New synthetic technology for the construction of oxocenes.
New synthetic technology for the construction of oxocenes.
复制标题
用于构建氧新族的新合成技术。
DOI：
10.1021/ja00269a067
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发表时间：
1986
影响因子：
15
通讯作者：
C. Hwang
中科院分区：
文献类型：
--
作者：
K. Nicolaou;M. Duggan;C. Hwang
氧杂环辛烯和氧杂环壬烯环系是在诸如短裸甲藻毒素Bv2和其他海洋天然产物等天然物质中经常遇到的结构单元。由于对这些生物活性分子的兴趣日益增加以及构建中等大小环时公认的难题，此类环系的合成成为一个具有挑战性的合成目标。在本文中，我们报道了用于构建和化学操作氧杂环辛烯的新型、实用且高效的合成技术，作为类似于短裸甲藻毒素B和相关化合物的多环框架的一部分。由于通过环化反应合成中等大小的环存在严重困难，这些困难归因于熵不利、角度变形、键的排斥力和跨环相互作用，我们设计进入这些体系的方法假定分子内捕获一种活性中间体，例如由结构A（方案I）表示的锍离子或其等价物。计算机生成的和德林分子模型表明，可以实现一种相对无应变的构象，其中A的亲电sp²碳的p轨道适当定向，以便被附近的亲核氧进行分子内捕获，从而产生稠合的氧杂环辛烯体系2（方案I）。当考虑到从二硫缩酮生成锍离子（或其等价物）的容易程度以及预期的硫基的丰富合成化学时，这种方法的吸引力就增强了。为了测试该策略的可行性，合成了中间体A的一种潜在前体，羟基二硫缩酮1（方案II）。在乙腈（CH₃CN）中，在2,6 - 二甲基吡啶（2.0当量）、硝酸银（AgNO₃，1.1当量）、分子筛（3A）和硅胶存在下，将1暴露于N - 氯代琥珀酰亚胺（NCS，1.1当量）中，在25℃下，5分钟内得到2，产率为95%。用1.1当量的间氯过氧苯甲酸（mCPBA，CH₂Cl₂，0℃）氧化2得到亚砜3（95%，单一立体异构体），而进一步氧化（额外1.1当量的mCPBA，CH₂Cl₂，0℃）得到砜4（92%），为无色棒状晶体，熔点97 - 98.5℃（乙醚 - 己烷）。X射线晶体学分析证实了该化合物及其前体3和2的预期立体化学（ORTEP图，方案II）
'The oxwene and oxwane ring systems are often-encountered structural units in naturally occurring substances such as the brevetoxins'v2 and other marine natural pr0ducts.j Due to increasing interest in these bioactive molecules and the well-recogni7ed problems in building midsize rings, the synthesis of such systems becomes a challenging synthetic objective. In this paper we report new, practical, and efficient synthetic technologies for the construction and chemical manipulation of oxocenes4 as part of polycyclic frameworks similar to brevetoxin BS and related compounds. Because of the severe difficulties involved in synthesizing medium-size rings by cyclization reactions attributed to entropic disfavor, angle deformations, bond opposition forces, and transannular interactions: our design for an entry into these systems postulated intramolecular capture of a reactive intermediate such as the sulfonium' ion represented by structure A (Scheme I ) or its equivalent. Computer-generated and Dreiding molecular models indicated that a relatively strain-free conformation could be realized in which the p-orbital of the electrophilic sp2 carbon of A is appropriately oriented for intramolecular capture by the nearby nucleophilic oxygen, giving rise to the fused oxOcene system 2 (Scheme I). The attractiveness of such a method is enhanced when one considers the ease by which sulfonium ions (or their equivalents) can be generated from diothioketals and the synthetically rich chemistry of the expected thio group. To test the feasibility of this strategy, a potential progenitor to intermediate A, hydroxy dithioketal 1 (Scheme 11) was synthesized.* Exposure of 1 to N-chlorosuccinimide (NCS, 1.1 equiv) in acetonitrile (CH,CN) and in the presence of 2,6-lutidine (2.0 equiv), silver nitrate (&NO,, 1.1 equiv): molecular sieves (MS 3A), and silica gello a t 25 "C led, in 5 min, to a 95% yield of 2. Oxidation of 2 with 1.1 equiv of mCPBA (CH2CI2, 0 "C) led to sulfoxide 3 (95%, single stereoisomer), whereas further oxidation (1 .I equiv of additional mCPRA, CH2CI2, 0 "C) furnished sulfone 4 (92%) as colorless rods, mp 97-98.5 OC (ether-hexane). An X-ray crystallographic analysis' ' confirmed the expected stereochemistry for this compound and its pregenitors 3 and 2 (ORTEP plot, Scheme 11).