New Strategies in Chemical Synthesis and Catalysis

This volume represents one of the two edited by inviting a selection of young researchers participating to the European Young Chemist Award 2010. The other volume concerns the area of Nanotechnology/Material Science and is titled: Molecules at Work. This book contains the contributions of selected young chemists from the field of synthetic chemistry. The contributions are grouped under the three following umbrella topics: Synthetic Methods Catalysis Combinatorial and Chemical Biology This volume is an indispensable read for all organic and inorganic chemists, biochemists, chemists working with/on organometallics, and Ph.D. students in chemistry interested in seeing what tomorrow′s chemistry will look like.

Preface XIII List of Contributors XIX Part I Synthetic Methods 1 Electrospray and Cryospray Mass Spectrometry: From Serendipity to Designed Synthesis of Supramolecular Coordination and Polyoxometalate Clusters 3 Haralampos N. Miras and Leroy Cronin 1.1 Introduction 3 1.2 Background to ESI–MS 5 1.2.1 Background to CSI–MS 5 1.3 Application of High–Resolution ESI–MS and CSI–MS to Polyoxometalate Cluster Systems 6 1.3.1 Probing Protonation Versus Heteroatom Inclusion with ESI 7 1.3.2 Solution Identification of Functionalized POMs 10 1.3.3 Solution Identification of New Isopolyoxotungstates and Isopolyoxoniobates 11 1.3.4 Solution Identification and Isolation of Mixed–Metal/Valence POMs with CSI–MS 13 1.3.5 Mixed–Metal/Valence Hetero–POMs V2 ⊂ {M17V1} 14 1.3.6 Periodate–Containing POMs 17 1.3.7 Probing the Formation of POM–Based Nano–Structures 17 1.3.8 Mechanistic Insights into POM Self–Assembly Using ESI– and CSI–MS 19 1.4 Species Identification and Probing Structural Transformations in Multi–Metallic Systems 25 1.5 Future Challenges and Conclusions 27 References 29 2 Efficient Synthesis of Natural Products Aided by Automated Synthesizers and Microreactors 33 Shinichiro Fuse, Kazuhiro Machida, and Takashi Takahashi 2.1 Efficient Synthesis of Natural Products Aided by Automated Synthesizers 33 2.1.1 The Process of Automating the Supply of Synthetic Intermediates 34 2.1.2 Efficient Synthesis of a Cyanohydrin Key Intermediate for Taxol Using Automated Synthesizers 40 2.1.3 Efficient Synthesis of a Cyclic Ether Key Intermediate for Nine–Membered Masked Enediyne, Using an Automated Synthesizer 44 2.1.4 List of Reactions Successfully Performed in Automated Synthesizers 50 2.2 Continuous–Flow Synthesis of Vitamin D3 52 2.3 Conclusions 55 Acknowledgments 55 References 56 3 Chemoselective Reduction of Amides and Imides 59 Shoubhik Das 3.1 Introduction 59 3.2 Reduction of Tertiary Amides 61 3.3 Reduction of Secondary Amides 70 3.4 Dehydration of Primary Amides 73 3.5 Reduction of Imides 74 3.6 Conclusion 76 Acknowledgment 76 References 76 4 Ionic Ozonides – From Simple Inorganic Salts to Supramolecular Building Blocks 79 Hanne Nuss and Martin Jansen 4.1 The Forgotten Oxygen Anion 79 4.2 The Synthesis of Ionic Ozonides 80 4.3 The Structural Variety of Ionic Ozonides 83 4.3.1 Simple Binary and Pseudo–Binary Ozonides 83 4.3.2 Cs5([12]crown–4)2(O3)5 – from Simple Salts to Supramolecular Building Blocks 87 4.4 Magnetic Properties 89 4.5 Conclusions and Perspectives 93 References 94 5 Chemistry and Biological Properties of Amidinoureas: Strategies for the Synthesis of Original Bioactive Hit Compounds 97 Daniele Castagnolo 5.1 Amidinoureas: an Introduction 97 5.2 Amidinoureas in Chemistry 99 5.3 Synthetic Strategies for the Preparation of Amidinoureas 102 5.3.1 Hydrolysis of Biguanides 103 5.3.2 Reaction of Guanidines with Isocyanates 103 5.3.3 Hydrolysis of Cyanoguanidines 105 5.3.4 Reaction of Acyl–S–Methylisothiourea with Amines 106 5.3.5 Reaction of Di–Boc–Guanidines with Amines 107 5.4 Macrocyclic Amidinoureas 110 5.4.1 Guanylated Polyamines 111 5.4.2 Conversion of Di–Boc–Guanylated Diamines into Amidinoureas 113 5.4.3 Synthesis of Cyclic Amidinoureas 115 5.4.4 Synthesis of Macrocyclic Amidinoureas from Di–Boc–Monoguanylated Triamines 118 5.4.5 Biological Properties of Cyclic Amidinoureas 120 5.5 Perspectives 123 Acknowledgments 124 References 124 Part II Catalysis 6 DNA Catalysts for Synthetic Applications in Biomolecular Chemistry 129 Claudia Höbartner and P.I. Pradeepkumar Abbreviations 129 6.1 Introduction 129 6.2 In vitro Selection of Deoxyribozymes 130 6.3 Scope of DNA–Catalyzed Reactions 132 6.4 Synthetic Applications of RNA–Cleaving Deoxyribozymes 133 6.5 DNA–Catalyzed Linear Ligation of RNA 137 6.6 DNA–Catalyzed Synthesis of 2,5–Branched Nucleic Acids 140 6.6.1 2,5–Branched RNA 143 6.6.2 2,5–Branched Nucleic Acids Containing RNA as Scaffold and DNA as Adaptor 144 6.6.3 2,5–Branched DNA 145 6.6.4 2,5–Branched Nucleic Acids Containing DNA as Scaffold and RNA as ‘‘Adaptor’’ 146 6.7 DNA–Catalyzed Synthesis of Nucleopeptide Conjugates 146 6.8 Mechanistic Aspects of DNA Catalysis 147 6.9 Conclusions and Outlook 150 References 150 7 Iron–Catalyzed Csp3 –H Oxidation with H2O2: Converting a Radical Reaction into a Selective and Efficient Synthetic Tool 157 Laura Gómez 7.1 Introduction and Scope 157 7.2 Environmentally Benign C–H Oxidation 158 7.3 Inspiration from Nature 158 7.4 Mechanistic Considerations 159 7.5 Bioinspired C–H Oxidation Catalysts 161 7.5.1 Porphyrinic Catalysts 161 7.5.2 Non–porphyrinic Mononuclear Iron Catalysts 162 7.6 Perspectives 171 References 172 8 Hydrogen Bonds as an Alternative Activation 175 Eugenia Marqués–López and Raquel P. Herrera 8.1 Introduction 175 8.1.1 Chiral Thiourea/Urea Organocatalysts 175 8.2 Thiourea Catalysts 178 8.2.1 Friedel–Crafts Alkylation Reaction 178 8.2.2 Michael Addition Reactions 183 8.2.2.1 Michael Addition Reaction of N , N –Dialkylhydrazones to Nitroalkenes 184 8.2.2.2 Michael Addition Reaction of Formaldehyde N , N –Dialkylhydrazones to β , γ –Unsaturated α –Keto Esters 186 8.2.2.3 Hydrophosphonylation Reaction of Nitroalkenes 188 8.2.3 Aza–Henry Reaction 191 8.3 Conclusions 193 Acknowledgments 194 References 194 9 Electrosynthesized Structured Catalysts for H2 Production 201 Patricia Benito, Francesco Basile, Giuseppe Fornasari, Marco Monti, Erika Scavetta, Domenica Tonelli, and Angelo Vaccari 9.1 Introduction 201 9.2 Preparation of Structured Catalysts 202 9.3 Electrosynthesis 203 9.4 Electrosynthesis of Hydrotalcite–Type Compounds 204 9.4.1 Experimental 204 9.4.2 Ni/Al and Rh/Mg/Al HT Compounds on FeCrAlloy Foams 207 9.4.3 Catalysts 210 9.4.4 Steam Reforming and Catalytic Partial Oxidation of Methane 212 9.5 Summary and Outlook 214 References 215 10 Microkinetic Analysis of Complex Chemical Processes at Surfaces 219 Matteo Maestri Notation 219 Greek letters 219 10.1 Introduction 219 10.2 Time and Length Scales in Heterogeneous Catalysis 221 10.3 Hierarchical Multiscale Approach for Microkinetic Model Development 223 10.3.1 Microkinetic Model Development 224 10.3.1.1 Prediction of Activation Energies Using the UBI–QEP Semiempirical Method 226 10.3.1.2 First–Principles Assessment of the UBI–QEP Semiempirical Method 227 10.3.2 Meso–Scale and Macroscale: Reaction and Reactor Engineering 229 10.3.3 Hierarchical Multiscale Refinement of the Microkinetic Model 230 10.4 Show Case: Microkinetic Analysis of CH4 Partial Oxidation on Rh 231 10.4.1 Microkinetic Model for the Conversion of CH4 to Syngas 232 10.4.2 Microkinetic Analysis of Isothermal CPOX Data in Annular Reactor 232 10.4.3 Microkinetic Analysis of Autothermal CPOX Data on Foams 239 10.5 Conclusions 241 Acknowledgments 242 References 242 11 Synthetic Potential behind Gold–Catalyzed Redox Processes 247 Cristina Nevado and Teresa de Haro 11.1 Introduction 247 11.2 Gold–Catalyzed Reactions Involving Oxygen Functionalities 247 11.2.1 Oxidation of Alkanes 247 11.2.2 Oxidation of Alcohols to Carbonyl Compounds 248 11.2.3 Oxidation of Alkenes 250 11.2.4 Oxidation of Sulfides to Sulfoxides 251 11.2.5 Oxidation of Gold–Carbene Intermediates 251 11.2.6 Substrates as Internal Oxidants 253 11.3 Gold–Catalyzed Reactions Involving Nitrogen Functionalities 255 11.4 Gold–Catalyzed Reactions Involving C–C Bond Formation 256 11.4.1 Ethynylation Reactions 256 11.4.2 Homocoupling Reactions 260 11.4.3 Cross–Coupling Involving B and Si Reagents 262 11.5 Gold–Catalyzed Reactions Involving Alkene Difunctionalization 264 11.6 Gold–Catalyzed Reactions Involving Halogen Functionalities 264 11.7 Summary and Outlook 266 References 266 12 Transition–Metal Complexes in Supported Liquid Phase and Supercritical Fluids –A Beneficial Combination for Selective Continuous–Flow Catalysis with Integrated Product Separation 273 Ulrich Hintermair, Tamilselvi Chinnusamy, and Walter Leitner 12.1 Strategies for Catalyst Immobilization Using Permanent Separation Barriers 273 12.2 Supported Liquid–Phase Catalysts Based on Organic Solvents (SLP) 274 12.3 Supported Aqueous–Phase Catalysts (SAP) 278 12.4 Supported Ionic Liquid–Phase Catalysts (SILP) 280 12.4.1 Synthetic Methods 280 12.4.2 Characteristics 281 12.4.3 Gas–Phase Applications 282 12.4.4 Liquid–Phase Applications 283 12.5 Supported Liquid–Phase Catalysts and Supercritical Fluids 287 12.6 Conclusion 290 References 292 Part III Combinatorial and Chemical Biology 13 Inhibiting Pathogenic Protein Aggregation: Combinatorial Chemistry in Combating Alpha–1 Antitrypsin Deficiency 299 Yi–Pin Chang 13.1 Introduction 299 13.2 α 1–Antitrypsin Deficiency 301 13.2.1 α 1–Antitrypsin and Serpin 301 13.2.2 The Polymerization Pathways of Serpins 303 13.2.3 Emerging Therapeutic Strategies 304 13.3 Targeting the s4A Site with the Peptide Annealing Method 305 13.3.1 Functional and Structural Studies of RCLs 305 13.3.2 Smaller RCL–Derived and Non–RCL Serpin–Binding Peptides 306 13.4 Expanding the Molecular Diversity 307 13.4.1 Alanine Scanning, Truncation, and D–Amino Acid Scanning Libraries 308 13.4.2 The β –Strand–Directed Library 309 13.4.3 The Positional Scanning Library 312 13.5 Characterization of the Combinatorially Selected Peptide 314 13.5.1 Validation of the Binding by SPR 314 13.5.2 Cytotoxicity of the Identified Peptide and the Proposed Structure of the Binary Complex 315 13.6 Conclusion and Outlook 316 Acknowledgments 317 References 317 14 Synthesis and Application of Macrocycles Using Dynamic Combinatorial Chemistry 325 Vittorio Saggiomo 14.1 Supramolecular Chemistry 325 14.2 Dynamic Combinatorial Chemistry 326 14.2.1 The Next Step: Applications 330 14.3 Ion Transport across Membranes Mediated by a Dynamic Combinatorial Library 331 References 341 15 Toward Tomorrow’s Drugs: the Synthesis of Compound Libraries by Solid–Phase Chemistry 343 Dagmar C. Kapeller and Stefan Bráse Abbreviations 343 15.1 Introduction 344 15.1.1 The History of Drug Discovery 344 15.1.2 Characteristics of Druglike Molecules 345 15.1.3 Drug Targets 345 15.1.4 Privileged Structures 347 15.2 Solid–Phase Synthesis of Selected Privileged Structures 347 15.2.1 Introduction to Solid–Phase Synthesis 347 15.2.2 Benzodiazepines 348 15.2.3 Benzopyrans 354 15.2.4 Indoles 360 15.2.5 Pyrazoles 364 15.3 Conclusions and Outlook 371 Acknowledgment 372 References 372 Index 377

Bruno Pignataro, born in Bologna in 1972, is Professor of Physical Chemistry at the University of Palermo. He received his degree in chemistry in 1995 from the University of Catania and his PhD in materials science five years later. He has helped establish a wide network of international collaborations and organized several scientific activities at national and international level, including coordinating the Young Chemists Group of the Italian Chemical Society and chairing the first three editions of the European Young Chemist Award. Professor Pignataro′s group research focus on the fields of nanoscience and nanotechnology, molecular electronics, and biotechnology.