selected total syntheses of discodermolide - amazon s3€¦ · nicolaou, k.c.; chen, j.s. classics...
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SelectedTotalSynthesesofDiscodermolide
KellyCra6SpecialTopicsPresenta9on
5/16/17
Discodermolide:Isola9on
• IsolatedbyGunasekeraandco-workersattheHarborBranchOceanographicIns9tute(1990)
• IsolatedfromtheCaribbeanmarinespongeDiscodermiadissoluta
• Absoluteconfigura9onnotdetermined,onlyrela9vestereochemistry
Gunasekara,S.P.;et.al.J.Org.Chem.1990,55,4912.Gunasekara,S.P.;et.al.J.Org.Chem.1991,56,1346.
(+)-discodermolide
Discodermolide:BiologicalAc9vity
• HarborBranchOceanographicIns9tute:Immunosuppressiveac9vi9esinvivoandinvitro– Suppressedprolifera9veresponsesofsplenocytesinmurinetwo-way
mixedlymphocytereac9on(MLR)assay– PotencysuperiortocyclosporinA– PotencycomparabletoFK506
• Schreiberandcoworkers:Bothenan9omerspossessbroadan9prolifera9veproper9esviadifferentmechanismsofac9on
• HarborBranchOceanographicIns9tuteandSchreibergroup:Potentmicrotubule-stabilizingac9vity– An9canceragent– Similarinterac9onwithtubulinasTaxolandepothiloneB
Nicolaou,K.C.;Chen,J.S.ClassicsinTotalSynthesisIII;Wiley-VCH:Weinheim,2011.
Discodermolide:StructuralFeatures
• Polyke9decontaining13stereogeniccenters• Tetrasubs9tutedδ-lactone• 1disubs9tuted(Z)-doublebond• 1trisubs9tuted(Z)-doublebond• Terminal(Z)-diene
• Commonstereotriad(methyl,hydroxyl,methyl)repeated39mes
Discodermolide:NotableTotalSyntheses
• StuartSchreiber(Harvard)– (-)-disocdermolide:J.Am.Chem.Soc.1993,115,12621.– (+)-discodermolide:J.Am.Chem.Soc.1996,118,11054.
• AmosSmithIII(UniversityofPennsylvania)– (-)-disocdermolide:J.Am.Chem.Soc.1995,117,12011.
– (+)-discodermolide:Org.LeB.1999,1,1823.
• IanPaterson(CambridgeUniversity)
– (+)-discodermolide:J.Am.Chem.Soc.2001,123,9535.
• StuartMickel(Novar9s)– (+)-discodermolide:Org.ProcessRes.Dev.2004,8,92-130.(5part)
Discodermolide:Addi9onalTotalSyntheses
• JamesMarshall(UniversityofVirginia)– (+)-discodermolide:J.Org.Chem.1998,63,7885.
• JamesPanek(BostonUniversity)– (+)-discodermolide:J.Am.Chem.Soc.2005,127,5596.
• DavidMyles(UniversityofCalifornia,LosAngeles)– (-)-discodermolide:J.Org.Chem.1997,62,6098.
• JanikArdisson(UniversitédeCergy-Pontoise(France))– (+)-discodermolide:Angew.Chem.2007,46,1917.
SchreiberSynthesisof(-)-Discodermolide
(R)-2-methyl-3-hydroxypropionateSchreiber,S.L.;et.al.J.Am.Chem.Soc.1993,115,12621.
• Synthe9cPlan:3fragmentsofroughlyequallycomplexitycontainingacommonstereochemicaltriadseparatedbyolefinicunits
SchreiberSynthesis:FragmentSyntheses
Schreiber,S.L.;et.al.J.Am.Chem.Soc.1993,115,12621.
SchreiberSynthesis:CouplingReac9ons
• CouplingofC1-C7andC8-C14fragments
• CouplingofC1-C14andC15-C24fragments
Schreiber,S.L.;et.al.J.Am.Chem.Soc.1993,115,12621.
SchreiberSynthesis:CouplingReac9ons
Schreiber,S.L.;et.al.J.Am.Chem.Soc.1993,115,12621.
SchreiberSynthesis:FinalSteps
3.2%overallyield,36totalsteps,longestlinearsequence=24steps
Schreiber,S.L.;et.al.J.Am.Chem.Soc.1993,115,12621.
SmithSynthesisof(+)-Discodermolide
Smith,A.B.;et.al.Org.LeB.1999,1,1823.
• Synthe9cPlan:generate3fragmentsseparatedby(Z)-olefiniclinakgesfromacommonprecursor
Smith,A.B.;et.al.J.Am.Chem.Soc.1995,117,12011.
SmithSynthesis:CommonPrecursorSynthesis
Smith,A.B.;et.al.Org.LeB.1999,1,1823.
SmithSynthesis:FragmentSyntheses
Smith,A.B.;et.al.Org.LeB.1999,1,1823.Zhao,K.;et.al.Tet.LeB.1994,35,2827.
SmithSynthesis:CouplingReac9ons
• FragmentsAandBcoupling
Smith,A.B.;et.al.Org.LeB.1999,1,1823.
YamamotoOlefina9on
Yamamoto,H.;et.al.Tetrahedron,1987,43,723.
SmithSynthesis:CouplingReac9ons
• FragmentsABandCcouplingandendgame
1.043g(+)-discodermolide,6%overallyieldSmith,A.B.;et.al.Org.LeB.1999,1,1823.
PatersonSynthesisof(+)-Discodermolide
Paterson,I.;et.al.J.Am.Chem.Soc.2001,123,9535.
• Synthe9cPlan:3fragmentsofsimilarstereochemicalandfunc9onalgroupcomplexitycoupledviatwoaldolreac9ons
PatersonSynthesis:FragmentSyntheses
(S)-2-methyl-3-hydroxypropionate
Paterson,I.;et.al.J.Am.Chem.Soc.2001,123,9535.
PatersonSynthesis:FragmentSyntheses
Paterson,I.;et.al.J.Am.Chem.Soc.2001,123,9535.
PatersonSynthesis:TerminalDieneInstalla9on
1-bromo-1-trimethylsilyl-2-propene
Paterson,I.;et.al.J.Am.Chem.Soc.2001,123,9535.
PatersonSynthesis:CouplingReac9ons
• FragmentsC9-C16andC17-C24coupling
Paterson,I.;et.al.J.Am.Chem.Soc.2001,123,9535.
PatersonSynthesis:CouplingReac9ons
• FragmentsC9-C16andC17-C24coupling
52,R=CHO
Paterson,I.;et.al.J.Am.Chem.Soc.2001,123,9535.
PatersonSynthesis:CouplingReac9ons
• FragmentsC9-C16andC17-C24couplingandendgame
10.3%overallyield,23totalsteps
Paterson,I.;et.al.J.Am.Chem.Soc.2001,123,9535.
MickelSynthesisof(+)-Discodermolide
• Largescalesynthesisof60gof(+)-discodermolide
• Synthe9cPlan:hybridapproachofSmithandPatersonpublishedsyntheses– StartedwithSmithsynthesis[(S)-Rocheester]becauseapproach
wasreadilyavailable– ClearthatSmith12.8kbarfacilitatedphosphinealkyla9onnot
viableonlargescale– UsePaterson’sreagent-controlled,chiralboronenolate
methodology– AldehydeneededforPatersonenolatereac9oncouldbeobtained
viaanadvancedsynthesisdescribedbySmith
Mickel,S.J.;et.al.Org.ProcessRes.Dev.2004,8,92-100.
MickelSynthesisof(+)-Discodermolide
Smithstar9ngmaterial
Smithcoupling
Patersoncoupling
Patersonfragment
Mickel,S.J.;et.al.Org.ProcessRes.Dev.2004,8,92-100.
MickelSynthesis:FragmentSynthesis
LiBH4
(>98%)
TEMPO/bleach(>99%)
(>98%)
(46-55%)
TiBA/CH3ONHCH3!HCl
(75-80%)
Tooexothermic
Mickel,S.J.;et.al.Org.ProcessRes.Dev.2004,8,92-100.
MickelSynthesis:FragmentSynthesis
(84%)
(75-80%)
(85%)
Mickel,S.J.;et.al.Org.ProcessRes.Dev.2004,8,92-100.
• AdaptedfromSmithsynthesis
MickelSynthesis:FragmentSynthesis
Mickel,S.J.;et.al.Org.ProcessRes.Dev.2004,8,101-106.
SmithusedDIBAL-H
“Oneofmostdifficultreac9onsforscale-up”
• AdaptedfromSmithsynthesis
MickelSynthesis:FragmentSynthesis
SmithusedDIBAL-H
“Oneofmostdifficultreac9onsforscale-up”
Smithprocedure Smithprocedure
SmithusedSO3!pyr
Patersonfragment Mickel,S.J.;et.al.Org.ProcessRes.Dev.2004,8,101-106.
• AdaptedfromSmithsynthesis
MickelSynthesis:FragmentSynthesis
(61%)
(91%)
(85%)
(>99%)(60%)* *unabletoreproduce
highyields(>80%)reportedbySmith
(90%)
Mickel,S.J.;et.al.Org.ProcessRes.Dev.2004,8,101-106.
• Transi9onfromSmithstrategytoendgameofPaterson
MickelSynthesis:CouplingReac9ons
(73%)
Marshallprocedure
Mickel,S.J.;et.al.Org.ProcessRes.Dev.2004,8,113-121.
MickelSynthesis:CouplingReac9ons
(81%)
Smithprocedure
(92%)
SmithusedDMP
(93%)Patersonprocedure
PatersonusedDMP
(80%)
(91%)
(76%)
(>99%)
(88%)
Mickel,S.J.;et.al.Org.ProcessRes.Dev.2004,8,101-106.
• Finalcoupling—Patersonchiralboronenolatealdolreac9on– “Onlargescale,thisreac9onprovedtobemuchmorecomplex
thanweexpected.”
MickelSynthesis:CouplingReac9ons
>60g(+)-discodermolideprepared,39totalsteps,17
chromatographicpurifica9ons
Mickel,S.J.;et.al.Org.ProcessRes.Dev.2004,8,122-130.
• “Thesuccessofthisprojectanditschemistrypavesthewayforother,perhapsevenmorecomplex,naturalproductstobepreparedforearly-phaseclinalevalua9onsandsendsaposi9vemessagetoboththeisola9onandsynthe9cacademiccommunityandpossiblyotherpharmaceu9calcompainesthat‘yourworkneednotjustbeofacademicinterest’anditmaybeworthtakingafewrisks.”
• Over43chemistspar9cipated
• Processtook~20monthstocomplete
MickelSynthesis:FinalComments
Mickel,S.J.;et.al.Org.ProcessRes.Dev.2004,8,122-130.
• Clincaltrialswerestoppedin2004duetothesurprisingtoxicityofthecompound
• Worktowardsproducinga500gbatchofdiscodermolidewasdiscon9nued2/3ofthewaythrough
• Smithgroupworkingincollabora9onwithKosanBiosciencesaimto:– Developdetailedstructure-ac9vityrela9onships– Characterize(+)-discodermolidebindingdomainoftubulin– Designandsynthesizenovelanalogswithsuperiortumorcellgrowth
inhibitoryac9vitytothatofnaturaldiscodermolide
Discodermolide:ClinicalFateandCurrentStanding
Nicolaou,K.C.;Chen,J.S.ClassicsinTotalSynthesisIII;Wiley-VCH:Weinheim,2011.