RetrosynthesisPracticeProblemsAnswerKey

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: