Name: a direct, early stage guanidinylation protocol for the synthesis of complex aminoguanidine-containing natural products
Uploaded: 2016-09-09T13:00:00
Description: Watch this Scientific Journal Video about A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products at JoVE.com

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.

Caution: Please consult and heed Safety Data Sheets (SDS) for each chemical prior to use. A few of the chemicals used in this synthesis are corrosive, toxic, carcinogenic, or otherwise harmful. Consequently, take every precaution to avoid inhalation, ingestion, or skin contact with these chemicals. Please wear appropriate Personal Protective Equipment (PPE) correctly. Proper PPE includes wrap-around safety goggles, nitrile gloves or more chemically resistant gloves, a lab coat, long pants that cover the tops of the shoes...

<ol>
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Initial efforts to prepare clavatadine A enlisted a traditional, indirect approach to guanidinylation from a suitable amine precursor, which in this case was a terminal azide. Central to this effort was the union of the two halves of the molecule to construct the carbamate moiety. Unfortunately, all attempts to realize an azide reduction in anticipation of a planned late-stage guanidinylation were unsuccessful.25,26 These setbacks inspired the pursuit of compound 7, which could be prepared in ...

The objective of this video is to show how using a direct and early guanidinylation method to make a terminal guanidine structure is more practical, rapid, and efficient than traditional guanidinylation methods in organic synthesis. The guanidine functional group, found on the amino acid arginine, is a key structural element in many complex natural products and pharmaceuticals. The discovery and design of new guanidine containing natural products and small molecules establish the need for a more efficient guanidinylation method. The commonly used circuitous approach features the introduction of a latent guanidine precursor that is unmasked at a late stage in the synthesis. In contrast, a straightforward tactic installs a protected guanidine onto a primary amine early in a synthetic route.
The reactive nature of guanidines generally precludes them from routine use without an appropriate protecting group strategy. Traditionally, methods to add a guanidine functional group involved an indirect approach that involved multiple protection steps followed by adding the guanidine at the end of the synthesis. Two recent syntheses illustrate the drawbacks inherent to indirect guanidinylation1,2. The direct method reported herein involves reacting a protected guanidine reagent with a primary amine early on in the synthesis of a given molecule and then deprotecting it at the end of the synthesis. This strategy was deployed successfully in recent total synthesis of biologically active marine alkaloids clavatadine A and phidianidine A and B3,4.
While this direct guanidinylation method does have its advantages over traditional methods of guanidinylation it still has its drawbacks. The chemical conditions that the protected guanidine can survive will depend on the protecting group employed. Despite these potential drawbacks, the direct guanidinylation method is an enabling strategy to add terminal guanidines to primary amines for use in the synthesis of complex organic molecules.

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		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Chloroform-d</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">612200-100G</td>
			<td style="width:419px;">99.8% D, 0.05% v/v tetramethylsilane, Caution:&#160; toxic&#160;</td>
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		<tr height="25">
			<td height="25" style="height:25px;width:216px;">Dimethylsulfoxide-d6</td>
			<td style="width:83px;"></td>
			<td style="width:119px;">185965-50G</td>
			<td>&#160;99.9% D, 1% v/v tetramethylsilane</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">sodium thiosulfate pentahydrate</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">S8503-2.5KG</td>
			<td></td>
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		<tr height="42">
			<td height="42" style="height:42px;width:216px;">sodium sulfate, anhydrous</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">238597-2.5KG</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">silica gel</td>
			<td style="width:83px;">Fisher Scientific</td>
			<td style="width:119px;">S825-25</td>
			<td>Merck, Grade 60, 230-400 mesh</td>
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		<tr height="42">
			<td height="42" style="height:42px;width:216px;">washed sea sand</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">274739-5KG</td>
			<td></td>
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		<tr height="42">
			<td height="42" style="height:42px;width:216px;">hexane</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">178918-20L</td>
			<td>Caution:&#160; flammable</td>
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			<td height="42" style="height:42px;width:216px;">ethyl acetate</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">319902-4L</td>
			<td></td>
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		<tr height="42">
			<td height="42" style="height:42px;width:216px;">methylene chloride</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">D65100-4L</td>
			<td></td>
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		<tr height="42">
			<td height="42" style="height:42px;width:216px;">sodium chloride</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">S9888-10KG</td>
			<td></td>
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			<td height="42" style="height:42px;width:216px;">sodium bicarbonate</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">S6014-2.5KG</td>
			<td></td>
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		<tr height="42">
			<td height="42" style="height:42px;width:216px;">acetic acid</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">695092-2.5L</td>
			<td></td>
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		<tr height="42">
			<td height="42" style="height:42px;width:216px;">hydrochloric acid</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">258248-2.5L</td>
			<td>Caution:&#160; Corrosive</td>
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		<tr height="42">
			<td height="42" style="height:42px;width:216px;">bromine</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">470864-50G</td>
			<td>&#62;99.99% trace metals basis&#160; Caution:&#160; Corrosive, causes severe burns</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">hydrobromic acid</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">244260-500ML</td>
			<td>48% aqueous, Caution:&#160; Corrosive</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">2,5-dimethoxyphenylacetic acid</td>
			<td style="width:83px;">ChemImpex</td>
			<td style="width:119px;">26909</td>
			<td></td>
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		<tr height="42">
			<td height="42" style="height:42px;width:216px;">chloroform</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">132950-4L</td>
			<td>Caution:&#160; Toxic</td>
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			<td height="42" style="height:42px;width:216px;">tetrahydrofuran</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">360589-4x4L</td>
			<td>Caution:&#160; highly flammable</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">N,N-diisopropylethylamine</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">D125806-500ML</td>
			<td>Caution:&#160; Corrosive</td>
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			<td height="42" style="height:42px;width:216px;">triethylamine</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">T0886-1L</td>
			<td>Caution:&#160; Corrosive</td>
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		<tr height="42">
			<td height="42" style="height:42px;width:216px;">3 Angstrom molecular sieves</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">208574-1KG</td>
			<td></td>
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			<td height="42" style="height:42px;width:216px;">calcium hydride</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">213268-100G</td>
			<td>Caution:&#160; Corrosive, reacts violently with water</td>
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			<td height="42" style="height:42px;width:216px;">ammonium molybdate</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">431346-50G</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">phosphomolybdic acid</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">221856-100G</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">cerium (IV) sulfate</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">359009-25G</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">1-butanol</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">537993-1L</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">1,4-butanediamine</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">D13208-100G</td>
			<td>Caution:&#160; Corrosive / warm in hot water bath to melt prior to use</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">triphosgene</td>
			<td style="width:83px;">VWR</td>
			<td style="width:119px;">200015-064</td>
			<td>Caution:&#160; Highly Toxic</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">methanol</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">646377-4X4L</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">sodium acetate</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">241245-100G</td>
			<td></td>
		</tr>
		<tr height="44">
			<td height="44" style="height:44px;width:216px;">Dimethylsulfoxide-d6</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">570672-50G</td>
			<td>Anhydrous, 99.9% D</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">sodium hydroxide</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">221465-500G</td>
			<td>Caution:&#160; Corrosive</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">guanidine hydrochloride</td>
			<td style="width:83px;">Sigma-Aldrich</td>
			<td style="width:119px;">G4505-25G</td>
			<td>Caution:&#160; Toxic, Corrosive</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">di-tert-butyl dicarbonate</td>
			<td style="width:83px;">VWR</td>
			<td style="width:119px;">200002-018%</td>
			<td>Caution:&#160; Toxic / may warm in hot water bath to melt prior to use</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">trifluoromethanesulfonic anhydride</td>
			<td style="width:83px;">Fisher Scientific</td>
			<td style="width:119px;">50-206-771</td>
			<td>98%, anhydrous, Caution:&#160; toxic, corrosive, extremely moisture sensitive</td>
		</tr>
	</tbody>
</table>

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

The guanidine functional group, displayed most prominently in the amino acid arginine, one of the fundamental building blocks of life, is an important structural element found in many complex natural products and pharmaceuticals. Owing to the continual discovery of new guanidine-containing natural products and designed small molecules, rapid and efficient guanidinylation methods are of keen interest to synthetic and medicinal organic chemists. Because the nucleophilicity and basicity of guanidines can affect subsequent chemical transformations, traditional, indirect guanidinylation is typically pursued. Indirect methods commonly employ multiple protection steps involving a latent amine precursor, such as an azide, phthalimide, or carbamate. By circumventing these circuitous methods and employing a direct guanidinylation reaction early in the synthetic sequence, it was possible to forge the linear terminal guanidine containing backbone of clavatadine A to realize a short and streamlined synthesis of this potent factor XIa inhibitor. In practice, guanidine hydrochloride is elaborated with a carefully constructed protecting array that is optimized to survive the synthetic steps to come. In the preparation of clavatadine A, direct guanidinylation of a commercially available diamine eliminated two unnecessary steps from its synthesis. Coupled with the wide variety of known guanidine protecting groups, direct guanidinylation evinces a succinct and efficient practicality inherent to methods that find a home in a synthetic chemist&#39;s toolbox.

Direct guanidinylation of a commercially available &#945;,&#969;-diamine, followed by reaction with triphosgene, afforded the reactive isocyanate 8 as the linear portion of clavatadine A (Figure 1b). Yields of this two-step reaction sequence are invariably high, 95% or greater. Guanidinylation reagent 6 was prepared exactly as described by Goodman.11,24
When isocyanat...

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.

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

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