Application of Direct Imine Acylation Methodology in the Synthesis of Nitrogen Heterocycles and Natural Products Sarah J. Chambers PhD University of York Chemistry September 2016 Abstract This thesis describes the use of direct imine acylation (DIA) methodology in a range of different applications. Firstly, the attempted synthesis of (±)-cytisine is described (Chapter 2). The use of DIA methodology in the formation of the pyridone ring scaffold of (±)-cytisine has been explored. In the most advanced synthesis towards (±)- cytisine achieved in this project, the generation of N-acyliminium ions from imine A and subsequent nucleophilic addition of organometallic allyl reagents was developed to give diene B. O O 1. T3P (50% in THF) N DIPEA, cinnamic acid Ph N N N 2. allyltrimethyl silane, R Lewis acid N NH A R B (±)-cytisine R = Boc or CO2Et DIA methodology has also been utilised in the synthesis of spirocyclic products from simple indole acids C and imines D (Chapter 3). The reaction provides a broad range of products E in good yields and the indole acid starting materials C are readily synthesised using Fischer indole methodology. The stereoselectivity of the reaction, derivatisation of the products E and 3D shape analysis are also described. O O O T3P (50% N N n n n X OH in THF), Spiro- N DIPEA X cyclisation X R R1 H R R1 R R1 N H N N C D H E 1 R = OMe, F, Br, Me; R = H, Me, Ph; X = C or N; n = 1 or 2 Finally, work towards the synthesis of (±)-aspidospermidine, using the spirocyclisation methodology developed in this project, is introduced (Chapter 4). Two strategies are proposed utilising an intramolecular Heck reaction or a ring-closing metathesis to complete the polycyclic scaffold. A key DIA reaction between the synthesised acid F and imine G is reported and shows formation of the spirocyclic scaffold H. O T3P (50% O N N N in THF), Et OH DIPEA H R H N R H N N H F G H R = Iodo or vinyl H (±)-aspidospermidine ii Table of Contents Abstract ...................................................................................................................... ii Table of Contents ..................................................................................................... iii List of Tables ............................................................................................................ vi List of Figures .......................................................................................................... vii Acknowledgements ................................................................................................... ix Author’s Declaration ................................................................................................ x 1. Introduction ............................................................................................................ 1 1.1. Introduction to N-Acyliminium Ions ............................................................. 1 1.1.1. Structure and Reactivity of N-Acyliminium Ions ........................................ 1 1.1.2. Synthesis of N-Acyliminium Ions ................................................................ 3 1.1.3. Direct Imine Acylation ................................................................................. 7 1.2. Brief Outline of the Project .......................................................................... 11 2. Attempted Synthesis of (±)-Cytisine using Direct Imine Acylation Methodology ......................................................................................................... 12 2.1. Introduction to Cytisine ................................................................................ 12 2.1.1. Biological Activity and the Use of (−)-Cytisine ........................................ 12 2.1.2. Previous Syntheses of Cytisine .................................................................. 13 2.2. Project Outline .............................................................................................. 18 2.3. Results and Discussion .................................................................................. 19 2.3.1. Direct Imine Acylation followed by Intramolecular Nucleophilic Addition of an Internal Carbon Nucleophile ........................................................... 19 2.3.2. Direct Imine Acylation followed by Intermolecular Nucleophilic Addition of an External Carbon Nucleophile ......................................................... 32 2.3.3. Synthesis and Reactions of Novel Bispidine Imines ................................. 33 2.3.4. Development of Lewis Acid-Free Conditions for the DIA Reaction with Addition of Intermolecular Nucleophile .................................................. 37 2.3.5. Reaction of Glutaconic Anhydride and Imidates as an Annelation Procedure ................................................................................................. 41 2.3.6. Towards the Synthesis of (±)-Cytisine: Oxidation of the Dihydropyridone Ring .......................................................................................................... 45 2.4. Conclusions and Future Work ..................................................................... 49 iii 3. Synthesis of Spirocyclic Compounds using Direct Imine Acylation Methodology ......................................................................................................... 51 3.1. Introduction ................................................................................................... 51 3.1.1. Spirocyclic Scaffolds in Biologically Active Natural Products and Pharmaceutical Compounds .................................................................... 51 3.1.2. Synthesis of Spirocyclic Indolenines via Interrupted Fischer Indole Reactions .................................................................................................. 53 3.1.3. Synthesis of Spirocyclic Indolenines via Dearomatisation of Indoles ....... 55 3.1.4. Spirocyclic Indolenines as Precursors for Other Privileged Hetereocycles ................................................................................................................. 58 3.2. Project Outline .............................................................................................. 61 3.3. Results and Discussion .................................................................................. 63 3.3.1. Background and Initial Result .................................................................... 63 3.3.2. Optimisation of the Synthesis of Spirocyclic Compounds via N- Acyliminium Ions .................................................................................... 66 3.3.3. Broadening the Substrate Scope of the Spirocyclisation Reaction ............ 69 3.3.3.1 Fischer Indole Synthesis of 2-Methyl Substituted Indoles .................. 69 3.3.3.2 Reaction of 2-Methyl Indole Substrates in DIA Spirocyclisation and Assignment of Stereochemistry ........................................................................ 76 3.3.4. DIA Spirocyclisation with Variation in the 2-Position of the Indole ........ 81 3.3.5. Pyrrole-based Acid Substrates in the DIA Spirocyclisation Reaction ....... 87 3.3.6. Preparation and Reaction of Different Imine Scaffolds in Spirocycle Synthesis .................................................................................................. 89 3.3.7. Addition of Lewis Acid to the Spirocyclisation Reaction ......................... 94 3.3.8. Equilibrium Studies on Spirocyclic Indolenines ........................................ 95 3.3.9. Derivatisation of Spirocyclic Products ...................................................... 98 3.3.10. 3D Shape Analysis of Spirocycles .......................................................... 106 3.4. Conclusions and Future Work ................................................................... 110 4. Attempted Synthesis of Aspidospermidine using Direct Imine Acylation Methodology ....................................................................................................... 112 4.1. Introduction to Aspidospermidine ............................................................ 112 4.1.1. Classification and Biological Activity of the Aspidosperma Family ...... 112 4.1.2. Previous Syntheses of Aspidospermidine ................................................ 113 iv 4.2. Project Outline ............................................................................................ 119 4.3. Results and Discussion ................................................................................ 120 4.3.1. Proposed Routes Towards (±)-Aspidospermidine ................................... 120 4.3.2. Synthesis of Indole Acid Components ..................................................... 123 4.3.3. Work Towards Synthesis of the Imine Component ................................. 125 4.3.4. Investigations into the DIA Spirocyclisation Step in the Synthesis of Aspidospermidine .................................................................................. 140 4.4. Conclusions and Future Work ................................................................... 143 5. Experimental ...................................................................................................... 146 5.1. General Information ................................................................................... 146 5.2. General Procedures ..................................................................................... 149 5.3. Reaction Procedures and Compound Characterisation .........................