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

考虑到许多药物和生物活性化合物的结构中都存在着带有杂原子取代基的连续立体异构中心，本论文通过杂原子中心亲核试剂与吸电子烯烃的立体专一亲核加成反应，探索了一种新的构建连续立体异构中心的方法。在所研究的亲核加成反应中，硫醇与α，β-不饱和酯的加成在少量硫酚锂存在下立体专一地进行，得到E-和Z-烯烃的邻位加成物和苏位加成物，加成反应制备的加合物被发现是潜在的配体，通过演示天然生物碱的合成与乙叉基团和一个著名的不对称合成，药物（+）-地尔硫卓。将新发展的硫醇的立体定向亲核加成与加成物的亚砜的顺式消除反应相结合，完成了异辛西利金类生物碱的全合成，硫醇与含有手性助剂的不饱和酸衍生物的加成反应顺利进行，得到手性加成物，该加成物可有效地转化为（+）-地尔硫卓。另一种手性加合物也通过立体选择性的锍亲核取代反应有效地转化为（+）-trans-whisky和cognac内酯，因此，我们发展了一种通过立体选择性的硫醇亲核加成反应构建含杂原子取代基的连续立体中心的新策略。

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.