Practical Alkaloid Synthesis on the axis of Asymmetric Azaelectrocyclization

取代胡椒碱是许多天然生物碱的核心结构，包括吲哚类生物碱。此外，这些功能化的六元氮杂环化合物因其具有良好的药理活性而引起了人们的广泛关注。因此，立体控制合成各种取代构型的哌啶是目前许多合成化学家研究的课题之一。最近，我们利用7-烷基取代的顺式氨基吲哚醇衍生物，建立了构象柔性的线性1-氮杂烯的高立体选择性6π-氮杂电环化反应。我们的不对称叠氮电环化是基于发现在c4 -羰基和c6 -烯基或芳基取代基存在时，1-叠氮杂氮的HOMO和LUMO之间显著的边界轨道相互作用显著加速了叠氮电环化。为了建立不对称6π-氮杂电环合成生物碱的新策略，本项目取得了以下丰硕成果：(1)在Pd(0)催化剂的作用下，将具有多种不饱和基团的乙烯基锡南、同时具有醛和酯基团的乙烯基碘化物以及手性氮源的顺式氨基吲哚衍生物进行不对称6π-氮杂电环化，采用高效的一锅法制备了手性2,4,6-三取代哌啶的立体选择性合成。(2)该方法成功地合成了吲哚吡啶生物碱(-)-树endroprimine，这是一个简单但具有挑战性的分子，可以在一个小的哌啶骨架上立体选择性地构建三个立体中心。(3)通过吲哚衍生物的不对称叠氮电环化，成功地实现了2,4,5,6-四取代哌啶衍生物合成吲哚类生物碱的立体控制结构。(4)采用上述2,4,5,6-太叔代哌啶构建法，通过单碳延伸、吲哚基裂解、Pummerer反应构建C环，最后进行官能团操纵，实现了吲哚类生物碱(-)-环壬烷醇的不对称立体控制全合成。少

Substituted piperidines can be regarded as a core structure of many naturally occurring alkaloids, including indol alkaloids. Furthermore, these functionalized six-member nitrogen heterocycles have drawn a great deal of attention because of their attractive pharmacological activities. Thus, the stereo-controlled synthesis of piperidines with various substitution patterns is one of the current topics for many synthetic chemists. Recently, we established the highly stereoselective asymmetric 6π-azaelectrocyclization of conformationally flexible linear 1-azatrienes using 7-alkyl-substituted cis-aminoindanol derivatives. Our asymmetric azaelectrocyclization is based on the discovery that the remarkable frontier-orbital interaction between the HOMO and LUMO of the 1-azatrienes significantly accelerates the azaelectrocyclization in the presence of C4-carbonyl and C6-alkenyl or aryl substituents. In order to establish our asymmetric 6π-azaelectrocyclization toward a new strategy for alkaloid … More synthesis, we succeeded the following fruitful results in this project : (1)The stereoselective synthesis of chiral 2,4,6-trisubstituted piperidines was achieved by an efficient one-pot procedure of asymmetric the 6π-azaelectrocyclization resulting from mixing vinylstannan possessing various unsaturated groups, vinyl iodides having both aldehyde and ester groups, and the cis-aminoindanol derivative of the chiral nitrogen source in the presence of Pd(0) catalyst. (2)The method was successfully applied to the synthesis of an indolidizine alkaloid, (-)-dendroprimine, a simple but a challenging molecule for the stereoselective construction of three stereogenic centers on a small piperidine skeleton. (3)The stereo-controlled construction of the 2,4,5,6-tetrasubsituted piperidine derivatives toward synthesis of indol alkaloids was successfully realized by the asymmetric azaelectrocyclization of indol derivatives. (4)Asymmetric stereocontrolled total synthesis of (-)-corynantheidol, an indol alkaloid, was achieved by utilizing the 2,4,5,6-tertasubstituted piperidine construction method described above, followed by one-carbon elongation, cleavage of the indanol group, the C ring construction by the Pummerer reaction, and then functional group manipulations. Less