METHODS FOR DIRECT CARBON–CARBON BOND FORMATION AND THEIR APPLICATION TO ...

188 Pages·2009·1.29 MB·English

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METHODS(cid:2)FOR(cid:2)DIRECT(cid:2)CARBON–CARBON(cid:2)BOND(cid:2)FORMATION(cid:2)AND(cid:2)THEIR(cid:2)
APPLICATION(cid:2)TO(cid:2)NATURAL(cid:2)PRODUCT(cid:2)SYNTHESIS(cid:2)
by(cid:2)
Guoqiang(cid:2)Zhou(cid:2)
Department(cid:2)of(cid:2)Chemistry(cid:2)
Duke(cid:2)University(cid:2)
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Date:_______________________(cid:2)
Approved:(cid:2)
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Don(cid:2)M.(cid:2)Coltart,(cid:2)Supervisor(cid:2)
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Steven(cid:2)W.(cid:2)Baldwin(cid:2)
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Katherine(cid:2)J.(cid:2)Franz(cid:2)
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Eric(cid:2)J.(cid:2)Toone(cid:2)
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Dissertation(cid:2)submitted(cid:2)in(cid:2)partial(cid:2)fulfillment(cid:2)of(cid:2)
the(cid:2)requirements(cid:2)for(cid:2)the(cid:2)degree(cid:2)of(cid:2)Doctor(cid:2)
of(cid:2)Philosophy(cid:2)in(cid:2)the(cid:2)Department(cid:2)of(cid:2)
Chemistry(cid:2)in(cid:2)the(cid:2)Graduate(cid:2)School(cid:2)
of(cid:2)Duke(cid:2)University(cid:2)
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2009(cid:2)
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ABSTRACT(cid:2)
METHODS(cid:2)FOR(cid:2)DIRECT(cid:2)CARBON–CARBON(cid:2)BOND(cid:2)FORMATION(cid:2)AND(cid:2)THEIR(cid:2)
APPLICATION(cid:2)TO(cid:2)NATURAL(cid:2)PRODUCT(cid:2)SYNTHESIS(cid:2)
by(cid:2)
Guoqiang(cid:2)Zhou(cid:2)
Department(cid:2)of(cid:2)Chemistry(cid:2)
Duke(cid:2)University(cid:2)
(cid:2)
Date:_______________________(cid:2)
Approved:(cid:2)
(cid:2)
___________________________(cid:2)
Don(cid:2)M.(cid:2)Coltart,(cid:2)Supervisor(cid:2)
(cid:2)
___________________________(cid:2)
Steven(cid:2)W.(cid:2)Baldwin(cid:2)
(cid:2)
___________________________(cid:2)
Katherine(cid:2)J.(cid:2)Franz(cid:2)
(cid:2)
___________________________(cid:2)
Eric(cid:2)J.(cid:2)Toone(cid:2)
(cid:2)
(cid:2)
(cid:2)
An(cid:2)abstract(cid:2)of(cid:2)a(cid:2)dissertation(cid:2)submitted(cid:2)in(cid:2)partial(cid:2)
fulfillment(cid:2)of(cid:2)the(cid:2)requirements(cid:2)for(cid:2)the(cid:2)degree(cid:2)
of(cid:2)Doctor(cid:2)in(cid:2)the(cid:2)Department(cid:2)of(cid:2)
Chemistry(cid:2)in(cid:2)the(cid:2)Graduate(cid:2)School(cid:2)
of(cid:2)Duke(cid:2)University(cid:2)
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2009(cid:2)
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Copyright(cid:2)by(cid:2)
Guoqiang(cid:2)Zhou(cid:2)
2009(cid:2)
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Abstract
Direct(cid:2)carbon–carbon(cid:2)bond(cid:2)formation(cid:2)via(cid:2)soft(cid:2)enolization(cid:2)and(cid:2)in(cid:2)situ(cid:2)enolate(cid:2)
generation(cid:2) provides(cid:2) a(cid:2) straightforward(cid:2) approach(cid:2) to(cid:2) certain(cid:2) key(cid:2) transformations(cid:2) of(cid:2)
synthetic(cid:2)organic(cid:2)chemistry.(cid:2)(cid:2)Reactions(cid:2)are(cid:2)generally(cid:2)operationally(cid:2)simple(cid:2)and(cid:2)proceed(cid:2)
under(cid:2)mild(cid:2)conditions(cid:2)using(cid:2)untreated,(cid:2)reagent(cid:3)grade(cid:2)solvent(cid:2)open(cid:2)to(cid:2)the(cid:2)air.(cid:2)(cid:2)Using(cid:2)this(cid:2)
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direct(cid:2)approach(cid:2)as(cid:2)a(cid:2)basis,(cid:2)we(cid:2)have(cid:2)developed(cid:2)methods(cid:2)for(cid:2)the(cid:2)synthesis(cid:2)of(cid:2) (cid:3)hydroxy(cid:2)
(cid:2)
thioesters,(cid:2) (cid:3)keto(cid:2)thioesters,(cid:2)and(cid:2)1,3(cid:3)diketones,(cid:2)which(cid:2)are(cid:2)key(cid:2)intermediates(cid:2)for(cid:2)the(cid:2)
synthesis(cid:2) of(cid:2) natural(cid:2) products,(cid:2) pharmaceuticals,(cid:2) and(cid:2) other(cid:2) biologically(cid:2) relevant(cid:2)
compounds.(cid:2)(cid:2)In(cid:2)particular,(cid:2)four(cid:2)methodology(cid:2)projects(cid:2)are(cid:2)described:(cid:2)1)(cid:2)a(cid:2)direct(cid:2)aldol(cid:2)
addition(cid:2)of(cid:2)simple(cid:2)thioesters,(cid:2)2)(cid:2)a(cid:2)direct(cid:2)synthesis(cid:2)of(cid:2)1,3(cid:3)diketones,(cid:2)3)(cid:2)a(cid:2)direct(cid:2)crossed(cid:3)
Claisen(cid:2)reaction,(cid:2)and(cid:2)4)(cid:2)an(cid:2)anti(cid:3)selective(cid:2)four(cid:3)component(cid:2)direct(cid:2)aldol(cid:2)cascade(cid:2)reaction.(cid:2)
OH O O O O O
R2 SR R2 SR R2 R
R1 R1 R1
(cid:2)-Hydroxythioester (cid:2)-Ketothioester 1,3-Diketone(cid:2)
Progress(cid:2)toward(cid:2)the(cid:2)total(cid:2)synthesis(cid:2)of(cid:2)apratoxin(cid:2)D(cid:2)is(cid:2)described.(cid:2)(cid:2)The(cid:2)key(cid:2)steps(cid:2)of(cid:2)
the(cid:2)synthesis(cid:2)involve(cid:2)the(cid:2)asymmetric(cid:2)alkylation(cid:2)via(cid:2)chiral(cid:2)N(cid:3)amino(cid:2)cyclic(cid:2)carbamate(cid:2)
(ACC)(cid:2)hydrazones,(cid:2)a(cid:2)new(cid:2)technology(cid:2)recently(cid:2)developed(cid:2)by(cid:2)our(cid:2)group.(cid:2)
S
(cid:2) H
PMB N
N
OH
O
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O O
N O O
(cid:2) N
O N
N O
ACChydrazone
(cid:2) t-Bu
ApratoxinD
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To My Family
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Contents
Abstract.........................................................................................................................................iv
List(cid:2)of(cid:2)Figures................................................................................................................................x
List(cid:2)of(cid:2)Schemes.............................................................................................................................xi
List(cid:2)of(cid:2)Tables..............................................................................................................................xiii
List(cid:2)of(cid:2)Abbreviations.................................................................................................................xiv
Acknowledgements...................................................................................................................xix
Chapter(cid:2)One:(cid:2)Direct(cid:2)Carbon–Carbon(cid:2)Bond(cid:2)Formation(cid:2)via(cid:2)Soft(cid:2)Enolization.......................1
1.1(cid:2)Background(cid:2)and(cid:2)Introduction..........................................................................................1
1.1.1(cid:2)Learning(cid:2)from(cid:2)Nature:(cid:2)Direct(cid:2)Carbon–Carbon(cid:2)Bond(cid:2)Formation.......................1
1.1.2(cid:2)Hard(cid:2)and(cid:2)Soft(cid:2)Enolization........................................................................................2
1.2(cid:2)A(cid:2)Mild(cid:2)and(cid:2)Direct(cid:2)Aldol(cid:2)Addition(cid:2)of(cid:2)Simple(cid:2)Thioesters.............................................3
1.2.1(cid:2)Aldol(cid:2)Reaction............................................................................................................3
1.2.2(cid:2)Acetyl(cid:2)Coenzyme(cid:2)A(cid:2)and(cid:2)Thioester.........................................................................4
1.2.3(cid:2)Initial(cid:2)Investigation....................................................................................................6
1.2.4(cid:2)Competition(cid:2)Experiments.........................................................................................7
1.2.5(cid:2)Effect(cid:2)of(cid:2)Thiol(cid:2)Component.......................................................................................8
1.2.6(cid:2)Substituting(cid:2)MgBr (cid:4)OEt (cid:2)for(cid:2)MgI ............................................................................9
2 2 2
1.2.7(cid:2)Solvent(cid:2)and(cid:2)Base(cid:2)Screen..........................................................................................11
1.2.8(cid:2)Reaction(cid:2)Scope..........................................................................................................12
1.2.9(cid:2)Catalytic(cid:2)Investigation............................................................................................14
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1.2.10(cid:2)Asymmetric(cid:2)Exploration.......................................................................................15
1.2.11(cid:2)Section(cid:2)Summary...................................................................................................16
1.3(cid:2)A(cid:2)Facile(cid:2)and(cid:2)Practical(cid:2)Approach(cid:2)to(cid:2)the(cid:2)Synthesis(cid:2)of(cid:2)1,3(cid:3)Diketone(cid:2)Compounds....17
1.3.1(cid:2)1,3(cid:3)Diketone(cid:2)Compounds.......................................................................................17
1.3.2(cid:2)Method(cid:2)Design.........................................................................................................19
1.3.3(cid:2)Initial(cid:2)Investigation..................................................................................................20
1.3.4(cid:2)Acylating(cid:2)Agent(cid:2)and(cid:2)Lewis(cid:3)Acid/Solvent(cid:2)Screen...............................................22
1.3.5(cid:2)Reaction(cid:2)Scope..........................................................................................................25
1.3.6(cid:2)Examination(cid:2)of(cid:2)Stereochemical(cid:2)Integrity.............................................................29
1.3.7(cid:2)Section(cid:2)Summary.....................................................................................................29
1.4(cid:2)An(cid:2)Exceptionally(cid:2)Simple(cid:2)and(cid:2)Versatile(cid:2)Crossed(cid:3)Claisen(cid:2)Reaction..........................30
1.4.1(cid:2)Crossed(cid:3)Claisen(cid:2)Reaction.......................................................................................30
1.4.2(cid:2)Nature’s(cid:2)Use(cid:2)of(cid:2)Thioesters(cid:2)in(cid:2)Crossed(cid:3)Claisen(cid:2)Reaction(cid:2)and(cid:2)Our(cid:2)Approach.31
1.4.3(cid:2)Thioester(cid:2)Screen(cid:2)and(cid:2)Comparison(cid:2)with(cid:2)Oxoester...............................................34
1.4.4(cid:2)Reaction(cid:2)Scope..........................................................................................................36
1.4.5(cid:2)Direct(cid:2)Transformations(cid:2)of(cid:2)(cid:2)(cid:3)Keto(cid:2)Thioester........................................................40
1.4.6(cid:2)Application(cid:2)to(cid:2)the(cid:2)Total(cid:2)Synthesis(cid:2)of(cid:2)LY294002..................................................41
1.4.7(cid:2)Section(cid:2)Summary.....................................................................................................43
1.5(cid:2)Conclusion........................................................................................................................44
1.6(cid:2)Experimental(cid:2)Section.......................................................................................................45
1.6.1(cid:2)Supporting(cid:2)Information(cid:2)for(cid:2)Direct(cid:2)Aldol(cid:2)Addition(cid:2)of(cid:2)Thioesters....................46
1.6.2(cid:2)Supporting(cid:2)Information(cid:2)for(cid:2)the(cid:2)Synthesis(cid:2)of(cid:2)1,3(cid:3)Diketones..............................61
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1.6.3(cid:2)Supporting(cid:2)Information(cid:2)for(cid:2)Crossed(cid:3)Claisen(cid:2)Reaction......................................80
Chapter(cid:2)Two:(cid:2)Direct(cid:2)Carbon(cid:3)Carbon(cid:2)Bond(cid:2)Formation(cid:2)via(cid:2)in(cid:2)situ(cid:2)Enolate(cid:2)Generation(cid:2)and(cid:2)
Domino(cid:2)Reaction.......................................................................................................................102
2.1(cid:2)Background(cid:2)and(cid:2)Introduction......................................................................................102
2.1.1(cid:2)Chemoselectivity(cid:2)Issue(cid:2)in(cid:2)Direct(cid:2)Aldol(cid:2)Reaction..............................................102
2.1.2(cid:2)Domino(cid:2)Reaction(cid:2)and(cid:2)in(cid:2)situ(cid:2)Enolate(cid:2)Generation.............................................103
2.1.3(cid:2)Reaction(cid:2)Design.....................................................................................................104
2.2(cid:2)An(cid:2)Efficient(cid:2)Anti(cid:3)Selective(cid:2)Four(cid:3)Component(cid:2)Direct(cid:2)Aldol(cid:2)Cascade(cid:2)Reaction.....105
2.2.1(cid:2)Condition(cid:2)Screen....................................................................................................105
2.2.2(cid:2)Reaction(cid:2)Pathway..................................................................................................106
2.2.3(cid:2)Reaction(cid:2)Scope........................................................................................................108
2.2.4(cid:2)Reversibility(cid:2)Test...................................................................................................109
2.2.5(cid:2)Thioester(cid:2)Effect.......................................................................................................110
2.2.6(cid:2)Reaction(cid:2)with(cid:2)PhSNa.............................................................................................110
2.2.7(cid:2)Li+(cid:2)Effect..................................................................................................................112
2.2.8(cid:2)Rationale(cid:2)of(cid:2)Reaction(cid:2)Mechanism.......................................................................113
2.2.9(cid:2)Subsequent(cid:2)Transformations(cid:2)and(cid:2)Applications................................................114
2.3(cid:2)Conclusion......................................................................................................................115
2.4(cid:2)Experimental(cid:2)Section.....................................................................................................116
Chapter(cid:2)Three:(cid:2)Progress(cid:2)toward(cid:2)the(cid:2)Total(cid:2)Synthesis(cid:2)of(cid:2)Apratoxin(cid:2)D...............................133
3.1(cid:2)Background(cid:2)and(cid:2)Introduction......................................................................................133
3.1.1(cid:2)Isolations,(cid:2)Biological(cid:2)Activities(cid:2)and(cid:2)Syntheses(cid:2)of(cid:2)Apratoxins.........................133
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3.1.2(cid:2)Retrosynthetic(cid:2)Analysis(cid:2)of(cid:2)Apratoxin(cid:2)D.............................................................135
3.2(cid:2)Result(cid:2)and(cid:2)Discussion...................................................................................................138
3.2.1(cid:2)Initial(cid:2)Synthesis(cid:2)of(cid:2)ACC(cid:2)Hydrazone...................................................................138
3.2.2(cid:2)Switching(cid:2)Protecting(cid:2)Groups...............................................................................141
3.2.3(cid:2)(cid:3)(cid:3)Alkylation(cid:2)Reactions(cid:2)with(cid:2)ACC(cid:2)Hydrazone..................................................143
3.2.4(cid:2)Removing(cid:2)ACC(cid:2)Auxiliary....................................................................................145
3.3(cid:2)Conclusion......................................................................................................................146
3.4(cid:2)Experimental(cid:2)Section.....................................................................................................146
References..................................................................................................................................162
Biography...................................................................................................................................168
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List of Figures
Figure(cid:2)1.(cid:2)The(cid:2)Citrate(cid:2)Synthase(cid:2)Reaction....................................................................................5
Figure(cid:2)2.(cid:2)Bis(cid:3)alkylated(cid:2)Byproduct............................................................................................12
Figure(cid:2)3.(cid:2)Representative(cid:2)Biologically(cid:2)Relevant(cid:2)1,3(cid:3)Diketones(cid:2)and(cid:2)Derivatives................18
Figure(cid:2)4.(cid:2)(cid:3),(cid:3)(cid:3)Bis(cid:3)acylation(cid:2)Byproduct(cid:2)and(cid:2)Self(cid:3)acylation(cid:2)Product.....................................21
Figure(cid:2)5.(cid:2)Typical(cid:2)Cyclized(cid:2)Product..........................................................................................27
Figure(cid:2)6.(cid:2)Fatty(cid:2)Acid(cid:2)Biosynthesis.............................................................................................32
Figure(cid:2)7.(cid:2)Qualitative(cid:2)Relationship(cid:2)between(cid:2)Brønsted(cid:2)Acidity,(cid:2)Lewis(cid:3)Basicity(cid:2)and(cid:2)Soft(cid:2)
Enolization...................................................................................................................................33
Figure(cid:2)8.(cid:2)Structures(cid:2)of(cid:2)Apratoxins(cid:2)A(cid:3)E..................................................................................133
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