Pour un soutien financier, nous tenons à remercier l&#39;EPSRC (Carrière Accélération Bourse de Commission paritaire de recours; EP/J001538/1), le Memorial Trust Ramsay (bourse de recherche de 2009 à 2011 à JAB), et l&#39;Imperial College de Londres. Merci à M. Alan Armstrong pour le soutien et les conseils généreux.

Une. Préparation de Iodoaziridines avec Diiodomethyllithium <ol><li> Flamme sécher un ballon de 100 ml à fond rond contenant un barreau d&#39;agitateur et équipé d&#39;un septum, sous un courant d&#39;argon, puis on laisse refroidir à la température ambiante sous une atmosphère d&#39;argon. REMARQUE: Verrerie séché dans un four pendant la nuit (125 ° C) et refroidi à température ambiante dans un mode analogue est également approprié. </li><li> Dans le ballon, ajouter 5,7 ml de THF anhydre et 2,7 ml de Et 2 O anhydre via une seringue, et l&#39;hexaméthyldisilazane fraîchement distillé (1,50 mmol, 315 ul) par l&#39;intermédiaire d&#39;une microseringue. </li><li> Agiter la solution résultante et on refroidit à -78 ° C dans un bain de glace / acétone sec dans un vase de Dewar de taille convenable pour permettre au ballon d&#39;être bien immergée. Couvrir le vase de Dewar de papier d&#39;aluminium, afin de minimiser l&#39;exposition de la cuve de réaction à la lumière. </li><li> Ajouter n BuLi (1,50 mmol, 0,60 ml, 2,5 M dans des hexanes) goutte à goutte via une seringue sur 2 à 3 min à la solution à -78 ° C.Laisser le mélange sous agitation à -78 ° C pendant encore 30 minutes pour former une solution 0,17 M de LiHMDS. ATTENTION: solution n BuLi est inflammable, corrosif pour la peau et pyrophore. L&#39;excès de réactif dans la seringue doit être arrêtée en conséquence. </li><li> Après 30 min, ajouter 1 ml de THF anhydre à un ballon à fond séché à la flamme 10 ml rondes moyen d&#39;une seringue, suivie par diiodométhane (1,70 mmol, 135 pi) par l&#39;intermédiaire d&#39;une micro-et de s&#39;assurer qu&#39;ils sont bien mélangés. </li><li> Ajouter goutte à goutte la solution de diiodométhane plus de 2 min à la solution de lithium de l&#39;hexaméthyldisilazane, à -78 ° C. Laissez cette solution pendant 20 min à -78 ° C. </li><li> Pendant ce temps, pesez N - [(E)-4-methylphenylmethylidene]-4-méthylbenzènesulfonamide (137 mg, 0,50 mmol) dans un autre séché à la flamme 10 ml flacon à fond rond et à se dissoudre dans 2,0 ml de THF anhydre. </li><li> Après le temps de la déprotonation de 20 min, ajouter goutte à goutte la solution d&#39;imine de la solution de diiodomethyllithium sur 5 min à -78 &amp; #176; C. </li><li> Immédiatement après l&#39;addition goutte à goutte est terminée, soulever la cuve de réaction du bain de glace carbonique, et la transfère à un bain de glace / eau à 0 ° C. Remettre la feuille d&#39;aluminium et laisser reposer pendant 15 min à 0 ° C. NOTE: La solution doit être de couleur orange. </li><li> Après 15 min à 0 ° C, arrêter la réaction par l&#39;addition de 30 ml de solution de bicarbonate de sodium aqueux saturé. Transférer le mélange dans une ampoule à décanter et ajouter 30 ml de CH 2 Cl 2. Agiter le mélange et retirer le CH 2 Cl 2 couche inférieure. Répétez cette procédure d&#39;extraction deux autres fois, et de combiner les deux couches CH 2 Cl. </li><li> Ajouter du sulfate de sodium pour les couches organiques pour éliminer toute l&#39;eau présente dans la solution, puis filtrer le sulfate de sodium et recueillir le filtrat dans 250 ml d&#39;un flacon à fond rond. </li><li> Eliminer le solvant sous pression réduite sur un évaporateur rotatif pour donner un échantillon impur du produit désiré iodoaziridine. </li></ol> 2. L&#39;évaluation de la stabilité du produit à des phases stationnaires pour la chromatographie <ol><li> Dissoudre l&#39;échantillon d&#39;aziridine brut dans CH 2 Cl 2 (16 ml) et ajouter le 1,3,5-triméthoxybenzène (28,0 mg, 0,167 mmol) comme étalon interne, en veillant à ce soit complètement dissous. Prélever une partie aliquote (2 ml) de ce mélange, éliminer le solvant sous pression réduite et d&#39;analyser cet échantillon par spectroscopie RMN 1 H. </li><li> Ouvrir le spectre RMN 1 H enregistré à l&#39;aide d&#39;un logiciel de traitement de RMN. En Mestrenova, cliquez droit sur le spectre et choisissez &quot;intégration&quot;, puis &quot;manuel&quot; pour fournir l&#39;outil d&#39;intégration. Cliquez et faites glisser pour couvrir la largeur des pics à 6,08 ppm et à 4,87 ppm d&#39;intégrer les signaux de la norme interne et le signal de CHI aziridine respectivement. Faites un clic droit sur l&#39;intégrale du pic à 6,08 ppm, sélectionnez &quot;modifier intégrante&quot; et modifiez la valeur &quot;normalisée&quot; à 3,0. NOTE: Des mesures similaires peuvent être appliquées à d&#39;autres logiciels. </li><li> Utiliser la valeur mise à jour de l&#39;intégrale du signal aziridine de CHI (4,87 ppm) afin de déterminer le rendement de la iodoaziridine, ici à l&#39;aide (100/3) × (l&#39;intégrale du signal CHI), ce qui donne un rendement calculé de 59%. NOTE: Compte tenu de la quantité connue de l&#39;étalon interne (0,167 mmol), et le pic de produit correspondant à 1 proton, le rendement en iodoaziridine est calculée par l&#39;équation suivante: 100 x (intégrante du pic du produit) x (moles de l&#39;étalon interne) / moles matière de départ. </li><li> Préparer des suspensions des phases suivantes fixes (25 g): la silice, la silice + 1% de NEt 3 (triéthylamine), de l&#39;alumine neutre, de l&#39;alumine basique (activité I), de l&#39;alumine basique (activité IV) et de Florisil, chacune 5% de EtOAc / hexane en (50 ml), dans six flacons de 250 ml coniques séparés contenant des barres d&#39;agitateur. Dans un autre erlenmeyer de préparer un mélange EtOAc / solution dans l&#39;hexane à 5% (50 ml), pour être utilisé comme une expérience témoin. ATTENTION: Silicun gel, d&#39;alumine et d&#39;autres phases stationnaires employés sont dangereux en cas d&#39;inhalation, devrait donc toujours être manipulé dans une hotte efficace. </li><li> Ajouter 2 ml d&#39;aliquotes de la / solution d&#39;étalon interne de iodoaziridine à chacune des fioles coniques à TA. Incorporer les mélanges de boues pour 30 min. REMARQUE: cela représente la durée du composé peut être exposé à la phase stationnaire au cours d&#39;une procédure de chromatographie sur colonne flash normal. </li><li> Filtrer les mélanges de boues à l&#39;aide d&#39;un entonnoir fritté, et recueillir le filtrat dans 250 ml d&#39;un flacon à fond rond. Laver le résidu à l&#39;entonnoir fritte avec CH 2 Cl 2 (2 x 30 ml). Répétez ce processus de filtrage pour les boues restantes. NOTE: Il convient de compenser le début de chaque phase stationnaire pour laisser le temps à la filtration et ainsi de maintenir en même temps pour chacun des matériaux en phase stationnaire. </li><li> Éliminer le solvant à partir des échantillons obtenus sous pression réduite, et l&#39;analyse par RMN 1 H spectroSCOPY pour calculer le montant de iodoaziridine récupéré dans chaque cas, comme décrit à la section 2.2. </li><li> Comparez les rendements de iodoaziridine obtenus à partir de chaque phase stationnaire testé avec celle obtenue à la section 2.1. NOTE: L&#39;échantillon donnant le rendement le plus élevé, de préférence le même que dans 2.1, indique la phase stationnaire pour chromatographie en phase optimale. Dans cet exemple, de l&#39;alumine basique (activité IV) a été considérée comme la meilleure phase stationnaire pour la purification. </li></ol> 3. Désactivation de l&#39;alumine basique et purification de la Iodoaziridine <ol><li> Répétez la section 1 pour générer le mélange iodoaziridine brut. </li><li> Pour générer de l&#39;alumine basique (activité IV), ajouter 100 g d&#39;alumine basique (activité I) pour 500 ml flacon à fond rond, puis ajouter 10 ml d&#39;eau dans le ballon et en forme avec un bouchon de verre. </li><li> Agiter le flacon vigoureusement jusqu&#39;à disparition des grumeaux sont visibles, indiquant une répartition uniforme de l&#39;eau tout au long de l&#39;alumine. Laisser refroidir l&#39;alumine à la température ambiante. ATTENTION: l&#39;adsorptiontion de l&#39;eau est exothermique, de sorte que le ballon peut faire chaud et peut entraîner une accumulation de pression. Libérer de toute pression fréquemment. </li><li> Purifier le iodoaziridine brut par Chromatographie sur colonne en utilisant de l&#39;alumine basique (activité IV) en tant que phase stationnaire, en éluant avec de l&#39;hexane, titrant à 5% de EtOAc / hexane. REMARQUE: Les fortes concentrations de EtOAc doivent pas être utilisés avec de l&#39;alumine basique. Dans ces cas, l&#39;éther diéthylique peuvent être utilisés à la place. </li><li> Combiner les fractions contenant le produit et éliminer le solvant sous pression réduite pour obtenir le iodoaziridine pure. </li></ol>

<ol>
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The authors declare that they have no competing financial interests.

Un procédé pour la préparation diastéréosélective de cis - N-Ts-iodoaziridines est décrite, et aussi d&#39;un protocole de l&#39;étude de stabilité pour indiquer quantitativement le meilleur phase stationnaire pour la purification de composés potentiellement instables par Chromatographie éclair sur colonne. Il est prévu que l&#39;accès à iodoaziridines grâce à cette approche permettra méthodes pour accéder à un large éventail de aziridines à être développé, par dérivation de l&...

Le but de cette méthode est de préparer iodoaziridines qui offrent un potentiel de fonctionnalisation de dérivés d&#39;aziridine. Le procédé comprend un protocole pour la sélection quantitative de la phase stationnaire pour chromatographie en phase optimale. Aziridines, comme des cycles à trois chaînons, possession inhérente souche anneau qui fait d&#39;eux des blocs de construction importants en chimie organique 1. Ils affichent une vaste gamme de réactivité impliquant souvent anneau aziridine ouverture 2,3, en particulier comme intermédiaires dans la synthèse des amines fonctionnalisées 4,5, ou la formation d&#39;autres hétérocycles contenant de l&#39;azote 6,7. La synthèse d&#39;une gamme de produits dérivés d&#39;aziridine par fonctionnalisation d&#39;un précurseur contenant un cycle aziridine intact a émergé comme une stratégie viable 8. Functional échange métal-groupe, pour générer un anion aziridinyle, et réaction avec des électrophiles a été montré pour être efficace <sup&gt; 9,10,11, et récemment déprotonation régio-et stéréosélective de aziridines N-protégées a également été atteint 12-15. Très récemment, catalysée par le palladium méthodes de couplage croisé pour former des aziridines d&#39;aryle à partir de précurseurs d&#39;aziridine fonctionnalisés a été développé par Vedejs 16,17, et nous 18. La chimie des hétéroatomes substitué aziridines ouvre de fascinantes questions de réactivité et de stabilité 19. Nous nous sommes intéressés à la préparation de iodoaziridines comme un groupe fonctionnel roman qui offre le potentiel de fournir des précurseurs à une large gamme de produits dérivés avec une réactivité complémentaire à des réactions de fonctionnalisation aziridine existants. En 2012, nous avons signalé la première préparation de aryle N-Boc-iodoaziridines 20, et très récemment rapporté la préparation de aryle et alkyle N-Ts-iodoaziridines 21 substitué. La méthode pour ACCEiodoaziridines ss diiodomethyllithium utilise un réactif qui a récemment également été employé dans la préparation de diiodoalkanes 22,23, 22,24 diiodomethylsilanes, et des iodures de vinyle de 25 à 27. La nature carbénoïde comme de ce réactif nécessite une préparation et l&#39;utilisation à des températures basses 22,28. Les techniques et les conditions utilisées pour la génération de diiodomethyllithium dans la préparation d&#39;iodoaziridines sont décrits ci-dessous. Alors que la silice est apparu comme le matériau de choix pour la chromatographie 29, il s&#39;est avéré inadapté pour la purification de N-Ts-iodoaziridines. Le gel de silice est généralement le premier et le seul matériau solide de phase utilisé en chromatographie flash en chimie organique en raison de la disponibilité et efficaces séparations. Cependant, la nature acide de gel de silice peut provoquer la décomposition de substrats sensibles au cours de la purification, la prévention de l&#39;isolement de la matière désirée. Alors que d&#39;autres stationary phases ou des gels de silice modifiés sont disponibles pour 30 la Chromatographie, il était impossible d&#39;évaluer la compatibilité de la molécule cible de ces différents matériaux. En raison de la nature sensible des iodoaziridines, nous avons établi un protocole pour évaluer la stabilité d&#39;un composé à un ensemble de phases stationnaires 21, ce qui est démontré ici. Ceci a des possibilités d&#39;application dans la synthèse d&#39;une large gamme de composés ayant des groupes fonctionnels sensibles. Le protocole suivant fournit un accès efficace à iodoaziridines N-Ts, permettant la synthèse diastéréosélective de deux alkyle et cis-iodoaziridines aromatiques avec un rendement élevé.

<table border="0" cellpadding="0" cellspacing="0" width="871">
	<tbody>
		<tr height="42">
			<td height="42" style="height:42px;width:209px;">Hexamethyldisilazane</td>
			<td style="width:273px;">999-97-3</td>
			<td style="width:197px;">Alfa Aesar</td>
			<td style="width:192px;">Distill from KOH under argon prior to use.</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:209px;">n-Butyllithium</td>
			<td style="width:273px;">109-72-8</td>
			<td style="width:197px;">Sigma Aldrich</td>
			<td style="width:192px;">2.5 M in hexanes, titrate prior to use.</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:209px;">Diiodomethane</td>
			<td style="width:273px;">75-11-6</td>
			<td style="width:197px;">Alfa Aesar</td>
			<td style="width:192px;">Contains copper as a stabilizer.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">1,3,5-Trimethoxybenzene</td>
			<td style="width:273px;">621-23-8</td>
			<td style="width:197px;">Sigma Aldrich</td>
			<td style="width:192px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">Silica</td>
			<td style="width:273px;">112945-52-5</td>
			<td style="width:197px;">Merck</td>
			<td style="width:192px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">Basic alumina</td>
			<td style="width:273px;">1344-28-1</td>
			<td style="width:197px;">Sigma Aldrich</td>
			<td style="width:192px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">Neutral alumina</td>
			<td style="width:273px;">1344-28-1</td>
			<td style="width:197px;">Merck</td>
			<td style="width:192px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">Florisil</td>
			<td style="width:273px;">1343-88-0</td>
			<td style="width:197px;">Sigma Aldrich</td>
			<td style="width:192px;"></td>
		</tr>
		<tr height="22">
			<td height="22" style="height:23px;width:209px;">THF</td>
			<td colspan="3" rowspan="3" style="width:663px;">All anhydrous solvents were dried through activated alumina purification columns.&#160;</td>
		</tr>
		<tr height="25">
			<td height="25" style="height:25px;width:209px;">Et2O</td>
		</tr>
		<tr height="25">
			<td height="25" style="height:25px;width:209px;">CH2Cl2</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">NMR spectrometer</td>
			<td>Bruker AV 400&#160;</td>
			<td>n/a</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:209px;">NMR processing software</td>
			<td>MestReNova&#160;</td>
			<td>7.0.2-8636</td>
			<td></td>
		</tr>
	</tbody>
</table>

synthesis and purification of iodoaziridines involving quantitative selection of the optimal stationary phase for chromatography

La préparation hautement diastéréosélective de cis - N-Ts-iodoaziridines par réaction de diiodomethyllithium avec N-Ts aldimines est décrite. Diiodomethyllithium est préparé par la déprotonation du diiodométhane avec LiHMDS, dans un mélange d&#39;éther THF / diéthylique, à -78 ° C dans l&#39;obscurité. Ces conditions sont essentielles pour la stabilité du réactif généré lichi 2. L&#39;addition goutte à goutte subséquente de N-Ts aldimines à la solution de diiodomethyllithium préformée offre un amino-diiodure intermédiaire, qui n&#39;est pas isolé. Un réchauffement rapide du mélange réactionnel à 0 ° C favorise la cyclisation pour donner iodoaziridines avec le cis-diastéréosélectivité exclusive. Les étapes d&#39;addition et de cyclisation de la réaction sont médiés dans un ballon de réaction par un contrôle soigneux de la température. En raison de la sensibilité des iodoaziridines pour la purification, l&#39;évaluation de procédés appropriés de l&#39;unité centralerification est nécessaire. Un protocole pour évaluer la stabilité des composés sensibles à des phases stationnaires pour la chromatographie sur colonne est décrite. Cette méthode convient d&#39;appliquer à de nouveaux iodoaziridines, ou d&#39;autres nouveaux composés potentiellement sensibles. Par conséquent, cette méthode peut trouver une application dans la gamme de projets de synthèse. La procédure consiste tout d&#39;abord l&#39;évaluation du rendement de la réaction, avant la purification, par une spectroscopie RMN H avec comparaison à un étalon interne. Une partie du mélange de produit impur sont ensuite exposées à des suspensions de diverses phases stationnaires pour la chromatographie appropriés, dans un système solvant approprié comme éluant en chromatographie flash. Après agitation pendant 30 min à imiter la Chromatographie, suivie par la filtration, les échantillons sont analysés par spectroscopie de 1H-RMN. Rendements calculés pour chaque phase stationnaire sont ensuite comparées à celle initialement obtenue à partir du mélange réactionnel brut. Les résultats obtenus donnent une évaluation quantitative de til stabilité du composé à différentes phases stationnaires; d&#39;où l&#39;optimal peut être sélectionné. Le choix de l&#39;alumine de base, modifiée à activité IV, en tant que phase stationnaire appropriée a permis l&#39;isolement de certaines iodoaziridines avec un excellent rendement et de la pureté.

La procédure décrite donne le cis - (±)-2-iodo-3-(4-tolyl) -1 - (4-tolylsulfonyl) aziridine en tant que diastéréoisomère unique et avec une pureté excellente (figure 1). Avant la purification, avec un rendement de 59% du produit de iodoaziridine a été calculée par spectroscopie RMN 1 H. Toutefois, ce iodoaziridine a été particulièrement difficile à purifier et a subi une décomposition importante de silice. Une purification sur de l&#39;alumine basique (activité IV) te...

Watch this Scientific Journal Video about Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography at JoVE.com

Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography

Un protocole pour la préparation diastéréosélective d&#39;un pot de cis - N-Ts-iodoaziridines est décrite. La génération de diiodomethyllithium, plus de N-Ts aldimines et cyclisation de la gemme-diiodure intermédiaire de iodoaziridines aminé est démontrée. Il comprend également un protocole pour évaluer rapidement et quantitativement la phase stationnaire la plus appropriée pour une purification par chromatographie.

Synthèse et purification de Iodoaziridines implication quantitative de sélection de la phase stationnaire optimale pour chromatographie

The highly diastereoselective preparation of cis-N-Ts-iodoaziridines through reaction of diiodomethyllithium with N-Ts aldimines is described. ...

synthesis-purification-iodoaziridines-involving-quantitative

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Chemistry

12.4K vues.  Imperial College London.  Un protocole pour la préparation diastéréosélective d'un pot de cis - N-Ts-iodoaziridines est décrite. La génération de diiodomethyllithium, plus de N-Ts aldimines et cyclisation de la gemme-diiodure intermédiaire de iodoaziridines aminé est démontrée. Il comprend également un protocole pour évaluer rapidement et quantitativement la phase stationnaire la plus appropriée pour une purification par chromatographie. 

Vidéo: Synthesis and Purification of Iodoaziridines Involving Quantitative Selection of the Optimal Stationary Phase for Chromatography

Determination of the Gas-phase Acidities of Oligopeptides

Amino acid residues located at different positions in folded proteins often exhibit different degrees of acidities. For example, a cysteine residue located at or near the N-terminus of a helix is often more acidic than that at or near the C-terminus 1-6. Although extensive experimental studies on the acid-base properties of peptides have been carried out in the condensed phase, in particular in aqueous solutions 6-8, the results are often complicated by solvent effects 7. In fact, most of the active sites in proteins are located near the interior region where solvent effects have been minimized 9,10. In order to understand intrinsic acid-base properties of peptides and proteins, it is important to perform the studies in a solvent-free environment.
We present a method to measure the acidities of oligopeptides in the gas-phase. We use a cysteine-containing oligopeptide, Ala3CysNH2 (A3CH), as the model compound. The measurements are based on the well-established extended Cooks kinetic method (Figure 1) 11-16. The experiments are carried out using a triple-quadrupole mass spectrometer interfaced with an electrospray ionization (ESI) ion source (Figure 2). For each peptide sample, several reference acids are selected. The reference acids are structurally similar organic compounds with known gas-phase acidities. A solution of the mixture of the peptide and a reference acid is introduced into the mass spectrometer, and a gas-phase proton-bound anionic cluster of peptide-reference acid is formed. The proton-bound cluster is mass isolated and subsequently fragmented via collision-induced dissociation (CID) experiments. The resulting fragment ion abundances are analyzed using a relationship between the acidities and the cluster ion dissociation kinetics. The gas-phase acidity of the peptide is then obtained by linear regression of the thermo-kinetic plots 17,18.
The method can be applied to a variety of molecular systems, including organic compounds, amino acids and their derivatives, oligonucleotides, and oligopeptides. By comparing the gas-phase acidities measured experimentally with those values calculated for different conformers, conformational effects on the acidities can be evaluated.

The determination of the gas-phase acidities of cysteine-containing oligopeptides is described. The experiments are performed using a triple quadrupole mass spectrometer. The relative acidities of the peptides are measured using collision-induced dissociation experiments, and the quantitative acidities are determined using the extended Cooks kinetic method.

Détermination des acidités en phase gazeuse d&#39;oligopeptides

Amino acid residues located at different positions in folded proteins often exhibit different degrees of acidities. For example, a cysteine residue ...

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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.

Split-et-piscine Synthèse et caractérisation de peptides tertiaire Amide Bibliothèque

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

Quantitative Detection of Trace Explosive Vapors by Programmed Temperature Desorption Gas Chromatography-Electron Capture Detector

The direct liquid deposition of solution standards onto sorbent-filled thermal desorption tubes is used for the quantitative analysis of trace explosive vapor samples. The direct liquid deposition method yields a higher fidelity between the analysis of vapor samples and the analysis of solution standards than using separate injection methods for vapors and solutions, i.e., samples collected on vapor collection tubes and standards prepared in solution vials. Additionally, the method can account for instrumentation losses, which makes it ideal for minimizing variability and quantitative trace chemical detection. Gas chromatography with an electron capture detector is an instrumentation configuration sensitive to nitro-energetics, such as TNT and RDX, due to their relatively high electron affinity. However, vapor quantitation of these compounds is difficult without viable vapor standards. Thus, we eliminate the requirement for vapor standards by combining the sensitivity of the instrumentation with a direct liquid deposition protocol to analyze trace explosive vapor samples.

Trace explosive vapors of TNT and RDX collected on sorbent-filled thermal desorption tubes were analyzed using a programmed temperature desorption system coupled to GC with an electron capture detector. The instrumental analysis is combined with direct liquid deposition method to reduce sample variability and account for instrumentation drift and losses.

Détection quantitative des traces de vapeurs explosives par désorption à température programmée gaz Détecteur à capture d&#39;électrons-chromatographie

The direct liquid deposition of solution standards onto sorbent-filled thermal desorption tubes is used for the quantitative analysis of trace explosive ...

Supercritical Nitrogen Processing for the Purification of Reactive Porous Materials

Supercritical fluid extraction and drying methods are well established in numerous applications for the synthesis and processing of porous materials. Herein, nitrogen is presented as a novel supercritical drying fluid for specialized applications such as in the processing of reactive porous materials, where carbon dioxide and other fluids are not appropriate due to their higher chemical reactivity. Nitrogen exhibits similar physical properties in the near-critical region of its phase diagram as compared to carbon dioxide: a widely tunable density up to ~1 g ml-1, modest critical pressure (3.4 MPa), and small molecular diameter of ~3.6 &#197;. The key to achieving a high solvation power of nitrogen is to apply a processing temperature in the range of 80-150 K, where the density of nitrogen is an order of magnitude higher than at similar pressures near ambient temperature. The detailed solvation properties of nitrogen, and especially its selectivity, across a wide range of common target species of extraction still require further investigation. Herein we describe a protocol for the supercritical nitrogen processing of porous magnesium borohydride.

Nitrogen is an effective supercritical fluid for extraction or drying processes due to its small molecular size, high density in the near-liquid supercritical regime, and chemical inertness. We present a supercritical nitrogen drying protocol for the purification treatment of reactive, porous materials.

Traitement de l&#39;azote supercritique pour la purification de réactifs matériaux poreux

Supercritical fluid extraction and drying methods are well established in numerous applications for the synthesis and processing of porous materials. ...

A Quantitative Glycomics and Proteomics Combined Purification Strategy

There is a growing desire in the biological and clinical sciences to integrate and correlate multiple classes of biomolecules to unravel biology, define pathways, improve treatment, understand disease, and aid biomarker discovery. N-linked glycosylation is one of the most important and robust post-translational modifications on proteins and regulates critical cell functions such as signaling, adhesion, and enzymatic function. Analytical techniques to purify and analyze N-glycans have remained relatively static over the last decade. While accurate and effective, they commonly require significant expertise and resources. Though some high-throughput purification schemes have been developed, they have yet to find widespread adoption and often rely on the enrichment of glycopeptides. One promising method, developed by Thomas-Oates et al., filter aided N-glycan separation (FANGS), was qualitatively demonstrated on tissues. Herein, we adapted FANGS to plasma and coupled it to the individuality normalization when labeling with glycan hydrazide tags strategy in order to achieve accurate relative quantification by liquid chromatography mass spectrometry and enhanced electrospray ionization. Furthermore, we designed new functionality to the protocol by achieving tandem, shotgun proteomics and glycosylation site analysis on hen plasma. We showed that N-glycans purified on filter and derivatized by hydrophobic hydrazide tags were comparable in terms of abundance and class to those by solid phase extraction (SPE); the latter is considered a gold standard in the field. Importantly, the variability in the two protocols was not statistically different. Proteomic data that was collected in-line with glycomic data had the same depth compared to a standard trypsin digest. Peptide deamidation is minimized in the protocol, limiting non-specific deamidation detected at glycosylation motifs. This allowed for direct glycosylation site analysis, though the protocol can accommodate 18O site labeling as well. Overall, we demonstrated a new in-line high-throughput, unbiased, filter based protocol for quantitative glycomics and proteomics analysis.

A high-throughput protocol was developed for combined proteomics and glycomics purification and LC-MS/MS quantification in plasma. Deamidation analysis of N-linked glycosylation motifs was specific to deglycosylated sites. Accurate quantitation of N-glycans was achieved by coupling filter aided N-glycan separation to the individuality normalization when labeling with glycan hydrazide tags strategy.

A Quantitative Glycomics et protéomique Stratégie Purification Combined

There is a growing desire in the biological and clinical sciences to integrate and correlate multiple classes of biomolecules to unravel biology, define ...

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of trifluoromethoxylated aromatic compounds remains a formidable challenge in organic synthesis. Conventional approaches often suffer from poor substrate scope, or require use of highly toxic, difficult-to-handle, and/or thermally labile reagents. Herein, we report a user-friendly protocol for the synthesis of methyl 4-acetamido-3-(trifluoromethoxy)benzoate using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagent II). Treating methyl 4-(N-hydroxyacetamido)benzoate (1a) with Togni reagent II in the presence of a catalytic amount of cesium carbonate (Cs2CO3) in chloroform at RT afforded methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2a). This intermediate was then converted to the final product methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3a) in nitromethane at 120 &#176;C. This procedure is general and can be applied to the synthesis of a broad spectrum of ortho-trifluoromethoxylated aniline derivatives, which could serve as useful synthetic building blocks for the discovery and development of new pharmaceuticals, agrochemicals, and functional materials.

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

An operationally simple procedure for the synthesis of ortho-trifluoromethoxylated aniline derivatives via a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxyacetamide followed by thermally induced intramolecular OCF3-migration is reported.

Protocole pour la synthèse du<em&gt; Ortho</em&gt; dérivés de l&#39;aniline -trifluoromethoxylated

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of ...

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the development of antibody drug conjugates (ADCs) and nanomedicine, fluorescent microscopy and systems chemistry. For many of these applications, specificity of the bioconjugation method used is of prime concern. The Michael addition of maleimides with cysteine(s) on the target proteins is highly selective and proceeds rapidly under mild conditions, making it one of the most popular methods for protein bioconjugation.
We demonstrate here the modification of the only surface-accessible cysteine residue on yeast cytochrome c with a ruthenium(II) bisterpyridine maleimide. The protein bioconjugation is verified by gel electrophoresis and purified by aqueous-based fast protein liquid chromatography in 27% yield of isolated protein material. Structural characterization with MALDI-TOF MS and UV-Vis is then used to verify that the bioconjugation is successful. The protocol shown here is easily applicable to other cysteine - maleimide coupling of proteins to other proteins, dyes, drugs or polymers.

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

This protocol details the important steps required for the bioconjugation of a cysteine containing protein to a maleimide, including reagent purification, reaction conditions, bioconjugate purification and bioconjugate characterization.

Synthèse des bioconjugués protéiques<em&gt; via</em&gt; Cystéine-maléimide Chemistry

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the ...

Facile Synthesis of Worm-like Micelles by Visible Light Mediated Dispersion Polymerization Using Photoredox Catalyst

Presented herein is a protocol for the facile synthesis of worm-like micelles by visible light mediated dispersion polymerization. This approach begins with the synthesis of a hydrophilic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) homopolymer using reversible addition-fragmentation chain-transfer (RAFT) polymerization. Under mild visible light irradiation (&#955; = 460 nm, 0.7 mW/cm2), this macro-chain transfer agent (macro-CTA) in the presence of a ruthenium based photoredox catalyst, Ru(bpy)3Cl2 can be chain extended with a second monomer to form a well-defined block copolymer in a process known as Photoinduced Electron Transfer RAFT (PET-RAFT). When PET-RAFT is used to chain extend POEGMA with benzyl methacrylate (BzMA) in ethanol (EtOH), polymeric nanoparticles with different morphologies are formed in situ according to a polymerization-induced self-assembly (PISA) mechanism. Self-assembly into nanoparticles presenting POEGMA chains at the corona and poly(benzyl methacrylate) (PBzMA) chains in the core occurs in situ due to the growing insolubility of the PBzMA block in ethanol. Interestingly, the formation of highly pure worm-like micelles can be readily monitored by observing the onset of a highly viscous gel in situ due to nanoparticle entanglements occurring during the polymerization. This process thereby allows for a more reproducible synthesis of worm-like micelles simply by monitoring the solution viscosity during the course of the polymerization. In addition, the light stimulus can be intermittently applied in an ON/OFF manner demonstrating temporal control over the nanoparticle morphology.

This article describes a process for producing polymeric self-assembled nanoparticles using visible light mediated dispersion polymerization. Using low energy visible light to control the polymerization allows for the reproducible formation of self-assembled worm-like micelles at high solids content.

Synthèse Facile de micelles Worm-like par lumière visible Mediated Dispersion Polymérisation En utilisant photoredox Catalyst

Presented herein is a protocol for the facile synthesis of worm-like micelles by visible light mediated dispersion polymerization. This approach begins ...

Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular methodology for applications in various fields and for different research purposes. The procedure described herein focuses on the synthesis, purification, and characterization of dodecamers of RNA 5&#39;-[CUA CGG AAU CAU]-3&#39; containing zero, one, or two modifications located at the C2&#39;-O-position. The probes are based on 2-thiophenylmethyl groups, incorporated into RNA nucleotides via standard organic synthesis and introduced into the corresponding oligonucleotides via their respective phosphoramidites. This report makes use of phosphoramidite chemistry via the four canonical nucleobases (Uridine (U), Cytosine (C), Guanosine (G), Adenosine (A)), as well as 2-thiophenylmethyl functionalized nucleotides modified at the 2&#39;-O-position; however, the methodology is amenable for a large variety of modifications that have been developed over the years. The oligonucleotides were synthesized on a controlled-pore glass (CPG) support followed by cleavage from the resin and deprotection under standard conditions, i.e., a mixture of ammonia and methylamine (AMA) followed by hydrogen fluoride/triethylamine/N-methylpyrrolidinone. The corresponding oligonucleotides were purified via polyacrylamide electrophoresis (20% denaturing) followed by elution, desalting, and isolation via reversed-phase chromatography (Sep-pak, C18-column). Quantification and structural parameters were assessed via ultraviolet-visible (UV-vis) and circular dichroism (CD) photometric analysis, respectively. This report aims to serve as a resource and guide for beginner and expert researchers interested in embarking in this field. It is expected to serve as a work-in-progress as new technologies and methodologies are developed. The description of the methodologies and techniques within this document correspond to a DNA/RNA synthesizer (refurbished and purchased in 2013) that uses phosphoramidite chemistry.

Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2&#039;-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

This article provides a detailed procedure on the solid-phase synthesis, purification, and characterization of dodecamers of RNA modified at the C2&#39;-O-position. UV-vis and circular dichroism photometric analyses are used to quantify and characterize structural aspects, i.e., single-strands or double-strands.

Protocole pour la synthèse en phase solide d&#39;oligomères d&#39;ARN contenant un 2&#39;-<em&gt; O</em&gt; -thiophénylméthyle Modification et caractérisation via le dichlorisme circulaire

Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular ...

Synthesis and Mass Spectrometry Analysis of Oligo-peptoids

Peptoids are sequence-controlled peptide-mimicking oligomers consisting of N-alkylated glycine units. Among many potential applications, peptoids have been thought of as a type of molecular information storage. Mass spectrometry analysis has been considered the method of choice for sequencing peptoids. Peptoids can be synthesized via solid phase chemistry using a repeating two-step reaction cycle. Here we present a method to manually synthesize oligo-peptoids and to analyze the sequence of the peptoids using tandem mass spectrometry (MS/MS) techniques. The sample peptoid is a nonamer consisting of alternating N-(2-methyloxyethyl)glycine (Nme) and N-(2-phenylethyl)glycine (Npe), as well as an N-(2-aminoethyl)glycine (Nae) at the N-terminus. The sequence formula of the peptoid is Ac-Nae-(Npe-Nme)4-NH2, where Ac is the acetyl group. The synthesis takes place in a commercially available solid-phase reaction vessel. The rink amide resin is used as the solid support to yield the peptoid with an amide group at the C-terminus. The resulting peptoid product is subjected to sequence analysis using a triple-quadrupole mass spectrometer coupled to an electrospray ionization source. The MS/MS measurement produces a spectrum of fragment ions resulting from the dissociation of charged peptoid. The fragment ions are sorted out based on the values of their mass-to-charge ratio (m/z). The m/z values of the fragment ions are compared against the nominal masses of theoretically predicted fragment ions, according to the scheme of peptoid fragmentation. The analysis generates a fragmentation pattern of the charged peptoid. The fragmentation pattern is correlated to the monomer sequence of the neutral peptoid. In this regard, MS analysis reads out the sequence information of the peptoids.

A protocol is described for the manual synthesis of oligo-peptoids followed by sequence analysis by mass spectrometry.

Synthèse et analyse de spectrométrie de masse des Oligo-peptoids

Peptoids are sequence-controlled peptide-mimicking oligomers consisting of N-alkylated glycine units. Among many potential applications, peptoids have ...