TetrahedronAssymmV1.docx

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