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Universitat Rovira I Virgili Hydroacylation and C-N Coupling Reactions

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Universitat Rovira I Virgili Hydroacylation and C-N Coupling Reactions UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL: T-1262-2008 UNIVERSITAT ROVIRA I VIRGILI Hydroacylation and C-N Coupling Reactions. Mechanistic Studies and Application in the Nucleoside Synthesis Patricia Marcé Villa Dissertation presented to receive the degree of Doctor of the Universitat Rovira i Virgili, European Mention UNIVERSITAT ROVIRA I VIRGILI Departament de Química Analítica i Química Orgànica Tarragona, Abril 2008 UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL: T-1262-2008 UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL: T-1262-2008 UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL: T-1262-2008 UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL: T-1262-2008 UNIVERSITAT ROVIRA I VIRGILI DEPARTAMENT DE QUIMICA ANALITICA I QUIMICA ORGANICA C/ Marcel.lí Domingo s/n Campus Sescelades 43007 Tarragona Tel. 34 977 55 97 69 Fax 34 977 55 84 46 e-mail: [email protected] Sergio Castillón Miranda, Catedràtic del Departament de Química Analítica i Química Orgànica de la Universitat Rovira i Virgili, CERTIFICA: Que el present treball titulat: “Hydroacylation and C-N Coupling Reactions. Mechanistic Studies and Application in the Nucleoside Synthesis”, que presenta Patricia Marcé per a optar al grau de Doctor, ha estat realitzat sota la meva immediata direcció als laboratoris de Química Orgànica del departament de Química Analítica i Química Orgànica de la Universitat Rovira i Virgili. Tarragona, Abril de 2008 Prof. Sergio Castillón Miranda UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL: T-1262-2008 UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL: T-1262-2008 Me gustaría agradecer a todas las personas que han hecho posible la realización de este trabajo. Empezando por mi director de tesis Prof. Sergio Castillón, muchas gracias por haberme dado la oportunidad de realizar la tesis en tu grupo y por tu apoyo en los momentos difíciles (que no han sido pocos), y por tener las puertas de tu despacho abiertas siempre que lo he necesitado. Tus consejos y tu perseverancia han hecho que este camino haya sido un poco más fácil. Además me llevo muy gratos recuerdos de todas las cenas que tanto tú como Carmen habéis organizado siempre con tanto cariño. Mis más sinceros agradecimientos al resto de doctores del Área de Química Orgánica, especialmente a la Dra. Yolanda Díaz y a la Dra. Maribel Matheu por todo el apoyo prestado y por estar siempre dispuestas a ayudar. También me gustaría agraceder al Dr. Carles Bo por haberme permitido trabajar en su grupo durante un tiempo y por todo su apoyo recibido y ayuda a la hora de hacer los cálculos teóricos que se presentan en este trabajo. Gracias por tu paciencia y por enseñar a una química orgánica a hacer algunos calculines. Gracias Marta por trabajar conmigo día a día la temporada que estuve en el ICIQ y a todos los compañeros por su cálida bienvenida. I would like to express my gratitude to Prof. Piet W. N. M. van Leeuwen from The University of Amsterdam for hosting me in his group and giving me the opportunity to work in such a beautiful place. I would also like to thank all the members of his research group for their kindly welcome, and especially Miguel, Fabrizio, Pierre, Ivo, Sanders and Franco for their friendship. Gracias a los compañeros de laboratorio con los que he pasado la mayoría del tiempo, con los que he trabajado codo a codo y me han aguantado mis malos momentos, me han sabido dar consejos y me han ayudado tanto durante estos cuatro años. A los que cuando llegué ya estaban en el laboratorio y con los que he compartido la mayoría de momentos, Miguel, Omar, y David. Tampoco puedo olvidarme de los compañeros del laboratorio vecino: Antonio con el que he compartido largas charlas sobre química y a Andrea. A los nuevos que se incorporan Javi e Irene y a los que ya no són tan nuevos Isidro y Pep. También me gustaría dar las gracias a los compañeros del área de química inorgánica, Jesús, Aitor, Vanesa y Bianca que aunque no hemos trabajado en el mismo laboratorio también he compartido con ellos muy buenos momentos y algún que otro congreso. Molt especialment volia agraïr a Clara, amiga i companya no només aquest quatre anys de doctorat sino també als quatre anys de carrera que vam compartir, amb qui he viscut molt bons moments i moltes nits sense dormir (i no només quan sortiem el dijous sinó que també alguna nit d’estudi intens les vespres dels exàmens). Gràcies per estar sempre que t’he necessitat. A Cyril con el UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL: T-1262-2008 que he pasado muchas horas de RMN y con el que sin su ayuda el último capítulo de mi tesis no habría sido posible. No quiero olvidarme de mis amigas Rosa, Cristina y Vero con las que he compartido muchos cafés y confidencias. Muchas gracias por escucharme y aguantarme en los malos momentos, sin vuestra compañía nada hubiése sido lo mismo. Voldria dedicar un especial agraïment a David, que no només ha sigut el meu company de laboratori. Gràcies per ajudarme amb la química fora i dins del laboratori, per saber-me escoltar i per estar a prop meu tant en els bons com en els mals moments. Gràcies per entendre’m més que ningú i per fer-me riure sempre que he estat baixa de moral. Sense tu aquests últims dos anys no hauríen sigut el mateix. A mis padres y a mi abuelita que han vivido tan de cerca toda mi trayectoria, gracias por vuestro apoyo y por vuestra paciencia, gracias por estar siempre tan próximos y siempre estar dispuestos a echarme una mano en todo lo referente a mi vida. Gracias por ser como sois. Gracias avi por haber tenido tanta fe en mí, y por creer que siempre sería capaz de hacer todo lo que me propusiera, siempre me diste muchos ánimos. Me hubiera gustado que estuvieses aquí para compartir estos momentos contigo. Siempre te llevaré en mi corazón. Muchas gracias a todos. UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL:____________________________________________________________Acronyms T-1262-2008 AcOH Acetic acid Ad Adenine ADF Amsterdam Density Functional Ar Aromatic B Nucleic Base BHT 2,6-di-t-butyl-4-methylphenoxide Bn Benzyl COD 1,5-Cyclooctadiene COSY Correlated spectroscopy dba dibenzylideneacetone DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCC N,N′-Dicyclohexylcarbodiimide de Diastereomeric excess DEAD Diethyl azodicarboxylate DFT Discrete Fourier Transformation DIBAL-H Diisobutylaluminium hydride DKR Dynamic Kinetic Resolution DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMSO Dimethylsulfoxide DMTCl 4,4'-Dimethoxytrityl chloride dppe 1,2-Bis(diphenylphosphino)ethane DPPF 1,1'-Bis(diphenylphosphino)ferrocene ee Enantiomeric excess ees Enantiomeric excesses en Ethylenediamine equiv Equivalent UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL:____________________________________________________________Acronyms T-1262-2008 Et2O Diethy ether EtOAc Ethyl Acetate GC Gas Chromathography HMBC Heteronuclear multiple-bond correlation HMPA Hexamethylphosphoric triamide HSQC Heteronuclear single-quantum correlation i-PrOH iso-Propanol KR Kinetic Resolution LiHMDS Lithium hexamethyldisilazide MeOH Methanol MeONa Sodium methoxide MHz Megaherzt MS Molecular sieve N-435 Novozyme 435 NaOAc Sodium acetate NaOtBu Sodium tert-butoxide NBD Norbornadiene NBS N-Bromosuccinimide n-BuLi n-Butyllithium NMP N-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance Ph Phenyl PMBCl p-Methoxybenzyl chloride PSC Pseudomonas Cepacea Py Pyridine RCM Ring-Closing Metathesis rt Room temperature TBAF Tetrabutylammonium fluoride UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL:____________________________________________________________Acronyms T-1262-2008 TBDPSCl tert-Butyldiphenylsilyl chloride t-BuLi tert-Butyllithium TC Thiophene 2-carboxylate TEMPO 2,2,6,6-Tetramethylpiperidine 1-oxyl Tf Triflate (Trifluoromethanesulfonic) TFA Trifluoroacetic acid THF Tetrahydrofuran Thy Thymine TIPSOTf Triisopropylsilyl triflate TLC Thin Layer Chromatography TMEDA N,N,N′,N′-Tetramethylethylenediamine TMNO Trimethylamine-N-oxide TMS Tetramethylsilane TMSCN Trimethylsilyl cyanide TS Transition state TsCl p-Toluenesulfonyl chloride ZORA Zero Order Approximation UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL: T-1262-2008 UNIVERSITAT ROVIRA I VIRGILI HYDROACYLATION AND C-N COUPLING REACTIONS. MECHANISTIC STUDIES AND APPLICATION IN THE NUCLEOSIDE SYNTHESIS Patricia Marcé Villa ISBN:978-84-691-8840-8/DL:_____________________________________________________________________ T-1262-2008 Table of Contents TABLE OF CONTENTS 1. Introduction 17 1.1. Synthesis of Dideoxynucleosides – From 2’, 3’-unsaturated precursors 20 – From lactones 24 – From 2,3-dihydrofuran derivatives 26 1.2.
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