Investigations of exo-Mode Oxacyclizations for the Synthesis of Cyclic Ethers Open Access

Setterholm, Noah Allen (2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/f7623d22v?locale=en
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Abstract

The marine natural product brevenal behaves as a non-toxic inhibitor of the neurotoxin brevetoxin B2. Our research has focused on the construction of the complex polycyclic core structures of brevenal and related compounds via diastereoselective exo-mode cycloetherifications. Strategies for closing the 7-membered brevenal D ring using exo-mode cyclizations of an epoxyalkene were investigated. Anhydrous benzenesulfonic acid in chloroform was found to catalyze the diastereoselective cyclization of epoxyalkenes to form 6-membered rings. NMR studies suggest the intermediacy of an allyl arene sulfonate generated from addition of the sulfonic acid to the alkene terminus of the epoxy alkene. Attempts to form 7-membered rings using benzenesulfonic acid were mostly unsuccessful, with the putative allyl arenesulfonate undergoing either hydration or elimination reactions. Also studied were palladium-catalyzed cycloisomerizations of epoxyalkenes. In the presence of triisopropyl phosphite, addition of a catalytic quantity of diphenylphosphinic acid activated the epoxyalkene for the addition of palladium. Subsequent displacement of the generated palladium π-allyl with a pendant alcohol allowed for the stereoselective synthesis of 6-membered rings. In some instances, replacing triisopropyl phosphite with trimethylolpropane phosphite enabled the formation of 7-membered rings, including the brevenal CD substructure, which was obtained in low yield after an extended reaction period. Efforts directed toward achieving exo-mode bicyclizations for the synthesis of 6,6-ring systems were met with limited success, the bis-allylic alcohol of the starting material being vulnerable to dehydration side reactions under the iodocyclization and oxymercuration conditions attempted.

Table of Contents

CHAPTER 1: The development of exo-mode oxacyclizations of epoxyalkenes

1.1 Introduction.............................................................................................................2

1.1.1 Brevetoxin & Brevenal............................................................................................2

1.1.2 Preparation of polycyclic ethers through endo-mode polyepoxide cascades....................3

1.1.3 Focus on exo-mode cyclizations...............................................................................5

1.2 Design of test substrates...........................................................................................7

1.2.1 Planning a model system for exo-mode cyclization of epoxyalkenes..............................7

1.2.2 Precedent for cycloetherification with π-allyl intermediates..........................................8

1.2.3 Dehydrative cyclizations by Uenishi.........................................................................10

1.2.4 Acid catalyzed cyclizations by Nicolaou.....................................................................11

1.2.5 Retrosynthetic analysis of cyclization substrates........................................................11

1.2.6 Olefin cross metathesis as an enabling strategy........................................................12

1.3 Synthesis of cyclization substrates.............................................................................14

1.3.1 Preparation of allylic alcohol/ester metathesis coupling partner...................................14

1.3.2 Synthesis of vinyl epoxide metathesis coupling partners.............................................14

1.3.3 Early cross metathesis results.................................................................................16

1.3.3.1 Problems with TBS deprotection of metathesis products..........................................17

1.3.4 Cross metathesis with unprotected alcohol...............................................................19

1.3.5 Synthesis of bisacetate metathesis coupling partner..................................................20

1.3.6 Metathesis of bisacetate with epoxyalkene and deprotection.......................................21

1.3.7 Switching to TMS group for protection of the primary hydroxyl...................................22

1.3.8 Cross metathesis using nitro-Grela catalyst..............................................................23

1.3.9 Chemoselective deprotection of cross-metathesis products.........................................24

1.4 Brønsted acid catalyzed cyclizations...........................................................................25

1.4.1 Cyclization of 6-membered rings with PPTS..............................................................26

1.4.2 Cyclization of 6-membered rings with TsOH•H2O......................................................26

1.4.3 Synthesis of 7-membered ring cyclization substrate...................................................27

1.4.4 Attempts at oxepane formation via Brønsted acid catalysis.........................................29

1.4.5 Cycloetherification of 6-membered rings with anhydrous benzenesulfonic acid..............31

1.4.5.1 Decomposition products with prolonged reaction times...........................................33

1.4.6 Attempts at oxepane synthesis with anhydrous benzenesulfonic acid............................36

1.4.7 Preparation of substrates lacking an allylic oxygen.....................................................37

1.4.8 Benzenesulfonic acid mediated cyclization of epoxyalkenes lacking allylic oxygen

substituents.................................................................................................................38

1.4.8.1 Decomposition of pyran products upon prolonged exposure to reaction

conditions....................................................................................................................39

1.4.9 NMR investigation of sulfonic acid reaction mechanism..............................................40

1.4.10 Comparison of acid-mediated cyclization of E and Z epoxyalkenes.............................42

1.4.11 Proposal for explanation of observed pyran stereochemistry.....................................48

1.4.12 Precedent for 1,4 addition of sulfonic acids to epoxy alkenes.....................................51

1.4.13 Preparation of substrate for investigation of reaction intermediate.............................51

1.4.14 Direct NMR evidence for allyl arenesulfonate intermediate........................................52

1.4.15 Preparation of 7-membered cyclization substrate lacking allylic oxygen......................54

1.4.16 Cyclization attempt for 7-membered ring not bearing an allylic oxygen......................55

1.4.17 Synthesis of C-ring appended 7-exo cyclization substrate.........................................55

1.4.18 Cyclization attempts of C-ring appended 7-exo substrate with

benzenesulfonic acid.....................................................................................................57

1.4.19 Conclusions about Brønsted acid cyclizations of epoxyalkenes..................................59

1.5 Palladium catalyzed cyclizations................................................................................60

1.5.1 Exploration of added acid to Pd-catalyzed cyclizations...............................................60

1.5.2 Solvent screening of Pd cyclizations with added diphenylphosphinic acid......................62

1.5.3 Investigation of different Pd ligands........................................................................62

1.5.4 Cyclization with optimized Pd conditions..................................................................64

1.5.5 Proposed catalytic cycle for Pd/phosphinic acid cycloetherification...............................64

1.5.6 Determination of the absolute stereochemistry of pyran centers.................................66

1.5.7 Pd cyclization of substrates bearing allylic oxygen substituents..................................67

1.5.8 Attempts at oxepane formation with Pd/phosphinic acid conditions.............................68

1.5.9 Preparation of 7-exo cyclization substrate with an aromatic group in the tether............69

1.5.10 Successful cyclization to give a benzooxepane.......................................................70

1.5.11 Investigation of the cyclization of C-ring appended substrate using Pd/phosphinic

acid conditions............................................................................................................71

1.5.12 Investigations replacing triisopropyl phosphite with trimethylolpropane

phosphite (EtCage)......................................................................................................72

1.5.13 Successful preparation of the brevenal CD substructure using Pd catalysis

with EtCage................................................................................................................74

1.5.16 Conclusions about Pd-catalyzed cyclizations..........................................................80

1.6 Experimental Details...............................................................................................81

CHAPTER 2: Investigations of exo-mode bicyclizations

2.1 Introduction.........................................................................................................168

2.1.1 Exo-mode oxacyclizations in the McDonald laboratory.............................................168

2.2 Preparation of bicyclization substrate.......................................................................169

2.2.1 Bicyclization substrate design...............................................................................169

2.2.2 Synthesis of bicyclization substrate.......................................................................171

2.3 Bicyclization studies...............................................................................................172

2.3.1 Bicyclizations with iodine.....................................................................................172

2.3.2 Bicyclization with mercury trifluoroacetate.............................................................174

2.3.3 Conclusions.......................................................................................................175

2.4 Experimental details..............................................................................................176

3.1 References...........................................................................................................185

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