Thursday, August 13, 2009

Cyclization Reactions and Angelmarin Synthesis

ResearchBlogging.orgThe first total synthesis of (+)-Angelmarin includes some neat cyclization reactions. They started with Umbelliferone which you can buy, and synthesized angelmarin by way of columbianetin.

I'm always curious about where the names of these compounds come from. The systematic names are probably rather cumbersome, so these common names are useful. Umbelliferone is found in plants of the Umbelliferae family - which includes carrots. Also named for plant species, angelmarin was isolated from Angelica pubescens, and columbianetin from Lomatium columbianum.

The first cyclization step is a Claisen rearrangement - three bonds all move in a circle, which causes the allyl group to migrate to the aromatic ring. The resulting ketone tautomerizes to the more stable phenol structure.

After an olefin cross-metathesis to introduce two methyl groups, the next step was in effect a double cyclization. First a stereoselective Shi epoxidation. Then the epoxide is opened during the second cyclization to form columbianetin.

This last cyclization is an an example of a 5-exo-tet cyclization according to Baldwin's Rules for ring formation. The resulting ring is a 5-membered ring. The bond broken to make the new ring is not part of the new ring (exo). And when the new ring is formed, the nucleophile is forming a bond to a tetrahedral atom (tet).
To convert columbianetin into the final product required the formation of an ester. This proved to be challenging - many standard esterification strategies either did not work, or it caused side reactions that destroyed the columbianetin portion of the molecule.

To get around this, they first converted it to a malonate ester under mild conditions. This was reacted with p-hydroxybenzaldehyde and catalytic piperidine to generate the final product by way of a Doebner-Knoevenagel condensation. In effect building the hydroxycinnamate group instead of adding it as a single piece.

Magolan, J., & Coster, M. (2009). Total Synthesis of (+)-Angelmarin The Journal of Organic Chemistry, 74 (14), 5083-5086 DOI: 10.1021/jo900613u

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