Atom economic Rhodium catalyzed cyclization of allenyl-/alkynyl indoles and tryptamines as key step for the synthesis of biologically active tetrahyrocarbazoles, tetrahydro-β-carbolines and tetrahydropyrido[1,2]indoles

吲哚生物碱是一类非常重要的天然产物，尤其是因为具有各种生物活性的大量已知代表物质。除了据说具有呼吸刺激和抗生素特性的(+)-阿司匹林和(+)-哈米辛(由于其与α2-肾上腺素受体的亲和力而被归因于镇静作用)外，吲哚生物碱(-)-醛胆碱A被发现显著刺激神经干细胞(NSCs)的生长。这些例子属于四氢咔唑、四氢-β-卡宾或四氢吡啶并[1，2-a]吲哚的重要亚类。此外，(+)-螺内酯也可归类为螺吲哚。尤其是由于这些原因，上述结构基序仍然是合成化学家感兴趣的目标分子。除了经典的环化策略外，过渡金属催化的分子内烯丙基取代反应从C2或C3取代的吲哚和烯丙基亲电试剂开始，已经成为获得这些结构基序的一种更有价值的选择。尽管这些方法的可靠性和高度的立体选择性，但它们也有相当大的缺点--特别是在原子经济性方面--因为它们属于取代反应的类别，因此，根据定义，在反应过程中会产生化学计量的废物。鉴于人们对化学工业可持续发展意识的增强和基础学术化学研究，因此开发更经济、更生态的替代品至关重要。作为我们对开发更可持续的有机合成方法的兴趣的一部分，我们的团队最近成功地建立了一种更经济的替代支链选择性的烯丙基取代反应的方法，该反应具有立体选择性的催化加成反应到烯烃和炔烃上。虽然我们最初的工作是开发各种分子间氢功能化的方法，但同时我们也成功地将这一概念转移到了分子内(环化)反应。所有这些方法都具有高度的立体选择性的特点，其中一些已经成功地应用于生物活性分子的合成。因此，在这个研究项目的过程中，我们计划开发合成四氢咔唑、-β-咔啉或-吡啶并[1，2-a]吲哚，以及从各种烯丙基和炔基取代吲哚开始的螺吲哚的合成策略。除了高度的原子经济性外，这些方法还应该具有高立体选择性的特点。在成功的优化和方法开发后，这些策略将在上述天然产物的全合成中进行测试。

Not least because of the large number of known representatives which display various biological activities, indole alkaloids represent a tremendously important class of natural products. Aside from (+)-aspidospermidine, which is said to have respiratory stimulating and antibiotic properties, and (+)-harmicine, to which sedative effects are ascribed due to its affinity to the α2-adrenoceptor, the indole alkaloid (–)-alstoscholarisine A was found to significantly stimulate the growth of neuronal stem cells (NSCs). These examples belong to the important subclasses of either tetrahydrocarbazoles, tetrahydro-β-carbolines or tetrahydropyrido[1,2-a]indoles. In addition, (+)-aspidospermidine can also be categorized as spiroindoline. Not least for these reasons, the mentioned structural motifs still represent interesting target molecules for synthetic chemists. In addition to classical cyclization strategies, transition metal-catalyzed intramolecular allylic substitutions starting from C2- or C3-substituted indoles and allylic electrophiles have emerged to a more than valuable alternative to access these structural motifs. Despite their reliability and their high degrees of stereoselectivity, these methods also have considerable disadvantages – especially with regard to their atom economy – because they belong to the class of substitution reactions and thus, by definition, generate stoichiometric amounts of waste products in course of the reaction. In light of an increased awareness of sustainability in the chemical industry and basic academic chemical research, the development of more economical and ecological alternatives is therefore of vital importance. As part of our interest in the development of more sustainable organic synthetic methods our group recently succeeded in establishing a more atom-economic alternative to branched-selective allylic substitutions with stereoselective rhodium-catalyzed addition reactions to allenes and alkynes. While our work initially aimed at the development of various methods for intermolecular hydrofunctionalizations, meanwhile we have also succeeded in transferring this concept to intramolecular (cyclization) reactions. All these methods are characterized by high degrees of stereoselectivity and some of them were already successfully implemented in the synthesis of biologically active molecules.In the course of this research project, we are therefore planning to develop general strategies for the synthesis of tetrahydrocarbazoles, -β-carbolines or -pyrido[1,2-a]indoles, as well as spiroindolines starting from various allenyl- and alkynyl-substituted indoles, based on the initial findings in the cyclization of tethered 3-allenylindoles. In addition to high degrees of atom economy, these methods should also be characterized by high stereoselectivities. After a successful optimization and method development, the strategies will be tested in the total synthesis of the above-mentioned natural products.