Organic Synthesis III - University of Oxforddonohoe.chem.ox.ac.uk/resources/2016H1.pdf · Prof Tim Donohoe: Strategies and Taccs in Organic Synthesis: Handout 1 2/33 Organic Synthesis

ProfTimDonohoe:StrategiesandTac5csinOrganicSynthesis:Handout1

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OrganicSynthesisIII8x1hrLectures:MichaelmasTerm

Weeks5-82016Monat10am;Wedat9amDysonPerrinslecturetheatre

CopiesofthishandoutwillbeavailableathEp://donohoe.chem.ox.ac.uk/page16/index.html


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OrganicSynthesisIIISynopsis

1)Introduc5ontosynthesis:(i)Whydowewanttosynthesisemolecules-whatsortofmoleculesdoweneedtomake?(ii)WhataspectsofselecAvitydoweneedtoaccomplishagoodsynthesis(chemo-,regio-andstereoselecAvity)?(iii)ProtecAnggroupchemistryiscentraltoanysyntheAceffort(examplesandprinciples)(iv)Whatistheperfectsynthesis(performedinindustryversusacademia)?

2)Thechiralpool:wheredoesabsolutestereochemistrycomefrom?

3)Retrosynthesis-learningtothinkbackwards(revisionfromfirstandsecondyear).ImportanceofmakingC-CbondsandcontrollingoxidaAonstate.Umpolung

4)Someproblemstothinkabout5)Examplesofretrosynthesis/synthesisinac5on.6)Tenhandyhintsforretrosynthesis7)Solu5onstotheproblems

Recommendedbooks:General:OrganicChemistry(Warrenetal)OrganicSynthesis:TheDisconnecRonApproach(S.Warren)ClassicsinTotalSynthesisVolumesIandII(K.C.Nicolaou)TheLogicofChemicalSynthesis(E.J.Corey)


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(i)Whydowewanttosynthesisecomplexmolecules?

Foralistofthestructuresofthetop200bandnamedrugsbyretaildollarssee:hEp://cbc.arizona.edu/njardarson/group/top-pharmaceuRcals-poster

IsolatedfromthePacificYewin1962Prescribedforprostate,breastandovariancancerUniquemodeofacRon1x100yearoldtree=300mgTaxol

619461 Strychniqae and BYucine. Pavt X L I I . 903

198. Strychnine and Brucine. Part XLII. Constitution of the neo-Series of Bases and their Oxidation Products.

By L. H. BRIGGS, H. T. OPENSHAW, and SIR ROBERT ROBINSON. An alternative strychnine (brucine and colubrine) formula is feasible in which N(b) is joined to position 4

of the tetrahydrocarbazole nucleus, instead of to position 3 as hitherto postulated. An advantage is gained in that the new possible structure contains a 8-collidine skeleton in addition to those of carbazole and tryptamine. In addition a biogenetic relation to cinchonine can be perceived.

The obstacles to consideration of this modification of the formulae were the formation and properties Of methoxymethylchanodihydrostrychnone and these have not yet been removed by a reinterpretation of the chemistry of the neo-series of bases.

The action of p-nitrobenzenediazonium chloride on neostrychnine and methoxymethyldihydroneostrychnine results in the formation of derivatives that are devoid of basic properties. They are undoubtedly p-nitro- phenylhydrazones of keto-amides containing :N(b).CO.. The consequences are discussed and it is concluded that a change of view in regard to the skeleton of the alkaloids could only be entertained after acceptance of one of two alternative theories of the structure of the oxidation products of the neo-bases. It is now found that the reduction of methylneostrychnidinium chloride by means of sodium amalgam does not afford methylchanodihydroneostvch- nidine des-base-A, m. p. 143", but instead methyldihydrostrychnidinium-A chloride. The des-base-A, m. p. 143", is therefore, in all probability, methylchanodihydrostrychnidine. The constitutions of the series of Hofmann elimination products on this basis are indicated.

UNAMBIGUOUS experimental proofs are now available covering the whole periphery of the strychnine molecule and what is certainly known * is formulated in the expression I.

* The hydrogen atom shown attached to the a-position of the indole nucleus is included because evidence has been This work will shortly obtained that one of the so-called " colourlegs " benzylidene derivatives is a benzyl-a-pyridone.

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View Article Online / Journal Homepage / Table of Contents for this issue

Isolatedin1818-poisonousStucturalelucidaRontookR.Robinson40years

DevelopedintheUK(Pfizer)


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(ii)Inordertoundertakethesynthesisofacomplexorganicmolecule,weneedtocontrolthefollowing:1)Carbonskeleton:iethecorrectCONNECTIVITY2)FuncRonalgroups:inthecorrectposiRon3)Stereochemistry:controlofBOTHrelaRveandabsoluteInordertocontrol1)and2)aboveweneedthefollowingaspectsA)ChemoselecRvity:PreferenRalreacRonofonefuncRonalgroupoveranother

AND


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B)RegioselecRvity:PreferenRalformaRonofonestructuralisomeroveranother;fourexamples

B2H6

NaOH,H2O2


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C)StereoselecRvity:PreferenRalformaRonofonestereoisomeroveranother(i)Usethebiasofthemolecule: Sterics

Direc5ngeffects

(ii)OranexternalchiralreagenttoIMPOSEstereochemistryonthemolecule

NaBH4gavea1:1mixtureofdiastereoisomers


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Protec5nggroups:SadlythesearesRllessenRaltomostchemicalsyntheses

BulkersilicongroupsmayrequireamorereacRvereagent:useR3Si-OSO2CF3=R3SiOTf

TherearetacRcsforprotecRngthemostANDtheleasthinderedfuncRonalgroups,eg


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CyclicprotecRnggroupscanbeusefulinachievingselecRvity

PrimaryOHisunabletoformastable,cyclicacetalandREMAINSunprotected

SomeRmestheirintrinsicproperRescanhelp


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(iii)Whatistheperfectsynthesis(performedinindustryversusacademia)?‘createsacomplexmolecule...inasequenceofonlyconstrucRonreacRonsinvolvingnointermediaryrefuncRonalizaRons,andleadingdirectlytothetarget,notonlyits skeletonbutalsoitscorrectlyplacedfuncRonality.”

IdeallyasynthesiswouldbeLength-Non-CommerciallySolventMildAtmosphereofPurificaRonYieldWaste

Academicresearchersandmedicinalchemistsarehighlyfocusedonatargetoranalogsthereofandemploywhatevermeanstogetthemmade.Processchemistsaimtowardsmore"ideal"construcRonofmoleculeswhichtendstowardminimizaRonofsteps/costsandanincreasedemphasisonyieldsandreproducibility.

Constraintsonanindustrialsynthesis:AmenabletoReliableAvailabilityandcostofToxicityofPurityofPRODUCTS;IntellectualPROPERTY(noIPinfringements)

Ideassuchas,atomeconomy,stepeconomy,redoxeconomyhaveemerged.Foranin-depthdiscussionofthe‘ideal’synthesissee:J.Org.Chem.2010,75,4657.


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2)Thechiralpool:wheredoesabsolutestereochemistrycomefrom?

NaturehasprovidedawiderangeofenanRopurecompoundsingreatabundanceAminoacids,carbohydrates,terpenes.CalledtheCHIRALPOOLNewcompoundsaddedbychemicalsynthesis-alsoavailableinscale.Thesecompoundscanbecomethetargetthemselves,oralsothebasisofreagents,ligandsandchiralauxiliaries,topassontheirstereochemicalinformaRonindirectly. Advantages:CHEAP;

availableonalargeSCALEDisadvantages:onlyoneenanRomerFuncRonalgroupinterconversionscanleadto

Aminoacids20proteinogenicAAsAllaminoacidsfoundinproteinsoccurintheL-configuraRonaboutthechiralcarbonatom.

Q.WorkouttheabsoluteconfiguraRonsofthefouraminoacidsshownabove.

D-alanine-£3perg(5g)L-alanine-30ppergram(1kg)DLalanineis6pperg(5Kg)

D-proline-£12perg(5g)L-proline-40ppergram(5kg)DLprolineis£10perg(5g)

RepresentaRveprices


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Carbohydrates:theDenanRomertendstofoundinNatureD-glucose1ppergram(>5Kg)L-glucose-UNAVAILABLE

However,LsugarsAREfoundinNature

TerpenesTheclassofterpenechemicalsareabundantamongnaturalproductsandmanycompoundshavecommercialapplicaRons,e.g.camphor.OthercompoundsofthisclassareusedinpharmaceuRcalpreparaRonsorasfragrants,e.g.limoninefromcitrusfruit.

Miscellaneousothers:α-hydroxyACIDSandalkaloids:Qlookupthestructuresofmandelicacid,malicacidandquinine.


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Howelsemightweobtainenan;opurecompounds?RESOLUTIONTartaricacid:isolatedfromthesaltinc.800AD.NaturallyoccurringacidisCHIRALFoundinfruitsandwine:UnnaturalenanRomerismadesyntheRcally

LouisPasteur(c.1848)AsoluRonoftartaricacidderivedfromlivingthings(specificallyWINE)rotatedtheplaneofpolarizaRonoflightpassingthroughit.However,tartaricacidderivedbychemicalsynthesishadnosucheffect,eventhoughitselementalcomposiRonwasthesame.DuringaninvesRgaRonoftheshapesofamonaiumsodiumtartratecrystals,hefoundthemtobeCHIRAL(iemirrorimagesofoneanother)

ManualsorRngunderaMICROSCOPE.AllowedtheproducRonofbothenanRomersoftartaricacid.HappenedbecausethissaltcrystallisesasaCONGLOMERATE


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AmoreClassicalResolu5ontechniqueisshownbelow:

3stepguidetoresoluRon:1)Makeaderiva5ve(useenan5opurereagent)ProductsareDIASTEREOISOMERS(iedifferentcompounds)3)Releasetheoriginalcompound(egbyaddingHCltoA).However,themaximumyieldis50%-wasteful

AmoresophisRcatedexampleofthisisfoundinanindustrialvariantofLilly’ssynthesisofduloxeRne(Cymbalta)Usedforthetreatmentofdepression.Annualsalesin2010were$2.6billion.


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CompleRonofthesynthesis


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RecyclingoftheunwantedenanAomer?

SeeOrganicProcessResearchandDevelopment,2006,10,905.

TherearemanyvariantsoftheresoluRonprocessincludingKine5cResolu5on(seetheSharplessAsymmetricEpoxidaRonandenzymaRcresoluRon).BasicprincipleofKine5cResolu5on:

Achiral(andenanRopure)reagent,reactsfasterwithONEenanRomerthantheOTHER.ProductsareDIFFERENTandusuallyseparable.TheenanRomersareobtainedasdifferentcompounds;bothareenanRoenriched(butnotusuallytothesamedegree).


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3)RETROSYNTHESISThetheory(Corey-Nobelprizein1990)1)Thinkaboutreac5onsinreverse

2)Usedisconnec5onstobreakdownmolecules

3)Synthons:Thesearesimplyhypothe5calreac5onintermediatesTherearetwowaysofanalysingasingledisconnecRon


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RemembertheconceptofUMPOLUNGishelpful(especially)withcarbonylgroups:1)NormalreacRvityofthecarbonylgroup


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2)UseUMPOLUNGtoreversethereacRvityofthecarbonylgroup

3)SomeRmesfuncRonalgroupinterconversiononthetargethelps


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Evenstereochemistrycanbealteredinthisway.

ForadvancedandfurtherreadingabouttheDielsAlderreacRoninnaturalproductssynthesisseeareviewbyK.C.Nicoloau,Angew.Chem.Int.Ed.2002,41,1668-1698.


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4)Someproblemstothinkabout

a)Suggestreagentsforthefollowingsynthons

b)SuggestsyntheAcroutestothefollowingfivecompoundsusingretrosyntheAcanalysis


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Synthesis1)Eletriptan(Pfizer)Migraine(salesin2008,$0.21billion)

Thesynthesis


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Synthesis2)Estradiol(HelveAcaChimicaActa,1980,63,1703)

Thesynthesis


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Theendgame


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Finally,

Synthesis3)(+)-Laurencin Isolatedin1965fromredalgae-LaurenciaglanduliferaStructureprovenbyX-raycrystallographyRepresentaRveofalargenumberofmediumringmarinemetabolitesfoundasnaturalproductsSynthesisofthemedium(here8)memberedringisaformidablechallenge


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Retrosynthesis

OnerecurringrequirementhereisamethodtocontrolthestereochemistryofenolatealkylaRon


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ASIDE;Evanschiralauxiliary(Xc)isaveryGENERALmethodwhichisusedwidelyinorganicsynthesis


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Organic Synthesis III - University of Oxforddonohoe.chem.ox.ac.uk/resources/2016H1.pdf · Prof Tim Donohoe: Strategies and Taccs in Organic Synthesis: Handout 1 2/33 Organic Synthesis

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