Asymmetric Synthesis of Decahydroquinolines via Organocatalysis: Total Synthesis of (+)-Lycoposerramine Z and (-)-Cermizine B Carlos Luque Corredera ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) i a través del Dipòsit Digital de la UB (diposit.ub.edu) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX ni al Dipòsit Digital de la UB. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX o al Dipòsit Digital de la UB (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. 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ASYMMETRICSYNTHESISOFDECAHYDROQUINOLINES VIAORGANOCATALYSIS:TOTALSYNTHESISOF (+)LYCOPOSERRAMINEZAND()CERMIZINEB CARLOSLUQUECORREDERA FACULTATDEFARMÀCIA DEPARTAMENTDEFARMACOLOGIAIQUÍMICATERAPÈUTICA 0-%0+"# -!2-02S3\+'!0%9,'!6.#0'+#,2*',"3120'* ASYMMETRICSYNTHESISOFDECAHYDROQUINOLINES VIAORGANOCATALYSIS:TOTALSYNTHESISOF (+)LYCOPOSERRAMINEZAND()CERMIZINEB #+0'.0#1#,2".#00*-13/3#-00#"#0 .#0-.20*2\2-*"# -!2-0.#0*!,'4#01'22"##0!#*-, '0'%'".#0S 0T%-1#.#-,(-!&(#1M 0T##,#0"1&5 0*-13/3#-00#"#0 #0!#*-,Q(3,7"#TRSV The experimental work included in this PhD thesis was carried out in the Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona under the direction of Prof. Josep Bonjoch and Dr. Ben Bradshaw between the period of January 2010 to January 2014. Calculations that appear in this work were performed by Carles Bo and Ruth Dorel at the Institute of Chemical Research of Catalonia (ICIQ). Funding was provided by MICINN (Spain CTQ2010-14846/BQU). El treball experimental recollit en aquesta memòria es va dur a terme al Laboratori de Química Orgànica de la Facultat de Farmàcia de la Universitat de Barcelona sota la direcció del Prof. Josep Bonjoch Sesé i del Dr. Ben Bradshaw en el període comprés entre gener de 2010 i gener de 2014. Els càlculs teòrics presentats en aquest treball van ser realitzats per el Dr. Carles Bo i Ruth Dorel de l’Institute of Chemical Research of Catalonia (ICIQ). Aquest treball ha estat finançat pel MICINN (Espanya, CTQ2010- 14846/BQU) Contents 1. Introduction and Objectives: The Phlegmarine Alkaloids ........................ 1 1.1. Introduction and Objectives ............................................................................................... 3 1.1.1. The phlegmarine alkaloids.......................................................................................... 3 1.1.2. Structural classification of the phlegmarine type alkaloids......................................... 4 1.1.3. Biosynthesis of the phlegmarine alkaloids ................................................................. 6 1.1.4. Phlegmarines: biosynthetic precursors of the lycopodium alkaloids.......................... 8 1.1.5. Bioactivities of the phlegmarine alkaloids................................................................. 10 1.2. Previous Synthesis of Phlegmarine Alkaloids.................................................................. 12 1.2.1. MacLean’s approach to the cis-phlegmarine skeleton ............................................. 12 1.2.2. Synthesis of N-methyl-N-acetylphlegmarine ......................................................... 14 1.2.3. Model Studies towards the synthesis of phlegmarine .............................................. 16 1.2.4. Total synthesis of phlegmarine and its derivatives................................................... 18 1.2.5. Total synthesis of lycoposerramines V and W ......................................................... 22 1.2.6. Total synthesis of lycoposerramine Z....................................................................... 24 1.2.7. Total synthesis of lycoposerramine X....................................................................... 26 1.2.8. Towards the total synthesis of dihydrolycolucine ..................................................... 27 1.2.9. Overview of phlegmarine alkaloids syntheses ......................................................... 29 1.3. Group precedents for the Synthesis of Nitrogen-containing Compounds via Intramolecular aza-Michael Processes................................................................................... 30 1.3.1. Synthesis of 6-octahydroindoles: application to aeruginosin 298-A......................... 30 1.3.2. Synthesis of decahydroquinolines. Approximation to lepadin alkaloids................... 31 1.3.3. Synthesis of 5-oxodecahydroquinolines................................................................... 32 1.4. Summary of Objectives and Synthetic Plan..................................................................... 34 2. A Unified Synthetic Approach to the Phlegmarine Nuclei: Stereoselective Formation of 5-Oxodecahydroquinolines ......................... 37 2.1. Synthetic Studies on the One-pot Robinson Annulation/Intramolecular aza-Michael Reaction .................................................................................................................................. 39 2.1.1. Preparation of starting material ................................................................................ 40 2.1.2. Initial attempts to effect the one-pot tandem reaction. ............................................. 41 2.1.3. Screening of conditions for the Michael Addition reaction ....................................... 42 2.1.4. Preparation of alternative -keto ester starting materials......................................... 43 2.1.5. Screening of conditions for the tandem reaction ...................................................... 44 2.1.6. Optimization of conditions for the tandem reaction .................................................. 46 2.1.7. Determination of type A stereochemistry via NMR................................................... 47 2.2. Mechanism of the Tandem Reaction Based on DFT Modelling Studies ......................... 49 2.2.1. Relative stability of the diastereoisomers. Access to type A stereochemistry.......... 49 2.2.2. Proposed mechanism of the tandem biscyclization ................................................. 50 2.3. Access to 5-oxodecahydroquinolines of type B ............................................................... 57 2.3.1. Relative stability of tosyl containing 5-oxodecahydroquinolines .............................. 57 2.3.2. Synthetic access to type B stereochemistry............................................................. 58 2.3.3. Determination of type A and B stereochemistries by NMR ...................................... 60 2.4. Access to 5-oxodecahydroquinolines of type C and type D ............................................ 61 2.4.1. Stability of decahydroquinolines bearing non electron withdrawing groups............. 61 2.4.2. Synthetic access to 5-oxodecahydroquinolines of type C........................................ 62 2.4.3. Synthetic access to 5-oxodecahydroquinolines of type D........................................ 64 2.4.4. Comparitive NMR analysis of type A-D 5-oxodecahydrohydrolines......................... 65 2.4.5. Overview of methods to access type A-D 5-oxodecahydroquinolines ..................... 66 i 3. Total Synthesis of (+)-Lycoposerramine Z............................................... 67 3.1. Total Synthesis of cis-Phlegmarine Alkaloids from a Common Intermediate.................