Total Synthesis of Gypsetin, Deoxybrevianamide E, Brevianamide E, and Tryprostatin B: Novel Constructions of 2,3-Disubstituted Indoles

A concise and efficient total synthesis of the acyl-CoA:cholesterol acyltransferase inhibitor gypsetin ( 1 ) is described. The route features a straightforward method for the introduction of a reverse prenyl group into the C2-position of an N -phthaloyl-protected tryptophan ( 11 ). The total synthesis of gypsetin was completed by the dimethyldioxirane-promoted double-oxidative cyclization of a prefashioned diketopiperazine ( 19 ). Total syntheses of deoxybrevianamide E ( 24 ) and brevianamide E ( 25 ) following similar procedures are also described. The reaction of nucleophiles with in situ-generated 3-chloroindolenines provides a route to 2,3-disubstituted indoles from 3-substituted precursors. Indications of the scope and limitations of such reactions are provided. A total synthesis of tryprostatin B ( 41 ), a diketopiperazine derived from an l -tryptophan derivative (bearing a prenyl group at the α position of the indole) and l -proline, was accomplished. The key step involved the introduction of the prenyl function onto a protected tryptophan congener ( 11 ). A route for the prenylation of ketones with virtually no competitive reverse prenylation is also provided.