Total Synthesis of (+)-Clavolonine, (-)-Deacetylfawcettiine and (+)-Acetylfawcettiine
Kai M. Laemmerhold and Bernhard Breit
It took some time but now it’s finished… I was very busy with studying, practicing and visiting the “Frontiers in Medicinal Chemistry”-symposium in Münster (Germany) the past weeks. Nice meeting with some cool posters and as the main act Prof. Fürstner himself. Really awesome stuff…
Ok, back to some chemistry: I found this paper on my desk almost a month after I printed it out during a period with only sporadically published total syntheses. It features a nice methodology and obviously that’s the one of the reasons why this work was done. Nevertheless the molecules we’re dealing with can easily be accomplished by making use of this (new) concept of synthesis the authors demonstrate here:
Syntheses of all 3 are rare and if published all except for one are racemic so an enantioselective approach might be useful for further biological evaluation.
The whole synthesis was built around this DPPB directing group which guides the rhodium catalyst and later the Lewis acid (BF3) during the synthesis. If you’re interested in this methodology in more detail you should have a look in this. Other steps include a neat Mannich- and aza-Wittig reaction. Furthermore an unusual addition of a cuprate on an alkyne
The synthesis starts right off with a simple alcohol which was oxidized and elongated using Swern- and Wittig-chemistry. Saponification, acid chloride formation and alkynone formation was followed by CBS reduction of the ketone moiety. Next the TMS was cleaved with TBAF and the propargylic alcohol transformed into an allylic one by addition of a Normant cuprate (Cuprate addition of propargylic alcohols).
Esterification with DPPBA was followed by the first of two hydroformylation reactions in this synthesis with very good regioselectively and yield. A stereoselective Prins-reaction then closes the first ring (or should it be named oxa-Alder-ene?). The alcohol was protected as the TIPS ether and the second alkene hydroformylated again with high yield and stereoselectivity giving this odd looking cyclohexane with 5 stereocenters already in place.
Grignard reaction and protection of the resulting alcohol as the TIPS ether was followed by reductive cleavage of the DPPB group and acetylation of the free alcohol. Azide formation under Finkelstein conditions, global TIPS deprotection and DMP oxidation yields a cyclohexanone intermediate ready for some ring closing chemistry.
The second ring was closed employing an aza-Wittig reaction resulting in an imine which was directly used to close the third ring by means of a Mannich reaction. The enol ether was opened with HBr in AcOH which results in cyclization and formation of (+)-clavolonine.
Nice stuff… This hydroformylation looks very promising to me especially in association with this Prins reaction.