STRATEGIES FOR THE CONCISE SYNTHESIS OF THE AKUAMMILINE ALKALOIDS Myles Warwick Smith Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2015 © 2015 Myles Warwick Smith All rights reserved ABSTRACT Strategies for the Concise Synthesis of the Akuammiline Alkaloids Myles Warwick Smith The akuammiline alkaloids are an intriguing class of natural products that display an array of biological activities and structural diversity. Despite being known for over 125 years, it is surprising that these complex monoterpene indole alkaloids have only recently elicited sustained interest from the synthetic community, especially given the storied history of this broad family in the development of the art of total synthesis, and, in particular, heterocyclic chemistry. This dissertation details our efforts to address these deficiencies through work initially directed at the unique akuammiline alkaloid scholarisine A, ultimately yielding a concise and enantiospecific preparation of this challenging target. Hereafter, we showcase our studies aiming to extend these advances to the akuammiline class as whole, through the development of a readily generalizable approach to this alkaloid family. Thus, Chapter 1 will serve to introduce this exciting class of alkaloids, beginning with the details of their proposed biosynthesis, followed by a summary of the diverse biological activities they display. Lastly, the reported synthetic approaches to this family will be described, starting with a select number of early efforts and culminating in the few, but impressive examples of completed total syntheses that have recently appeared. Next, Chapter 2 will detail the evolution of our synthetic approach to the highly rearranged akuammiline alkaloid scholarisine A, a strategy guided throughout by a key pyrone Diels–Alder logic. That discussion will include out early attempts to fashion its characteristic framework through intramolecular Diels–Alder approaches and how those efforts informed the development of our eventual synthetic solution based on an intermolecular process. Finally, it will be demonstrated that advances made during our early work have led to a method with potential utility in both natural product synthesis and the assembly of medicinally-relevant building blocks. Finally, in Chapter 3, our efforts to develop a general approach to the akuammiline alkaloids will be described, studies that initially focused on the prototypical member of this class, strictamine. These efforts have culminated in a concise and readily scalable route to a number of advanced tetracyclic intermediates, empowered by a number of methodological advances. These intermediates, many embodying all the carbon atoms of strictamine and related targets, are poised for a final ring formation to complete their total syntheses. In addition, we disclose promising discoveries that should allow for broad access to akuammiline class, having identified facile means to transition from the strictamine series to other subfamilies. TABLE OF CONTENTS List of Abbreviations iv Acknowledgements vii Chapter 1. The Akuammiline Alkaloids: Background, Biosynthesis and Previous Synthetic Approaches 1 1.1 Introduction 2 1.2 Biological Activity and Biosynthesis 3 1.2.1 Biological Activity 3 1.2.2 Biosynthesis 5 1.3 Synthetic Studies in the Akuammiline Class 6 1.3.1 Early Synthetic Efforts 7 1.3.2 Total Syntheses of Vincorine 9 1.3.3 Total Syntheses of Aspidophylline A 15 1.3.4 The Smith Synthesis of (+)-Scholarisine A 19 1.3.5 The Garg Synthesis of (±)-Picrinine 22 1.4 Conclusions 24 1.5 References 25 i Chapter 2. A Concise Total Synthesis of (+)-Scholarisine A 28 2.1 Introduction 29 2.2. Isolation and Proposed Biosynthesis 30 2.3. Our Synthetic Approach to Scholarisine A: Pyrone Diels–Alder Logic 31 2.4. Early, Unsuccessful Intramolecular Pyrone Diels–Alder Approaches 37 2.4.1 Initial Macrocylic Pyrone IMDA Strategy 37 2.4.2. Pyrone IMDA Strategy Employing a Traceless Sulfide Tether 43 2.5. Intermolecular Pyrone Diels–Alder Approach 48 2.5.1. Initial 3,5-dibromopyrone-based Strategy 48 2.5.2. Optimization of the Synthesis of Alcohol 125 54 2.5.3. Regiochemistry of the Diels–Alder reaction 57 2.5.4. Studies with a Carbon-based Radical Trap – Forging the C-20 Quaternary Center 60 2.5.5. Completion of the Full Cage Framework of Scholarisine A 63 2.5.6. Arylation Studies 68 2.5.7. Elaboration of 174 to Scholarisine A 78 2.6. Extension of Early Unsuccessful IMDA Method to the Preparation of Aromatic and Non-aromatic Heterocycles 88 2.7 Conclusions and Outlook 94 ii 2.8 References 97 2.9 Experimental Section 100 Chapter 3. Studies toward Strictamine and Related Akuammiline Alkaloids 171 3.1. Introduction 172 3.2 Isolation, Biological Activity and Biosynthesis of Strictamine 173 3.2.1 Isolation and Structure Determination 173 3.2.2 Biological Activity 174 3.2.3 Biosynthesis 175 3.3 Previous Synthetic Efforts toward Strictamine 175 3.4 Our Approach to Strictamine 179 3.5 Development of Expedient Access to the Akuammiline Core 181 3.6 Carbonylative Heck Approach 186 3.7 Traditional Heck Approach 196 3.8 Alternate Radical Cyclization Approach 208 3.9 Conclusions and Outlook 216 3.10 References 220 3.11 Experimental Section 224 iii LIST OF ABBREVIATIONS ACCN 1,1’-azobis(cyclohexanecarbonitrile) AIBN azobisisobutyronitrile BHT 2,6-di-tert-butyl-4-methylphenol brsm based on recovered starting material Bt 1-benzotriazole BTPP tert-Butylimino-tri(pyrrolidino)phosphorane COD 1,4-cyclooctadiene DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DMA N,N-dimethylacetamide DMAP 4-(N,N-dimethylamino)pyrine DMF N,N-dimethylformamide DMP Dess–Martin periodinane HAT hydrogen-atom transfer HRMS high-resolution mass spectrometry IMDA intramolecular Diels–Alder IR infrared iv LR Lawesson’s reagent LRMS low-resolution mass spectrometry mCPBA meta-chloroperbenzoic acid MeOH methanol Ms methanesulfonyl MS molecular sieves NMM N-methylmorpholine NMR nuclear magnetic resonance NOESY nuclear Overhauser effect spectroscopy Ns 2-nitrobenzenesulfonyl o-DCB 1,2-dichlorobenzene pin pinacolato PMP 1,2,2,6,6-pentamethylpiperidine PPTS pyridinium p-toluenesulfonate PTSA p-toluenesulfonic acid Ra-Ni Raney nickel TBAF tetrabutylammonium fluoride TBDPS tert-butyldiphenylsilyl v TBS tert-butyldimethylsilyl TEMPO 2,2,6,6-Tetramethylpiperidine 1-oxyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofurn TIPB 1,3,5-triisopropylbenzene TMG N,N,N’,N’-tetramethylguanidine TMS trimethylsilyl Ts p-toluenesulfonyl UV ultraviolet VT-NMR variable temperature nuclear magnetic resonance vi