DOCSLIB.ORG

Pyoxp and Pyoxb: the Oxyma-Based Novel Family of Phosphonium Salts†

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pyoxp and Pyoxb: the Oxyma-Based Novel Family of Phosphonium Salts† View Online PAPER www.rsc.org/obc | Organic & Biomolecular Chemistry PyOxP and PyOxB: the Oxyma-based novel family of phosphonium salts† Ramon Subiros-Funosas,´ a,b Ayman El-Faham*a,c,d and Fernando Albericio*a,b,e Received 12th March 2010, Accepted 19th May 2010 First published as an Advance Article on the web 17th June 2010 DOI: 10.1039/c003719b Recent studies described the great impact of a non-benzotriazolic family of coupling reagents based on ethyl 2-cyano-2-(hydroxyimino)acetate, Oxyma, as a powerful coupling methodology for peptide synthesis. Here we present the synthesis and evaluation of the derived phosphonium salts O-[(1-cyano-2-ethoxy-2-oxoethylidene)amino]-oxytri(pyrrolidin-1-yl) phosphonium hexafluorophosphate (PyOxP) and tetrafluoroborate (PyOxB). Both coupling reagents exhibited higher capacity to suppress racemization in various peptide models and enhanced solubility in DMF and DCM than benzotriazole-based reagents. In addition, the hexafluorophosphate analog PyOxP, combined excellent stability with outstanding efficiency in the assembly of demanding penta and decapeptides that include consecutive Aib residues. Cyclization models revealed the advantages of PyOxP, which rendered a higher percentage of cyclic material than other known potent phosphonium salts. Introduction side reactions, usually during slow couplings, such as cyclizations or in the introduction of hindered residues. In these situations, an Success in peptide synthesis is highly dependent on the coupling excess of such a coupling reagent usually causes the attachment of 1,2 strategy used to form the peptide bond. Traditionally, carbodi- a guanidine moiety to the free N-terminus of the growing peptide imides were considered an efficient approach to assemble low chain, thereby blocking any further reaction.11 Moreover, these to moderate sequences, in consumption with additives (HOBt 1, reagents are costly for peptide synthesis purposes. Phosphonium HOAt 2 and 6-Cl–HOBt 3; Fig. 1 left), which lower the likelihood salts differ from the former in the nature of the electrophilic 3–5 of racemization and other side reactions. However, the need for core as they have a positively charged phosphorus center and stronger activating reagents led to the introduction of stand-alone they do not undergo the above mentioned termination of the onium salts (mainly aminium/uronium and phosphonium ones), peptide chain when added in excess. Thus phosphonium salts which have become the preferred coupling choice in solution- and show similar potency to their aminium/uronium counterparts.12 Downloaded by Universitat de Barcelona on 30 June 2011 6 solid-phase peptide synthesis. These types of onium salts were first introduced by Kenner Published on 17 June 2010 http://pubs.rsc.org | doi:10.1039/C003719B The most powerful onium salts are the aminium/uronium and coworkers in 1969, although they did not gain general ones. Their structure comprises a carbocation skeleton and an acceptance until the 1990s, when many became commercially additive, usually benzotriazole-based (HATU 4, HBTU 5/TBTU available.13 The most predominant phosphonium salts display a 7–9 6,HCTU7/TCTU 8; Fig. 1 center). The tetramethylamino tris(pyrrolidino)phosphonium-type electrophilic core (PyAOP 12, group included in the carbocation skeleton of these classical PyBOP 13, PyClock, 14;Fig.2)14–16 while their tris(dimethylamino) coupling reagents has recently evolved to a dimethylmorpholino analogs, of which BOP is the most representative, are slightly less 10 moiety (HDMA 9, HDMB 10, 6-Cl–HDMB 11;Fig.1right), reactive and also originate HMPA as a byproduct, which is a thereby resulting in improved stability and solubility in common carcinogenic and toxic phosphoramide.17–19 solvents used in peptide synthesis, as well as an increase in In both classes of onium salts, aminium/uronium and phos- optical purity and reactivity. The high reactivity of both types phonium, the same trend is observed: HOAt (2)analogsshowed of aminium/uronium salts may also lead to the appearance of superiority to HOBt (1) and 6-Cl–HOBt (3) ones in activation and coupling steps and also in reducing the loss of optical a Institute for Research in Biomedicine, Barcelona Science Park, purity.12 In addition, derivatives of 6-Cl–HOBt (3) are generally Baldiri Reixac 10, 08028, Barcelona, Spain. E-mail: aymanel_faham@ 9 hotmail.com, [email protected]; Fax: +34 93-403-71-26; Tel: +34 less hazardous and more reactive than HOBt (1) counterparts. 93-403-70-88 This relative performance is connected to the acidity of the bCIBER-BBN, Networking Centre on Bioengineering, Biomaterials and additive, which is linked to the reactivity of the corresponding Nanomedicine Barcelona Science Park, Baldiri Reixac 10, 08028, Barcelona, active ester. Therefore, PyAOP (12) is considered the most reactive Spain phosphonium salt (pK of HOAt=3.28), whereas PyClock (14)is cDepartment of Chemistry, College of Science, King Saud University, a P.O. Box 2455, Riyadh, 11451, Kingdom of Saudi Arabia a good alternative to PyBOP (13), because the presence of Cl at dDepartment of Chemistry, Faculty of Science, Alexandria University, position 6 of the benzotriazole ring results in a better leaving group 20 Ibrahimia, 21321, Alexandria, Egypt (pK a of 6-Cl–HOBt=3.35 vs. pK a of HOBt=4.60). However, eDepartment of Organic Chemistry, University of Barcelona, Mart´ıi additional factors contribute to the great difference in reactivity. Franques´ 1-11, 08028, Barcelona, Spain Thus, it has been proposed that the nitrogen at the 7-position † Electronic supplementary information (ESI) available: 1Hand13C-NMR spectra for PyOxP and PyOxB, and HPLC characterization of racemiza- of HOAt creates a neighboring group effect, which results in tion and coupling efficiency experiments. See DOI: 10.1039/c003719b enhanced reactivity and solubility of its analogs. This journal is © The Royal Society of Chemistry 2010 Org. Biomol. Chem., 2010, 8, 3665–3673 | 3665 View Online Fig. 1 Benzotriazole-based additives (left), tetramethyl (center) and dimethylmorpholino (right) aminium salts. was not tested.26 In the present study, we compared the capacity of O-[(cyano-(ethoxycarbonyl)methyliden)-amino]- yloxytripyrrolidinophosphonium hexafluorophosphate and tetrafluoroborate (PyOxP 17 and PyOxB 18,Fig.4)tolower racemization and enhance coupling extension in linear and cyclic peptide models with the abovementioned benzotriazole-based phosphonium salts PyAOP (12), PyBOP (13) and PyClock (14). Fig. 2 Benzotriazole-based phosphonium salts. Recently, we reported ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma 15, Fig. 3) and its derived uronium salt 1-[(1- (cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino- morpholinomethylene)] methanaminium hexafluorophosphate (COMU 16, Fig. 3) as efficient additive and coupling reagent Downloaded by Universitat de Barcelona on 30 June 2011 21,22 for peptide synthesis. The active esters formed by these Fig. 4 Structure of the hexafluorophosphate and tetrafluoroborate Published on 17 June 2010 http://pubs.rsc.org | doi:10.1039/C003719B reagents are extremely reactive due to the low hindrance and tris(pyrrolidino)phosphonium salts derived from Oxyma. acidity of Oxyma (pK a = 4.60), which results in an excellent leaving group.23 Oxyma (15) and COMU (16) show superiority to HOBt (1) derivatives and a similar or even higher potency than Results and discussion HOAt (2) analogs in suppressing racemization and assembling demanding peptide models. In terms of safety, 15 and 16 also have The Oxyma-based phosphonium salts PyOxP (17) and PyOxB a considerably lower risk of explosion than benzotriazole-based (18) were successfully synthesized in one-pot fashion from Oxyma reagents and are compatible with microwave irradiation.24,25 (15) (Scheme 1). The first step consisted of the rapid formation of the intermediate potassium salt of the oxime with potassium carbonate (K2CO3) after 10 min of gently stirring. Subsequent addition of PyBroP or the analogous tetrafluoroborate salt to the reaction mixture afforded, after 4 h, the desired phosphonium salts 17 and 18, in 76% yield after recrystallization from DCM–hexane. Previous formation of the potassium salt is preferred over the addition of a tertiary base to Oxyma (15), like Et3N, to generate + - the anion, since this method yields Et3N Br , which is difficult to separate from the desired phosphonium salt. Fig. 3 Oxyma and its derived uronium salt, COMU. The stability of phosphonium salts is a basic feature for their optimal performance in peptide synthesis, since they are predom- In view of these outstanding results, the next step was to inantly used in slow-rate couplings, specially cyclizations, and include Oxyma (15) in a tris(pyrrolidino)-type phosphonium therefore a rapid hydrolysis of the reagent dramatically decreases salt, in both hexafluorophosphate and tetrafluoroborate their efficiency. In order to check and compare the stability of the forms. The synthesis and structure determination of the proposed oxime-based phosphonium salts with their benzotriazole hexafluorophosphate version was accomplished by Hoffmann counterparts, we conducted hydrolysis experiments in an NMR et al. in 2003, although its suitability as a coupling reagent tube (3 days in acetone) and in an open vial (5 days in DMF) 3666 | Org. Biomol. Chem., 2010, 8, 3665–3673 This journal is © The Royal Society of Chemistry 2010 View Online Scheme 1 Table 1 Hydrolytic stability (%) of phosphonium salts during NMR and Table 2 Solubility of phosphonium salts in DMF and DCM HPLC assays DMF DCM Method of analysis Entry Coupling Reagent Wt/g mL-1 Molarity Wt/g mL-1 Molarity Entry Coupling Reagent NMR, 3 days (%)a HPLC, 5 h (%)b 1 PyAOP (12) 1.04 1.99 0.92 1.79 1 PyAOP (12)1029 2 PyBOP (13) 0.80 1.54 0.64 1.23 2 PyBOP (13)2039 3 PyClock (14) 0.80 1.44 0.40 0.72 3 PyClock (14)50 35 4 PyOxP (17) 1.36 2.58 1.04 1.97 4 PyOxP (17)6040 5 PyOxB (18) 1.52 3.24 1.32 2.82 5 PyOxB (18)3025 a The samples were dissolved in acetone-d6 and placed in an NMR tube (closed vial).
Load more

Recommended publications
  • Amide Bond Formation and Peptide Coupling
    Tetrahedron 61 (2005) 10827–10852 Tetrahedron report number 740 Amide bond formation and peptide coupling Christian A. G. N. Montalbetti* and Virginie Falque Evotec, 112 Milton Park, Abingdon OX14 4SD, UK Received 2 August 2005 Available online 19 September 2005 Contents 1. Introduction ................................................................. 10828 2. Amide bond formation: methods and strategies ....................................... 10828 2.1. Acyl halides . .......................................................... 10829 2.1.1. Acyl chlorides .................................................... 10829 2.1.1.1. Acyl chloride formation ...................................... 10829 2.1.1.2. Coupling reactions with acyl chlorides ........................... 10831 2.1.1.3. Limitations of acyl chlorides .................................. 10831 2.1.2. Acyl fluorides .................................................... 10831 2.1.3. Acyl bromides .................................................... 10832 2.2. Acyl azides . .......................................................... 10832 2.3. Acylimidazoles using CDI ................................................. 10833 2.4. Anhydrides . .......................................................... 10834 2.4.1. Symmetric anhydrides .............................................. 10834 2.4.2. Mixed anhydrides .................................................. 10834 2.4.2.1. Mixed carboxylic anhydrides .................................. 10834 2.4.2.2. Mixed carbonic anhydrides ...................................
    [Show full text]
  • Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis
    molecules Article Sustainable Triazine-Based Dehydro-Condensation Agents for Amide Synthesis Roberto Sole 1 , Vanessa Gatto 2 , Silvia Conca 1 , Noemi Bardella 1, Andrea Morandini 1 and Valentina Beghetto 1,2,* 1 Dipartimento di Scienze Molecolari e Nanosistemi, Università Ca’ Foscari di Venezia, Via Torino 155, 30172 Venezia, Italy; [email protected] (R.S.); [email protected] (S.C.); [email protected] (N.B.); [email protected] (A.M.) 2 Crossing srl, Viale della Repubblica 193/b, 31100 Treviso, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-041-2348928 Abstract: Conventional methods employed today for the synthesis of amides often lack of economic and environmental sustainability. Triazine-derived quaternary ammonium salts, e.g., 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM(Cl)), emerged as promising dehydro-condensation agents for amide synthesis, although suffering of limited stability and high costs. In the present work, a simple protocol for the synthesis of amides mediated by 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a tert-amine has been described and data are compared to DMTMM(Cl) and other CDMT-derived quaternary ammonium salts (DMT-Ams(X), X: − − Cl or ClO4 ). Different tert-amines (Ams) were tested for the synthesis of various DMT-Ams(Cl), but only DMTMM(Cl) could be isolated and employed for dehydro-condensation reactions, while all CDMT/tert-amine systems tested were efficient as dehydro-condensation agents. Interestingly, in best reaction conditions, CDMT and 1,4-dimethylpiperazine gave N-phenethyl benzamide in 93% yield in 15 min, with up to half the amount of tert-amine consumption.
    [Show full text]
  • Application in Solution Peptide Synthesis
    Molecules 2010, 15, 9403-9417; doi:10.3390/molecules15129403 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Article Synthesis of 2-(4,6-Dimethoxy-1,3,5-triazin-2-yloxyimino) Derivatives: Application in Solution Peptide Synthesis Tarfah I. Al-Warhi 1,*, Hassan M.A. AL-Hazimi 2, Ayman El-Faham 2,3 and Fernando Albericio 4,5,6 1 Women Students-Medical Studies and Sciences Sections, Chemistry Department, College of Science, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia 2 Chemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia 3 Chemistry Department, Faculty of Science, Alexandria University, 426 Ibrahimia, 21321 Alexandria, Egypt 4 Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, Barcelona 08028, Spain 5 CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, Barcelona 08028, Spain 6 Department of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11, Barcelona 08028, Spain * Author to whom correspondence should be addressed; E-Mail: [email protected]. Received: 29 November 2010; in revised form: 14 December 2010 / Accepted: 15 December 2010 / Published: 20 December 2010 Abstract: A new class of 1,3,5-triazinyloxyimino derivatives were prepared, characterized and tested for reactivity in solution peptide synthesis. The new triazinyloxyimino derivatives failed to activate the carboxyl group during formation of peptide bonds, but gave the corresponding N-triazinyl amino acid derivatives as a major product. The oxyma (ethyl 2-cyano-2-(hydroxyimino)acetate) uronium salt was superior to other uronium salts in terms of racemization, while 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 9) gave the best results.
    [Show full text]
  • Coupling Additives 3
    Issue in Honor of Drs. Cynthia A. and Bruce E. Maryanoff ARKIVOC 2010 (viii) 189-250 Evolution of amide bond formation Madeleine M. Joullié and Kenneth M. Lassen Department of Chemistry , University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, U. S. A. E-mail: [email protected] This paper is dedicated to Drs Bruce E. Maryanoff and Cynthia A. Maryanoff for their outstanding contribution to organic chemistry as industrial chemists Abstract The presence of carboxamide groups is found in a large array of biologically important compounds. Peptides and proteins play an important role in modern biology. A key step in peptide production is the formation of the peptide bond, which involves amide bond formation. Chemical synthesis of large peptides by intermolecular coupling of smaller peptides using conventional peptide bond-forming techniques did not realize its potential advantages until recently. Using an approach based on highly specific and efficient chemical ligation of two peptide segments, the two subunits were ligated to form a new peptide bond. Native chemical ligation extended the concept by creating a native peptide bond and providing new approaches to protein engineering. Keywords: Amide bond formation, coupling reagent, peptide, chemical ligation, native chemical ligation Table of Contents Introduction 1. Amide Bond Formation 1.1. Approaches to amide bond formation 1.2. Racemization 2. Coupling Additives 3. Common Coupling Reagents 3.1. Azides 3.2. Active esters 3.3. Acyl halides 3.4. Anhydrides ISSN 1551-7012 Page 189 ©ARKAT USA, Inc. Issue in Honor of Drs. Cynthia A. and Bruce E. Maryanoff ARKIVOC 2010 (viii) 189-250 3.5.
    [Show full text]
  • Evolution of Amide Bond Formation
    Issue in Honor of Drs. Cynthia A. and Bruce E. Maryanoff ARKIVOC 2010 (viii) 189-250 Evolution of amide bond formation Madeleine M. Joullié and Kenneth M. Lassen Department of Chemistry , University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, U. S. A. E-mail: [email protected] This paper is dedicated to Drs Bruce E. Maryanoff and Cynthia A. Maryanoff for their outstanding contribution to organic chemistry as industrial chemists DOI: http://dx.doi.org/10.3998/ark.5550190.0011.816 Abstract The presence of carboxamide groups is found in a large array of biologically important compounds. Peptides and proteins play an important role in modern biology. A key step in peptide production is the formation of the peptide bond, which involves amide bond formation. Chemical synthesis of large peptides by intermolecular coupling of smaller peptides using conventional peptide bond-forming techniques did not realize its potential advantages until recently. Using an approach based on highly specific and efficient chemical ligation of two peptide segments, the two subunits were ligated to form a new peptide bond. Native chemical ligation extended the concept by creating a native peptide bond and providing new approaches to protein engineering. Keywords: Amide bond formation, coupling reagent, peptide, chemical ligation, native chemical ligation Table of Contents Introduction 1. Amide Bond Formation 1.1. Approaches to amide bond formation 1.2. Racemization 2. Coupling Additives 3. Common Coupling Reagents 3.1. Azides 3.2. Active esters ISSN 1551-7012 Page 189 ARKAT USA, Inc. Issue in Honor of Drs. Cynthia A. and Bruce E.
    [Show full text]
  • The Effects of Nacl on the Triple Helix Structure of Collagen and the Reinforcement of Tung Oil-Based Polymers with Collagen Peptides
    Georgia Southern University Digital Commons@Georgia Southern Electronic Theses and Dissertations Graduate Studies, Jack N. Averitt College of Spring 2021 The Effects of NaCl on the Triple Helix Structure of Collagen and the Reinforcement of Tung oil-based Polymers with Collagen Peptides Christopher Dzorkpata Follow this and additional works at: https://digitalcommons.georgiasouthern.edu/etd Part of the Materials Chemistry Commons Recommended Citation Dzorkpata, Christopher, "The Effects of NaCl on the Triple Helix Structure of Collagen and the Reinforcement of Tung oil-based Polymers with Collagen Peptides" (2021). Electronic Theses and Dissertations. 2261. https://digitalcommons.georgiasouthern.edu/etd/2261 This thesis (open access) is brought to you for free and open access by the Graduate Studies, Jack N. Averitt College of at Digital Commons@Georgia Southern. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Digital Commons@Georgia Southern. For more information, please contact [email protected]. THE EFFECTS OF NaCl ON THE TRIPLE HELIX STRUCTURE OF COLLAGEN, AND THE REINFORCEMENT OF TUNG OIL-BASED POLYMERS WITH COLLAGEN PEPTIDES by CHRISTOPHER DZORKPATA (Under the Direction of Rafael L. Quirino) ABSTRACT In this research, a collagen-reinforced bio-composite from tung oil was prepared using free radical initiation and thermal polymerization, leading to polyolefinic tung oil-based matrix. Two peptides (long and short) were synthesized and their secondary features were analyzed using circular dichroism spectroscopy. After this analysis, the long peptide exhibited more triple helix characteristics as compared to the short peptide. The full protein will ultimately have a better interaction with the tung oil, was used in the synthesis of the collagen-reinforced bio-composite.
    [Show full text]
  • Cross-Linking and Chromatography Derivatization Reagents Ontology
    XLMOD: Cross-linking and chromatography derivatization reagents ontology Authors: Gerhard Mayer1 1 Ruhr University Bochum, Faculty of Medicine, Medizinisches Proteom-Center, D-44801 Bochum, Germany Abbreviations: CID Collision Induced Dissociation CV Controlled Vocabulary CX-MS Cross-Linking-Mass Spectrometry Da Dalton (atomic mass unit) ESI ElectroSpray Ionization HUPO-PSI HUman Proteome Organization – Proteomics Standards Initiative IUPAC International Union of Pure and Applied Chemistry InChI International Chemical Identifier MS Mass Spectrometry NMR Nuclear Magnetic Resonance SMILES Simplified Molecular Input Line Entry Specification XRC X-Ray Crystallography Summary/Abstract: Mass spectrometry has experienced a rapid development since its first application for protein analysis in the 1980s. While the most common use of mass spectrometry for protein analysis is identification and quantification workflows on peptides (digested from their parent protein), there is also a rapidly growing use of mass spectrometry for “structural proteomics”. One example is the analysis of cross-linked proteins that can give valuable structural information, complementing the information gained by classical protein structure determination methods, useful for integrated methods of structure determination and modeling. For a broad and reproducible application of cross-linking mass spectrometry a standardized representation of cross-linking experimental results is necessary. This paper describes the developing and release of the xlmod ontology from the HUPO-PSI. xlmod contains terms for the description of reagents used in cross-linking experiments and of cross-linker related chemical modifications together with their main properties relevant for planning and performing cross-linking experiments. We also describe how xlmod is used within the new release of HUPO-PSI’s mzIdentML data standard, for reporting the used cross-linking reagents and results in a consistent manner.
    [Show full text]
  • Industrial Application of Coupling Reagents in Peptides
    Industrial application of coupling reagents in peptides OLEG MARDER 1 FERNANDO ALBERICIO 2,3 ABSTRACT In the actual pharmaceutical market, peptides Peptides play a key role in the post-genomic and are not only considered as hormones, as in the PEPTIDES proteomic era. From an industrial basis, the past, but also as active pharmaceutical formation of the amide bond is crucial for ingredients (API), in antibiotics, antiviral and in obtaining an efficient and economic process. other therapeutic areas such as cancer as Mechanisms associated with the different methods immunomodulators and anti-angiogenesis agents, are reviewed. Cl-HOBt as additive and CNS and neurogogical disorders as analgetics HCTU/TCTU are excellent alternatives to the most and anti-obesity drugs, immune disorders for the classic coupling methods. treatment of allergy, asthma and autoimmune disease (1). Furthermore, over 200 new peptide-based drugs are under different stages of development with INTRODUCTION 50% of them under clinical trials and prior to approval (2). Nowadays, peptides represent 1% of There is no doubt that the last years are recognised total API with a market of US$ 300-500 M per year as the renaissance of the peptide world. The and a growth rate of 15-25% annually (1), with the important advances in molecular biology and gene expectation of a 100% increase in the next two technology are bringing significant changes in years when generic and recently approved new biomedical sciences. The elucidation of the human chemical entities enter the market (3). This is genome, followed by advancements in functional reflected by the fact that over ten known bulk genomics and proteomics, will revolutionize our peptide producers and over twenty companies are understanding of the detailed molecular offering custom peptides synthesis and these mechanisms, underlying a broad spectrum of numbers, as well as capacity are growing (4).
    [Show full text]
  • Peptide Coupling Reagents, More Than a Letter Soup Ayman El-Faham*,†,‡ and Fernando Albericio*,†,§,||
    REVIEW pubs.acs.org/CR Peptide Coupling Reagents, More than a Letter Soup Ayman El-Faham*,†,‡ and Fernando Albericio*,†,§,|| † Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain ‡ Alexandria University, Faculty of Science, Department of Chemistry, P.O. Box 426, Ibrahimia, 21321 Alexandria, Egypt §CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain. Department) of Organic Chemistry, University of Barcelona, Martí i Franques 1-11, 08028-Barcelona, Spain CONTENTS 7.1.2. Triazine Chlorinating Reagents 6568 À 1. Introduction 6558 7.1.3. Triphenylphosphine CCl4 6568 R 2. Carbodiimide-Mediated Reactions 6559 7.1.4. Tetramethyl- -chloroenamine Chlorinat- 2.1. Carbodiimides 6559 ing Reagents 6568 2.2. Carbodiimides and Additives 6559 7.1.5. Bis(trichloromethyl)carbonate Chlorinat- 3. Anhydrides 6562 ing Reagents 6568 3.1. Symmetric Anhydrides 6562 7.1.6. Coupling Reactions with Acyl Chlorides 6568 3.2. Mixed Anhydrides 6562 7.2. Acid Fluorides 6568 3.2.1. Mixed Carbonic Anhydrides 6562 7.2.1. Fluorinating Reagents 6569 3.2.1.1. Chorofor-mate-Mediated Reaction 6562 8. Phosphonium Salts 6570 3.2.1.2. 2-Ethoxy-1-ethoxycarbonyl- 8.1. HOBt Phosphonium Salt Derivatives 6571 1,2-dihydroquinoline (EDDQ)-Mediated 8.1.1. BOP Coupling Reagent 6571 Reaction 6562 8.1.2. PyBOP Coupling Reagent 6571 3.2.2. Cyclic Anhydrides 6562 8.2. HOAt Phosphonium Salt Derivatives 6571 4. Active Esters 6563 8.3. Oxyma-Based Phosphonium Salts 6571 4.1. Procedure for the Preparation of Active Ester 6564 8.4.
    [Show full text]
  • Syntheses and Applications of Small Molecule Inhibitors of Mirnas Mir-21 and Mir-122
    Syntheses and applications of small molecule inhibitors of miRNAs miR-21 and miR-122 by Méryl Thomas Bachelor of sciences, ESCPE Lyon, 2009 Master degree, ESCPE Lyon, 2012 Submitted to the Graduate Faculty of the Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2015 UNIVERSITY OF PITTSBURGH Dietrich School of Arts and Sciences This thesis was presented by Méryl Thomas It was defended on July 24th, 2015 and approved by Dr. Andrew W. Duncan, Assistant Professor, Department of Pathology Dr. Seth Horne, Associate Professor, Department of Chemistry Dr. Kabirul Islam, Assistant Professor, Department of Chemistry Committee Chair: Dr. Alexander Deiters, Professor, Department of Chemistry ii Copyright © by Méryl Thomas 2015 iii Syntheses and applications of small molecule inhibitors of miRNA miR-21 and miR-122 Méryl Thomas, PhD University of Pittsburgh, 2015 MicroRNAs (miRNAs) are regulatory RNA molecules of 22 nucleotides that (in part) control up to 60% of all genes in humans. They act by binding to the 3' untranslated regions of target messenger RNAs, leading either to translational repression or mRNA degradation. In addition to being involved in the regulation of several fundamental cellular processes, the misregulation of miRNAs has been linked to a wide range of diseases including cancer. Particularly, miR-21 is significantly upregulated in nearly all types of human cancers, and its overexpression is often associated with poor prognosis. The downregulation of miR-122 is found in more than 70% of hepatocellular carcinoma cases and miR-122 is a required factor for the replication of the HCV virus.
    [Show full text]
  • UC Berkeley UC Berkeley Electronic Theses and Dissertations
    UC Berkeley UC Berkeley Electronic Theses and Dissertations Title Heterocycles Old and New: Carbonylazoles as Chemoselective Acylation Reagents and the Synthesis and Applications of Benzindolizinones Permalink https://escholarship.org/uc/item/3k03p8kt Author Heller, Stephen Todd Publication Date 2012 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California Heterocycles Old and New: Carbonylazoles as Chemoselective Acylation Reagents and the Synthesis and Applications of Benzindolizinones by Stephen Todd Heller A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Richmond Sarpong, Chair Professor Robert G. Bergman Professor Daniel Nomura Fall 2012 1 Abstract Heterocycles Old and New: Carbonylazoles as Chemoselective Acylation Reagents and the Synthesis and Applications of Benzindolizinones By Stephen Todd Heller Doctor of Philosophy in Chemistry University of California, Berkeley Professor Richmond Sarpong, Chair Carbonylazole derivatives have been shown to be chemoselective and efficient acylating reagents under a variety of conditions. Catalysis with pyridinium salts, as well as with DBU or DABCO are discussed, as is the thermal reaction of imidazole carbamates with carboxylic acids to provide esters. The application of a protic solvent-mediated cycloisomerization approach to two isomers of benzindolizinone – a relatively unstudied heterocyclic system – and the syntheses of two Erythrina alkaloids are also discussed. Chapter 1 provides an overview of the fundamental importance of the carbonyl group in the chemistry of life, as well as in the service of man. Key processes through which these versatile groups react are illustrated with an emphasis on the chemistry of esters.
    [Show full text]
  • Screening of N-Alkyl-Cyanoacetamido Oximes As Substitutes for N-Hydroxysuccinimide Sherine N
    DOI: 10.1002/open.201200012 Screening of N-Alkyl-Cyanoacetamido Oximes as Substitutes for N-Hydroxysuccinimide Sherine N. Khattab,[a] Ramon Subirs-Funosas,[b, c] Ayman El-Faham,*[a, b, d] and Fernando Albericio*[b, c, e, f] Peptide-bond formation is a pivotal process in the synthesis of (HOSu) esters, are often required to obtain stability under peptide oligomers. Among the various coupling methodolo- aqueous conditions. In the present study, we report on a new gies described, carbodiimides combine strong acylation poten- family of water-soluble N-alkyl-cyanoacetamido oximes, most cy and smooth reaction conditions, and they are commonly of which have proven useful in the construction of active car- used in the presence of N-hydroxylamine additives. In recent bonates for the introduction of fluorenylmethoxycarbonyl years, acidic oxime templates, mainly ethyl 2-cyano-2-(hydrox- (Fmoc) with minimal impact of dipeptide impurities. We per- yimino) acetate (Oxyma), have emerged as highly reactive al- formed a direct comparison of these new N-alkyl-cyanoaceta- ternatives to the classic and explosive-prone benzotriazolic ad- mido oximes with HOSu in order to evaluate their capacity to ditives, 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-aza- retain optical purity and their coupling efficiency in the assem- benzotriazole (HOAt). However, to achieve certain biochemical bly of bulky residues. targets, less reactive species, such as N-hydroxysuccinimide Introduction The choice of the active acylating species used to form a pep- strongly acidic oxime, ethyl 2-cyano-2-(hydroxyimino)acetate tide bond is crucial in peptide synthesis.[1–4] Highly reactive (Oxyma, 3) as a potential replacement, which represented moieties, such as acid halides, are suitable to acylate very poor a hallmark in the field.[16,17] nucleophilic amines.
    [Show full text]