A Diels-Alder Approach to (-)-Ovalicin

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114131886/ABSTRACT

From Prof. Johann Mulzer's group at Institut fur Organische ChemieUniversitat Wien (University of Vienna)

(-)-Ovalicin and structurally related (-)-fumagillin possess potent antiangiogenic activity.

The total synthesis of 1 started with Diels-Alder reaction of 2-bromoacrolein with Trost-auxiliary-equipped diene in 75%.

Functional group manipulations then lead to the desired epoxy-ketone. The notable processes include epoxidation by substitution, dihydroxylation with high disatereoselectivity and selective mono-protection of the diol (with TBSCl).

Synthesis of the bromodiene fragment followed, starting from 2,3-dihydrofuran, followed by bromination, oxidation, and Julia-Kocienski reaction.

After obtaining this vinyl bromide, this compound was subjected to lithium-bromine exchange, and addition to the ketone in good selectivity. The final key steps include hydroxy-directed epoxidation and oxidation. I think this is a good synthesis overall - convergent, good example of substrate-control reactions in several key steps, short overall steps (15) with good overall yield (15%).