Investigations of exo-Mode Oxacyclizations for the Synthesis of Cyclic Ethers Öffentlichkeit
Setterholm, Noah Allen (2017)
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
About this Dissertation
School | |
---|---|
Department | |
Degree | |
Submission | |
Language |
|
Research Field | |
Stichwort | |
Committee Chair / Thesis Advisor | |
Committee Members |
Primary PDF
Thumbnail | Title | Date Uploaded | Actions |
---|---|---|---|
Investigations of exo-Mode Oxacyclizations for the Synthesis of Cyclic Ethers () | 2018-08-28 15:30:35 -0400 |
|
Supplemental Files
Thumbnail | Title | Date Uploaded | Actions |
---|