Total Synthesis of Sarcodictyins A and B

Abstract

The total synthesis of cytotoxic marine natural products possessing tubulin polymerization and microtubule stabilization properties, sarcodictyins A ( 7 ) and B ( 8 ), is described. Two related approaches to these target molecules have been developed, both utilizing (+)-carvone ( 9 ) as starting material. The first approach involves a stereoselective construction of acetylenic aldehyde 27 (Scheme 2) while the second approach proceeds through a more direct but less selective sequence to the similar intermediate 36 (Scheme 3). Both strategies involve ring closures of the acetylenic aldehyde precursors to 10-membered rings under basic conditions followed by elaboration and selective reduction of the acetylenic linkage to a cis double bond. This promotes bridging to form the required tricyclic skeleton of the sarcodictyins ( 27 → 37 → 38 → 39 → 4, Scheme 4 and 37 → 44 → 45 → 46 → 47 → 42, Scheme 5) and ( 36 → 48 → 45, Scheme 6). Installation of the ( E )- N (6‘)-methylurocanic acid residue was achieved by esterification with mixed anhydride 52, while the C-3 ester moieties were installed by standard deprotection, oxidation, and esterification procedures.