Desymmetrization of a,a'-dimethoxy-g-pyrone, a highway to molecular diversity – GPYRONE
Desymmetrization of a,a'-dimethoxy-g-pyrone for a rapid and broad access to molecular diversity
the strategy of desymetrization that we designed and previously demonstrated for the synthesis of aureothin, was the basis to the preparation of analogues that could display similar biological activity.<br />In parallel, we led synthetic study toward the asymmetric access to ocellanopyrone. <br />
Understanding of the photo sensitivity of aureothin and establishment of an asymmetric pathway to ocellanopyrone
The main issue of aureothin is that the molecule is unstable to light while exhibiting strong antitumoral properties. The objective was therefore to understand the origin of the sensitivity and to tune the structure of the molecule to prevent this process.<br />In parrallel, we devised an access to ocellanopyrone with solutions that could be innovative.
To understand the origin of the sensitivity of the molecule toward light, we prepared analogues and examined their stabilities.
To reach ocellanopyrone, we intended to use epoxide as a mean to forge the structural elements of the target.
Using this method, we were able to discern a pattern of unstable molecules. We therefore are looking now to prepare a structurally close analogue of aureothin that could sustain light and exhibit interesting bioactivity.
The synthetic study of aureothin is currently suspended due to the difficult ring opening of the epoxide.
We are targeting an analogue that could be more stable to light and still display anti-tumoral activities.
For preparing ocellanopyrone, we have devised two strategies that could open an access to the target while being innovative and elegant.
ongoing
The innovative preparation of natural products and analogues containing the a'-methoxy-g-pyrone scaffold is the driving force of this project.
Having designed a new access to this class of compounds by desymmetrization of the readily available a,a'-dimethoxy-g-pyrone, we were able to evaluate biological properties of some of them through a collaboration with a pharmaceutical company. In order to understand and optimize the unusual mode of action of these molecules, we plan in task 1 to prepare analogues for further biological evaluations by the same company.
In task 2, we intend to reach a complex target in a stereo- and enantioselective manner thanks to a concise strategy based on preliminary results. The challenging target features two stereogenic quaternary carbons. In case of success, we will evaluate the biological activity of the target.
To summarize, this project's aim is to considerably improve the access to biomolecules and natural products containing the a'-methoxy-g-pyrone scaffold.
The strategies are convergent, relatively user-friendly and step-saving. Given the need of economies in organic synthesis, this project is part of the spirit of the times.
Project coordination
Michael De Paolis (Laboratoire COBRA)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
Laboratoire COBRA
Help of the ANR 135,200 euros
Beginning and duration of the scientific project:
September 2014
- 36 Months
