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RetrosynthesisPracticeProblemsAnswerKey October1,2013 1.Drawaretrosynthesisforhowtomakethecompoundshownbelowfromstartingmaterialswitheight orfewercarbonatoms.

 ThefirststepistoconverttheOHtoacarbonylgroupsothatyoucanobtainthekeya,b‐unsaturated carbonylmotifthatistheproductofanaldolreaction:

 Thisisagoodpointtoretrosyntheticallydisconnecttheestertogiveyouthealcohol(whichinthe forwarddirectionundergoesaFisheresterificationreaction):

 Fromhereweknowhowtoanaldolreactionretrosynthetically–addanOHtothebetacarbon,and thenbreakthebondbetweenthealphaandbetacarbontoformadicarbonyl:

 Icancountthreesaturatedcarbonsbetweenthetwocarbonylsinmyintermediate,whichmeansthat wecanuseaMichaelreactionasthenextretrosyntheticstep:



Thealphabetaunsaturatedketonenowhaslessthan8carbons,sothathasbeendisconnected sufficiently.Weneedtodoabitmoreworkonthecyclohexenonefragment.Luckilythathasan alpha,betaunsaturatedcarbonylalreadyinit,whichwecandisconnectviaanaldolreaction:

 Luckilythisintermediatehasthreesaturatedcarbonsbetweenthecarbonyls,whichagainpointstoa Michaelreaction:

 Andnowallofthestartingmaterialshave8orfewercarbonatoms,sowehavesucceeded. 2.Makethefollowingmoleculefromstartingmaterialswithtwelveorfewercarbons(hint:youcan leavetheheterocycleintact):

 Thisisagreatmolecule,becausetherearesomanyplacesalongthemacrocyclethatcanbe retrosyntheticallydisconnected.Ishowafewexamplesofthatbelow:

 Wearegoingtofocusonthedisconnectionsthatwehavetalkedaboutinclass–theFisherlactonization andthetwoaldolreactions,anduseeachoneinturntobreakapartthering.

Fisheresterification:

 Aldolreaction:

 Secondaldolreaction:

 Thisiswherethisproblemstartstogetalittletricky.ThemiddleOHcouldhavebeenacarbonylthat wasattackedbyanorganometallicnucleophile.However,youwouldneedtofirstprotectthealdehyde groupbeforedoingthatsequencesothatthealdehydedoesn’t alsogetattackedbytheorganometallic nucleophile:

 Intheforwarddirection,thisisabroadlyapplicablewaytoprotectcarbonylcompounds–bytreating themwithadioltogenerateacyclicacetal:

 Withtheprotectedaldehydeinhand,wearesettodothenextkeyretrosyntheticdisconnection:

 Thisgivesmetwostartingmaterials,eachofwhichhas12orfewercarbonatoms,sowehave succeededhereaswell. 3.Howwouldyousynthesizethecompoundshownbelowfromanaldolreaction?Drawthestructures ofbothprecursors(8points).

  Wehaveaprocedureforthis:breakthedoublebond,putahydroxylontheβ‐carbon,andthenbreak thebondbetweentheαandβcarbontoformtwocarbonylstartingmaterials.

 Onethingtonotehereisthatthestartingmaterialdoesnothavethedoublebondinthepositionthat youwouldexpect–i.e.itisnotbetweenthealphaandbetacarbons.however,ifyoubreakthatbond, youcanstillputtheOHonthebetacarbon,andthatgetsyourightbacktoanintermediatethatis straightforwardtodisconnectviaanaldolretrosynthesis. 4.Providearetrosyntheticpathwayforthefollowingtargetfrom“simple,readilyavailable”starting materials:

 Herethetrickisfindingwherethealpha,betaunsaturatedketoneis.Wecangettothealphabeta unsaturatedketoneintwosteps. Step1:OxidizingtheOHtoacarbonylcompound:

 Step2:Gettingridofthecyclopropaneringandconvertingittothedesiredalkene:

 Intheforwarddirection,wecanaccomplishthistransformationwithaSimmons‐Smith cyclopropanationreaction.Youareresponsibleforthistransformation,butnotforthemechanism.The mechanisminvolvesacarbeneintermediate:

 Gettingbacktotheretrosynthesis,nowwehaveanalphabetaunsaturatedcarbonylthatwecan disconnectviaanaldolretrosynthesis:

 AndwecanfollowthatwithaMichaelretrosynthesis:

 5.Thestructureoftestosteroneacetateisshownbelow.Drawaretrosyntheticpathwaytosynthesize thiscompoundfromstartingmaterialsthathavenomorethan10carbonatoms(30points).

 Thisisprettycomplicated,solet’stakeitonestepatatime. Step1:Theeasiestthingtogetridofistheester,tobringitbacktoanalcohol(thatwasesterifiedvia Fischeresterification):

 Wealsohaveanalphabetaunsaturatedketonethatweknowhowtodealwithretrosynthetically:

 NextstepisaMichaelreaction:

 Intheforwarddirection,wewillbeabletoformtheenolateatthepositionthatwewant(themore substitutedalphacarbon),becausethatisthethermodynamicenolate.

NowIcanputadoublebondbetweenthealphaandbetacarbonstogivemeanotheralpha,beta unsaturatedketone:

 ToanswerthequestionaboutwhyIamallowedtodothis,inaretrosynthesis,youcandoanythingin thereversedirectionthatisfeasibleintheforwarddirection.Soaskyourself,canyouselectively hydrogenatethedoublebondonthatalpha,betaunsaturatedcarbonyltogivethesaturatedproduct? Sure.Inwhichcase,itisanallowedtransformationintheretrosyntheticdirection. OnceIdothat,Icandealwiththislikeanyotheralpha,betaunsaturatedcarbonyl:

 AndwecandoaMichaelreactiontoo:

  ...