Organocatalysis at the service of total synthesis: Madangamine alkaloids

Informations projet

ORSETOSY

N° de convention de subvention: 660125

DOI

10.3030/660125

Projet clôturé

Date de signature de la CE 20 Mars 2015

Date de début 27 Avril 2015

Date de fin 26 Avril 2017

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 183 454,80

Contribution de l’UE

€ 183 454,80

Coordonné par

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom

Periodic Reporting for period 1 - ORSETOSY (Organocatalysis at the service of total synthesis: Madangamine alkaloids)

Période du rapport: 2015-04-27 au 2017-04-26

Résumé du contexte et des objectifs généraux du projet

During the course of this project, we have developed a new synthetic methodology toward 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.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

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 and excellent enantioselectivty. 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 photoredox approach allows the umpolung functionalisation of in situ formed imines through the generation of an alpha amino radical which can react with electron deficient alkenes. This methodology could be of great use in total synthesis but also in the creation of libraries of compounds.
Additionally, a new high yield and highly chemoselective Ir catalysed tertiary amide cyanation has been developed and 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 nitrile group, which can be converted into a bunch of different functional groups, this reaction could be of great interest.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

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 industry 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 complex molecules are synthesized.

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