Total synthesis of (+)-phyllantidine
Total synthesis of (+)-phyllantidine
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DOI：
10.1002/anie.200602569
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发表时间：
2006-01-01
影响因子：
16.6
通讯作者：
Kerr, Michael A.
中科院分区：
文献类型：
--
作者：
Carson, Cheryl A.;Kerr, Michael A.
6560 2006 Wiley-VCH Verlag GmbH & Co. KGaA，魏因海姆Angew. 2006，45，6560-6563中所述的核嵌入在氮杂双环[3.2. 1]环系这是融合到丁烯二酰亚胺部分形成一个相当有趣的和结构复杂的分子框架。Securinine（1）和它的C2差向异构体aloosecurinine（2）是一叶独叶的成分，[2]而对映体化合物virosecurinine（3）和viroaloosecurinine（4）在一叶独叶独叶中发现。[3]虽然这些化合物在中枢神经系统（CNS）中以γ-氨基丁酸（GABA）受体的拮抗作用的形式显示出有趣的活性，[4]合成化学家被这些化合物的紧凑和复杂的结构所吸引。事实上，已经报道了一叶秋碱系列化合物的几种合成方法。[5]我们感兴趣的不是indolizidines 1-4，而是一种相关且更稀有的生物碱叶下珠碱5（分离自叶下珠和Seurinega suffruticosa）[6]及其对映体（来自Breynia coronata）。[7]到目前为止，还没有报道叶下珠定（或对映-叶下珠定）的合成，尽管叶下珠定可通过病毒一叶秋碱的过氧化物（或过酸）氧化获得。[8]这是通过N-氧化物进行的，其经历Meisenheimer重排产生叶绿替啶。由于一叶秋碱生物碱的合成路线相当复杂和漫长，因此叶下珠定的合成路线不太吸引人。本文介绍了一种简便、直接的合成（+）-叶兰替啶的方法。叶绿替啶最重要的结构特征可能是四氢-1，2-恶嗪环。这种杂环基序在天然产物中不常见，在FR-900482（和一些相关化合物）中发现[9]。由于直接制备四氢-1，2-恶嗪的方法很少，这种结构特征也使得叶绿替啶成为难以实现的目标。然而，最近，我们报道硝酮（无论是作为单独的化合物或在现场产生的）与1，1-环丙烷二酯在刘易斯酸的影响下顺利地反应，形成四氢-1，2-恶嗪，我们称之为“同-1，3-偶极环加成”。[10]该反应是非对映选择性的，并且仅产生3，6-顺式加合物。从这个环加成反应的加合物的取代模式和相对立体化学将满足叶绿替啶的实际合成路线的要求（方案1）。
6560 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2006, 45, 6560–6563 core imbedded within an azabicyclo [3.2. 1] ring system. This is fused to a butenolide moiety forming a rather interesting and structurally complex molecular framework. Securinine (1) and its C2 epimer allosecurinine (2) are constituents of Securinega suffruticosa,[2] and the antipodal compounds virosecurinine (3) and viroallosecurinine (4) are found in Securinega virosa.[3] While these compounds show interesting activity in the central nervous system (CNS) in the form of antagonism of the γ-aminobutyric acid (GABA) receptor,[4] the synthetic chemist is drawn to the compact and complex architecture of the compounds. Indeed several syntheses of the securinine series of compounds have been reported.[5] Of interest to us are not the indolizidines 1–4 but a related and much rarer alkaloid phyllantidine 5 (isolated from Phyllanthus discoides and Seurinega suffruticosa)[6] and its enantiomer (from Breynia coronata).[7] To date, no syntheses of phyllantidine (or ent-phyllantidine) have been reported, although phyllantidine is available through the peroxide (or peracid) oxidation of virosecurinine.[8] This proceeds via the N-oxide which undergoes a Meisenheimer rearrangement yielding phyllantidine. Since the synthetic routes to the securinine alkaloids are quite complex and lengthy, this route to phyllantidine is less than appealing. Herein, we present a convenient and direct synthesis of (+)-phyllantidine. Perhaps the most significant structural feature of phyllantidine is the tetrahydro-1, 2-oxazine ring. This heterocyclic motif is uncommon in natural products and is found in FR-900482 (and a few related compounds)[9]. This structural feature also makes phyllantidine an elusive target since there are few ways to directly prepare tetrahydro-1, 2-oxazines. Recently, however, we reported that nitrones (either as isolated compounds or generated in situ) react smoothly with 1, 1-cyclopropane diesters under the influence of Lewis acids to form tetrahydro-1, 2-oxazines in what we have termed a “homo-1, 3-dipolar cycloaddition”.[10] The reactions are diastereoselective and yield only 3, 6-cis adducts. Both the substitution pattern and relative stereochemistry of the adducts from this cycloaddition would fulfill the requirements of a practical synthetic route to phyllantidine (Scheme 1).