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 acyltra nsferase inhibitor gypsetin (1) is described. The route features a straight forward method for the introduction of a reverse prenyl group into the C2-p osition of an N-phthaloyl-protected tryptophan fill. The total synthesis of gypsetin was completed by the dimethyldioxirane-promoted double-oxidative cyclization of a prefashioned diketopiperazine (19). Total syntheses of deo xybrevianamide E (24) and brevianamide E (25) following similar procedures are also described. The reaction of nucleophiles with in situ-generated 3-c hloroindolenines provides a route to 2,3-disubstituted indoles from 3-subst ituted precursors. Indications of the scope and limitations of such reactio ns are provided. A total synthesis of tryprostatin B (41), a diketopiperazi ne derived from an L-tryptophan derivative (bearing a prenyl group at the a lpha position of the indole) and L-proline, was accomplished. The key step involved the introduction of the prenyl function onto a protected tryptopha n congener (11). A route for the prenylation of ketones with virtually no c ompetitive reverse prenylation is also provided.