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Synthetic Studies Toward Methanoquinolizidine-Containing Akuammiline Alkaloids

Andreansky, Eric (2017)
Dissertation (276 pages)
Committee Chair / Thesis Adviser: Blakey, Simon
Committee Members: McDonald, Frank ; Liebeskind, Lanny S
Research Fields: Organic chemistry
Keywords: Natural Product; Organic Synthesis; Alkaloids; Akuammiline; Strictamine; Cascade Reaction
Program: Laney Graduate School, Chemistry
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The akuammiline alkaloids are family of indole monoterpenoids that are characterized by their congested, polycyclic cores. A subset of these alkaloids containing a methanoquinolizidine core has been the subject of much synthetic interest, but only recently have been the subject of successful total syntheses. A cascade annulation toward a tetracyclic akuammiline alkaloid core has been developed beginning from an accessible N-Cbz hemiaminal ether substrate containing pendant indole and allylsilane moieties. Unlike related cascades toward the Malagasy alkaloids, these cascade substrates were only tolerant of (Z)-allylsilane geometries, with the other isomers only providing an undesired diene product. Studies were performed on making this and related cascade enantioselective with both a chiral auxiliary and enantioselective catalysis. This tetracyclic intermediate was converted into a pentacyclic methanoquinolizidine core for the natural product strictamine. Additionally, this core could be converted into a pentacyclic furoindoline core that maps onto the currently unsynthesized natural product pseudoakuammigine. While successfully leading us to these structures, the currently developed routes require a significant number of steps. Studies are currently underway to develop a more succinct route to these natural products.

Table of Contents

1. The Akuammiline Alkaloids: Structure, Biology, and Synthesis

1.1. Introduction 1

1.2. Biological Activity 6

1.3. Akuammiline Alkaloids: Prior Synthetic Studies 7

1.3.1. Total Syntheses of Vincorine 8

1.3.2. Total Syntheses of Aspidophylline A 11

1.3.3. Total Syntheses of Scholarisine A 15

1.3.4. Total Syntheses of Other Akuammiline Alkaloids 17

1.4. Methanoquinolizidine Alkaloids: Prior Synthetic Studies and Total Syntheses of Strictamine 21

1.5. Conclusion 33

1.6. References 33

2. Development of a Cascade Annulation Toward an Akuammiline Alkaloid Core

2.1. Previous Studies: Iminium Ion Cascades Toward the Malagasy Alkaloids 37

2.2. Unexpected Regiodivergent Cascade Products During Malagasy Alkaloid Studies 41

2.3. Synthesis and Reactivity of N,N'-Bistosyltryptamine Hemiaminal Ether Substrates 2.31 and 2.32 44

2.4. Development of (N-Ts-N'-Cbz)Tryptamine-Based Substrates for Akuammiline Alkaloid Cascade Reactions 50

2.5. Optimization of Cascade with Z-Allylsilane Containing Substrate 2.62 59

2.6. Studies Toward the Development of Asymmetric Iminium Ion Cascades 60

2.6.1. Examination of Diastereoselective Additions to Hemiaminal Ethers Substituted with Ellman's Auxiliary 61

2.6.2. Studies Toward the Development of an Asymmetric Cascade Reaction with Ion-Pairing Catalysis 67

2.7. Conclusion 79

2.8. Experimental Procedures 80

2.9. Spectral Data for Key Intermediates 128

2.10. References 148

3. Synthetic Studies Toward Methanoquinolizidine-Containing Akuammiline Alkaloids

3.1. Initial Strategy: Homologation of Exocyclic Olefin and Lactamization 150

3.2. Ketone Addition/Deoxygenation Strategy for Synthesis of the E Ring 155

3.3. Intramolecular Conjugate Addition Strategy for Synthesis of the E Ring 161

3.4. Lactamization Revisited: Cross-Coupling/Hydrogenation Strategy for the Synthesis of the E Ring 168

3.5. Synthesis of Pseudoakuammigine Furoindoline Core Model 177

3.6. New Directions: Development of an Alternative Akuammiline Alkaloid Cascade Annulation 181

3.7. Conclusion and Future Directions 188

3.8. Experimental Procedures 189

3.9. Spectral Data for Key Intermediates 216

3.10. References 253


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