Asymmetric total synthesis of the epoxykinamycin FL-120ýýýB'.
Asymmetric total synthesis of the epoxykinamycin FL-120ýýýB'.
复制标题
环氧激酶FL-120×××B的不对称全合成。
DOI：
10.1002/anie.201104504
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
PorcoJr,JohnA
中科院分区：
文献类型：
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作者：
Scully,StephenS;PorcoJr,JohnA
重氮苯并芴天然产物是一类结构复杂的分子，具有带有重氮部分的四环 (ABCD) 框架，这是自然界中很少见的功能（方案 1）。 [1]该家族的成员在环己烯部分（D 环）的官能化水平上有所不同。运动霉素 C (1),[2] 是通过生物合成 [3] 衍生自含环氧化物的酮脱水运动霉素 (2),[4]，含有一个具有四个连续立体中心的 D 环。其他环氧激霉素包括 FL-120B (3) 和密切相关的 FL-120B’(4)。 [5]单体重氮苯并芴已被证明具有抗肿瘤特性。 [2, 6] 大量研究表明，这些生物活性可能是由生物还原途径介导的 DNA 损伤导致的，从而导致重氮官能团的丢失。 [6b, 7] 这种独特的天然产物家族在 He 等人分离出二聚重氮苯并芴 lomaiviticins A (5) 和 B (6) 后受到了广泛关注。 2001年。[8] Lomaiviticins 被证明是 DNA 损伤剂，对革兰氏阳性菌具有抗生素活性，并对多种癌细胞系具有有效的细胞毒性。 C2 对称的洛马霉素可能源自与单体运动霉素非常相似的前体的 C2-C2' 连接。自2006年以来，许多研究小组报道了单体重氮苯并芴天然产物的全合成[9]以及二聚Lomaiviticins的研究。 [10]最近，赫尔佐恩等人。报道了 lomaiviticin 苷元的 11 步合成。 [11]他们的二聚方法利用源自受保护单体的硅烯醇醚的氧化自偶联，类似于 7（方案 2a）。鉴于大量在 C2 位带有环氧化物或氧化官能团的重氮苯并芴天然产物，我们相信 lomaiviticins 的生物合成前体也可以由所提出的单体 8 描述（方案 2 b）。这种二聚过程可能是由于还原性环氧化物打开[12]事件导致关键的碳-碳键形成。[13]在这方面，我们报告了FL-120B'(4)的全合成以及用完整环氧化物制备重氮苯并芴的方法的开发；这些方法还可能允许将来获得洛马维霉素和相关化合物。
Diazobenzofluorene natural products are a family of structurally complex molecules with a tetracyclic (ABCD) framework bearing a diazo moiety, a functionality rarely found in nature (Scheme 1).[1] Members of this family differ in the levels of functionalization of the cyclohexene moiety (D ring). Kinamycin C (1),[2] which is biosynthetically [3] derived from the epoxide-containing ketoanhydrokinamycin (2),[4] contains a D ring with four contiguous stereocenters. Other epoxykinamycins include FL-120B (3) and the closely related FL-120B’(4).[5] Monomeric diazobenzofluorenes have been shown to exhibit antitumor properties.[2, 6] Numerous studies have suggested that these biological activities may result from damage to DNA mediated by bioreductive pathways, thus leading to loss of the diazo functional group.[6b, 7] This unique family of natural products gained significant attention upon isolation of the dimeric diazobenzofluorenes lomaiviticins A (5) and B (6) by He et al. in 2001.[8] Demonstrated to be DNA-damaging agents, the lomaiviticins were found to display antibiotic acitivity against Gram-positive bacteria and potent cytotoxicity in several cancer cell lines. The C2-symmetric lomaiviticins may originate from the C2ÀC2’linkage of precursors that closely resemble the monomeric kinamycins. Since 2006, numerous research groups have reported total syntheses of monomeric diazobenzofluorene natural products [9] as well as studies towards the dimeric lomaiviticins.[10] Recently, Herzon et al. reported a remarkable 11-step synthesis of the lomaiviticin aglycon.[11] Their dimerization approach utilizes an oxidative homocoupling of a silyl enol ether derived from a protected monomer, which resembles 7 (Scheme 2a). Given the abundance of diazobenzofluorene natural products bearing an epoxide or oxygenated functionality at the C2-position, we believe that a biosynthetic precursor to the lomaiviticins may also be depicted by the proposed monomer 8 (Scheme 2 b). This dimerization process may result from a reductive epoxide-opening [12] event leading to a pivotal carbon–carbon bond formation.[13] In this regard, we report the total synthesis of FL-120B’(4) and development of methods to prepare diazobenzofluorenes with intact epoxides; these methods may also allow future access to the lomaiviticins and related compounds.