一个直接的，早期胍基协议的复杂含氨基胍，天然产物合成
Summary
Here, we present a protocol for direct, early stage guanidinylation that enables rapid total synthesis of aminoguanidine-containing small organic molecules. An advanced synthetic intermediate used in the synthesis of a blood coagulation factor XIa inhibitor was prepared using this protocol.
Abstract
胍官能团的氨基酸精氨酸，生命的基本构建模块之一最显着位置，是许多复杂的天然产物和药物发现的重要结构元素。由于新的含胍天然产品和设计的小分子，不断发现快速，高效的胍基化方法是浓厚的兴趣，合成和药物有机化学的。由于胍的亲核性和碱性会影响后续的化学变化，传统的，间接的胍基通常追求。间接方法通常采用涉及潜胺的前体多重保护步骤，例如叠氮化物，邻苯二甲酰亚胺，或氨基甲酸酯。通过绕过这些迂回的方法和早期采用直接胍基反应在合成序列中，有可能伪造含clavatadine A的骨干实现线性终端胍这种强效因子XIa抑制剂短小精炼合成。在实践中，盐酸胍阐述与优化生存的合成步骤来精心构造的保护阵列。在clavatadine A的制备，市售二胺直接胍基消除其合成2不必要的步骤。再加上多种已知胍保护基，直接胍基evinces所固有的发现在合成化学家的工具箱中的Home方法简洁，高效的实用性。
Introduction
此视频的目的是用来说明如何使用一个直接和早期胍基的方法，使一个终端胍结构更实用，快速，效率比在有机合成传统胍基的方法。胍官能基，在氨基酸精氨酸发现，在许多复杂的天然产物和药物的重要结构元件。发现和含天然产物和小分子新胍的设计建立一个更有效的胍基化的方法的需要。常用的迂回的方式设有引入是在合成的后期阶段揭露潜胍前体。与此相反，一个简单的战术安装了一个受保护的胍到伯胺在合成路线的早期。
胍的被动性通常阻止他们从日常使用没有适当的保护基策略。传统上，方法添加胍官能团参与，参与随后在合成的末尾添加胍多重保护措施的间接方式。最近的两个合成说明固有的间接胍基1,2缺点。本文所报道的直接方法包括被保护的胍试剂与伯胺早在一个给定的分子的合成反应，然后在合成结束时脱保护。这一战略在最近的生物活性生物碱海洋全合成成功部署clavatadine A和phidianidine A和B 3,4。
虽然这种直接胍基方法确实有过胍基的传统方法其优点它还是有它的缺点。的化学条件，该受保护的胍可以生存将取决于所使用的保护基。尽管有这些潜在的缺点，直接胍基方法是一个有利的战略到终端胍添加伯胺为在复杂的有机分子的合成中使用。
Protocol
注意：对于使用前每种化学物质，请咨询并注意安全数据表（SDS）。一些在该合成中使用的化学品是腐蚀性的，有毒的，致癌的，或以其他方式危害。因此，采取一切预防措施，以避免吸入，食入，或与这些化学物质接触皮肤。请正确佩戴适当的个人防护装备（PPE）。正确的PPE包括环绕安全眼镜，丁腈手套以上的耐化学腐蚀手套，实验室外套，裤长覆盖的鞋子顶部，封闭趾鞋。以尽可能低的高度?…
Representative Results
市售的α直接胍基，ω二胺，接着用三光气反应，得到作为clavatadine A的线性部分上的反应性异氰酸酯8（ 图1b）。这两步反应序列产率总是较高，95％或更高。胍基试剂6由古德曼描述的方法制备完全相同。11,24 当异氰酸酯8用二溴苯酚3（其合成在图1a</s…
Discussion
准备clavatadine初始努力入伍传统的，间接的方法来胍基的适合的胺的前体，在这种情况下是一个终端叠氮化物。中央这一努力是在分子的两半的结合来构造氨基甲酸酯部分。不幸的是，为了实现在一个计划晚期胍基的预期的叠氮化物还原的所有尝试均告失败。25,26这些挫折启发追求化合物7，这可能在从市售材料的单步通过直接胍基来制备。虽然这种方法已在现有全合成中使用?…
Divulgations
The authors have nothing to disclose.
Acknowledgements
We thank Dr. John Greaves and Ms. Soroosh Sorooshian, Department of Chemistry, University of California, Irvine Mass Spectrometry Facility, for mass spectrometric analyses. We also thank Mr. Jacob Buchanan for helpful discussions, as well as Miss Stephanie J. Conn, Mrs. Shannon M. Huffman (Vreeland), and Miss Alexandra N. Wexler for early stage work on this project. Partial funding was provided by the Central Washington University (CWU) School of Graduate Studies (C.E.M), the CWU Seed Grant Program, and the CWU Faculty Research Program.
Materials
| Chloroform-d | Sigma-Aldrich | 612200-100G | 99.8% D, 0.05% v/v tetramethylsilane, Caution: toxic |
| Dimethylsulfoxide-d6 | 185965-50G | 99.9% D, 1% v/v tetramethylsilane | |
| sodium thiosulfate pentahydrate | Sigma-Aldrich | S8503-2.5KG | |
| sodium sulfate, anhydrous | Sigma-Aldrich | 238597-2.5KG | |
| silica gel | Fisher Scientific | S825-25 | Merck, Grade 60, 230-400 mesh |
| washed sea sand | Sigma-Aldrich | 274739-5KG | |
| hexane | Sigma-Aldrich | 178918-20L | Caution: flammable |
| ethyl acetate | Sigma-Aldrich | 319902-4L | |
| methylene chloride | Sigma-Aldrich | D65100-4L | |
| sodium chloride | Sigma-Aldrich | S9888-10KG | |
| sodium bicarbonate | Sigma-Aldrich | S6014-2.5KG | |
| acetic acid | Sigma-Aldrich | 695092-2.5L | |
| hydrochloric acid | Sigma-Aldrich | 258248-2.5L | Caution: Corrosive |
| bromine | Sigma-Aldrich | 470864-50G | >99.99% trace metals basis Caution: Corrosive, causes severe burns |
| hydrobromic acid | Sigma-Aldrich | 244260-500ML | 48% aqueous, Caution: Corrosive |
| 2,5-dimethoxyphenylacetic acid | ChemImpex | 26909 | |
| chloroform | Sigma-Aldrich | 132950-4L | Caution: Toxic |
| tetrahydrofuran | Sigma-Aldrich | 360589-4x4L | Caution: highly flammable |
| N,N-diisopropylethylamine | Sigma-Aldrich | D125806-500ML | Caution: Corrosive |
| triethylamine | Sigma-Aldrich | T0886-1L | Caution: Corrosive |
| 3 Angstrom molecular sieves | Sigma-Aldrich | 208574-1KG | |
| calcium hydride | Sigma-Aldrich | 213268-100G | Caution: Corrosive, reacts violently with water |
| ammonium molybdate | Sigma-Aldrich | 431346-50G | |
| phosphomolybdic acid | Sigma-Aldrich | 221856-100G | |
| cerium (IV) sulfate | Sigma-Aldrich | 359009-25G | |
| 1-butanol | Sigma-Aldrich | 537993-1L | |
| 1,4-butanediamine | Sigma-Aldrich | D13208-100G | Caution: Corrosive / warm in hot water bath to melt prior to use |
| triphosgene | VWR | 200015-064 | Caution: Highly Toxic |
| methanol | Sigma-Aldrich | 646377-4X4L | |
| sodium acetate | Sigma-Aldrich | 241245-100G | |
| Dimethylsulfoxide-d6 | Sigma-Aldrich | 570672-50G | Anhydrous, 99.9% D |
| sodium hydroxide | Sigma-Aldrich | 221465-500G | Caution: Corrosive |
| guanidine hydrochloride | Sigma-Aldrich | G4505-25G | Caution: Toxic, Corrosive |
| di-tert-butyl dicarbonate | VWR | 200002-018% | Caution: Toxic / may warm in hot water bath to melt prior to use |
| trifluoromethanesulfonic anhydride | Fisher Scientific | 50-206-771 | 98%, anhydrous, Caution: toxic, corrosive, extremely moisture sensitive |
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Citer Cet Article
Malmberg, C. E., Chamberland, S. A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products. J. Vis. Exp. (115), e53593, doi:10.3791/53593 (2016).