein the benzenesulfonate is sodium benzenesulfonate.
14 . The method of claim 12 , wherein the quaternary ammonium salt is tetrabutylammonium chloride.
15 . The method of claim 12 , further comprising:
forming a fourth reaction mixture comprising a strong base, the chloride compound of formula (I), and the sulfone compound of formula (I), under conditions sufficient to form a compound of formula (IV) having the structure:
and
forming a fifth reaction mixture comprising a reducing agent, a palladium catalyst, and a compound of formula (IV), under conditions sufficient to form a compound of formula (V) having the structure:
16 . The method of claim 15 , wherein the fourth reaction mixture further comprises a copper catalyst.
17 . The method of claim 16 , wherein the copper catalyst comprises copper iodide.
18 . The method of claim 15 , wherein the strong base comprises potassium tert-butoxide or sodium hydride.
19 . The method of claim 15 , wherein the reducing agent comprises a borohydride reducing agent.
20 . The method of claim 15 , wherein the reducing agent comprises lithium.
21 . The method of claim 19 , wherein the reducing agent is lithium triethylborohydride.
22 . The method of claim 15 , wherein the palladium catalyst comprises palladium chloride.
23 . The method of claim 22 , wherein the palladium catalyst comprises [1,2-bis(diphenylphosphino)propane]dichloropalladium(II).
24 . The method of claim 1 , wherein the compound of formula (II) has the structure:
25 . The method of claim 1 , further comprising:
preparing the compound of formula (II) by a process comprising culturing a microorganism using a carbon source.
26 . The method of claim 25 , wherein the carbon source is derived from a saccharide.
27 . The method of claim 1 , wherein the amine compound of formula (I) has the structure:
28 . The method of claim 1 , wherein the chloride compound of formula (I) has the structure:
29 . The method of claim 8 , wherein the ester compound of formula (I) has the structure:
30 . The method of claim 10 , wherein the alcohol compound of formula (I) has the structure:
31 . The method of claim 12 , wherein the sulfone compound of formula (I) has the structure:
32 . The method of claim 15 , wherein the compound of formula (V) has the structure:
33 . A composition comprising one or more farnesene derivatives prepared using the method of claim 1 .
34 . The composition of claim 33 , comprising from 0.1 wt % to 3 wt % (2Z,5E)-farnesol relative to the total amount of the one or more farnesene derivatives in the composition.
35 . The composition of claim 33 , comprising from 0.1 wt % to 99.9 wt % (E,E)-farnesol relative to the total amount the one or more farnesene derivatives in the composition.
36 . The composition of claim 32 , comprising from 0.1 wt % to 99.9 wt % farnesyl acetate relative to the total amount of the one or more farnesene derivatives in the composition.
37 . The composition of claim 32 , comprising from 0.1 wt % to 99.9 wt % squalene relative to the total amount of the one or more farnesene derivatives in the composition.
38 . The composition of claim 37 , further comprising an antigen.