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Total Synthesis of the Tetracyclic Antimalarial Myrioneuron Alkaloid (±)-Myrioneurinol

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Total Synthesis of the Tetracyclic Antimalarial Myrioneuron Alkaloid (±)-Myrioneurinol The Pennsylvania State University The Graduate School Eberly College of Science TOTAL SYNTHESIS OF THE TETRACYCLIC ANTIMALARIAL MYRIONEURON ALKALOID (±)-MYRIONEURINOL A Dissertation in Chemistry by Anthony J. Nocket © 2015 Anthony J. Nocket Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy August 2015 The dissertation of Anthony J. Nocket was reviewed and approved* by the following: Steven M. Weinreb Russell and Mildred Marker Professor of Natural Products Chemistry Dissertation Advisor Chair of Committee Kenneth E. Feldman Professor of Chemistry Alexander Radosevich Assistant Professor of Chemistry Edward G. Dudley Associate Professor of Food Science Tom Mallouk Evan Pugh Professor of Chemistry, Physics, Biochemistry, and Molecular Biology Head of the Department of Chemistry *Signatures are on file in the Graduate School ii ABSTRACT The first total synthesis of the tetracyclic antimalarial alkaloid myrioneurinol (19) in racemic form has been completed in twenty-seven steps and in 1.8% overall yield from commercially available materials. The spiranic A/D-ring subunit of the metabolite with the attendant C5,6-stereocenters was constructed via a highly diastereoselective intramolecular Michael addition (IMA) of N-Cbz lactam/(E)-α,β-unsaturated ester cyclization precursor 61 to afford spirocycle 62. After a series of failed attempts to alkylate various ester enolate and pyrrolidinoenamine derivatives of 62 at C7, an umpolung strategy involving the conjugate addition of a malonate enolate to the nitrosoalkene intermediate 124, derived from α-chloro-O- silylaldoxime 122, provided oxime geometric isomers 123a/b. Both of these isomers possessed the correct C7-stereochemistry for the natural product. Several methods were then explored to accomplish the pivotal C9,10 carbon-carbon bond formation to construct the B-ring within the cis- decahydroquinoline (DHQ) scaffold of the alkaloid. These approaches included the unsuccessful nitrile α-anion/imidate cyclization of precursor 133 and the olefin/lactam Rainier metathesis of N- sulfonyllactam precursors 156 and 160 to provide tricyclic enesulfonamides 157 and 161, respectively. Although the latter ring-closing metathesis method was successful, we were unable to functionalize tricycles 157 and 161 at C9 in order to complete the total synthesis. We were pleased to discover that an intramolecular allyl silane/N-sulfonyliminium ion variant of the Sakurai reaction could be utilized to construct the B-ring of the cis-DHQ system, resulting in a single diastereomer of tricycle 191 with the desired C9,10 relative configuration, which we were able to elaborate to (±)-myrioneurinol. iii TABLE OF CONTENTS LIST OF FIGURES vii ACKNOWLEDGEMENTS viii CHAPTER 1. INTRODUCTION AND BACKGROUND 1.1. Myrioneuron and Nitraria Alkaloids: Typical Structures and a Unified Biosynthetic Pathway 1 1.2. A Novel Tetracyclic Myrioneuron Alkaloid: (+)-Myrioneurinol 5 1.3. Previous Synthetic Studies toward the Myrioneuron Alkaloids 9 1.4. First Generation Retrosynthesis of (±)-Myrioneurinol 12 1.5. Background on Diastereoselective Intramolecular Michael Additions (IMAs) and Related Reactions 13 1.6. Preliminary Studies on the IMA Spirocyclization toward Myrioneurinol 17 CHAPTER 2. IMA STRATEGY TO CONSTRUCT A/D-RING SUBUNIT 2.1. ‘Soft’ Enolization Inspired by Evans, et al. 19 2.2. First Generation Route to N-Cbz Lactam Cyclization Precursor 20 2.3. Attempted ‘Soft’ IMA of Lactam Enoate 61 21 2.4. Determination of the Relative C5,6-Configuration of Spirocycle 62 23 2.5. Second Generation Route to Cyclization Precursor 61 25 2.6. Optimization Studies on the Pivotal IMA Spirocyclization 26 2.7. Exploration of Some Homologous IMA Spirocyclizations 28 2.7.1. Studies with Five-Membered Lactam Analog 74 29 2.7.2. Studies with Seven-Membered Lactam Analog 81 30 2.7.3. Rationalization for Failure of Enoates 74 and 81 to Spirocyclize 31 2.7.4. Modification of the Ester Tether Length 31 2.7.5. Studies with Homologues Pre-Functionalized at C7 33 iv 2.8. Attempted Asymmetric IMA Spirocyclization 35 2.8.1. Studies with (-)-Menthyl Carbamate Cyclization Precursor 103 35 2.8.2. Studies with (+)-TCC Ester Cyclization Precursor 107 36 CHAPTER 3: HOMOLOGATION OF A/D-RING SUBUNIT AT C7 3.1. Attempts to Homologate via Formation of C7 Ester Enolates 39 3.2. Attempts to Homologate at C7 via Enamine Chemistry 41 3.2.1. Studies with N-H Lactam (E)-Pyrrolidinoenamine 112 41 3.2.2. Studies with N-Bn Lactam (E)-Pyrrolidinoenamine 116 43 3.3 C7-Homologation via Nitrosoalkene Umpolung Conjugate Addition 44 3.3.1. Background on Nitrosoalkene Conjugate Additions 44 3.3.2. Nitrosoalkene Michael Addition of α-Chloro-O-Silylaldoxime 122 46 3.3.3. Rationalization of Observed C7-Diastereoselectivity 49 CHAPTER 4: B-RING CLOSURE STRATEGIES 4.1. Imidate/Nitrile α-Anion Cyclization Strategy 50 4.1.1. Preparation of Cyclization Precursor 50 4.1.2. Imidate/Nitrile α-Anion Cyclization Studies 52 4.2. Rainier Metathesis Strategy 54 4.2.1. Background on the Rainier Metathesis Reaction 54 4.2.2. Second Generation Retrosynthesis 55 4.2.3. Preparation of N-Tosyllactam/Terminal Olefin Cyclization Precursor 56 4.2.3.1. Lactam Nitrile System 56 4.2.3.2. Methoxymethyl (MOM) Ether System 57 4.2.3.3. Rainier Metathesis of N-Tosyllactam 156 59 4.2.3.4. Attempted Elaboration of N-Ts Enesulfonamide 157 60 4.2.4. N-SES-Lactam System 62 4.3. Allyl Silane/N-Sulfonyliminium Aza-Sakurai Strategy 63 4.3.1. Background: Weinreb Synthesis of the Sarain A Core Structure 63 v 4.3.2. Third Generation Myrioneurinol Retrosynthesis 66 4.3.3. Preparation of Cyclization Precursor 67 4.3.3.1. Attempted Allyl Silane Formation via Fleming Cuprate Methodology in Nitrile System 67 4.3.3.2. Attempted Allyl Silane Formation in Methoxymethyl (MOM) Ether-Protected System 68 4.3.3.3. Seyferth-Wittig Homologation of Aldehyde 182 70 4.3.4. Aza-Sakurai Reaction of N-Tosyllactam/Allyl Silane 189 72 4.3.5. Confirmation of the C9,10 Stereochemistry of Tricycle 191 74 CHAPTER 5: COMPLETION OF THE MYRIONEURINOL SYNTHESIS 5.1. Attempted Elaboration of N-Ts Tricyle 191 76 5.2. Alternative Protecting Groups for the Lactam Nitrogen 78 5.2.1. N-SES-Lactam System 78 5.2.2. N-Nosyllactam System 79 5.2.3. Acid-Labile Sulfonamides 80 5.2.4. Attempted Cyclization of N-Cbz Lactam 82 5.3. N-Tosyllactam System Revisted 82 5.4. Endgame: Closure of the 1,3-Oxazine C-Ring 84 5.5. Concluding Remarks 85 CHAPTER 6: EXPERIMENTAL SECTION 89 REFERENCES 163 vi LIST OF FIGURES Figure 1. Structures of Some Representative Myrioneuron Alkaloids 2 Figure 2. Structures of Some Representative Spiranic Nitraria Alkaloids 3 Figure 3. Structure and Conformation of (+)-Myrioneurinol (19) 5 Figure 4. Two-Dimensional NMR Analysis of (+)-Myrioneurinol (19) 6 Figure 5. NOESY Correlations for Tricycle 191 75 vii ACKNOWLEDGEMENTS Over the past five and a half years, I have had the great pleasure of pursuing my fascination with organic chemistry under the guidance of my advisor, Professor Steven M. Weinreb. I credit my growth as a scientist both to the challenging nature of natural product synthesis itself, and to the degree of independence and freedom of thought I have gained while working in his laboratory. Furthermore, I would like to acknowledge the insightful discussions, assistance, and training I have received from other members of the Weinreb laboratory, both past and present. My most heartfelt thanks must also be extended to the many wonderful friends I have made during my time here at Penn State, to whom I owe a great deal of my sanity. Finally, I would be remiss if I did not acknowledge the unwavering support of my beloved family, to whom I dedicate this dissertation. Without their constant words of encouragement in the face of the uncertainties and unavoidable setbacks of research, none of my accomplishments would have been possible. viii CHAPTER 1: INTRODUCTION AND BACKGROUND 1.1. Myrioneuron and Nitraria Alkaloids: Typical Structures and a Unified Biosynthetic Pathway The higher plant genus Myrioneuron (family Rubiaceae) includes approximately fifteen species distributed across southeast Asia. In recent years, M. nutans, a diminutive tree endemic to the forests of North Vietnam, has yielded a number of unusual secondary metabolites isolated from its aerial structures.1 These so-called ‘Myrioneuron alkaloids’ typically contain an array of chair six-membered rings including a cis-decahydroquinoline (cis-DHQ) moiety tightly fused to various carbocyclic or heterocyclic structural elements such as 1,3-oxazine and/or 1,3-diazine subunits. These natural products range in complexity from the simple tricyclic compounds (+)-myrioxazines A (Figure 1, 1) and B (2)2 to tetracycles such as (-)-schoberine (3) and (+)-myrionamide (4),3 pentacycles such as (+)-myriberine A (5),4 the hexacyclic compound (+)-myrobotinol (6),5 to the most complex metabolite isolated to date, the dimeric decacycle (+)-myrifabine (7).6 Myrioneuron alkaloids exhibit a variety of differing types of biological activity. For example, (+)-myriberine A (5) was reported to effectively inhibit the hepatitis C virus. Moreover, some alkaloids, including an ester derivative of (+)-myrobotinol (6) as well as (+)-myrifabine (7), have shown promising cytotoxicity against KB cell lines. 1 H H H H H H H H H H H N O N N R N H N H H H O O N O H (+)-myrioxazine A (1) (+)-myrioxazine B (2) R = H2, (-)-schoberine (3) R = O, (+)-myrionamide (4) H H H H H O H N H N H N N H N N N O N H N H H N N H O H H H H HO OH (+)-myriberine A (5) (+)-myrobotinol (6) (+)-myrifabine (7) Figure 1. Structures of Some Representative Myrioneuron Alkaloids. Bodo, et al. have suggested that these metabolites all share a common biosynthetic pathway from L-lysine, despite their structural diversity.1 Even more intriguing is the proposed intersection of Myrioneuron alkaloid biosynthesis with that of the alkaloids of the somewhat distantly related higher plant genus Nitraria (family Nitrariaceae) via a common intermediate (vide infra).
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