108(P-32) 抗腫瘍活性天然物Fostriecin (CI-920)の合成研究(ポスター発表の部)

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Fostriecin (1), a novel antibiotic produced by Streptomyces pulveraceus, displays efficacious in vivo antitumor activity against L1210 leukemia in mice and the phase I clinical trials have already started at NCI for developing a new anticancer drug. This compound has a very unique structure characterized by the α,β-unsaturated δ-lactone with the highly oxygenated long chain containing C9-phosphate ester, C8-quaternary center, and conjugated (12Z,14Z,16E)-triene. Recently, its absolute configuration was determined to be (5R,8R,9R,11R) by Boger and co-workers. We describe here an enantioselective synthesis of the 8,9-acetonide of dephosphorylated fostriecin, a promising precursor for the synthesis of fostriecin (1). We first focused on Sharpless asymmetric dihydroxylation of two conjugated dienes 13 and 18 to construct the (8R,9R)-diol functionality. Upon treatment of 13 with AD-mix-β, regio- and diastereoselective dihydroxylation took place at the tri-substituted double bond to afford (8R,9R)-diol 14 as a major product. Interestingly, the dihydroxylation of 18 was found to proceed with complete regio- and diastereoselectivity to give (8R,9R)-diol 19 exclusively. After conversion of 14 to aldehyde 25, we then proceeded to install the C12-C18 chain having (12Z,14Z,16E)-triene. When 25 was reacted with the alkenyllithium prepared from 24, the desired product 26 was obtained as 2:1 epimeric mixture in very poor yield. However, we were gratified to find that palladium catalyzed Stille coupling of alkenyl iodide 30, prepared from 25, with butadienylstannane 31 proceeded very smoothly to produce 32 almost quantitatively. Compound 32 thus obtained is the 8,9-acetonide of dephosphorylated fostriecin.
天然有機化合物討論会の論文
2000-10-01

108(P-32) 抗腫瘍活性天然物Fostriecin (CI-920)の合成研究(ポスター発表の部)

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