Name: one-pot microwave-assisted conversion of anomeric nitrate-esters to trichloroacetimidates
Uploaded: 2018-01-15T13:00:00
Description: Watch this Scientific Journal Video about One-pot Microwave-assisted Conversion of Anomeric Nitrate-esters to Trichloroacetimidates at JoVE.com

The authors would like to acknowledge Vanderbilt University and the Institute of Chemical Biology for financial support. Mr. Berkley Ellis and Prof. John McLean are acknowledged for High-Resolution Mass Spectral Analysis. 
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1. Representative Microwave-Assisted Denitration
<ol>
	<li>Place the azido nitrate ester (1.0 equiv., 0.2 mmol) in an 8 mL microwave reaction vial. The scale of the reaction can be increased to several mmol without any adverse effect on reaction progress.</li>
	<li>Dissolve the azido-nitrate ester in 20% aq. acetone (0.1 M, 2.0 mL). Add pyridine (5.0 equiv., 0.08 mL, 1.0 mmol) to the reaction vessel. Cap the microwave irradiation vial and place the reaction vessel in a microwave reactor cavity.</li>
	<li>Irradiate the ...

<ol>
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E., Ottosson, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Armed-Disarmed+Effects+in+Glycosyl+Donors+-+Rationalization+and+Sidetracking.">Armed-Disarmed Effects in Glycosyl Donors - Rationalization and Sidetracking.</a> J. Org. Chem. 55 (25), 6068-6070 (1990).</li><li>Bohe, L., Crich, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+propos+of+glycosyl+cations+and+the+mechanism+of+chemical+glycosylation;+the+current+state+of+the+art.">A propos of glycosyl cations and the mechanism of chemical glycosylation; the current state of the art.</a> Carbohydr. 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History and recent advances.</a> Carbohydrate Research. 344 (9), 1110-1122 (2009).</li><li>Lian, G., Zhang, X., Yu, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Thioglycosides+in+carbohydrate+research.">Thioglycosides in carbohydrate research.</a> Carbohydr. Res. 403, 13-22 (2015).</li><li>Schmidt, R. R., Kinzy, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Anomeric-Oxygen+Activation+for+Glycoside+Synthesis+-+the+Trichloroacetimidate+Method.">Anomeric-Oxygen Activation for Glycoside Synthesis - the Trichloroacetimidate Method.</a> Advances in Carbohydrate Chemistry and Biochemistry. 50, 21-123 (1994).</li><li>Schmidt, R. R., Toepfer, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Glycosylation+with+highly+reactive+glycosyl+donors:+efficiency+of+the+inverse+procedure.">Glycosylation with highly reactive glycosyl donors: efficiency of the inverse procedure.</a> Tetrahedron Lett. 32 (28), 3353-3356 (1991).</li><li>Keith, D. J., Townsend, S. D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Direct,+microwave-assisted+substitution+of+anomeric+nitrate-esters.">Direct, microwave-assisted substitution of anomeric nitrate-esters.</a> Carbohydr. 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The protocol described in this tutorial provides a method to convert nitrate esters to useful, reactive functionality. In a broader sense, employing a microwave reactor to complete specific maneuvers over the course of a carbohydrate synthesis has the potential to make difficult transformations facile and routine. Our goal in this tutorial is to demonstrate how to handle carbohydrates in the context of microwave irradiation.
In the case of the parent reaction, previous efforts to achieve denit...

Due to their ubiquity in molecular biology, carbohydrates have been longstanding targets for chemical synthesis.1,2,3 At the core of any successful synthetic campaign is the correct deployment of glycosylation reactions to build the oligosaccharide chain.4,5,6,7,8,9,10,11,12 Not surprisingly, there are a large number of methods to install glycosidic bonds.13,14 The Koenigs-Knorr method is one of the earliest known procedures and involves coupling a glycosyl chloride or bromide with an alcoholic component, usually under heavy metal (mercury or silver) activation.15 Related glycosyl fluorides were first introduced as donors in 1981 by the Mukaiyama group and have found widespread application due to their increased thermal and chemical stability.16 On the opposite end of the reactivity spectrum are glycosyl iodides, which are far more reactive than the other halides. Increased reactivity is accompanied by increased stereocontrol, particularly when forming &#945;-linked oligosaccharides.17 In addition to &#34;haloglycosides&#34;, thioglycosides have found wide utility, in part, due to their ease of formation, stability to a multitude of reaction conditions, and activation with electrophilic reagents.18
The methods described above focus on converting an anomeric alcohol to a &#34;non-oxygen&#34; containing, latent leaving group that is activated and ultimately displaced by an alcohol from an acceptor molecule. Anomeric oxygen activation as described by the Schmidt school, focuses on converting the C1 oxygen itself, to a leaving group.19 This method is the most powerful and widely used in chemical glycosylation reactions. Trichloroacetimidate donors are readily prepared from a reducing sugar and trichloroacetonitrile in the presence of a base such as potassium carbonate (K2CO3) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). These species are then activated using Lewis acids.20
Recently, we have reported that 2-azido-1-trichloroacetimidate donors can be directly prepared from glycals. The process involves a two reaction, one-pot procedure from 2-azido-1-nitrate esters.21 This detailed protocol is intended to assist practitioners in successfully completing the transformation in high yield. Of particular interest is the first step of the sequence, which focuses on thermal denitration under microwave- assisted heating. We also hope to provide a visual tutorial on employing microwave reactors in organic synthesis.

<table>
	<tbody>
		<tr>
			<td>230 400 mesh silica gel</td>
			<td>SiliCycle Inc</td>
			<td>R10030B</td>
			<td></td>
		</tr>
		<tr>
			<td>TLC plates</td>
			<td>SiliCycle Inc</td>
			<td>TLG-R10014B-527</td>
			<td></td>
		</tr>
		<tr>
			<td>Ceric ammonium molybdate</td>
			<td>Sigma-Aldrich</td>
			<td>A1343</td>
			<td></td>
		</tr>
		<tr>
			<td>Solvent Still</td>
			<td>Mbraun</td>
			<td>MB-SPS-800</td>
			<td></td>
		</tr>
		<tr>
			<td>Infared spectrometer</td>
			<td>Thermo</td>
			<td>Thermo Electron IR100</td>
			<td></td>
		</tr>
		<tr>
			<td>Nuclear Magnetic Resonance</td>
			<td>Bruker</td>
			<td></td>
			<td>400, 600 MHz</td>
		</tr>
		<tr>
			<td>LC/MS</td>
			<td>Thermo/Dionex</td>
			<td></td>
			<td>Single quad, ESI</td>
		</tr>
		<tr>
			<td>HRMS</td>
			<td>Agilent</td>
			<td>Synapt G2 S HDMS</td>
			<td></td>
		</tr>
		<tr>
			<td>Microwave reactor</td>
			<td>Anton Parr</td>
			<td>Anton Parr G10 Monowave 200</td>
			<td></td>
		</tr>
		<tr>
			<td>DBU</td>
			<td>Sigma-Aldrich</td>
			<td>139009</td>
			<td></td>
		</tr>
		<tr>
			<td>CCl3CN</td>
			<td>Sigma-Aldrich</td>
			<td>T53805</td>
			<td></td>
		</tr>
		<tr>
			<td>Pyridine</td>
			<td>Sigma-Aldrich</td>
			<td>270970</td>
			<td></td>
		</tr>
		<tr>
			<td>Acetone</td>
			<td>Fisher Scientific</td>
			<td>A18-20</td>
			<td>Tech. grade</td>
		</tr>
		<tr>
			<td>Phase separator</td>
			<td>Biotage</td>
			<td>120-1901-A</td>
			<td></td>
		</tr>
		<tr>
			<td>Rotary evaporator</td>
			<td>Buchi</td>
			<td>R-100</td>
			<td></td>
		</tr>
	</tbody>
</table>

one-pot microwave-assisted conversion of anomeric nitrate-esters to trichloroacetimidates

The goal of the following procedure is to provide a demonstration of the one-pot conversion of a 2-azido-1-nitrate-ester to a trichloroacetimidate glycosyl donor. Following azido-nitration of a glycal, the product 2-azido-1-nitrate ester can be hydrolyzed under microwave-assisted irradiation. This transformation is usually achieved using strongly nucleophilic reagents and extended reaction times. Microwave irradiation induces hydrolysis, in the absence of reagents, with short reaction times. Following denitration, the intermediate anomeric alcohol is converted, in the same pot, to the corresponding 2-azido-1-trichloroacetimidate.

The technology described herein was demonstrated on a pool of three 2-azido-1-nitrate esters. In each case the first step of the reaction was complete within 20 minutes.
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/56610/56610fig2v3.jpg" /> 
Figure 2. Representative example of hydrolysis (1 -&#62;2), and one-pot conversion of 2-azido-1-nitrate ester of <strong...

Watch this Scientific Journal Video about One-pot Microwave-assisted Conversion of Anomeric Nitrate-esters to Trichloroacetimidates at JoVE.com

One-pot Microwave-assisted Conversion of Anomeric Nitrate-esters to Trichloroacetimidates

A 2-azido-1-nitrate-ester can be converted to the corresponding 2-azido-1-trichloroacetimidate in a one-pot procedure. The goal of the manuscript is to demonstrate utility of the microwave reactor in carbohydrate synthesis.

The goal of the following procedure is to provide a demonstration of the one-pot conversion of a 2-azido-1-nitrate-ester to a trichloroacetimidate ...

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