百部叶碱核心骨架新合成策略探索:含三个连续手性中心双环中间体的对映选择性构筑

Investigation of a novel approach to the core of stemofoline:enantioselective construction of a bicyclic intermediate with three contiguous chiral centers

本文研究了百部叶碱核心骨架新合成策略中一个含三个连续手性中心双环中间体的对映选择性构筑.以本实验室发展的(S)-苹果酰亚胺为手性源,后者经三步反应转化为氮上带亲核性烯丙基硅烷取代基的苹果酰亚胺.正丁基格氏试剂对上述苹果酰亚胺的加成区域选择性地引入百部叶碱的C-3侧链.关键的环化反应为三氟化硼合乙醚引发的分子内氮杂Sakurai反应.该反应能高产率地进行,但生成4个非对映立体异构体.通过细致的二维核Overhauser效应(NOESY)研究确定了上述4个非对映立体异构体中两新形成手性中心的立体化学,并确定了主要立体异构体(产率:35%)为合成百部叶碱天然对映体所需.Wacker氧化生成标题化合物及少量区域异构体(醛),比例为18:1,合并产率50%.

The enantioselective synthesis of a bicyclic intermediate containing three contiguous chiral centers for a novel approach to the core of stemofoline is described.A(S)-malimide derivative developed in this laboratory was used as the chiral building block.The latter was converted in three steps(N-deprotection,a Mitsunobu reaction,and a crossolefin metathesis)into another malimide with the N-substituent bearing a nucleophilic allylic silane moiety.The Grignard reagent addition took place regioselectively at the C-2 carbonyl to yield a hemiaminal.The key intramolecular aza-Sakurai reaction was promoted by trifluoroboron etherate,which led to the desired cyclization in good to excellent combined yields.Four diastereomers were formed from this reaction,whose stereochemistries were determined by NOESY technique.The latter revealed that the major diastereomer(obtained in 35%yield)possessed the correct stereochemistries required for the total synthesis of natural enantiomer of stemofoline.A regioselective Wacker oxidation resulted in the formation of the title compound along with a minor regioisomer(an aldehyde)in a ratio of 18:1(combined yield:50%).