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

原子经济铑催化联烯基/炔基吲哚和色胺的环化作为合成生物活性四氢咔唑、四氢-β-咔啉和四氢吡啶并[1,2]吲哚的关键步骤

• 批准号: 450762957
• 负责人: Professor Dr. Bernhard Breit
• 金额: --
• 依托单位: Institut für Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/450762957?language=en
• 关键词: Atom; economic; Rhodium; catalyzed; cyclization

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.

尤其是由于大量已知的表现出各种生物活性的代表，吲哚生物碱代表了一类极其重要的天然产物。除了 (+)-aspidospermidine（据说具有呼吸刺激和抗生素特性）和 (+)-harmicine（由于其与 α2-肾上腺素受体的亲和力而具有镇静作用）之外，吲哚生物碱 (-)-alstoscholarisine A 被发现可以显着刺激神经元干细胞 (NSC) 的生长。这些实例属于四氢咔唑、四氢-β-咔啉或四氢吡啶并[1,2-a]吲哚的重要子类。此外，(+)-aspidospermidine也可归类为螺吲哚啉。尤其是由于这些原因，所提到的结构基序仍然代表了合成化学家感兴趣的目标分子。除了经典的环化策略之外，从 C2 或 C3 取代的吲哚和烯丙基亲电子试剂开始的过渡金属催化的分子内烯丙基取代已成为获取这些结构基序的更有价值的替代方案。尽管它们具有可靠性和高度的立体选择性，但这些方法也有相当大的缺点——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。鉴于化学工业和基础学术化学研究的可持续性意识不断增强，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原子经济的替代方案，通过立体选择性铑催化的丙二烯和炔烃加成反应来替代支链选择性烯丙基取代。虽然我们的工作最初旨在开发各种分子间氢官能化方法，但同时我们也成功地将这一概念转移到分子内（环化）反应。所有这些方法都具有高度立体选择性的特点，其中一些方法已经成功地应用于生物活性分子的合成中。因此，在本研究项目的过程中，我们计划开发从各种丙二烯基-和 炔基取代的吲哚，基于系链 3-烯基吲哚环化的初步发现。除了高度的原子经济性之外，这些方法还应该具有高立体选择性的特点。经过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。