Synthetic Studies on Antitumor Marine Natural Products, Discorhabdin Alkaloids, and Their Congeners

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The discorhabdin alkaloids (discorhabdin A-D) were isolated from the sponge of Latrunculia du Bocage in New Zealand and exhibit extreme toxicity toward tumor cells (P388 and L2110 leukemia). These novel molecules have a unique molecular skeleton incorporating an azacarbocyclic dibromospirohexadienone system and a highly oxidized indol system in which the tryptamine side chain is cyclized onto an indoloquinone. Recently, much attention has been paid to the total synthesis of these challenging targets. As a part of our continuous studies on hypervalent iodine chemistry, we have established a general route to the azacarbocyclic spiro dienone systems by an oxidative coupling reaction of the O-silylated phenol derivatives bearing both electron-poor and electron-rich aminoquinones at the para position, using phenyliodine(III) bis(trifluoroacetate)(PIFA). This method was applied to the first total synthesis of discorhabdin C. During this synthesis, a new effective method for the aminoindoloquinone imine systems was also developed.The synthetic studies of the other discorhabdin alkaloids (A,B,D), which have the thioether bonds in the molecule are still on line, including development of a new synthetic method for the optically active thioether bond formation.