Studies on a total synthesis of the microbial immunosuppresive agent FR901483
Studies on a total synthesis of the microbial immunosuppresive agent FR901483
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DOI：
10.1021/jo052466b
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发表时间：
2006-03-03
影响因子：
3.6
通讯作者：
Weinreb, SM
中科院分区：
文献类型：
--
作者：
Kropf, JE;Meigh, IC;Weinreb, SM
[附图]概述了构建真菌免疫抑制剂FR901483(1)的策略。1，4-环己二酮单乙烯缩酮可以通过5个简单的步骤转化为碘乙酰胺酮10，再经环合得到含有天然产物的A/B-2-氮杂双环-[3.3.1]正庚烷环系的键桥酮内酰胺11。该中间体可转化为N-Boc内酰胺16，其衍生的烯醇与Davis恶氮杂环丙烷进行立体选择性羟基化，生成具有所需C-2构型的醇17。然后，化合物17分三步转化为烷氧基氨基甲酸酯20。中间体20衍生的N-酰亚胺离子可与对甲氧基苄基氯化镁进行总收率较高的烷基化反应，以得到所需的PMB产物21和同分异构体23的5：4混合物。为了提高烷基化反应的立体选择性，合成了反式C-4保护醇N-Boc内酰胺33，并对其烯醇进行了羟基化。令人费解的是，这个反应的产物是不受欢迎的赤道醇34。对天然产物C环的环化反应模型体系进行了研究。结果发现，高烯丙基胺40可以在硅胶存在下与PhSCl环合，以适中的产率得到所需的5-内酯四环产物42。这种环化方案也被成功地应用于实际的FR901483系统22，从而产生了所需的三轮车43。
[GRAPHICS]A strategy is outlined for construction of the fungal immunosuppressant FR901483 (1). It was possible to convert 1,4-cyclohexanedione monoethylene ketal in five simple steps to iodoacetamide ketone 10, which was cyclized in good yield to the key bridged keto lactam 11 containing the A/B 2-azabicyclo-[3.3.1]nonane ring system of the natural product. This intermediate could be transformed to N-Boc lactam 16, whose derived enolate underwent stereoselective hydroxylation with the Davis oxaziridine to produce alcohol 17 having the desired C-2 configuration. Compound 17 was then converted in three steps to alkoxy carbamate 20. The N-acyliminium ion derived from intermediate 20 could be alkylated in good overall yield with p-methoxybenzylmagnesium chloride to afford a 5:4 mixure of the desired PMB product 21 and the epimer 23. In an attempt to improve the stereoselectivity in this alkylation, the inverted C-4 protected alcohol N-Boc lactam 33 was prepared and its enolate was hydroxylated. Inexplicably, the product of this reaction was the undesired equatorial alcohol 34. Some model systems were investigated toward annulation of the C-ring of the natural product. It was found that homoallylic amine 40 could be cyclized with PhSCl in the presence of silica gel to generate the desired 5-endo tetracyclic product 42 in moderate yield. This cyclization protocol was also successfully applied to the actual FR901483 system 22, leading to the requisite tricycle 43.