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.

<ol>
	<li>Adabala, P. J. P., Legresley, E. B., Bance, N., Niikura, M., Pinto, B. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Exploitation+of+the+Catalytic+Site+and+150+Cavity+for+Design+of+Influenza+A+Neuraminidase+Inhibitors.">Exploitation of the Catalytic Site and 150 Cavity for Design of Influenza A Neuraminidase Inhibitors.</a> J. Org. Chem. 78 (21), 10867-10877 (2013).</li><li>Trost, B. M., Kaneko, T., Andersen, N. G., Tappertzhofen, C., Fahr, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Total+Synthesis+of+Aeruginosin+98B.">Total Synthesis of Aeruginosin 98B.</a> J. Am. Chem. Soc. 134 (46), 18944-18947 (2012).</li><li>Conn, S. J., Vreeland, S. M., Wexler, A. N., Pouwer, R. H., Quinn, R. J., Chamberland, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Total+Synthesis+of+Clavatadine.">Total Synthesis of Clavatadine.</a> A. J. Nat. Prod. 78, 120-124 (2014).</li><li>Buchanan, J. C., Petersen, B. P., Chamberland, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Concise+Total+Synthesis+of+Phidianidine+A+and+B.">Concise Total Synthesis of Phidianidine A and B.</a> Tetrahedron Lett. 54, 6002-6004 (2013).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Technical Bulletin AL-134: Handling Air-Sensitive Reagents. , (2012).</li><li>Castagnolo, D., Raffi, F., Giorgi, G., Botta, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Macrocyclization+of+Di-Boc-guanidino-alkylamines+Related+to+Guazatine+Components:+Discovery+and+Synthesis+of+Innovative+Macrocyclic+Amidinoureas.">Macrocyclization of Di-Boc-guanidino-alkylamines Related to Guazatine Components: Discovery and Synthesis of Innovative Macrocyclic Amidinoureas.</a> Eur. J. Org. Chem. 2009 (3), 334-337 (2009).</li><li>Zubrick, J. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> The Organic Chem Lab Survival Manual: A Student's Guide to Techniques. , (2012).</li><li>Pirrung, M. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> The Synthetic Organic Chemist's Companion. , (2007).</li><li>Padias, A. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Making the Connections 2: A How-To Guide for Organic Chemistry Lab Techniques, Second Edition. , (2011).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Digital Lab Techniques Manual: Volumetric Techniques. , (2007).</li><li>Baker, T. J., Tomioka, M., Goodman, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preparation+and+Use+of+N,N'-Di-Boc-N&amp;#34;-Triflylguanidine.">Preparation and Use of N,N'-Di-Boc-N&amp;#34;-Triflylguanidine.</a> Org. Synth. 78, 91-98 (2002).</li><li>Baker, T. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+Biologically+Important+Guanidine-Containing+Molecules+Using+Triflyl-Diurethane+Protected+Guanidines.">Synthesis of Biologically Important Guanidine-Containing Molecules Using Triflyl-Diurethane Protected Guanidines.</a> Synthesis. S1, 1423-1426 (1999).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Digital Lab Techniques: Using a Balance. , (2007).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Digital Lab Techniques: Reaction Work-Up I: Extraction, Washing, and Drying. , (2007).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Digital Lab Techniques: Filtration. , (2007).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Digital Lab Techniques: Reaction Work-Up II: Using the Rotovap. , (2007).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Digital Lab Techniques: Column Chromatography. , (2007).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Flash Chromatography 101. , (2015).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Digital Lab Techniques Manual: TLC - The Basics. , (2007).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Digital Lab Techniques: TLC - Advanced. , (2007).</li><li>Massachusetts Institute of Technology Department of Chemistry Instrumentation Facility. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> NMR Tips and Tricks. , (2015).</li><li>Krohn, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthese+des+Bactereostatischen+2.4-Dibrom-homogentisins&#228;ure+-+Amids+und+Verwandter+Verbindungen.">Synthese des Bactereostatischen 2.4-Dibrom-homogentisins&#228;ure - Amids und Verwandter Verbindungen.</a> Tetrahedron Lett. 16 (52), 4667-4668 (1975).</li><li>Wolkowitz, H., Dunn, M. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Homogentisic+Acid.">Homogentisic Acid.</a> Biochem. Prep. 4, 6-11 (1955).</li><li>Feichtinger, K., Zapf, C., Sings, H. L., Goodman, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diprotected+Triflylguanidines:+A+New+Class+of+Guanidinylation+Reagents.">Diprotected Triflylguanidines: A New Class of Guanidinylation Reagents.</a> J. Org. Chem. 63, 3804-3805 (1998).</li><li>Ariza, X., Urp&#236;, F., Vilarrasa, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+practical+procedure+for+the+preparation+of+carbamates+from+azides.">A practical procedure for the preparation of carbamates from azides.</a> Tetrahedron Lett. 40, 7515-7517 (1999).</li><li>Ariza, X., Urp&#236;, F., Viladomat, C., Vilarrasa, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-Pot+Conversion+of+Azides+to+Boc-Protected+Amines+with+Trimethylphosphine+and+Boc-ON.">One-Pot Conversion of Azides to Boc-Protected Amines with Trimethylphosphine and Boc-ON.</a> Tetrahedron Lett. 39, 9101-9102 (1998).</li><li>Snider, B. B., Song, F., Foxman, B. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Total+Syntheses+of+(&#177;)-Anchinopeptolide+D+and+(&#177;)-Cycloanchinopeptolide.">Total Syntheses of (&#177;)-Anchinopeptolide D and (&#177;)-Cycloanchinopeptolide.</a> D. J. Org. Chem. 65 (3), 793-800 (2000).</li><li>Barykina, O., Snider, B. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+(+-)-Eusynstyelamide+A.">Synthesis of (+-)-Eusynstyelamide A.</a> Org. Lett. 12 (11), 2664-2667 (2010).</li><li>Yu, M., Pochapsky, S. S., Snider, B. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+(&#177;)-Bistellettadine+A.">Synthesis of (&#177;)-Bistellettadine A.</a> Org. Lett. 12 (4), 828-831 (2010).</li><li>Exp&#242;sito, A., Fern&#225;ndez-Su&#225;rez, M., Iglesias, T., Mu&#241;oz, L., Riguera, R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Total+Synthesis+and+Absolute+Configuration+of+Minalemine+A,+a+Guanidine+Peptide+from+the+Marine+Tunicate+Didemnum+rodriguesi.">Total Synthesis and Absolute Configuration of Minalemine A, a Guanidine Peptide from the Marine Tunicate Didemnum rodriguesi.</a> J. Org. Chem. 66, 4206-4213 (2001).</li><li>Wuts, P. G. M., Greene, T. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Greene's Protective Groups in Organic Synthesis. , (2007).</li><li>Malmberg, C. E., Chamberland, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Total+synthesis+of+clavatadine+A+analogues+to+produce+a+viable+reversible+inhibitor+for+factor+XIa.">Total synthesis of clavatadine A analogues to produce a viable reversible inhibitor for factor XIa.</a> , (2015).</li><li>Bhonde, V. R., Looper, R. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Stereocontrolled+Synthesis+of+(+)-Saxitoxin.">A Stereocontrolled Synthesis of (+)-Saxitoxin.</a> J. Am. Chem. Soc. 133, 20172-20174 (2011).</li><li>Lin, H. Y., Snider, B. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+Phidianidines+A+and+B.">Synthesis of Phidianidines A and B.</a> J. Org. Chem. 77, 4832-4836 (2012).</li><li>Hickey, S. M., Ashton, T. D., Pfeffer, F. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Facile+Synthesis+of+Guanidine+Functionalised+Building+Blocks.">Facile Synthesis of Guanidine Functionalised Building Blocks.</a> Asian J. Org. Chem. 4 (4), 320-326 (2015).</li><li>Looper, R. E., Haussener, T. J., Mack, J. B. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chlorotrimethylsilane+Activation+of+Acylcyanamides+for+the+Synthesis+of+Mono-N-acylguanidines.">Chlorotrimethylsilane Activation of Acylcyanamides for the Synthesis of Mono-N-acylguanidines.</a> J. Org. Chem. 76, 6967-6971 (2011).</li><li>Shimokawa, J., Ishiwata, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Total+Synthesis+of+(+)-Batzelladine+A+and+(+)-Batzelladine+D,+and+Identification+of+Their+Target+Protein.">Total Synthesis of (+)-Batzelladine A and (+)-Batzelladine D, and Identification of Their Target Protein.</a> Chem. Eur. J. 11, 6878-6888 (2005).</li><li>Katritzky, A. R., Rogovoy, B. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recent+Developments+in+Guanylating+Agents.">Recent Developments in Guanylating Agents.</a> ARKIVOC. iv, 49-87 (2005).</li><li>Berlinck, R. G. S., Trindade-Silva, A. E., Santos, M. F. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+chemistry+and+biology+of+organic+guanidine+derivatives.">The chemistry and biology of organic guanidine derivatives.</a> Nat. Prod. Rep. 29, 1382-1406 (2012).</li><li>Ebada, S., Proksch, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chemical+and+Pharmacological+Significance+of+Natural+Guanidines+from+Marine+Invertebrates.">Chemical and Pharmacological Significance of Natural Guanidines from Marine Invertebrates.</a> Mini-Rev. Med. Chem. 11 (3), 225-246 (2011).</li></ol>

The authors have nothing to declare.

clavatadine Aを準備するための初期の努力は、この場合には、端末アジドた適切なアミン前駆体からグアニジニルに伝統的な、間接的なアプローチを入隊しました。この取り組みの中心には、カルバミン酸部分を構築するために、分子の2つの半分の労働組合でした。残念ながら、すべての計画後期グアニジニルを見越してアジド化を実現する試みが失敗に終わった。25,26これらの挫折は...

このビデオの目的は、端末グアニジン構造を作るために、直接、早期グアニジニルメソッドを使用するより、実用的な迅速、かつ有機合成における伝統的なグアニジニル方法よりも効率的である方法を示すことです。アミノ酸アルギニンに見られるグアニジン官能基は、多くの複雑な天然物及び医薬品における重要な構成要素です。天然産物および小分子を含む新たなグアニジンの発見および設計は、より効率的なグアニジニル方法の必要性を確立します。一般的に使用される遠回りのアプローチは、合成の遅い段階でマスクされていない潜在グアニジン前駆体の導入を提供しています。これとは対照的に、簡単な戦術は、合成経路における初期の第一級アミンに保護されたグアニジンをインストールします。 グアニジンの反応性質は、一般的に、適切な保護基戦略なしに日常的な使用からそれらを排除します。伝統的に、方法グアニジンを追加する官能基は、合成の終わりにグアニジンを添加すること、続いて複数の保護ステップを含ん間接的なアプローチを含みました。最近の二つの合成は、間接的なグアニジニル1,2に固有の欠点を示しています。本明細書で報告ダイレクトメソッドは、指定された分子の合成の初期に第一級アミンと、保護グアニジン試薬を反応させ、次いで、合成の終了時に、それを脱保護することを含みます。この戦略は、生物学的に活性海洋アルカロイドの最近の全合成に正常にデプロイされたが、Aとphidianidine AとB 3,4を clavatadine。 この直接グアニジニル方法はグアニジニルの伝統的な方法よりもその利点を持っていないが、それはまだその欠点を有しています。保護されたグアニジンを用いた保護基に依存して生き残ることができる化学的条件。これらの潜在的な欠点にもかかわらず、直接グアニジニル法が可能な戦略であります複雑な有機分子の合成に使用するための第一級アミンに、端末グアニジンを追加します。

<table><tbody><tr><td>Chloroform-d</td><td>Sigma-Aldrich</td><td>612200-100G</td><td>99.8% D, 0.05% v/v tetramethylsilane; Caution: toxic</td></tr><tr><td>Dimethylsulfoxide-d&lt;sub&gt;6&lt;/sub&gt;</td><td></td><td>185965-50G</td><td>99.9% D, 1% v/v tetramethylsilane</td></tr><tr><td>sodium thiosulfate pentahydrate</td><td>Sigma-Aldrich</td><td>S8503-2.5KG</td><td></td></tr><tr><td>sodium sulfate, anhydrous</td><td>Sigma-Aldrich</td><td>238597-2.5KG</td><td></td></tr><tr><td>silica gel</td><td>Fisher Scientific</td><td>S825-25</td><td>Merck, Grade 60, 230-400 mesh</td></tr><tr><td>washed sea sand</td><td>Sigma-Aldrich</td><td>274739-5KG</td><td></td></tr><tr><td>hexane</td><td>Sigma-Aldrich</td><td>178918-20L</td><td>Caution: flammable</td></tr><tr><td>ethyl acetate</td><td>Sigma-Aldrich</td><td>319902-4L</td><td></td></tr><tr><td>methylene chloride</td><td>Sigma-Aldrich</td><td>D65100-4L</td><td></td></tr><tr><td>sodium chloride</td><td>Sigma-Aldrich</td><td>S9888-10KG</td><td></td></tr><tr><td>sodium bicarbonate</td><td>Sigma-Aldrich</td><td>S6014-2.5KG</td><td></td></tr><tr><td>acetic acid</td><td>Sigma-Aldrich</td><td>695092-2.5L</td><td></td></tr><tr><td>hydrochloric acid</td><td>Sigma-Aldrich</td><td>258248-2.5L</td><td>Caution: Corrosive</td></tr><tr><td>bromine</td><td>Sigma-Aldrich</td><td>470864-50G</td><td>&gt;99.99% trace metals basis; Caution: Corrosive, causes severe burns</td></tr><tr><td>hydrobromic acid</td><td>Sigma-Aldrich</td><td>244260-500ML</td><td>48% aqueous; Caution: Corrosive</td></tr><tr><td>2,5-dimethoxyphenylacetic acid</td><td>ChemImpex</td><td>26909</td><td></td></tr><tr><td>chloroform</td><td>Sigma-Aldrich</td><td>132950-4L</td><td>Caution: Toxic</td></tr><tr><td>tetrahydrofuran</td><td>Sigma-Aldrich</td><td>360589-4x4L</td><td>Caution: highly flammable</td></tr><tr><td>&lt;em&gt;N,N&lt;/em&gt;-diisopropylethylamine</td><td>Sigma-Aldrich</td><td>D125806-500ML</td><td>Caution: Corrosive</td></tr><tr><td>triethylamine</td><td>Sigma-Aldrich</td><td>T0886-1L</td><td>Caution: Corrosive</td></tr><tr><td>3 Angstrom molecular sieves</td><td>Sigma-Aldrich</td><td>208574-1KG</td><td></td></tr><tr><td>calcium hydride</td><td>Sigma-Aldrich</td><td>213268-100G</td><td>Caution: Corrosive, reacts violently with water</td></tr><tr><td>ammonium molybdate</td><td>Sigma-Aldrich</td><td>431346-50G</td><td></td></tr><tr><td>phosphomolybdic acid</td><td>Sigma-Aldrich</td><td>221856-100G</td><td></td></tr><tr><td>cerium(IV) sulfate</td><td>Sigma-Aldrich</td><td>359009-25G</td><td></td></tr><tr><td>1-butanol</td><td>Sigma-Aldrich</td><td>537993-1L</td><td></td></tr><tr><td>1,4-butanediamine</td><td>Sigma-Aldrich</td><td>D13208-100G</td><td>Caution: Corrosive / warm in hot water bath to melt prior to use</td></tr><tr><td>triphosgene</td><td>VWR</td><td>200015-064</td><td>Caution: Highly Toxic</td></tr><tr><td>methanol</td><td>Sigma-Aldrich</td><td>646377-4X4L</td><td></td></tr><tr><td>sodium acetate</td><td>Sigma-Aldrich</td><td>241245-100G</td><td></td></tr><tr><td>Dimethylsulfoxide-d&lt;sub&gt;6&lt;/sub&gt;</td><td>Sigma-Aldrich</td><td>570672-50G</td><td>Anhydrous, 99.9% D</td></tr><tr><td>sodium hydroxide</td><td>Sigma-Aldrich</td><td>221465-500G</td><td>Caution: Corrosive</td></tr><tr><td>guanidine hydrochloride</td><td>Sigma-Aldrich</td><td>G4505-25G</td><td>Caution: Toxic, Corrosive</td></tr><tr><td>di-tert-butyl dicarbonate</td><td>VWR</td><td>200002-018%</td><td>Caution: Toxic / may warm in hot water bath to melt prior to use</td></tr><tr><td>trifluoromethanesulfonic anhydride</td><td>Fisher Scientific</td><td>50-206-771</td><td>98%, anhydrous; Caution: toxic, corrosive, extremely moisture sensitive</td></tr></tbody></table>

a direct, early stage guanidinylation protocol for the synthesis of complex aminoguanidine-containing natural products

グアニジン官能基、アミノ酸アルギニン、生命の基本的なビルディングブロックの1つの中で最も目立つように表示は、多くの複雑な天然物及び医薬品に見出される重要な構成要素です。新しいグアニジン含有天然物と設計された小型分子の継続的な発見のために、迅速かつ効率的なグアニジニル方法は、合成および医薬品有機化学者に関心のあります。グアニジンの求核及び塩基性が、その後の化学変換に影響を与える可能性があるため、伝統的な、間接的なグアニジニルは、一般的に追求されています。間接的な方法は、一般に、アジド、フタルイミド、またはカルバメートなどの潜在アミン前駆体を含む複数の保護ステップを採用します。これらの回りくどい方法を回避し、早期の合成配列で直接グアニジニル反応を採用することにより、実現するclavatadine Aのバックボーンを含む線形端末グアニジンを偽造することが可能でしたこの強力なXIa因子阻害剤の短期および合理化合成。実際には、塩酸グアニジンが来て、合成手順を生き残るために最適化されて慎重に構築保護アレイに詳述されています。 clavatadine Aの製造において、市販のジアミンの直接グアニジニルは、その合成から2不要な手順を排除しました。知らグアニジン保護基の多種多様と相まって、直接グアニジニルは、合成化学者のツールボックスの家を見つける方法に固有の簡潔かつ効率的な実用性をevinces。

トリホスゲンとの反応、続いて市販のαの直接グアニジニル、ωジアミンは、clavatadineのAの直線部分のような反応性イソシアネート8に （ 図1B）を得ました 。この二段階反応シーケンスの収率は、95％以上常に高いです。グッドマンによって記載されているようにグアニジニル試薬6は正確に調製した。...

Watch this Scientific Journal Video about A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products at JoVE.com

A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products

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.

複雑なアミノグアニジン含有天然物の合成のための直接、早期グアニジニルプロトコル

The guanidine functional group, displayed most prominently in the amino acid arginine, one of the fundamental building blocks of life, is an important ...

a-direct-early-stage-guanidinylation-protocol-for-synthesis-complex

Research

JoVE Journal

Chemistry

10.5K ビュー.  Central Washington University. 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. 

ビデオ: A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products

Free Radicals in Chemical Biology: from Chemical Behavior to Biomarker Development

The involvement of free radicals in life sciences has constantly increased with time and has been connected to several physiological and pathological processes. This subject embraces diverse scientific areas, spanning from physical, biological and bioorganic chemistry to biology and medicine, with applications to the amelioration of quality of life, health and aging. Multidisciplinary skills are required for the full investigation of the many facets of radical processes in the biological environment and chemical knowledge plays a crucial role in unveiling basic processes and mechanisms. We developed a chemical biology approach able to connect free radical chemical reactivity with biological processes, providing information on the mechanistic pathways and products. The core of this approach is the design of biomimetic models to study biomolecule behavior (lipids, nucleic acids and proteins) in aqueous systems, obtaining insights of the reaction pathways as well as building up molecular libraries of the free radical reaction products. This context can be successfully used for biomarker discovery and examples are provided with two classes of compounds: mono-trans isomers of cholesteryl esters, which are synthesized and used as references for detection in human plasma, and purine 5',8-cyclo-2'-deoxyribonucleosides, prepared and used as reference in the protocol for detection of such lesions in DNA samples, after ionizing radiations or obtained from different health conditions.

Radical-based biomimetic chemistry has been applied to building-up libraries necessary for biomarker development.

ケミカルバイオロジーのフリーラジカル：化学的挙動からバイオマーカー探索·開発へ

The involvement of free radicals in life sciences has constantly increased with time and has been connected to several physiological and pathological ...

化学

Modification and Functionalization of the Guanidine Group by Tailor-made Precursors

The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. In this article, an easy method for the modification of the guanidine group in peptidic ligands is provided, with an example of RGD-binding integrin ligands. It was recently demonstrated that the distinct modification of the guanidine group in these ligands allows for the selective modulation of the subtype (e.g., between the subtypes &#945;v and &#945;5). Moreover, a formerly unknown strategy for the functionalization via the guanidine group was demonstrated, and the synthetic approach is reviewed in this document. The modifications described here involve terminally (N&#969;) alkylated and acetylated guanidine groups. For the synthesis, tailor-made precursor molecules are synthesized, which are then subjected to a reaction with an orthogonally deprotected amine to transfer the pre-modified guanidine group. For the synthesis of alkylated guanidines, precursors based on N,N&#8242;-Di-Boc-1H-pyrazole-1-carboxamidine are used to synthesize acylated compounds, the precursor of choice being a correspondingly acylated derivative of N-Boc-S-methylisothiourea, which can be obtained in one- and two-step reactions.

A protocol for the synthesis of alkyl-modified guanidines based on the use of the corresponding precursors is presented.

オーダーメイドの前駆体によってグアニジン基の修飾と機能化

The guanidine group is one of the most important pharmacophoric groups in medicinal chemistry. The only amino acid carrying a guanidine group is arginine. ...

生化学

Split-and-pool Synthesis and Characterization of Peptide Tertiary Amide Library

Peptidomimetics are great sources of protein ligands. The oligomeric nature of these compounds enables us to access large synthetic libraries on solid phase by using combinatorial chemistry. One of the most well studied classes of peptidomimetics is peptoids. Peptoids are easy to synthesize and have been shown to be proteolysis-resistant and cell-permeable. Over the past decade, many useful protein ligands have been identified through screening of peptoid libraries. However, most of the ligands identified from peptoid libraries do not display high affinity, with rare exceptions. This may be due, in part, to the lack of chiral centers and conformational constraints in peptoid molecules. Recently, we described a new synthetic route to access peptide tertiary amides (PTAs). PTAs are a superfamily of peptidomimetics that include but are not limited to peptides, peptoids and N-methylated peptides. With side chains on both &#945;-carbon and main chain nitrogen atoms, the conformation of these molecules are greatly constrained by sterical hindrance and allylic 1,3 strain. (Figure 1) Our study suggests that these PTA molecules are highly structured in solution and can be used to identify protein ligands. We believe that these molecules can be a future source of high-affinity protein ligands. Here we describe the synthetic method combining the power of both split-and-pool and sub-monomer strategies to synthesize a sample one-bead one-compound (OBOC) library of PTAs.

Peptide tertiary amides (PTAs) are a superfamily of peptidomimetics that include but are not limited to peptides, peptoids and N-methylated peptides. Here we describe a synthetic method which combines&#160;both split-and-pool and sub-monomer strategies to synthesize a one-bead one-compound library of PTAs.

ペプチド第三級アミドライブラリのスプリット·アンド·プールの合成とキャラクタリゼーション

Peptidomimetics are great sources of protein ligands. The oligomeric nature of these compounds enables us to access large synthetic libraries on solid ...

Hydrolysis of a Ni-Schiff-Base Complex Using Conditions Suitable for Retention of Acid-labile Protecting Groups

Unnatural amino acids, amino acids containing side-chain functionalities not commonly seen in nature, are increasingly found in synthetic peptide sequences. Synthesis of some unnatural amino acids often includes the use of a precursor consisting of a Schiff-base stabilized by a nickel cation. Unnatural side-chains can be installed on an amino acid backbone found in this Schiff-base complex. The resulting unnatural amino acid can then be isolated from this complex using hydrolysis of the Schiff-base, typically by employing reflux in strongly acidic solution. These highly acidic conditions may remove acid-labile side-chain protecting groups necessary for the unnatural amino acids to be used in microwave-assisted solid-phase peptide synthesis. In this work, we present an efficient hydrolysis and subsequent Fmoc protection of an amino acid isolated from a Ni-Schiff base complex. Hydrolysis conditions presented in this work are suitable for retention of acid-labile side-chain protecting groups and may be adaptable to a variety of unnatural amino acid substrates.

Here, we present an efficient hydrolysis and subsequent Fmoc protection of an amino acid isolated from a Ni-Schiff-base complex. Hydrolysis conditions presented here are suitable for use when retention of acid-labile side-chain protecting groups is required. This technique may be adaptable to a variety of unnatural amino acid substrates.

酸に不安定な保護基を保持するのに適したNi-シッフ塩基錯体の使用条件の加水分解

Unnatural amino acids, amino acids containing side-chain functionalities not commonly seen in nature, are increasingly found in synthetic peptide ...

Facile Protocol for the Synthesis of Self-assembling Polyamine-based Peptide Amphiphiles (PPAs) and Related Biomaterials

Polyamine-based Peptide Amphiphiles (PPAs) are a new class of self-assembling amphiphilic biomaterials-related to the peptide amphiphiles (PAs). Traditional PAs possess charged amino acids as solubilizing groups (lysine, arginine), which are directly connected to a lipid segment or can contain a linker region made of neutral amino acids. Tuning the peptide sequence of PAs can yield diverse morphologies. Similarly, PPAs possess a hydrophobic segment and neutral amino acids, but also contain polyamine molecules as water solubilizing (hydrophilic) groups. As is the case with PAs, PPAs can also self-assemble into diverse morphologies, including small rods, twisted nano-ribbons, and fused nano-sheets, when dissolved in water. However, the presence of both primary and secondary amines on a single polyamine molecule poses a significant challenge when synthesizing PPAs. In this paper, we show a simple protocol, based on literature precedents, to achieve a facile synthesis of PPAs using solid phase peptide synthesis (SPPS). This protocol can be extended to the synthesis of PAs and other similar systems. We also illustrate the steps that are needed for cleavage from the resin, identification, and purification.

Facile Protocol for the Synthesis of Self-assembling Polyamine-based Peptide Amphiphiles PPAs and Related Biomaterials

The synthesis of polyamine-based peptide amphiphiles (PPAs) is a significant challenge due to the presence of multiple amine nitrogens, which requires judicious use of protecting groups to mask these reactive functionalities. In this paper, we describe a facile method for the preparation of these new class of self-assembling molecules.

自己組織化ペプチドのポリアミンによる両親媒性物質 (Ppa の) と関連生体材料の合成のための安易なプロトコル

Polyamine-based Peptide Amphiphiles (PPAs) are a new class of self-assembling amphiphilic biomaterials-related to the peptide amphiphiles (PAs). ...

The Synthesis of RGD-functionalized Hydrogels as a Tool for Therapeutic Applications

The use of polymers as biomaterials has provided significant advantages in therapeutic applications. In particular, the possibility to modify and functionalize polymer chains with compounds that are able to improve biocompatibility, mechanical properties, or cell viability allows the design of novel materials to meet new challenges in the biomedical field. With the polymer functionalization strategies, click chemistry is a powerful tool to improve cell-compatibility and drug delivery properties of polymeric devices. Similarly, the fundamental need of biomedicine to use sterile tools to avoid potential adverse-side effects, such as toxicity or contamination of the biological environment, gives rise to increasing interest in the microwave-assisted strategy.
The combination of click chemistry and the microwave-assisted method is suitable to produce biocompatible hydrogels with desired functionalities and improved performances in biomedical applications. This work aims to synthesize RGD-functionalized hydrogels. RGD (arginylglycylaspartic acid) is a tripeptide that can mimic cell adhesion proteins and bind to cell-surface receptors, creating a hospitable microenvironment for cells within the 3D polymeric network of the hydrogels. RGD functionalization occurs through Huisgen 1,3-dipolar cycloaddition. Some PAA carboxyl groups are modified with an alkyne moiety, whereas RGD is functionalized with azido acid as the terminal residue of the peptide sequence. Finally, both products are used in a copper catalyzed click reaction to permanently link the peptide to PAA. This modified polymer is used with carbomer, agarose and polyethylene glycol (PEG) to synthesize a hydrogel matrix. The 3D structure is formed due to an esterification reaction involving carboxyl groups from PAA and carbomer and hydroxyl groups from agarose and PEG through microwave-assisted polycondensation. The efficiency of the gelation mechanism ensures a high degree of RGD functionalization. In addition, the procedure to load therapeutic compounds or biological tools within this functionalized network is very simple and reproducible.

We present a protocol for the synthesis of RGD-functionalized hydrogels as devices for cell and drug delivery. The procedure involves copper catalyzed alkyne-azide cycloaddition (CuAAC) between alkyne-modified polyacrylic acid (PAA) and a RGD-azide derivative. The hydrogels are formed using microwave-assisted polycondensation and their physicochemical properties are investigated.

治療用途のためのツールとしてのRGD官能ヒドロゲルの合成

The use of polymers as biomaterials has provided significant advantages in therapeutic applications. In particular, the possibility to modify and ...

生物工学

Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine

Nitrogen-containing heterocycle aziridines are synthetically very valuable for the preparation of azacyclic and acyclic molecules. However, it is very difficult and laborious to make aziridines in optically pure forms on a large scale to apply asymmetric synthesis of aza compounds. Fortunately, we successfully achieved both enantiomers (2R)- and (2S)-aziridine-2-carboxylates with the electron-donating &#945;-methylbenzyl group at the ring nitrogen as non-activated aziridines. These starting aziridines have two distinct functional groups-highly reactive three-membered ring and versatile carboxylate. They are applicable in ring-opening or ring-transformation with aziridine and in functional group transformation to others from carboxylate. Both of these enantiomers were utilized in the preparation of biologically important amino acyclic and/or aza-heterocyclic compounds in an asymmetric manner. Specifically, this report describes the first expedient asymmetric synthesis of both enantiomers of 5, 6-dihydrouracil-type marine natural products biemamide B and D as potential TGF-&#946; inhibitors. This synthesis consisted of regio- and the stereoselective ring-opening reaction of aziridine-2-carboxylate and subsequent formation of 4-aminoteterahydropyrimidine-2,4-dione. One more example in this protocol dealt a highly stereoselective Mukaiyama reaction of aziridine-2-carboxylate and silyl enol ether, following intramolecular aziridine ring-opening to provide easy and facile access to (-)-epiallo-isomuscarine.

Preparation of Enantiopure Non-Activated Aziridines and Synthesis of Biemamide B, D, and epiallo-Isomuscarine

In this study, we prepare both enantiomers of aziridine-2-carboxylate, which are used in the asymmetric synthesis of alkaloids, including biemamide B and D, and (-)-epiallo-isomuscarine.

エナンチオピュア非活性化アジリジンの調製およびビエマミドB、D、および エピアロイソムスカリンの合成

Nitrogen-containing heterocycle aziridines are synthetically very valuable for the preparation of azacyclic and acyclic molecules. However, it is very ...

Targeted Antibody Blocking by a Dual-Functional Conjugate of Antigenic Peptide and Fc-III Mimetics (DCAF)

Elimination of harmful antibodies from organisms is a valuable approach for the intervention of antibody-associated diseases, such as Dengue hemorrhagic fever and autoimmune diseases. Since thousands of antibodies with different epitopes are circulating in blood, no universal method, except for the dual-functional conjugate of antigenic peptide and Fc-III mimetics (DCAF), was reported to target specific harmful antibodies. The development of DCAF molecules makes significant contribution to the progress of targeted therapy, which were demonstrated to eliminate the antibody dependent enhancement (ADE) effect in a Dengue virus (DENV) infection model and to boost the acetylcholine receptor activity in a myasthenia gravis model. Here, we describe a protocol for the synthesis of a DCAF molecule (DCAF1), which can selectively block 4G2 antibody to attenuate ADE effect during Dengue virus infection, and illustrate the binding of DCAF1 to 4G2 antibody by an ELISA assay. In our method, DCAF1 is synthesized by the conjugation of a hydrazine derivative of a Fc-III peptide and a recombinant expressed long &#945;-helix with antigenic sequence through native chemical ligation (NCL). This protocol has been successfully applied to DCAF1 as well as other DCAF molecules for targeting their cognate antibodies.

Targeted Antibody Blocking by a Dual-Functional Conjugate of Antigenic Peptide and Fc-III Mimetics DCAF

Development of a dual-functional conjugate of antigenic peptide and Fc-III mimetics (DCAF) is novel for the elimination of harmful antibodies. Here, we describe a detailed protocol for the synthesis of DCAF1 molecule, which can selectively block 4G2 antibody to eliminate antibody dependent enhancement effect during Dengue virus infection.

抗原ペプチドとFc-III模倣体(DCAF)の二重機能コンジュゲートによる標的抗体遮断

Elimination of harmful antibodies from organisms is a valuable approach for the intervention of antibody-associated diseases, such as Dengue hemorrhagic ...

免疫・感染学

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay

Spirocyclic heterocycles have recently been reported in literature to be potential drugs for cancer therapy. The synthesis of these novel orthogonal ring systems is challenging. An efficient methodology to synthesize these compounds was recently published that described the solid phase synthesis in four steps rather than the previously reported five steps. The advantage of this shorter synthesis is the elimination of the use of toxic reagents. Low-loading Regenerating Michael (REM) linker-based resin was found to be crucial in the synthesis as high-loading versions prevented the addition of reagents containing bulky phenyl and aromatic side chains. The colorimetric 3-(4&#8242;,5&#8242;-dimethylthiazol-2&#8242;-yl)-2,5- diphenyltetrazolium bromide (MTT) assay was used to examine the cytotoxicity of micromolar concentrations of these novel spirocyclic molecules in vitro. MTT is readily available commercially and produces relatively fast, reliable results, making this assay ideal for these spirocyclic heterocycles. Orthogonal ring structures as well as furfurylamine (a precursor in the synthesis method containing a similar 5-member ring motif) were tested.

Here, we describe a bioassay using 3-(4&#8242;,5&#8242;-dimethylthiazol-2&#8242;-yl)-2,5- diphenyltetrazolium bromide (MTT) to test previously synthesized spirocyclic oximes.

官能化スピロ環複素環合成および細胞毒性アッセイ

Spirocyclic heterocycles have recently been reported in literature to be potential drugs for cancer therapy. The synthesis of these novel orthogonal ring ...

生物学

Preparation of 1&deg; Amines: Azide Synthesis

Direct alkylation of ammonia produces polyalkylated amines, along with a quaternary ammonium salt. To exclusively prepare primary amines, the azide synthesis method can be used.
Azide ions act as good nucleophiles and react with unhindered alkyl halides to form alkyl azides. Alkyl azides do not participate in further nucleophilic substitution reactions, thereby eliminating the chances of polyalkylated products. Alkyl azides are reduced by hydride-based reducing agents, like lithium aluminum hydride, or by catalytic hydrogenation to primary amines. The driving force for such reactions is the elimination of nitrogen gas.
Azide synthesis also works with other electrophiles like epoxides to produce amino alcohols through stereoselective ring-opening reactions. Alkyl azides have an explosive nature and must be carefully handled.

Preparation of 1&amp;deg; Amines: Azide Synthesis

1°アミンの調製:アジド合成

Direct alkylation of ammonia produces polyalkylated amines, along with a quaternary ammonium salt. To exclusively prepare primary amines, the azide ...

複雑なアミノグアニジン含有天然物の合成のための直接、早期グアニジニルプロトコル

要約

さらに動画を探す

この動画の章

ケミカルバイオロジーのフリーラジカル：化学的挙動からバイオマーカー探索·開発へ

オーダーメイドの前駆体によってグアニジン基の修飾と機能化

ペプチド第三級アミドライブラリのスプリット·アンド·プールの合成とキャラクタリゼーション

酸に不安定な保護基を保持するのに適したNi-シッフ塩基錯体の使用条件の加水分解

自己組織化ペプチドのポリアミンによる両親媒性物質 (Ppa の) と関連生体材料の合成のための安易なプロトコル

治療用途のためのツールとしてのRGD官能ヒドロゲルの合成

エナンチオピュア非活性化アジリジンの調製およびビエマミドB、D、およびエピアロイソムスカリンの合成

抗原ペプチドとFc-III模倣体(DCAF)の二重機能コンジュゲートによる標的抗体遮断

官能化スピロ環複素環合成および細胞毒性アッセイ

1°アミンの調製:アジド合成

複雑なアミノグアニジン含有天然物の合成のための直接、早期グアニジニルプロトコル

要約

さらに動画を探す

この動画の章

ケミカルバイオロジーのフリーラジカル：化学的挙動からバイオマーカー探索·開発へ

オーダーメイドの前駆体によってグアニジン基の修飾と機能化

ペプチド第三級アミドライブラリのスプリット·アンド·プールの合成とキャラクタリゼーション

酸に不安定な保護基を保持するのに適したNi-シッフ塩基錯体の使用条件の加水分解

自己組織化ペプチドのポリアミンによる両親媒性物質 (Ppa の) と関連生体材料の合成のための安易なプロトコル

治療用途のためのツールとしてのRGD官能ヒドロゲルの合成

エナンチオピュア非活性化アジリジンの調製およびビエマミドB、D、および エピアロイソムスカリンの合成

抗原ペプチドとFc-III模倣体(DCAF)の二重機能コンジュゲートによる標的抗体遮断

官能化スピロ環複素環合成および細胞毒性アッセイ

1°アミンの調製:アジド合成

エナンチオピュア非活性化アジリジンの調製およびビエマミドB、D、およびエピアロイソムスカリンの合成