TetrahedronAssymmV1.docx
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TetrahedronAssymmV1.docx
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TetrahedronAssymmV1
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Pergamon
TETRAHEDRON:
ASYMMETRY
Binap-AuTFAandBinap-AgTFA:
Twoefficientcoinagemetalcomplexesinthesynthesisofchiralpyrrolidinesthrough1,3-dipolarcycloaddditionofazomethineylides
CarmenNájera,a*MaríaMartín-Rodríguez,aFeng-LiuWu,bJoséM.Sansanoa
aDepartamentodeQuímicaOrgánica,InstitutodeSíntesisOrgánica(ISO).UniversidaddeAlicante,03080-Alicante(Spain)
bSchoolofChemistryandMolecularBiosciences,UniversityofQueensland,Brisbane,Qld4072,Australia.
DeticatedtoProf.H.B.Kaganontheoccasionofhis80birhtday
Abstract—Inthiswork,acomparisonbetweenchiralBINAP-AuTFA-andchiralBINAP-AgTFA-promotedcatalyticenantioselective1,3-dipolarcycloadditionsofazomethineylidesandalkenes.Maleimidesreactedsmoothlyinverygoodyieldsandenantioselectionsandtrans-1,2-bis(phenylsulfonyl)ethylenereactedafterlongerreactiontimesbutusingsmalleramountsofcatalystloadinginordertoachievethehighestenantioselectivities.Inspiteofthescarceinductionofthesetwocomplexeswhentert-butylacrylateisusedasdipolarophile,chiralgold(I)catalystafforded,unexpectedly,anexcellentenantioselectioninthereactionoftheiminoesterprecursorofkeyintermediateinthesynthesisofhepatitisCvirusinhibitor.©2018ElsevierScience.Allrightsreserved
Coinagemetalsattractparticularinterestfromsyntheticorganicchemists,becausethosemetalsbecomeusefulcatalystsforsynthesizingthecoreofmanyimportantdrugscontainingheterocyclicstructures.Themainfeaturesofthesemetalcomplexesarethegoodchemoselectivity,goodfunctionalgroupcompatibility,stability,traitsthatarecrucialforapplicationincomplexmolecularenvironments.Oneofthemostrepresentativeexamplesconcernsthesynthesisofenantiomericallyenrichedpyrrolidinesthroughthecatalyticenantioselective1,3-dipolarcycloaddition(1,3-DC)betweenazomethineylideandalkenes.Infact,silver(I),andcopper(I)catalyzed1,3-DCareverywellknownandconstitutethemostreliable,sureandinexpensiveenantioselectivemethodologytobuiltuptofourstereogeniccentresoftheresultingprolinederivatives,inonlyonereactionstep.Inaddition,theyexhibitmoreversatilityandwiderscopethantheanalogousenantioselectiveorganocatalysed1,3-dipolarcycloadditions.3a,
Chiralgoldcomplexeshavebeenemployedinenantioselectiveactivationofallenesandnucleophilicadditionsontoalkynes,buttheyhavenotsoextensivelystudiedascatalystsinthesecycloadditions.OnlyTosteetal.reportedaveryefficientenantioselectivecycloaddtionofmünchnonesandelectron-defficientalkenesemploying(Sa)-Cy-SEGPHOS(AuOBz)2(3.5mol%).Thistransformation,followedbyanester/amideformation,furnishedpyrrolineswithveryhighenantioselection.
Inthiscommunication,andcontinuingwiththeresearchlineinvolvingthechiralBINAPcomplex-promoted1,3-DC,wesurveytheefficiencyof(Ra)-or(Sa)-BINAP-AuTFA(TFA=trifluoroacetateanion)intheclassicalintermolecular1,3-DCemployingiminoestersandelectrophilicalkenes,establishingadirectcomparisonwiththeanalogousprocessescatalyzedby(Ra)-or(Sa)-Binap-AgTFAcomplexes.
Oneofthebesttesttoprovetheabilityofachiralcatalystinasilver(I)catalysedenantioselective1,3-dipolarcycloadditionisthetransformationofazomethineylides(generatedfromiminoesters1)andN-methylmaleimide(NMM)inenantiomericallyenrichedprolines2(Scheme1).Thechiralgoldcomplexeswerepreparedinsitufrom(Me2S)AuClandthecorrespondingamountofthechiraldiphosphaneligand,followedbytheanioninterchangewiththecorrespondingsilversalt(approx.1h).Theresultingsuspensionwasfilteredthroughacelitepathandthesolutionwasevaporatedtoyieldthetitledcomplexes.10TheanioninterchangewasnecessarybecausetheinitialcomplexBinap-AuClwasinactiveintermsofenantiodiscrimination.Thereactionscarriedoutwithdiisopropylethylamine(DIPEA)affordedcleanerreactioncrudesthantheanalogoustransformationsperformedwithtriethylamine(Table1,entries1and2).Theanioninterchangeontheoriginal(Sa)-Binap-AuClcomplexwasdonewithseveralsilversalts(Table1,entries3-8)runningthecycloadditioninthepresenceofDIPEA.ThebestresultswereachievedwhenusingthebenzoateorTFAanions(highconversionsand74%eeeach,Table1,entries7and8).Thechiralgold(I)-TFAcomplexwasselectedbecausehigherenantiodiscriminationswereachievedandthereactionproductswereobtainedwithhighpurity.Anotherbases,suchasEt3N,DABCOorDBUdidnotimprovetheresultsachievedemployingDIPEAasbase(Table1,9-11).OthersolventslikeTHF,Et2O,andDCMdidnotimprovetheresultdescribedinthereactionrunwithtoluene.
Averyimportantfeatureofthesecarboxylateanionsistheweakbasicity,whichwasenoughtopromotetheidenticalenantioselectivecycloadditionsintheabsenceofbaseassociatedwithanunexpectedincrementoftheenantioslectivity(Table1,entries12-18).TFAanionwasthemostsuitableinternalbasetopromotethisreactioninhighconversions,goodenantioselectivitiesandaffordingverycleancrudereactionproducts.Alowercatalystloading(5mol%)decreasedtheconversionandtheenantioselectionoftheprocess(Table1,entry17),whilsttheformationofthegold(I)complexovernightdidnotaffecttothefinalresultofthereaction(Table1,entry18).
Scheme1.
Table1.Optimizationofthechiralgold(I)-catalyzed1,3-DCbetweeniminoester1aandNMM.
Entry
Gold(I)catalyst
(10mol%)
Base
(10mol%)
Conv.
(%)a,b
ee
(%)c
1
(Sa)-Binap-AuCl
Et3N
>95
rac.
2
(Sa)-Binap-AuCl
DIPEA
>95
rac.
3
(Sa)-Binap-AuCl/AgSbF6
DIPEA
<10
___
4
(Sa)-Binap-AuCl/AgClO4
DIPEA
>95
60
5
(Sa)-Binap-AuCl/AgOAc
DIPEA
>95
62
6
(Sa)-Binap-AuCl/AgOTf
DIPEA
>95
59
7
(Sa)-Binap-AuCl/AgOBz
DIPEA
>95
74
8
(Sa)-Binap-AuCl/AgTFA
DIPEA
>95
74
9
(Sa)-Binap-AuCl/AgTFA
Et3N
>95
92d
10
(Sa)-Binap-AuCl/AgTFA
DABCO
<50
___d
11
(Sa)-Binap-AuCl/AgTFA
DBU
<30
___d
12
(Sa)-Binap-AuCl/AgOAc
_____
>95
70
13
(Sa)-Binap-AuCl/AgOBz
_____
>95
94d
14
(Sa)-Binap-AuCl/AgTFA
_____
>95
94
15
(Ra)-Binap-AuCl/AgTFA
_____
>95
ent-94
16
(Sa)-Binap-(AuCl)2/AgTFA
_____
>95
rac.
17
(Sa)-Binap-AuCl/AgTFAe
_____
<90
60
18
(Sa)-Binap-AuCl/AgTFAf
_____
>96
94
aDeterminedby1HNMRofthecrudesamples.
bTheobservedendo:
exoratiowasalways>98:
2(1HNMR)
cDeterminedbychiralHPLCanalysis(Daicel,ChiralpakAS).
dNotableamountsofunidentifiedsideproductswereobserved(1HNMR).
eThereactionwasperformedwith5mol%ofgold(I)complex.
fTheanioninterchangewasallowedovernightinsteadof1h.
Aseriesofiminoestersandmaleimidesweretestedfollowingthebestreactionconditionsdescribedinentry14ofTable1anddirectlycomparedwithidenticaltransformationscarriedoutwithAgTFA(Scheme2andTable2).InalloftheexamplesdescribedinthisTable2theendo:
exodiastereoselectivitywasveryhigh(>98:
2,determinedby1HNMRspectroscopy)independentlyofthecentralmetalnature(10mol%).Ingeneralthebase-assistedreactionwascompletein16hgivingrisetoelevatedchemicalyieldsandbetterenantioselectionswiththechiralsilvercomplex.However,theabsenceofbaseismuchmorebeneficialforthereactionsrunwithchiralgold(I)complexaffordingbothexcellentyieldsandenantioselections(Table2,compareentries1-6).ItwasremarkabletheresultobtainedwhenNPMwasemployedasdipolarophile.Aracemicproduct2accouldbeonlyobtainedwiththesilver(I)catalyst,whilsta80%eeofthiscycloadductwasobtainedinthegold(I)-promotedcycloaddition(Table2,entries5and6).Forotherarylideneaminoesters1b-dthebehaviourwasverysimilarobtainingahigherenantiodiscriminationforthegold(I)-catalysedprocesses(Table2,entries7-9).Whensubstrate1e(derivedfrom2-naphthalenecarbaldehyde)theenantioselectivityofthesilver(I)-catalysedprocesswashigherthantheeegeneratedbytheanalogousreactiondevelopedbythe(Sa)-BinapAuTFAcomplex(Table2,entry10).
Scheme2.
Theinsertionofabulkysubstituentattheα-positionofthe1,3-dipoleprecursorwasnextevaluated.Thus,methylbenzylideneiminophenylalaninate3wasallowedtoreactwithNMMunderthestandardreactionconditions(Scheme3).Thereactionperformedwiththegold(I)complexneeded24hmorethanthecorrespondingreactionusingtheanalogoussilver(I)complexforachievingalmosttotalconversions.Thehighenantioselectionshowedby(Sa)-BinapAuTFAcomplex(99%ee)versusthe65%eeinducedby(Sa)-BinapAgTFAcomplexjustifiedtheimportanceofthiscomplexinthiscycloaddtition.
Scheme3.
AccordingtoourexperiencewiththeresultsobtainedfromtheapplicationofchiralBinap-silver(I)complexesintheenantioselective1,3-DCofazomethineylideandelectrophilicalkenes,5j,k,mwealsotestedtheefficiencyofthetwocomplexesintheenantioselectivecycloadditionofazomethineylidesandtrans-1,2-bis(phenylsulfonyl)ethyleneassyntheticequivalentofacetylene(Scheme4andTable3).Thereactionperformedwithgold(I)catalystofferthebestenantioselectivitiesofcycloadducts5usinga5mol%loadingandidenticalquivalentsofDIPEA(Table
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