 | 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 = 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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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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