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

• Applicant: Professor Dr. Bernhard Breit
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450762957

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.

• DFG Programme: Research Grants