Catalytic asymmetric construction of spiro pyrrolidines with contiguous quaternary centers via 1,3-dipolar cycloaddition of azomethine ylides

Article abstract of DOI:10.1016/S1872-2067(14)60204-7

Bioactive 5-aza-spiro[2,4]heptanes with high functionality and up to three contiguous all-carbon quaternary stereogenic centers were synthesized by Cu(I)-catalyzed asymmetric endo-selective 1,3-dipolar cycloaddition of azomethine ylides with cyclopropylid

Full text of DOI:10.1016/S1872-2067(14)60204-7

ChineseꢀJournalꢀofꢀCatalysisꢀ36ꢀ(2015)ꢀ68–77
ꢀ
ꢀ ꢀ ꢀ
ꢀ ꢀ ꢀ ꢀ
ava i l a b l e a t w w w. s c i e n c ed i r e c t . c o m
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j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e /c h n j c
ꢀ
ꢀ
Article (Special Issue on Catalysis in Organic Synthesis)
Catalyticꢀasymmetricꢀconstructionꢀofꢀspiroꢀpyrrolidinesꢀwithꢀ
contiguousꢀquaternaryꢀcentersꢀviaꢀ1,3‐dipolarꢀcycloadditionꢀ ꢀ
ofꢀazomethineꢀylidesꢀ
ꢀa
ꢀa
ꢀa
ꢀa
ꢀa,b,
TanglinꢀLiu ,ꢀQinghuaꢀLi ,ꢀZhaolinꢀHe ,ꢀJiaweiꢀZhang ,ꢀChunjiangꢀWang *
ꢀ
aꢀCollegeꢀofꢀChemistryꢀandꢀMolecularꢀSciences,ꢀWuhanꢀUniversity,ꢀWuhanꢀ430072,ꢀHubei,ꢀChinaꢀ
bꢀStateꢀKeyꢀLaboratoryꢀofꢀOrganometallicꢀChemistry,ꢀShanghaiꢀInstituteꢀofꢀOrganicꢀChemistry,ꢀChineseꢀAcademyꢀofꢀSciences,ꢀShanghaiꢀ230032,ꢀChinaꢀ
A R T I C L E ꢀ I N F O ꢀ
A B S T R A C T ꢀ
Articleꢀhistory:ꢀ
Bioactiveꢀ5‐aza‐spiro[2,4]heptanesꢀwithꢀ highꢀfunctionalityꢀandꢀ upꢀtoꢀthreeꢀcontiguousꢀall‐carbonꢀ
quaternaryꢀ stereogenicꢀ centersꢀ wereꢀ synthesizedꢀ byꢀ Cu(I)‐catalyzedꢀ asymmetricꢀ endo‐selectiveꢀ
1,3‐dipolarꢀcycloadditionꢀofꢀazomethineꢀylidesꢀwithꢀcyclopropylideneꢀacetates.ꢀThisꢀsynthesisꢀsys‐
temꢀ performsꢀ wellꢀ forꢀ aꢀ broadꢀ scopeꢀ ofꢀ substrates.ꢀ α‐unsubstituted/α‐substitutedꢀ azomethineꢀ
ylidesꢀandꢀcyclopropylideneꢀacetatesꢀareꢀcompatibleꢀ1,3‐dipolesꢀandꢀdipolarophiles,ꢀwhichꢀaffordꢀ
theꢀspiroꢀheterocyclesꢀwithꢀcontiguousꢀquaternaryꢀcentersꢀatꢀ2‐,ꢀ3‐ꢀandꢀ4‐positionsꢀofꢀtheꢀpyrroli‐
dineꢀringꢀinꢀgoodꢀyieldꢀ(upꢀtoꢀ97%)ꢀandꢀhighꢀdiastereoselectivityꢀ(95:5–>98:2ꢀ d.r)ꢀ andꢀ excellentꢀ
enantioselectivityꢀ(87%–98%ꢀee).ꢀ
Receivedꢀ26ꢀJuneꢀ2014ꢀ
Acceptedꢀ22ꢀJulyꢀ2014ꢀ
Publishedꢀ20ꢀJanuaryꢀ2015ꢀ
Keywords:ꢀ
Asymmetricꢀcatalysisꢀ
Quaternaryꢀstereogenicꢀcenterꢀ
©ꢀ2015,ꢀDalianꢀInstituteꢀofꢀChemicalꢀPhysics,ꢀChineseꢀAcademyꢀofꢀSciences.
1,3‐Dipolarꢀcycloadditionꢀ
PublishedꢀbyꢀElsevierꢀB.V.ꢀAllꢀrightsꢀreserved.
Azomethineꢀylideꢀ
Cyclopropylideneꢀacetateꢀ
5‐Aza‐spiro[2,4]heptane
1.ꢀ ꢀ Introductionꢀ
allylationꢀ [13],ꢀ Pd‐catalyzedꢀ asymmtericꢀ [3+2]ꢀ annulationꢀ ofꢀ
5‐vinyloxazolizinonesꢀwithꢀtrisubstitutedꢀalkenesꢀ[14],ꢀsequen‐
All‐carbonꢀquarternaryꢀcentersꢀinꢀaꢀvarietyꢀofꢀnaturalꢀprod‐
tialꢀMichaelꢀreactionsꢀ[15]ꢀandꢀalkylationꢀofꢀ3‐bromooxinodolesꢀ
withꢀ3‐substitutedꢀindolesꢀ[16].ꢀ
uctsꢀandꢀpharmacruticalꢀdrugsꢀareꢀincreasinglyꢀdifficultꢀchemi‐
calꢀsynthesis.ꢀOverꢀtheꢀpastꢀdecades,ꢀchiralꢀquaternaryꢀstereo‐
genicꢀcentersꢀhaveꢀbeenꢀconstructedꢀbyꢀseveralꢀmethodsꢀ[1–7],ꢀ
butꢀtheꢀconstructionꢀofꢀcontiguousꢀquaternaryꢀcentersꢀinꢀaꢀsin‐
gleꢀenantioselectiveꢀtransformationꢀisꢀaꢀdauntingꢀchallengeꢀinꢀ
naturalꢀproductꢀsynthesisꢀ[8].ꢀRecently,ꢀaꢀfewꢀmethodsꢀforꢀtheꢀ
constructionꢀofꢀ adjacentꢀ quaternaryꢀ centersꢀhaveꢀbeenꢀ devel‐
opedꢀ[9–11],ꢀsuchꢀasꢀPd‐catalyzedꢀdecarboxylationꢀasymmetricꢀ
allylicꢀ alkylationꢀ (Pd‐DAAA)ꢀ [12]ꢀ orꢀ doubleꢀ decarboxylationꢀ
Nitrogenꢀheterocyclicꢀpyrrolidinesꢀareꢀkeyꢀstructuralꢀmotifsꢀ
frequentlyꢀpresentꢀinꢀbiologicalꢀcompoundsꢀandꢀbuildingꢀblocksꢀ
thatꢀoccupyꢀaꢀprivilegedꢀpositionꢀinꢀorganicꢀsynthesisꢀ[17,18].ꢀ
Moreover,ꢀ pyrrolidineꢀ derivativesꢀ haveꢀ alsoꢀ beenꢀ utilizedꢀ asꢀ
ꢀ
organocatalystsꢀ inꢀ recentꢀ yearsꢀ [19–21]. Theꢀ generalꢀ strategyꢀ
forꢀconstructingꢀfive‐memberedꢀheterocyclesꢀwasꢀtheꢀcycload‐
ditionꢀ reactionꢀ ofꢀ variousꢀ 1,3‐dipolesꢀ withꢀ electron‐deficientꢀ
alkenesꢀ orꢀ alkynesꢀ asꢀ theꢀ dipolarophilesꢀ [22–27].ꢀ Althoughꢀ
*ꢀCorrespondingꢀauthor.ꢀFax:ꢀ+86‐27‐68754067;ꢀE‐mail:ꢀcjwang@whu.edu.cnꢀ ꢀ ꢀ
ThisꢀworkꢀwasꢀsupportedꢀbyꢀtheꢀNationalꢀBasicꢀResearchꢀProgramꢀofꢀChinaꢀ(973ꢀProgram,ꢀ2011CB808600),ꢀtheꢀNationalꢀNaturalꢀScienceꢀFoundationꢀ
ofꢀChinaꢀ(21172176,ꢀ21372180),ꢀHubeiꢀProvinceꢀNaturalꢀScienceꢀFoundationꢀ(ZRZ0273),ꢀFundamentalꢀResearchꢀFundsꢀforꢀtheꢀCentralꢀUniversities,ꢀ
andꢀanꢀAcademicꢀAwardꢀforꢀExcellentꢀPhDꢀCandidatesꢀFundedꢀbyꢀtheꢀMinistryꢀofꢀEducationꢀofꢀChinaꢀ(5052011203011).ꢀ ꢀ
DOI:ꢀ10.1016/S1872‐2067(14)60204‐7ꢀ|ꢀhttp://www.sciencedirect.com/science/journal/18722067ꢀ|ꢀChin.ꢀJ.ꢀCatal.,ꢀVol.ꢀ36,ꢀNo.ꢀ1,ꢀJanuaryꢀ2015ꢀ ꢀ ꢀ

ꢀ
TanglinꢀLiuꢀetꢀal.ꢀ/ꢀChineseꢀJournalꢀofꢀCatalysisꢀ36ꢀ(2015)ꢀ68–77ꢀ
69ꢀ
metal‐stabilizedꢀ azomethineꢀ ylidesꢀ haveꢀ beenꢀ employedꢀ asꢀ
readilyꢀ availableꢀ 1,3‐dipoleꢀ inꢀ theꢀ chiral‐auxiliary‐inducedꢀ
asymmetricꢀ 1,3‐dipolarꢀ cycloadditionꢀ forꢀ theꢀ constructionꢀ ofꢀ
enantiomericallyꢀenrichedꢀpyrrolidinesꢀ[28–37],ꢀtheꢀfirstꢀcata‐
lyticꢀasymmetricꢀvariantꢀofꢀtheꢀ1,3‐dipolarꢀcycloadditionꢀreac‐
tionꢀofꢀazomethineꢀylidesꢀwasꢀreportedꢀbyꢀZhang’sꢀgroupꢀ[38]ꢀ
Tableꢀ1ꢀ ꢀ
Asymmetricꢀ 1,3‐dipolarꢀ cycloadditionꢀ ofꢀ variousꢀ glycinate‐derivedꢀ
iminoꢀestersꢀ2ꢀwithꢀethylꢀcyclopropylideneꢀacetateꢀ1aꢀforꢀtheꢀsynthesisꢀ
ofꢀ5‐aza‐spiro[2,4]heptanes.
ꢀ
CO Et
2
1
a
CuBF /L1 (3 mol%)
Et N (15 mol%), 20 oC
EtO2C
CO2Me
+
4
ꢀ
-
usingꢀ aꢀ Ag(I)/xylyl‐FAP complexꢀ andꢀ Jörgensen’sꢀ groupꢀ [39]ꢀ
NH
MeO C
N
R
3
2
-
usingꢀaꢀZn(II)/bisoxazolineꢀcomplexꢀonlyꢀinꢀ2002.ꢀSinceꢀthen,ꢀ
enormousꢀeffortsꢀhaveꢀbeenꢀmadeꢀonꢀtheꢀdevelopmentꢀofꢀcata‐
lyticꢀ stereoselectiveꢀ 1,3‐dipolarꢀ cycloadditionꢀ ofꢀ azomethineꢀ
ylidesꢀwithꢀelectron‐deficientꢀolefinsꢀtoꢀgiveꢀaꢀvarietyꢀofꢀhighlyꢀ
functionalizedꢀ pyrrolidinesꢀ withꢀ multipleꢀ stereogenicꢀ centersꢀ
R
CH Cl , 0.5 2 h
2
2
3
2
ꢀ
a
ꢀb
ꢀb
Entryꢀ
Rꢀ(2)ꢀ
p‐Cl‐C 4ꢀ(2a)ꢀ
o‐Cl‐C 4ꢀ(2b)ꢀ
p‐Br‐C
p‐F‐C
3ꢀ
Yield ꢀ(%)ꢀ endo:exo ee ꢀ(%)
1
ꢀ
6
H
3aaꢀ
3abꢀ
3acꢀ
3adꢀ
3aeꢀ
3afꢀ
3agꢀ
3ahꢀ
3aiꢀ
3ajꢀ
3akꢀ
3alꢀ
90ꢀ
97ꢀ
87ꢀ
85ꢀ
81ꢀ
78ꢀ
90ꢀ
87ꢀ
78ꢀ
82ꢀ
89ꢀ
76ꢀ
>98:2ꢀ
ꢀ 97:3ꢀ
ꢀ 95:5ꢀ
ꢀ 97:3ꢀ
ꢀ 95:5ꢀ
ꢀ 96:4ꢀ
>98:2ꢀ
>98:2ꢀ
>98:2ꢀ
>98:2ꢀ
>98:2ꢀ
>98:2ꢀ
98ꢀ
97ꢀ
98ꢀ
97ꢀ
95ꢀ
97ꢀ
98ꢀ
96ꢀ
98ꢀ
92ꢀ
94ꢀ
93ꢀ
2
ꢀ
6
H
3
ꢀ
6
H
4ꢀ(2c)ꢀ
H4ꢀ(2d)ꢀ
[40–55].ꢀTheꢀconstructionꢀofꢀquaternary,ꢀespeciallyꢀspiroꢀqua‐
4
ꢀ
6
ternary,ꢀstereogenicꢀcentersꢀhasꢀalsoꢀbeenꢀdevelopedꢀ[56–61].ꢀ
Mostꢀrecently,ꢀtheꢀcatalyticꢀasymmetricꢀ1,3‐dipolarꢀcycloaddi‐
tionꢀ reactionsꢀ ofꢀ azomethineꢀ ylidesꢀ withꢀ trisubstitutedꢀ elec‐
5
ꢀ
Phꢀ(2e)ꢀ
p‐Me‐C 4ꢀ(2f)ꢀ
m‐Me‐C 4ꢀ(2g)ꢀ
o‐Me‐C 4ꢀ(2h)ꢀ
p‐MeO‐C 4ꢀ(2i)ꢀ
6ꢀ
6
H
H
7
ꢀ
6
8
ꢀ
6
H
tron‐deficientꢀ alkenesꢀ forꢀ theꢀ constructionꢀ ofꢀ spiro[oxindole‐
ꢀ
9
ꢀ
6
H
pyrrolidine]sꢀwereꢀdevelopedꢀbyꢀGong’sꢀgroupꢀ[62–64],ꢀWald‐
mann’sꢀgroupꢀ[65,66],ꢀArai’sꢀgroupꢀ[67],ꢀWang’sꢀgroupꢀ[68,69]ꢀ
andꢀourꢀgroupꢀ[70–74].ꢀHowever,ꢀtheꢀsynthesisꢀofꢀchiralꢀsprioꢀ
pyrrolidineꢀ heterocyclesꢀ withꢀ vicinalꢀ quaternaryꢀ stereogenicꢀ
centersꢀbyꢀ1,3‐dipolarꢀ cycloadditionꢀofꢀ azomethineꢀylidesꢀhasꢀ
beenꢀseldomꢀreported.ꢀ
10ꢀ
1‐Naphthylꢀ(2j)ꢀ
2‐thienylꢀ(2k)ꢀ
cinnamylꢀ(2l)ꢀ
1
12 ꢀ
1ꢀ
c
Allꢀreactionsꢀwereꢀcarriedꢀoutꢀwithꢀ0.20ꢀmmolꢀofꢀ1aꢀandꢀ0.40ꢀmmolꢀofꢀ2
inꢀ2ꢀmLꢀofꢀCH
2 2
Cl .ꢀCuBF
4
ꢀ=ꢀCu(CH
3
CN)
4
4
BF .ꢀ ꢀ
a
ꢀ
ꢀ
Isolatedꢀyield.ꢀ ꢀ
b
Enantiomericꢀexcessesꢀandꢀdiastereomericꢀratioꢀwereꢀdeterminedꢀbyꢀ
Cyclopropaneꢀstructuresꢀareꢀcommonꢀcomponentsꢀinꢀmanyꢀ
naturalꢀ productsꢀ suchꢀ asꢀ terpenoidsꢀ andꢀ steroidsꢀ exhibitingꢀ
significantꢀbiologicalꢀactivityꢀ[75–77].ꢀMethylenecyclopropanesꢀ
chiralꢀHPLCꢀanalysis.ꢀMinorꢀexo‐isomerꢀwasꢀnotꢀdetectedꢀonꢀtheꢀcrudeꢀ
1
HꢀNMR.ꢀ ꢀ
cꢀReactionꢀwasꢀcarriedꢀoutꢀatꢀ0ꢀ°Cꢀinꢀ1ꢀh.ꢀ
(MCPs)ꢀ haveꢀ beenꢀ wellꢀ documentedꢀ asꢀ importantꢀ syntheticꢀ
intermediatesꢀinꢀorganicꢀsyntheticꢀchemistryꢀinꢀtheꢀpastꢀthreeꢀ
decadesꢀ [78,79],ꢀ andꢀ MCPsꢀ wereꢀ usedꢀ asꢀ aꢀ three‐carbonꢀ unitꢀ
fromꢀbothꢀα‐unsubstitutedꢀandꢀα‐substitutedꢀα‐aminoꢀacidꢀwithꢀ
aꢀ varietyꢀ ofꢀ α‐substitutedꢀ cyclopropylideneꢀ acetatesꢀ (Schemeꢀ
1).ꢀ
dipoleꢀinꢀaꢀvarietyꢀofꢀtheꢀtransitionꢀmetal‐catalyzedꢀring‐
open‐
ꢀ
ingꢀprocessesꢀ[80,81]ꢀdueꢀtoꢀtheꢀpotentꢀthermodynamicꢀdrivingꢀ
forceꢀ renderedꢀ byꢀ theꢀ reliefꢀ ofꢀ theꢀ 3‐memberedꢀ ringꢀ strain.ꢀ
Examplesꢀonꢀ ring‐untouchedꢀtransformationsꢀ employingꢀ MCPꢀ
derivativesꢀasꢀdipolarophilesꢀ[82]ꢀhaveꢀalsoꢀbeenꢀreportedꢀinꢀ
2.ꢀ ꢀ Experimentalꢀ
Generalꢀprocedureꢀforꢀtheꢀasymmetricꢀ1,3‐dipolarꢀcycload‐
ditionꢀ ofꢀ azomethineꢀ ylidesꢀ withꢀ ethylꢀ cyclopropylideneꢀ ace‐
1,3‐dipolarꢀ cycloadditionꢀ reactions,ꢀ inꢀ whichꢀ nitrones,ꢀ nitrileꢀ
oxides,ꢀ azides,ꢀ diazoalkanes,ꢀ nitrileꢀ ylidesꢀ andꢀ oximesꢀ wereꢀ
employedꢀasꢀtheꢀcorrespondingꢀ1,3‐dipoles.ꢀ
Inꢀ aꢀ previousꢀ communication,ꢀ weꢀ developedꢀ aꢀ highlyꢀ effi‐
cientꢀ Cu(I)/TF‐BiphamPhos‐catalyzedꢀ asymmetricꢀ 1,3‐dipolarꢀ
cycloadditionꢀofꢀazomethineꢀylidesꢀwithꢀethylꢀcyclopropylideneꢀ
tatesꢀ catalyzedꢀ byꢀ Cu(CHC
plex.ꢀUnderꢀanꢀargonꢀatmosphere,ꢀ(S)‐TF‐BiphamPhosꢀ(0.0072ꢀ
mmol)ꢀ andꢀ Cu(CHC CN) BF ꢀ (2.0ꢀ mg,ꢀ 0.006ꢀ mmol)ꢀ wereꢀ dis‐
solvedꢀinꢀ2ꢀmLꢀCH Cl ꢀandꢀstirredꢀatꢀroomꢀtemperatureꢀforꢀ1ꢀh.ꢀ
Then,ꢀtheꢀimineꢀsubstrateꢀ(0.4ꢀmmol),ꢀEt Nꢀ(0.03ꢀmmol),ꢀandꢀ
3
CN)
4
BF
4
/(S)‐TF‐BiphamPhosꢀ com‐
3
4
4
2
2
3
acetatesꢀ leadingꢀ toꢀ theꢀ synthesisꢀ ofꢀ spiroꢀ [cyclopropan‐3,3'‐
pyrrolidine]ꢀ withꢀ excellentꢀ endo‐selectivityꢀ andꢀ enantioselec‐
tivityꢀ (Tableꢀ 1)ꢀ [71].ꢀ Theꢀ spiro[cyclopropan‐3,3'‐pyrrolidine],ꢀ
thatꢀ is,ꢀ 5‐aza‐spiro[2,4]heptane,ꢀ structureꢀ motifꢀ withꢀ aꢀ spiroꢀ
carbonꢀconnectingꢀtwoꢀkeyꢀunitsꢀofꢀcyclopropaneꢀandꢀpyrroli‐
dineꢀplaysꢀanꢀimportantꢀroleꢀinꢀtheꢀstructure‐activityꢀrelation‐
ꢀ
ethylꢀ cyclopropylideneꢀ acetatesꢀ (0.2ꢀ mmol)ꢀ wereꢀ addedꢀ se‐
quentially.ꢀ Onceꢀ theꢀ startingꢀ materialꢀ wasꢀ consumedꢀ (moni‐
toredꢀbyꢀTLC),ꢀtheꢀmixtureꢀwasꢀfilteredꢀthroughꢀceliteꢀandꢀtheꢀ
filtrateꢀwasꢀconcentratedꢀtoꢀdryness.ꢀTheꢀproductꢀwasꢀpurifiedꢀ
byꢀcolumnꢀchromatographyꢀtoꢀgiveꢀtheꢀcorrespondingꢀcycload‐
ditionꢀ product,ꢀ whichꢀ wasꢀ thenꢀ directlyꢀ analyzedꢀ byꢀ chiralꢀ
HPLCꢀtoꢀdetermineꢀtheꢀenantiomericꢀexcess.ꢀ
ꢀ
shipꢀofꢀmanyꢀantibacterialꢀagents.ꢀTheꢀuniqueꢀ5‐aza‐spiro[2,4]
ꢀ
heptaneꢀ scaffoldꢀ canꢀ remarkablyꢀ enhanceꢀ theꢀ carbapenemsꢀ
analogs,ꢀsubstitutedꢀoxazolidinonesꢀandꢀquinoloneꢀantibiotics,ꢀ
especiallyꢀagainstꢀbothꢀgram‐positiveꢀ andꢀ gram‐negativeꢀ bac‐
teriaꢀ[83–89].ꢀ
Asꢀpartꢀofꢀourꢀcontinuingꢀeffortsꢀinꢀthisꢀarea,ꢀhereꢀweꢀreportꢀ
aꢀfullꢀaccountꢀofꢀtheꢀcatalyticꢀasymmetricꢀsynthesisꢀofꢀdiversi‐
fiedꢀ 5‐aza‐spiro[2,4]heptanesꢀ withꢀ highꢀ functionalitiesꢀ andꢀ
threeꢀ stereogenicꢀ centersꢀ includingꢀ upꢀ toꢀ threeꢀ contiguousꢀ
3.ꢀ ꢀ Resultsꢀandꢀdiscussionꢀ
3.1.ꢀ ꢀ Cu(I)‐catalyzedꢀ1,3‐dipolarꢀcycloadditionꢀofꢀα‐substitutedꢀ
azomethineꢀylidesꢀwithꢀethylꢀcyclopropylideneꢀacetatesꢀ
Encouragedꢀ byꢀ theꢀ excellentꢀ resultsꢀ achievedꢀ withꢀ
α‐unsubstitutedꢀ azomethineꢀ ylidesꢀ derivedꢀ fromꢀ glycinateꢀ inꢀ
ourꢀpreviousꢀcommunicationꢀ[71],ꢀweꢀfurtherꢀinvestigatedꢀtheꢀ
possibilityꢀ ofꢀ employingꢀ α‐substitutedꢀ iminoꢀ estersꢀ asꢀ theꢀ di‐
all‐carbonꢀ quaternaryꢀ centersꢀ byꢀ Cu(I)/TF‐BiphamPhos‐
ꢀ
cata‐
lyzedꢀ 1,3‐dipolarꢀ cycloadditionꢀ ofꢀ azomethineꢀ ylidesꢀ derivedꢀ

7
0ꢀ
TanglinꢀLiuꢀetꢀal.ꢀ/ꢀChineseꢀJournalꢀofꢀCatalysisꢀ36ꢀ(2015)ꢀ68–77ꢀ
Tableꢀ2ꢀ ꢀ
R3
EtO2C
CO2Me
EtO2C
O
Asymmetricꢀ 1,3‐dipolarꢀ cycloadditionꢀ ofꢀ α‐substitutedꢀ iminoꢀ estersꢀ 2
withꢀethylꢀ2‐cyclopropylideneꢀacetateꢀ1a.ꢀ
NH
NH
R1
O
R4
6
3
1,3-Dipolar
Cycloaddition
R2 = H
R3 = H
R3 = H
MeO2C
N
R1
R4
CO2Et
R2
2
1
+ 2
R3
+
or
1 + 5
3ꢀ Yieldꢀaꢀ(%)ꢀ d.rꢀb
eeꢀbꢀ(%)
>98:2 98ꢀ
O
Entryꢀ
1ꢀ
Productꢀ
ꢀ
N
3amꢀ
89ꢀ
1
O
5
2
R
R
= H
= H
Cu(I)/TF-BiphamPhos
R3 = H
3
2
ꢀ
3anꢀ
3aoꢀ
87ꢀ
87ꢀ
>98:2
95:5ꢀ
97ꢀ
97ꢀ
R3
R2
R3
EtO2C
O
EtO2C
CO Me
2
NH
NH
R1
O
3ꢀ
7
R4
8
CF3
R2
L1: R1 = Ph, R2 = H
L2: R1 = 3,5-(CF3)2-C6H3, R2 = H
L3: R1 = Cy, R2 = H
4ꢀ
3apꢀ
74ꢀ
>98:2
97ꢀ
F3C
F3C
NH2
NHPR1
2
L4: R1 = Ph, R2 = Br
R2
CF3
5
ꢀ
3aqꢀ
3arꢀ
81ꢀ
62ꢀ
>98:2
95:5ꢀ
97ꢀ
96ꢀ
(
S)-TF-BiphamPhos
Schemeꢀ1.ꢀConstructionꢀofꢀspiroꢀpyrrolidineꢀheterocyclesꢀwithꢀcontig‐
uousꢀ quaternaryꢀ centersꢀ viaꢀ Cu(I)‐catalyzedꢀ 1,3‐dipolarꢀcycloadditionꢀ
ofꢀazomethineꢀylidesꢀwithꢀcyclopropylideneꢀacetates.ꢀ
6ꢀ
poleꢀ precursors.ꢀ Theseꢀ areꢀ challengingꢀ substratesꢀ dueꢀ toꢀ theꢀ
unfavourableꢀstericꢀhindranceꢀbecauseꢀtwoꢀcontiguousꢀquater‐
naryꢀcentersꢀcanꢀbeꢀformedꢀandꢀtheꢀlowerꢀacidityꢀofꢀtheꢀcorre‐
spondingꢀ metheneꢀ CHꢀ groupꢀ betweenꢀ theꢀ imineꢀ andꢀ ester.ꢀ
Hence,ꢀalthoughꢀtheꢀgeneratedꢀpyrrolidinesꢀcontainingꢀaꢀuniqueꢀ
quaternaryꢀ stereogenicꢀ centerꢀ areꢀ ofꢀ greatꢀ importanceꢀ andꢀ
syntheticꢀ potential,ꢀ α‐substitutedꢀ iminoꢀ estersꢀ haveꢀ beenꢀ sel‐
domꢀ employedꢀ inꢀ theꢀ asymmetricꢀ 1,3‐dipolarꢀ cycloadditionꢀ
comparedꢀ withꢀ α‐unsubstitutedꢀ iminoꢀ estersꢀ derivedꢀ fromꢀ
glycinate.ꢀ Toꢀ ourꢀ delight,ꢀ underꢀ theꢀ optimalꢀ conditionsꢀ inꢀ theꢀ
previousꢀ communication,ꢀ variousꢀ iminoꢀ estersꢀ derivedꢀ fromꢀ
α‐substitutedꢀ aminoꢀ acid,ꢀ suchꢀ asꢀ (±)‐alanine,ꢀ (±)‐leucine,ꢀ
Allꢀreactionsꢀwereꢀcarriedꢀoutꢀwithꢀ0.20ꢀmmolꢀofꢀ1aꢀandꢀ0.40ꢀmmolꢀofꢀ2
inꢀ2ꢀmLꢀofꢀCH
2
Cl
2
,ꢀCuBF
4
ꢀ=ꢀCu(CH
3
CN)
4
BF .ꢀ ꢀ
4
a
ꢀIsolatedꢀyield.ꢀ ꢀ
b
ꢀ
Enantiomericꢀexcessesꢀandꢀdiastereomericꢀratiosꢀwereꢀdeterminedꢀbyꢀ
chiralꢀHPLCꢀanalysis.ꢀMinorꢀexo‐isomerꢀwasꢀnotꢀdetectedꢀonꢀtheꢀcrudeꢀ
1
HꢀNMR.ꢀ
theꢀ3ꢀandꢀ7ꢀ positionsꢀofꢀtheꢀspiroꢀ pyrrolidineꢀ ringsꢀwereꢀex‐
pected.ꢀUnderꢀtheꢀoptimalꢀreactionꢀconditions,ꢀweꢀsuccessfullyꢀ
extendedꢀ theꢀ dipolarophileꢀ scopeꢀ toꢀ variousꢀ α‐substitutedꢀ
2‐cyclopropylideneꢀ acetates.ꢀ Asꢀ shownꢀ inꢀ Tableꢀ 3,ꢀ ethylꢀ
2‐cyclopropylideneꢀ acetatesꢀ bearingꢀ alkylꢀ substitutesꢀ suchꢀ asꢀ
methylꢀ(1b,ꢀentryꢀ1),ꢀethylꢀ(1c,ꢀentryꢀ2),ꢀn‐propylꢀ(1d,ꢀentryꢀ3),ꢀ
andꢀbenzylꢀ(1e,ꢀentryꢀ4),ꢀandꢀaromaticꢀringꢀsubstitutesꢀsuchꢀasꢀ
phenylꢀ(1f,ꢀentryꢀ5)ꢀgroupsꢀatꢀtheꢀαꢀpositionꢀofꢀtheꢀesterꢀgroupꢀ
wereꢀ allꢀ provenꢀ compatibleꢀ inꢀ thisꢀ annulationꢀ processꢀ withꢀ
azomethineꢀ ylideꢀ 2a,ꢀ smoothlyꢀ affordingꢀ theꢀ correspondingꢀ
spiroꢀcycloadductsꢀexclusivelyꢀinꢀgoodꢀyieldsꢀandꢀexcellentꢀdia‐
stereoselectivitiesꢀ andꢀ highꢀ enantioselectivitiesꢀ (upꢀ toꢀ >98:2ꢀ
d.r,ꢀ andꢀ 92%–96%ꢀ ee).ꢀ Thisꢀ isꢀ theꢀ firstꢀ exampleꢀ ofꢀ theꢀ
α,α,β,β‐tetrasubstitutedꢀ electron‐deficientꢀ alkenesꢀ usedꢀ asꢀ theꢀ
dipolarophilesꢀinꢀtheꢀcatalyticꢀasymmetricꢀ1,3‐dipolarꢀcycload‐
dition.ꢀTheꢀabsoluteꢀconfigurationꢀofꢀspiroꢀpyrrolidineꢀ3caꢀwasꢀ
determinedꢀasꢀ(4R,6R,7R)ꢀbyꢀX‐rayꢀanalysisꢀofꢀitsꢀcorrespond‐
ingꢀN‐tosylatedꢀderivativeꢀ4ꢀ(Fig.ꢀ1.ꢀCCDCꢀ962660ꢀ(4)ꢀcontainsꢀ
theꢀsupplementaryꢀcrystallographicꢀdataꢀforꢀthisꢀpaper).ꢀ
(±)‐2‐aminobutyricꢀacidꢀandꢀ(±)‐phenylalanineꢀwereꢀtoleratedꢀ
inꢀ thisꢀ catalyticꢀ system,ꢀ whichꢀ providedꢀ theꢀ correspondingꢀ
highlyꢀ functionalizedꢀ pyrrolidinesꢀ containingꢀ aꢀ uniqueꢀ nitro‐
gen‐substitutedꢀquaternaryꢀstereogenicꢀcenterꢀadjacentꢀtoꢀtheꢀ
spiroꢀquaternaryꢀcarbonꢀcenterꢀinꢀexclusiveꢀdiastereoselectivi‐
tiesꢀandꢀexcellentꢀenantioselectivitiesꢀ(Tableꢀ2).ꢀ
3.2.ꢀ ꢀ Cu(I)/TF‐BiphamPhos‐catalyzedꢀ1,3‐dipolarꢀcycloadditionꢀ
ofꢀazomethineꢀylidesꢀwithꢀα‐substitutedꢀethylꢀ2‐cyclopropylideneꢀ
acetatesꢀ ꢀ
Toꢀbetterꢀdefineꢀtheꢀsubstrateꢀscopeꢀwithꢀrespectꢀtoꢀtheꢀdi‐
polarophiles,ꢀ theꢀ moreꢀ stericallyꢀ hinderedꢀ α‐substitutedꢀ ethylꢀ
2
‐cyclopropylideneꢀ acetatesꢀ wereꢀ employed.ꢀ Spiro
ꢀ
[cyclopro‐
pan‐3,3'‐pyrrolidine]ꢀwithꢀtwoꢀadjacentꢀquaternaryꢀcentersꢀatꢀ

ꢀ
TanglinꢀLiuꢀetꢀal.ꢀ/ꢀChineseꢀJournalꢀofꢀCatalysisꢀ36ꢀ(2015)ꢀ68–77ꢀ
Tableꢀ4ꢀ ꢀ
71ꢀ
Tableꢀ3ꢀ ꢀ
Asymmetricꢀ 1,3‐dipolarꢀ cycloadditionꢀ ofꢀ 2aꢀ withꢀ variousꢀ ofꢀ
α‐substitutedꢀethylꢀ2‐cyclopropylideneꢀacetatesꢀ1.ꢀ
Optimizationꢀofꢀtheꢀreactionꢀconditionsꢀforꢀcycloꢀiminoꢀestersꢀ5.ꢀ
ꢀ
a
ꢀb
ꢀ
Yield ꢀ
(
ee ꢀ
Entryꢀ
1ꢀ
Productꢀ
3ꢀ
d.rꢀb
ꢀ
aꢀ
ꢀb
%)ꢀ
(%)
Entryꢀ
[M]ꢀ
Cu(CH CN)
AgOAcꢀ
Lꢀ
Yield (%)ꢀ
55ꢀ
ee ꢀ(%)ꢀ
82ꢀ
31ꢀ
31ꢀ
61ꢀ
1
ꢀ
3
4
BF
4
ꢀ
L1ꢀ
L1ꢀ
L2ꢀ
L3ꢀ
L4ꢀ
2
ꢀ
25ꢀ
25ꢀ
29ꢀ
80ꢀ
1ꢀ
3baꢀ 80ꢀ 95:5 96
3caꢀ 72ꢀ >98:2 96
3daꢀ 70ꢀ 96:4 95
3
ꢀ
Cu(CH
Cu(CH
Cu(CH
3
3
3
CN)
CN)
CN)
4
4
4
BF
4
BF
4
BF
4
ꢀ
ꢀ
ꢀ
1bꢀ
ꢀ
4ꢀ
5ꢀ
95ꢀ
Allꢀreactionsꢀwereꢀcarriedꢀoutꢀwithꢀ0.40ꢀmmolꢀofꢀ5eꢀandꢀ0.20ꢀmmolꢀofꢀ
aꢀinꢀ2ꢀmLꢀCH Cl .ꢀ ꢀ
Isolatedꢀyield.ꢀ ꢀ
bꢀEnantiomericꢀexcessesꢀandꢀdiastereomericꢀratiosꢀwereꢀdeterminedꢀbyꢀ
chiralꢀ HPLCꢀ analysis.ꢀ Theꢀ minorꢀ exo‐isomerꢀ wasꢀ notꢀ detectedꢀ onꢀ theꢀ
2ꢀ
1
aꢀ
2
2
1cꢀ
ꢀ
Pr
CO2Me
EtO2C
3ꢀ
NH
1
1dꢀ p-Cl-C6H4
crudeꢀ HꢀNMR.ꢀ
ꢀ
4
ꢀ
3eaꢀ 66ꢀ >98:2 96
3faꢀ 64ꢀ >98:2 92
ethylꢀ cyclopropylideneꢀ acetateꢀ 1aꢀ reactedꢀ withꢀvariousꢀ cyclicꢀ
iminoꢀ estersꢀ generatedꢀ fromꢀ aldehydesꢀ andꢀ homoserineꢀ lac‐
toneꢀ smoothlyꢀ affordingꢀ theꢀ desiredꢀ adductsꢀ inꢀ highꢀ yieldsꢀ
(40%–82%)ꢀ withꢀ exclusiveꢀ diastereoselectivitiesꢀ (>98:2ꢀ d.r)ꢀ
andꢀ excellentꢀ enantioselectivitiesꢀ (87%–96%ꢀ ee).ꢀ Theꢀ
1
eꢀ
ꢀ
5ꢀ
1
fꢀ
ꢀ
Allꢀreactionsꢀwereꢀcarriedꢀoutꢀwithꢀ0.20ꢀmmolꢀofꢀ1ꢀandꢀ0.40ꢀmmolꢀofꢀ2a
10‐positionꢀ ofꢀ theꢀ spiro‐pyrrolidinesꢀ canꢀ beꢀ substitutedꢀ withꢀ
inꢀ2ꢀmLꢀofꢀCH
Cl
2 2
,ꢀCuBF
4
ꢀ=ꢀCu(CH
3
CN)
4
BF .ꢀ ꢀ
4
arenesꢀcontainingꢀelectron‐withdrawingꢀ(Tableꢀ5,ꢀentriesꢀ1–4),ꢀ
electron‐neutralꢀ (Tableꢀ 5,ꢀ entryꢀ 5)ꢀ andꢀ electron‐donatingꢀ
groupsꢀ(Tableꢀ5,ꢀentriesꢀ6–9)ꢀasꢀwellꢀasꢀheterocyclesꢀsuchꢀasꢀ
2‐furanylꢀ(6ak)ꢀandꢀ2‐thienylꢀ(6al).ꢀCyclicꢀiminoꢀestersꢀderivedꢀ
fromꢀα‐naphthylaldehydeꢀalsoꢀworkedꢀwellꢀinꢀthisꢀreaction,ꢀandꢀ
theꢀ desiredꢀ spirocyclicꢀ 6ajꢀcanꢀbeꢀobtainedꢀinꢀ70%ꢀyieldꢀandꢀ
90%ꢀeeꢀ(Tableꢀ5,ꢀentryꢀ10).ꢀHowever,ꢀtheꢀlessꢀreactiveꢀaliphaticꢀ
cyclicꢀiminoꢀestersꢀdidꢀnotꢀworkꢀinꢀthisꢀcycloadditionꢀreactionꢀ
underꢀ theꢀ re‐optimizedꢀ reactionꢀ condition.ꢀ Theꢀ absoluteꢀ con‐
figurationꢀ ofꢀ theꢀ spiro‐pyrrolidinesꢀ 6adꢀ wasꢀ establishedꢀ byꢀ
X‐rayꢀdiffractionꢀanalysisꢀ(Fig.ꢀ1.ꢀCCDCꢀ962659ꢀ(6ad)ꢀcontainsꢀ
theꢀsupplementaryꢀcrystallographicꢀdataꢀforꢀthisꢀpaper).ꢀ
a
ꢀ
ꢀ
Isolatedꢀyield.ꢀ ꢀ
b
Enantiomericꢀexcessesꢀandꢀdiastereomericꢀratiosꢀwereꢀdeterminedꢀbyꢀ
chiralꢀ HPLCꢀ analysis.ꢀ Theꢀ minorꢀ exo‐isomerꢀ wasꢀ notꢀ detectedꢀ inꢀ theꢀ
crudeꢀ HꢀNMR.ꢀ
1
3
.3.ꢀ ꢀ Cu(I)/TF‐BiphamPhos‐catalyzedꢀ1,3‐dipolarꢀcycloadditionꢀ
ofꢀhomoserineꢀlactoneꢀderivedꢀcyclicꢀazomethineꢀylidesꢀwithꢀethylꢀ
2
‐cyclopropylideneꢀacetateꢀ
Toꢀ furtherꢀ probeꢀ theꢀ applicabilityꢀ ofꢀ thisꢀ 1,3‐dipolarꢀ cy‐
cloadditionꢀ reactionꢀ toꢀ constructꢀ theꢀ moreꢀ complexꢀ spi‐
ro[cyclopropan‐3,3'‐pyrrolidine],ꢀ weꢀ turnedꢀ ourꢀ attentionꢀ toꢀ
theꢀcyclicꢀazomethineꢀylidesꢀderivedꢀfromꢀhomoserineꢀlactones.ꢀ
Aꢀ tricyclicꢀ spiroꢀ heterocycleꢀ bearingꢀ oneꢀ cyclopropane,ꢀ oneꢀ
pyrrolidineꢀ andꢀ oneꢀ butylactoneꢀ moietyꢀ wouldꢀ beꢀ expectedꢀ
alongꢀwithꢀtwoꢀgeneratedꢀquaternaryꢀcentersꢀinꢀthisꢀtransfor‐
mation.ꢀ Whenꢀ theꢀ cyclicꢀ iminoꢀ esterꢀ 5eꢀ reactedꢀ withꢀ ethylꢀ
3.4.ꢀ ꢀ Cu(I)/TF‐BiphamPhos‐catalyzedꢀ1,3‐dipolarꢀcycloadditionꢀ
ofꢀα‐substitutedꢀazomethineꢀylidesꢀwithꢀα‐substitutedꢀethylꢀ
2‐cyclopropylideneꢀacetateꢀforꢀtheꢀconstructionꢀofꢀspiroꢀ
heterocyclesꢀwithꢀthreeꢀadjacentꢀquaternaryꢀcentersꢀ
2
‐cyclopropylideneꢀ acetateꢀ 1aꢀ inꢀ theꢀ presenceꢀ ofꢀ 3ꢀ mol%ꢀ ofꢀ
Cu(CH
CN) BF /(S)‐TF‐BiphamPhosꢀ(L1)ꢀandꢀ15ꢀmol%ꢀEt Nꢀinꢀ
CH Cl ꢀ atꢀ roomꢀ temperature,ꢀ theꢀ designedꢀ productꢀ wasꢀ ob‐
tainedꢀwithꢀaꢀmoderateꢀyieldꢀalthoughꢀonlyꢀwithꢀ82%ꢀeeꢀ(Tableꢀ
,ꢀentryꢀ1).ꢀThus,ꢀtheꢀreactionꢀconditionsꢀwereꢀre‐optimizedꢀtoꢀ
improveꢀtheꢀasymmetricꢀinductionꢀefficiency.ꢀHavingꢀscreenedꢀ
theꢀreactionꢀparametersꢀincludingꢀtheꢀmetalꢀsource,ꢀchiralꢀlig‐
andꢀandꢀreactionꢀtemperature,ꢀitꢀwasꢀelucidatedꢀthatꢀtheꢀbestꢀ
resultꢀ inꢀ termsꢀ ofꢀ bothꢀ theꢀ yieldꢀ andꢀ enantioselectivityꢀ wasꢀ
achievedꢀ whenꢀ theꢀ reactionꢀ wasꢀ catalyzedꢀ byꢀ theꢀ complexꢀ ofꢀ
3
4
4
3
Inꢀ addition,ꢀ weꢀ testedꢀ theꢀ constructionꢀ ofꢀ spi‐
ro[cyclopropan‐3,3'‐pyrrolidine]ꢀ bearingꢀ threeꢀ adjacentꢀ qua‐
ternaryꢀcenters,ꢀtwoꢀofꢀwhichꢀareꢀquaternaryꢀstereogenicꢀcen‐
ters,ꢀ generatedꢀ byꢀ 1,3‐dipolarꢀ cycloadditionꢀ ofꢀ theꢀ α‐methylꢀ
substitutedꢀazomethineꢀylideꢀ2nꢀorꢀcyclicꢀazomethineꢀylideꢀ5eꢀ
withꢀα‐benzylꢀethylꢀ2‐cyclopropylideneꢀacetateꢀ1eꢀ(Schemeꢀ2).ꢀ
Theꢀ reactionsꢀ wereꢀ carriedꢀ outꢀ successfullyꢀ inꢀ theꢀ
Cu(I)‐catalyticꢀsystemꢀemployingꢀchiralꢀligandsꢀL1ꢀandꢀL4,ꢀre‐
spectively.ꢀ Theꢀ targetꢀ productsꢀ wereꢀ obtainedꢀ withꢀ excellentꢀ
diastereoselectivitiesꢀ andꢀ enantioselectivitiesꢀ (96%ꢀ eeꢀ forꢀ 7ꢀ
andꢀ 93%ꢀ eeꢀ forꢀ 8)ꢀ althoughꢀ withꢀ moderateꢀ yields.ꢀ Thisꢀ con‐
structionꢀ ofꢀ chiralꢀ pyrrolidinesꢀ withꢀ contiguousꢀ threeꢀ quater‐
naryꢀ centersꢀ viaꢀ theꢀ 1,3‐dipolarꢀ cycloadditionꢀ reactionꢀ wasꢀ
developedꢀforꢀtheꢀfirstꢀtime.ꢀ
2
2
4
Cu(CH
3
CN) BF4ꢀ andꢀ chiralꢀ L4ꢀ atꢀ roomꢀ temperatureꢀ (Tableꢀ 4,ꢀ
4
entryꢀ5).ꢀ ꢀ
Theꢀsubstrateꢀscopeꢀandꢀlimitationꢀofꢀtheꢀcyclicꢀiminoꢀestersꢀ
inꢀthisꢀannulationꢀwasꢀfurtherꢀextendedꢀunderꢀtheꢀre‐optimizedꢀ
reactionꢀcondition.ꢀTheꢀresultsꢀareꢀlistedꢀinꢀTableꢀ5.ꢀInꢀgeneral,ꢀ

72ꢀ
TanglinꢀLiuꢀetꢀal.ꢀ/ꢀChineseꢀJournalꢀofꢀCatalysisꢀ36ꢀ(2015)ꢀ68–77ꢀ
Tableꢀ5ꢀ ꢀ
Asymmetricꢀ 1,3‐dipolarꢀ cycoladditionꢀ ofꢀ variousꢀ cycloꢀ iminoꢀ estersꢀ 5
withꢀcyclopropyl‐ideneacetateꢀ1a.ꢀ
ꢀ
ꢀ
ꢀa
Entryꢀ
Yield ꢀ
%)ꢀ
ꢀ
b
ꢀb
Productꢀ
6ꢀ
d.r ꢀ
ee ꢀ(%)
(
1ꢀ
6
aaꢀ
82ꢀ
67ꢀ
67ꢀ
>ꢀ98:2
95ꢀ
92ꢀ
89ꢀ
ꢀ
2ꢀ
ꢀ
6abꢀ
95:5ꢀ
Fig.ꢀ1.ꢀTheꢀstructuresꢀofꢀ(4R,6R,7R)‐4ꢀandꢀ(4R,10S,11R)‐6ad.ꢀ
ꢀ
3
ꢀ
posed.ꢀTheꢀtransitionꢀstateꢀmodelꢀinꢀFig.ꢀ2ꢀaccountsꢀforꢀtheꢀob‐
servedꢀendo‐selectivityꢀofꢀtheꢀ1,3‐dipolarꢀcycloadditionꢀofꢀiminoꢀ
estersꢀwithꢀethylꢀ2‐cyclopropylideneꢀacetatesꢀinꢀtheꢀpresenceꢀofꢀ
6
acꢀ
>ꢀ98:2
ꢀ
4ꢀ
Cu(CH
3
CN)
4
BF /(S)‐TF‐BiphamPhosꢀ (L1).ꢀ Theꢀ in‐situꢀ formedꢀ
4
6
adꢀ
62ꢀ
80ꢀ
61ꢀ
61ꢀ
>ꢀ98:2
>ꢀ98:2
>ꢀ98:2
>ꢀ98:2
96ꢀ
96ꢀ
93ꢀ
96ꢀ
azomethineꢀylideꢀisꢀcoordinatedꢀtoꢀtheꢀmetallicꢀcenterꢀandꢀori‐
entedꢀasꢀdeterminedꢀbyꢀtheꢀstericꢀrepulsionꢀbetweenꢀtheꢀtwoꢀ
phenylꢀgroupꢀinꢀtheꢀylideꢀandꢀonꢀtheꢀphosphorusꢀatomꢀofꢀtheꢀ
chiralꢀligand.ꢀTheꢀ dipolarophileꢀethylꢀ2‐cyclopropylideneꢀace‐
tateꢀ 1ꢀ approachesꢀ theꢀ less‐hinderedꢀ faceꢀ ofꢀ theꢀ azomethineꢀ
ylide,ꢀthatꢀis,ꢀtheꢀSiꢀ(C=N)ꢀfaceꢀinꢀthisꢀcase,ꢀtoꢀavoidꢀstericꢀcon‐
ꢀ
5ꢀ
6
aeꢀ
ꢀ
6ꢀ
EtO2C
p-Me-C6H4
O
6
afꢀ
NH
gestion,ꢀ andꢀ henceꢀ formꢀ theꢀ endo‐selectiveꢀ (4R,6S,7R)‐5‐aza‐
ꢀ
O
ꢀ
spiro[2,4]‐heptaneꢀ observedꢀ inꢀ theꢀ experimentalꢀ results.ꢀ Theꢀ
possibleꢀ hydrogenꢀ bondꢀ interactionꢀ betweenꢀ theꢀ carbonylꢀ
7ꢀ
6
agꢀ
groupꢀ ofꢀ theꢀ dipolarophileꢀ 1ꢀandꢀtheꢀNH
S)‐TF‐BiphamPhosꢀ ligandꢀ (L1)ꢀ wouldꢀ stabilizeꢀ theꢀ transitionꢀ
stateꢀ[96,97].ꢀ
2
ꢀgroupꢀofꢀtheꢀchiralꢀ
ꢀ
(
8ꢀ
6ahꢀ
71ꢀ
40ꢀ
70ꢀ
>ꢀ98:2
>ꢀ98:2
>ꢀ98:2
93ꢀ
91ꢀ
90ꢀ
9ꢀ
6
aiꢀ
ajꢀ
ꢀ
10ꢀ
11ꢀ
12ꢀ
6
ꢀ
6akꢀ
80ꢀ
82ꢀ
>ꢀ98:2
>ꢀ98:2
90ꢀ
87ꢀ
ꢀ
6
alꢀ
Schemeꢀ2.ꢀ1,3‐Dipolarꢀcycloadditionꢀofꢀα‐substitutedꢀazomethineꢀylidesꢀ
withꢀα‐substitutedꢀcyclopropylideneꢀacetateꢀ1eꢀforꢀtheꢀconstructionꢀofꢀ
ꢀ
ꢀ
Allꢀreactionsꢀwereꢀcarriedꢀoutꢀwithꢀ0.20ꢀmmolꢀofꢀ1aꢀandꢀ0.40ꢀmmolꢀofꢀ5
spiroꢀpyrrolidinesꢀwithꢀthreeꢀadjacentꢀquaternaryꢀcenters.
inꢀ2ꢀmLꢀofꢀCH
2
Cl
2
.ꢀCuBF
4
ꢀ=ꢀCu(CH
3
CN)
4
BF .ꢀ ꢀ
4
a
ꢀIsolatedꢀyield.ꢀ ꢀ
b
ꢀ
Enantiomericꢀexcessesꢀandꢀdiastereomericꢀratiosꢀwereꢀdeterminedꢀbyꢀ
chiralꢀ HPLCꢀ analysis.ꢀ Theꢀ minorꢀ exo‐isomerꢀ wasꢀ notꢀ detectedꢀ inꢀ theꢀ
1
crudeꢀ HꢀNMR.ꢀ
3.5.ꢀ ꢀ PossibleꢀtransitionꢀstateꢀinꢀtheꢀCu(I)/TF‐BiphamPhos‐ꢀ
catalyzedꢀ1,3‐dipolarꢀcycloadditionꢀofꢀazomethineꢀylidesꢀwithꢀ
cyclopropylideneꢀacetateꢀ
BasedꢀonꢀtheseꢀresultsꢀandꢀpreviousꢀDFTꢀstudiesꢀ[90,91],ꢀaꢀ
stepwiseꢀ Michael/Mannichꢀ mechanismꢀ [92–95]ꢀ canꢀ beꢀ pro‐
ꢀ
Fig.ꢀ2.ꢀTransitionꢀstatesꢀleadingꢀtoꢀendo‐5‐aza‐spiro[2,4]heptane.ꢀ

ꢀ
TanglinꢀLiuꢀetꢀal.ꢀ/ꢀChineseꢀJournalꢀofꢀCatalysisꢀ36ꢀ(2015)ꢀ68–77ꢀ
73ꢀ
4.ꢀ ꢀ Conclusionsꢀ
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0:ꢀ2434ꢀ
[
Weꢀ haveꢀ developedꢀ aꢀ generalꢀ methodologyꢀ forꢀ theꢀ directꢀ
5
andꢀ facileꢀ synthesisꢀ ofꢀ variousꢀ enantiomericallyꢀ enrichedꢀ en‐
do‐5‐aza‐spiro[2,4]heptaneꢀ derivativesꢀ byꢀ theꢀ highlyꢀ efficientꢀ
[
14] OhmatsuꢀK,ꢀImagawaꢀN,ꢀOoiꢀT.ꢀNatꢀChem,ꢀ2014,ꢀ6:ꢀ47ꢀ
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[
Cu(I)‐catalyzedꢀ 1,3‐dipoalrꢀ cycloadditionꢀofꢀaꢀ varietyꢀofꢀ α‐un‐
ꢀ
substitutedꢀ andꢀ α‐substitutedꢀ azomethineꢀ ylidesꢀ withꢀ variousꢀ
cyclopropylideneꢀacetates.ꢀThisꢀreactionꢀprovidesꢀaꢀconvenientꢀ
[16] ZhangꢀHꢀL,ꢀHongꢀL,ꢀKangꢀH,ꢀWangꢀR.ꢀJꢀAmꢀChemꢀSoc,ꢀ2013,ꢀ135:ꢀ
14098ꢀ
methodꢀ toꢀ accessꢀ highlyꢀ substitutedꢀ spiro[cyclopropan‐3,3'‐
ꢀ
[
17] HarwoodꢀLꢀM,ꢀVickersꢀRꢀJ.ꢀIn:ꢀPadwaꢀA,ꢀPeassonꢀWꢀHꢀeds.ꢀSyntheticꢀ
Applicationsꢀ ofꢀ 1,3‐Dipolarꢀ Cycloadditionꢀ Chemistryꢀ Towardꢀ
Heterocyclesꢀandꢀ Naturalꢀ Products.ꢀ German:ꢀJohnꢀWileyꢀ &ꢀ Sons,ꢀ
2003.ꢀ169ꢀ
pyrrolidine]ꢀwithꢀupꢀtoꢀthreeꢀcontiguousꢀquaternaryꢀcentersꢀinꢀ
highꢀyieldsꢀandꢀexcellentꢀdiastereoselectivitiesꢀ(upꢀtoꢀ>98:2ꢀdr)ꢀ
andꢀenantioselectivitesꢀ(upꢀtoꢀ98%ꢀee).ꢀ
[
[
[
[
18] PyneꢀSꢀG,ꢀDavisꢀAꢀS,ꢀGatesꢀNꢀJ,ꢀHartleyꢀJꢀP,ꢀLindsayꢀKꢀB,ꢀMachanꢀT,ꢀ
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Acknowledgmentsꢀ ꢀ
44:ꢀ1758ꢀ
WeꢀthankꢀProf.ꢀHuaꢀLiꢀatꢀWuhanꢀUniversityꢀforꢀsolvingꢀtheꢀ
crystalꢀstructure.ꢀ
20] CondeꢀE,ꢀBelloꢀD,ꢀdeꢀCozarꢀA,ꢀSanchezꢀM,ꢀVazquezꢀMꢀA,ꢀCossioꢀFꢀP.ꢀ
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TanglinꢀLiu,ꢀQinghuaꢀLi,ꢀZhaolinꢀhe,ꢀJiaweiꢀZhang,ꢀChunjiangꢀWang*ꢀ
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R3
R1
CO Me
2
EtO C
CF3
2
NH
R
MeO C
N
R2
2
R2
R1
CO Et
24 examples, 55-97% yield
92-98% ee, 95:5->98:2 dr
F3C
NH2
2
R3
Cu(I)/L
3 mol%)
F3C
NHPPh2
(
O
O
N
R4
R1
EtO C
R
O
CF
3
2
NH
TF-BiphamPhos
L1: R = H
O
R4
L4: R = Br
1
8
3 examples, 40-82% yield
7-96% ee, 95:5->98:2 dr
ꢀ
Bioactiveꢀ5‐aza‐spiro[2,4]heptanesꢀwithꢀhighꢀfunctionalityꢀandꢀupꢀtoꢀthreeꢀcontiguousꢀall‐carbonꢀquaternaryꢀcentersꢀwereꢀsynthesizedꢀbyꢀ
Cu(I)‐catalyzedꢀasymmetricꢀendo‐selectiveꢀ1,3‐dipolarꢀcycloadditionꢀofꢀazomethineꢀylidesꢀwithꢀcyclopropylideneꢀacetates.ꢀ

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