Total synthesis of the potent antitumor macrolides pladienolide B and D
Total synthesis of the potent antitumor macrolides pladienolide B and D
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DOI：
10.1002/anie.200604997
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Kotake, Yoshihiko
中科院分区：
文献类型：
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作者：
Kanada, Regina M.;Itoh, Daisuke;Kotake, Yoshihiko
2004年，酒井等人。报道了从钝顶链霉菌Mer-11107中鉴定出7个12元大环内酯类化合物(PladienolidesA-G)。[1]最有效的类大环内酯类化合物(B(2)和D(3))的IC50值在低纳摩尔范围(方案1)。它们还能抑制多种低纳米分子IC50值的癌细胞株的体外生长。通过对39个人类癌细胞株的比较分析和小组筛选表明，这些化合物具有与目前临床使用的抗癌药物不同的独特的抗肿瘤作用模式。[2]在几种人类癌症异种移植模型中，白花烯内酯B和D还导致体内肿瘤消退。[2]这些结果鼓励我们寻找基于这些独特的先导化合物的新型抗肿瘤药物。经过深入研究，我们发现了Padadienolide D的氨基甲酸酯衍生物E7107(4)，它具有更强的体内效力和更好的物理化学性质。[3]E7107连续5天静脉治疗几种肿瘤移植模型，已导致各种肿瘤移植瘤的完全缓解和肿瘤缩小。[4]鉴于这些有希望的临床前数据，E7107将很快进入临床试验。PladienolideB的绝对结构最近由Asai等人阐明。[5]为了验证这种结构和PladienolideD的结构，并促进发现具有有利药用特征的新型类似物，我们进行了首次PladienolideB和D的全合成。我们的合成确认了化合物的绝对结构，并为基于有效应用烯烃歧化技术制备新型合成类似物提供了一种策略。我们的逆合成分析如方案2所示。我们希望以试剂控制的方式安装立体合成中心，这样我们就可以简单地通过改变试剂的立体化学来合成其他立体异构体。C14±C15双键被断开以提供一个侧链部分和一个大环内酯单元；这一策略使我们能够有效地获得每个部分的结构变体。我们对二烯内酯A(1)中羟基的反应性的了解使我们相信C7羟基可以区域选择性地乙酰化。我们希望能够通过酯化反应和随后的在C1-C8单元和C9-C14单元之间的闭环烯烃复分解(RCM)来获得大环内酯部分。[6]据我们所知，仅有少数报道将RCM用于构建脂肪族(不包含作为环成员的苯基部分)12元大环内酯结构，[7]我们希望能够通过Julia-Kocienski烯化反应[8]和Shih等人发展的不对称环氧化反应[9]从C15-C18单元和C19-C23单元制备侧链部分。我们的合成始于大环内酯部分的构建(方案3)。由橙花醇经PMB基团保护和区域选择性臭解制备的醛5，[10]经历了Fukuzawa等人描述的SmII介导的不对称Reformsky反应。以溴乙酰唑烷酮6为手性助剂合成了非对映选择性较好的β羟胺7(De=82%)。
In 2004 Sakai etal. reported the identification of seven 12-membered macrolides (pladienolides A–G), from Streptomyces platensis Mer-11107 by way of a cell-based assay that evaluated the suppression of hypoxia-induced gene expression controlled by the human VEGF promoter.[1] The most potent pladienolides (B (2) and D (3)) have IC50 values in the low nanomolar range (Scheme1). They also inhibit the growth of a variety of cancer cell lines invitro with low nanomolar IC50 values. COMPARE analysis with panel screening of 39 human cancer cell lines indicated that the compounds have a unique mode of antitumor action unlike those of anticancer drugs currently in clinical use.[2] Pladienolides B and D also cause in vivo tumor regression in several human cancer xenograft models.[2] These results encouraged us to search for novel antitumor agents based on these unique lead compounds. After intensive studies, we discovered E7107 (4), a urethane derivative of pladienolide D that possesses enhanced in vivo potency and better physicochemical properties.[3] Intravenous treatment of several tumor xenograft models with E7107 for five consecutive days has led to complete remission as well as tumor shrinkage in a variety of tumor xenografts.[4] In light of these promising preclinical data, E7107 will soon enter clinical trials. The absolute structure of pladienolideB was recently elucidated by Asai et al.[5] To verify this structure, and that of pladienolideD, and to facilitate the discovery of novel analogues with advantageous pharmaceutical profiles we have executed the first total syntheses of pladienolidesB and D. Our syntheses confirm the absolute structures of the compounds and provide a strategy for the preparation of novel synthetic analogues based on the efficient application of olefin metathesis technology.Our retrosynthetic analysis is shown in Scheme2. We wanted to install the stereogenic centers in a reagentcontrolled fashion so that we could synthesize other stereoisomers simply by changing the stereochemistry of the reagents. The C14ÀC15 double bond was disconnected to afford a side-chain moiety and a macrolide unit; this strategy gave us efficient access to structural variants of each moiety. Our knowledge of the reactivity of the hydroxy groups of pladienolide A (1) led us to believe that the C7 hydroxy group could be acetylated regioselectively. We expected to be able to obtain the macrolide moiety by an esterification reaction and a subsequent ring-closing olefin metathesis (RCM) between a C1–C8 unit and a C9–C14 unit.[6] To our knowledge, there have been only a few reported uses of RCM for the construction of an aliphatic (not containing phenyl moieties as ring members) 12-membered macrolide structure, but there is no precedent for sterically hindered and highly functionalized ones.[7] We expected to be able to prepare the side-chain moiety by means of a Julia–Kocienski olefination [8] and the asymmetric epoxidation developed by Shi and coworkers [9] from a C15–C18 unit and a C19–C23 unit. Our syntheses commenced with the construction of the macrolide moiety (Scheme 3). Aldehyde 5, prepared from nerol by protection with a PMB group and regioselective ozonolysis,[10] was subjected to the SmII-mediated asymmetric Reformatsky reaction described by Fukuzawa etal. using bromoacetyloxazolidinone 6 as a chiral auxiliary to afford βhydroxyamide 7 with good diastereoselectivity (82% de).[11]