New Method for Construction of Contiguous Chiral Centers with Hetero-atom Substituent

构建杂原子取代基连续手性中心的新方法

基本信息

批准号：
03671022
负责人：
NAITO Takeaki
金额：
$ 1.34万
依托单位：
Kobe Women's College of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

Considering that contiguous stereogenic centers with hetero-atom substituent are shown in the structures of not only many medicinals but also the biologically active compounds, we investigated to explore a new method for the construction of contiguous stereogenic centers via the route involving the stereospecific nucleophilic addition reaction of hetero-atom centered nucleophiles to electron-withdrawing olefins. Among the nucleophilic addition reactions investigated, the addition of thiols to alpha, beta- unsaturated esters proceeded stereospecifically in the presence of small amount of lithium thiophenoxide to give the erythro- and threoadducts from E- and Z-olefins, respectively.Adducts prepared by the addition reaction were found to be potential synthons by demonstrating the synthesis of natural alkaloids with ethylidene group and asymmetric synthesis of a famous drug (+)-diltiazem. Combination of the newly developed stereospecific nucleophilic addition of thiols and syn-elimination of the corresponding sulfoxide of the resulting adducts completed the total synthesis of the whole alkaloids of isositsirikine group.Addition reactions of thiols to the unsaturated acid derivatives having chiral auxiliary proceeded smoothly to give the chiral adducts diastereoselectively which was effectively converted into (+)-diltiazem, a cardiac drug. The other chiral ad-duct was also effectively converted to (+)-trans-whisky and cognac lactones via stereoselective nucleophilic substitution of the corresponding sulfonium group.Thus, we have now developed a new strategy for construction of the contiguous stereogenic centers with hetero-atom substituent via stereospecific nucleophilic addition reaction of thiols.

考虑到具有异性原子取代基的连续立体生成中心不仅在许多药物的结构中，而且还显示了生物活性化合物的结构中，我们研究了通过涉及定点核化核定型核能中心型核定型核定型核定型核定型核能反应的途径来探索一种新方法，以构建连续的立体中心。在研究的亲核添加反应中，在α上添加硫醇，在存在少量的硫酚锂的情况下，β-不饱和酯分别进行了定型，以分别从E-和Z-烯蛋白中获得红细胞和三核，从而通过添加的反应构成的依据。乙烯组和一种著名药物（+） - diltiazem的不对称合成。新开发的硫醇的新定型亲核的添加以及所得加合物的相应硫氧化物的合成结合完成了同甲西里氨酸基团的整个生物碱的总合成。转化为（+） - diltiazem，一种心脏药物。还通过对相应磺基组的立体选择性亲核取代的旋转和干酪乳酮有效地转化为（+） - 反晶型和黑白乳酸内酯。因此，我们现在已经开发了一种新的策略，用于通过构型源代替构造构造的定向中心的构造构建，这是通过构型化的构成反应的。