3-烷基-2，3-二氢-1H-异吲哚-1-酮的不对称合成

【作者】 黄利强；

【导师】 陈明德； 黄培强；

【作者基本信息】 厦门大学 ， 有机化学， 2001， 硕士

【摘要】 3-烷基-2，3-二氢-1H-异吲哚-1-酮(Ⅰ)类化合物存在于许多天然有机物和生理活性物质的核心结构中，具有广阔的医学和生化应用前景。此外，这类化合物还可作为不对称合成的手性辅助剂，还原后可作为手性配体，在不对称合成中具有潜在的应用前景。 本论文的目的是在本实验室以往研究工作的基础上，开发手性异吲哚酮合成子的合成路线，建立一种灵活多用的合成方法，以期为不对称合成提供新型手性辅助剂，用于不对称合成反应。 首先，从邻苯二甲酸酐(Ⅱ)和(R)-(-)-苯基甘氨醇(Ⅲ)出发，合成了N-取代邻苯二甲酰亚胺(Ⅴ)。把Ⅴ的羟基用苄基保护后的产物Ⅵ进行还原烷基化反应，即格氏试剂加成—三氟化硼合乙醚催化下的三乙基硅烷还原去羟基反应，应用甲基格氏试剂可得到一对非对映异构体Ⅷ，两异构体比例约为3:2，但R_f值相同，无法用常规方法分开。幸运的是，直接对Ⅴ进行还原烷基化反应，结果得到了可用柱层析法分离的一对非对映异构体Ⅸ。与文献的方法对比，我们的方法具有灵活多用的优点，可用格氏试剂方便地引入侧链，现已引入甲基、乙基、丁基、异丁基、庚基、苯基、苄基等多种基团，加成反应产率一般可达到96％，还原反应产率一般大于85％，d.e.值在42％到82％之间。并经X-射线单晶衍射测定，证实了主产物为(1′R)-(3R)构型。 其次，将Ⅶ环化制得Ⅹ，再在四氯化钛催化下用三乙基硅烷还原，可以以较高的立体选择性得到Ⅸ，当R为甲基时d.e.值90％，产率66％。此外，用价廉易得的亚苄基酞Ⅳ代替Ⅱ作为原料与Ⅲ缩合，环化后还原，可以得到侧链R为苄基的产物Ⅸ(d.e.值84％，产率98％)。 最后，对化合物Ⅸ的去除手性辅助基进行了初步研究，用先消除成烯再断C—N键的方法，可以得到具有光学活性的3－取代2，3－二氢－IH－异吼跺－卜酮U＊为异丁基），e上．值为69％。尽管观察到发生了一定的外消旋化，但也为制备异吼跺酮合成子互积累了一些经验。更多还原

【Abstract】 The 3-substituted-2,3-dihydro-JHisoindol-l-ones (I) are found as core units in many natural and/or bioactive compounds, they have broad prospect in fields of medicine and biochemistry. After amide carbonyl reduction, they can serve as a group of promising cbiraL auxiliaries in asymmetric synthesis.Our laboratory has developed a general method for the asymmetric synthesis of pyrrolidines, 2-pyrrolidinones and related compounds, starting from cheap and easily available (S)- malic acid. On this ground, the aim of this thesis has been to develop a new and versatile asymmetric synthetic method to isoindolone, so as to provide new chiral auxiliaries for asymmetric synthesis.First, starting from phthalic anhydride (II) and (R)- (-)-phenylglycinol(III), we prepared N-substituted phthalimide(V). After protecting the hydroxy group VI was formed, then it was subject to reductive alkylation process( Grignard reagent then reduced by Et3SiH in the presence of BF3OEt2). When methyl magnesium iodide was used, compound VIII was obtained as a mixture of two inseparable diastereoisomers in the ratio of 3:2. To overcome the difficulties, we studied the direct reductive alkylation of V. Grignard reagent addition led to two diastereoisomers that can be separated through column chromatography. Comparing with the literature methods, our method present advantages of flexibility and versatility, since side chain can be introduced easily through Grignard addition. We have introduced in such way methyl, ethyl, butyl, isobutyl, heptyl, phenyl and benzyl. The yield of Grignard addition was about 96%; in the reduction step, the yield was generally above 85% and the d.e. ranged from 42 to 82% . X-ray analysis showed that the major products have (1 R ) - (3R) configurations.Second, X was prepared through cyclization of VII, then it was reduced byEt3SiH in the presence of TiC14 affording TX with higher diastereoselectivity(when R=Me, d.e.=90%, y~66%). And benzal phthalide IV, a cheap and easily available compound, can condense with III in place of II, and give IX with a benzyl side chain after cyclization and reduction(d.e.=84%, y’98%).Finally, removal of protecting group of IX has been attempted, optically active 3-substituted-2,3-dihydro--JH-isoindol-1-one J( R i- Bu ) can be obtained (e.e. 69%) although racemization can not be excluded under the conditions used.更多还原