Abstract EN:

Allosteric modulation of nicotinic receptors is a novel and promising approach for the treatment of Alzheimer’s disease. The binding of an allosteric modulator to the nicotinic receptor enhances the neurotransmission in response to the natural agonist, acetylcholine. Compared to the therapeutic approach consisting in the administration of agonists, this novel approach could lead to the diminution of side effects. Galanthamine and codeine present structural similarities, have the same activity as allosteric modulators but different activities toward acetylcholinesterase. In order to identify the structural properties required for allosteric modulation, we have carried out a total synthesis of codeine that could be extended to the synthesis of analogues. In the first part of the synthesis, we have prepared a spirocyclohexadienone intermediate whose quaternary center is created by an intramolecular Heck reaction. This intermediate presents a double reactivity : a rearrangement in basic conditions leads to dihydrotropone products whereas the reaction with nucleophiles leads to tetrahydrodibenzofuran products. In the second part of the synthesis, starting from the tetrahydrodibenzofuran compounds, we have considered three synthetic paths for the construction of the pentacyclic scaffold of the codeine. These paths differ by the order of the ring closures and the final synthesis leads to codeine in 9 steps starting from the spirocyclohexadienone intermediate. This diastereoselective synthesis includes a Claisen-Eschenmoser rearrangement, an electrophilic aromatic substitution ring closure, an allylic oxydation and an hydroamination ring closure.