Mayer T. Studies in the field of natural product chemistry: synthesis of a photoaffinnity probe, synthetic studies on pladienolide B and Gold(I) - catalyzed enantioselective polycyclization reactions (Tubingen, 2011). - ОГЛАВЛЕНИЕ / CONTENTS

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ОбложкаMayer T. Studies in the field of natural product chemistry: synthesis of a photoaffinnity probe, synthetic studies on pladienolide B and Gold(I) - catalyzed enantioselective polycyclization reactions = Studien auf dem Gebiet der Naturstoffchemie: Synthese einer Photoaffinitatssonde, Sytnthesestudien zu Pladienolid B sowie Gold(I)-Katalysierte Enantioselektive Polycyclisierungsreaktionen: Diss. … Dr. rer. nat. - Tubingen: Eberhard-Karls Universitat, 2011. - viii, 364 p.: ill. - Bibliogr.: p.356-364.
 

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Оглавление / Contents
 
Chapter I  Synthesis of a Tag-Free Chemical Probe for
Photoafftnity Labeling and its Application to Binding
Studies of V-ATPase Inhibitors
Abbreviations ................................................... V
1  Introduction ................................................. 1
2  Literature Review ............................................ 3
   2.1  The Photoaffinity Labeling Routine ...................... 3
   2.2  Photoprobe Design ....................................... 4
   2.3  Photoreactive Groups .................................... 5
        2.3.1  Chronological Aspects ............................ 5
        2.3.2  Phenylazides ..................................... 6
        2.3.3  Diazirines ....................................... 8
        2.3.4  Benzophenones .................................... 9
   2.4  PAL: Labeling Methods .................................. 10
        2.4.1  Classical PAL Route ............................. 10
        2.4.2  Non-Radioisotopic Labeling: Biotinylation ....... 11
        2.4.3  Post-PAL Modification ........................... 12
3  Goal of Research ............................................ 22
4  Results and Discussion ...................................... 24
   4.1  Retrosynthesic Analysis ................................ 24
   4.2  Construction of the Photoreactive Group ................ 25
   4.3  Completion of the Synthesis of the Photoaffinity 
        Probe .................................................. 29
   4.4  Model Study to Mimic the PAL Route ..................... 33
        4.4.1  Esterification of the Carboxylic Acid ........... 33
        4.4.2  Establishing Suitable Irradiation Conditions .... 34
        4.4.3  Photolysis of the Trifluoromethyl
               Phenyldiazirine Moiety .......................... 37
        4.4.4  Click Chemistry ................................. 39
   4.5  Attachment of the Photoaffinity Probe to the V-ATPase
        Inhibitor Bafllomycin А ................................ 41
   4.6  Attachment of the Photoaffinity Probe to the V-ATPase
        Inhibitor Apicularen A ................................. 45
   4.7  Inhibition Assays of the V1/V0 Holoenzyme Activity ...... 51
5  Conclusion .................................................. 55

Chapter II  Approach towards the Total Synthesis of the
Antitumor Macrolide Pladienolide В
6  Introduction ................................................ 63
7  Literature Review ........................................... 66
   7.1   Biological Activity of Pladienolide В ................. 66
   7.2  Published Synthetic Approaches towards Pladienolide В .. 71
        7.2.1  Total Synthesis of Pladienolide В by Kotake
               (2007) .......................................... 71
        7.2.2  Synthesis of the Macrocyclic Core of (-) -
               Pladienolide В by Skaanderup .................... 79
        7.2.3  Synthesis of the Pladienolide В Side Chain by
               Burkart ......................................... 83
8  Goal of Research ............................................ 88
9  Results and Discussion ...................................... 90
   9.1  Retrosynthetic Analysis ................................ 90
   9.2  Synthesis of the C3-C8 Submit .......................... 91
        9.2.1  Attempt I ....................................... 91
        9.2.2  Attempt II ..................................... 106
        9.2.3  Interlude: Model Study ......................... 109
        9.2.4  Final Attempt .................................. 120
   9.3  Synthesis of the C9-C13 Submit ........................ 127
   9.4  Assembly of the C3-C8 and C9-C13 Submit ............... 130
   9.5  Anticipated Route towards the Completion of the
        Total Synthesis ....................................... 136
10 Conclusion ................................................. 138

Chapter III  Gold(I)-Catalyzed Enantioselective
Polycyclization Reactions
11 Introduction ............................................... 145
12 Literature Review .......................................... 147
   12.1 Cationic Olefin Polyannulations ....................... 147
        12.1.1 Steroid Biosynthesis ........................... 147
        12.1.2 The Stork Eschenmoser Hypothesis ............... 148
   12.2 Mimicking Polyene Carbocyclizations ................... 151
        12.2.1 The Johnson Story .............................. 151
        12.2.2 The Yamamoto LBA Story ......................... 151
        12.2.3 Ishihara's Enantioselective Halocyclization
               of Isoprenoids ................................. 152
        12.2.4 Catalytic Approaches ........................... 154
   12.3 Catalysis by Gold к Acids ............................. 156
        12.3.1 Introduction ................................... 156
        12.3.2 Relativistic Effects ........................... 156
        12.3.З Practical Considerations ....................... 157
        12.3.4 Cationic Au(I) Species: Superior Alkynophilic
               я Acids ........................................ 158
   12.4 Electrophilic Activation of Enynes by Gold: Creation
        of Molecular Complexity ............................... 162
   12.5 Gold Complexes in Homogenous Catalysis ................ 173
        12.5.1 Introduction ................................... 173
        12.5.2 Making it Enantioselective! .................... 174
13 Goal of Research ........................................... 183
14 Results and Discussion ..................................... 185
   14.1 Synthetic Route towards 1,6-Enynes as Polycylization
        Substrates ............................................ 185
        14.1.1 General Retrosynthetic Approach ................ 185
        14.1.2 Synthesis of Malonate-Enyne Substrates ......... 186
        14.1.3 Synthesis of a N-Tosylate-Enyne Substrate ...... 191
        14.1.4 Synthesis of a Bissulfone-Enyne Substrate ...... 192
        14.1.5 Formation of Amide-Substrates .................. 192
        14.1.6 Formation of a.a-Dimethyl-Enyne Substrates ..... 193
        14.1.7 Formation of the (Z)-Malonate-Enyne Substrate .. 194
   14.2 Chiral Ligand/Chlorogold (I) Complexes ................ 198
        14.2.1 Preparation .................................... 198
        14.2.2 Structures ..................................... 199
   14.3 Gold(I)-Catalyzed 1,6-Enyne Polycylizations ........... 202
        14.3.1 Introduction ................................... 202
        14.3.2 General Experimental Procedure for Au(I)-
               Catalyzed Polycyclizations ..................... 202
        14.3.3 JV-Tosylated Enyne Acid 14-24 as Substrate ..... 203
        14.3.4 N-Tosylated Enyne Alcohol 14-25 as Substrate ... 204
        14.3.5 Bissulfone Enyne Acid 14-29 as Substrate ....... 207
        14.3.6 Malonate Enyne Acid 14-8 as Substrate .......... 212
        14.3.7 Internal Alkyne 14-19 as Substrate ............. 227
        14.3.8 Amides 14-31 and 14-32 as Substrates ........... 228
        14.3.9 (Z)-Alkene 14-42 as Substrate .................. 228
15 Conclusion ................................................. 230
16 Experimental Section ....................................... 233
   16.1  General Information for the PAL and the Pladienolide
        В Project ............................................. 233
        16.1.1 Chemicals and Working Techniques ............... 233
        16.1.2 NMR-Spectroscopy ............................... 233
        16.1.3 Mass Spectrometry .............................. 234
        16.1.4 Polarimetry .................................... 234
        16.1.5 Melting Points ................................. 234
        16.1.6 Chromatographic Methods ........................ 234
   16.2 General Information for the Au-Catalyzed
        Polycyclization Study ................................. 235
   16.3 Experimental Procedures ............................... 236
17 Appendix ................................................... 335
   17.1 NMR Spectra ........................................... 335
   17.2 HPLC Traces ........................................... 354
   17.3 Crystal Structure of the Malonate Product 14-67 ....... 355
   17.4 Bibliography .......................................... 356


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