"The combination of an organocatalyst and a metal catalyst in a single transformation provides novel reactivity and high control in the creation of new bonds. However, this approach has never been applied to the synthesis of complex natural alkaloids. The aim of DOMDICAS is the development of a novel dual-catalysed asymmetric desymmetrisation methodology and its application to the synthesis of Strychnos alkaloids leuconicines A and B. In the first stage of the proposed research, a dual catalytic system, formed by an organocatalyst and a metal catalyst, will be developed for the construction of the key morphan core of leuconicines. The transformation will be carefully studied in order to obtain optimal reactivity and stereocontrol. The methodology will then be extended to a two-component arylative/vinylative version, which will make the desymmetrisation approach more general and useful. The development of this powerful methodology will be crucial for the proposed synthesis of leuconicines A and B. In the key desymmetrisation step the morphan core of the alkaloids will be constructed and the configuration of 3 of their 4 stereocenters will be established. The proposed synthesis permits the diversification of a common late-stage intermediate to other Strychnos alkaloids. The application of this novel methodology to the total synthesis of bioactive natural products such as leuconicines will provide enough amounts of material for thorough biological studies and would also constitute a milestone for the study of structure-activity relationships. Apart from the impact of the high-quality scientific results expected from this project, DOMDICAS will strongly enhance the future career prospects of the applicant as a mature and independent researcher in the European Research Area."
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