UNIVERSITY of CALIFORNIA, SAN DIEGO Synthetic Studies Towards

UNIVERSITY OF CALIFORNIA, SAN DIEGO Synthetic Studies towards the Total Synthesis of Norzoanthamine A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Chemistry by Fatima R. Rivas Committee in charge: Professor Emmanuel A. Theodorakis, Chair Professor Laurence L. Brunton Professor Kyriacos C. Nicolaou Professor Susan Taylor Professor Michael VanNieuwenhze 2006 Copyright© Fatima R. Rivas, 2006 All rights reserved. SIGNATURE PAGE The dissertation of Fatima R. Rivas is approved, and it is acceptable in quality and form for publication on microfilm. Chair University of California, San Diego 2006 iii DEDICATION To my family, and TT: I thank you for your love, and support. iv EPIGRAPH The end of the road, While no one can go back and change the past to make a marvelous beginning, everyone can make an amazing ending. v TABLE OF CONTENTS Signature page…...……………………………………………………............iii Dedication….……………...…………………………………………..............iv Epigraph………...………………...……………………………………............v Table of Contents……………...………………………………………............vi List of Symbols and Abbreviations…………………………………................ix List of Figures……………...………………………………………...............xiii List of Schemes……………………………………………………….............xv List of Tables……………………...…………………………………...........xvii List of Graphs..……...………………………………………………...........xviii List of Spectra…………………...…………………………………...............xix Acknowledgements…………...……………………………………............xxxii Vita…………………………………………………………………..........xxxiii Abstract of the Dissertation………………………………………….........xxxvi CHAPTER 1 An Introduction to the Norzoanthamine Family....…...…...............1 1.1 Natural Origins of Norzoanthamine…..…….…………...………..........2 1.2 Phytochemistry …..……………………………………….....................4 1.2.1 Isolated Natural Products and Structural Analysis…………………………………..................4 1.2.2 Biosynthesis…...………………..…………………...................6 1.3 Biological Activity…………………...………………………...............8 1.4 Synthetic Studies of Norzoanthamine…..……....………............….....13 1.5 Conclusion………...……………………….………………………....19 1.6 References…………………………………………….........................20 CHAPTER 2 ABC Ring Construction and Functionalization of the BC Ring vi System of Norzoanthamine……….............................................23 2.1 Introduction…………..……………………..…………………….......24 2.2 Stereoselective Synthesis of the ABC Ring of Norzoanthamine………………………………………………………25 2.3 Synthesis of the Fully Functionalized BC Ring Motif of Norzoanthamine……..…………………………………...………...30 2.4 Conclusion….…………………………………………………….......38 2.5 Experimental Section…………...……………………….....................39 2.5.1 General Techniques………………………………...................39 2.5.2 Experimental Procedures and Data…………………...............41 2.5.3 1H NMR and 13C NMR Spectra……………………................89 2.5.4 References……………………………………………….......192 CHAPTER 3 A Biomimetic Approach towards the Total Synthesis of Norzoanthamine.......................................................................195 3.1 Introduction………...…………………………………………..........196 3.2 Construction of a Polyene System…...…………………...................197 3.2.1 Attempts to Construct the C ring of Norzoanthamine via an Intramolecular Diels-Alder Reaction………….................205 3.2.2 Attempts to construct the A ring of Norzoanthamine via a Sigmatropic Reaction…………...…...………….................211 3.3 Model System Using Carvone as the A ring of Norzoanthamine …………………………….....................................220 3.3.1 Synthesis of (-)-Isocarvone and (+)-Isocarvone.…….............221 3.3.2 Attempts to Construct the BC Ring of Norzoanthamine via an intramolecular Diels-Alder Reaction...……….............225 3.4 A Study of [4+2] cycloaddition Reactions of 2-Amino 1, 3- Dienes: Access to the BC Ring of Norzoanthamine…...…...………………..231 3.4.1 Introduction…………...…………………….…….................231 3.4.2 Bio-inspired Model System to Construct the 2-Amino 1, 3-Diene…...………….....………..................232 3.4.3 Studies of the cycloaddition Reaction of 2-(-N-Acylamino) 1, 3-Dienes: An Intermolecular Study…...…….…................232 3.5 Experimental Section…………………………………...……….......251 3.5.1 General Techniques…………………………………….........251 3.5.2 Experimental Procedures and Data…………...………..........253 3.5.3 Experimental Procedures and Kinetic Studies..………..........324 3.5.4 1H NMR and 13C NMR Spectra…………...…………...........334 3.6 References……………………...……………………………493 vii CHAPTER 4 Conclusion…………………..………………...…………….....498 4.1 Conclusion…...………………….………………………….............499 viii LIST OF SYMBOLS AND ABBREVIATIONS Ac acetyl ACN acetonitrile Boc (t-BOC) tert-butoxycarbonyl Bu butyl calcd calculated CAN ceric ammonium nitrate CCDC Cambridge Crystallographic Data Center CI chemical ionization DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC 1,3-dicyclohexylcarbodiimide DCM dichloromethane DEA diethylaniline DIBAL diisobutylaluminum hydride DIPEA diisopropylethylamine DMA N,N-dimethylacetamide DMAP N,N-dimethylaminopyridine DMF N,N-dimethylformamide DMP Dess – Martin periodinane DMS dimethylsulfide ix DMSO dimethylsulfoxide ED50 mean effective dose Et ethyl FAB fast atom bombardment FT-IR Fourier transform-infrared [H] reduction hν irradiation with light HMPA hexamethylphosphoramide KHMDS potassium bis(trimethylsilyl)amide HRMS high-resolution mass spectrometry IBX o-iodoxybenzoic acid IC50 mean inhibitory concentration IR infrared LHMDS lithium bis(trimethylsilyl)amide LTA lead tetraacetate m-CPBA m-chloroperoxybenzoic acid Me methyl MEM methoxy ethoxy methyl MOM methoxymethyl MHz megahertz NBS N-bromosuccinimide NIS N-iodosuccinimide x NMO 4-methylmorpholine N-oxide NMR nuclear magnetic resonance [O] oxidation ORTEP Oak Ridge thermal ellipsoid plot PG protecting group Piv pivaloyl Ph phenyl PMA phosphomolybdic acid PPTS pyridinium p-toluenesulfonate Rf retention factor SAR structure – activity relationship TBAF tetrabutylammonium fluoride TBABr tetrabutylammonium bromide TBS t-butyldimethylsilyl TEA triethylamine TES triethylsilyl Tf trifluoromethanesulfonate TFA trifluoroacetic acid TFE trifluoroethanol TFAA trifluoroacetic anhydride TFPA trifluoroperacetic acid THF tetrahydrofuran xi TIPS triisopropylsilyl TLC thin-layer chromatography TMS trimethylsilyl UV ultraviolet xii LIST OF FIGURES Chapter 1 Figure 1.1: Head of a coral of the Class Anthozoa, subclass: Zoantharia...………………………………………..............3 Figure 1.2: Zoanthid colonies from India and Canary Island respectively............4 Figure 1.3: Variety and similarity of the zoanthamines natural products...............5 Figure 1.4: Reductive trasformation that led to the absolute configuration of norzoanthamine….……………………….................6 Figure 1.5: Normal bone (left) and osteoporatic bone (right)....…………...........10 Figure 1.6: Osteoporatic bones treated with norzoanthamine by Uemura’s group………...…………………………………..........11 Chapter 2 Figure 2.1: Retrosynthetic analysis of norzoanthamine....….…………………...25 Chapter 3 Figure 3.1: Our key proposed disconnections based on the proposed biogenesis of zoanthamine....………………...……..……………..197 Figure 3.2: Successful applications of the TADA reaction..…………………..201 Figure 3.3: Proposed model system toward the C ring formation of norzoanthamine………………………………………….…….…..202 Figure 3.31: Possible transition states for the TADA reaction…………….…..204 Figure 3.32: Possible stereoisomers and their corresponding heat of formation energies via the two most probable transition states that give rise to the CAT and TAC products………….…..204 Figure 3.4: Palladium-mediated hydrostannylation versus stannylcupration: regioselectivity…………………………………………………….209 Figure 3.5: Electrocyclization reactions……………………………………….212 xiii Figure 3.6: Proposed construction of the A ring system of norzoanthamine…………………………………...…………..213 Figure 3.7: Previous studies to form the 6π cyclization via heat or palladium- mediated reaction…………...…………………………………….215 Figure 3.8: Proposed mechanism for the palladium-mediated 6π reaction…………………………...…………………………...219 Figure 3.9: Proposed formation of the ABC ring of norzoanthamine from R-(-)-carvone………………………………………………..221 Figure 3.10: Natural carvone and its potential isomers….......……..……...…..222 Figure 3.11: Retrosynthetic analysis of (-)-isocarvone and (+)-isocarvone……...………...…………………………………..222 Figure 3.12: Diels-Alder reaction studies by Zaragoza and Tanner……...........230 Figure 3.13: Proposed formation of the C ring of norzoanthamine via 2-amino 1,3-diene cyclization..…………...………..………….…231 Figure 3.14: Proposed model study to the ABCE ring of norzoanthamine.….……….……………………………………...233 Figure 3.15: Expected enamine isomerization.…...………………..…………..233 Figure 3.16: Bond disconnection of an intermolecular model system.………………….………………………………………..240 Figure 3.17: Preparation of 2-(-N-acyl-amino)-1,3-diene 141 and its cycloaddition reaction with N-Benzylmaleimide (NBMI)..……..243 Figure 3.18: Air isomerization of 150 to 150-1 and spontaneous bond isomerization of 143 to 143-1......………………………………..248 xiv LIST OF SCHEMES Chapter 1 Scheme 1.1: Proposed biosynthesis of the zoanthamines by Uemura...................7 Scheme 1.2: Miyashita’s approach to the total synthesis of norzoanthamine……………………………...…………………15 Scheme 1.3: Kobayashi’s approach to the CDEFG ring system of norzoanthamine………….……...…... …………….…...……..…..16 Scheme 1.4: William’s synthetic approach to the AB ring system and CEFG ring system respectively.…………..………...……………16 Scheme 1.5: Tanner’s synthetic approach to the ABC ring system using

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