12 糸状菌の生産する新規細胞接着阻害剤Macrosphelidesの構造と合成研究(口頭発表の部)

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Clinical early events in inflammation, the allergic response, and tumor metastasis involve interactions between leukocytes and endothelial cells. A variety of cytokinins and related chemical mediators control both leukocyte adhesion and subsequent intercellular invasion via the regulation and expression of cellular adhesion molecules, inhibition of cell-cell adhesion thus holds promise for the treatment of diverse pathologies. In the course of a screening program aimed at cell adhesion inhibitors obtained from microoragnisms, macrosplelides A (1) to D (4) were discovered from the fermentation broth of Microsphaeropsis sp. FO-5050. Macrosphelides are the first 16-membered-ring antibiotics embodying three lactone linkages (e.g., Macrotriolides). The macrosphelide A (1) strongly inhibit the adhesion of human-leukemia (HL-60) cells to human-umbilical-vein endothelical cells (HUVEC) in dose-dependent fasion (IC_<50>=3.5μM). Preliminary studies suggest that 1 prevents cell-cell adhesion by inhibiting the binding of sialyl Lewis^x to E-selectin. 1 also proved to be orally active against B-16 tumor metastasis to the lung in mice. We detemined the complete relative and absolute stereochemistries of 1, via X-ray crystallography and the Kakisawa-Kashman modification of Mosher's NMR method. The stereostructure of 2 was determined by chemical correlation with 1. Moreover, we accomplished the first total synthesis of 1. As our point of departure we selected the asymmetric dihydroxylation of (E,E)-hexa-2,4-dienoic acid t-butyl ester (5), which affords the (4S,5S)-diol (6) (85%ee). Selective monosilylation of 6 (TBDMSCl, DMAP, CH_2Cl_2) provided the desired ether (7). Mitsunobu inversion (PPH_3, DEAD, HCOOH; NH_3/MeOH) at C(4) of 7 furnished 8. Protection of 8 as the MEM ether and hydrolysis (0.2N NaOH, MeOH/THF/H_2O) then gave 10, whereas desilylation of 9 generated the second building block (11) (Bu_4NF, THF). Condensation of carboxylic acid (10) and alcohol (11) via the Keck protocol (DCC, DMAP, CSA, CH_2Cl_2) and desilylation of the resultant ester (12) (AcOH/THF/H_2O) produced 13. The third fragment, TBDMS ether (14) of (3S)-hydroxybutyric acid and coupled with 13 (DCC, DMAP, CSA, CH_2Cl_2). Removal of the silyl and t-butyl moieties in 15 (TFA/CH_2Cl_2/thioanisole) provided seco acid (16), which smoothly underwent Yamaguchi macrolactonization (DMAP, 2,4,6-trichlorobenzoyl chloride). Finally, deprotection of 17 (TFA/CH_2Cl_2) gave synthetic 1, identical in all respects with a sample of the natural product. The first total synthesis of 1 has thus been achieved via a highly convergent, efficient strategy (11 steps, 10.6% overall yield).
天然有機化合物討論会の論文
1997-07-20

12 糸状菌の生産する新規細胞接着阻害剤Macrosphelidesの構造と合成研究(口頭発表の部)

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