Multi-Step Organic Synthesis: A Guide Through Experiments

Combining theoretical knowledge of synthetic transformations, practical considerations, structural elucidation by interpretation of spectroscopic data as well as rationalization of structure-property relations, this textbook presents a series of 16 independent exercises, including detailed descriptions of experimental procedures, questions, and answers. The experimental descriptions are very helpful for guiding less experienced students towards a better understanding of practical aspects in synthetic organic chemistry, while the broad scope of the questions and answers is excellent for learning purposes. The exercises are based on published research articles, adapted for didactic purposes, and will thus inspire students by way of having to solve real-life problems in chemistry. A must-have for MSc and PhD students as well as postdocs in organic chemistry and related disciplines, and lecturers and organizers of lab courses in organic chemistry.

Table of Contents:
Preface xi List of Abbreviations xiii 1 Atovaquone: An Antipneumocystic Agent 1 Answers 4 References 8 2 SEN794: An SMO Receptor Antagonist 9 Answers 13 References 20 3 Synthesis of an H1–H3 Antagonist 21 3.1 Synthesis of Fragment 2 21 3.2 Synthesis of Fragment 3 26 3.3 Fragment Assembly and End of Synthesis 27 Answers 29 References 40 4 Synthesis of Eletriptan 41 Answers 45 References 50 5 Total Synthesis and Structure Revision of Streptophenazine A 51 Answers 54 References 59 6 Synthesis of Leiodermatolide, A Biologically Active Macrolide 61 6.1 Access to Fragment C 62 6.1.1 Preparation of Compound 2 62 6.1.2 Preparation of Compound 7 63 6.1.3 Preparation of Compound 12 63 6.1.4 Preparation of Fragment C 65 6.2 Access to Fragment D 65 6.2.1 Preparation of Compound 26 65 6.2.2 Preparation of Fragment D 66 6.3 Final Steps 67 6.3.1 Assembly of B and Formation of A by Ring‐Closing Alkyne Metathesis 67 6.3.2 Coupling of Sugar and Macrocycle 68 Answers 68 References 76 7 Azobenzene-Thiourea Catalysts for the Control of Chemical Reactivity with Light 77 7.1 Synthesis of Azobenzene-Thiourea Derivatives 77 7.2 Investigation of Catalytic Properties 82 Answers 85 References 92 8 Synthesis and Properties of a Photo-activatable Mimic of Pyridoxal 5ʹ-Phosphate 93 Answers 99 References 105 9 Fluorescent Peptides for Monitoring Activity of Autophagy-Initiating Enzyme 107 9.1 Solid-Phase Synthesis of a Putative Fluorogenic Peptide Substrate for ATG4B 107 9.2 Evaluation as Fluorogenic Substrates for ATG4B 108 9.3 Solution-Phase Synthesis of a Fluorogenic Substrate Analog Containing a Self-Immolating Linker 111 Answers 112 References 118 10 Fluorescent Peptide Probes for Cathepsin B 119 10.1 Solution Synthesis of a Water-Soluble Cyanine Fluorophore 119 10.2 Synthesis of a Water-Soluble Cyanine Fluorophore Using a Polymeric Support 121 10.3 Synthesis and Evaluation of Cyanine-Based NIR Peptide Probes for Monitoring Cathepsin B Activity 123 Answers 129 References 138 11 Total Synthesis of Stemoamide 141 11.1 Radical Approach to the Construction of the Tricyclic Core of Stemoamide 141 11.2 Formal Synthesis of (±)-Stemoamide 143 11.3 Enantioselective Total Synthesis of (−)-Stemoamide 145 Answers 148 References 158 12 Total Synthesis and Structure Revision of Caraphenol B 159 12.1 Synthesis of the Proposed Structure of Caraphenol B 159 12.2 Synthesis of the Revised Structure of Caraphenol B 162 Answers 164 References 170 13 Synthetic Routes Toward Muricatacin and Analogs 171 13.1 Synthesis of (+)-Muricatacin 171 13.2 Synthesis of (+)-epi-Muricatacin by Enantioselective Ketone Reduction 173 13.3 Synthesis of (−)-Muricatacin 176 Answers 178 References 187 14 Asymmetric Synthesis of (−)-Martinellic Acid 189 14.1 Preliminary Studies: Toward the Formation of a Model Tricyclic Compound 189 14.2 Synthesis of an Advanced Intermediate 192 14.3 Completion of the Synthesis 194 Answers 196 References 203 15 Cyclic Pseudopeptides as Potent Integrin Antagonists 205 15.1 Conformational Analysis 205 15.2 Synthesis of Bicyclic Lactam Templates 208 15.3 Solid Phase Peptide Synthesis 211 15.4 Pharmacological Study 214 Answers 215 References 224 16 Enantioselective Synthesis of Nonnatural Amino Acids for Incorporation in Antimicrobial Peptides 227 16.1 First Generation Mimetics: Synthesis and Biological Evaluation 227 16.2 Structural Analysis and Mechanism of Action 229 16.3 Sequence Optimization: Synthesis of Nonnatural Amino Acids 231 16.3.1 Synthesis of Homophenylalanine (Hfe) 231 16.3.2 Synthesis of Phenylglycine (Phg) 232 16.3.3 Synthesis of 4‐Chlorophenylalanine (ClF) 234 16.3.4 Synthesis of 2‐Naphtylalanine (2‐Nal) 235 16.3.5 Synthesis of 1‐Naphtylalanine (1‐Nal) 235 16.3.6 Synthesis of Cyclohexylalanine (Cha) 236 16.3.7 Synthesis of Norleucine (Nle) 237 16.3.8 Synthesis of Biphenylalanine (Bip) 238 Answers 240 References 256 Further Reading 259 Index 261

About the Author :
Nicolas Bogliotti is Assistant Professor at Ecole normale superieure Paris-Saclay, France. After his undergraduate studies at Universite Nice Sophia-Antipolis, France, he obtained his MSc and PhD Degrees at Universite Pierre et Marie Curie in Paris, France. He was a postdoc at ETH Zurich, Switzerland and Institut Curie, France, before his current position. His research interests focus on the synthesis of photosensitive molecules allowing visualization of recognition events, induction of a biological response and modulation of chemical reactivity. Roba Moumne is Assistant Professor at Universite Pierre et Marie Curie, France. She studied chemistry and completed her MSc and PhD at the same university. Before her current position, she was also a postdoctoral fellow at Max-Planck-Institut in Mulheim and der Ruhr, Germany, at University of Zurich, Switzerland and at Universite Paris Descartes, France. Her research interests include bioorganic chemistry and peptide synthesis.