9 中性スフィンゴミエリナーゼ阻害剤(+)-スキホスタチンの全合成(口頭発表の部)

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Scyphostatin(1), isolated from Dasyscyphus mollisimus SANK-13892 by Ogita et al. in 1997, has been shown to be a potent and specific inhibitor of neutral sphingomyelinase (IC_<50>=1.0μM). This natural product is anticipated to be a promising lead compound for the treatment of ceramide-mediated pathogenic states such as inflammation and immunological and neurological disorders. As well as this remarkable biological activity, its unique structural feature make 1 an exceptionally intriguing and timely target for total synthesis. While a number of synthetic approaches have appeared recently, no total synthesis has been reported to date. We embarked on the project directed toward the total synthesis of 1 in an optically active form, and our earnest endeavors culminated in completing the first total synthesis of (+)-1. Retrosynthetically, scyphostatin can be divided into two segments, the cyclohexene part 2 and the fatty acid part 6. We envisaged that the labile epoxycylohexenone moiety should be elaborated after formation of the amide linkage between 2, readily derived from 17, and 6. Our synthetic strategy for the preparation of 17 and 6 features the following three key steps: i) a coupling reaction of ester 5 with Garner aldehyde (4) to install an amino propanol moiety with the desired C-4 quaternary asymmetric carbon center (5→14); ii) ring closing metathesis reaction of 3 to elaborate the cyclohexene ring (3→16); iii) Negishi coupling reaction between alkyl iodide 9 and vinyl iodide 8 to produce tri-substituted olefin 22 (9+8→22). Our synthesis of the cyclohexene part 17 was commenced with the conversion of the known compound 11 to ester 5. The stereoselective alkylation of 5 with Garner aldehyde (4) was achieved by using NaN(TMS)_2 as a base in THE at -78℃ for 4h. After several steps, crucial ring closing metathesis reaction of the diene 3 was conducted by employing Grubbs catalysis, producing 16, which was then converted to the cyclohexene part 17. On the other hand, the fatty acid side chain 6 was prepared from the known aldehyde 19 and olefin 21. Negishi coupling of vinyl iodide 8 and alkyl iodide 9, which were readily accessible from 19 and 21, respectively, was accomplished by applying Smith's modified condition (t-BuLi, ZnCl_2, Pd(PPh_3)_4) to give rise to tri-substituted olefin 22. After several steps including one carbon elongation and HWE reaction, the acid chloride 6 was obtained. With 17 and 6 in hand, we focused our attention on completion of the synthesis of (+)-1. Towards this end, 17 was transformed to enone 31 in 6 steps involving amide formation between 28 and 6. Finally, 31 was converted to the target (+)-1 by hydrolysis of acetal 31 with CCl_3CO_2H, epoxide formation with base, and the Lipase-catalyzed removal of an acetyl group. The synthesized (+)-1 was identical with a natural sample of 1 in all spectroscopic properties.
天然有機化合物討論会の論文
2003-09-01

9 中性スフィンゴミエリナーゼ阻害剤(+)-スキホスタチンの全合成(口頭発表の部)

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