4 Pinnatoxin Aの全合成(口頭発表の部)

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Pinnatoxin A (1) was isolated in 1995 by Uemura and co-workers from the Pinna muricata shellfish. Pinnatoxin A is one of the major toxic principles responsible for outbreaks of Pinna shellfish intoxication in China and Japan. It is also believed to be a calcium ion channel activator. The Uemura group determined pinnatoxin's structure and relative stereochemistry using a variety of 2D NMR techniques; however, the absolute stereochemistry was not assigned. They also proposed a biosynthetic route of 1 (2→1), i. e., an intramolecular Diels-Alder reaction, to construct the G-ring as well as the macrocycle followed by imine formation to establish the 6,7-spiro-ring system or vice versa. Since we were interested in this unique biogenetic pathway, we planned to synthesize 1 based on Uemura's proposal with the intramolecular Diels-Alder reaction as a key step. The requisite diene 18 for the intramolecular Diels-Alder reaction was prepared via a dithiane-based coupling of bis-spiroketal 3 with iodide 4 to form the C.25-C.26 bond and sequential Ni(II)/Cr(II)-mediated couplings between vinyliodides 5 and 6 with suitable advanced C.6 and C.32 aldehydes. During the synthesis of 18, we encountered difficulties of epimerization at the C.19 bis-spiroketal stereocenter during formation of the EF bicyclic ring system with acid treatment (15→16). Fortunately, the C.19 stereocenter could be epimerized back to the desired configuration under silylation conditions (16→17). With the diene 18 in hand, we next attempted the intramolecular Diels-Alder reaction. Heating the diene 18 in toluene at 70℃ for 24h gave a 1:1:1 mixture of three products (19a-19c), including the desired exo adduct 19a, out of the eight possible intramolecular Diels-Alder products, which were separated by HPLC. Changing the solvent from toluene into dodecane gave 19a as the major adduct. After deprotection of the TBS group and Alloc group of 19a, imine formation was employed with heating at 200℃ under high vacuum for 1h to give 21 in 70% yield. Finally, the t-butyl ester was cleaved with TFA to furnish synthetic pinnatoxin A (1), identical in all respects to natural pinnatoxin A except for the sign of optical rotation and biological activities. From this information, we concluded that the absolute stereochemistry of natural pinnatoxin A was the antipode of structure (-)-1. Thus, we employed the synthesis of the natural form of (+)-pinnatoxin A (1) in an almost similar way and, at last, synthetic (+)-1 was completely in accord with natural pinnatoxin A.
天然有機化合物討論会の論文
1999-09-01

4 Pinnatoxin Aの全合成(口頭発表の部)

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