Exo-mode oxacyclization strategies for synthesis of trans-fused polycyclic ethers: the ABC ring sector of brevenal Open Access

Abstract

Chapter 1. Fused polycyclic ether natural products

Brevenal is a non-toxic metabolite of the dinoflagellate Karenia brevis, and acts as a competitive inhibitor of red tide toxins including brevetoxin. Both brevenal and brevetoxin B2 share a trans-fused polycyclic ether core. Our research explores exo-mode sequential cyclization pathways for the synthesis of polycyclic ether natural products from both alkyne and alkene substrates. This work culminates with synthesis of the ABC domain of the core structure of brevenal. Chapter 2. Mercury-promoted reductive oxacyclization reactions of alkynyl alcohols Mercury-promoted reductive oxacyclization reactions provide opportunity to construct polycyclic ether structures rapidly from alkynol substrates. Alkynyldiols undergo oxacyclization with substoichiometric Hg(OTf)2, and the resulting oxocarbenium ion either undergoes hydration, resulting in formation of hemiketals, or diastereoselective reduction with Et3SiH, furnishing trans-fused tetrahydropyrans. Beta-oxygen substituents are incompatible with this methodology as they are prone to elimination, and 8-endo cyclization predominates over 7-exo cyclization. Thus, thus this methodology is limited to cascade synthesis of 6,8-fused ethers. Chapter 3. Alkenol oxacyclizations: Synthesis of the ABC ring substructure of brevenal Our research explores regio- and stereoselective exo-mode cyclization pathways to the trans, syn, trans- fused polycyclic ether structure of brevenal. Sequential oxacyclizations of linear triene or diene precursors form the ABC ring substructure of brevenal. Our strategy constructs each cyclic ether with various hydroxy-alkene cyclizations, with stereoinduction from allylic oxygen substituents in the C-O bond forming/ ring-closing steps.

Table of Contents

Chapter 1. Fused polycyclic ether natural products

1.1 Background ............................................................................................................... 2 1.1.1 Red Tide Events and the Brevetoxins .......................................................................... 2 1.1.2 Biogenesis of fused polycyclic ether marine natural products ......................................... 5 1.1.3 Biomimetic synthesis: endo-mode polyepoxide cascades ............................................... 6 1.1.4 Brevenal ................................................................................................................14 1.1.5 Synthesis of brevenal ............................................................................................. 15 1.2 Introduction ............................................................................................................. 19 1.2.1 Exo-mode oxacyclization ......................................................................................... 19 Chapter 2. Mercury-promoted reductive oxacyclization reactions of alkynyl alcohols 2.1. Introduction and Background ..................................................................................... 22 2.1.1 Motivation for catalytic mercury-promoted oxacyclization.............................................. 22 2.1.2 Mercury(II) triflate promoted oxacyclization ............................................................... 24 2.1.3. Catalytic mercury: demercuration ............................................................................ 27 2.2. Results and Discussion .............................................................................................. 31 2.2.1. Synthesis of alkynyldiol 30 ..................................................................................... 31 2.2.2. Reductive cyclization of alkynyldiol 30...................................................................... 32 2.2.3. Synthesis of 1,4- diyne 39 ..................................................................................... 37 2.2.4. Alternative synthesis of 1,4- diyne 39 ..................................................................... 40 2.2.5 Cyclization of 1,4- diyne 39 .................................................................................... 42 2.2.6 Synthesis of 1,5- diyne 64 ...................................................................................... 45 2.2.7 Cyclization of 1,5- diyne 64 ..................................................................................... 47 2.2.8 Synthesis of tetrahydropyran- templated alkynol 76.................................................... 49 2.2.9 Cyclization of tetrahydropyran- templated alkynol 76 .................................................. 52 2.3 Conclusion ............................................................................................................... 56 2.4 Experimental Details ................................................................................................. 57 2.5 NMR spectra of selected compounds .......................................................................... 104 Chapter 3. Alkenol oxacyclization: Synthesis of the ABC ring substructure of brevenal 3.1. Background and Introduction .................................................................................. 126 3.1.1 Background ........................................................................................................ 126 3.1.2 Individual ring precedents: A and B rings ............................................................... 127 3.1.2.1 Individual ring precedent: A ring ........................................................................ 127 3.1.2.2 Individual ring precedent: B ring ........................................................................ 128 3.1.3 Exo-mode oxacyclization strategy for brevenal ........................................................ 130 3.1.3 C ring ................................................................................................................ 134 3.2. Results and Discussion .......................................................................................... 135 3.2.1 Electrophile-promoted oxacyclization of alkenyl alcohols .......................................... 135 3.2.1.1 Synthesis of acetonide-protected diol 37 ............................................................ 135 3.2.1.2 Synthesis of benzylidene protected diol 49 ......................................................... 137 3.2.1.3 Synthesis of vicinal diol 60 ............................................................................... 139 3.2.1.4 Cyclization of acetonide protected diol 37 ........................................................... 140 3.2.1.5 Cyclization benzylidene protected diol 49 ........................................................... 142 3.2.1.6 Cyclization of vicinal diol 60 ............................................................................. 143 3.2.2 AB ring model ................................................................................................... 145 3.2.2.1 Synthesis of bis-acetate-diene 74 ..................................................................... 145 3.2.2.2 Cyclization of bis-acetate-diene 74 ................................................................... 148 3.2.2.3 Synthesis of diene 22 ..................................................................................... 150 3.2.2.4 Cyclization of diene 22 ................................................................................... 151 3.2.3 BC ring model .................................................................................................. 155 3.2.3.1 Synthesis of dienyl ketone 96 .......................................................................... 157 3.2.3.2 Cyclization of saturated dienyl ketone 96 .......................................................... 159 3.2.3.3 Synthesis of unsaturated dienyl ketones 113 and 114 ........................................ 160 3.2.3.4 Cyclization of unsaturated dienyl ketones 113 and 114 ...................................... 162 3.2.4 ABC linear precursor ......................................................................................... 166 3.2.4.1 Synthesis of triene 126 .................................................................................. 167 3.2.4.2 Cyclization of triene 124 ................................................................................. 169 3.2.5 ABC model ....................................................................................................... 170 3.2.5.1 Synthesis of C-ring precursor 130 .................................................................... 171 3.2.5.2 Cyclizations of C-ring precursor 130 ................................................................. 173 3.2.5.3 Demercuration and deiodination of tricyclic compound 132 .................................. 174 3.3 Conclusion .......................................................................................................... 178 3.4 Experimental Details ............................................................................................ 180 3.5 X-RAY data of compounds 78 and 84 ..................................................................... 268 3.6 NMR spectra of selected compounds ....................................................................... 296 References ................................................................................................................ 329

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Keyword	total synthesis oxacyclization polycyclic ether brevenal
Committee Chair / Thesis Advisor	McDonald, Frank, Emory University
Committee Members	Jui, Nathan T, Emory University Blakey, Simon, Emory University

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