Total syntheses of the telomerase inhibitors dictyodendrin B, C, and E
Total syntheses of the telomerase inhibitors dictyodendrin B, C, and E
复制标题
DOI：
10.1021/ja0617800
复制
发表时间：
2006-06-21
影响因子：
15
通讯作者：
Scheiper, Bodo
中科院分区：
文献类型：
--
作者：
Fuerstner, Alois;Domostoj, Mathias M.;Scheiper, Bodo
本文报道了吡咯并[2，3-c]咔唑生物碱Dictyodendrin B（2）、C（3）和E（5）的全合成方法。这些海洋来源的多环端粒酶抑制剂衍生自共同的中间体18，其以多克规模通过以下序列制备，所述序列包括形成吡咯A环的TosMIC环加成、产生相邻吲哚核的钛诱导的还原性氧代酰胺偶联反应和形成吡咯并咔唑核的光化学6 π-电环化/芳构化串联。将18转化为dictyodendrin C需要选择性地操作侧保护基团和用过氧异辛酸氧化以形成目标的乙烯基苯醌核心。锌诱导的三氯乙基硫酸酯的还原裂解然后完成了3的第一个全合成。其相关物2和5也分别通过吡咯实体的选择性溴化、随后通过金属-卤素交换或交叉偶联化学精制所得溴化物27而源自化合物18。在这方面特别值得注意的是，通过钯催化的苄基交叉偶联反应，然后用DDQ对所得产物41进行乙烯基氧化，产生了非常不稳定的dictyodendrin E的对醌甲基基序。Suzuki步骤只能借助于由对甲氧基苄基氯化镁和9-MeO-9-BBN原位形成的硼酸盐络合物40来实现，而采用苄基硼酸盐、β-三氟硼酸盐或β-锡烷的替代方法失败。
Concise and flexible total syntheses of the pyrrolo[2,3-c] carbazole alkaloids dictyodendrin B (2), C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC cycloaddition with formation of the pyrrole A-ring, a titanium- induced reductive oxoamide coupling reaction to generate an adjacent indole nucleus, and a photochemical 6 pi-electrocyclization/aromatization tandem to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal-halogen exchange or cross- coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or -stannanes met with failure.