Self-assembled ion-pair organocatalysis - Asymmetric Baeyer-Villiger oxidation mediated by flavinium-cinchona alkaloid dimer

Article abstract of DOI:10.1039/c6cc00663a

An ion-pair catalyst generated by assembly of a chiral flavinium and a cinchona alkaloid dimer for use in asymmetric Baeyer-Villiger oxidation is presented. Ion-pair formation is essential for enhancing the catalytic activity and stereoselectivity. The catalyst is applicable to structurally diverse 3-substituted cyclobutanones, providing good to excellent enantioselectivities (up to 98: 2 e.r.). This study provides the first example of self-assembly of a flavin derivative and a base to form a chiral reaction site that enables a highly stereoselective reaction to occur.

Full text of DOI:10.1039/c6cc00663a

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Pleaseꢀd Co hꢀ ne omt ꢀ Ca do j mu s mt ꢀmarginsꢀ
View Article Online
DOI: 10.1039/C6CC00663A
ChemicalꢀCommunicationsꢀ
COMMUNICATIONꢀ
ꢀ
Self-AssembledꢀIon–pairꢀꢀOrganocatalysisꢀ–ꢀAsymmetricꢀBaeyer-
VilligerꢀOxidationꢀMediatedꢀbyꢀFlavinium-CinchonaꢀAlkaloidꢀDimerꢀꢀ
Receivedꢀ00thꢀJanuaryꢀ20xx,ꢀ
Acceptedꢀ00thꢀJanuaryꢀ20xxꢀ
ab
ac
ab
PramodꢀPrasadꢀPoudel, ꢀKenjiꢀArimitsu ꢀandꢀKanaꢀYamamoto* ꢀ
DOI:ꢀ10.1039/x0xx00000xꢀ
www.rsc.org/ꢀ
Abstract:ꢀAnꢀion–pairꢀꢀcatalystꢀgeneratedꢀbyꢀassemblyꢀofꢀaꢀchiralꢀ
flaviniumꢀ andꢀ aꢀ cinchonaꢀ alkaloidꢀ dimerꢀ forꢀ useꢀ inꢀ asymmetricꢀ mediatedꢀ byꢀ flavinꢀ derivatives. Theseꢀ derivativesꢀ showꢀ highꢀ
Baeyer–Villigerꢀ oxidationꢀ isꢀ presented.ꢀ Ion–pairꢀ formationꢀ isꢀ catalyticꢀ activitiesꢀ andꢀ unusualꢀ chemoselectivities, butꢀ limitedꢀ
essentialꢀforꢀenhancingꢀtheꢀcatalyticꢀactivityꢀandꢀstereoselectivity.ꢀ stereoselectivities. Withꢀ theꢀ exceptionꢀ ofꢀ biocatalyzedꢀ reactions, ꢀ
Theꢀ catalystꢀ isꢀ applicableꢀ toꢀ structurallyꢀ diverseꢀ 3-substitutedꢀ catalyticꢀBVꢀoxidationsꢀusingꢀsustainableꢀoxidantsꢀandꢀreachingꢀhighꢀ
cyclobutanones,ꢀ providingꢀ goodꢀ toꢀ excellentꢀ enantioselectivitiesꢀ regio-ꢀ andꢀ stereoselectivitiesꢀ areꢀ stillꢀ challenging,ꢀ andꢀ areꢀ
Theꢀ BVꢀ oxidationꢀ isꢀ oneꢀ suchꢀ oxidationꢀ reactionꢀ thatꢀ isꢀ
6
ꢀ
7
ꢀ
4
ꢀ
8ꢀ
9
ꢀ
(
upꢀ toꢀ 98:2ꢀ e.r.).ꢀ Thisꢀ studyꢀ providesꢀ theꢀ firstꢀ exampleꢀ ofꢀ self- extensivelyꢀresearched. ꢀ
assemblyꢀofꢀaꢀflavinꢀderivativeꢀandꢀaꢀbaseꢀtoꢀformꢀaꢀchiralꢀreactionꢀ
siteꢀthatꢀenablesꢀaꢀhighlyꢀstereoselectiveꢀreactionꢀtoꢀoccur.ꢀꢀꢀ
ꢀ
Theꢀ difficultyꢀ inꢀ attainingꢀ asymmetricꢀ controlꢀ usingꢀ flavinꢀ
derivativesꢀ stemsꢀ fromꢀ theirꢀ conformationalꢀ changes;ꢀ theyꢀ cycleꢀ
betweenꢀ aꢀ “bentꢀ (chiral)”ꢀ formꢀ andꢀ aꢀ “planar”ꢀ formꢀ duringꢀ theꢀ
10ꢀ
redoxꢀ cycle. Previouslyꢀ developedꢀ catalystsꢀ wereꢀ designedꢀ toꢀ
blockꢀ oneꢀ faceꢀ ofꢀ theꢀ heterocycleꢀ withꢀ aꢀ covalentlyꢀ boundꢀ chiralꢀ
component.ꢀTheꢀsubstrateꢀthereforeꢀapproachesꢀandꢀreactsꢀonꢀtheꢀ
oppositeꢀfaceꢀfromꢀtheꢀchiralꢀcomponent,ꢀresultingꢀinꢀlittleꢀchiralityꢀ
transfer.ꢀ Theseꢀ catalystsꢀ stillꢀ induceꢀ aꢀ modestꢀ levelꢀ ofꢀ
stereoselectivityꢀforꢀsomeꢀaromaticꢀsubstrates,ꢀbecauseꢀofꢀinherentꢀ
Recently,ꢀ thereꢀ hasꢀ beenꢀ emergingꢀ interestꢀ inꢀ theꢀ useꢀ ofꢀ
supramolecularꢀcatalysts,ꢀi.e.,ꢀcatalystsꢀformedꢀbyꢀself-assemblyꢀofꢀ
smallꢀ moleculesꢀ throughꢀ non-covalentꢀ interactions,ꢀ inꢀ asymmetricꢀ
1ꢀ
synthesis. Thisꢀmodularꢀsystemꢀhasꢀtheꢀadvantageꢀofꢀfacileꢀcatalystꢀ
preparation,ꢀwhichꢀenablesꢀrapidꢀaccessꢀtoꢀcompoundꢀlibraries.ꢀItꢀisꢀ
particularlyꢀ usefulꢀ forꢀ asymmetricꢀ reactionsꢀ inꢀ whichꢀ aꢀ chiralꢀ
componentꢀ andꢀ aꢀ catalyticallyꢀ activeꢀ moduleꢀ canꢀ beꢀ assembledꢀ
together.ꢀHere,ꢀweꢀpresentꢀourꢀstudyꢀinꢀwhichꢀaꢀcatalyticallyꢀactiveꢀ
flaviniumꢀ speciesꢀ wasꢀ pairedꢀ withꢀ aꢀ chiralꢀ baseꢀ throughꢀ ionicꢀ
π−πꢀ interactionsꢀ betweenꢀ theꢀ catalystꢀ andꢀ theꢀ substratesꢀ thatꢀ
11ꢀ
controlꢀtheirꢀbindingꢀorientation. ꢀꢀ
ꢀ
ꢀ
12ꢀ
13ꢀ
We andꢀothers ꢀhaveꢀdesignedꢀandꢀpreparedꢀaꢀseriesꢀofꢀchiralꢀ
flaviniumꢀ saltsꢀ 1–5,ꢀ inꢀ opticallyꢀ pureꢀ formsꢀ (Figureꢀ 1).ꢀ Theseꢀ
catalystsꢀ showꢀ highꢀ catalyticꢀ activitiesꢀ butꢀ marginalꢀ
stereoselectivitiesꢀ inꢀ theꢀ BVꢀ reaction.ꢀ Weꢀ hypothesizedꢀ thatꢀ
additionꢀofꢀaꢀbasicꢀco-catalystꢀthatꢀinteractsꢀwithꢀtheseꢀmoleculesꢀ
throughꢀ acid–baseꢀ reactionsꢀ couldꢀ aidꢀ theꢀ transferꢀ ofꢀ chiralꢀ
informationꢀ toꢀ theꢀ substrate.ꢀ Ourꢀ initialꢀ attemptsꢀ showedꢀ thatꢀ
additionꢀ ofꢀ aꢀ tertiaryꢀ amineꢀ toꢀ theꢀ reactionꢀ mixtureꢀ significantlyꢀ
enhancedꢀ bothꢀ theꢀ reactionꢀ conversionꢀ andꢀ stereoselectivity,ꢀ
leadingꢀusꢀtoꢀembarkꢀonꢀaꢀfullꢀscreeningꢀprogram.ꢀꢀ
2ꢀ
assembly, andꢀ successfullyꢀ usedꢀ toꢀ achieveꢀ highꢀ stereocontrolꢀ inꢀ
Baeyer–Villigerꢀ(BV)ꢀoxidation.ꢀꢀ
Riboflavinꢀ (Figureꢀ 1)ꢀ isꢀ aꢀ centralꢀ componentꢀ ofꢀ aꢀ familyꢀ ofꢀ
majorꢀ cofactorsꢀ thatꢀ areꢀ involvedꢀ inꢀ manyꢀ flavoenzymesꢀ thatꢀ
3ꢀ
mediateꢀ redoxꢀ transformations. Itsꢀ simplerꢀ syntheticꢀ derivativesꢀ
haveꢀ beenꢀ studiedꢀ inꢀ recentꢀ decades,ꢀ providingꢀ newꢀ catalystsꢀ forꢀ
4
,ꢀ5ꢀ
diverseꢀoxidationꢀreactions. Theseꢀcatalystsꢀuseꢀmolecularꢀoxygenꢀ
orꢀ hydrogenꢀ peroxideꢀ asꢀ anꢀ end-oxidant,ꢀ makingꢀ themꢀ attractiveꢀ
leadsꢀ forꢀ atom-economicalꢀ andꢀ environmentallyꢀ benignꢀ oxidationꢀ
catalysts.ꢀꢀ
ꢀ
ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ1ꢀꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

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COMMUNICATIONꢀ
JournalꢀNameꢀ
ꢀ
View Article Online
R'
Ph
Ph
Ph
Ph
PDh OI: 10 .P1 h0 39/C6CC 0ꢀ 0663A
OH
HO
ꢀ
OH
O
N
N
O
O
N
N
O
N
N
O
N
N
N
O
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
OH
NR
NR
NR
NR
N
N
N
N
10a
N
Cl
Cl
Cl
Cl
1
0
1
O
O
O
2
5
3NH
4
1a: R = H
b: R = Me
a: R = H; R' = Ph
b: R = H, R' = i-Pr
c: R = Me, R' = i-Pr
3a: R = H
4a: R = H
4b: R = Me
5a: R = H;
antipode of 3a
5
a
N
1
2
2
2
3b: R = Me
3c: Bn
O
Riboflavin
N
N
N
N
N
N
O
O
OH
OH
O
O
O
O
N
N
N
: quinine
N
6
7: quinidine
8: (DHQ)2PHAL: Dihydroquinine dimer (shown)
: (DHQD) PHAL: Dihydroquinidine dimer
9
2
Figureꢀ1.ꢀꢀThe structures of synthetic flavinium species, cinchona alkaloids and their derivatives.
Theꢀ co-catalystꢀ screeningꢀ wasꢀ performedꢀ byꢀ simplyꢀ mixingꢀ
flaviniumꢀ3aꢀwithꢀvariousꢀcommerciallyꢀavailableꢀamineꢀbasesꢀ(Tableꢀ
).ꢀAꢀcinchonaꢀalkaloid,ꢀnamelyꢀquinineꢀ(6)ꢀorꢀquinidineꢀ(7),ꢀ(Figureꢀ
2
3
4
5
6
7
8
9
1
1
–
7 (100)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
12.4
60.5
49.2
16.9
21.3
3.1
52:48
62:38
74:26
77:23
74:26
53:47
59:41
43:57
39:61
67:33
51:49
48:52
48:52
1
1
3a
3a
3a
3a
4a
1a
5a
5a
3a
3a
3c
5a
3
Et N (100)
)ꢀprovidedꢀtheꢀbestꢀselectivityꢀamongꢀtheꢀexaminedꢀbasesꢀ(Tableꢀ1,ꢀ
[
b]
1
2
7 (100)
6 (100)
7 (20)
7 (20)
7 (20)
7 (20)
6 (20)
7 (100)
7 (20)
7 (20)
entriesꢀ 1–5), ꢀ thereforeꢀ ourꢀ earlyꢀ studiesꢀ wereꢀ performedꢀ usingꢀ
theseꢀbases.ꢀNeitherꢀtheꢀflaviniumꢀcatalystꢀnorꢀtheꢀbaseꢀaloneꢀgaveꢀ
highꢀconversionꢀorꢀenantioselectivityꢀ(entriesꢀ1ꢀandꢀ2).ꢀAlthoughꢀ6ꢀ
andꢀ 7ꢀ areꢀ consideredꢀ toꢀ beꢀ quasi-enantiomeric,ꢀ eachꢀ ofꢀ themꢀ inꢀ
combinationꢀ withꢀ 3aꢀ gaveꢀ riseꢀ toꢀ (S)-γ-lactonesꢀ (entriesꢀ 4ꢀ andꢀ 5).ꢀ
Similarly,ꢀreplacingꢀ3aꢀwithꢀitsꢀcisꢀdiastereomerꢀ4aꢀorꢀwithꢀachiralꢀ
flaviniumꢀ 1aꢀ alsoꢀ favoredꢀ formationꢀ ofꢀ theꢀ sameꢀ (S)ꢀ enantiomerꢀ
whenꢀusedꢀwithꢀ7ꢀ(entriesꢀ9ꢀandꢀ10).ꢀHowever,ꢀaꢀcombinationꢀofꢀ5aꢀ
13.6
12.0
13.3
22.7
94.6
6.8
(
antipodeꢀ ofꢀ 3a)ꢀ andꢀ 6ꢀ orꢀ 7ꢀ producedꢀ (R)-γ-lactonesꢀ withꢀ lowꢀ
0
1
selectivitiesꢀ(entriesꢀ9ꢀandꢀ10).ꢀTheꢀcombinedꢀeffectꢀofꢀtheꢀflaviniumꢀ
andꢀ theꢀ baseꢀ thereforeꢀ contributesꢀ toꢀ theꢀ observedꢀ chiralityꢀ
transfer.ꢀFurtherꢀstudiesꢀindicatedꢀthatꢀasꢀlittleꢀasꢀ2ꢀequivꢀofꢀbaseꢀ
relativeꢀ toꢀ theꢀ flaviniumꢀ catalystꢀ wasꢀ sufficientꢀ toꢀ produceꢀ theꢀ
optimalꢀeffectꢀ(entriesꢀ4ꢀandꢀ6).ꢀScreeningꢀwasꢀperformedꢀatꢀ–35ꢀtoꢀ
[
d]
12
TFE
1
3
MeCN
MeCN
–
40ꢀ °Cꢀ showingꢀ aꢀ reasonableꢀ reactionꢀ rate.ꢀ Aꢀ surveyꢀ ofꢀ solventsꢀ
[
c]
indicatedꢀthatꢀethylꢀacetate,ꢀacetonitrile,ꢀandꢀchlorinatedꢀsolventsꢀ
performedꢀ best,ꢀ providingꢀ similarꢀ selectivitiesꢀ inꢀ mostꢀ cases,ꢀ
whereasꢀ polarꢀ alcoholicꢀ solventsꢀ enhancedꢀ theꢀ reactionꢀ rateꢀ butꢀ
14
7
(20)
1.7
[
a] Conditions: 0.1 mmol scale; [10] = 100 mM; [flavinium] = 10 mM;
[base] = 20–110 mM; solvent (1 mL); 30% H (1.1–1.5 equiv.); –35 to –40
2
O
2
12
°C; 15–24 h; [b] 83% conversion after 50 h. [c] N-benzylquinidinium salt. [d]
Use of MeOH led to low conversion and selectivity as well as acetal by-
product formation. [e] Determined by chiral HPLC analysis.
decreasedꢀtheꢀselectivityꢀ(entriesꢀ4,ꢀ11ꢀandꢀ12). ꢀThisꢀsolventꢀeffectꢀ
differsꢀ fromꢀ thoseꢀ reportedꢀ inꢀ previousꢀ studiesꢀ ofꢀ flavinium–
catalyzedꢀasymmetricꢀoxidations,ꢀinꢀwhichꢀ(polar)ꢀalcoholicꢀsolventsꢀ
aloneꢀ orꢀ inꢀ mixturesꢀ withꢀ otherꢀ solventsꢀ wereꢀ oftenꢀ favored,ꢀ
suggestingꢀthatꢀtheꢀreactionꢀinꢀourꢀsystemꢀisꢀmechanisticallyꢀdistinctꢀ
fromꢀthoseꢀinꢀotherꢀsystemsꢀinꢀwhichꢀπ−πꢀinteractionsꢀplayꢀaꢀmajorꢀ
Ion–pairꢀ ꢀ formationꢀ betweenꢀ flaviniumꢀ andꢀ theꢀ baseꢀ wasꢀ
3
confirmedꢀ byꢀ theꢀ followingꢀ observations:ꢀ useꢀ ofꢀ N -protectedꢀ 3cꢀ
Tableꢀ 1,ꢀ entryꢀ 13)ꢀ orꢀ N-benzylquinidiniumꢀ (Tableꢀ 1,ꢀ entryꢀ 14)ꢀ
decreasedꢀbothꢀtheꢀenantioselectivityꢀandꢀreactionꢀconversion;ꢀJobꢀ
plotsꢀ basedꢀ onꢀ aꢀ UV-visꢀ spectroscopicꢀ studyꢀ ofꢀ 3aꢀ andꢀ 7ꢀ showedꢀ
clearꢀ1:1ꢀinteractions; ꢀonꢀmixing,ꢀaꢀdownfieldꢀshiftꢀofꢀallꢀtheꢀsignalsꢀ
andꢀdisappearanceꢀofꢀtheꢀN protonꢀofꢀ3aꢀandꢀanꢀupfieldꢀshiftꢀofꢀtheꢀ
baseꢀwereꢀseenꢀinꢀtheꢀ H-NMRꢀspectra.ꢀPresumably,ꢀtheꢀroleꢀofꢀtheꢀ
(
11,ꢀ14ꢀ
role.
ꢀ
Tableꢀ 1.ꢀ Asymmetric BV oxidation of 3-phenylcyclobutanone
1
2
O
O
3ꢀ
O
Flavinium (10 mol%), Base
0% H O2 (~1.5 eq),
1
3
2
Ph
Solvent, -35 to -40 °C
Ph
secondꢀ equivalentꢀ ofꢀ baseꢀ withꢀ respectꢀ toꢀ theꢀ catalystꢀ isꢀ toꢀ
deprotonateꢀhydrogenꢀperoxide,ꢀwhichꢀpromotesꢀtheꢀrate-limitingꢀ
1
0
[
a]
15ꢀ
catalyzed by a flavin derivative and a base
hydroperoxyflavinꢀformation.
ꢀ
[
e]
Weꢀ speculatedꢀ thatꢀ useꢀ ofꢀ aꢀ dimericꢀ baseꢀ mightꢀ furtherꢀ promoteꢀ
thisꢀ reactionꢀ throughꢀ theꢀ proximityꢀ effect.ꢀ Commerciallyꢀ availableꢀ
dihydroquinidineꢀ (DHQD)ꢀ andꢀ dihydroquinineꢀ (DHQ)ꢀ dimersꢀ wereꢀ
Entry
Cat.
Base [mol%]
Solvent
Conv. [%]
na
e.r. [S/R]
1
3a
–
MeCN
51:49
2
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
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ꢀCOMMUNICATIONꢀ
examinedꢀinꢀcombinationꢀwithꢀeitherꢀflaviniumꢀ3aꢀorꢀ5aꢀ(Tableꢀ2).ꢀ
Ph
View Article Online
H
Amongꢀ theꢀ commercialꢀ dimersꢀ examined,ꢀ phthalimideꢀ (PHAL)ꢀ
DOI: 10.1039/C6CC00663A
12
O
N
dimersꢀ(Figureꢀ1)ꢀhaveꢀshownꢀtheꢀbestꢀselectivity. ꢀThereꢀareꢀclearꢀ
indicationsꢀofꢀ“matched”ꢀdimersꢀforꢀ3aꢀbeingꢀDHQꢀdimersꢀandꢀthatꢀ
ofꢀantipodeꢀ5aꢀbeingꢀDHQDꢀdimers.ꢀUnlikeꢀtheꢀflaviniumꢀcatalystsꢀ
withꢀ aꢀ monomericꢀ alkaloid,ꢀ aꢀ combinationꢀ ofꢀ 3aꢀ orꢀ 5aꢀ withꢀ theꢀ
respectiveꢀ“matched”ꢀdimerꢀbehavedꢀsimilarlyꢀtoꢀenantiomersꢀandꢀ
gaveꢀ riseꢀ toꢀ theꢀ oppositeꢀ antipode,ꢀ withꢀ comparableꢀ selectivityꢀ
Ph
N
N -
O
O
H
O
Ph
O
N
H-Bonding
π−π Interaction
Ionic
Interaction
(
“
entriesꢀ 2ꢀ vsꢀ 8;ꢀ 10ꢀ vsꢀ 11),ꢀ whereasꢀ combinationꢀ withꢀ theꢀ
mismatched”ꢀdimerꢀresultedꢀinꢀlowerꢀselectivityꢀ(entriesꢀ1ꢀvsꢀ5;ꢀ6ꢀ
vsꢀ7)).ꢀInꢀaddition,ꢀtheꢀuseꢀofꢀCHCl ꢀasꢀtheꢀsolventꢀgreatlyꢀimprovedꢀ
H
N
N
H
3
O
theꢀ selectivityꢀ (entryꢀ 4ꢀ vsꢀ 1–3).ꢀ Finally,ꢀ byꢀ raisingꢀ theꢀ reactionꢀ
temperatureꢀtoꢀ–15ꢀ°C,ꢀtheꢀreactionꢀconversionꢀincreasedꢀtoꢀ>90%ꢀ
afterꢀ 24ꢀ hꢀ (entryꢀ 9).ꢀ Asꢀ expected,ꢀ theꢀ stoichiometryꢀ ofꢀ theꢀ dimerꢀ
couldꢀbeꢀreducedꢀtoꢀ1ꢀequivꢀrelativeꢀtoꢀtheꢀbaseꢀwithoutꢀsacrificingꢀ
theꢀreactionꢀselectivityꢀ(entryꢀ10).ꢀ
H
O
O
H
N
N
O
N
N
ꢀ
ꢀ
Figureꢀ 2.ꢀ Proposed transition state of BV oxidation of 3-
phenylcyclobutanone catalyzed by 3a and (DHQ) PHAL (8).ꢀ
Tableꢀ 2.ꢀ Asymmetric BV oxidation of 3-phenylcyclobutanone
[
a]
2
catalyzed by a flavin derivative and a base
ꢀ
ꢀ
O
O
O
Flavinium (10 mol%), Base (20 mol%)
0% H O2 (~1.5 eq),
Next,ꢀ theꢀ scopeꢀ andꢀ limitationꢀ ofꢀ theꢀ optimizedꢀ conditionsꢀ
wereꢀexploredꢀusingꢀaꢀseriesꢀofꢀ3-substitutedꢀcyclobutanonesꢀ(Tableꢀ
3
2
Ph
Solvent, -35 to -40 °C
Ph
17ꢀ
3
).
ꢀ Asꢀ expected,ꢀ 3-naphthylcyclobutanoneꢀ (11)ꢀ providedꢀ
1
0
comparableꢀ selectivityꢀ toꢀ thatꢀ ofꢀ 3-phenylcyclobutanoneꢀ (10)ꢀ
(entriesꢀ 1ꢀ vsꢀ 2).ꢀ Gratifyingly,ꢀ substratesꢀ withꢀ noꢀ aromaticꢀ
componentsꢀproximalꢀtoꢀtheꢀreactionꢀcenterꢀgaveꢀgoodꢀtoꢀexcellentꢀ
selectivitiesꢀ(entriesꢀ3–6),ꢀexceptꢀforꢀ3-tert-butylcyclobutanoneꢀ(16)ꢀ
thatꢀ gaveꢀ fairꢀ selectivityꢀ (entryꢀ 7).ꢀ Inꢀ particular,ꢀ N-Boc-
aminocyclobutanoneꢀ (14)ꢀ providedꢀ excellentꢀ selectivityꢀ (entryꢀ 5,ꢀ
98:2ꢀ e.r.),ꢀ theꢀ bestꢀ ofꢀ allꢀ theꢀ previouslyꢀ developedꢀ flaviniumꢀ
catalysts.ꢀItꢀisꢀofꢀnoteꢀthatꢀtheꢀproductꢀofꢀthisꢀsubstrate,ꢀaꢀβ-aminoꢀ
acidꢀ derivative,ꢀ isꢀ anꢀ importantꢀ intermediateꢀ inꢀ aꢀ numberꢀ ofꢀ
[
e]
Entry
cat.
Base
Solvent
Temp. [°C]
Conv. [%]
e.r. [S/R]
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
5a
5a
5a
3a
3a
5a
8
8
8
8
9
8
9
9
8
MeCN
EtOAc
DCM
–38
–38
–38
–38
–40
–38
–38
–35
–15
–15
–15
33.7
27.6
21.5
16.6
28.5
7.4
72:28
74:26
80:20
92:8
CHCl
3
18ꢀ
MeCN
DCM
53:47
49:51
24:76
25:75
94:6
pharmaceuticalꢀandꢀnaturalꢀproductꢀsyntheses. Theꢀutilityꢀofꢀtheꢀ
methodꢀwasꢀdemonstratedꢀbyꢀconductingꢀtheꢀoxidationꢀwithꢀ10ꢀonꢀ
aꢀ0.3ꢀgꢀscale;ꢀtheꢀreactionꢀprovidedꢀtheꢀγ-lactoneꢀinꢀ98.5:1.5ꢀe.r.ꢀandꢀ
1
2,ꢀ 19ꢀ
DCM
18
52%ꢀyieldꢀafterꢀaꢀsingleꢀrecrystallization.
Thisꢀproductꢀandꢀtheꢀ
relatedꢀ 3-aryl-γ-butyrolactonesꢀ areꢀ precursorsꢀ ofꢀ clinicallyꢀ
EtOAc
9.4
20ꢀ
B
importantꢀGABA ꢀreceptorꢀagonists.ꢀ ꢀꢀ
ꢀ
CHCl
CHCl
CHCl
3
3
3
92
Tableꢀ 3.ꢀ Scope and Limitation of 3a-Catalyzed Asymmetric
[
b]
[c]
1
1
0
1
8
9
86.2
94:6
[a]
Baeyer–Villiger oxidation of cyclobutanones
[
d]
O
O
O
78
10:90
3
a (20 mol%), (DHQ) PHAL (20 mol%)
2
3
0% H O (~1.5 eq),
2 2
[
2
a] Conditions: 0.1 mmol scale; [10] = 100 mM; [flavinium] = 10 mM; [base] =
0 mM; solvent (1 mL); 30% H (1.1–1.5 equiv.); 24 h. [b] 10 mol% of the
R
R
2
O
2
CHCl3, -15 °C, 24h
Conv. (%)
97
base was used. [c] 42 h (70% conversion after 24 h). [d] 72% isolated yield. [e]
Determined by chiral HPLC analysis.
[
b]
[c]
Entry
R =
Yield (%)
e.r. [S/R]
Ourꢀ workingꢀ modelꢀ ofꢀ theꢀ transitionꢀ stateꢀ thatꢀ explainsꢀ theꢀ
[
i]
selectivityꢀisꢀillustratedꢀinꢀFigureꢀ2.ꢀInitially,ꢀ3aꢀbindsꢀtoꢀeitherꢀsideꢀ
ofꢀ theꢀ dimerꢀ withꢀ aꢀ selectiveꢀ orientationꢀ setꢀ byꢀ π−πꢀ andꢀ ionicꢀ
interactions.ꢀ Thisꢀ bindingꢀ modeꢀ alsoꢀ explainsꢀ theꢀ matchedꢀ
combinationꢀ ofꢀ 3aꢀ andꢀ 8,ꢀ whereꢀ noꢀ stericꢀ interferenceꢀ occursꢀ
betweenꢀtheꢀphenylꢀgroupꢀnextꢀtoꢀN ꢀandꢀtheꢀethylꢀgroupꢀofꢀDHQ.ꢀ
Subsequently,ꢀ theꢀ otherꢀ baseꢀ deprotonatesꢀ hydrogenꢀ peroxide,ꢀ
whichꢀ attacksꢀ theꢀ iminiumꢀ ofꢀ 3aꢀ toꢀ formꢀ hydroperoxyꢀ species.
Hydroperoxideꢀthenꢀattacksꢀtheꢀless-hinderedꢀsideꢀofꢀtheꢀsubstrateꢀ
possiblyꢀ activatedꢀ byꢀ hydrogenꢀ bondingꢀ withꢀ ammonium),ꢀ whichꢀ
1
2
3
4
5
6
7
Phenyl (10)
87
92
85
58
92
85
80
95:5
97:3
82:18
1-Naphthyl (11)
92
89
70
100
86
–
BnOCH - (12)
2
1
[
f]
BnOOC- (13)
BocNH- (14)
Cyclohexyl (15)
tert-Butyl (16)
11:89
16ꢀ
ꢀ
[
d], [f]
2:98
[
j]
[e], [g]
67:33
57:43
(
[
h]
leadsꢀ toꢀ formationꢀ ofꢀ aꢀ Criegeeꢀ intermediateꢀ (shown)ꢀ thatꢀ
undergoesꢀrearrangement.ꢀꢀ
ꢀ
ꢀ
[
a] Conditions: 0.1 mmol scale; [substrate] = 100 mM; [3a] = 20 mM; [8] = 20
mM; CHCl (1 mL); –15 °C; 24 h. [b] Isolated yield. [c] Determined by chiral
3
HPLC analysis. [d] Determined by optical rotation. [e] Determined after
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ3ꢀ
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COMMUNICATIONꢀ
JournalꢀNameꢀ
1
2
conversion to hydroxyl benzylamide derivative. [f] Note the change in
substituent priorities in the Cahn-Ingold-Prelog system. [g] Ratio: (–/+). [h]
The configuration was not determined. [i] Also conducted on 0.3 g scale
8.ꢀ M.ꢀ T.ꢀ Reetzꢀ andꢀ S.ꢀ Wu,ꢀ J.ꢀ Am.ꢀ Chem.ꢀ Soc.,ꢀ 2009V,iꢀe1w3A1rt,iꢀc1le5O4n2li4ne-
DOI: 10.1039/C6CC00663A
1
2
5432;ꢀZ.-G.ꢀZhang,ꢀL.ꢀP.ꢀParraꢀandꢀM.ꢀT.ꢀReetz,ꢀChem.ꢀ-ꢀEur.ꢀJ.ꢀ,ꢀ
012,ꢀ18,ꢀ10160-10172.ꢀ
1
2
using 10 mol% 3a that gave rise to 87% yield after 64 h (92:8 e.r.). [j] 88 h.
9
1
1
.ꢀ Selectedꢀ reviews:ꢀ M.ꢀ Uyanikꢀ andꢀ K.ꢀ Ishihara,ꢀ ACSꢀ Catalysis,ꢀ
013,ꢀ3,ꢀ513-520;ꢀK.ꢀIto,ꢀinꢀCompr.ꢀChirality,ꢀElsevier,ꢀLtd.,ꢀ2012,ꢀ
2
vol.ꢀ5,ꢀpp.ꢀ1-35;ꢀRecentꢀresearchꢀarticles:ꢀM.ꢀW.ꢀGiuliano,ꢀC.-Y.ꢀ
Lin,ꢀ D.ꢀ K.ꢀ Romney,ꢀ S.ꢀ J.ꢀ Millerꢀ andꢀ E.ꢀ V.ꢀ Anslyn,ꢀ Adv.ꢀ Synth.ꢀ
Catal.,ꢀ2015,ꢀ357,ꢀ2301-2309;ꢀN.ꢀYang,ꢀZ.ꢀSu,ꢀX.ꢀFengꢀandꢀC.ꢀHu,ꢀ
Chem.ꢀ-ꢀEur.ꢀJ.,ꢀ2015,ꢀ21,ꢀ7264-7277.ꢀ
Conclusionsꢀ
Weꢀhaveꢀdevelopedꢀanꢀion–pairꢀcatalystꢀderivedꢀbyꢀinꢀsituꢀassemblyꢀ
ofꢀ aꢀ chiralꢀ flaviniumꢀ andꢀ aꢀ cinchonaꢀ alkaloidꢀ dimerꢀ forꢀ useꢀ inꢀ
asymmetricꢀ BVꢀ reactions.ꢀ Ourꢀ observationsꢀ confirmedꢀ acid–baseꢀ
interactionsꢀ betweenꢀ theꢀ flaviniumꢀ andꢀ theꢀ dimerꢀ byꢀ ion–pairing,ꢀ
presumablyꢀleadingꢀtoꢀformationꢀofꢀanꢀartificialꢀchiralꢀreactionꢀsite,ꢀ
andꢀ enablingꢀ theꢀ reactionꢀ toꢀ proceedꢀ withꢀ highꢀ stereoselectivity.ꢀ
Ourꢀstudyꢀrepresentsꢀtheꢀfirstꢀexampleꢀofꢀuseꢀofꢀaꢀsupramolecularꢀ
assemblyꢀ forꢀ controllingꢀ theꢀ stereoselectivityꢀ ofꢀ aꢀ flavinium-
catalyzedꢀreaction.ꢀWeꢀbelieveꢀthatꢀthisꢀapproachꢀcanꢀbeꢀextendedꢀ
toꢀ otherꢀ reactionsꢀ catalyzedꢀ byꢀ cofactorsꢀ orꢀ redox-activeꢀ smallꢀ
molecules,ꢀandꢀwidenꢀtheꢀscopeꢀofꢀtheirꢀapplications.ꢀꢀꢀ
0.ꢀS.ꢀ Shinkai,ꢀ H.ꢀ Nakaoꢀ andꢀ O.ꢀ Manabe,ꢀ Tetrahedronꢀ Lett.,ꢀ 1985,ꢀ
2
6,ꢀ 5183-5186;ꢀ S.ꢀ Shinkai,ꢀ S.ꢀ Kawanabe,ꢀ A.ꢀ Kawase,ꢀ T.ꢀ
Yamaguchi,ꢀO.ꢀManabe,ꢀS.ꢀHarada,ꢀH.ꢀNakamuraꢀandꢀN.ꢀKasai,ꢀ
Bull.ꢀChem.ꢀSoc.ꢀJpn.ꢀ,ꢀ1988,ꢀ61,ꢀ2095-2102;ꢀS.ꢀShinkai,ꢀH.ꢀNakao,ꢀ
T.ꢀTsuno,ꢀO.ꢀManabeꢀandꢀA.ꢀOhno,ꢀChem.ꢀCommun.,ꢀ1984,ꢀ849-
8
50.ꢀ
1.ꢀS.-I.ꢀ Murahashi,ꢀ S.ꢀ Onoꢀ andꢀ Y.ꢀ Imada,ꢀ Angew.ꢀ Chem.ꢀ Int.ꢀ Ed.ꢀ ,ꢀ
002,ꢀ114,ꢀ2472-2474.ꢀ
2
1
1
2.ꢀSeeꢀtheꢀElectronicꢀSupportingꢀInformation.ꢀꢀ
3.ꢀW.-S.ꢀLiꢀandꢀL.ꢀM.ꢀSayre,ꢀTetrahedron,ꢀ2001,ꢀ57,ꢀ4523-4536;ꢀW.-
S.ꢀ Li,ꢀ N.ꢀ Zhangꢀ andꢀ L.ꢀ M.ꢀ Sayre,ꢀ Tetrahedron,ꢀ 2001,ꢀ 57,ꢀ 4507-
Acknowledgementsꢀ
4
522;ꢀ J.ꢀ Žurek,ꢀ R.ꢀ Cibulka,ꢀ H.ꢀ Dvořákováꢀ andꢀ J.ꢀ Svoboda,ꢀ
This research was supported by the University of Toledo (Faculty
start-up fund for KY). We thank Dr. Yong-Wah Kim for his support
with NMR analyses.ꢀ
TetrahedronꢀLett.,ꢀ2010,ꢀ51,ꢀ1083-1086;ꢀJ.ꢀZelenka,ꢀT.ꢀHartman,ꢀ
K.ꢀ Klímová,ꢀ F.ꢀ Hamplꢀ andꢀ R.ꢀ Cibulka,ꢀ ChemCatChem,ꢀ 2014,ꢀ 6,ꢀ
2
843-2846;ꢀA.ꢀT.ꢀMurray,ꢀP.ꢀMatton,ꢀN.ꢀW.ꢀG.ꢀFairhurst,ꢀM.ꢀP.ꢀ
JohnꢀandꢀD.ꢀR.ꢀCarbery,ꢀOrg.ꢀLett.,ꢀ2012,ꢀ14,ꢀ3656-3659;ꢀA.ꢀT.ꢀ
Murray,ꢀM.ꢀJ.ꢀH.ꢀDowley,ꢀF.ꢀPradaux-Caggiano,ꢀA.ꢀBaldansuren,ꢀ
A.ꢀJ.ꢀFielding,ꢀF.ꢀTuna,ꢀC.ꢀH.ꢀHendon,ꢀA.ꢀWalsh,ꢀG.ꢀC.ꢀLloyd-Jones,ꢀ
M.ꢀP.ꢀJohnꢀandꢀD.ꢀR.ꢀCarbery,ꢀAngew.ꢀChem.ꢀInt.ꢀEd.,ꢀ2015,ꢀ127,ꢀ
Notesꢀandꢀreferencesꢀ
1
.ꢀ Selectedꢀrecentꢀreviews:ꢀM.ꢀC.ꢀHollandꢀandꢀR.ꢀGilmour,ꢀAngew.ꢀ
Chem.,ꢀ Int.ꢀ Ed.,ꢀ 2015,ꢀ 54,ꢀ 3862-3871;ꢀ K.ꢀ Ohmatsuꢀ andꢀ T.ꢀ Ooi,ꢀ
Tetrahedronꢀ Lett.,ꢀ 2015,ꢀ 56,ꢀ 2043-2048;ꢀ K.ꢀ Brakꢀ andꢀ E.ꢀ N.ꢀ
Jacobsen,ꢀ Angew.ꢀ Chem.ꢀ Int.ꢀ Ed.ꢀ ,ꢀ 2012,ꢀ 52,ꢀ 534-561;ꢀ R.ꢀ R.ꢀ
Knowlesꢀ andꢀ E.ꢀ N.ꢀ Jacobsen,ꢀ Proc.ꢀ Nat.ꢀ Acad.ꢀ Sci.ꢀ USA,ꢀ 2010,ꢀ
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125-9128.ꢀ
1
1
1
4.ꢀR.ꢀJurok,ꢀR.ꢀCibulka,ꢀH.ꢀDvořáková,ꢀF.ꢀHamplꢀandꢀJ.ꢀHodačová,ꢀ
Eur.ꢀJ.ꢀOrg.ꢀChem.,ꢀ2010,ꢀ2010,ꢀ5217-5224.ꢀ
5.ꢀP.ꢀMénováꢀandꢀR.ꢀCibulka,ꢀJ.ꢀMol.ꢀCatal.ꢀA,ꢀ2012,ꢀ363-364,ꢀ362-
1
07,ꢀ 20678-20685;ꢀ J.ꢀ Meeuwissenꢀ andꢀ J.ꢀ N.ꢀ H.ꢀ Reek,ꢀ Natureꢀ
3
70.ꢀ
Chem.,ꢀ 2010,ꢀ 2,ꢀ 615-621;ꢀ D.ꢀ Uraguchi,ꢀ Y.ꢀ Uekiꢀ andꢀ T.ꢀ Ooi,ꢀ
Science,ꢀ2009,ꢀ326,ꢀ120-123.ꢀ
6.ꢀAttackꢀ ofꢀ H
2 2
O ꢀ toꢀ alloxaziniumꢀ wasꢀ suggestedꢀ toꢀ beꢀ theꢀ rate-
limitꢀ ofꢀ itsꢀ catalyticꢀ cycle,ꢀ andꢀ itsꢀ deprotonationꢀ mayꢀ beꢀ
requiredꢀ inꢀ ourꢀ system.ꢀ See:ꢀ Ménová,ꢀ P.;ꢀ Cibulka,ꢀ R.ꢀ J.ꢀ Mol.ꢀ
Catal.ꢀA,ꢀ2012,ꢀ363-364,ꢀ362-370.ꢀ
2
.ꢀ Examplesꢀofꢀion-pairꢀsupramolecularꢀcatalyst:ꢀT.ꢀMandalꢀandꢀC.-
G.ꢀ Zhao,ꢀ Angew.ꢀ Chem.ꢀ Int.ꢀ Ed.,ꢀ 2008,ꢀ 47,ꢀ 7714-7717;ꢀ N.ꢀ K.ꢀ
Rana,ꢀH.ꢀHuangꢀandꢀJ.ꢀC.ꢀG.ꢀZhao,ꢀAngew.ꢀChem.,ꢀInt.ꢀEd.,ꢀ2014,ꢀ
1
1
7.ꢀAttemptedꢀoxidationꢀofꢀ4-substitutedꢀcyclohexanonesꢀwithꢀthisꢀ
catalystꢀ systemꢀ gaveꢀ riseꢀ toꢀ noꢀ reactionꢀ evenꢀ atꢀ roomꢀ
tempeartureꢀandꢀextendedꢀperiodꢀofꢀtime.ꢀꢀ
5
3,ꢀ 7619-7623;ꢀ X.ꢀ Wangꢀ andꢀ B.ꢀ List,ꢀ Angew.ꢀ Chem.ꢀ Int.ꢀ Ed.,ꢀ
008,ꢀ47,ꢀ1119-1122;ꢀC.ꢀMerten,ꢀC.ꢀH.ꢀPollok,ꢀS.ꢀLiaoꢀandꢀB.ꢀList,ꢀ
2
Angew.ꢀ Chem.,ꢀ Int.ꢀ Ed.,ꢀ 2015,ꢀ 54,ꢀ 8841-8845;ꢀ L.ꢀ Pignataro,ꢀ B.ꢀ
Lynikaite,ꢀJ.ꢀCvengroš,ꢀM.ꢀMarchini,ꢀU.ꢀPiarulliꢀandꢀC.ꢀGennari,ꢀ
LiebigsꢀAnn.ꢀChem.ꢀ,ꢀ2009,ꢀ2009,ꢀ2539-2547.ꢀ
8.ꢀG.ꢀLuppiꢀandꢀC.ꢀTomasini,ꢀSynlett,ꢀ2003,ꢀ797-800;ꢀY.ꢀBergman,ꢀ
M.ꢀ Ciampini,ꢀ S.ꢀ Jalal,ꢀ H.ꢀ R.ꢀ Lagiakos,ꢀ M.-I.ꢀ Aguilarꢀ andꢀ P.ꢀ
Perlmutter,ꢀ Tetrahedron:ꢀ Asymmetry,ꢀ 2008,ꢀ 19,ꢀ 2861-2863;ꢀ
Unitedꢀ Statesꢀ Pat.,ꢀ US72291ꢀ 2014;ꢀ Europeanꢀ Pat.,ꢀ EP72934ꢀ
3
4
.ꢀ C.ꢀT.ꢀWalshꢀandꢀT.ꢀA.ꢀWencewicz,ꢀNat.ꢀProd.ꢀRep.,ꢀ2013,ꢀ30,ꢀ175-
2
00.ꢀ
2
015.ꢀ
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1
2
9.ꢀ87%ꢀisolatedꢀyieldꢀandꢀ92:8ꢀe.r.ꢀbeforeꢀrecrystalization.ꢀꢀ
0.ꢀN.ꢀ Sommer,ꢀ P.ꢀ A.ꢀ Loeschmann,ꢀ G.ꢀ H.ꢀ Northoff,ꢀ M.ꢀ Weller,ꢀ A.ꢀ
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CNSꢀDrugꢀRev.,ꢀ2001,ꢀ7,ꢀ471-481.ꢀ
9
2
32;ꢀH.ꢀIida,ꢀY.ꢀImadaꢀandꢀS.-I.ꢀMurahashi,ꢀOrg.ꢀBiomol.ꢀChem.,ꢀ
015,ꢀ13,ꢀ7599-7613.ꢀ
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2
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9
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4
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
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