deuterium as a stereochemically invisible blocking group for chiral ligand synthesis 2017 ross a. arthurs资料.pdf

该【deuterium as a stereochemically invisible blocking group for chiral ligand synthesis 2017 ross a. arthurs资料 】是由【雪雁】上传分享，文档一共【4】页，该文档可以免费在线阅读，需要了解更多关于【deuterium as a stereochemically invisible blocking group for chiral ligand synthesis 2017 ross a. arthurs资料 】的内容，可以使用淘豆网的站内搜索功能，选择自己适合的文档，以下文字是截取该文章内的部分文字，如需要获得完整电子版，请下载此文档到您的设备，方便您编辑和打印。Letterpubs./*SchoolofChemistry,UniversityofEastAnglia,NorwichResearchPark,NorwichNR47TU,.*SSupportingInformation?°ABSTRACT:Highlydiastereoselectivelithiation(s-BuLi/2O,78C,2h)of(S)-2-ferrocenyl-4-(substituted)-oxazolinesfollowedbyadditionofMeOH-d4gaveupto95%(n-BuLiinTHF,?78°C,2h),followedbyadditionofanelectrophile,resultedinareversalofdiastereoselectivitycontrolledprimarilybythehighkH/kDvalueforlithiation(isomerratiotypicallybetween10:1and20:1).anynonracemicligandsemployedinmetal-catalyzedwhichreversestheselectivityoflithiation(drupto6:1inaMasymmetricreactionscontainmorethanoneelementstudywhichemployedMeSSMeastheelectrophile,R=i-Pr,-symmetricligandcontainingtwosuchMe).Thismethodologyshouldpermitthedirectsynthesisofelements,?erentreactionproductenantioselectivities,andthereareaofthisprocedureis,however,restrictedbythelowyield(28%)?merciallyunavailable(t-Bu)2-,nodiastereoselectivityresultedwithcases,however,liganddiastereoisomersarenotexploredin(t-Bu)2-DGMEonlithiationofthet-Buoxazolineprecursorcatalysis,merciallyunavailableto1b/2b,andtheapplicationofthisproceduretotheCH2i-Prand/oraredi?,respectively,Forexample,i-Pr-andt-Bu-containing(S,Sp)-1a/-basedInthispaper,ess?2PNligands(Figure1).?ect??reportedforCDvsCHlithiationforwhichvaluesofkH/?ecthasbeenexploitedtoaidthecontrolofreactionselectively(chemoselectivity,regiose-lectivity,andenantioselectivity),,,followingintroductionofdeuterium,byexploitationofhighvaluesofkH/-diastereoselectivelithiationofaferrocenyloxazolineprecursor3tivegenerationofadiastereoisomerrequiresthatconditionsfollowedbyintroductionofthediphenylphosphinemoietyexistforboththehighlyselectiveandpoorly/nonselectiveusingPh2PCl,methodologythathasbeenappliedalsotothe???rstinstancesynthesisof(S,Sp)-(S,Rp)-2achavebeensynthesizedbyuseofaremovableTMSblockinglithiationfollowedbytheadditionofadeuteroacidwillresultgroup,-,thedeuteriumwillprincipallycontrolthepositionofreportsontheuseofligands2a/bincatalysis,:December28,2016employtheadditivedi-tert-butyldiglyme[(t-Bu)2-DGME],?XXXXAmericanChemicalSocietyADOI:.,XXX,XXX?XXXOrganicLettersLetterselectivity,,followedbytheadditionof9inferred,(S)-valinol-derivedferrocenyloxazoline(S)-3ameetsmethanol-d4,gave(S,Rp)-2-d-3ainwhichonlyasingletheserequirements,aslithiationselectivityishighlydependentcyclopentadienylα-hydrogenwasdeuterated,-incorporationof94%asdeterminedby1HNMRspectroscopylectivityresultswhenadiethylethersolutionistreatedat(Table1,entry1).Subsequentapplicationoflithiationcon-3lowtemperaturewiths-(S,Rp)-2-d-3a,followedbyadditionoftrimethylsilylRepetitionoftheseconditions(conditionsA)followedbychloride,resultedintheformationof(S,Rp)-5-d-5aasthetheadditionoftrimethylsilylchlorideresultedintheessentiallymajordiastereoisomerinaratioof10:1(Figure2).Usingtheexclusive(>100:1)formationof(S,Sp)-4a(Scheme1).Incontrast,(S)-?NMRspectrum(CDCl3,CH(CH3)3)oftheunpuriedproductmixturearisingfromthereactionillustratedby(a)Scheme2,conditionsB(R=i-Pr),and(b)Scheme1,-deuterated(S)-3a(2:1)anddeuterated(S,Rp)-2-d-3a(1:10),togetherwiththepercentagedeuteriumincorporation(94%),～useofn-BuLiinTHFatlowtemperature(conditionsB),gaveacalculatedvalueforkH/,resultedina2:1Thissequenceofreactionswasalsoappliedtooxazolines3b?dratioofdiastereoisomericproductsduetothesigni?cant(Table1,entries2?4)resultinginhighoveralldiastereoselectivityformationof(S,Rp)-(3c)andisobutyl(3d)substitutedoxazolinesThesehighandlowlithiationstereoselectivities,togetherbutinareducedyieldandmodestdiastereoselectivityforthewiththeuseofdeuterium,wereusedtobringaboutanover-tert-butylderivative(3b).Thelatterresultislikelyduetotheallreversalinthestereochemistryofα-silylation(Scheme2).?(,p)-5--5adbyDeuterium-Thereversalindiastereoselectivitywithdeuteratedferroce-DirectedReversalofDiastereoselectivitynyloxazolineswasextendedtothesynthesisofP?Nligands?(S,Rp)-5-d-2ad(Scheme3,Table2).ThesewereformedasSRd?-DirectedSynthesisof(,p)-5--2adthemajorisomerwhenchlorodiphenylphosphinewasusedastheelectrophilefollowinglithiationunderconditionsB,?(,p)-5--5adbyDeuterium-DirectedReversalofDiastereoselectivity?a??bca,dentrysubstrate(R)yieldof(S,Rp)-2-d-3ad(%)(%D)ratioof5ad/4adyield(%)(%D)13a(i-Pr)95(94)10:178e(98)23b(t-Bu)95(90):141(94)33c(Me)85(95)21:159e(92)43d(CH2i-Pr)93(95)17:149(94)a1bcDeterminedbyHNMRspectroscopy(500MHz,CDCl3).-detography(SiO2).:.,XXX,XXX?XXXOrganicLettersLetterSRd?-DirectedSynthesisof(,p)-5--2ad?aa,bba,centrysubstrate(S,Rp)-2-d-3ad(R)substrate(%D)ratioof(S,Rp)-5-d-2:(S,Sp)-1%yield(%D)13a(R=i-Pr)9221:149d(98)23b(R=t-Bu):150(98)33c(R=Me)855:139e(92)43d(R=CH2i-Pr)9517:120(94)a1bcdDeterminedbyHNMRspectroscopy(500MHz,CDCl3).Determinedaftercolumnchromatography(SiO2).%%?(,p)-5--711and(,p)-5--12products(videinfra),butpuri?cationwasreadilyachievedforentryelectrophileproductisomerratioa,byieldc,d(%)(%Da,e)(S,Rp)-5-d-2aand(S,Rp)-5-d--substituted1ClP(O)Ph2722:123(92):186(94)3PhSSPh912:185(98)followedbyadditionofmethanol-d4resultedin(S,Rp)-2-d-3ein45%yieldwithareasonable(80%)levelofdeuteriumincor-4MeSSMe1013:150(96)5PhSeSePh1113:161(96):168(94)a1isolatedbycolumnchromatographydiastereomericallypureDeterminedbyHNMRspectroscopy(500MHz,CDCl3).bDeterminedbeforecolumnchromatographyunlessotherwisestated.(S,Rp)-5-d-2eandenamide(Rp)-2-d-6(Scheme4).ThelattercdDeterminedaftercolumnchromatography(SiO2).Diastereomeri-(,p)-2---catalyzedasym-,,thesimilaritybetweenaC?DandaC?,the?ve-bondseparationbetweendeuteriumandametalcoordinatedlikelyarisesfromlithiationatposition4oftheoxazolinebyoneofthebidentateligandslistedinTables2and3would?followedbyring-openingandnitrogenprotonationonworkup,appeartoruleoutthepossibilityofsecondaryisotopeeects?14,15aprocessreportedpreviouslywithanotherphenyl-,preventionofthefavoredlithiationFinally,thatdeuteriumcanbereplacedinasubsequentpathwaybydeuteriumintroductioncanleadtoanundesirablereactionwasillustratedbytwoproceduresstartingwith??reactionpathwayinadditiontotheformationofthealternative(S,Rp)-5-d-5athatdisplayCDvsCSiselectivity(Scheme6).-Pr-?DvsC?SiLithiationand(S)-3a/(S,Rp)-2-d-3aundergolithiationledustoextendthisCycloiridationmethodologytothesynthesisofarangeofbidentateliganddiastereoisomers(Scheme5,Table3).UseofdiphenylphosphinicSRd?-DirectedSynthesisof(,p)-5--711SSdand(,p)-5--12LithiationusingconditionsB,withs-BuLisubstitutedforchloride(entry1),chlorodicyclohexylphosphine(entry2),n-BuLi,followedbyadditionofchlorodiphenylphosphineled??11phenylandmethyldisuldes(entries3and4),diphenylselenidetotheisolationofsilylatedNPligand(S,Sp)-*(entry5),andbenzophenone(entry6)aselectrophilesalldisplayingthisselectivitywascycloiridationwith[CpIrCl2],themajorwhichresultediniridacycle(S,Sp,RIr)-14beingformedasaCDOI:.,XXX,XXX?,58,113.(i)Cho,C.-W.;Son,J.-H.;Ahn,:Asymmetry2006,17,(5)Herbert,.;Castell,.;Clayden,J.;Arnott,G..,15,,binationofhighandlowdiaster-(6)(a)Hoppe,D.;Paetow,M.;Hintze,.,,32,394.(b)Clayden,J.;Pink,.;Westlund,N.;Wilson,?Hlithiationandtheuseofthe?,39,(7)(a)Knaus,G.;Meyers,..,39,?DvsC?Hlithiationprovidethebasisforlargelyreversing(b)Jacobs,.;Cortez,C.;Harvey,.,,1215.(c)Ahmed,A.;Clayden,J.;Rowley,-stepsynthesisofaseriesofferrocenyloxazoline-,39,(8)Clayden,J.;Pink,,38,.(9)poundsthatdi?,position1of■ASSOCIATEDCONTENTthesubstitutedcyclopentadienylringisattachedtotheoxazoline*?gurationsareassignedbytheSchlo?:(a)Schlo?gl,K.;Fried,,95,TheSupportingInformationisavailablefreeofchargeonthe558.(b)Schlo?gl,K.;Fried,M.;Falk,,95,:.(10)Ahn,.;Cho,C.-W.;Baek,H.-H.;Park,J.;Lee,S..,61,(11)(PDF)thesereactions,diastereoselectivitiesweredeterminedafterprelimi-narySiO2columnchromatographyasthisprocedurereduced■AUTHORINFORMATIONoxidationofthetargetP?,thephosphineligandsarestabletooxidation.(12)Stark,M.;Jones,G.;Richards,