CiNii Fulltext PDF
Pinnatoxins were isolated from the shellfish Pinna muricata and characterized by Uemura and co-workers in 1995. Their unprecedented molecular architecture, combined with the associated biological activity and scarcity of natural supply, has prompted a major effort toward the synthesis of pinnatoxins. In 1998. Kishi and co-workers accomplished the first total synthesis of (-)-pinnatoxin A utilizing a biomimetic intramolecular Diels-Alder reaction to construct the G ring as well as the macrocycle, establishing the absolute stereochemistry of natural pinnatoxin A, as shown in 1. Herein we wish to report our studies on the synthesis of pinnatoxin A. The majority of reported synthetic strategies for the construction of dispiroketals rely on the acid-catalyzed cyclization of open-chain hydroxyketones. However, since pinnatoxin A has a latent carbonyl group at C25. the strategy based on intramolecular hetero-Michael reaction would not only benefit from the construction of the BCD ring system but also from the direct assembly of the EF ring system. We envisaged that the tandem double hemiketal formation/hetero-Michael addition sequence would be triggered by desilylation of 6 under thermodynamic conditions. The synthesis of 6 began with alkylation of dithiane 10 with iodide 9. After protective groups manipulations, 11 was converted to 12 by the three-step sequence. Aldol coupling of 12 with 13 followed by successive acetylation, elimination, and conjugate reduction produced 14 in 78% yield. Chelation-controlled alkylation of 14 with MeMgI and protective groups manipulations were followed by oxidation to furnish 7 in 73% yield. At this juncture, installation of the C24-C31 fragment 8 was accomplished by aldol coupling of 7 with 8 and dehydration to give enone 15 in 78% yield. Deprotection of the MPM ether followed by Dess-Martin oxidation and removal of the dithiane protective group afforded the targeted triketone 6 in 68% yield. Prior to experimentation with 6, we explored the reaction of triketone 16 to simplify structure determination of the products. Upon exposure of 16 to 1N aqueous HCl, selective liberation of the C12 hydroxyl group provided an equilibrium mixture of 17, 18 and 19, which was treated with alkaline metal methoxide to afford the desired dispiroketal 20 as the major product out of the eight possible stereoisomers, together with a small amount of three undesired stereoisomers. Of the base screened, LiOMe was found to be by far the superior choice for the desired cyclization. Stereo-chemical assignments of 20-23 were obtained from ^1H NOE experiments. The stereochemistry of 20 was further established from the X-ray crystal structure of the derived semicarbazone 24. We then proceeded to complete the BCDEF ring system. Removal of the TES group in 6 followed by the intramolecular hetero-Michael reaction using LiOMe furnished 5 in 75% overall yield. Finally, internal ketalization of 5 gave bicycloketal 25. To construct the G ring portion, we explored Diels-Alder reaction using diene 27 in a model system. Diels-Alder reaction of 27 with α-methylene lactone 28 exhibited good exo-selectivity to give 29 in 29% yield. Studies toward pinnatoxin A as well as further efforts to improve the stereoselectivity are in progress.