Studies of Halogenated Lipids andProgress Toward the Synthesis of Crotogoudin

242 Pages·2017·6.44 MB·English

by  Dmitriy Igorovich Uchenik

UC Irvine
UC Irvine Electronic Theses and Dissertations
Title
Studies of Halogenated Lipids and Progress Toward the Synthesis of Crotogoudin
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https://escholarship.org/uc/item/2hc28159
Author
Uchenik, Dmitriy
Publication Date
2017
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UNIVERSITYOFCALIFORNIA,
IRVINE
StudiesofHalogenatedLipidsand
ProgressTowardtheSynthesisofCrotogoudin
DISSERTATION
submittedinpartialsatisfactionoftherequirements
forthedegreeof
DOCTOROFPHILOSOPHY
inChemistry
by
DmitriyIgorovichUchenik
DissertationCommittee:
ProfessorChristopherD.Vanderwal,Chair
ProfessorElizabethR.Jarvo
ProfessorKennethJ.Shea
2017
(cid:13)c 2017DmitriyIgorovichUchenik
DEDICATION
Tomyfamily.
Tomyfriends.
ii
TABLE OF CONTENTS
Page
LISTOFSCHEMES v
LISTOFFIGURES vii
LISTOFTABLES viii
LISTOFEQUATIONS ix
ACKNOWLEDGMENTS xiii
CURRICULUMVITAE xiv
ABSTRACTOFTHEDISSERTATION xvi
Chapter1: StereochemicalDichotomyinDehydrohalogenationofLipids 1
1.1 Introduction 1
1.2 MechanismofBasePromotedVicinalEliminationReactions 2
1.2.1 VariabilityintheE2Mechanism 4
1.2.2 ConsequencesofBaseSpeciesonE2Eliminations 6
1.2.3 ConsequencesofLeavingGrouponE2EliminationReactions 9
1.3 Dehydrohalogenationofβ-chlorosulfates 12
1.3.1 HypothesisBasedonComputationalModels 13
1.3.2 EliminationResults 14
1.4 ExperimentalProcedures 18
Chapter2: ProgressTowardtheSynthesisofMollenyneA 31
2.1 HalogenatedlipidsfromSpirastrellamollis 31
2.2 RetrosyntheticAnalysis 33
2.3 SynthesisofVicinalBromo-ChlorideFragment 34
2.4 Pursuingabis-MetallatedNucleophile 35
2.5 ARingClosingMetathesisApproach 37
2.6 Conclusion 44
2.7 ExperimentalProcedures 45
Chapter3: ProgressTowardtheSynthesisofCrotogoudin 59
3.1 Biosynthesisofrelatedent-diterpenenaturalproductfamilies. 59
3.2 IsolationofCrotogoudin 62
3.3 Bioactivity 64
3.4 Synthesisofbicyclo[2.2.2]octanes 66
3.4.1 Diels–AlderanddoubleMichaelstrategies 66
3.4.2 Radicalcyclizationsandrearrangements. 72
3.4.3 Aldolstrategies. 74
3.4.4 Miscellaneousstrategies. 76
3.5 Synthesisof(+)-crotogoudinbytheCarreiragroup. 80
iii
3.6 LiuSynthesisof(±)-crotogoudinand(±)-crotobarin 84
3.7 Effortstowardsthesynthesisof(±)-crotogoudinandageneralsynthesisof
atisanediterpenes. 88
3.8 ABiomimeticApproach 89
3.9 OxygenDependenceinCopperHydrideReduction 92
3.10 SimpleKetonesinManganeseMediatedRadicalCyclization 97
3.11 AScalableSynthesis 103
3.12 Conclusion 106
3.13 ExperimentalProcedures 107
AppendixA:NMRDataforChapter1 127
AppendixB:NMRDataforChapter2 149
AppendixC:NMRDataforChapter3 177
iv
LIST OF SCHEMES
Page
Scheme1.1 MechanismofE1elimination. 2
Scheme1.2 MechanismofE1 elimination. 3
cB
Scheme1.3 MechanismofE2elimination 3
◦
Scheme1.4 EliminationStereochemistry—3 alkenes 10
◦
Scheme1.5 EliminationStereochemistry—2 alkenes 10
◦
Scheme1.6 EliminationStereochemistry—1 alkenes 10
Scheme1.7 Theimportanceofdiastereoselectivedehydrochlorination. 12
Scheme1.8 Dr.GrantShibuya’sobservedeliminationselectivity 12
Scheme1.9 Synthesisofβ-chlorosulfates. 14
Scheme2.1 RetrosyntheticanalysisofmollenyneA. 33
Scheme2.2 Synthesisofthevicinalbromo-chloridefragment. 34
Scheme2.3 Reproduction of the Walsh borotropic shift / transmetallation
approachto(Z)-allylicalcohols. 35
Scheme2.4 DesiredapplicationofWalshchemistry 36
Scheme2.5 Synthesisofmodelalkynesforhydrobrominationexperiments. 36
Scheme2.6 RevisedretrosyntheticanalysisofmollenyneA. 37
Scheme2.7 Hydrobrominationapproachto2.27. 38
Scheme2.8 Directalkenylationwith1-TIPS-1-bromoethylene. 39
Scheme2.9 Directalkenylationwith1-bromo-1-lithioethene. 39
Scheme2.10 Ringclosingmetathesiswith1,1-disubstitutedalkenylbromide. 41
Scheme2.11 ImportanceoftheThorpe–Ingoldeffectinring-closingmetathesis. 42
Scheme2.12 Attemptsatring-closingmetathesisofprotectedalkenylbromide. 43
Scheme3.1 Biosynthesis of ent-beyerene, ent-atisane, ent-kaurene, and
ent-trachylobanediterpenes. 60
Scheme3.2 Examplesofditerpenealkaloidsderivedfromatiserineandkaurene. 61
Scheme3.3 Fukumoto’ssynthesisof(+)-atiserine. 67
Scheme3.4 TheFukumotogroupsxylyleneDiels–Alderstrategy 68
Scheme3.5 Nicolaou’sinverseelectrondemandDiels–Alderenroutetoplatencin. 68
Scheme3.6 The Singh group’s oxidative dearomatization/oxidation approach to
platencin. 69
Scheme3.7 SorensenandSpangler’ssynthesisofeasternfragmentofandibeninB. 70
Scheme3.8 Banwellgroup’sapproachto(–)-platencin. 71
Scheme3.9 TheMaiergroup’sapproachtobicyclo[2.2.2]octanes. 71
Scheme3.10 Snider’sapproachto(–)-nor-platencin. 72
Scheme3.11 Toyota’sapproachto(–)-methylatisenoate. 72
Scheme3.12 Toyota’s direct radical bicyclization en route to (±)-methyl
gummiferolate. 73
Scheme3.13 Yadav’sformalsynthesisofplatencin. 74
Scheme3.14 Baran’ssemi-synthesisofatisanediterpenes. 75
Scheme3.15 The Abad group’s unified strategy employs a carbene to access the
trachylobanescaffold. 76
v
Scheme3.16 Rutjes’sformalsynthesisofplatencin. 77
Scheme3.17 TheMulzergroup’srapidassemblyoftheplatencincore. 78
Scheme3.18 Firstsynthesisofanarcutanediterpene. 79
Scheme3.19 Carreira’sretrosyntheticanalysisof(+)-crotogoudin. 80
Scheme3.20 Carreira’ssynthesisofthebicyclo[2.2.2]octanemoietyofcrotogoudin. 81
Scheme3.21 Carreira’skeyradicalcyclopropanefragmentation-cyclizationcascade. 82
Scheme3.22 Carreira’scrotogoudinendgame. 83
Scheme3.23 BicyclooctaneformationinLiu’s(±)-crotogoudinsynthesis. 85
Scheme3.24 M06-2X/6-31G(d,p)transitionstateenergiesforLiu’sinverseelectron
demandDiels–Alder 85
Scheme3.25 Liu’scrotogoudinendgame. 86
Scheme3.26 Liu’scrotobarinendgame 87
Scheme3.27 Proposedone-potassemblyofthecrotogoudinskeleton. 89
Scheme3.28 Dr. Mai’sretrosyntheticanalysisofcrotogoudin. 90
Scheme3.29 Abiomimeticapproachtocrotogoudin. 91
Scheme3.30 Palladiumcatalyzedmonooxidationof1,2-dppbz 95
Scheme3.31 Attemptsatfunctionalizationofenone3.154. 97
Scheme3.32 Mn(III)mediatedradicalbicyclizationreactionbySnider 99
Scheme3.33 Snider’sapproachtogymnomitrol.102 100
Scheme3.34 SolventeffectsonMn(III)mediatedfree-radicalcyclizations. 100
Scheme3.35 Mn(III)radicalbicyclizationofallyldecaloneand3.176 103
Scheme3.36 Anexpedientsynthesisofkeyenone3.154 104
Scheme3.37 UnexpectedlossofreactivityintheSakuraiallylation. 105
vi
LIST OF FIGURES
Page
Figure1.1 Selectbioactivenaturalproductswithcomplexalkenegeometry. 1
Figure1.2 PossibleE2transitionstates. 4
Figure1.3 Idealized More O’Ferrall plot of an E2 reaction. Enthalpy increases
greentoyellowtored. 4
Figure1.4 Groundstateenergiesofneutralandanionicβ,β-dichlorosulfate 14
Figure2.1 Selectpotentlybioactive,polyhalogenatedalgalnaturalproducts. 31
Figure2.2 MollenynesA-EisolatedfromSpirastrellamollisbytheMolinskigroup. 32
Figure2.3 Novikov and Sampson’s reactor for the synthesis and use of 1-bromo-
1-lithioethene. 40
Figure3.1 Crotogoudinandcrotobarin. 59
Figure3.2 ExamplesofnaturalproductsisolatedfromtheCrotonplantgenus. 62
Figure3.3 KeyNOESYcorrelationsobservedbytheRasoanaivogroup. 63
Figure3.4 Parthenolide,areportedTCPinhibitoranditsinactivederivative. 64
Figure3.5 Bicyclo[2.2.2]octanecontainingnaturalproducts. 66
vii
LIST OF TABLES
Page
Table1.1 E2eliminationreactionsasafunctionofsolventpolarity. 7
Table1.2 E2eliminationreactionsasafunctionofbaseconcentration. 7
Table1.3 E2eliminationreactionsasafunctionofbasestrength. 8
Table1.4 E2eliminationreactionsasafunctionofleavinggroup. 9
Table1.5 StereochemistryofE2dehydrohalogenationreactions 11
Table1.6 Selectivityindehydrochlorinationofβ-chlorosulfates. 15
Table1.7 Preliminarydehydrochlorinationwithvaryingsulfatecountercation. 16
Table2.1 TheDortagroup’sdiscoveryof 41
Table3.1 Cytotoxicityofcrotogoudin(3.1)andcrotobarin(3.2). 65
Table3.2 Exploration of the oxygen dependence of Lipshutz’s (BDP)-CuH
conjugatereductionreaction. 93
Table3.3 Attemptstooptimize(BDP)-CuHreductionunderoxygenatmosphere. 94
Table3.4 Conjugatereductionsusing1,2-dppbzOligatedCuH. 96
Table3.5 Explorationofbicyclo[2.2.2]octaneformationviaMn(III)mediateradical
cyclization. 101
viii