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Enantioselective Synthesis of Madangamine Alkaloids via Organocatalytic Desymmetrization

Periodic Reporting for period 1 - ESOMAVOD (Enantioselective Synthesis of Madangamine Alkaloids via Organocatalytic Desymmetrization)

Reporting period: 2016-08-16 to 2018-08-15

During the course of this project, we have developed a new synthetic methodology towards the core of madangamine alkaloids, a family of six complex alkaloids isolated from a marine sponge, which have already shown cytotoxicity against different cancer cell lines. However, some of these compounds have not been studied yet due to the difficulty in isolation from the natural organisms. Therefore, it is highly desirable to develop a new methodology to prepare these compounds in a scalable fashion and in high yield. At the same time, the development of new reactions towards the preparation of fully substituted highly decorated amines is desirable because it can be applied as a new tool in the arsenal of reactions used in total synthesis.
After considering different alternatives and screening a diversity of organocatalysts, the synthesis of madangamine core has been accomplished from simple and readily available starting materials, using a chiral cyclohexanediamine-derived organocatalyst, which has allowed us to obtain the initial core in good yield with excellent enantioselectivity. Given its reliability and scalability, this transformation is currently in use for the total synthesis of different natural products.
Also, new methodologies towards the formation of highly decorated fully substituted amines have been developed. A new bio-inspired quinone mediated approach allows an efficient generation of reactive ketimine intermediates in situ which are primed to react with carbon-centered nucleophiles such as organomagnesium and organolithium reagents and TMSCN. Due to the versatility of the nitrile group, which can be converted into a bunch of different functional groups, this reaction could be of great interest. The discovery of new synthetic pathways which are extremely interesting in total synthesis which allows to change the disconnection approach of complex molecules in order to invent new synthetic routes.
Additionally, a quinone mediated efficient synthesis of 1,4-benzoxazines has been developed via sp3 α-C–H functionalization/C-O bond formation of amine. This method was applied to the synthesis of different compounds of interest as well as for the late stage functionalization of complex molecules. Due to the versatility of the imine functionality in 1,4-oxazines, which can be converted into a group of different functional groups.
In summary, we have successfully developed a new enantioselective approach to madangamine alkaloids core, which could also be used in the synthesis of many other morphan like alkaloids. This transformation is currently in use towards the total synthesis of natural products. Also, novel methodologies for the functionalisation of amines have been achieved. Moreover, the results of this project should be of great interest to the organic synthetic community and for industries as well, as it advances the state-of-the-art of organocatalysis with interesting applications, but also has allowed the development of new methodologies which could change the way of synthesizing complex molecules.