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October1,2013
1.Drawaretrosynthesisforhowtomakethecompoundshownbelowfromstartingmaterialswitheight
orfewercarbonatoms.
ThefirststepistoconverttheOHtoacarbonylgroupsothatyoucanobtainthekeya,bunsaturated
carbonylmotifthatistheproductofanaldolreaction:
Thisisagoodpointtoretrosyntheticallydisconnecttheestertogiveyouthealcohol(whichinthe
forwarddirectionundergoesaFisheresterificationreaction):
FromhereweknowhowtoanaldolreactionretrosyntheticallyaddanOHtothebetacarbon,and
thenbreakthebondbetweenthealphaandbetacarbontoformadicarbonyl:
Icancountthreesaturatedcarbonsbetweenthetwocarbonylsinmyintermediate,whichmeansthat
wecanuseaMichaelreactionasthenextretrosyntheticstep:
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.
Fisheresterification:
Aldolreaction:
Secondaldolreaction:
Thisiswherethisproblemstartstogetalittletricky.ThemiddleOHcouldhavebeenacarbonylthat
wasattackedbyanorganometallicnucleophile.However,youwouldneedtofirstprotectthealdehyde
groupbeforedoingthatsequencesothatthealdehydedoesntalsogetattackedbytheorganometallic
nucleophile:
Intheforwarddirection,thisisabroadlyapplicablewaytoprotectcarbonylcompoundsbytreating
themwithadioltogenerateacyclicacetal:
Withtheprotectedaldehydeinhand,wearesettodothenextkeyretrosyntheticdisconnection:
Thisgivesmetwostartingmaterials,eachofwhichhas12orfewercarbonatoms,sowehave
succeededhereaswell.
3.Howwouldyousynthesizethecompoundshownbelowfromanaldolreaction?Drawthestructures
ofbothprecursors(8points).
Wehaveaprocedureforthis:breakthedoublebond,putahydroxylonthecarbon,andthenbreak
thebondbetweentheandcarbontoformtwocarbonylstartingmaterials.
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:
AndwecanfollowthatwithaMichaelretrosynthesis:
5.Thestructureoftestosteroneacetateisshownbelow.Drawaretrosyntheticpathwaytosynthesize
thiscompoundfromstartingmaterialsthathavenomorethan10carbonatoms(30points).
Thisisprettycomplicated,soletstakeitonestepatatime.
Step1:Theeasiestthingtogetridofistheester,tobringitbacktoanalcohol(thatwasesterifiedvia
Fischeresterification):
Wealsohaveanalphabetaunsaturatedketonethatweknowhowtodealwithretrosynthetically:
NextstepisaMichaelreaction:
Intheforwarddirection,wewillbeabletoformtheenolateatthepositionthatwewant(themore
substitutedalphacarbon),becausethatisthethermodynamicenolate.
NowIcanputadoublebondbetweenthealphaandbetacarbonstogivemeanotheralpha,beta
unsaturatedketone:
ToanswerthequestionaboutwhyIamallowedtodothis,inaretrosynthesis,youcandoanythingin
thereversedirectionthatisfeasibleintheforwarddirection.Soaskyourself,canyouselectively
hydrogenatethedoublebondonthatalpha,betaunsaturatedcarbonyltogivethesaturatedproduct?
Sure.Inwhichcase,itisanallowedtransformationintheretrosyntheticdirection.
OnceIdothat,Icandealwiththislikeanyotheralpha,betaunsaturatedcarbonyl:
AndwecandoaMichaelreactiontoo: