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Modified Amino Acids Synthesis and Applications

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Modified Amino Acids Synthesis and Applications MODIFIED AMINO ACIDS: SYNTHESIS AND APPLICATIONS Stefania Capone Dottorato in Scienze Biotecnologiche – XVIII ciclo Indirizzo Biotecnologie Industriali Università di Napoli Federico II Dottorato in Scienze Biotecnologiche – XVIII ciclo Indirizzo Biotecnologie Industriali Università di Napoli Federico II MODIFIED AMINO ACIDS: SYNTHESIS AND APPLICATIONS Stefania Capone Dottoranda: Stefania Capone Relatore: Prof. Romualdo Caputo Coordinatore: Prof. Gennaro Marino A mio fratello e ai miei genitori. Part of this thesis published 1. Publications • Capone, S.; Guaragna, A.; Palumbo, G.; Pedatella, S. Efficient synthesis of orthogonally protected anti-2,3-diamino acids Tetrahedron 2005, 61, 6575. 2. Poster Presentations • Sintesi stereoselettiva di 2,3-diamminoacidi, Stefania Capone, Romualdo Caputo, Giovanni Palumbo, Silvana Pedatella. XXVIII Corso Estivo di Sintesi in Chimica Organica “A. Corbella”, Gargnano (Italy), June 16th-20th, 2003. • Synthesis of dipeptide taste ligands containing β2,3-disubstituted amino acids: mimics of aspartame, Stefania Capone, Romualdo Caputo, Annalisa Guaragna, Giovanni Palumbo, Silvana Pedatella. XXIX Corso Estivo di Sintesi in Chimica Organica “A. Corbella”, Gargnano (Italy), June 14th-18th, 2004. • β2- and β2,2- long chain substituted amino acids towards amphiphilic peptides. Stefania Capone, Romualdo Caputo, Annalisa Guaragna, Giovanni Palumbo Silvana Pedatella. Ischia Advanced School of Organic Chemistry 2004, Ischia (Italy), September 18th-23th, 2004 (selected for oral presentation). • Una facile sintesi di sin- e anti-β2,3-ammino acidi enantiopuri, Adele Bolognese, Stefania Capone, Romualdo Caputo, Antonio Lavecchia, Luigi Longobardo, Ettore Novellino, Antonello Santini, Angela Tuzi. Giornate Scientifiche Interpolo - Polo delle Scienze e delle Tecnologie per la Vita - Polo delle Scienze e delle Tecnologie, Napoli (Italy), May 26th-27th, 2005. • Synthetic efforts towards oligomers of amino acids bearing two hexadecyl or two arginine side chains for cell-wall interaction and cell penetration. Albert. K. Beck; Stefania Capone, Romualdo Caputo, Dieter Seebach. FEBS Summer School – Chemistry Meets Biology, Spetses Island (Greece), July 17th-29th, 2005. 3. Oral Presentations • β2- and β2,2- long chain substituted amino acids towards amphiphilic peptides. Ischia Advanced School of Organic Chemistry 2004, Ischia (Italy), September 18th-23th, 2004. Ringraziamenti Al termine di questa esperienza di ricerca, studio e lavoro, desidero ringraziare tutti coloro che hanno reso possibile questa impresa. Ringrazio in modo particolare il mio supervisore, Prof Romualdo Caputo, per avermi incoraggiata ad affrontare un argomento innegabilmente interessante, per le numerose discussioni e gli utili consigli. Ringrazio il Prof Giovanni Palumbo per aver messo a mia disposizione la sua grande esperienza. La Dott.sa Silvana Pedatella e la Dott.sa Annalisa Guaragna per aver contribuito in maniera determinante alla realizzazione di questo lavoro e per l’amicizia sempre mostrata. Il Dott. Mauro De Nisco per il contributo offertomi con i calcoli di dinamica molecolare. Sara Auriemma, Guido Smiraglia, Gianluca Varriale e Maria Piscitelli: gli studenti che hanno collaborato con me in questi anni e che con il loro lavoro di tesi di laurea hanno contribuito significativamente ad alcuni dei risultati discussi in questa Tesi. Tutti coloro che hanno fatto parte o fanno ancora parte dell’ex gruppo CTS, ora gruppo DSB, per aver reso indimenticabili e irripetibili gli anni trascorsi insieme. Sono grata al Prof Giovanni Sannia oltre che per i suggerimenti e le critiche costruttive, soprattutto per la fiducia che ha sempre riposto in me e nelle mie capacità. Sono inoltre grata al Prof Dieter Seebach per avermi fatto trascorrere presso il Dipartimento di Chimica Organica dell’ETH di Zurigo un proficuo periodo di studio e lavoro. Con lui tutto il suo gruppo per la collaborazione e l’amicizia mostratami in quel periodo. Un ringraziamento particolare va a Giulio, per essere riuscito a starmi vicino nel momento delicatissimo della stesura di questa tesi. Un grazie di cuore anche ai miei genitori per i tanti anni di sostegno incondizionato e per aver sempre mostrato una fiducia cieca e priva di incertezze per quello che faccio, spronandomi sempre ad andare avanti per la mia strada. Infine tutti coloro che, in veste ufficiale o non ufficiale, reggono la struttura del Dottorato di Ricerca in Scienze Biotecnologiche dell’università di Napoli. Table of Contents Table of Contents Abbreviations............................................................................................................................1 Panoramica Generale delle Tematiche Trattate nel Lavoro di Tesi....................................3 Summary ...................................................................................................................................9 Proteins and Peptides .............................................................................................................11 Peptidomimetics ...................................................................................................................12 Peptidomimetic Drug Design ...............................................................................................13 de novo Design .................................................................................................................13 Rational Drug Design.......................................................................................................14 Bioconjugation .............................................................................................................14 Non-Ribosomal Peptide Synthesis ...............................................................................14 tRNA Engineering Method...........................................................................................15 Peptide Ligation............................................................................................................16 Peptides Constructed from non-Proteinogenic Amino Acids.......................................17 References ............................................................................................................................18 β-Amino Acids and Derivatives.............................................................................................21 β-Amino Acids in Nature .....................................................................................................21 2,3-Diamino Acids ...............................................................................................................23 2-Alkyl-β3-Amino Acids ......................................................................................................25 Isotopically Labeled β-Amino Acids ...................................................................................27 References ............................................................................................................................27 Synthesis of β-Amino Acids ...................................................................................................31 Introduction ..........................................................................................................................31 The Chiral Pool Approach: α-Amino Acids as Starting Materials ..................................31 Stereoselective Synthesis of β-Amino Acids Starting from Aspartic Acid..................31 Stereoselective Synthesis of β-Amino Acids from Asparagine and Derivatives .........32 Arndt–Eistert Homologation ........................................................................................34 Results and Discussion.........................................................................................................34 Synthesis of Isotopically Labeled β-Amino Acids...........................................................35 References ............................................................................................................................38 Synthesis of 2,3-Diamino Carboxylic Acids .........................................................................39 Electrophilic Amination of Nucleophilic Carbons ...............................................................40 Results and Discussion.....................................................................................................40 Conclusions ......................................................................................................................44 References ............................................................................................................................45 Synthesis of 2,3-Disubstituted β-Amino Acids.....................................................................47 Introduction ..........................................................................................................................47 Synthetic Strategy.................................................................................................................48 α-Alkylation Reactions ....................................................................................................49 α-Hydroxymethylation Reaction......................................................................................51 Lipo-amino Acids and Lipo-peptides...............................................................................52 Mono-α-alkylation .......................................................................................................54
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