Total synthesis of (+)-geldanamycin and (-)-o-quinogeldanamycin:: Asymmetric glycolate aldol reactions and biological evaluation
Total synthesis of (+)-geldanamycin and (-)-o-quinogeldanamycin:: Asymmetric glycolate aldol reactions and biological evaluation
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DOI：
10.1021/jo034870l
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发表时间：
2003-10-17
影响因子：
3.6
通讯作者：
Ma, W
中科院分区：
文献类型：
--
作者：
Andrus, MB;Meredith, EL;Ma, W
(+)-格尔达那霉素(GA)的全合成采用线性路线，最后一步是脱甲基醌生成反应。关键步骤包括使用两个新的不对称乙醇酸硼醛缩合反应。为了确定抗C11，12羟甲氧基官能团，使用了(S，S)-5，6-二-4-甲氧基苯基二氧杂环己酮8。由去甲麻黄碱5衍生的乙醇酸甲酯形成了C6，7甲氧基氨基甲酸酯立体化学。以硝酸为溶剂的苯二酚合成步骤得到了非天然邻喹-GA产物，产物比为55：10。其他已知的氧化剂产生了一种不寻常的氮喹酮产物49。O-Quino-GA 55与Hsp90具有良好的亲和力，但与GA相比细胞毒性较小。
The total synthesis of (+)-geldanamycin (GA), following a linear route, has been completed using a demethylative quinone-forming reaction as the last step. Key steps include the use of two new asymmetric boron glycolate aldol reactions. To set the anti-C11,12 hydroxymethoxy functionality, (S,S)-5,6-bis-4-methoxyphenyldioxanone 8 was used. Methylglycolate derived from norephedrine 5 set the C6,7 methoxyurethane stereochemistry. The quinone formation step using nitric acid gave the non-natural o-quino-GA product 55 10:1 over geldanamycin. Other known oxidants gave an unusual azaquinone product 49. o-Quino-GA 55 binds Hsp90 with good affinity but is less cytotoxic compared to GA.