Synthesis Of Carotenoids

In this dissertation, the research work of total synthesis of three carotenoids includingβ-carotene, canthaxanthin and astaxanthin is described in details. The main work includes:Trans-1,4-dibromo-2-butene is prepared via addition of butadiene and bromine, trans and cis mixture of 1,4-dichloro-2-butene also prepared via butadiene and chlorine, the following isomerization catalyzed by NBS afforded the predominant trans isomer of 1,4- dichloro-2-butene. The chloride or bromide compounds are subjected to Abrozov reaction with triethyl phosphite to give 2-butenyl-1,4-bisphosphonate, further condensation with pyruvic aldehyde dimethyl acetal by Wittig-Horner reaction lead to 1,1,8,8-tetramethyl-2,7-dimethyl- 2,4,6-octatriene, and finally, the key intermediate of 2,7-dimethyl-2,4,6-octatriene-1,8-dial for the synthesis of carotenoids is given by acid hydrolysis treatment.An improved method of Wittig-Horner reaction is adopted to prepareβ-carotene. In the method, 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-pentadienyl phosphonate is condensed directly with 2,7-dimethyl-2,4,6-octantrien-1,8-dial to afford crudeβ-carotene in 80% yield, which is recrystallized with dichloromethylene to give the high quality one with the purity more than 96% by ultraviolet testing method.Canthaxanthin was synthesized in overall yield of 37% from the starting material ofα-ionone. As the starting material,α-ionone was treated with peracid and subsequently subjected to isomerization in the presence of base to yield the crude product of 4-(2,6,6-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-buten-2-one, purification of this crude product by prior esterification with cycloanhydride followed by hydrolysis afforded the pure product of 4-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-3-buten-2-one, which converted to 2-methyl-4-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-3-butenal via Darzens reaction, the following step of condensation with tetraethyl methylene bisphosphonate to afford diethyl 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-1,3-pentadien-phosphonate, which was then rearranged to diethyl, 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-2,4-pentadien-phosphonate. These two C₁₅ compound were condensed with 2,7-dimethyl-2,4,6-octatriene-1,8-dial by Wittig-Horner reaction to yield 4,4'-dihydroxy-β-carotene, subsequent oxidation give the desired product of canthaxanthin.The intermediate 4-(2,6,6-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-buten-2-one for the synthesis of canthaxanthin is also used as the starting material to synthesize astaxanthin. The addition with Grignard reagent of vinyl chloride and subsequent oxidative treatment with aluminum isopropoxide gave 5-(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)-3-hydroxy-3-methyl-1,4-pentadiene, which is treated with trimethyl chlorosilane and m-CPBA respectively to provide the key intermediate 6-hydroxy-3-(3-hydroxy-3-methyl-1,4-pentadien-1-yl)-2,4,4-trimethyl-2-cyclohexen-1-one. Transformation of this key intermediate with HBr and PPh₃ lead to the C₁₅ building phosphonium, followed addition reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial in the presence of base yielded the desired product of astaxanthin. The overall yield of 7 steps was 38%.Innovation points in the dissertation:1,Developed a novel method in which trans and cis mixture of 1,4-dichloro-2-butene is isomerized to the predominant trans isomer.2,Developed a novel method of purifying the key intermediate of 4-(2,6,6-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-buten-2-one by prior esterification of the crude product with cycloanhydride such as succinic anhydride followed hydrolysis.3,Propound the mechanism and method of one-step combining rearrangement and reaction. Catalyzed by base, 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-pentadienyl phosphonate were rearranged and condensed with different aldehyde compounds to synthesize vitamin A andβ-carotene.4,4-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-3-buten-2-one, was converted to 2-methyl-4-(2,6,6- trimethyl-3- hydroxycyclohexen-1-yl)-3-butenal via Darzens reaction, then condensed with tetraethyl methylene bisphosphonate to afford diethyl 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-1,3-pentadien-phosphonate, which was then rearranged to diethyl 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1 -yl)-2,4-pentadien-phosphonate (C₁₅) catalyzed by strong base. The C₁₅ compounds were condensed with 2,7-dimethyl-2,4,6-octatriene-1,8-dial by Wittig-Horner reaction to yield 4,4'-dihydroxy-β-carotene, which was subsequently oxidized to the desired product of canthaxanthin. The entire procedure is creative.5,The intermediate 5-(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)-3-hydroxy-3-methyl-1,4-pentadiene was protected with trimethyl chlorosilane and then subjected to selective epoxidation with m-CPBA and further hydrolysis to provide the key intermediate 6-hydroxy-3-(3-hydroxyl-3-methyl-1,4-pentadien-1-yl)-2,4,4- trimethyl-2-cyclohexen-1-one, which is the key material for the synthesis of astaxanthin, and in formerly published articles it was prepared from the material of 4-oxo-isophorone. So in this dissertation a novel route of preparing this key intermediate is developed.