Palladium-catalyzed enantioselective domino reaction for the efficient synthesis of vitamin E
Palladium-catalyzed enantioselective domino reaction for the efficient synthesis of vitamin E
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DOI：
10.1002/anie.200461629
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发表时间：
2005-01-01
影响因子：
16.6
通讯作者：
Stecker, F
中科院分区：
文献类型：
--
作者：
Tietze, LF;Sommer, KM;Stecker, F
维生素E是一种脂溶性维生素，是所有生育酚和生育三烯酚的统称。维生素E家族由八种天然化合物组成，根据其芳环的甲基化程度，将其指定为a、B、g和d。它们都具有在C2处具有R构型的立体中心的苯并二氢吡喃骨架（实例：α-生育酚：1，α-生育三烯酚：2）。[1]在所有立体中心具有R构型的天然α-生育酚（1）具有最显著的生物活性。维生素E作为一种抗氧化剂，被认为是防止脂质过氧化的重要保护因子;特别是，它通过捕获体内形成的高活性自由基来保护动物和人类代谢所必需的多不饱和脂肪酸，这些自由基是正常氧化代谢的副产物，并导致细胞膜的不可逆破坏。[2]在工业上，α-生育酚（1）通过三甲基氢醌（3）与全外消旋异植醇（4;参见方案1）的酸催化反应大规模生产，由此形成八种立体异构体的混合物。然而，在该反应中，也形成了在苯并二氢吡喃骨架中具有S构型的化合物，因此具有低得多的抗氧化作用。[3]因此，从工业的角度来看，对开发有效的对映选择性构建α-生育酚（1）的方法有相当大的兴趣;这尤其适用于在色满环上立体中心的立体选择性形成，如果可能的话伴随引入侧链。已经有许多1的对映选择性合成方法，然而，这些方法不适合于工业应用。[4]在这里，我们描述了一种新的对映选择性钯催化方法[5]，该方法不仅允许形成手性苯并二氢吡喃框架[6]，对映选择性为96%ee，而且还允许在多米诺反应的背景下同时引入维生素E的部分侧链。[7]的第14段。该序列包括对映选择性Wacker氧化[8]和随后的Heck反应（方案1）。[9]多米诺反应的底物烯烃5是由三甲基氢醌（3）通过酸催化与甲基乙烯基酮缩合并与Lombardo试剂反应在几个步骤中以60%的总产率获得的。[10]5与丙烯酸甲酯在二氯甲烷中的反应，
Vitamin E is one of the fat-soluble vitamins and a collective term for all tocopherols and tocotrienols. The vitaminE family consists of eight natural compounds which, depending upon the degree of methylation of their aromatic ring, are specified as a, b, g and d. All possess a chroman framework with a stereogenic center at C2 with R configuration (examples: a-tocopherol: 1, a-tocotrienol: 2).[1] Natural a-tocopherol (1) with the R configuration at all stereogenic centers has the most pronounced biological activity. Vitamin E acts as an antioxidant and is considered an essential protective factor against lipid peroxidation; in particular, it protects polyunsaturated fatty acids essential for animal and human metabolism by capturing highly reactive free radicals formed in the body as by-products of normal oxidative metabolism and which cause irreversible destruction of cell membranes.[2] Industrially a-tocopherol (1) is produced on a large scale by the acid-catalyzed reaction of trimethylhydroquinone (3) with all-rac-isophytol (4; see Scheme 1), whereby a mixture of eight stereoisomers is formed. However, in this reaction compounds with an S configuration in the chroman framework and thus of far lower antioxidant action are also formed.[3] Thus, from the point of view of industry there is considerable interest in the development of a process for the efficient enantioselective construction of a-tocopherol (1); this applies especially to the stereoselective formation of the stereogenic center on the chroman ring, if possible with the concomitant introduction of the side chain. There are already a number of enantioselective synthetic methods for 1, which are not suitable, however, for industrial use.[4] Here we describe a new enantioselective palladiumcatalyzed method [5] which allows not only the formation of the chiral chroman framework [6] with an enantioselectivity of 96% ee but also the simultaneous introduction of part of the side chain of vitaminE within the context of a domino reaction.[7]. This sequence comprises an enantioselective Wacker oxidation [8] and a subsequent Heck reaction (Scheme 1).[9]The substrate for the domino reaction, alkene 5, was obtained in an overall yield of 60% from trimethylhydroquinone (3) in a few steps by acid-catalyzed condensation with methyl vinyl ketone and reaction with the Lombardo reagent.[10] The reaction of 5 with methyl acrylate in dichloro-