类胡萝卜素合成工艺研究
摘要
本文研究了三个类胡萝卜素：β-胡萝卜素，角黄素和虾青素的全合成工艺，主要工作如下：
1．以基本化工原料丁二烯为起始原料，与溴素加成得到反式1，4-二溴-2-丁烯，以及将丁二烯与氯气加成得到1，4-二氯-2-丁烯的顺反混合物，以溴代丁二酰亚胺为催化剂将1，4-二氯-2-丁烯从顺式体转为高含量的反式体，以上两种方法得到的反式1，4-二卤-2-丁烯再与亚磷酸三乙酯发生Abrozov重排得到2-丁烯-1，4-双磷酸酯，进而与丙酮醛缩二甲醇发生Wittig-Horner反应生成2,7-二甲基-2,4,6-辛三烯-1，8-二醛缩四甲醇，最后酸水解得到本文关键中间体2,7-二甲基-2,4,6-辛三烯-1，8-二醛。
2．3-甲基-5-(2,6,6-三甲基环己烯-1-基)-1，3-戊二烯膦酸二乙酯与2,7-二甲基-2,4,6-辛三烯-1，8-二醛发生Wittig-Horner反应生成β-胡萝卜素，省去重排步骤，简化了操作，β-胡萝卜素收率80％；β-胡萝卜素粗产品用二氯甲烷烷重结晶提纯得到紫外含量大于96％的β-胡萝卜素精品。
3．以α-紫罗兰酮为起始原料，用过氧酸环氧化，继而在碱催化下异构化形成4-(2，6，6-三甲基-3-羟基-1-环己烯-1-基)-3-丁烯-2-酮粗品，采用与环二酸酐先成酯后水解的方法纯化后，再经过Darzens反应得到2-甲基-4-(2，6,6-三甲基-3-羟基环己烯-1-基)-3-丁烯醛，后者与亚甲基双膦酸四乙酯缩合反应得到3-甲基-5-(2,6,6-三甲基-3-羟基环己烯-1-基)-1，3-戊二烯膦酸二乙酯，重排成3-甲基-5-(2,6,6-三甲基-3-羟基环己烯-1-基)-2,4-戊二烯膦酸二乙酯。此两个C_(15)膦酸酯化合物都与2,7-二甲基-2,4,6-辛三烯-1,8-二醛发生Wittig-Horner反应生成4，4’-二羟基-β-胡萝卜素，用Oppennauer氧化和活性二氧化锰氧化两种方法均得到角黄素。以α-紫罗兰酮为起始原料计算，反应总收率37％。
4．以上述合成角黄素的中间体4-(2,6,6-三甲基-3-羟基-1-环己烯-1-基)-3-丁烯-2-酮为原料与氯乙烯格氏试剂加成，加成产物再用异丙醇铝氧化得到5-(2,6,6-三甲基-3-氧代-1-环己烯-1-基)-3-羟基-3-甲基-1，4-戊二烯，用三甲基氯硅烷保护形成烯醇硅醚化合物，再用间氯过氧苯甲酸选择性环氧化烯醇硅醚，并水解得到关键中间体6-羟基-3-(3-羟基-3-甲基-1，4-戊二烯)-2,4,4-三甲基-2-环己烯-1-酮，进而与氢溴酸和三苯基膦反应得到C_(15)三苯基膦盐，在碱存在下与2,7-二甲基-2,4,6-辛三烯-1，8-二醛反应得到虾青素。反应总收率38％。
本文的创新工作：
1、本论文研究中发明了以溴代丁二酰亚胺为催化剂将1,4-二氯-2-丁烯从顺式体转为高含量的反式体的方法。
2、解决了关键中间体化合物4-(2,6,6-三甲基-3-羟基-1-环己烯-1-基)-3-丁烯-2-酮粗品的纯化方法，即采用与环二酸酐先成酯后水解的方法纯化。
3、提出了一步重排并反应的机理和方法，即以3-甲基-5-(2,6,6-三甲基环己烯-1-基)-1，3-戊二烯膦酸二乙酯在碱存在下重排并分别与不同的醛反应，应用于维生素A和β-胡萝卜素的合成。
4、以4-(2,6,6-三甲基-3-羟基-1-环己烯-1-基)-3-丁烯-2-酮为原料，经过Darzens反应得到新化合物2-甲基-4-(2，6,6-三甲基-3-羟基环己烯-1-基)-3-丁烯醛，后者与亚甲基双膦酸四乙酯缩合反应得到新化合物3-甲基-5-(2,6,6-三甲基-3-羟基环己烯-1-基)-1，3-戊二烯膦酸二乙酯，重排成3-甲基-5-(2,6,6-三甲基-3-羟基环己烯-1-基)-2,4-戊二烯膦酸二乙酯。此两个C_(15)膦酸酯化合物都可与2,7-二甲基-2,4,6-辛三烯-1，8-二醛发生Wittig-Horner反应生成4,4'-二羟基β-胡萝卜素，用Oppennauer氧化和活性二氧化锰氧化两种方法均得到角黄素，整条路线为创新路线。
5、以5-(2,6,6-三甲基-3-氧代-1-环己烯-1-基)-3-羟基-3-甲基-1，4-戊二烯为原料，用三甲基氯硅烷保护形成烯醇硅醚化合物，再用间氯过氧苯甲酸选择性环氧化烯醇硅醚，并水解得到合成虾青素的关键中间体6-羟基-3-(3-羟基-3-甲基-1，4-戊二烯)-2,4,4-三甲基-2-环己烯-1-酮。而以往的文献均是以4-氧代异佛尔酮为原料经多步反应得到。本文提出了合成此关键中间体的新方法。
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 C_(15) 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 PPh_3 lead to the C_(15) 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 (C_(15)) catalyzed by strong base. The C_(15) 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.
1．以基本化工原料丁二烯为起始原料，与溴素加成得到反式1，4-二溴-2-丁烯，以及将丁二烯与氯气加成得到1，4-二氯-2-丁烯的顺反混合物，以溴代丁二酰亚胺为催化剂将1，4-二氯-2-丁烯从顺式体转为高含量的反式体，以上两种方法得到的反式1，4-二卤-2-丁烯再与亚磷酸三乙酯发生Abrozov重排得到2-丁烯-1，4-双磷酸酯，进而与丙酮醛缩二甲醇发生Wittig-Horner反应生成2,7-二甲基-2,4,6-辛三烯-1，8-二醛缩四甲醇，最后酸水解得到本文关键中间体2,7-二甲基-2,4,6-辛三烯-1，8-二醛。
2．3-甲基-5-(2,6,6-三甲基环己烯-1-基)-1，3-戊二烯膦酸二乙酯与2,7-二甲基-2,4,6-辛三烯-1，8-二醛发生Wittig-Horner反应生成β-胡萝卜素，省去重排步骤，简化了操作，β-胡萝卜素收率80％；β-胡萝卜素粗产品用二氯甲烷烷重结晶提纯得到紫外含量大于96％的β-胡萝卜素精品。
3．以α-紫罗兰酮为起始原料，用过氧酸环氧化，继而在碱催化下异构化形成4-(2，6，6-三甲基-3-羟基-1-环己烯-1-基)-3-丁烯-2-酮粗品，采用与环二酸酐先成酯后水解的方法纯化后，再经过Darzens反应得到2-甲基-4-(2，6,6-三甲基-3-羟基环己烯-1-基)-3-丁烯醛，后者与亚甲基双膦酸四乙酯缩合反应得到3-甲基-5-(2,6,6-三甲基-3-羟基环己烯-1-基)-1，3-戊二烯膦酸二乙酯，重排成3-甲基-5-(2,6,6-三甲基-3-羟基环己烯-1-基)-2,4-戊二烯膦酸二乙酯。此两个C_(15)膦酸酯化合物都与2,7-二甲基-2,4,6-辛三烯-1,8-二醛发生Wittig-Horner反应生成4，4’-二羟基-β-胡萝卜素，用Oppennauer氧化和活性二氧化锰氧化两种方法均得到角黄素。以α-紫罗兰酮为起始原料计算，反应总收率37％。
4．以上述合成角黄素的中间体4-(2,6,6-三甲基-3-羟基-1-环己烯-1-基)-3-丁烯-2-酮为原料与氯乙烯格氏试剂加成，加成产物再用异丙醇铝氧化得到5-(2,6,6-三甲基-3-氧代-1-环己烯-1-基)-3-羟基-3-甲基-1，4-戊二烯，用三甲基氯硅烷保护形成烯醇硅醚化合物，再用间氯过氧苯甲酸选择性环氧化烯醇硅醚，并水解得到关键中间体6-羟基-3-(3-羟基-3-甲基-1，4-戊二烯)-2,4,4-三甲基-2-环己烯-1-酮，进而与氢溴酸和三苯基膦反应得到C_(15)三苯基膦盐，在碱存在下与2,7-二甲基-2,4,6-辛三烯-1，8-二醛反应得到虾青素。反应总收率38％。
本文的创新工作：
1、本论文研究中发明了以溴代丁二酰亚胺为催化剂将1,4-二氯-2-丁烯从顺式体转为高含量的反式体的方法。
2、解决了关键中间体化合物4-(2,6,6-三甲基-3-羟基-1-环己烯-1-基)-3-丁烯-2-酮粗品的纯化方法，即采用与环二酸酐先成酯后水解的方法纯化。
3、提出了一步重排并反应的机理和方法，即以3-甲基-5-(2,6,6-三甲基环己烯-1-基)-1，3-戊二烯膦酸二乙酯在碱存在下重排并分别与不同的醛反应，应用于维生素A和β-胡萝卜素的合成。
4、以4-(2,6,6-三甲基-3-羟基-1-环己烯-1-基)-3-丁烯-2-酮为原料，经过Darzens反应得到新化合物2-甲基-4-(2，6,6-三甲基-3-羟基环己烯-1-基)-3-丁烯醛，后者与亚甲基双膦酸四乙酯缩合反应得到新化合物3-甲基-5-(2,6,6-三甲基-3-羟基环己烯-1-基)-1，3-戊二烯膦酸二乙酯，重排成3-甲基-5-(2,6,6-三甲基-3-羟基环己烯-1-基)-2,4-戊二烯膦酸二乙酯。此两个C_(15)膦酸酯化合物都可与2,7-二甲基-2,4,6-辛三烯-1，8-二醛发生Wittig-Horner反应生成4,4'-二羟基β-胡萝卜素，用Oppennauer氧化和活性二氧化锰氧化两种方法均得到角黄素，整条路线为创新路线。
5、以5-(2,6,6-三甲基-3-氧代-1-环己烯-1-基)-3-羟基-3-甲基-1，4-戊二烯为原料，用三甲基氯硅烷保护形成烯醇硅醚化合物，再用间氯过氧苯甲酸选择性环氧化烯醇硅醚，并水解得到合成虾青素的关键中间体6-羟基-3-(3-羟基-3-甲基-1，4-戊二烯)-2,4,4-三甲基-2-环己烯-1-酮。而以往的文献均是以4-氧代异佛尔酮为原料经多步反应得到。本文提出了合成此关键中间体的新方法。
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 C_(15) 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 PPh_3 lead to the C_(15) 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 (C_(15)) catalyzed by strong base. The C_(15) 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.
引文
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