复杂天然产物合成中的卡宾配合物：Calphostins 的全合成,Journal of the American Chemical Society

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复杂天然产物合成中的卡宾配合物：Calphostins 的全合成
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2000-04-01 , DOI: 10.1021/ja994313+
Craig A Merlic ₁ , Courtney C Aldrich , Jennifer Albaneze-Walker , Alan Saghatelian

Affiliation

Calphostin A、B、C 和 D (1-4) 于 1989 年从日本大阪发现的真菌 Cladosporium cladosporioides 中分离出来，属于一类天然存在的苝醌。 1,2 Calphostin 被发现是有效的特异性抑制剂蛋白激酶 C (PKC) 并表现出强烈的细胞毒活性，但没有抗真菌或抗生素活性。3 有趣的是，这种生物活性也被发现是光依赖性的，4 尽管具体机制尚未阐明。PKC 代表细胞内信号通路的一个分支，它的过度刺激与从癌症到糖尿病的多种疾病状态有关。 5 作为不受控制的细胞增殖的特定介质，通过它们对蛋白激酶 C 的作用，钙磷蛋白作为抗癌治疗的潜在药物引起了相当大的关注。6 事实上，已经报道了该组中最简单成员的三种全合成。7 然而，这些合成需要从市售材料中进行 20 多个步骤和/或缺乏有效控制轴向手性。此外，迄今为止尚未报道该组中最具生物活性的钙磷蛋白 C 的全合成。我们在此报告了 calphostin A、B、C 和 D 的简洁和对映选择性合成，其特征是对映纯 Fischer 卡宾复合物的苯环化以及用于控制轴向手性的选择性热异构化。calphostins 的关键结构特征是五环苝醌核心，由于 C1 和 C12 的侧链与 C6 和 C7 位置的甲氧基的相互作用而扭曲。除了侧链手性之外，这种扭曲引入了螺旋手性8，这是一种在天然产品中很少见的不寻常的手性元素。Calphostin A 和 D 具有 C2 对称轴，而 Calphostin B 和 C 是不对称取代的。我们寻求通往五环核心的有效途径以及控制轴向手性的方法。逆合成（方案 1），我们按照 Diwu 和 Lown 的先例，采用两个邻萘醌部分的仿生氧化二聚化来组装苝醌核心。这些实验室利用铬卡宾配合物。首先，形式上的二烯基铬卡宾配合物的光解通过铬配合的乙烯酮中间体的电环化导致邻烷氧基苯酚产物（路径 A，方案 2）。 10 第二种环化方法涉及异腈热加成反应一种二烯基铬卡宾配合物，通过与铬配合的烯酮亚胺中间体的电环化，提供邻烷氧基芳香胺产物（路径 B，方案 2）。 11 这些产物中的任何一种的氧化都会产生与苝醌所需的相同的邻萘醌合成。方案1 方案2 钙磷蛋白的合成开始于市售苯甲醇5 的区域选择性溴化，然后转化为碘化物（方案3）。Michaelis-Arbuzov 与亚磷酸三乙酯的反应提供了膦酸酯 6 和随后的 Horner-Wadsworth-Emmons 烯化与对映纯醛 712 完全提供了 E-烯烃 8。 8 与叔丁基锂的锂化，然后添加六羰基铬和三氟甲磺酸甲酯的甲基化产生了关键卡宾配合物 9. 由于芳香核的富电子性质阻碍了 CO 插入，光化学诱导的苯环化产率低。然而，我们能够通过使用互补异腈反应来规避这个问题。因此，在 THF 中用叔丁基异腈处理卡宾配合物 9 将卡宾配合物转化为烯酮亚胺。回流加热影响中间体烯酮亚胺的电环化，得到邻烷氧基萘胺，用硝酸铈铵 (CAN) 将其直接氧化为邻萘醌 10。方案 3 使用邻萘醌 10，使用 FeCl3 仿生氧化二聚化为苝醌乙腈中的反应伴随三异丙基甲硅烷基 (TIPS) 的脱保护发生，以 70% 的产率提供 11。该产品与钙磷蛋白 D 仅在甲基化模式上有所不同。然而，对烯醇甲基化或侧链功能化的所有尝试都收效甚微。此外，非对映选择性很差，产生了约 55:45 的不可分离非对映异构体混合物，有利于通过 CD 光谱分析确定的所需 P 异构体。无法继续前进，我们推测将侧链醇保护基团改为苯甲酸酯可能会缓解这个问题。TIPS 邻萘醌 10 的直接脱保护存在问题；然而，在较早阶段安装苯甲酸酯很容易完成（方案 4）。卡宾配合物 9 与 t-BuNC 反应生成邻烷氧基萘胺中间体，用 TBAF 将其原位脱保护得到 12。再保护为苯甲酸酯并用 2,3-二氯-4,5-二氰基苯醌 (DDQ) 氧化提供苯甲酰化萘醌 13. 方案 4 我们很高兴地发现使用三氟乙酸 (TFA) 和空气作为氧化剂的改进程序可以顺利进行二聚反应，以 71% 的产率提供苯醌 14，苯甲酸酯完整。 13 令人失望的是， 2：获得了有利于不希望的M异构体的轴向异构体的1混合物。幸运的是，我们能够对这些进行热平衡以提供 3:1 的混合物，有利于所需的 P 异构体。回收 14M 导致 13 的 14P 的总产率为 56%。从分子模型和 NMR 数据，我们解释了观察到的选择性是由于侧链苯甲酸酯与苝醌核的稳定 π 相互作用引起的，这是有利的P 异构体，但 M 异构体在构象上难以接近。1H NMR 很好地说明了这一点，因为 P 异构体的侧链苯甲酸酯基团相对于 M 异构体被屏蔽了 0.4 ppm。通过建立对映异构和轴向纯苝醌 14P 的成功途径，完成了钙磷蛋白 C 的合成（方案 5）。使用 TBAF 作为碱用甲基碘进行甲基化提供了常见的六甲氧基苝醌中间体 15。 calphostin 侧链的去对称化通过精心控制的 15 甲醇分解成功完成，基于 58% 的转化率，这提供了显着的 84% 单苯甲酸酯 16 产率. 剩下的最后一项任务是安装混合碳酸盐链。这是通过使 16 侧链的仲醇与光气反应得到氯甲酸酯，然后与 4-乙酰氧基苯酚原位反应提供混合碳酸酯 17 形成的。最后，用 MgI214 区域选择性脱甲基，然后在苯甲酸酯和碳酸酯键的存在提供了钙磷蛋白 C (3)。类似地，其余的calphostins 由常见的六甲氧基苝醌中间体15 有效制备。15 与MgI2 的区域选择性去甲基化产生calphostin A (1)。Calphostin D (2) 又通过 calphostin A 的甲醇分解制备。 16 的去甲基化提供了 calphostin B (2)。通过比较 1H NMR、13C NMR、CD、UV、IR 和 HRMS 光谱数据，合成钙磷蛋白 A、B、C 和 D 与天然样品相同。方案 5 总之，我们已经公开了仅用 12 个步骤合成钙磷蛋白 C。该合成的特点是使用铬卡宾配合物的苯并环化快速有效地构建邻萘醌。o-萘醌是多种天然产物的亚结构，本文所述的方法应可用于构建此类不同类别的化合物。此外，我们通过使用热力学控制提供所需的异构体，确定了导致选择性的分子相互作用，成功地解决了轴向手性的关键问题。此外，我们合成路线的简洁性和多功能性允许制备将在适当时候报告的类似物。calphostins 是迷人的结构，它们对 PKC 的无与伦比的有效和选择性抑制值得进一步探索。钙磷蛋白的类似物有望作为 PKC 的同工酶选择性抑制剂，并且可以更好地了解单个 PKC 同工酶的作用。 15 我们合成路线的简洁性和多功能性允许制备类似物，并将在适当的时候报告。calphostins 是迷人的结构，它们对 PKC 的无与伦比的有效和选择性抑制值得进一步探索。钙磷蛋白的类似物有望作为 PKC 的同工酶选择性抑制剂，并且可以更好地了解单个 PKC 同工酶的作用。 15 我们合成路线的简洁性和多功能性允许制备类似物，并将在适当的时候报告。calphostins 是迷人的结构，它们对 PKC 的无与伦比的有效和选择性抑制值得进一步探索。钙磷蛋白的类似物有望作为 PKC 的同工酶选择性抑制剂，并且可以更好地了解单个 PKC 同工酶的作用。 15

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Carbene Complexes in the Synthesis of Complex Natural Products: Total Synthesis of the Calphostins

Calphostins A, B, C, and D (1–4) were isolated in 1989 from the fungi Cladosporium cladosporioides found in Osaka Japan and belong to a class of naturally occurring perylenequinones.1,2 The calphostins were found to be potent and specific inhibitors of protein kinase C (PKC) and exhibited strong cytotoxic activity, but no antifungal or antibiotic activities.3 Intriguingly, this biological activity was also found to be light dependent,4 although a specific mechanism has yet to be delineated. PKC represents one arm of the intracellular signaling pathway and its overstimulation has been implicated in a wide range of disease states from cancer to diabetes.5 As specific mediators of uncontrolled cellular proliferation through their action on protein kinase C, the calphostins have generated considerable attention as potential agents for anticancer therapy.6 Indeed, three total syntheses of the simplest members of this group have been reported.7 However, these syntheses required more than 20 steps from commercially available materials and/or lacked efficient control of the axial chirality. Furthermore, a total synthesis of calphostin C, which is the most biologically active of the group, has not been reported to date. We report herein on concise and enantioselective syntheses of calphostins A, B, C, and D which feature a benzannulation of an enantiopure Fischer carbene complex as well as a selective thermal isomerization to control the axial chirality. The key structural feature of the calphostins is the pentacyclic perylenequinone core, which is twisted due to eclipsing interactions of the side chains at C1 and C12 and the methoxy groups at positions C6 and C7. This twisting introduces helical chirality,8 an unusual chiral element rarely seen in natural products, in addition to the side chain chirality. Calphostins A and D possess a C2 axis of symmetry, while calphostins B and C are unsymmetrically substituted. We sought an efficient route to the pentacyclic core as well as a way of controlling the axial chirality. Retrosynthetically (Scheme 1), we employ a biomimetic oxidative dimerization of two o-naphthoquinone moieties to assemble the perylenequinone core, following the precedent of Diwu and Lown.9 The requisite o-naphthoquinone precursors can be prepared by either of two benzannulation strategies developed in these laboratories utilizing chromium carbene complexes. In the first, photolysis of a formally dienyl chromium carbene complex leads, via electrocyclization of a chromium complexed ketene intermediate, to an o-alkoxy phenol product (Path A, Scheme 2).10 The second annulation method involves an isonitrile thermal addition reaction with a dienyl chromium carbene complex which provides, via electrocyclization of a chromium-complexed ketenimine intermediate, an o-alkoxy aromatic amine product (Path B, Scheme 2).11 Oxidation of either of these products would yield the same o-naphthoquinone required for perylenequinone synthesis. Scheme 1 Scheme 2 Synthesis of the calphostins commenced with regioselective bromination of commercially available benzyl alcohol 5, followed by conversion to the iodide (Scheme 3). Michaelis–Arbuzov reaction with triethyl phosphite provided phosphonate 6 and subsequent Horner–Wadsworth–Emmons olefination with enantiopure aldehyde 712 exclusively furnished E-alkene 8. Lithiation of 8 with tert-butyllithium followed by addition of chromium hexacarbonyl and methylation with methyl triflate yielded the key carbene complex 9. The photochemically induced benzannulation was low yielding owing to the electron-rich nature of the aromatic nucleus which hindered CO insertion. However, we were able to circumvent this problem by using the complementary isonitrile reaction. Thus, treatment of carbene complex 9 with tert-butylisonitrile in THF converted the carbene complex to the ketenimine. Heating at reflux effected electrocyclization of the intermediate ketenimine to afford an o-alkoxynaphthylamine which was directly oxidized with ceric ammonium nitrate (CAN) to o-naphthoquinone 10. Scheme 3 With o-naphthoquinone 10 in hand, biomimetic oxidative dimerization9 to the perylenequinone using FeCl3 in acetonitrile occurred with concomitant deprotection of the triisopropylsilyl groups (TIPS) to provide 11 in 70% yield. This product only differs from calphostin D by the methylation pattern. However, all attempts at either methylating the enols or functionalizing the side chains met with little success. In addition, the diastereoselectivity was meager producing an approximately 55:45 mixture of inseparable diastereomers favoring the desired P isomer as determined by analysis of the CD spectrum. Unable to continue forward, we surmised that changing the side chain alcohol protecting group to a benzoate might alleviate this problem. Direct deprotection of TIPS o-naphthoquinone 10 was problematic; however, installation of the benzoate at an earlier stage was readily accomplished (Scheme 4). Reaction of carbene complex 9 with t-BuNC led to an o-alkoxynaphthylamine intermediate, which was deprotected in situ with TBAF to afford 12. Reprotection as the benzoate ester and oxidation with 2,3-dichloro-4,5-dicyanobenzoquinone (DDQ) provided the benzoylated naphthoquinone 13. Scheme 4 We were delighted to find that dimerization proceeded smoothly using a modified procedure employing trifluoroacetic acid (TFA) and air as the oxidant to provide the perylenequinone 14 in 71% yield with the benzoate intact.13 Disappointingly, a 2:1 mixture of axial isomers favoring the undesired M isomer was obtained. Fortunately, we were able to thermally equilibrate these to provide a 3:1 mixture, favoring the desired P isomer. Recycling 14M led to an overall yield of 56% for 14P from 13. From molecular modeling, as well as NMR data, we explain the observed selectivity as arising from a stabilizing π interaction of the side chain benzoate with the perylenquinone core, which is favorable for the P isomer, but conformationally inaccessible for the M isomer. The 1H NMR beautifully illustrates this, as the side chain benzoate groups of the P isomer are shielded by 0.4 ppm relative to the M isomer. With a successful route to enantiomerically and axially pure perylenequinone 14P established, completion of the synthesis of calphostin C was undertaken (Scheme 5). Methylation with methyl iodide using TBAF as a base provided the common hexamethoxyperylenequinone intermediate 15. Desymmetrization of the calphostin side chains was successfully accomplished by a carefully controlled methanolysis of 15, which provided a remarkable 84% yield of the monobenzoate 16 based on a 58% conversion. The final task remaining was installation of the mixed carbonate linkage. This was formed by reacting the secondary alcohol of the side chain of 16 with phosgene to give the chloroformate ester followed by in situ reaction with 4-acetoxyphenol providing the mixed carbonate 17. Finally, regioselective demethylation with MgI214 followed by chemoselective methanolysis of the acetate in the presence of the benzoate and carbonate linkages provided calphostin C (3). Analogously, the remaining calphostins were efficiently prepared from the common hexamethoxyperylenequinone intermediate 15. Regioselective demethylation of 15 with MgI2 yielded calphostin A (1). Calphostin D (2) was in turn prepared by methanolysis of calphostin A. Demethylation of 16 provided calphostin B (2). Synthetic calphostins A, B, C, and D were identical with natural samples by comparison of 1H NMR, 13C NMR, CD, UV, IR, and HRMS spectral data. Scheme 5 In summary, we have disclosed the first synthesis of calphostin C in only 12 steps. This synthesis features a rapid and efficient construction of an o-naphthoquinone using benzannulation of a chromium carbene complex. o-Naphthoquinones are substructures in a variety of natural products and the methodology described herein should find applications in constructing this diverse class of compounds. Additionally, we successfully tackled the crucial issue of axial chirality by using thermodynamic control to provide the desired isomer, identifying the molecular interactions responsible for selectivity. Furthermore, the brevity and versatility of our synthetic route has allowed preparation of analogues which will be reported in due course. The calphostins are fascinating structures and their unparalleled potent and selective inhibition of PKC warrants further exploration. Analogues of the calphostins hold promise as isozyme selective inhibitors of PKC and may provide a better understanding of the role of individual PKC isozymes.15

更新日期：2000-04-01

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