Total synthesis of (+)-ikarugamycin. 2. Elaboration of the macrocyclic lactam and tetramic acid substructures and complete assembly of the antibiotic

Abstract

The antibiotic ikarugamycin (5) has been synthesized in a triply convergent and enantioselective manner. The previously prepared ketone 1 was first converted to acetylenic ester 2, an intermediate in which all eight of the stereogenic centers present in the carbotricyclic segment of 5 have been set in their proper absolute configuration. Very high levels of kinetic resolution were achieved during 1,4-addition of vinylmagnesium bromide to aldimine 9. Following coupling of 2 to the ornithine segment 20, the aldehyde group was unmasked and condensation was effected with phosphonate 23. After arrival at 3, the acyl ketene was liberated thermally and macrocyclization occurred smoothly. The total synthesis was completed by partial hydrogenation of the triple bond, dehydrative removal of the hydroxyl group in ring B, Dieckmann cyclization to form the tetramic acid, and deblocking of the amide nitrogen. The spectral properties of the synthetic material were identical with those of the natural product