基于多种合成策略的细胞毒性生物碱melodinine及相关分子的不对称合成

Indole derivatives are important compounds that occur widespread in nature and exhibit significant biological activity and all-carbon quaternary centers at the C3 position of indoles are known to possess a variety of biological activities. For example, The genus Melodinus (Apocynaceae) comprises 53 species all over the world, and 11 of them are distributed in Guangxi. The phytochemical constituents of Melodins sp.have been investigated extensively. Up to now, more than 80 compounds have been isolated and characterized. Most of them have for a long time attracted great interest of synthetic organic chemists as challenging targets due to their marked diversity and complicated architectures. In this research project, we will focus on the all-carbon quaternary centers protocol bulding at the C3 position of indoles and the asymmetric synthesis of some exhibiting significant biological activity compounds. First, we will develop some general all-carbon quaternary centers at the C3 position of indoles. This is the basis of the project. As an important part of this project, we then will finish the asymmetric synthesis of melodinine and analogs (significant cytotoxic and complicated architectures), spiroindimicin (spiroindimicin represent the first example of unusual spiro-ring containing bisindole alkaloids of bacteria origin), NITD609 (new clinical candidate for the treatment of malaria) from ihdoles to prove their utility and versatility as useful methods. By utility of these research results, we can understand the reactivities, regioselectivities and stereoselectivities in the all-carbon quaternary centers bulding at the C3 position of indoles. Moreover, we can build the all-carbon quaternary centers protocol at the C3 position of indoles, as well as build some flexible, convenient and efficient asymmetric synthesis methods.

含季碳结构的吲哚类生物碱广泛存在于动植物和海洋天然产物中，它们大多具有重要的生物活性。本项目拟开展以下研究工作：1、以吲哚、2-吲哚酮等为原料利用TEMPO/过渡金属/空气催化氧化的交叉偶联反应、不对称催化接力等策略，通过一步或一锅化方法在吲哚环的C-3位构筑手性季碳结构，并包含螺环或多环结构，从而建立一些步骤简单、操作方便的在吲哚环的C-3位构筑手性季碳结构的一般方法。2、将已建立的合成方法应用于具有细胞毒活性吲哚生物碱melodinine及类似物、抗肿瘤活性生物碱spiroindimicin和高效抗疟疾临床候选药物NITD609及类似物的不对称合成。3、将合成的上述化合物用于小白鼠体内外抗血吸虫成虫活性研究。通过以上研究可以了解在吲哚类化合物C3位构筑季碳结构的反应性和有关的区域选择性及立体选择性，为探索在吲哚类化合物中寻找抗血吸虫药物打下基础。

含季碳结构的吲哚类生物碱广泛存在于动植物和海洋天然产物中，它们大多具有重要的生物活性。例如，罗布麻属(Melodinus，夹竹桃科)在全世界有53种，其中11种分布在广西。植物化学成分已被广泛研究。到目前为止，已分离鉴定出80多种化合物。长期以来，它们以其显著的多样性和复杂的结构吸引了合成有机化学家的极大兴趣，成为具有挑战性的研究对象。. 本项目开展了以下研究工作：1、以吲哚、2-吲哚酮等吲哚衍生物为原料利用TEMPO/过渡金属/空气催化氧化的交叉偶联反应、催化接力等策略，通过一步或一锅化方法在吲哚环的C-3或C-2位构筑手性季碳结构，并包含螺环或多环结构，从而建立一些步骤简单、操作方便的在吲哚环的C-3或C-2位位构筑季碳结构的一般方法。2、将已建立的合成方法应用于具有细胞毒活性吲哚生物碱melodinine及类似物和高效抗疟疾临床候选药物NITD609及类似物的全合成。3、将上面合成的NITD609及类似物和吲哚的二聚及三聚化合物用于小白鼠体外抗血吸虫成虫活性研究和抗肿瘤活性研究。. 此外，我们还增加了三氮唑的胺基化、硫化以及芳基化研究；增加了TEMPO催化空气氧化吲哚化合物进行二聚或三聚研究；增加了氧化石墨烯（GO）用于远端醇和抗癌药物来那度胺（lenalidomide）衍生物的合成研究。. 通过以上研究可以了解在吲哚类化合物C3或C-2位构筑季碳结构的反应性和有关的区域选择性及立体选择性，为探索在吲哚类化合物中寻找抗血吸虫药物和抗肿瘤药物打下基础。