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Totally Synthetic by Paul H. Docherty, 27 July 2008

Total Synthesis of Trichodermamide B


C.-D. Lu, A. Zakarian, Angew. Chem. Int. Ed. 2008, 47, 6829-6831.

DOI: 10.1002/anie.200801652

Trichodermamide B is reasonable active against human colon carcinoma, and offers ‘moderate antimicrobial’ activity. More interesting is the inactivity of the related trichodermamide A. The only difference is that trichodermamide A has a third hydroxyl group in place of the chlorine.

The total synthesis starts with a Diels-Alder reaction between a cyclohexadienone and vinylene carbonate, resulting in a bridged, bicyclic carbonate. Saponification with lithium hydroxide was accompanied by ‘virtually complete inversion of stereochemistry at C7′. Zakarian suggests a retro-aldol, aldol reaction mechanism in which the product is the more stable trans isomer. Interesting!

The methoxy groups were removed using samarium diiodide followed by protection of the hydroxyl groups and we’re set for the pièce de résistance: a nitrosation/oxaza-Cope rearrangement. This chemistry is really straightforward, with very good yield, although some debenzylation occured.

A Grieco-Mitsunobu inversion of stereochemistry yielded an allylic selanide in there steps from the last scheme. Treatment with peroxide resulted in an in situ [2,3]-sigmatropic rearrangement leaving them with the required stereochemistry. Not new chemistry, but still a nice sequence.

Completion of the molecule was expedient; esterification went well, leaving them with deprotection of the acetal (zinc triflate in the presence of ethanethiol), and displacement of an allylic mesylate with chloride in a surprisingly good yield. A nice total synthesis!