Enantioselective synthesis of the central ring system of lomaiviticin a in the form of an unusually stable cyclic hydrate
Enantioselective synthesis of the central ring system of lomaiviticin a in the form of an unusually stable cyclic hydrate
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DOI：
10.1002/anie.200704830
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Shair, Matthew D.
中科院分区：
文献类型：
--
作者：
Krygowski, Evan S.;Murphy-Benenato, Kerry;Shair, Matthew D.
天然产物的洛麦替星家族是具有显著C2对称结构的有效细胞毒性分子（方案1）。它们分离自放线菌的菌株，Micromonospora lomaivitiensis，其本身分离自宿主海鞘的内核。[1]1对一组24种培养的癌细胞系的GI 50值为0.007 - 72 nm，并且1和2都是针对革兰氏阳性细菌的有效抗生素。he等人[1]报道了1和2损伤DNA，尽管尚未公开它们与核酸或其它生物聚合物相互作用的详细研究。洛麦替星的重氮苯并芴环系统似乎是其细胞毒性的原因。[2]这种罕见的环系统只在抗生素的卡那霉素家族中发现过（参见方案1中的卡那霉素C），[3]它们类似于洛麦维他辛的单体亚基。化合物1和2是令人生畏的合成目标，因为它们的大小，潜在的不稳定性，以及不同官能团的并列。特别复杂的是洛麦替星的中心CD/C "D"-环系统。这些环通过空间上拥挤且合成上具有挑战性的C2-C2 'σ键连接，其中心是1和2的对称轴。迄今为止，Nicolaou等报道了合成洛麦替星的唯一方法，即1和2的模型D/D ′-环系统。[4]考虑到合成1和2的全局策略，我们得出结论，制备这些C2-对称分子的最收敛的方法是在最后可能的阶段立体选择性地形成C2-C2 '键，从而减少双重加工的量（方案2）。由于C2-C2 ′键是1，4-二酮（C1-C2-C2 ′-C1 ′）的一部分，我们希望在后期立体选择性氧化烯醇化物偶联反应中连接1和2的两个四环"半体"（参见方案2中的3）。然而，这种转变有两个严重的问题。首先，酮烯醇化物4将倾向于β消除，从而导致D环的芳构化。其次，没有明显的方法来控制在C2和C2 '处新形成的立构中心的构型。我们的假设是将C3叔甲醇连接到C6并形成7-氧杂降冰片烷酮5将解决这两个问题。在5的烯醇化物中，C3烷氧基的β消除被烯醇化物π体系的近正交取向和桥连C3 O键的反键σ * 轨道所阻止。[5]氧化烯醇化物偶联在该体系中也应该是立体选择性的，二聚化发生在凸面α面（syn到氧桥），从而在C2-C2 '键上提供所需的α，α立体化学。在此，我们报道了使用这种策略合成洛麦维他星A（1）的中心环系统。最初，我们试图确定7-氧杂降冰片烷酮的氧化烯醇化物偶联是否可以立体选择性地完成并且没有β消除。将6（85%ee）[6]转化为7并在100 ℃下暴露于DMSO中的Ag2O [7]，得到所需的氧化烯醇偶联加合物
The lomaiviticin family of natural products are potent cytotoxic molecules with remarkable C2-symmetric structures (Scheme1). They were isolated from a strain of actinomycetes, Micromonospora lomaivitiensis, which was itself isolated from the inner core of a host ascidian.[1] The GI50 values of 1 against a panel of 24 cultured cancer cell-lines are 0.007–72 nm, and both 1 and 2 are potent antibiotics against Gram-positive bacteria. He et al.[1] reported that 1 and 2 damage DNA, although detailed studies of their interactions with nucleic acids or other biopolymers have not been disclosed. The diazobenzofluorene ring system of the lomaiviticins would appear to be responsible for their cytotoxicity.[2] This rare ring system has only ever been found in the kinamycin family of antibiotics (see kinamycin C in Scheme 1),[3] which resemble the monomeric subunits of the lomaiviticins.Compounds 1 and 2 are daunting synthetic targets because of their size, potential lability, and juxtaposition of diverse functional groups. Of particular complexity are the central CD/C’D’-ring systems of the lomaiviticins. These rings are linked by a sterically congested and synthetically challenging C2ÀC2’σ bond, the center of which is the axis of symmetry for 1 and 2. To date, Nicolaou et al. have reported the only approach to the lomaiviticins with the syntheses of model D/D’-ring systems of 1 and 2.[4] Considering a global strategy for syntheses of 1 and 2, we concluded that the most convergent approach to prepare these C2-symmetric molecules would be to stereoselectively form the C2ÀC2’bond at the latest possible stage, thereby reducing the amount of double processing (Scheme 2). Since the C2ÀC2’bond is part of a 1, 4-diketone (C1-C2-C2’-C1’), our desire was to link the two tetracyclic “halves” of 1 and 2 in a late-stage stereoselective oxidative enolate coupling reaction (see 3 in Scheme 2). However, this transformation has two serious problems. Firstly, the ketone enolate 4 will be prone to β elimination, thus leading to aromatization of the D ring. Secondly, there is no obvious means of controlling the configurations of the newly formed stereocenters at C2 and C2’. Our hypothesis is that linking the C3 tertiary carbinol to C6 and forming the 7-oxanorbornanone 5 will resolve both issues. β Elimination of the C3 alkoxy group is prevented in enolates of 5 by the nearly orthogonal orientation of the enolate π system and the antibonding σ* orbital of the bridging CÀO bond.[5] Oxidative enolate coupling should also be stereoselective in this system, with dimerization occurring from the convex, α faces (syn to the oxygen bridge), thus delivering the desired α, α stereochemistry across the C2ÀC2’bond. Herein we report the synthesis of the central ring system of lomaiviticin A (1) using this strategy. Initially, we sought to determine whether oxidative enolate coupling of 7-oxanorbornanones could be accomplished stereoselectively and without β elimination. Conversion of 6 (85% ee)[6] into 7 and exposure to Ag2O in DMSO [7] at 1008C afforded the desired oxidative enol coupling adduct