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SPIRolactones from ALkylidene butenolides : An efficicient entry towards the preparation of complex highly oxygenated polycyclic structures – SPIRAL

NEW ACCESS TOWARDS THE PREPARATION OF COMPLEX POLYCYCLIC STRUCTURES

Synthesis of spirolactone moities from alkylidene butenolides : an efficient entry towards the preparation of complex highly oxygenated polycyclic structures

Synthesis of spirolactone moities from alkylidene butenolides

This proposal is centered on the development of new synthetic methodologies and their application towards the total synthesis of complex biologically important natural products. The synthesis of high molecular complexity structure in a step economical fashion from simple achiral substrate remains challenging. The objective is to use gamma-alkylidene butenolides to design stereoselectively [4.4.0] et [6.4.0] spirolactones using cycloaddition or peryciclic reactions. The application of these methodologies was devoted to the synthesis of complex natural products and high molecular complexity and diversity.

We propose to apply our expertise in the field of the synthesis of gamma-alkylidene butenolides and the total synthesis of natural products for the preparation of spirolactones moities present in polycyclic complex natural products. The project is divided in two parts. The first one deals with the synthesis of [6.4.0]- et [4.4.0]-spirolactones from gamma-alkylidène buténolides using domino reaction (task 1), [3+2]-cycloadition reaction (task 2) and [3+2] annulation reaction (task 4). The second part is devoted to the use of the methodologies developped above to the synthesis of polycyclic complex natural products (task 3).

The spiro (7,5) ring system is a recurring structural motif in numerous natural products such as Lancifodilactones, Micrandilactones and Rubriflordilactones. These polycyclic structures represent a synthetic challenge for organic chemists. Indeed, these molecules present at least nine stereogenic centers including several quaternary ones. The main goal of this work was developing new metal-catalyzed reactions as key steps to obtain quickly and efficiently the polycyclic core of those natural products. The first part of these studies was dedicated to the development of a new palladium-catalyzed domino reaction leading to, depending on the conditions used, different polycyclic cores of nortriterpenoids from Schisandra genus. Two others approaches were developed around the same key reaction: a [2+2+2] cycloaddition reaction of an acyclic triynic compound to acces the tricyclic skeleton of this nortriterpenoids. The second part of this project was dedicated to the development of an intra- and intermolecular [3+2] cycloaddition using a gamma-alkylidene-butenolide as dipolarophile. This approach provides rapid and facile access to highly functionnalized polycyclic molecules. In addition, thanks to computational studies, an overall picture of the mechanism of the intermolecular rhodium catalysed cycloaddition was apprehended and experimental results have been rationnalized. Finally, an approach to the trycyclic core of molecules isolated from the Schisandra genus was developped using an intermolecular [3+2] cycloaddition followed by a Diels-alder reaction.

The two main perspectives are to develop an enatioselective [3+2]-cyloaddition and to perform the [3+2]-annulation reaction.

This project allowed the publication of 4 articles in peer reviews journals, allowed to present our results in one invited lecture, several oral communications (5) and national (7) and international (4) poster communications.

1. Construction of Spirolactones with Concomitant Formation of the Fused Quaternary Centre -Application to the Synthesis of Natural Products
Bartoli, A.; Rodier, F.; Commeiras, L.; Parrain, J.-L.; Chouraqui, G. Nat. Prod. Rep. 2011, 28, 763-782

2. Collective Domino Approach toward the Core of Molecules Isolated from the Genus Schisandra
Bartoli, A.; Chouraqui, G.; Parrain, J.-L., Org. Lett. 2012, 14, 122-125

3. Diastereoselective Access to Polyoxygenated Polycyclic Spirolactones through a Rhodium-Catalyzed [3+2] Cycloaddition Reaction: Experimental and Theoretical Studies
Rodier, F.; Rajzmann, M.; Parrain, J.-L.; Chouraqui, G.; Commeiras, L. Chem. Eur. J. 2013, 19, 2467-2477.

4. First Studies Directed Towards the Diastereoselective Synthesis of the Complex BCD Tricyclic Core of Brownin F
Rodier, F.; Parrain, J.-L.; Chouraqui, G.; Commeiras, L. Org. Biomol. Chem. 2013, 11, 4178-4185.

Nature has produced a diverse array of natural products with an exceptional range of activities. Organic synthesis can often compete with nature in supplying these molecules. However as the complexity of the natural products increases, the length of syntheses also increases, often leading to a decreased impact on supply. One way to resolve this problem is developing new reactions and synthetic strategies that allow for shorter routes to a target. This new research program centers on the development of new synthetic methodologies and their application to the total synthesis of complex biologically important natural products. It is noteworthy that this approach rely on synthetic innovation and is driven by the importance of step economy. Our initial plan is to use gamma-alkylidene butenolides to design stereoselectively spirolactones in a step economical fashion and quickly increase the molecular complexity. Having cyclic structures fused at a central carbon are of great interest due to their interesting conformational features and their structural implications on biological systems. In addition the development of synthetic methodologies has been truly impressive, but the stereoselective construction of quaternary centers remains a significant challenge in the total synthesis of natural products. This proposal will be divided in three different axis. The first axis deals mainly with gamma-alkylidene butenolides involved in new [5+2] and formal [3+2] cycloadditions reactions to reach [6.4.0] and [4.4.0] spirolactones moieties. The second axis consists in studies directed towards the synthesis of the core of three families of natural products : the lancifodilactones, micrandilactones and sieboldine. We suggest to develop a new domino reaction as a key step to obtain quickly and efficiently the [6.4.0] spiro moiety. The third axis will be devoted to the application of these new methodologies to the synthesis of complex natural products and high molecular complexity and diversity such as dichotomains A and B.

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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.

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