Selectivity in the Synthesis of Cyclic Sulfonamides: Application in the Synthesis of Natural Products (Springer Theses)

In the area of organic chemistry one major challenge we are currently faced with is how to assemble potentially useful molecules in new ways that generate molecular complexity and in sequences that are as efficient as possible. Our efforts in this regard, specifically for the preparation of amino containing compounds incorporating an aromatic ring, are described in this doctoral thesis. We discovered an interesting regioselectivity in an intramolecular Heck reaction, which we studied for a series of substrates that are unbiased in terms of the size of the newly formed ring, where very high levels of selectivity in relation to the new carbon-carbon bond are typically observed. DFT calculations were performed to attempt to shed light on the reaction sequence. This regioselective Heck reaction, combined with the reductive removal of the temporary amino-protecting group, allowed us to synthesize the Sceletium alkaloids: mesembrane, mesembranol and mesembrine. Supervisor’s Foreword 7 Contents 9 Abbreviations 11 1 Introduction 14 1.1emspAlkaloids 14 1.2emspSceletium Alkaloids 14 1.3emspThe First Total Synthesis of Mesembrine 17 1.4emspAnnulation of Endocyclic Enamine 18 1.5emspFirst Asymmetric Synthesis of Mesembrine 18 1.6emspPhotocycloaddition of Vinylogous Amides 19 1.7emspZirconium-Promoted Cyclisation 20 1.8emspC&hx2013;H Insertion Construction of Quaternary Carbon Centres 21 1.9emspStereocontrolled ZnBr2-Catalysed Rearrangement of 2,3-Aziridino Alcohols 22 1.10emspOxy-Cope/Alkylation Sequence for the Formation of Quaternary Carbon Centres 23 1.11emspPalladium-Catalysed Sequential Arylation and Alkylation 23 1.12emspAromatic Ring Umpolung 24 1.13emspAsymmetric Hydrogenation Approach 25 1.14emspAim 26 References 27 2 Regioselectivity in the Heck (Mizoroki-Heck) Reaction 29 2.1emspGeneral Introduction 29 2.2emspIntermolecular Heck Reaction 31 2.3emspIntramolecular Heck Reaction 32 2.4emspRegioselectivity in the Intramolecular Heck Reaction of Sulfonamides 33 References 52 3 Wagner-Meerwein Rearrangement of Cyclic Sulfonamides 54 3.1emspIntroduction 54 3.2emspBromonium Ion Mediated Migration of Bicyclic Compounds 56 3.3emspBromonium Ion Migration of Tricyclic Compounds 62 References 65 4 An Investigation into the One-Pot Heck Olefination-Hydrogenation Reaction 66 4.1emspIntroduction 66 4.2emspIntramolecular Heck-Hydrogenation Sequence 69 4.3emspIntermolecular Heck-Hydrogenation Sequence with Bromobenzene 71 4.4emspIntermolecular Heck-Hydrogenation Sequence with Methyl Acrylate 73 References 76 5 Double Reduction of Cyclic Aromatic Sulfonamides 77 5.1emspIntroduction 77 5.2emspTotal Synthesis of (±)-Mesembrane 79 5.3emspTotal Synthesis of (−)-Mesembrine 82 References 88 6 Experimental 90 6.1emspGeneral Directions 90 6.2emspExperimental 90 References 149 Appendix 151 Front Matter....Pages i-xiii Introduction....Pages 1-15 Regioselectivity in the Heck (Mizoroki-Heck) Reaction....Pages 17-41 Wagner-Meerwein Rearrangement of Cyclic Sulfonamides....Pages 43-54 An Investigation into the One-Pot Heck Olefination-Hydrogenation Reaction....Pages 55-65 Double Reduction of Cyclic Aromatic Sulfonamides....Pages 67-79 Experimental....Pages 81-141 Back Matter....Pages 143-151