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Enantioselective syntheses of substituted piperidines and morpholines
Piperidines and morpholines are of great interest as they are present in a wide number of natural products and/or biologically active molecules. For these reasons, preparations of these compounds are of great interest.
The first part of my PhD consisted in the synthesis of two non peptidic antagonists of NK1 receptors as well as the synthesis of 3-hydroxypipecolic acids using a ring expansion of prolinols into piperidines. This ring expansion is induced by the treatement with trifluoroacetic anhydride and triethylamine and give access to piperidines with excellent yields and enantiomeric excesses. Having 2 phenyl-3-hydroxypiperidines in hand we were able to complete the syntheses.
The second part of my work concerned the development of a new stereoselective method to access optically active substituted 3-aminopiperidines. Treatment of prolinols by XtalFluor-E and tetrabutylammonium azide induced a ring expansion leading to 3 azidopiperidines, with excellent diastereoselectivities and yields, which upon treatment under Staudinger conditions were converted into 3-aminopiperidines.
The last part of my PhD consisted in the enantioselective synthesis of a biologically active compound, SSR 241586, using an enantioselective organo-catalyzed Henry reaction. SSR 241586 was obtained in 15 steps with a global yield of 3% and an enantiomeric excess of 93%.