A Unified Route to Polycyclic Terpenes

Informations projet

Route2polyTepr

N° de convention de subvention: 894948

DOI

10.3030/894948

Projet clôturé

Date de signature de la CE 7 Avril 2020

Date de début 1 Novembre 2020

Date de fin 31 Octobre 2022

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 184 707,84

Contribution de l’UE

€ 184 707,84

Coordonné par

ECOLE POLYTECHNIQUE
France

Periodic Reporting for period 1 - Route2polyTepr (A Unified Route to Polycyclic Terpenes)

Période du rapport: 2020-11-01 au 2022-10-31

Résumé du contexte et des objectifs généraux du projet

Polycyclic terpenes are a very important class of compounds within natural products and drug molecules. Despite their medicinal properties, the complexity of their structures makes them extremely challenging synthetic targets for organic chemists. Currently the access to these molecules is mostly limited to multi-step and tedious preparations. 

In order to address this problem, we envisaged that xanthate radical precursors can play a strategic role in construction of core structures of polycyclic terpenes. In the first line of research we proposed the use of alpha-ketonyl radicals, derived from xanthates which can be formed from cyclic enones through epoxides. The second line of research involved utilization of subsequent radical and polar reactions (Horner–Wadsworth–Emmons) in order to form difficult polycyclic scaffolds. Our initial plan included the demonstration of the utility of the method by its application to total synthesis of the natural product Maritimol. 

The first objective of the project was to develop the new synthetic methodology which will allow access to a library of disubsituted enones via radical / polar pathway from easily available starting materials. Products of this reaction can be further transformed into bicyclic and polycylic structures, allowing new and facile approach to a number of medicinally relevant terpenes. The second objective was to carry out the total synthesis of Maritimol.

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

The project resulted in development of two important synthetic methodologies relevant for the synthesis of polycyclic terpenes. During its course we found the unexpected new reaction between readily available epoxy enones and potassium O-ethyl xanthate. This discovery allowed the formation of entirely new class of reagents, β-hydroxy α-xanthtyl ketones, which were subsequently used as synthetic equivalents of high energy, difficult to tame sp2 type radicals. The reaction was optimized as a facile, one pot process allowing α-functionalisation of enones in a few simple synthetic steps, allowing access to previously inaccessible molecular architectures. The method was found to be scalable to 2.0 mmol scale. We also discovered that the new reagents, developed previously in Prof. Zard’s research group, α-xanthtyl enones, undergo a clean 1,4-addition with a range of organocuprate reagents. This constitutes a major breakthrough in xanthate chemistry, allowing preparation of a new class of xanthate radical precursors. A library of new building blocks for terpene synthesis were prepared from a few easily accessible, highly versatile starting materials. The utility of radical precursors was demonstrated by their intermolecular additions to unactivated olefins, followed by cyclisation to form bicyclic and tricyclic systems, which are the core structure of many natural products, including polycyclic terpenes. We also progressed the total synthesis of natural product Maritimol, however this project was not completed due to the time constraints that were exacerbated by the Covid pandemic. 

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)

The progress beyond state of the art and scientific impact is reflected by two peer reviewed articles published before the end of the scholarship. For the first time xanthates have been successfully prepared from readily available epoxides. We also found the new class of reagents, which can be derivatised by addition of organocuprate reagents without effecting xanthate moiety. Finally, we discovered and developed the new method of alpha-functionalisation of enones with unprecedented scope. It is envisaged that the developed methodologies will find significant application in the design and execution of syntheses of complex organic molecules, both in academia and in industry. 

A Radical Route to α-Substituted Enones

An Ionic-Radical Approach to Vicinally Functionalized Cyclopentanones and Cyclohexanones