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RetrosynthesisPracticeProblemsAnswerKey

October1,2013

1.Drawaretrosynthesisforhowtomakethecompoundshownbelowfromstartingmaterialswitheight

orfewercarbonatoms.

ThefirststepistoconverttheOHtoacarbonylgroupsothatyoucanobtainthekeya,bunsaturated

carbonylmotifthatistheproductofanaldolreaction:

Thisisagoodpointtoretrosyntheticallydisconnecttheestertogiveyouthealcohol(whichinthe

forwarddirectionundergoesaFisheresterificationreaction):

FromhereweknowhowtoanaldolreactionretrosyntheticallyaddanOHtothebetacarbon,and

thenbreakthebondbetweenthealphaandbetacarbontoformadicarbonyl:

Icancountthreesaturatedcarbonsbetweenthetwocarbonylsinmyintermediate,whichmeansthat

wecanuseaMichaelreactionasthenextretrosyntheticstep:

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Thealphabetaunsaturatedketonenowhaslessthan8carbons,sothathasbeendisconnected

sufficiently.Weneedtodoabitmoreworkonthecyclohexenonefragment.Luckilythathasan

alpha,betaunsaturatedcarbonylalreadyinit,whichwecandisconnectviaanaldolreaction:

Luckilythisintermediatehasthreesaturatedcarbonsbetweenthecarbonyls,whichagainpointstoa

Michaelreaction:

Andnowallofthestartingmaterialshave8orfewercarbonatoms,sowehavesucceeded.

2.Makethefollowingmoleculefromstartingmaterialswithtwelveorfewercarbons(hint:youcan

leavetheheterocycleintact):

Thisisagreatmolecule,becausetherearesomanyplacesalongthemacrocyclethatcanbe

retrosyntheticallydisconnected.Ishowafewexamplesofthatbelow:

WearegoingtofocusonthedisconnectionsthatwehavetalkedaboutinclasstheFisherlactonization

andthetwoaldolreactions,anduseeachoneinturntobreakapartthering.

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Fisheresterification:

Aldolreaction:

Secondaldolreaction:

Thisiswherethisproblemstartstogetalittletricky.ThemiddleOHcouldhavebeenacarbonylthat

wasattackedbyanorganometallicnucleophile.However,youwouldneedtofirstprotectthealdehyde

groupbeforedoingthatsequencesothatthealdehydedoesntalsogetattackedbytheorganometallic

nucleophile:

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Intheforwarddirection,thisisabroadlyapplicablewaytoprotectcarbonylcompoundsbytreating

themwithadioltogenerateacyclicacetal:

Withtheprotectedaldehydeinhand,wearesettodothenextkeyretrosyntheticdisconnection:

Thisgivesmetwostartingmaterials,eachofwhichhas12orfewercarbonatoms,sowehave

succeededhereaswell.

3.Howwouldyousynthesizethecompoundshownbelowfromanaldolreaction?Drawthestructures

ofbothprecursors(8points).

Wehaveaprocedureforthis:breakthedoublebond,putahydroxylonthecarbon,andthenbreak

thebondbetweenthe and carbontoformtwocarbonylstartingmaterials.

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Onethingtonotehereisthatthestartingmaterialdoesnothavethedoublebondinthepositionthat

youwouldexpecti.e.itisnotbetweenthealphaandbetacarbons.however,ifyoubreakthatbond,

youcanstillputtheOHonthebetacarbon,andthatgetsyourightbacktoanintermediatethatis

straightforwardtodisconnectviaanaldolretrosynthesis.

4.Providearetrosyntheticpathwayforthefollowingtargetfromsimple,readilyavailablestarting

materials:

Herethetrickisfindingwherethealpha,betaunsaturatedketoneis.Wecangettothealphabeta

unsaturatedketoneintwosteps.

Step1:OxidizingtheOHtoacarbonylcompound:

Step2:Gettingridofthecyclopropaneringandconvertingittothedesiredalkene:

Intheforwarddirection,wecanaccomplishthistransformationwithaSimmonsSmith

cyclopropanationreaction.Youareresponsibleforthistransformation,butnotforthemechanism.The

mechanisminvolvesacarbeneintermediate:

Gettingbacktotheretrosynthesis,nowwehaveanalphabetaunsaturatedcarbonylthatwecan

disconnectviaanaldolretrosynthesis:

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AndwecanfollowthatwithaMichaelretrosynthesis:

5.Thestructureoftestosteroneacetateisshownbelow.Drawaretrosyntheticpathwaytosynthesize

thiscompoundfromstartingmaterialsthathavenomorethan10carbonatoms(30points).

Thisisprettycomplicated,soletstakeitonestepatatime.

Step1:Theeasiestthingtogetridofistheester,tobringitbacktoanalcohol(thatwasesterifiedvia

Fischeresterification):

Wealsohaveanalphabetaunsaturatedketonethatweknowhowtodealwithretrosynthetically:

NextstepisaMichaelreaction:

Intheforwarddirection,wewillbeabletoformtheenolateatthepositionthatwewant(themore

substitutedalphacarbon),becausethatisthethermodynamicenolate.

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NowIcanputadoublebondbetweenthealphaandbetacarbonstogivemeanotheralpha,beta

unsaturatedketone:

ToanswerthequestionaboutwhyIamallowedtodothis,inaretrosynthesis,youcandoanythingin

thereversedirectionthatisfeasibleintheforwarddirection.Soaskyourself,canyouselectively

hydrogenatethedoublebondonthatalpha,betaunsaturatedcarbonyltogivethesaturatedproduct?

Sure.Inwhichcase,itisanallowedtransformationintheretrosyntheticdirection.

OnceIdothat,Icandealwiththislikeanyotheralpha,betaunsaturatedcarbonyl:

AndwecandoaMichaelreactiontoo: