P-39新規な血小板凝集抑制物質、PI-091の全合成(ポスター発表の部)

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PI-091 (1) was recently isolated by the group of Taisho Pharmaceutical Co. from Paecilomyces sp. F-3430. The relative stereochemistry of 1 was determined by ^1H- and ^<13>C-NMR spectral analysis, however, its absolute stereochemistry has not been established. This natural product shows a remarkable platelet aggregation inhibitory activity against rabbit platelet (in vitro). The structure of 1 consists of a 2-hydroxy-2-methyloctanoyl function as a side chain at α-position of a γ-lactam structure, and both methoxy and isopropyl groups at the γ-position of the γ-lactam ring. Furthermore, this trisubstituted γ-lactam derivative possesses an asymmetric tertiary alcohol part in the side chain. Consequently, the synthesis of this structurally intriguing natural product 1 seems to be formidable. We present herein the first enantiospecific total synthesis of PI-091, and also disclose its unsettled absolute stereochemistry. First, we took notice of the asymmetric carbon at the tertiary alcohol part in the side chain, and assumed its configuration to be S. Thus, as an enantiomerically pure starting material of the total synthesis, we chose configurationally defined branched sugar 3, which was prepared from D-glucose in five steps. Introduction of the side chain in 1 was achieved efficiently by a Wittig olefination protocol to give 7. Then, after appropriate modification to ketone 10, the aldol reaction with 3-methyl-2-butanone and 10 was investigated. Using LDA as a base, the desired aldol product 11 was obtained efficiently as a diastereomeric mixture, which possesses all of the carbons in 1. In further synthetic venture, an important intermediate γ-hydroxy-γ-lactone 15 was obtained from 11 efficiently via the photochemical singlet oxygen addition of α-silylfuran 14, which was derived from 11 via deprotection, acid treatment, followed by silylation. Finally, after five steps from 14 including the ammonolysis of lactone derivative 17 to the corresponding lactam derivative, we have accomplished the total synthesis of PI-091(1), of which absolute stereochmistry was confirmed as estimated.
天然有機化合物討論会の論文
1995-09-01

P-39新規な血小板凝集抑制物質、PI-091の全合成(ポスター発表の部)

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