Name: preparation of stable bicyclic aziridinium ions and their ring-opening for the synthesis of azaheterocycles
Uploaded: 2018-08-22T13:30:00
Description: Watch this Scientific Journal Video about Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles at JoVE.com

This work was supported by the National Research Foundation of Korea (NRF-2012M3A7B4049645 and HUFS Research Fund (2018).

1. Synthesis of (6R)-1-[(R)-1-Phenylethyl)-1-Azoniabicyclo[4.1.0]Heptane Tosylate (4)
<ol>
	<li>Synthesis of 4-(R)-[1-(R)-1-phenylethyl)aziridin-2-yl]butyl 4-methylbenzenesulfonate (2)
	<ol>
		<li>Add 100 mg of 4-[(R)-1-(R)-1-phenylethyl)aziridin-2-yl]butan-1-ol (1)12 (0.46 mmol, 1.0 equiv), 140 &#181;L of triethylamine (Et3N, 1.0 mmol, 2.2 equiv), and a magnetic stir-bar into an oven-dried 25 mL two-neck round-bott...

<ol>
	<li>Singh, G. S., D'hooghe, M., De Kimpe, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+and+Reactivity+of+C-Heteroatom-Substituted+Aziridines.">Synthesis and Reactivity of C-Heteroatom-Substituted Aziridines.</a> Chem. Rev. 107, 2080-2135 (2007).</li><li>Yudin, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Aziridines and Epoxides in Organic Synthesis. , (2006).</li><li>Lee, W. K., Ha, H. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Highlight+of+the+Chemistry+of+Enantiomerically+Pure+Aziridine-2-carboxylates.">Highlight of the Chemistry of Enantiomerically Pure Aziridine-2-carboxylates.</a> Aldrichimica Acta. 36, 57-63 (2003).</li><li>Ghorai, M. K., Bhattacharyya, A., Das, S., Chauhan, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ring+Expansions+of+Activated+Aziridines+and+Azetidines.">Ring Expansions of Activated Aziridines and Azetidines.</a> Top. Heterocycl. Chem. 41, 49-142 (2016).</li><li>Kim, Y., Ha, H. -. J., Yun, S. Y., Lee, W. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+preparation+of+stable+aziridinium+ions+and+their+ring-openings.">The preparation of stable aziridinium ions and their ring-openings.</a> Chem. Commun. , 4363-4365 (2008).</li><li>D&#8217;hooghe, M., Van Speybroeck, V., Waroquier, M., De Kimpe, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Regio-+and+stereospecific+ring+opening+of+1,1-dialkyl-2-(aryloxymethyl)aziridinium+salts+by+bromide.">Regio- and stereospecific ring opening of 1,1-dialkyl-2-(aryloxymethyl)aziridinium salts by bromide.</a> Chem. Commun. , 1554-1556 (2006).</li><li>Stankovic, S., D'hooghe, M., Catak, S., Eum, H., Waroquier, M., Van Speybroeck, V., De Kimpe, N., Ha, H. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Regioselectivity+in+the+ring+opening+of+non-activated+aziridines.">Regioselectivity in the ring opening of non-activated aziridines.</a> Chem. Soc. Rev. 41, 643-665 (2012).</li><li>Ji, M. K., Hertsen, D., Yoon, D. H., Eum, H., Goossens, H., Waroquier, M., Van Speybroeck, V., D'hooghe, M., De Kimpe, N., Ha, H. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nucleophile-Dependent+Regio-+and+Stereoselective+Ring+Opening+of+1-Azoniabicyclo[3.1.0]hexane+Tosylate.">Nucleophile-Dependent Regio- and Stereoselective Ring Opening of 1-Azoniabicyclo[3.1.0]hexane Tosylate.</a> Chem. Asian J. 9, 1060-1067 (2014).</li><li>Mtro, T. -. X., Duthion, B., Gomez Pardo, D., Cossy, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rearrangement+of+&#946;-amino+alcohols+viaaziridiniums:+a+review.">Rearrangement of &#946;-amino alcohols viaaziridiniums: a review.</a> Chem. Soc. Rev. 39, 89-102 (2010).</li><li>Dolfen, J., Yadav, N. N., De Kimpe, N., D'hooghe, M., Ha, H. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Bicyclic+Aziridinium+Ions+in+Azaheterocyclic+Chemistry-Preparation+and+Synthetic+Application+of+1-Azoniabicyclo[n.1.0]alkanes.">Bicyclic Aziridinium Ions in Azaheterocyclic Chemistry-Preparation and Synthetic Application of 1-Azoniabicyclo[n.1.0]alkanes.</a> Adv. Synth. Catal. 358, 3485-3511 (2016).</li><li>Choi, J., Yadav, N. N., Ha, H. -. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preparation+of+a+Stable+Bicyclic+Aziridinium+Ion+and+Its+Ring+Expansion+toward+Piperidines+and+Azepanes.">Preparation of a Stable Bicyclic Aziridinium Ion and Its Ring Expansion toward Piperidines and Azepanes.</a> Asian J. Org. Chem. 6, 1292-1307 (2017).</li><li>Yadav, N. N., Choi, J., Ha, H. -. 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+multiple+reactions:+asymmetric+synthesis+of+2,6-cis-disubstituted+piperidine+alkaloids+from+chiral+aziridine.">One-pot multiple reactions: asymmetric synthesis of 2,6-cis-disubstituted piperidine alkaloids from chiral aziridine.</a> Org. Biomol. Chem. 14, 6426-6434 (2016).</li><li>Angoli, M., Barilli, A., Lesma, G., Passarella, D., Riva, S., Silvani, A., Danieli, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Remote+Stereocenter+Discrimination+in+the+Enzymatic+Resolution+of+Piperidine-2-ethanol.+Short+Enantioselective+Synthesis+of+Sedamine+and+Allosedamine.">Remote Stereocenter Discrimination in the Enzymatic Resolution of Piperidine-2-ethanol. Short Enantioselective Synthesis of Sedamine and Allosedamine.</a> J. Org. Chem. 68, 9525-9527 (2003).</li><li>Shaikh, T. M., Sudalai, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Enantioselective+Synthesis+of+(+)-&#945;-Conhydrine+and+(-)-Sedamine+by+L-Proline-Catalysed+&#945;-Aminooxylation.">Enantioselective Synthesis of (+)-&#945;-Conhydrine and (-)-Sedamine by L-Proline-Catalysed &#945;-Aminooxylation.</a> Eur. J. Org. Chem. , 3437-3444 (2010).</li><li>Miyabe, H., Torieda, M., Inoue, K., Tajiri, K., Kiguchi, T., Naito, T. <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+(&#8722;)-Balanol.">Total Synthesis of (&#8722;)-Balanol.</a> J. Org. Chem. 63, 4397-4407 (1998).</li><li>Castillo, J. A., Calveras, J., Casas, J., Mitjans, M., Vinardell, M. P., Parella, T., Inoue, T., Sprenger, G. A., Joglar, J., Clapes, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fructose-6-phosphate+Aldolase+in+Organic+Synthesis:+Preparation+of+d-Fagomine,+N-Alkylated+Derivatives,+and+Preliminary+Biological+Assays.">Fructose-6-phosphate Aldolase in Organic Synthesis: Preparation of d-Fagomine, N-Alkylated Derivatives, and Preliminary Biological Assays.</a> Org. Lett. 8, 6067-6070 (2006).</li><li>Kikuchi, H., Yamamoto, K., Horoiwa, S., Hirai, S., Kasahara, R., Hariguchi, N., Matsumoto, M., Oshima, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Exploration+of+a+New+Type+of+Antimalarial+Compounds+Based+on+Febrifugine.">Exploration of a New Type of Antimalarial Compounds Based on Febrifugine.</a> J. Med. Chem. 49, 4698-4706 (2006).</li></ol>

Piperidine and azepane are two most abundant azaheterocycles in many life-saving drugs and antibiotics including various biologically active natural products16. In order to access both enantiopure piperidine (5) and azepane (6) with diverse substituents, we develped an efficient synthetic method through the formation of 1-azoniabicyclo[4.1.0]heptane tosylate from entiopure 2-(4-hydroxybutyl)aziridne followed by regiospecific nucleophilic attack either at the bridg...

Among three membered cyclic compounds, aziridine has similar ring strain energy as cyclopropane and oxirane to afford various nitrogen-containing cyclic and acyclic compounds via ring opening1,2,3. However, the characteristics and reactivity of aziridine depend on the substituent of ring nitrogen. Aziridine with an electron-withdrawing group at the ring nitrogen4, is called &#34;activated aziridine&#34;, which is activated to react with the incoming nucleophile without any additional activating reagent. On the other hand, &#34;non-activated aziridine&#34; with electron-donating substituent at nitrogen is quite stable and inert to the nucleophiles, unless it is activated as an aziridinium ion as Ia (Figure 1a)5,6,7. The ring opening of a non-activated aziridine depends on various factors such as the substituents at C2 and C3 carbon of aziridine, the electrophile to activate the aziridine ring and the incoming nucleophile. The isolation and characterization of an aziridinium ion is not possible due to its high reactivity towards ring-opening reaction by nucleophiles, but its formation and characteristics were observed spectroscopically with a non-nucleophilic counter anion5,8,9,10. The regio- and stereoselective ring-opening reaction of aziridinium ion by a suitable nucleophile yields nitrogen-containing acyclic valuable molecules (Pi and Pii)5,6,7,8,9,10.
Similarly, a bicyclic aziridinium ion (Ib) is possibly generated via the removal of the leaving group by the nucleophilic attack of ring nitrogen of aziridine in intramolecular fashion (Figure 1b). Then, this intermediate undergoes ring-expansion with the incoming nucleophile via the release of ring strain. The formation and stability of bicyclic aziridinium ion are dependent on many factors such as the substituents, the size of the ring, and solvent medium9. The regio- and stereoselectivity of the aziridine ring-expansion is a pivotal aspect of its synthetic utility, which depends on the nature of the substituents in the starting substrate and the characteristics of applied nucleophile.
In our early study, we succeeded to prepare 1-azoniabicyclo [3.1.0]hexane tosylate Ib (n = 1) whose subsequent ring-expansion resulted in the formation of a pyrrolidine and a piperidine (Piii and Piv, n = 1, Figure 1)8. As a part of our continuing study on the bicyclic aziridinium ion chemistry, we describes herein the formation of 1-azoniabicyclo [4.1.0]heptane tosylate Ib (n = 2) as a representative example. This was prepared from 2-(4-toluensulfonyloxybutyl)aziridine and its ring-expansion was trigged by a nucleophile to afford valuable piperidine and azepane (Pi and Pii, n = 2, Figure 1) with diverse substituents around the ring11. The ring-expansion of enantiopure aziridine 4-[(R)-1-(R)-1-phenylethyl)aziridin-2-yl]butan-1-ol (1) resulted in the asymmetric synthesis of substituted azaheterocycles which are applicable to build biologically active molecules with piperidine and azepane skeleton. This synthetic protocol has been applied for various compounds ranging from simple 2-cyanomethylpiperidine 5f, 2-acetyloxymethylpiperidine 5h and 3-hydroxyazepane 6j to more complex molecules including natural products such as fagomine (9), febrifugine analogue (12) and balanol (15) in optically pure forms11.

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	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Thin Layer Chromatography (TLC)</td>
			<td style="width:260px;">Merck</td>
			<td style="width:207px;">100390</td>
			<td style="width:183px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">UV light</td>
			<td style="width:260px;">Sigma-Aldrich</td>
			<td>Z169625-1EA</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Bruker AVANCE III HD (400 MHz) spectrometer</td>
			<td style="width:260px;">Bruker</td>
			<td style="width:207px;">NA</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">JASCO P-2000</td>
			<td style="width:260px;">JASCO</td>
			<td style="width:207px;">P-2000</td>
			<td>For optical rotation</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">High resolution mass spectra/ MALDI-TOF/TOF Mass Spectrometry</td>
			<td style="width:260px;">AB SCIEX</td>
			<td style="width:207px;">4800 Plus&#160;</td>
			<td>High resolution mass spectra</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">(2R)-1-[(1R)-1-Phenylethyl]-2-aziridinecarboxylic acid (&#8211;)-menthol ester, 98%</td>
			<td style="width:260px;">Sigma-Aldrich</td>
			<td style="width:207px;">57,054-0</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">(2S)-1-[(1R)-1-Phenylethyl]-2-aziridinecarboxylic acid (&#8211;)-menthol ester</td>
			<td style="width:260px;">Sigma-Aldrich</td>
			<td style="width:207px;">57,051-6</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Triethylethylamine</td>
			<td style="width:260px;">DAEJUNG</td>
			<td style="width:207px;">8556-4400-1L</td>
			<td>CAS No: 121-44-8</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Dichloromethane</td>
			<td style="width:260px;">SAMCHUN</td>
			<td style="width:207px;">M0822-18L</td>
			<td>CAS No: 75-09-2</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">p-Toluenesulfonic anhydride</td>
			<td style="width:260px;">Sigma-Aldrich</td>
			<td style="width:207px;">259764-25G</td>
			<td>CAS No: 4124-41-8</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">n-Hexane</td>
			<td style="width:260px;">SAMCHUN</td>
			<td style="width:207px;">H0114-18L</td>
			<td>CAS No: 110-54-3</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Ethyl acetate</td>
			<td style="width:260px;">SAMCHUN</td>
			<td style="width:207px;">E0191-18L</td>
			<td>CAS No: 141-78-6</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Sodium sulfate</td>
			<td style="width:260px;">SAMCHUN</td>
			<td style="width:207px;">S1011-1kg</td>
			<td>CAS No: 7757-82-6</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Acetonitrile-d3</td>
			<td style="width:260px;">Cambridge Isotope Laboratories, Inc</td>
			<td style="width:207px;">15G-744-25g</td>
			<td>CAS No: 2206-26-0</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Acetonitrile</td>
			<td style="width:260px;">SAMCHUN</td>
			<td style="width:207px;">A0127-18L</td>
			<td>CAS No: 75-05-8</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">1,4-Dioxane</td>
			<td style="width:260px;">SAMCHUN</td>
			<td style="width:207px;">D0654-1kg</td>
			<td>CAS No: 123-91-1</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Sodium hydroxide</td>
			<td style="width:260px;">DUKSAN</td>
			<td style="width:207px;">A31226-1kg</td>
			<td>CAS No: 1310-73-2</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Sodium acetate</td>
			<td style="width:260px;">Alfa Aesar</td>
			<td style="width:207px;">11554-250g</td>
			<td>CAS No: 127-09-3</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Lithium aluminum hydride</td>
			<td style="width:260px;">TCI</td>
			<td style="width:207px;">L0203-100g</td>
			<td>CAS No: 16853-85-3</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Tetrahydrofuran</td>
			<td style="width:260px;">SAMCHUN</td>
			<td style="width:207px;">T0148-18L</td>
			<td>CAS No: 109-99-9</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Sodium azide</td>
			<td style="width:260px;">D.S.P</td>
			<td style="width:207px;">703301-500g</td>
			<td>CAS No: 26628-22-8</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Cesium fluoride</td>
			<td style="width:260px;">aldrich</td>
			<td style="width:207px;">18951-0250-25g</td>
			<td>CAS No: 13400-13-0</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Tetrabutylammonium bromide</td>
			<td style="width:260px;">aldrich</td>
			<td style="width:207px;">426288-25g</td>
			<td>CAS No: 1643-19-2</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Sodium iodide</td>
			<td style="width:260px;">aldrich</td>
			<td style="width:207px;">383112-100g</td>
			<td>CAS No: 7681-82-5</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Sodium cyanide</td>
			<td style="width:260px;">Acros Organics</td>
			<td style="width:207px;">424301000-100g</td>
			<td>CAS No: 143-33-9</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Sodium thiocyanate</td>
			<td style="width:260px;">aldrich</td>
			<td style="width:207px;">467871-250g</td>
			<td>CAS No: 540-72-7</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Sodium methoxide</td>
			<td style="width:260px;">aldrich</td>
			<td style="width:207px;">156256-1L</td>
			<td>CAS No: 124-41-4</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Benzylamine</td>
			<td style="width:260px;">Alfa Aesar</td>
			<td style="width:207px;">A10997-1000g</td>
			<td>CAS No: 100-46-9</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Phenol</td>
			<td style="width:260px;">TCI</td>
			<td style="width:207px;">P1610-500g</td>
			<td>CAS No: 108-95-2</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Sodium benzoate</td>
			<td style="width:260px;">Alfa Aesar</td>
			<td style="width:207px;">A15946-250g</td>
			<td>CAS No: 532-32-1</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:564px;">Chloroform-d</td>
			<td style="width:260px;">Cambridge Isotope Laboratories, Inc</td>
			<td style="width:207px;">DLM-7TB-100S/16H-239, 100g</td>
			<td>CAS No: 865-49-6</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Dimethyl sulfoxide-d6</td>
			<td style="width:260px;">Cambridge Isotope Laboratories, Inc</td>
			<td style="width:207px;">DLM-10-25, 25g</td>
			<td>CAS No: 2206-27-1</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Methanol</td>
			<td style="width:260px;">SAMCHUN</td>
			<td style="width:207px;">M0585-18L</td>
			<td>CAS No: 67-56-1</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Ninhydrin</td>
			<td style="width:260px;">Alfa Aesar</td>
			<td style="width:207px;">A10409-250g</td>
			<td>CAS No: 485-47-2</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">Phosphomolybdic acid hydrate</td>
			<td style="width:260px;">TCI</td>
			<td style="width:207px;">P1910-100g</td>
			<td>CAS No: 51429-74-4</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:564px;">p-Anisaldehyde</td>
			<td style="width:260px;">aldrich</td>
			<td style="width:207px;">A88107-5g</td>
			<td>CAS No: 123-11-5</td>
		</tr>
	</tbody>
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preparation of stable bicyclic aziridinium ions and their ring-opening for the synthesis of azaheterocycles

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the aziridine ring. The utility of bicyclic aziridinium ions, specifically 1-azoniabicyclo[3.1.0]hexane and 1-azoniabicyclo[4.1.0]heptane tosylate highlighted in the aziridine ring openings by the nucleophile with the release of the ring strain to yield the corresponding ring-expanded azaheterocycles such as pyrrolidine, piperidine and azepane with diverse substituents on the ring in regio- and stereospecific manner. Herein, we report a simple and convenient method for the preparation of the stable 1-azabicyclo[4.1.0]heptane tosylate followed by selective ring opening via a nucleophilic attack either at the bridge or at the bridgehead carbon to yield piperidine and azepane rings, respectively. This synthetic strategy allowed us to prepare biologically active natural products containing piperidine and azepane motif including sedamine, allosedamine, fagomine and balanol in highly efficient manner.

The reaction of 4-[(R)-1-(R)-1-phenylethyl)aziridin-2-yl]butan-1-ol (1)12 with p-toluenesulfonic anhydride and triethylamine in CH2Cl2 at room temperature for 1.0 h yielded the corresponding 2-(4-tosyloxybutyl)aziridine 2 in 96% yield11. 1H NMR (400 MHz) spectrum of compound 2 in CD3CN at different time intervals shows th...

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Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles

Bicyclic aziridinium ions such as 1-azoniabicyclo[4.1.0]heptane tosylate were generated from 2-[4-tolenesulfonyloxybutyl]aziridine, which was utilized for the preparation of substituted piperidines and azepanes via regio- and stereospecific ring-expansion with various nucleophiles. This highly efficient protocol allowed us to prepare diverse azaheterocycles including natural products such as fagomine, febrifugine analogue and balanol.

Bicyclic aziridinium ions were generated by the removal of an appropriate leaving group through internal nucleophilic attack by nitrogen atom in the ...

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Nucleophilic Substitution and Elimination Reactions of Alkyl Halides

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