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Totally Synthetic by Paul H. Docherty, 21 July 2009

Total Synthesis of Tricholomalide A & B


Z. Whang; S.-J. Min, S. J. Danishefsky, J. Am. Chem. Soc. 2009, 131, 10848-10849.

DOI: 10.1021/ja9049433

Initial work on the target was published in a rather nice paper in Tetrahedron Lett. last year, and that’s where the synthetic action starts. A well known Robinson Annulation created a 6,5-fused enone in a racemic fashion, which Danishefsky cyclopropanated in a rather interesting way. Enolisation and silylation gave them an activated alkene, which was treated with a carbene derived from dichloroethane. This method isn’t new by any means, but I like how effective it was. Treatment of the somewhat volatile chlorocyclopropane with silver nitrate allowed an oxidative cleavage of the cyclopropane in an endo fashion to give the ring expanded product. Very Nice.

A couple of steps later, the creation of another ring followed, and like the previous modus operandi, Danishefsky firstly installed a small ring, which was then expanded. In this case, sonochemical reaction of trichloroacetyl chloride with zinc caused formation of a ketene, which underwent a [2+2] cycloaddition to give a dichlorocyclobutane as a single diastereomer. More zinc in the presence of an acid allowed a selective reduction of the gem-dichloride, which was the expanded to a γ-lactone using a Baeyer-Villiger oxidation. All in a very high yield.

The total synthesis is nearly finished. Oxidation of the free alcohol to the ketone, followed by alkylation using cerium chloride and a Grignard reagent for the required sidechain of tricholomalide B. A base converted B into tricholomalide A. A neat and efficient work!