P-66 抗腫瘍活性天然物irciniastatinA/psymberinの全合成研究(ポスター発表の部)
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概要
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Irciniastatin A / psymberin (1) is a new member of the pederin family of natural products, isolated by the research group of Pettit and Crews independently in 2004 via bioassay-guided fractionation of the marine sponge Ircina ramose and Psammocinia sp., responsively. This compound shows extremely potent cytostatic activity (GI_<50><1nM in some cell lines) and intriguing selective cytotoxicity against several cancer cell lines. Complete stereochemical assignment of 1 is established in 2005 by De Brabander et al. through elegant total synthesis of the proposed structures. Structurally, 1 differs from other member of the pederin class in that it contains a pendant dihydroisocoumarine moiety and lacks a ring system in the carboxyl segment. These differences coupled with the resultant antitumor activity suggest a fertile possibility of this class of natural products. We describe here the convergent synthetic approach to 1 based on coupling of three segments, namely, the left segment 3, the central segment 4, and the right segment 7, to develop a divergent route that allows us to access to a panel of irciniastatin A / psymberin derivatives. The right segment 7 was synthesized form (E)-5-methylhexa-2,5-dien-1-ol via Sharpless asymmetric epoxidation and regio-, and stereoselective ring opening of the resultant glycidol by a methanol as the key steps. Chiral THP 19, a viable precursor of the central segment 4 possessing four stereogenic centers, was constructed by BF_3・OEt_2-mediated 6-exo-tet-mode cyclization of γ,δ-epoxyalcohol TES ether 18, which was elaborated from commercially available (-)-pantolactone (12) via 13-step sequence involving n-tributylallyltin / MgBr_2 mediated highly diastereoselective allylation reaction. The left segment 3 was synthesized in 8 steps from 2,4,6-trihydroxybenzoic acid (21) by employing the Suzuki-Miyaura coupling of alkenyl boronic acid and Sharpless asymmetric dihydroxylation as the key reactions. The details of the synthesis and progress toward the total synthesis of irciniastatin A / psymberin will be discussed.
- 天然有機化合物討論会の論文
- 2006-09-15
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