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(cid:2) (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) 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) (cid:2) 2009(cid:2) (cid:2) (cid:2) (cid:2) (cid:2) 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) (cid:2) 2009(cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) Copyright(cid:2)by(cid:2) Guoqiang(cid:2)Zhou(cid:2) 2009(cid:2) (cid:2) (cid:2) (cid:2) 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) (cid:2) 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 (cid:2) N O O O N O O (cid:2) N O N N O ACChydrazone (cid:2) t-Bu ApratoxinD iv (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) (cid:2) To My Family (cid:2) (cid:2) v (cid:2) 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 (cid:2) vi (cid:2) 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 (cid:2) vii (cid:2) 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 (cid:2) viii (cid:2) 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 (cid:2) (cid:2) ix (cid:2) 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 (cid:2) (cid:2) x

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