Chapter 1: The development of a model system for the B-ring of brevenal and methods for the formation of seven-membered rings. Chapter 2: Iterative alkyne-epoxide cross-couplings toward the total synthesis of PM toxin A. Chapter 3: The development of synthons for 1,3-dimethylallylation of aldehydes. Open Access

Stoltz, Kristen Layne (2014)

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The natural product brevenal is a non-toxic competitive inhibitor of red tide toxins including brevetoxin B2, and shares a trans-syn-trans-fused polycyclic ether core with the brevetoxin family. Our research explores an exo-mode cascade cyclization pathway for the core structure of brevenal. Iodocyclizations of hydroxyalkenes provided the 8-membered ring regioisomer, and the approach was modified to develop stereoselective conjugate additions of oxygen nucleophiles onto unsaturated carbonyls to provide 7-membered rings. The enantioselective total synthesis of PM-toxin A via iterative alkyne-epoxide couplings was also explored. A new method of preparing functionalized homoallylic alcohols by employing stereospecific [3,3]-sigmatropic rearrangements of aldehydes with a family of synthons that contain three elements of stereochemistry was investigated.

Table of Contents

Table of Contents

List of Illustrations






List of Abbreviations

CHAPTER 1: The development of a model system for the B-ring of brevenal and methods for the formation of seven-membered rings.

1.2 Introduction and Background 2

1.1.1 Red tide events 2

1.1.2 Polycyclic ether marine natural products 2

1.1.21 Brevetoxin family 4

1.1.3 Strategies for polycyclic ether synthesis 6

1.1.31 Previous syntheses of brevenal 9

1.1.4 A new approach to polycyclic ether synthesis 12

1.1.41 Exo-mode cyclizations from the McDonald laboratory 13

1.1.42 A model system for the B ring of brevenal 14

1.2 Results and Discussion 15

1.2.1 Electrophile-promoted oxacyclization of alkenyl alcohols 15 Preliminary results from iodocyclizations 16 Synthesis of hydroxy-diene substrates 17 results and discussion 22

1.2.2 Conjugate additions for 7-membered ring formation 28 Re-evaluation of synthetic plan for brevenal 30 Synthesis of conjugate addition substrates 31 Conjugate addition results and discussion 37

1.3 Conclusions and Future Work 42

1.4 Chemistry Experimental Detail 44

CHAPTER 2: Iterative alkyne-epoxide cross-couplings toward the total synthesis of PM-toxin A.

2.1 Introduction and Background 104

2.1.1 Classical alkyne-epoxide couplings 104

2.1.2 Mild activations of alkyne nucleophiles and various electrophiles 106

2.1.3 Mild conditions for alkyne-epoxide couplings 108

2.2 Biological significance of PM-toxin A 110

2.2.1 Previous syntheses of PM-toxin A 111

2.2 Novel approach to PM-toxin synthesis 112

2.2.1 Retrosynthetic Analysis Toward PM-toxin A 112

2.3 Results and Discussion 114

2.3.1 Preliminary results for hydrosilylation and oxidation of multiple

homopropargylic alcohols 114

2.3.2 Synthesis of carbon skeleton 115

2.4 Conclusions 122

2.5 Chemistry Experimental Detail 124

CHAPTER 3: The development of synthons for the 1,3-dimethylallylation of aldehydes.

3.1 Introduction and Background 140

3.1.1 Homoallylic alcohols in natural products and current methods

for preparation 140

3.1.2 Allyl transfer via the oxonia-Cope rearrangement to form linear

homoallylic alcohols 141

3.1.3 1,3-dimethylallylation of aldehydes to synthesize branched

homoallylic alcohols 144

3.2 New concepts and design for allyl transfer 149

3.2.1 Previous results in the McDonald lab 149

3.3 Results and Discussion 152

3.3.1 Synthon preparation 152

3.3.2 Initial results from 2-oxonia-Cope rearrangement 153

3.3.3 Revised synthetic route toward syn-synthon. 156

3.3.4 Revised synthetic route toward anti-synthon. 158

3.4 Conclusions 161

3.6 Experimental Details 162

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