Total synthesis and determination of the absolute configuration of frondosin B
Total synthesis and determination of the absolute configuration of frondosin B
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DOI：
10.1021/ja0021060
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发表时间：
2001-03-07
影响因子：
15
通讯作者：
Danishefsky, SJ
中科院分区：
文献类型：
--
作者：
Inoue, M;Carson, MW;Danishefsky, SJ
两种简明合成(+/-)-frondosin B (I)，一种白细胞介素-8受体拮抗剂；从市售的5-甲氧基氨基甲酸醛中获得。酮33中的七元环是这两种合成的常见中间体，是通过经典的弗里德尔-克拉夫特反应形成的。第一条路线的关键步骤是将乙烯基苯并呋喃与三取代烯烃（30—> 16 + 38）进行易阳离子环化，构建六元碳环。虽然这条路线证明了逐步接近frondosin环体系的有效性，但它也导致在酸性条件下容易异构化的烯烃异构体。在第二种途径中，我们利用Diels-Alder反应在空间要求高的二烯42和亚硝基乙烯之间进行合成；为了确定frondosin b的绝对构型，设计了第三次全合成。它达到了二烯42，这次是以对映体定义的形式。从这一点上，自然配置的frondosin B以对映体富集的形式得到。这些研究确定了紫花菌素B仲甲基中心的绝对构型为R。
Two concise syntheses of (+/-)-frondosin B (I), an interleukin-8 receptor antagonist, have been;achieved from commercially available 5-methoxysaricylaldehyde. The seven-membered ring in ketone 33, the common intermediate for both syntheses, was built by a classical Friedel-Crafts reaction. The key step of the first route was facile cationic cyclization of the vinylogous benzofuran to the trisubstituted olefin (30 --> 16 + 38) to construct a six-membered carbocycle. Although this route demonstrated the efficacy of the stepwise approach to the frondosin ring-system, it also resulted in olefinic isomers that were easily isomerized in acidic conditions. In the second route, we utilized a Diels-Alder reaction between sterically demanding diene 42 and nitroethylene to fir;the double bond in its required position in the resultant dimethylcyclohexane ring, A third total synthesis was devised for the purpose of determining the absolute configuration of frondosin B. It reached diene 42, this time in the enantiomerically defined form. From this point, naturally configured frondosin B was obtained in the enantiometically enriched form. These studies establish the absolute configuration of the secondary methyl center in frondosin B to be R.