Toueg, Julie (2007) Synthesis of the DEF Tricyde of FR 182877. PhD thesis DCSO, DCSO, EP/X p.255.

Alternative Locations: http://www.imprimerie.polytechnique.fr/Theses/Files/Toueg.pdf

Abstract

We have explored several routes towards the ABC-ring system of hexacyclinic acid, a molecule isolated in 2000 from a Streptomyces strain and exhibiting a mild cytotoxic activity.
We have first designed a straightforward and efficient synthesis of 2 precursors of the A-ring based on a new type of ring-closing metathesis.
Then we have pursued the synthesis using a highly diastereoselective Michael addition with a bridged tricyclic enolate, followed by a Mn(III)-promoted radical cyclisation. After optimization of this reaction on a racemic model, this route has allowed us to synthesize an advanced precursor of the targeted ABC-tricyle.
We have also investigated the use of a less hindered enolate for the Michael addition key-step, as the previously obtained yields proved unsatisfactory within the context of total synthesis. This new route has allowed us to obtain with better results another advanced precursor of the ABC-tricyle, with all required stereocenters.
Finally, we have developped a new methodology the for the synthesis of cyclic 5- and 6-membered α-carbalcoxyenone, via a ring-closing metathesis involving a doubly deactivated olefin. The usefulness of this methodology has been demonstrated by several synthetic applications.

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