Enantioselective synthesis of the lomaiviticin aglycon full carbon skeleton reveals remarkable remote substituent effects during the dimerization event.
Enantioselective synthesis of the lomaiviticin aglycon full carbon skeleton reveals remarkable remote substituent effects during the dimerization event.
复制标题
lomaiviticin aglycon全碳骨架的对映选择性合成在二聚事件期间揭示了显着的远程取代效应。
DOI：
10.1002/chem.201002157
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发表时间：
2010-11-22
影响因子：
4.3
通讯作者：
Shair, Matthew D.
中科院分区：
文献类型：
--
作者：
Lee, Hong Geun;Ahn, Jae Young;Lee, Amy S.;Shair, Matthew D.
Lomaiviticin A (1) 和 lomaiviticin B (2) 是新型 C2 对称重氮苯并芴苷海洋天然产物（图 1）。 [1] Lomaiviticin A (1) 可有效抑制培养的癌细胞系的生长（GI50 值范围为 0.007 至 72.0 nM），1 和 2 均对革兰氏阳性菌表现出令人印象深刻的生长抑制活性。化合物 1 在体外会对 DNA 造成损伤。据推测，源自1和2的重氮苯并芴酮的活性物质会对核酸造成损害，从而导致这些分子的细胞毒性活性。实验研究为重氮芴酮结构形成活性物质提供了支持。[2]然而，1和2的完整结构在生理相关条件下如何反应以及哪些细胞成分受到1和2的干扰仍有待确定。1和2的结构是前所未有的和惊人的。 1和2的不寻常结构提出了关于它们如何生物合成的有趣问题，特别是C2-C2'键是如何形成的，以及如何实现这些分子的合成的问题。虽然 1 或 2 的合成尚未实现，但已经报道了这些分子的许多方法，[3] 包括我们自己对 1 的中心 (CD-D'-C') 环系统的对映选择性合成。[3b] 1 和 2 的完整碳骨架的合成尚未完成。为了实现 1 和 2 的合成，需要克服重大挑战；其中最困难的可能是C2-C2′δ键的形成。 C2-C2' 键连接两个高度功能化的“一半”1 和 2，与相关的天然产物运动霉素非常相似。 [4] C2-C2'键周围的拥挤环境、键形成过程中的立体化学控制以及D和D'环的潜在不稳定性使得该键的形成极具挑战性。后期二聚化和 C2-C2' 键的形成（其中双重加工保持在最低限度）将是合成 1 和 2 的最有效方法。由于 1 和 2 中的 C2-C2' 键是 1, 4-二酮 (C1-C2-C2'-C1') 的一部分，因此后期氧化烯醇化物偶联将是构建该键的理想反应。然而，从 C1-C2 烯醇化物中β-消除 C3 叔甲醇的高潜力，加上这种氧化烯醇化物偶联反应可能较差的立体选择性，使得这种方法没有吸引力。为了克服这些障碍，我们开发了一种利用氧化烯醇偶联的策略
Lomaiviticin A (1) and lomaiviticin B (2) are novel C2-symmetric diazobenzofluorene glycoside marine natural products (Figure 1).[1] Lomaiviticin A (1) potently inhibits the growth of cultured cancer cell lines (GI50 values ranging from 0.007 to 72.0 nM), and both 1 and 2 exhibit impressive growth inhibition activity against Gram-positive bacteria. Compound 1 causes damage to DNA in vitro. It has been speculated that a reactive species derived from the diazobenzofluorenones of 1 and 2 causes damage to nucleic acids, leading to the cytotoxic activities of these molecules. Experimental studies have provided support for the formation of reactive species from diazofluorenone structures.[2] However, it remains to be determined how the full structures of 1 and 2 react under physiologically relevant conditions and what cellular components are perturbed by 1 and 2.The structures of 1 and 2 are unprecedented and striking. The unusual structures of 1 and 2 pose interesting questions about how they are biosynthesized, especially how the C2–C2′ bond is made, and questions about how to achieve syntheses of these molecules. Although a synthesis of 1 or 2 has not yet been achieved, many approaches to these molecules have been reported,[3] including our own enantioselective synthesis of the central (CD-D’-C’) ring system of 1.[3b] A synthesis of the full carbon skeleton of 1 and 2 has not yet been accomplished. To achieve syntheses of 1 and 2, there are significant challenges to overcome; the most difficult of which is likely formation of the C2–C2′ δ bond. The C2–C2′ bond links two highly functionalized “halves” of 1 and 2, which closely resemble the related natural product kinamycins.[4] The congested environment surrounding the C2–C2′ bond, stereochemical control during bond formation, and the potential lability of the D and D’rings render the formation of this bond extremely challenging. Late-stage dimerization and formation of the C2–C2′ bond, in which double-processing is kept at a minimum, would be the most efficient means of synthesizing 1 and 2. Since the C2–C2′ bond in 1 and 2 is part of a 1, 4-diketone (C1-C2-C2′-C1′), a late-stage oxidative enolate coupling would be the ideal reaction to construct this bond. However, the high potential for β-elimination of the C3 tertiary carbinol from a C1–C2 enolate, coupled with the likely poor stereoselectivity of such an oxidative enolate coupling reaction, renders this approach unattractive. To circumvent these obstacles, we developed a strategy utilizing the oxidative enolate coupling
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影响因子：
15
作者：
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Krygowski, Evan S.;Murphy-Benenato, Kerry;Shair, Matthew D.
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通讯作者：
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影响因子：
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作者：
OKAZAKI, K;NOMURA, K;YOSHII, E
通讯作者：
YOSHII, E