BLANC - Blanc

Target-oriented eco-conception of synthetic organic strategies – SYNTHECO

Submission summary

After the limited success of the combinatorial approach in drug discovery over the last fifteen years, the pharmaceutical industry is turning back to the natural products kingdom to find new lead molecules. To get these active substances on a large scale, the pharmaceutical industry thus relies on organic synthesis. However, the total synthesis of natural products and their derivatives is generally an unproductive and polluting task. The view of synthesis has altered in recent years; the synthetic chemical community now have to answer a double challenge: continue to provide the society more and more complex and efficient drugs to fight the most terrible diseases, as well as taking into account the required criteria of step, atom, raw material and energy economy. This new area, commonly designed as 'green chemistry', but which might be better called eco-compatible chemistry, is the major focus of the research developed in our group. Multicomponent reactions (MCRs) involving domino processes have emerged as powerful tools for the rapid and eco-compatible creation of molecular complexity and chemical diversity. They are becoming a corner stone in modern organic chemistry from both academic and industrial points of view, due to the combination of the two essential economical and environmental aspects. In recent years, the development of new domino and multicomponent reactions has generated new opportunities, and the first achievements in natural products synthesis have been reported. This new concept is at the early stage of its development but promised to a great future. The aim of this proposal is to apply our expertise in the field of multicomponent domino reactions and organocatalysis to the eco-conception of new synthetic routes to potentially bioactive compounds related to complex natural products. Of course, we have to address the essential issue of the optical activity of our targets and sulfoximines appear as ideal candidates for our purpose. Our very recent preliminary work in this field has shown sulfonimidoyl substituted α-alkylidenetetrahydrofurans and 2-oxo-cyclopentanesulfoximines can be accessed under eco-compatible conditions by means of domino reactions of optically active sulfoximines with α,ω-haloesters. The synthetic exploitation of these valuable building blocks in subsequent cycloadditions or multicomponent/domino reactions would provide an unprecedented exceptionally direct access to a variety of naturally occurring compounds or scaffolds known for their high potential in drug discovery. The first part of the proposal deals with the optimization of the synthesis of optically active sulfonimidoyl substituted α-alkylidenetetrahydrofurans and 2-oxo-cyclopentanesulfoximines. Then, we propose to use the sulfonimidoyl-substituted α-alkylidenetetrahydrofurans for the direct synthesis of optically active spiroketal and spiroaminal scaffolds. Our approach focuses on the synthetic exploitation of stereoselective hetero Diels-Alder cycloadditions to generate the 6,5-spiro systems, and we propose to apply the method to a highly concise synthesis of the ABCD ring system of azaspiracid. The complementary 5,5-spiro systems would be obtained by means of a new anionic domino ring opening/hetero Michael addition sequence. The method will be applied to the expeditious total synthesis of a highly potent naturally occurring antibiotic. In the last part of the project, we propose to perform our recently developed new MCR named the MARDi cascade with the optically active 2-oxo-cyclopentanesulfoximines. After a study on the scope of the reaction, we will focus on its applications to the synthesis of some guaiane natural products (bicyclo[5.3.0]decanes) and also some related bicyclo[5.4.0]undecane compounds. The approach to bridged bicyclic compounds would involve a ring closing metathesis of the products of the MARDi cascade. This proposal is at the core of modern synthetic chemistry. Its aim is first to further develop eco-compatible processes such as domino reactions and MCRs, and to demonstrate the high value of this approach in natural products total synthesis. The success of this broad and ambitious proposal, primary aimed at the eco-conception of new synthetic strategies toward complex natural products, should result in dramatic simplifications in our view of total synthesis. It should contribute very positively to the current re-discovery of natural products as an endless source of new lead molecules by rendering their synthetic approaches both economically and ecologically compatible.

Project coordination

Jean Antoine RODRIGUEZ (Université)

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

Help of the ANR 320,000 euros
Beginning and duration of the scientific project: - 36 Months

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