Fast & easy preparation of 3D scaffolds from methyl benzoate by a diversity oriented synthesis strategy based on Diels-Alder and ene-reactions

Article abstract of DOI:10.1039/c7ob01236e

Thermic dimerization of methyl 1,3-cyclohexadiene 2-carboxylate gave original 3D-shape compounds by Diels-Alder cycloaddition and original [6 + 4]-ene reaction. Further selective modifications on an endo [4 + 2] cycloadduct via a diversity oriented synthesis (DOS) strategy quickly led to the preparation of a small library of original 3D scaffolds, providing access to a larger and unexplored chemical space for drug discovery processes.

Full text of DOI:10.1039/c7ob01236e

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Organic &
Biomol ec ular
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Volume 14 Number
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January 2016 Pages 1–372
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COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Org aP nl ei ca s &e ꢀ dB oi oꢀ nmo ot ꢀ lae dc j uu ls at ꢀr mCa hr eg imn si sꢀ try
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DOI: 10.1039/C7OB01236E
JournalꢀNameꢀ
ꢀ
ARTICLEꢀ
Fastꢀ&ꢀeasyꢀpreparationꢀofꢀ3Dꢀscaffoldsꢀfromꢀmethylꢀbenzoateꢀbyꢀ
aꢀdiversityꢀorientedꢀsynthesisꢀstrategyꢀbasedꢀonꢀDiels-Alderꢀandꢀ
ene-reactionsꢀ
Receivedꢀ00thꢀJanuaryꢀ20xx,ꢀ
Acceptedꢀ00thꢀJanuaryꢀ20xxꢀ
a
a
a
b
a
DominiqueꢀPetit, ꢀPascalꢀRetailleau, ꢀVincentꢀDumontet, ꢀPhilippeꢀBreton, ꢀSandyꢀDesrat* ꢀandꢀ
FannyꢀRoussi* ꢀ
DOI:ꢀ10.1039/x0xx00000xꢀ
a
www.rsc.org/ꢀ
8
Thermicꢀdimerizationꢀofꢀmethylꢀ1,3-cyclohexadieneꢀ2-carboxylateꢀ traditionalꢀpropertyꢀspace. ꢀ
gaveꢀ originalꢀ 3D-shapeꢀ compoundsꢀ byꢀ Diels-Alderꢀ cycloadditionꢀ
ꢀ
Toꢀ overcomeꢀ thisꢀ issue,ꢀ oneꢀ ofꢀ theꢀ strategiesꢀ isꢀ toꢀ
andꢀoriginalꢀ[6+4]-eneꢀreaction.ꢀFurtherꢀselectiveꢀmodificationsꢀonꢀ elaborateꢀ newꢀ generationsꢀ ofꢀ chemicalꢀ librariesꢀ asꢀ itꢀ wasꢀ
endoꢀ [4+2]ꢀ cycloadductꢀ viaꢀ aꢀ diversityꢀ orientedꢀ synthesisꢀ (DOS)ꢀ demonstratedꢀ thatꢀ moreꢀ complexꢀ molecules,ꢀ ieꢀ withꢀ higherꢀ
3
3
3
strategyꢀquicklyꢀledꢀtoꢀtheꢀpreparationꢀofꢀaꢀsmallꢀlibraryꢀofꢀoriginalꢀ Fractionalꢀsp ꢀcharacterꢀ(Fsp :ꢀnumberꢀofꢀsp ꢀhybridizedꢀcarbonꢀ
Dꢀscaffolds,ꢀprovidingꢀaccessꢀtoꢀaꢀlargerꢀandꢀunexploredꢀchemicalꢀ atoms/totalꢀ carbonꢀ atoms)ꢀ correlatedꢀ withꢀ theirꢀ threeꢀ
3
9
spaceꢀforꢀdrugꢀdiscoveryꢀprocesses.ꢀꢀꢀ
dimensionalꢀ (3D)ꢀ shape,ꢀ accessꢀ greaterꢀ chemicalꢀ space ꢀ andꢀ
thus,ꢀpotentiateꢀtheꢀdrugꢀdiscoveryꢀprocess.ꢀ
ꢀ
toꢀ generateꢀ suchꢀ aꢀ molecularꢀ diversityꢀ inꢀ anꢀ efficientꢀ
Diversityꢀorientedꢀsynthesisꢀ(DOS)ꢀisꢀaꢀhighlyꢀvaluableꢀtoolꢀ
Introductionꢀ
1,10ꢀ
manner. DOSꢀcorrespondsꢀtoꢀtheꢀsimultaneousꢀsynthesisꢀofꢀ
multipleꢀtargetꢀcompoundsꢀstartingꢀfromꢀaꢀsingleꢀreagent.ꢀThisꢀ
allowsꢀ fastꢀ andꢀ efficientꢀ generationꢀ ofꢀ smallꢀ collectionsꢀ ofꢀ
compoundsꢀwithꢀhighꢀdegreeꢀofꢀstructuralꢀdiversityꢀandꢀwideꢀ
Oneꢀofꢀtheꢀmainꢀchallengesꢀforꢀmedicinalꢀchemistsꢀisꢀtoꢀdealꢀ
withꢀnewꢀclassesꢀofꢀtherapeuticꢀtargetsꢀandꢀtoꢀdevelopꢀsuitableꢀ
newꢀdrugsꢀfromꢀhitsꢀoftenꢀdiscoveredꢀbyꢀscreeningꢀofꢀmassiveꢀ
collectionsꢀofꢀcompounds.ꢀNevertheless,ꢀaꢀtrickyꢀlimitationꢀinꢀ
theseꢀlibrariesꢀisꢀtheꢀintrinsicꢀnatureꢀofꢀtheꢀmolecules,ꢀasꢀmostꢀ
ꢀ
coverageꢀ ofꢀ bioactiveꢀ chemicalꢀ space. Inꢀ theꢀ cornucopiaꢀ ofꢀ
2
availableꢀ organicꢀ reactions,ꢀ theꢀ thermalꢀ dimerizationꢀ ofꢀ 1,3-
cyclohexadieneꢀ mayꢀ beꢀ regardedꢀ asꢀ aꢀ particularꢀ exampleꢀ ofꢀ
DOSꢀstrategyꢀasꢀitꢀprovidesꢀaꢀsetꢀofꢀmoleculesꢀwithꢀdifferentꢀ
skeletons.ꢀHammondꢀetꢀal.ꢀshowedꢀthat,ꢀatꢀ200ꢀ°C,ꢀaꢀmixtureꢀ
ofꢀ endo-2ꢀ andꢀ exo-2ꢀ compoundsꢀ (4:1)ꢀ isꢀ formedꢀ byꢀ classicalꢀ
ofꢀthemꢀareꢀplanarꢀcompoundsꢀ(2D),ꢀbuiltꢀonꢀsp -richꢀaromaticꢀ
1ꢀ
ꢀ
orꢀheteroaromaticꢀcores. Thisꢀisꢀmainly dueꢀtoꢀtheꢀadaptationꢀ
2
ofꢀ methodsꢀ forꢀ sp -sp ꢀ couplingsꢀ toꢀ high-throughputꢀ
2
2ꢀ
synthesis. Theꢀconsequenceꢀisꢀthatꢀtheseꢀlibrariesꢀonlyꢀcoverꢀaꢀ
tinyꢀ partꢀ ofꢀ theꢀ chemicalꢀ space,ꢀ aꢀ conceptꢀ thatꢀ hasꢀ recentlyꢀ
emergedꢀ andꢀ encompassesꢀ allꢀ possibleꢀ smallꢀ organicꢀ
11
[
belowꢀ150ꢀ°C,ꢀnotꢀonlyꢀendo-2ꢀandꢀexo-2ꢀcompoundsꢀbutꢀalsoꢀ
4+2]ꢀ Diels-Alderꢀ cycloadditionꢀ (Schemeꢀ 1). ꢀ Nevertheless,ꢀ
3
molecules. ꢀAꢀfewꢀyearsꢀago,ꢀLipkusꢀetꢀal.ꢀhaveꢀshownꢀthatꢀonlyꢀ
1
[
2+2]-cycloadductsꢀsyn-3ꢀandꢀanti-3ꢀandꢀanꢀoriginalꢀ[6+4]-eneꢀ
productꢀ threo-4ꢀ couldꢀ beꢀ isolatedꢀ (ratioꢀ 74:11:4:3:8ꢀ atꢀ
43ꢀframeworkꢀshapesꢀcanꢀdescribeꢀhalfꢀofꢀtheꢀcompoundsꢀofꢀ
theꢀorganicꢀsubsetꢀofꢀtheꢀCASꢀRegistry,ꢀwhichꢀmeansꢀthatꢀtheꢀ
explorationꢀ ofꢀ theꢀ chemicalꢀ spaceꢀ concentratesꢀ onꢀ relativelyꢀ
12
1
10ꢀ°C). ꢀ
4
smallꢀ numbersꢀ ofꢀ structuralꢀ scaffolds. ꢀ Thisꢀ lackꢀ ofꢀ structuralꢀ
diversityꢀ hasꢀ thusꢀ aꢀ dramaticꢀ impactꢀ onꢀ theꢀ drugꢀ discoveryꢀ
process.ꢀ Indeed,ꢀ compoundsꢀ centredꢀ onꢀ aꢀ narrowꢀ chemicalꢀ
spaceꢀareꢀpotentꢀforꢀaꢀdefinedꢀrangeꢀofꢀbiologicalꢀactivitiesꢀandꢀ
H
H
H
H
H
H
H
5
targets ꢀ(mainlyꢀGPCR,ꢀkinasesꢀandꢀproteases)ꢀbutꢀfailꢀforꢀmanyꢀ
7ꢀ
6
otherꢀhighlyꢀimportantꢀones.ꢀTheseꢀlatterꢀ(antibiotics ꢀorꢀPPIs
endo-2
anti-3
threo-4
forꢀ example)ꢀ mayꢀ beꢀ regardedꢀ asꢀ “undruggableꢀ targets”ꢀ ieꢀ
targetsꢀ thatꢀ lackꢀ ofꢀ smallꢀ moleculesꢀ startingꢀ pointsꢀ inꢀ theꢀ
1
H
H
H
H
H
>
<
150 °C
150 °C
H
H
exo-2
syn-3
erythro-4
[4+2]
[2+2]
[6+4]-ene
ꢀ
Schemeꢀ1ꢀCycloadditionꢀandꢀeneꢀreactionꢀproductsꢀresultingꢀfromꢀtheꢀdimerizationꢀofꢀ
,3-cyclohexadieneꢀ1.ꢀ
1
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ1ꢀꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Org aP nl ei ca s &e ꢀ dB oi oꢀ nmo ot ꢀ lae dc j uu ls at ꢀr mCa hr eg imn si sꢀ try
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COMMUNICATIONꢀ
JournalꢀNameꢀ
[
a]
Tableꢀ1ꢀOptimisationꢀofꢀtheꢀmethylꢀcyclohexa-1,5-diene-1-carboxylateꢀ6ꢀdimerization.
ꢀ
Threo-4ꢀ resultedꢀ fromꢀ anꢀ unprecedentedꢀ 10-electronꢀ eneꢀ
reactionꢀinvolvingꢀtwoꢀ4-electronꢀπ-systemsꢀandꢀaꢀC-Hꢀσ-bond.ꢀ
Thisꢀdimerizationꢀreaction,ꢀrationalizedꢀbyꢀcalculation, ꢀshowsꢀ Entryꢀ
View Article Online
DOI: 10.1039/C7OB01236E
[
e]
Relativeꢀratiosꢀ(%) ꢀ
13
Conditionsꢀ(solvent)ꢀ
[f]
5
ꢀ
6ꢀ
7+8+9 ꢀ
howꢀoneꢀsubstrateꢀasꢀsimpleꢀasꢀ1,3-cyclohexadieneꢀ1ꢀcanꢀleadꢀ
[b],[c]
1
2
3
4
ꢀ
ꢀ
ꢀ
ꢀ
Toluene
ꢀ
48ꢀ
36ꢀ
26ꢀ
12ꢀ
43ꢀ
12ꢀ
16ꢀ
12ꢀ
15ꢀ
8ꢀ
38ꢀ
56ꢀ
58ꢀ
48ꢀ
52ꢀ
56ꢀ
84ꢀ
84ꢀ
toꢀ aꢀ setꢀ ofꢀ differentꢀ scaffolds.ꢀ Despiteꢀ itsꢀ potential,ꢀ thisꢀ
[c]
Toluene ꢀ
Tolueneꢀ
Neatꢀ
14
dimerizationꢀ hasꢀ beenꢀ littleꢀ studied ꢀ andꢀ theꢀ molecularꢀ
diversityꢀ thatꢀ mayꢀ beꢀ generatedꢀ isꢀ stillꢀ underexploitedꢀ
althoughꢀQuideauꢀetꢀal.ꢀhaveꢀelegantlyꢀsynthesizedꢀnaturalꢀ(+)-
aquaticolꢀ byꢀ theꢀ [4+2]ꢀ cyclodimerizationꢀ ofꢀ cyclohexa-2,4-
16ꢀ
40ꢀ
5ꢀ
5ꢀ
6ꢀ
7ꢀ
Methanolꢀ
Waterꢀ
33ꢀ
0ꢀ
15ꢀ
dienone.
ꢀ
1,2-Dichloroethaneꢀ
[
d]
8
ꢀ
1,2-Dichloroethane ꢀ
4ꢀ
Weꢀ wonderedꢀ ifꢀ properlyꢀ functionalizedꢀ 1,3-
cyclohexadieneꢀ derivativesꢀ couldꢀ generate,ꢀ underꢀ thermicꢀ
[
a]ꢀReactionꢀconditions:ꢀhydroquinoneꢀ(10ꢀmol%),ꢀunderꢀArꢀatm.,ꢀ120ꢀ°C,ꢀsealedꢀ
conditions,ꢀ unprecedentedꢀ setsꢀ ofꢀ originalꢀ compoundsꢀ tube,ꢀ4ꢀdays.ꢀ[b]ꢀPerformedꢀunderꢀair.ꢀ[c]ꢀPerformedꢀwithoutꢀhydroquinone.ꢀ[d]ꢀ
1
occupyingꢀ aꢀ newꢀ chemicalꢀ space.ꢀ Weꢀ thusꢀ haveꢀ studiedꢀ theꢀ Performedꢀinꢀ2ꢀdays.ꢀ[e]ꢀMeasuredꢀbyꢀcomparativeꢀintegrationꢀofꢀ HꢀNMRꢀsignals.ꢀ
[
f]ꢀCompoundsꢀ7,ꢀ8ꢀandꢀ9ꢀwereꢀformedꢀinꢀaꢀratioꢀofꢀ4:1:3ꢀrespectively.ꢀ
thermicꢀ dimerizationꢀ ofꢀ methylꢀ 1,3-cyclohexadieneꢀ 2-
16
carboxylateꢀ6ꢀasꢀitꢀwasꢀshownꢀtoꢀbehaveꢀeitherꢀasꢀaꢀdiene ꢀorꢀ
17
asꢀ aꢀ dienophile ꢀ inꢀ [4+2]ꢀ cycloadditionsꢀ dependingꢀ onꢀ theꢀ
experimentalꢀ conditions.ꢀ Thisꢀ promisingꢀ compoundꢀ couldꢀ beꢀ
preparedꢀinꢀthreeꢀstepsꢀfromꢀmethylꢀbenzoateꢀ5ꢀ(Schemeꢀ2),ꢀaꢀ
O
a-b
CsO
7
1
0
O
OMe
16
cheapꢀcommercialꢀsource. ꢀ
ꢀ
Resultsꢀandꢀdiscussionꢀ
Schemeꢀ3ꢀORTEPꢀviewꢀandꢀsynthesisꢀofꢀcompoundꢀ10:ꢀa)ꢀLiOH.H
2
Oꢀ(1ꢀeq),ꢀTHF/H
2
O,ꢀr.t.,ꢀ
2
ꢀhꢀthenꢀ1ꢀMꢀHCl;ꢀb)ꢀCs CO ,ꢀmethanol/waterꢀ9:1,ꢀr.t.,ꢀ99%ꢀ(2ꢀsteps).ꢀ
2
3
Weꢀfirstꢀstudiedꢀtheꢀdimerizationꢀofꢀmethylꢀ1,3-cyclohexadieneꢀ
2
-carboxylateꢀ 6ꢀ underꢀ thermicꢀ conditions.ꢀ Whateverꢀ theꢀ
Aꢀlowerꢀconversionꢀwasꢀobservedꢀforꢀtheꢀneatꢀdimerizationꢀofꢀ
compoundꢀ 6ꢀ althoughꢀ theꢀ aromatizationꢀ couldꢀ beꢀ almostꢀ
completelyꢀavoidedꢀ(entryꢀ4).ꢀContraryꢀtoꢀtheꢀuseꢀofꢀmethanolꢀ
orꢀ waterꢀ (entriesꢀ 5ꢀ andꢀ 6),ꢀ significantꢀ improvementsꢀ wereꢀ
notedꢀ whenꢀ 1,2-dichloromethaneꢀ wasꢀ employedꢀ insteadꢀ ofꢀ
tolueneꢀ (entriesꢀ 7ꢀ andꢀ 8).ꢀ Theseꢀ conditionsꢀ preventedꢀ theꢀ
aromatizationꢀ upꢀ toꢀ 12%ꢀ onlyꢀ andꢀ 84%ꢀ ofꢀ theꢀ desiredꢀ
compoundsꢀwereꢀobservedꢀinꢀprotonꢀNMR.ꢀFinally,ꢀafterꢀ2ꢀdaysꢀ
inꢀdegassedꢀDCEꢀatꢀ120ꢀ°Cꢀ(sealedꢀtube)ꢀinꢀtheꢀpresenceꢀofꢀ10%ꢀ
ofꢀhydroquinone,ꢀcompoundsꢀofꢀinterestꢀ7-9ꢀcouldꢀbeꢀobtainedꢀ
withꢀ aꢀ ratioꢀ ofꢀ 4:1:3ꢀ respectivelyꢀ inꢀ 64%ꢀ combinedꢀ yield.ꢀ
Interestingly,ꢀ whateverꢀ theꢀ reactionꢀ conditions,ꢀ noꢀ [2+2]-
cycloadductsꢀcouldꢀbeꢀdetectedꢀinꢀtheꢀcrudeꢀmixture,ꢀcontraryꢀ
toꢀtheꢀresultsꢀdescribedꢀbyꢀHammondꢀetꢀal..ꢀEachꢀcompoundꢀ7-
9ꢀwasꢀisolatedꢀandꢀtheꢀstructureꢀofꢀendo-7ꢀwasꢀconfirmedꢀbyꢀX-
rayꢀdiffractionꢀofꢀcrystalꢀofꢀtheꢀmono-cesiumꢀcarboxylateꢀsaltꢀ
reactionꢀconditions,ꢀaꢀmixtureꢀofꢀ5ꢀseparableꢀcompoundsꢀwasꢀ
obtained,ꢀ includingꢀ remainingꢀ startingꢀ materialꢀ 6,ꢀ
aromatizationꢀ productꢀ 5,ꢀ endoꢀ andꢀ exoꢀ [4+2]ꢀ cycloadductsꢀ 7ꢀ
andꢀ8,ꢀasꢀwellꢀasꢀanꢀoriginalꢀthreoꢀ[6+4]-eneꢀproductꢀ9ꢀ(Tableꢀ
1).ꢀ Theꢀ reactionꢀ performedꢀ inꢀ refluxingꢀ tolueneꢀ forꢀ 4ꢀ daysꢀ
withoutꢀ hydroquinoneꢀ andꢀ underꢀ airꢀ mainlyꢀ ledꢀ toꢀ theꢀ
aromatizationꢀofꢀtheꢀstartingꢀdieneꢀ6ꢀintoꢀmethylꢀbenzoateꢀ5ꢀ
(
entryꢀ1).ꢀInꢀtheseꢀconditions,ꢀtheꢀobservedꢀratioꢀofꢀtargetedꢀ
1
compoundsꢀ7-9ꢀbyꢀ HꢀNMRꢀanalysisꢀreachedꢀ38%ꢀinꢀtheꢀcrudeꢀ
reactionꢀ mixture.ꢀ Byꢀ performingꢀ theꢀ reactionꢀ inꢀ degassedꢀ
tolueneꢀunderꢀinertꢀatmosphereꢀandꢀafterꢀadditionꢀofꢀ10%ꢀofꢀ
hydroquinone,ꢀtheꢀamountꢀofꢀaromatizedꢀcompoundꢀ5ꢀcouldꢀ
beꢀreducedꢀtoꢀ36%ꢀandꢀ26%ꢀ(entriesꢀ2ꢀandꢀ3).ꢀꢀ
O
MeO
1
0ꢀ(Schemeꢀ3).ꢀ
Asꢀ theirꢀ alkeneꢀ andꢀ esterꢀ functionsꢀ areꢀ differentlyꢀ
O
OMe 7
ꢀ
O
O
O
positionedꢀ inꢀ space,ꢀ theseꢀ 3Dꢀ scaffoldsꢀ 7-9ꢀ wereꢀ promisingꢀ
startingꢀpointsꢀtoꢀdesign,ꢀbyꢀaꢀDOSꢀapproach,ꢀoriginalꢀbuildingꢀ
blocksꢀusefulꢀinꢀmedicinalꢀchemistryꢀforꢀexample.ꢀWeꢀchoseꢀtoꢀ
illustrateꢀtheꢀversatilityꢀofꢀtheseꢀcompoundsꢀbyꢀmodifyingꢀtheꢀ
pureꢀendoꢀ[4+2]ꢀcycloadductꢀ7ꢀinꢀorderꢀtoꢀprepareꢀaꢀlibraryꢀofꢀ
originalꢀ 3D-shapeꢀ compoundsꢀ (Schemeꢀ 4).ꢀ Thanksꢀ toꢀ theirꢀ
differenceꢀofꢀreactivity,ꢀtheꢀlessꢀhinderedꢀesterꢀfunctionꢀofꢀ7ꢀ
a-c
O
MeO
MeO
MeO
OMe
5
6
8
O
MeO
MeO
9
O
ꢀ
Schemeꢀ2ꢀFromꢀmethylꢀbenzoateꢀ5ꢀtowardsꢀdimerizationꢀcompoundsꢀ7-9:ꢀa)ꢀNa,ꢀNH
EtOH,ꢀ-78ꢀ°C,ꢀ3ꢀh;ꢀb)ꢀ10%ꢀKOHꢀinꢀH O,ꢀhydroquinoneꢀ(10ꢀmol%),ꢀ100ꢀ°C,ꢀ4ꢀh;ꢀc)ꢀ(COCl)
THF,ꢀr.t.,ꢀ12ꢀhꢀthenꢀMeOH,ꢀPy,ꢀr.t.,ꢀ1ꢀh,ꢀ75%ꢀ(3ꢀsteps).ꢀ
3
,ꢀ couldꢀ beꢀ selectivelyꢀ saponifiedꢀ byꢀ treatmentꢀ withꢀ oneꢀ
,ꢀ equivalentꢀofꢀLiOH.H OꢀatꢀroomꢀtemperatureꢀinꢀaꢀTHF/waterꢀ
2
2
2
mixture.ꢀAmongꢀtheꢀorganicꢀreactionsꢀthatꢀcouldꢀbeꢀperformedꢀ
onꢀ theꢀ mono-carboxylicꢀ acidꢀ 11,ꢀ twoꢀ wereꢀ selected.ꢀ
2
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
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COMMUNICATIONꢀ
JournalꢀNameꢀ
View Article Online
DOI: 10.1039/C7OB01236E
O
N3
O
1
6
O
N3
g
1
4
O
OMe
d
f
O
O
O
N3
HO
NH
1
7
O
1
3
O
OMe
1
5
O
OH
c
O
e
HO
HO
i
AcO
a
h
O
O
b
11
O
OMe
18
OH
1
9
OAc
Me
MeO
1
2
O
OMe
7
O
OMe
j
l
k
O
O
Br
MeO
MeO
O
n
RHN
OH
MeO
α−23
β−23
O
OMe
α−22
β−22
O
O
O
OAc
20 R = Bn
21 R = Ph
O
2
6
O
m
O
Spontaneously
O
OH
MeO
MeO
+
HO
O
O
OH
OMe
25
2
4
O
ꢀ
Schemeꢀ4ꢀFunctionalizationsꢀofꢀendoꢀ[4+2]ꢀcycloadductꢀ7:ꢀa)ꢀLiOH.H
5%;ꢀc)ꢀDPPAꢀ(1.1ꢀeq),ꢀEt Nꢀ(1.5ꢀeq),ꢀbenzene,ꢀr.t.,ꢀ2ꢀh,ꢀ90%;ꢀd)ꢀTol.,ꢀ120ꢀ°C,ꢀ1ꢀhꢀthenꢀHClꢀ1ꢀMꢀinꢀdioxane,ꢀr.t.,ꢀ2ꢀh,ꢀ60%;ꢀe)ꢀNaOHꢀ(4ꢀeq),ꢀTHF/H
Et Nꢀ(3ꢀeq),ꢀbenzene,ꢀr.t.,ꢀ2ꢀh,ꢀ62%;ꢀg)ꢀTol.,ꢀ120ꢀ°C,ꢀ1ꢀhꢀthenꢀHClꢀ1ꢀMꢀinꢀdioxane,ꢀr.t.,ꢀ2ꢀh,ꢀ58%;ꢀh)ꢀDIBALꢀ(2ꢀeq),ꢀTol.,ꢀ0ꢀ°C,ꢀ1ꢀh,ꢀ79%;ꢀi)ꢀAc Oꢀ(3ꢀeq),ꢀDMAPꢀ(0.4ꢀeq),ꢀCH
8%;ꢀj)ꢀRNH ꢀ(4ꢀeq),ꢀn-BuLiꢀ(4ꢀeq),ꢀTHF,ꢀ-78ꢀ°C,ꢀ3ꢀh,ꢀ56%ꢀforꢀ20,ꢀ35%ꢀforꢀ21;ꢀk)ꢀNBSꢀ(2.2ꢀeq),ꢀsuccinimideꢀ(0.2ꢀeq),ꢀpiperidineꢀ(0.2ꢀeq),ꢀCHCl ,ꢀ60ꢀ°C,ꢀsealedꢀtube,ꢀ17ꢀh,ꢀ36%;ꢀl)ꢀDMDOꢀ(1ꢀ
eq),ꢀacetone,ꢀr.t.,ꢀ3ꢀh,ꢀ64%,ꢀα−23/β−23ꢀ(8:2);ꢀm)ꢀfromꢀα−23:ꢀAlCl ꢀ(4ꢀeq),ꢀTHF,ꢀ60ꢀ°C,ꢀ48ꢀh,ꢀ44%ꢀforꢀ24,ꢀ57%ꢀforꢀ25;ꢀn)ꢀfrom β−23:ꢀAlCl ꢀ(4ꢀeq),ꢀTHF,ꢀ60ꢀ°C,12ꢀh,ꢀ40%.ꢀ
2
Oꢀ(1ꢀeq),ꢀTHF/H
2
O,ꢀr.t.,ꢀ48ꢀh,ꢀ100%;ꢀb)ꢀSOCl
2
ꢀ(5.4ꢀeq),ꢀ50ꢀ°C,ꢀ3ꢀh,ꢀthenꢀMeCu.LiIꢀ(1.1ꢀeq),ꢀTHF,ꢀ-78ꢀ°C,ꢀ15ꢀmin,ꢀ
O,ꢀ80ꢀ°C,ꢀ2ꢀh,ꢀ99%;ꢀf)ꢀDPPAꢀ(2.2ꢀeq),ꢀ
Cl ,ꢀr.t.,ꢀ1ꢀh,ꢀ
8
3
2
3
2
2
2
9
2
3
3
3
Onꢀ oneꢀ hand,ꢀ theꢀ preparationꢀ ofꢀ methylketoneꢀ 12ꢀ wasꢀ structureꢀ wasꢀ confirmedꢀ byꢀ X-rayꢀ diffractionꢀ analysisꢀ (Figureꢀ
achievedꢀ byꢀ additionꢀ ofꢀ methylcuprateꢀ onꢀ intermediateꢀ acylꢀ 1),ꢀ wasꢀ isolatedꢀ afterꢀ obtentionꢀ ofꢀ theꢀ unstableꢀ dicarbonylꢀ
chlorideꢀ inꢀ 85%ꢀ yield.ꢀ Onꢀ theꢀ otherꢀ hand,ꢀ keto-esterꢀ 14ꢀ wasꢀ azideꢀesterꢀintermediateꢀ16.ꢀItsꢀformationꢀcanꢀbeꢀexplainedꢀbyꢀ
preparedꢀviaꢀanꢀoriginalꢀ2-stepꢀprocedureꢀinꢀgoodꢀyield.ꢀAfterꢀ theꢀintramolecularꢀtrappingꢀofꢀtheꢀisocyanateꢀinꢀringꢀjunctionꢀ
classicalꢀformationꢀofꢀtheꢀα,β-unsaturatedꢀcarbonylꢀazideꢀesterꢀ positionꢀbyꢀtheꢀtransientꢀenamineꢀgeneratedꢀonꢀtheꢀexternalꢀ
1
9
1
3,ꢀaꢀsimpleꢀrefluxꢀinꢀtolueneꢀfollowedꢀbyꢀacidicꢀwork-upꢀledꢀtoꢀ position. ꢀ Theꢀ diesterꢀ 7ꢀ couldꢀ alsoꢀ beꢀ reducedꢀ toꢀ theꢀ
theꢀ ketoneꢀ 14.ꢀ Thisꢀ formalꢀ reductionꢀ ofꢀ aꢀ methyleneꢀ unitꢀ correspondingꢀdiolꢀ18ꢀinꢀtheꢀpresenceꢀofꢀDIBALꢀinꢀ79%ꢀyield.ꢀ
resultsꢀ fromꢀ theꢀ hydrolysisꢀ ofꢀ theꢀ imminiumobtainedꢀ afterꢀ Afterꢀ doubleꢀ acetylation,ꢀ theꢀ resultingꢀ compoundꢀ 19ꢀ wasꢀ
formationꢀ ofꢀ theꢀ transientꢀ conjugatedꢀ isocyanateꢀ byꢀ Curtiusꢀ transformedꢀintoꢀtwoꢀnewꢀcompoundsꢀ20ꢀandꢀ21ꢀbyꢀselectiveꢀ
18
rearrangement. ꢀ Theꢀ dicarboxylicꢀ acidꢀ 15ꢀ couldꢀ beꢀ obtainedꢀ functionalizationꢀ ofꢀ theꢀ allylicꢀ acetalꢀ byꢀ aꢀ Tsuji-Trostꢀ
quantitativelyꢀ fromꢀ startingꢀ esterꢀ 7ꢀ whenꢀ theꢀ saponificationꢀ reactionwithꢀ benzylamineꢀ andꢀ anilineꢀ respectively.ꢀ Afterꢀ
wasꢀperformedꢀwithꢀanꢀexcessꢀofꢀsodiumꢀhydroxideꢀatꢀ80ꢀ°C.ꢀꢀ
selectiveꢀmodificationsꢀofꢀtheꢀesterꢀfunctions,ꢀtheꢀreactivityꢀofꢀ
theꢀ non-conjugatedꢀ doubleꢀ bondꢀ wasꢀ investigated.ꢀ First,ꢀ aꢀ
halolactonizationꢀ withꢀ NBSꢀ ledꢀ toꢀ theꢀ formationꢀ ofꢀ theꢀ
bromolactonesꢀ α−ꢀ andꢀ β−22ꢀ inꢀ aꢀ ratioꢀ ofꢀ 1:1,ꢀ whichꢀ X-rayꢀ
diffractionꢀanalysisꢀ(Figureꢀ1)ꢀconfirmedꢀnoꢀmodificationꢀonꢀtheꢀ
conjugatedꢀ doubleꢀ bond.ꢀ Then,ꢀ treatmentꢀ ofꢀ 7ꢀ withꢀ DMDOꢀ
gaveꢀaꢀ8:2ꢀmixtureꢀofꢀseparableꢀepoxideꢀisomersꢀα−ꢀandꢀβ−23ꢀ
inꢀ64%ꢀyield.ꢀTheꢀmajorꢀone,ꢀα−23,ꢀarisesꢀfromꢀepoxidationꢀonꢀ
theꢀlessꢀhinderedꢀlowerꢀface.ꢀThisꢀcompoundꢀcouldꢀbeꢀopenedꢀ
1
7
β−22
25
ꢀ
Figureꢀ1ꢀORTEPꢀviewꢀofꢀcompoundsꢀ17,ꢀβ−24,ꢀ25.ꢀ
Usingꢀ theꢀ previousꢀ two-stepꢀ strategyꢀ developedꢀ forꢀ theꢀ inꢀtheꢀpresenceꢀofꢀAlCl ꢀatꢀ60ꢀ°CꢀinꢀTHF,ꢀthusꢀyieldingꢀtoꢀdiolꢀ24ꢀ
3
synthesisꢀofꢀketo-esterꢀ14,ꢀanꢀoriginalꢀketo-lactameꢀ17,ꢀwhichꢀ andꢀlactoneꢀ25.ꢀItsꢀformationꢀisꢀprobablyꢀdueꢀtoꢀtheꢀadditionꢀofꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ3ꢀꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Org aP nl ei ca s &e ꢀ dB oi oꢀ nmo ot ꢀ lae dc j uu ls at ꢀr mCa hr eg imn si sꢀ try
Page 4 of 7
COMMUNICATIONꢀ
JournalꢀNameꢀ
waterꢀ duringꢀ theꢀ work-upꢀ onꢀ theꢀ lessꢀ hinderedꢀ faceꢀ ofꢀ theꢀ colorlessꢀoil,ꢀexo-8ꢀ(0.66ꢀg,ꢀ6%)ꢀasꢀwhiteꢀsolidꢀandꢀVtihewreAort-ic9leꢀ(O3n.l1in0eꢀ
DOI: 10.1039/C7OB01236E
chelatedꢀ intermediateꢀ (upperꢀ face).ꢀ Theꢀ latterꢀ diolꢀ 24ꢀ g,ꢀ21%)ꢀasꢀcolourlessꢀoil.ꢀ
ꢀ
1
spontaneouslyꢀcyclizedꢀinꢀfewꢀhoursꢀtoꢀlactoneꢀ26ꢀthatꢀcould,ꢀ
besides,ꢀbeꢀobtainedꢀdirectlyꢀfromꢀepoxydeꢀβ−23ꢀwithꢀAlCl3.ꢀ
ꢀ
Endo-7. HꢀNMRꢀ(500ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.23ꢀ(d,ꢀJꢀ=ꢀ6.5ꢀ
Hz,ꢀ1H),ꢀ6.19-6.15ꢀ(m,ꢀ1H),ꢀ5.55ꢀ(dd,ꢀJꢀ=ꢀ10.0,ꢀ1.5ꢀHz,ꢀ1H),ꢀ3.73ꢀ
(
(
s,ꢀ3H),ꢀ3.60ꢀ(s,ꢀ3H),ꢀ3.14-3.06ꢀ(m,ꢀ1H),ꢀ3.05-3.00ꢀ(m,ꢀ1H),ꢀ2.44ꢀ
t,ꢀJꢀ=ꢀ9.5ꢀHz,ꢀ1H),ꢀ2.09-2.05ꢀ(m,ꢀ2H),ꢀ1.85-1.79ꢀ(m,ꢀ2H),ꢀ1.69-
Conclusionsꢀ
1
.65ꢀ(m,ꢀ1H),ꢀ1.38-1.33ꢀ(m,ꢀ1H),ꢀ1.17-1.11ꢀ(m,ꢀ1H),ꢀ1.00-0.94ꢀ
13
(
m,ꢀ 1H);ꢀ Cꢀ NMRꢀ (125ꢀ MHz,ꢀCDCl3,ꢀ 25ꢀ °C)ꢀ:ꢀ δꢀ 176.2,ꢀ 165.2,ꢀ
Startingꢀfromꢀsimpleꢀmethylꢀbenzoateꢀ5,ꢀcompoundsꢀwithꢀanꢀ
increasedꢀ complexityꢀ andꢀ chemicalꢀ diversityꢀ wereꢀ easilyꢀ
elaboratedꢀ inꢀ fewꢀ steps,ꢀ providingꢀ newꢀ originalꢀ
stereochemicallyꢀ richꢀ chiralꢀ scaffoldsꢀ withꢀ readilyꢀ
functionalizableꢀ handles.ꢀ Thus,ꢀ inꢀ thermicꢀ conditions,ꢀ threeꢀ
separableꢀcompoundsꢀcouldꢀbeꢀobtainedꢀbyꢀcyclodimerizationꢀ
ofꢀ 5,ꢀ amongꢀ whichꢀ anꢀ originalꢀ threoꢀ [6+4]-eneꢀ productꢀ 9.ꢀ
Furthermore,ꢀ selectiveꢀ chemicalꢀ modificationsꢀ couldꢀ beꢀ
performedꢀ onꢀ cycloadductꢀ 7,ꢀ takingꢀ advantageꢀ ofꢀ theꢀ
differenceꢀ inꢀ reactivityꢀ ofꢀ theꢀ twoꢀ esterꢀ functions.ꢀ Thisꢀ workꢀ
ledꢀtoꢀ18ꢀnewꢀoriginalꢀ3D-shapeꢀbuildingꢀblocksꢀ11-26,ꢀwhichꢀ
areꢀonlyꢀaꢀflavorꢀofꢀwhatꢀcanꢀbeꢀdoneꢀonꢀsuchꢀstructuresꢀviaꢀ
DOSꢀ strategy.ꢀ Allꢀ ofꢀ theseꢀ newꢀ compoundsꢀ possessꢀ aꢀ chiralꢀ
quaternaryꢀcenterꢀandꢀhaveꢀaꢀmoreꢀglobularꢀshapeꢀthanꢀmostꢀ
ofꢀtheꢀcompoundsꢀinꢀtraditionalꢀmedicinalꢀchemistryꢀlibraries,ꢀ
1
2
43.5,ꢀ 139.9,ꢀ 134.6,ꢀ 129.4,ꢀ 52.3,ꢀ 51.5,ꢀ 50.6,ꢀ 39.2,ꢀ 36.4,ꢀ 35.1,ꢀ
5.4,ꢀ 23.7,ꢀ 19.8,ꢀ 18.5;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ C16H24NO4ꢀ
+
[
M+NH4] :ꢀ294.1705;ꢀfound:ꢀ294.1699.ꢀ
1
Exo-8.ꢀ HꢀNMRꢀ(500ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.14ꢀ(dd,ꢀJꢀ=ꢀ7.0,ꢀ
ꢀ
1
3
.5ꢀHz,ꢀ1H),ꢀ5.86-5.81ꢀ(m,ꢀ1H),ꢀ5.54ꢀ(d,ꢀJꢀ=ꢀ10ꢀHz,ꢀ1H),ꢀ3.74ꢀ(s,ꢀ
H),ꢀ3.71ꢀ(s,ꢀ3H),ꢀ3.15-3.11ꢀ(m,ꢀ1H),ꢀ3.03ꢀ(s,ꢀ1H),ꢀ2.84ꢀ(t,ꢀJꢀ=ꢀ6.0ꢀ
Hz,ꢀ 1H),ꢀ 1.84-1.78ꢀ (m,ꢀ 2H),ꢀ 1.71-1.65ꢀ (m,ꢀ 2H),ꢀ 1.58-1.54ꢀ (m,ꢀ
13
1
1
3
H),ꢀ 1.31-1.15ꢀ (m,ꢀ 3H);ꢀ Cꢀ NMRꢀ (125ꢀ MHz,ꢀCDCl3,ꢀ 25ꢀ °C):ꢀ δꢀ
75.4,ꢀ165.8,ꢀ143.2,ꢀ137.4,ꢀ131.7,ꢀ129.5,ꢀ52.4,ꢀ52.3,ꢀ51.6,ꢀ40.1,ꢀ
9.9,ꢀ 36.9,ꢀ 27.1,ꢀ 25.9,ꢀ 21.9,ꢀ 21.3;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ
+
C16H24NO4ꢀ[M+NH4] :ꢀ294.1705;ꢀfound:ꢀ294.1699.ꢀ
1
Threo-9. HꢀNMRꢀ(500ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.05ꢀ(d,ꢀJꢀ=ꢀ5.0ꢀ
ꢀ
Hz,ꢀ1H,),ꢀ6.90ꢀ(t,ꢀJꢀ=ꢀ3.5ꢀHz,ꢀ1H),ꢀ6.04-5.98ꢀ(m,ꢀ2H),ꢀ3.71ꢀ(s,ꢀ3H),ꢀ
3
2
.66ꢀ(s,ꢀ3H),ꢀ3.12-3.08ꢀ(m,ꢀ1H),ꢀ2.98-2.94ꢀ(m,ꢀ1H),ꢀ2.37-2.34ꢀ(m,ꢀ
H),ꢀ2.21-2.08ꢀ(m,ꢀ2H),ꢀ1.70-1.66ꢀ(m,ꢀ2H),ꢀ1.53-1.45ꢀ(m,ꢀ2H);ꢀ
CꢀNMRꢀ(125ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ168.4,ꢀ167.8,ꢀ141.0,ꢀ134.4,ꢀ
32.5,ꢀ 132.3,ꢀ 128.6,ꢀ 123.5,ꢀ 51.5,ꢀ 51.3,ꢀ 34.2,ꢀ 32.0,ꢀ 26.1,ꢀ 25.8,ꢀ
3
thanksꢀtoꢀtheirꢀhigherꢀFsp ꢀcharacter.ꢀConsequently,ꢀitꢀallowsꢀ
accessꢀ toꢀ aꢀ largerꢀ andꢀ unexploredꢀ chemicalꢀ spaceꢀ forꢀ drugꢀ
discoveryꢀprocesses.ꢀ
13
1
2
2
ꢀ
+
3.8,ꢀ 18.4;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ C16H24NO4ꢀ [M+NH4] :ꢀ
94.1705;ꢀfound:ꢀ294.1699.ꢀ
Cesiumꢀ saltꢀ 10.ꢀ Monoacidꢀ 11ꢀ (20ꢀ mg,ꢀ 7.2ꢀ mmol)ꢀ wasꢀ
Experimentalꢀsectionsꢀ
dissolvedꢀinꢀaꢀ9:1ꢀmixtureꢀofꢀmethanol/waterꢀ(300ꢀμL).ꢀAꢀ20%ꢀ
aqueousꢀ solutionꢀ ofꢀ cesiumꢀ carbonateꢀ wasꢀ addedꢀ dropwiseꢀ
Generalꢀexperimentalꢀdetailsꢀ
Allꢀ reagentsꢀ andꢀ solventsꢀ wereꢀ usedꢀ asꢀ purchasedꢀ fromꢀ untilꢀ theꢀ pHꢀ reachedꢀ 7.ꢀ Theꢀ solventꢀ wasꢀ removedꢀ underꢀ
commercialꢀ suppliersꢀ orꢀ wereꢀ purified/driedꢀ accordingꢀ toꢀ vacuumꢀ andꢀ theꢀ residueꢀ wasꢀ carefullyꢀ driedꢀ byꢀ additionꢀ ofꢀ
20
ArmaregoꢀandꢀChai. ꢀPurificationsꢀbyꢀcolumnꢀchromatographyꢀ acetonitrileꢀ(3ꢀxꢀ1ꢀmL)ꢀtoꢀformꢀanꢀazeotrope.ꢀTheꢀresidueꢀwasꢀ
onꢀsilicaꢀgelꢀwereꢀperformedꢀusingꢀMerckꢀSilicaꢀGelꢀ60ꢀ(70-230ꢀ solubilizedꢀinꢀhotꢀCHCl3ꢀtoꢀslowlyꢀrecrystalized.ꢀ
1
mesh).ꢀ Hꢀ andꢀ Cꢀ NMRꢀ spectraꢀ wereꢀ recordedꢀ onꢀ Brukerꢀ
13
ꢀ
Monoacidꢀ 11.ꢀ Compoundꢀ 7ꢀ (200ꢀ mg,ꢀ 0.72ꢀ mmol)ꢀ wasꢀ
ARX300ꢀ andꢀ ARX500ꢀ instrumentsꢀ usingꢀ CDCl3ꢀ orꢀ DMSO-d6ꢀ asꢀ stirredꢀwithꢀLiOH.H2Oꢀ(30ꢀmg,ꢀ0.72ꢀmmol,ꢀ1ꢀeq)ꢀatꢀr.t.ꢀforꢀ2ꢀhꢀinꢀ
internalꢀ references.ꢀ Chemicalꢀ shiftsꢀ (δꢀ values)ꢀ areꢀ givenꢀ inꢀ aꢀ1:1ꢀmixtureꢀofꢀTHF/waterꢀ(4ꢀmL).ꢀTheꢀreactionꢀmixtureꢀwasꢀ
partsꢀperꢀmillionꢀ(ppm),ꢀandꢀmultiplicityꢀofꢀsignalsꢀareꢀreportedꢀ cooledꢀ downꢀ andꢀ aꢀ 1Mꢀ HClꢀ solutionꢀ (1ꢀ mL)ꢀ wasꢀ added.ꢀ Theꢀ
asꢀfollows:ꢀs,ꢀsinglet;ꢀbs,ꢀbroadꢀsinglet;ꢀd,ꢀdoublet;ꢀt,ꢀtriplet;ꢀq,ꢀ productꢀ wasꢀ extractedꢀ withꢀ CH2Cl2ꢀ (3ꢀtimes).ꢀ Theꢀ combinedꢀ
quartet;ꢀdd,ꢀdoubletꢀofꢀdoublets;ꢀm,ꢀmultiplet.ꢀHRMSꢀanalysesꢀ organicꢀ phasesꢀ wereꢀ driedꢀ overꢀ MgSO4ꢀ andꢀ concentratedꢀ
wereꢀ obtainedꢀ usingꢀ aꢀ Watersꢀ LCTꢀ Premierꢀ instrumentꢀ byꢀ underꢀreducedꢀpressureꢀtoꢀgiveꢀcompoundꢀ11ꢀ(201ꢀmg,ꢀ100%ꢀ
ElectroSprayꢀ Ionizationꢀ (ESI).ꢀ IRꢀ spectraꢀ wereꢀ recordedꢀ onꢀ aꢀ yield),ꢀ asꢀ colourlessꢀ oilꢀ thatꢀ wasꢀ usedꢀ withoutꢀ furtherꢀ
1
Perkinꢀ Elmerꢀ Spectrumꢀ BX-FTIRꢀ spectrometer.ꢀ X-rayꢀ singleꢀ purification.ꢀ HꢀNMRꢀ(500ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.39ꢀ(dd,ꢀJꢀ=ꢀ
diffractionꢀ dataꢀ wereꢀ recordedꢀ eitherꢀ onꢀ aꢀ Nonius-Enrafꢀ 6.6,ꢀ1.8ꢀHz,ꢀ1H),ꢀ6.20-6.14ꢀ(m,ꢀ1H),ꢀ5.54ꢀ(dd,ꢀJꢀ=ꢀ10.2,ꢀ2.1ꢀHz,ꢀ
kappaCCDꢀ diffractometerꢀ withꢀ graphite-monochromatedꢀ 1H),ꢀ 3.60ꢀ (s,ꢀ 3H),ꢀ 3.16-3.11ꢀ (m,ꢀ 1H),ꢀ 3.04-2.99ꢀ (m,ꢀ 1H),ꢀ 2.48-
MoKαꢀradiationꢀatꢀroomꢀtemperatureꢀ(forꢀ10,ꢀ17,ꢀandꢀβ-22)ꢀorꢀ 2.41ꢀ(m,ꢀ1H),ꢀ2.09-2.04ꢀ(m,ꢀ2H),ꢀ1.88-1.81ꢀ(m,ꢀ2H),ꢀ1.74-1.64ꢀ
onꢀaꢀRigakuꢀmm007HFꢀcopperꢀrotatingꢀanodeꢀequippedꢀwithꢀ (m,ꢀ 1H),ꢀ 1.40-1.31ꢀ (m,ꢀ 1H),ꢀ 1.20-1.10ꢀ (m,ꢀ 1H),ꢀ 1.04-0.94ꢀ (m,ꢀ
ꢀ
13
CMFꢀmirrorsꢀandꢀRapid2ꢀIPꢀdetectorꢀatꢀlowꢀtemperatureꢀforꢀ25.ꢀ 1H); CꢀNMRꢀ(125ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ176.1,ꢀ169.6,ꢀ146.5,ꢀ
ꢀ
139.4,ꢀ 134.7,ꢀ 129.2,ꢀ 52.4,ꢀ 50.6,ꢀ 39.5,ꢀ 36.4,ꢀ 34.8,ꢀ 25.3,ꢀ 23.7,ꢀ
+
Dimerizationꢀofꢀmethylꢀ1,3-cyclohexadieneꢀ2-carboxylateꢀ 19.8,ꢀ 18.4;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ C15H19O4ꢀ [M+H] :ꢀ
ꢀ
6
g,ꢀ11.5ꢀmmol,ꢀ0.1ꢀeq)ꢀwereꢀdissolvedꢀinꢀ1,2-dichloroethaneꢀ(20ꢀ
.ꢀCompoundꢀ6ꢀ(15.9ꢀg,ꢀ115.2ꢀmmol)ꢀandꢀhydroquinoneꢀ(1.27ꢀ 263.1268;ꢀfound:ꢀ263.1281.ꢀ
ꢀ
Methylꢀketoneꢀ12.ꢀCompoundꢀ11ꢀ(334ꢀmg,ꢀ1.3ꢀmmol)ꢀwasꢀ
mL)ꢀ andꢀ refluxedꢀ inꢀ aꢀ sealedꢀ tubeꢀ forꢀ 48ꢀ hꢀ beforeꢀ stirredꢀatꢀ50ꢀ°Cꢀforꢀ3ꢀhꢀinꢀthionylꢀchlorideꢀ(500ꢀmL,ꢀ6.9ꢀmmol,ꢀ
concentrationꢀ underꢀ reducedꢀ pressure.ꢀ Theꢀ residueꢀ wasꢀ 5.4ꢀ eq)ꢀ underꢀ Arꢀ atm,ꢀ thenꢀ theꢀ solventꢀ wasꢀ concentratedꢀ
purifiedꢀ byꢀ columnꢀ chromatographyꢀ onꢀ silicaꢀ gelꢀ usingꢀ underꢀreducedꢀpressure.ꢀInꢀparallel,ꢀaꢀ1.37ꢀMꢀsolutionꢀofꢀMeLiꢀ
heptane/EtOAcꢀ10:0ꢀtoꢀ8:2ꢀtoꢀobtainꢀendo-7ꢀ(5.48ꢀg,ꢀ35%)ꢀasꢀ inꢀEt2Oꢀ(1.3ꢀmL,ꢀ1.4ꢀmmol,ꢀ1.1ꢀeq)ꢀwasꢀaddedꢀdropwiseꢀunderꢀ
Arꢀatm.ꢀtoꢀaꢀsuspensionꢀofꢀCuIꢀ(267ꢀmg,ꢀ1.4ꢀmmol,ꢀ1.1ꢀeq)ꢀinꢀ
4
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Page 5 of 7
Org aP nl ei ca s &e ꢀ dB oi oꢀ nmo ot ꢀ lae dc j uu ls at ꢀr mCa hr eg imn si sꢀ try
JournalꢀNameꢀ
ꢀCOMMUNICATIONꢀ
THFꢀ(15ꢀmL)ꢀatꢀ0ꢀ°C.ꢀTheꢀmixtureꢀwasꢀstirredꢀforꢀ10ꢀminꢀatꢀ0ꢀ°Cꢀ wereꢀ driedꢀ overꢀ MgSO4ꢀ andꢀ concentratedꢀ unVdieewrꢀArrtieclde uOncleindeꢀ
DOI: 10.1039/C7OB01236E
beforeꢀ theꢀ dropwiseꢀ addition,ꢀ atꢀ -78ꢀ °C,ꢀ ofꢀ theꢀ acidꢀ chlorideꢀ pressureꢀ toꢀ giveꢀ compoundꢀ 15ꢀ (200ꢀ mg,ꢀ 100%ꢀ yield)ꢀ asꢀ
1
issuedꢀ fromꢀ 11,ꢀ dissolvedꢀ inꢀ THFꢀ (1ꢀ mL).ꢀ Theꢀ mixtureꢀ wasꢀ colourlessꢀ oilꢀ thatꢀ wasꢀ usedꢀ withoutꢀ furherꢀ purification.ꢀ Hꢀ
ꢀ
stirredꢀ forꢀ 15ꢀminꢀ thenꢀ MeOHꢀ (3ꢀ mL)ꢀ wasꢀ addedꢀ andꢀ theꢀ NMRꢀ(500ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.50ꢀ(dd,ꢀ Jꢀ=ꢀ6.3,ꢀ1.2ꢀHz,ꢀ1H),ꢀ
ꢀ
reactionꢀ wasꢀ warmedꢀ toꢀ r.t.ꢀ Afterꢀ additionꢀ ofꢀ aꢀ saturatedꢀ 6.29-6.21ꢀ(m,ꢀ1H),ꢀ5.53ꢀ(d,ꢀ Jꢀ=ꢀ9.6ꢀHz,ꢀ1H),ꢀ3.10-3.04ꢀ(m,ꢀ1H),ꢀ
solutionꢀ ofꢀ NH4Cl,ꢀ theꢀ productꢀ wasꢀ extractedꢀ withꢀ CH2Cl2ꢀ 3.00ꢀ(s,ꢀ1H),ꢀ2.37-2.29ꢀ(m,ꢀ1H),ꢀ2.16-2.09ꢀ(m,ꢀ2H),ꢀ1.89-1.81ꢀ(m,ꢀ
(3ꢀtimes)ꢀ andꢀ theꢀ combinedꢀ organicꢀ phasesꢀ wereꢀ driedꢀ overꢀ 1H),ꢀ1.71-1.61ꢀ(m,ꢀ2H),ꢀ1.39-1.27ꢀ(m,ꢀ1H),ꢀ1.22-1.13ꢀ(m,ꢀ1H),ꢀ
MgSO4ꢀandꢀconcentratedꢀunderꢀreducedꢀpressure.ꢀTheꢀcrudeꢀ 1.04-0.95ꢀ(m,ꢀ1H);ꢀ CꢀNMRꢀ(125ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ183.0,ꢀ
mixtureꢀ wasꢀ filtratedꢀ onꢀ aꢀ padꢀ ofꢀ silicaꢀ (CH2Cl2)ꢀ toꢀ giveꢀ theꢀ 170.5,ꢀ148.0,ꢀ138.5,ꢀ135.8,ꢀ128.8,ꢀ51.5,ꢀ38.8,ꢀ37.6,ꢀ34.6,ꢀ25.0,ꢀ
13
1
expectedꢀcompoundꢀasꢀcolourlessꢀoilꢀ(283ꢀmg,ꢀ85%).ꢀ HꢀNMRꢀ 23.8,ꢀ 19.7,ꢀ 18.1;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ C14H15O4ꢀ [M-H] :ꢀ
-
ꢀ
300ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.20ꢀ(dd,ꢀ Jꢀ=ꢀ6.6,ꢀ1.8ꢀHz,ꢀ1H),ꢀ6.20- 247.0970;ꢀfound:ꢀ247.0966.ꢀ
(
ꢀ
.15ꢀ(m,ꢀ1H),ꢀ5.53ꢀ(dd,ꢀ Jꢀ=ꢀ9.9,ꢀ2.1ꢀHz,ꢀ1H),ꢀ3.59ꢀ(s,ꢀ3H),ꢀ3.22-
6
3
2
1
ꢀ Dicarbonylꢀ azideꢀ 16.ꢀ Diphenylphosphorylazideꢀ (345ꢀ mL,ꢀ
.18ꢀ(m,ꢀ1H),ꢀ3.15-3.09ꢀ(m,ꢀ1H),ꢀ2.35-2.31ꢀ(m,ꢀ1H),ꢀ2.26ꢀ(s,ꢀ3H),ꢀ 1.28ꢀmmol,ꢀ2.2ꢀeq)ꢀandꢀEt3Nꢀ(300ꢀmL,ꢀ0.73ꢀmmol,ꢀ3ꢀeq)ꢀwereꢀ
.11-2.05ꢀ(m,ꢀ2H),ꢀ1.87-1.80ꢀ(m,ꢀ2H),ꢀ1.76-1.70ꢀ(m,ꢀ1H),ꢀ1.44- addedꢀ toꢀ compoundꢀ 15ꢀ (180ꢀ mg,ꢀ 0.72ꢀ mmol)ꢀ dissolvedꢀ inꢀ
13
.33ꢀ(m,ꢀ1H),ꢀ1.22-1.14ꢀ(m,ꢀ1H),ꢀ0.95-0.82ꢀ(m,ꢀ1H);ꢀ CꢀNMRꢀ(75ꢀ benzeneꢀ(20ꢀmL).ꢀTheꢀreactionꢀmixtureꢀwasꢀstirredꢀatꢀr.t.ꢀforꢀ2ꢀ
MHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ195.2,ꢀ175.8,ꢀ148.8ꢀ,ꢀ144.3,ꢀ134.7,ꢀ129.2,ꢀ hꢀ beforeꢀ concentrationꢀ underꢀ reducedꢀ pressure.ꢀ Theꢀ residueꢀ
2.3,ꢀ50.9,ꢀ39.4,ꢀ36.3,ꢀ32.9,ꢀ25.3,ꢀ24.7,ꢀ23.7,ꢀ19.6,ꢀ18.8;ꢀHRMSꢀ wasꢀ purifiedꢀ byꢀ columnꢀ chromatographyꢀ onꢀ silicaꢀ gelꢀ usingꢀ
5
+
ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ C16H21O3ꢀ [M+H] :ꢀ 261,1491;ꢀ found:ꢀ heptane/EtOAcꢀ 10:0ꢀ toꢀ 95:5ꢀ toꢀ obtainꢀ theꢀ azideꢀ 16ꢀ asꢀ
(
2
ꢀ
61.1482.ꢀ
colourlessꢀoilꢀ(135ꢀmg,ꢀ62%).ꢀAsꢀthisꢀcompoundꢀwasꢀunstable,ꢀ
ꢀ
1
Carbonylꢀazideꢀ13.ꢀDiphenylphosphorylazideꢀ(92ꢀmL,ꢀ0.43ꢀ itꢀ wasꢀ immediatelyꢀ engagedꢀ inꢀ theꢀ nextꢀ step. Hꢀ NMRꢀ
mmol,ꢀ1.1ꢀeq)ꢀandꢀEt3Nꢀ(81ꢀmL,ꢀ0.58,ꢀ1.5ꢀeq)ꢀwereꢀaddedꢀtoꢀ (300ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.39ꢀ(dd,ꢀJꢀ=ꢀ6.6,ꢀ1.5ꢀHz,ꢀ1H),ꢀ6.31-
ꢀ
compoundꢀ11ꢀ(102ꢀmg,ꢀ0.39ꢀmmol)ꢀdissolvedꢀinꢀbenzeneꢀ(10ꢀ 6.24ꢀ(m,ꢀ1H),ꢀ5.50ꢀ(dd,ꢀ Jꢀ=ꢀ9.6,ꢀ2.4ꢀHz,ꢀ1H),ꢀ3.13-3.11ꢀ(m,ꢀ1H),ꢀ
mL).ꢀ Theꢀ reactionꢀ mixtureꢀ wasꢀ stirredꢀ atꢀ r.t.ꢀ forꢀ 2ꢀ hꢀ beforeꢀ 3.10-3.06ꢀ(m,ꢀ1H),ꢀ2.41-2.37ꢀ(m,ꢀ1H),ꢀ2.15-2.09ꢀ(m,ꢀ2H),ꢀ1.89-
concentrationꢀ underꢀ reducedꢀ pressure.ꢀ Theꢀ residueꢀ wasꢀ 1.83ꢀ(m,ꢀ2H),ꢀ1.76-1.63ꢀ(m,ꢀ1H),ꢀ1.42-1.29ꢀ(m,ꢀ1H),ꢀ1.27-1.18ꢀ
-1
purifiedꢀ byꢀ columnꢀ chromatographyꢀ onꢀ silicaꢀ gelꢀ usingꢀ (m,ꢀ1H),ꢀ1.03-0.93ꢀ(m,ꢀ1H);ꢀIRꢀ(neat):ꢀνꢀ2167ꢀcm ꢀ(N3).ꢀ
heptane/EtOAcꢀ 10:0ꢀ toꢀ 95:5ꢀ toꢀ obtainꢀ theꢀ azideꢀ 13ꢀ asꢀ Keto-lactameꢀ 17.ꢀ Diazideꢀ 16ꢀ (135ꢀ mg,ꢀ 0.45ꢀ mmol)ꢀ wasꢀ
colourlessꢀoilꢀ(100ꢀmg,ꢀ90%).ꢀAsꢀthisꢀcompoundꢀwasꢀunstable,ꢀ refluxedꢀinꢀdryꢀtolueneꢀ(20ꢀmL)ꢀforꢀ1ꢀhꢀbeforeꢀconcentrationꢀ
ꢀ
ꢀ
1
itꢀ wasꢀ immediatelyꢀ engagedꢀ inꢀ theꢀ nextꢀ step. Hꢀ NMRꢀ underꢀ reducedꢀ pressure.ꢀ Theꢀ crudeꢀ mixtureꢀ wasꢀ dissolvedꢀ inꢀ
500ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.37ꢀ(dd,ꢀJꢀ=ꢀ6.5,ꢀ1.5ꢀHz,ꢀ1H),ꢀ6.21- dioxaneꢀ andꢀ 0.5ꢀ mLꢀ ofꢀ 1Mꢀ HClꢀ solutionꢀ wasꢀ added.ꢀ Afterꢀ
(
ꢀ
.15ꢀ(m,ꢀ1H),ꢀ5.53ꢀ(dd,ꢀ Jꢀ=ꢀ9.8,ꢀ2.0ꢀHz,ꢀ1H),ꢀ3.60ꢀ(s,ꢀ3H),ꢀ3.15- additionꢀofꢀaꢀsolutionꢀofꢀNaOHꢀ10%,ꢀtheꢀproductꢀwasꢀextractedꢀ
6
3
.07ꢀ(m,ꢀ2H),ꢀ2.43-2.37ꢀ(m,ꢀ1H),ꢀ2.13-2.02ꢀ(m,ꢀ2H),ꢀ1.89-1.80ꢀ withꢀCH2Cl2ꢀ(3ꢀtimes).ꢀTheꢀcombinedꢀorganicꢀphasesꢀwereꢀdriedꢀ
(
m,ꢀ 2H),ꢀ 1.74-1.66ꢀ (m,ꢀ 1H),ꢀ 1.40-1.31ꢀ (m,ꢀ 1H),ꢀ 1.19-1.11ꢀ (m,ꢀ overꢀ MgSO4ꢀ andꢀ concentratedꢀ underꢀ reducedꢀ pressure.ꢀ Theꢀ
13
1
1
2
H),ꢀ 1.00-0.91ꢀ (m,ꢀ 1H);ꢀ Cꢀ NMRꢀ (125ꢀ MHz,ꢀCDCl3,ꢀ 25ꢀ °C):ꢀ δꢀ residueꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀonꢀsilicaꢀgelꢀ
76.0,ꢀ169.8,ꢀ147.0,ꢀ141.3,ꢀ134.8,ꢀ129.0,ꢀ52.4,ꢀ39.6,ꢀ36.4,ꢀ34.6,ꢀ usingꢀ heptane/EtOAcꢀ 10:0ꢀ toꢀ 7:3ꢀ +ꢀ 1%ꢀ Et3N)ꢀ toꢀ obtainꢀ
-1
5.2,ꢀ23.7,ꢀ20.4,ꢀ19.7,ꢀ18.4;ꢀIRꢀ(neat):ꢀνꢀ2168ꢀcm ꢀ(N3),ꢀ1725ꢀ compoundꢀ17ꢀasꢀaꢀwhiteꢀamorphousꢀsolidꢀ(57ꢀmg,ꢀ58%).ꢀThisꢀ
-1
-1
1
cm ꢀ(CO),ꢀ1683ꢀcm ꢀ(C=C).ꢀ
Ketoesterꢀ 14.ꢀ Monoazideꢀ 13ꢀ (20ꢀ mg,ꢀ 0.07ꢀ mmol)ꢀ wasꢀ (500ꢀMHz,ꢀ DMSO-d6,ꢀ 25ꢀ °C):ꢀ δꢀ 8.03-7.97ꢀ (brs,ꢀ 1H),ꢀ 6.23-6.18ꢀ
compoundꢀwasꢀthenꢀcrystallizedꢀinꢀhotꢀethylꢀacetate.ꢀ HꢀNMRꢀ
ꢀ
refluxedꢀ inꢀ dryꢀ tolueneꢀ forꢀ 1ꢀ hꢀ beforeꢀ concentrationꢀ underꢀ (m,ꢀ1H),ꢀ5.43ꢀ(dd,ꢀ Jꢀ=ꢀ9.9,ꢀ2.7ꢀHz,ꢀ1H),ꢀ2.90ꢀ(d,ꢀ Jꢀ=ꢀ4.2ꢀHz,ꢀ1H),ꢀ
reducedꢀpressure.ꢀTheꢀcrudeꢀmixtureꢀwasꢀdissolvedꢀinꢀdioxaneꢀ 2.57-2.53ꢀ(m,ꢀ1H),ꢀ2.40-2.37ꢀ(m,ꢀ1H),ꢀ2.20-2.06ꢀ(m,ꢀ3H),ꢀ1.99-
ꢀ
ꢀ
13
andꢀaꢀdropꢀofꢀaꢀ1ꢀMꢀHClꢀsolutionꢀwasꢀadded.ꢀTheꢀreactionꢀwasꢀ 1.90ꢀ(m,ꢀ1H),ꢀ1.70ꢀ1.48ꢀ(m,ꢀ4H);ꢀ CꢀNMRꢀ(125ꢀMHz,ꢀDMSO-d6,ꢀ
stirredꢀ atꢀ r.t.ꢀ forꢀ 2ꢀ hꢀ beforeꢀ concentrationꢀ underꢀ reducedꢀ 25ꢀ°C):ꢀδꢀ206.8,ꢀ169.4,ꢀ134.7,ꢀ127.7,ꢀ59.0,ꢀ58.4,ꢀ48.8,ꢀ46.1,ꢀ44.0,ꢀ
-1
pressure.ꢀTheꢀresidueꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀ 25.4,ꢀ 23.0,ꢀ 19.9,ꢀ 14.3;ꢀ IRꢀ (neat):ꢀ νꢀ 1740ꢀ cm ꢀ (CO),ꢀ 1700ꢀ
+
onꢀ silicaꢀ gelꢀ usingꢀ heptane/EtOAcꢀ 10:0ꢀ toꢀ 5:5ꢀ toꢀ obtainꢀ theꢀ (CONH)ꢀ;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ C13H16NO2ꢀ [M+H] :ꢀ
1
ketoneꢀ 14ꢀ asꢀ colourlessꢀ oilꢀ (10ꢀ mg,ꢀ 63%).ꢀ Hꢀ NMRꢀ Hꢀ NMRꢀ 218.1176;ꢀfound:ꢀ218.1177.ꢀ
1
ꢀ
500ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ6.14-6.09ꢀ(m,ꢀ1H),ꢀ5.65ꢀ(d,ꢀ Jꢀ=ꢀ10.0ꢀ
(
Hz,ꢀ 1H),ꢀ 3.68ꢀ (s,ꢀ 3H),ꢀ 2.97-2.92ꢀ (m,ꢀ 1H),ꢀ 2.54-2.50ꢀ (m,ꢀ 1H),ꢀ eq)ꢀwasꢀaddedꢀdropwiseꢀtoꢀaꢀsolutionꢀofꢀcompoundꢀ7ꢀ(200ꢀmg,ꢀ
ꢀ
Diolꢀ18.ꢀAtꢀ0ꢀ°C,ꢀunderꢀArꢀatm.,ꢀDIBALꢀ(3.6ꢀmL,ꢀ3.6ꢀmmol,ꢀ5ꢀ
2
1
.25-2.20ꢀ(m,ꢀ3H),ꢀ2.08-2.00ꢀ(m,ꢀ2H),ꢀ1.96-1.90ꢀ(m,ꢀ2H),ꢀ1.86- 0.72ꢀmmol)ꢀinꢀdryꢀtolueneꢀ(10ꢀmL).ꢀTheꢀmixtureꢀwasꢀstirredꢀatꢀ
ꢀ13
.80ꢀ(m,ꢀ2H),ꢀ1.56-1.49ꢀ(m,ꢀ2H); CꢀNMRꢀ(125ꢀMHz,ꢀCDCl3,ꢀ25ꢀ theꢀ sameꢀ temperatureꢀ forꢀ 1ꢀ h.ꢀ Afterꢀ additionꢀ ofꢀ CH2Cl2,ꢀ theꢀ
°
C):ꢀδꢀ215.2,ꢀ175.4,ꢀ132.5,ꢀ129.4,ꢀ52.5,ꢀ48.6,ꢀ48.5,ꢀ41.4,ꢀ36.4,ꢀ organicꢀphaseꢀwasꢀwashedꢀwithꢀanꢀaqueousꢀsaturatedꢀsolutionꢀ
2.6,ꢀ 24.7,ꢀ 22.5,ꢀ 20.3,ꢀ 17.5;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ ofꢀNaHCO3,ꢀdriedꢀoverꢀMgSO4ꢀandꢀconcentratedꢀunderꢀreducedꢀ
3
+
C14H22NO3ꢀ[M+NH4] :ꢀ252.1600;ꢀfound:ꢀ252.1609.ꢀ
Diacidꢀ 15.ꢀ Sodiumꢀ hydroxideꢀ (116ꢀ mg,ꢀ 2.89ꢀ mmol,ꢀ 4ꢀ eq)ꢀ colourlessꢀoil. HꢀNMRꢀ(500ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ6.23-6.16ꢀ(m,ꢀ
pressure.ꢀ Theꢀ pureꢀ diolꢀ 18ꢀ (126ꢀ mg,ꢀ 79%)ꢀ wasꢀ obtainedꢀ asꢀ
ꢀ
1
ꢀ
ꢀ
wasꢀaddedꢀtoꢀaꢀsolutionꢀofꢀcompoundꢀ7ꢀ(200ꢀmg,ꢀ0.72ꢀmmol)ꢀ 1H),ꢀ6.04ꢀ(dd,ꢀ Jꢀ=ꢀ6.6,ꢀ1.5ꢀHz,ꢀ1H),ꢀ5.52ꢀ(dd,ꢀJꢀ=ꢀ10.0,ꢀ2.1ꢀHz,ꢀ
inꢀaꢀ1:1ꢀmixtureꢀofꢀTHF/waterꢀ(8ꢀmL)ꢀandꢀtheꢀreactionꢀmixtureꢀ 1H),ꢀ4.20ꢀ(d,ꢀJꢀ=ꢀ1.5ꢀHz,ꢀ2H),ꢀ3.16ꢀ(d,ꢀJꢀ=ꢀ2.4ꢀHz,ꢀ2H),ꢀ2.36-2.30ꢀ
wasꢀrefluxedꢀforꢀ2ꢀh.ꢀTheꢀreactionꢀmixtureꢀwasꢀcooledꢀdownꢀ (m,ꢀ 2H,),ꢀ 2.14-2.05ꢀ (m,ꢀ 1H),ꢀ 1.97-1.77ꢀ (m,ꢀ 3H),ꢀ 1.73-1.62ꢀ (m,ꢀ
ꢀ
andꢀ aꢀ 1Mꢀ HClꢀ solutionꢀ (2ꢀ mL)ꢀ wasꢀ added.ꢀ Theꢀ productꢀ wasꢀ 2H),ꢀ1.51-1.39ꢀ(m,ꢀ3H),ꢀ1.18-1.08ꢀ(m,ꢀ1H),ꢀ1.05-0.96ꢀ(m,ꢀ1H);
extractedꢀwithꢀCH2Cl2ꢀ(3ꢀtimes).ꢀTheꢀcombinedꢀorganicꢀphasesꢀ
13
CꢀNMRꢀ(125ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ147.4,ꢀ133.3,ꢀ132.6,ꢀ125.1,ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ5ꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Org aP nl ei ca s &e ꢀ dB oi oꢀ nmo ot ꢀ lae dc j uu ls at ꢀr mCa hr eg imn si sꢀ try
Page 6 of 7
COMMUNICATIONꢀ
JournalꢀNameꢀ
7
2.0,ꢀ63.9,ꢀ44.9,ꢀ38.4,ꢀ37.3,ꢀ37.0,ꢀ26.0,ꢀ23.7,ꢀ21.4,ꢀ20.2;ꢀHRMSꢀ 130.6,ꢀ 129.2ꢀ (2C),ꢀ 126.2,ꢀ 117.8,ꢀ 113.4ꢀ (2C),ꢀ 72.9V,ieꢀw47Ar.t0ic,leꢀ 4O1nl.in6e,ꢀ
DOI: 10.1039/C7OB01236E
+
ESI):ꢀm/zꢀcalcd.ꢀforꢀC16H23NO2ꢀ [M+CH3CN] :ꢀ261.1128;ꢀfound:ꢀ 39.3,ꢀ37.2,ꢀ37.0,ꢀ25.8,ꢀ23.4,ꢀ21.3,ꢀ21.0,ꢀ20.1;ꢀHRMSꢀ(ESI):ꢀm/zꢀ
(
+
2
ꢀ
61.1117.ꢀ
Diacetateꢀ19.ꢀCompoundꢀ18ꢀ(96ꢀmg,ꢀ0.44ꢀmmol)ꢀandꢀDMAPꢀ
calcd.ꢀforꢀC22H28NO2ꢀ[M+H] :ꢀ338.2053;ꢀfound:ꢀ338.2093.ꢀ
Bromolactonesꢀα−ꢀandꢀβ−22.ꢀNBSꢀ(28ꢀmg,ꢀ0.16ꢀmmol,ꢀ2.2ꢀ
ꢀ
(21ꢀ mg,ꢀ 0.17ꢀ mmol,ꢀ 0.4ꢀ eq)ꢀ wereꢀ dissolvedꢀ inꢀ CH2Cl2ꢀ (5ꢀ mL)ꢀ eq),ꢀsuccinimideꢀ(1ꢀmg,ꢀ0.01ꢀmmol,ꢀ0.2ꢀeq)ꢀandꢀpiperidineꢀ(2ꢀ
underꢀArꢀatm..ꢀAceticꢀanhydrideꢀ(124ꢀmL,ꢀ1.30ꢀmmol,ꢀ3ꢀeq)ꢀwasꢀ mL,ꢀ0.01ꢀmmol,ꢀ0.2ꢀeq)ꢀwereꢀaddedꢀtoꢀcompoundꢀ 7ꢀ(20ꢀmg,ꢀ
addedꢀdropwiseꢀandꢀtheꢀreactionꢀmixtureꢀwasꢀstirredꢀatꢀr.t.ꢀforꢀ 0.07ꢀ mmol)ꢀ dissolvedꢀ inꢀ CHCl3ꢀ (300ꢀ mL).ꢀ Theꢀ mixtureꢀ wasꢀ
1
ꢀhꢀbeforeꢀtheꢀadditionꢀofꢀaꢀsaturatedꢀsolutionꢀofꢀNaHCO3.ꢀTheꢀ stirredꢀ forꢀ 17ꢀ hꢀ atꢀ 60ꢀ °C,ꢀ thenꢀ theꢀ solventꢀ wasꢀ removedꢀ inꢀ
organicꢀphaseꢀwasꢀdriedꢀoverꢀMgSO4ꢀandꢀconcentratedꢀunderꢀ vacuo.ꢀTheꢀresidueꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀonꢀ
reducedꢀ pressure.ꢀ Theꢀ pureꢀ diacetateꢀ 19ꢀ (130ꢀ mg,ꢀ 98%)ꢀ wasꢀ silicaꢀ gelꢀ usingꢀ heptane/EtOAcꢀ 10:0ꢀ toꢀ 9:1ꢀ toꢀ obtainꢀ theꢀ
ꢀ
obtainedꢀasꢀcolourlessꢀoil. HꢀNMRꢀ(500ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ lactonesꢀ β−22ꢀ (4ꢀ mg,ꢀ 18%)ꢀ andꢀ α−22ꢀ ꢀ (4ꢀ mg,ꢀ 18%)ꢀ asꢀ
1
6
.10ꢀ(dd,ꢀJꢀ=ꢀ6.3,ꢀ1.2ꢀHz,ꢀ1H),ꢀꢀ6.07-6.01ꢀ(m,ꢀ1H),ꢀ5.56ꢀ(dd,ꢀJꢀ=ꢀ colourlessꢀ oils.ꢀ Compoundꢀ β−22ꢀ couldꢀ beꢀ crystallizedꢀ inꢀ hotꢀ
0.2,ꢀ1.5ꢀHz,ꢀ1H),ꢀ4.62ꢀ(s,ꢀ2H),ꢀ3.76ꢀ(d,ꢀJꢀ=ꢀ10.2ꢀHz,ꢀ1H),ꢀ3.53ꢀ(d,ꢀ EtOAc.ꢀ
1
Jꢀ=ꢀ10.2ꢀHz,ꢀ1H),ꢀ2.47-2.41ꢀ(m,ꢀ1H),ꢀ2.33-2.29ꢀ(m,ꢀ1H),ꢀ2.14-2.09ꢀ
ꢀ
Compoundꢀα−22. HꢀNMRꢀ(300ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.51ꢀ
1
ꢀ
m,ꢀ1H),ꢀ2.08ꢀ(s,ꢀ3H),ꢀ2.02ꢀ(s,ꢀ3H),ꢀ1.97-1.91ꢀ(m,ꢀ1H),ꢀ1.84-1.77ꢀ (dd,ꢀJꢀ=ꢀ6.9,ꢀ1.5ꢀHz,ꢀ1H),ꢀ4.78ꢀ(d,ꢀJꢀ=ꢀ6.0ꢀHz,ꢀ1H),ꢀ4.61ꢀ(s,ꢀ1H),ꢀ
(
(
m,ꢀ 1H),ꢀ 1.75-1.65ꢀ (m,ꢀ 2H),ꢀ 1.48-1.40ꢀ (m,ꢀ 1H),ꢀ 1.35-1.31ꢀ (m,ꢀ 3.76ꢀ(s,ꢀ3H),ꢀ3.10-3.06ꢀ(m,ꢀ1H),ꢀ3.04-3.00ꢀ(m,ꢀ1H),ꢀ2.26-2.11ꢀ(m,ꢀ
ꢀ
1
3
1
MHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ171.1,ꢀ170.9,ꢀ142.4,ꢀ133.0,ꢀ130.7,ꢀ128.5,ꢀ
H),ꢀ 1.15-1.08ꢀ (m,ꢀ 1H),ꢀ 1.05-0.99ꢀ (m,ꢀ 1H);ꢀ Cꢀ NMRꢀ (125ꢀ 1H),ꢀ2.12-2.05ꢀ(m,ꢀ1H),ꢀ1.92-1.63ꢀ(m,ꢀ5H),ꢀ1.28-1.15ꢀ(m,ꢀ2H);
13
CꢀNMRꢀ(75ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ191.0,ꢀ171.2,ꢀ147.8,ꢀ143.9,ꢀ
2.7,ꢀ64.9,ꢀ41.3,ꢀ38.4,ꢀ37.0,ꢀ36.9,ꢀ25.6,ꢀ23.4,ꢀ20.9ꢀ(2ꢀC),ꢀ19.9;ꢀ 82.6,ꢀ54.5,ꢀ51.7,ꢀ44.9,ꢀ34.3,ꢀ33.2,ꢀ29.7,ꢀ28.6,ꢀ21.2,ꢀ19.5,ꢀ16.5;ꢀ
7
+
+
HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ C18H28NO4ꢀ [M+NH4] :322.2018;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ C15H21BrNO4ꢀ [M+NH4] :ꢀ 358.0654;ꢀ
found:ꢀ322.2004.ꢀ found:ꢀ358.0638.ꢀ
Compoundꢀ 20.ꢀ Underꢀ Arꢀ atm.,ꢀ diacetateꢀ 19ꢀ (50ꢀ mg,ꢀ 0.16ꢀ Compoundꢀβ−22.ꢀ HꢀNMRꢀ(300ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.47ꢀ
1
ꢀ
ꢀ
mmol)ꢀ wasꢀ dissolvedꢀ inꢀ dryꢀ THFꢀ (3ꢀ mL).ꢀ (dd,ꢀJꢀ=ꢀ6.9,ꢀ1.8ꢀHz,ꢀ1H),ꢀ4.66ꢀ(t,ꢀJꢀ=ꢀ5.5ꢀHz,ꢀ1H),ꢀ4.35ꢀ(d,ꢀJꢀ=ꢀ5.5ꢀ
Tetrakis(triphenylphosphine)palladiumꢀ (19ꢀ mg,ꢀ 0.016ꢀ mmol,ꢀ Hz,ꢀ 1H),ꢀ 3.68ꢀ (s,ꢀ 3H),ꢀ 2.95-2.93ꢀ (m,ꢀ 1H),ꢀ 2.81-2.77ꢀ (m,ꢀ 1H),ꢀ
0
eq)ꢀwereꢀadded.ꢀAfterꢀ24ꢀhꢀatꢀreflux,ꢀtheꢀcrudeꢀmixtureꢀwasꢀ 1.86ꢀ(m,ꢀ1H),ꢀ1.81-1.75ꢀ(m,ꢀ2H),ꢀ1.57-1.50ꢀ(m,ꢀ2H),ꢀ1.30-1.20ꢀ
.1ꢀeq)ꢀandꢀfreshlyꢀdistilledꢀbenzylamineꢀ(54ꢀmL,ꢀ0.49ꢀmmol,ꢀ3ꢀ 2.60-2.47ꢀ(m,ꢀ1H),ꢀ2.28-2.18ꢀ(m,ꢀ1H),ꢀ2.04-1.97ꢀ(m,ꢀ1H),ꢀ1.96-
®
13
filteredꢀ throughꢀ aꢀ padꢀ ofꢀ Celite ꢀ andꢀ theꢀ solventꢀ wasꢀ (m,ꢀ2H);ꢀ CꢀNMRꢀ(75ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ168.6,ꢀ166.5,ꢀ145.7,ꢀ
concentratedꢀ inꢀ vacuo.ꢀ Theꢀ residueꢀ wasꢀ purifiedꢀ byꢀ columnꢀ 131.3,ꢀ78.3,ꢀ51.8,ꢀ51.7,ꢀ45.7,ꢀ43.3,ꢀ35.1,ꢀ33.6,ꢀ29.7,ꢀ25.6,ꢀ21.6,ꢀ
+
chromatographyꢀonꢀsilicaꢀgelꢀusingꢀheptane/EtOAcꢀ10:0ꢀtoꢀ8:2ꢀ 18.5,ꢀ16.9;ꢀHRMSꢀ(ESI):ꢀm/zꢀcalcd.ꢀforꢀC15H21BrNO4ꢀ [M+NH4] :ꢀ
ꢀ
toꢀobtainꢀcompoundꢀ20ꢀasꢀcolourlessꢀoilꢀ(33ꢀmg,ꢀ56%). HꢀNMRꢀ 358.0654;ꢀfound:ꢀ358.0668.ꢀ
1
ꢀ
300ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.32ꢀ(d,ꢀ Jꢀ=ꢀ4.5ꢀHz,ꢀ4H),ꢀ7.28-7.20ꢀ
(
(
(
ꢀ Epoxydesꢀ α−23ꢀ andꢀ β−23.ꢀ Underꢀ Arꢀ atm.,ꢀ freshlyꢀ
m,ꢀ1H),ꢀ6.07-5.99ꢀ(m,ꢀ1H),ꢀ5.95ꢀ(dd,ꢀJꢀ=ꢀ6.3,ꢀ1.5ꢀHz,ꢀ1H),ꢀ5.57ꢀ preparedꢀ dimethyldioxiraneꢀ (10ꢀ mL,ꢀ 0.72ꢀ mmol,ꢀ 1ꢀ eq)ꢀ inꢀ
ꢀ
dd,ꢀJꢀ=ꢀ10.2,ꢀ1.8ꢀHz,ꢀ1H),ꢀ3.83-3,75ꢀ(m,ꢀ3H),ꢀ3.56ꢀ(d,ꢀ Jꢀ=ꢀ10.2ꢀ acetoneꢀ wasꢀ addedꢀ toꢀ aꢀ solutionꢀ ofꢀ esterꢀ 7ꢀ (200ꢀ mg,ꢀ 0.72ꢀ
Hz,ꢀ1H),ꢀ3.31ꢀ(d,ꢀJꢀ=ꢀ1.5ꢀHz,ꢀ2H),ꢀ2.42-2.35ꢀ(m,ꢀ1H),ꢀ2.34-2.28ꢀ mmol)ꢀinꢀacetoneꢀ(5ꢀmL).ꢀTheꢀreactionꢀmixtureꢀwasꢀstirredꢀatꢀ
m,ꢀ 1H),ꢀ 2.15-2.06ꢀ (m,ꢀ 1H),ꢀ 2.01ꢀ (s,ꢀ 3H),ꢀ 1.89-1.82ꢀ (m,ꢀ 1H),ꢀ r.t.ꢀforꢀ3ꢀhꢀbeforeꢀconcentrationꢀunderꢀreducedꢀpressureꢀ(coldꢀ
(
1
0
1
5
.86-1.61ꢀ(m,ꢀ4H),ꢀ1.51-1.38ꢀ(m,ꢀ1H),ꢀ1.35-1.27ꢀ(m,ꢀ1H),ꢀ1.19- bath)ꢀtoꢀgiveꢀaꢀmixtureꢀ2ꢀisomersꢀα−23/β−23ꢀ(8:2)ꢀwhichꢀwereꢀ
13
.94ꢀ(m,ꢀ2H);ꢀ CꢀNMRꢀ(75ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ171.2,ꢀ146.3,ꢀ separatedꢀ byꢀ columnꢀ chromatographyꢀ onꢀ silicaꢀ gelꢀ usingꢀ
40.3,ꢀ133.3,ꢀ130.5,ꢀ128.3ꢀ(2C),ꢀ128.2ꢀ(2ꢀC),ꢀ126.9,ꢀ125.4,ꢀ73.0,ꢀ heptane/EtOAcꢀ10:0ꢀtoꢀ8:2ꢀtoꢀobtainꢀpureꢀcompoundꢀα−23ꢀ(95ꢀ
3.4,ꢀ51.8,ꢀ41.5,ꢀ39.6,ꢀ37.2,ꢀ36.9,ꢀ25.8,ꢀ23.5,ꢀ21.4,ꢀ21.0,ꢀ20.0;ꢀ mg,ꢀ50%)ꢀandꢀcompoundꢀβ−23ꢀ(34ꢀmg,ꢀ16%ꢀcontainingꢀ20%ꢀofꢀ
+
HRMSꢀ(ESI):ꢀm/zꢀcalcd.ꢀforꢀC23H30NO2ꢀ[M+H] :ꢀ352.2277;ꢀfound:ꢀ anꢀinseparableꢀimpurity)ꢀasꢀcolourlessꢀoils.ꢀ
ꢀ
Compoundꢀα−23. HꢀNMRꢀ(300ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.04ꢀ
1
3
ꢀ
52.2271.ꢀ
ꢀ
Compoundꢀ21.ꢀUnderꢀArꢀatm.,ꢀdiacetateꢀ19ꢀ(128ꢀmg,ꢀ0.42ꢀ (dd,ꢀJꢀ=ꢀ11.0,ꢀ2.5ꢀHz,ꢀ1H),ꢀ3.66ꢀ(s,ꢀ3H),ꢀ3.65ꢀ(s,ꢀ3H),ꢀ3.33-3.32ꢀ
mmol)ꢀ wasꢀ dissolvedꢀ inꢀ dryꢀ THFꢀ (5ꢀ mL).ꢀ Tetrakisꢀ (m,ꢀ1H),ꢀ3.21ꢀ(d,ꢀJꢀ=ꢀ6.5ꢀHz,ꢀ1H),ꢀ3.18-3.15ꢀ(m,ꢀ1H),ꢀ2.97-2.96ꢀ
triphenylphosphine)palladiumꢀ(49ꢀmg,ꢀ0.04ꢀmmol,ꢀ0.1ꢀeq)ꢀandꢀ (m,ꢀ 1H),ꢀ 2.11-2.09ꢀ (m,ꢀ 1H),ꢀ 2.00-1.98ꢀ (m,ꢀ 1H),ꢀ 1.97-1.95ꢀ (m,ꢀ
(
freshlyꢀdistilledꢀanilineꢀ(57ꢀmL,ꢀ1.02ꢀmmol,ꢀ1.5ꢀeq)ꢀwereꢀaddedꢀ 1H),ꢀ1.81-1.79ꢀ(m,ꢀ1H),ꢀ1.43-1.37ꢀ(m,ꢀ2H),ꢀ1.19-1.05ꢀ(m,ꢀ3H);
ꢀ
13
andꢀtheꢀmixtureꢀwasꢀrefluxedꢀforꢀ12ꢀh.ꢀTheꢀcrudeꢀmixtureꢀwasꢀ
®
CꢀNMRꢀ(75ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ174.8,ꢀ164.6,ꢀ141.6,ꢀ141.1,ꢀ
filteredꢀ throughꢀ aꢀ padꢀ ofꢀ Celite ꢀ andꢀ theꢀ solventꢀ wasꢀ 56.1,ꢀ52.6,ꢀ51.5,ꢀ46.2,ꢀ39.0,ꢀ37.9,ꢀ31.6,ꢀ21.7,ꢀ21.7,ꢀ20.2,ꢀ20.0,ꢀ
+
concentratedꢀ inꢀ vacuo.ꢀ Theꢀ residueꢀ wasꢀ purifiedꢀ byꢀ columnꢀ 19.6;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ C16H21O5ꢀ [M+H] :ꢀ 293.1389;ꢀ
chromatographyꢀonꢀsilicaꢀgelꢀusingꢀheptane/EtOAcꢀ10:0ꢀtoꢀ9:1ꢀ found:ꢀ293.1379.ꢀ
1
toꢀobtainꢀcompoundꢀ21ꢀasꢀcolourlessꢀoilꢀ(50ꢀmg,ꢀ35%).ꢀ HꢀNMRꢀ
1
Compoundꢀβ−23.ꢀ HꢀNMRꢀ(300ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.25ꢀ
ꢀ
300ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.18ꢀ(t,ꢀ Jꢀ=ꢀ7.5ꢀHz,ꢀ2H),ꢀ6.73ꢀ(t,ꢀ Jꢀ=ꢀ (dd,ꢀ Jꢀ=ꢀ10.5,ꢀ2.5ꢀHz,ꢀ1H),ꢀ3.70ꢀ(s,ꢀ3H),ꢀ3.65ꢀ(s,ꢀ3H),ꢀ3.27-3.23ꢀ
ꢀ
ꢀ
ꢀ
(
ꢀ
.5ꢀHz,ꢀ1H),ꢀ6.68ꢀ(d,ꢀ Jꢀ=ꢀ7.5ꢀHz,ꢀ2H),ꢀ6.04-6.01ꢀ(m,ꢀ2H),ꢀ5.56ꢀ (m,ꢀ 1H),ꢀ 3.18-3.13ꢀ (m,ꢀ 1H),ꢀ 3.11-3.08ꢀ (m,ꢀ 1H),ꢀ 2.85-2.83ꢀ (m,ꢀ
7
ꢀ
ꢀ
dd,ꢀ Jꢀ=ꢀ10.0,ꢀ1.5ꢀHz,ꢀ1H),ꢀ3.85ꢀ(dd,ꢀ Jꢀ=ꢀ10.0,ꢀ1.8ꢀHz,ꢀ2H),ꢀ3.75ꢀ 1H),ꢀ2.25-2.15ꢀ(m,ꢀ1H),ꢀ2.05-2.02ꢀ(m,ꢀ1H),ꢀ1.98-1.97ꢀ(m,ꢀ1H),ꢀ
(
ꢀ
d,ꢀ Jꢀ=ꢀ0.2ꢀHz,ꢀ1H),ꢀ3.57ꢀ(d,ꢀ Jꢀ=ꢀ10.2ꢀHz,ꢀ1H),ꢀ2.42-2.39ꢀ(m,ꢀ1H),ꢀ 1.94-1.93ꢀ(m,ꢀ1H),ꢀ1.76-1.70ꢀ(m,ꢀ1H),ꢀ1.42-1.37ꢀ(m,ꢀ1H),ꢀ1.17-
ꢀ
(
13
2
1
.35-2.34ꢀ(m,ꢀ1H),ꢀ2.09-2.05ꢀ(m,ꢀ2H),ꢀ2.02ꢀ(s,ꢀ3H),ꢀ1.82-1.78ꢀ(m,ꢀ 1.09ꢀ(m,ꢀ1H),ꢀ1.05-1.00ꢀ(m,ꢀ1H);ꢀ CꢀNMRꢀ(75ꢀMHz,ꢀCDCl3,ꢀ25ꢀ
H),ꢀ1.74-1.66ꢀ(m,ꢀ2H),ꢀ1.34-1.27ꢀ(m,ꢀ2H),ꢀ1.16-1.00ꢀ(m,ꢀ2H);ꢀ °C):ꢀδꢀ175.4,ꢀ165.1,ꢀ144.1,ꢀ139.3,ꢀ56.0,ꢀ52.5,ꢀ51.4,ꢀ50.8,ꢀ49.3,ꢀ
CꢀNMRꢀ(75ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ171.2,ꢀ147.8,ꢀ144.8,ꢀ133.2,ꢀ
13
6
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Page 7 of 7
Org aP nl ei ca s &e ꢀ dB oi oꢀ nmo ot ꢀ lae dc j uu ls at ꢀr mCa hr eg imn si sꢀ try
JournalꢀNameꢀ
8.9,ꢀ36.5,ꢀ34.2,ꢀ22.2,ꢀ19.8,ꢀ18.9,ꢀ18.2;ꢀHRMSꢀ(ESI):ꢀm/zꢀcalcd.ꢀ
ꢀCOMMUNICATIONꢀ
5
6
C.ꢀLipinski,ꢀA.ꢀHopkins,ꢀNature,ꢀ2004,ꢀ432,ꢀ855-861.ꢀ
D.ꢀJ.ꢀPayne,ꢀM.ꢀN.ꢀGwynn,ꢀD.ꢀJ.ꢀHolmes,ꢀD.ꢀL.ꢀPompliano,ꢀNat.ꢀ
3
View Article Online
DOI: 10.1039/C7OB01236E
+
forꢀC16H21O5ꢀ[M+H] :ꢀ293.1389;ꢀfound:ꢀ293.1379.ꢀ
Diolꢀ 24ꢀ andꢀ lactoneꢀ 25.ꢀ AlCl3ꢀ (182ꢀ mg,ꢀ 1.37ꢀ mmol,ꢀ 4ꢀ eq)ꢀ
Rev.ꢀDrugꢀDiscov.,ꢀ2007,ꢀ6,ꢀ29-40.ꢀ
X.ꢀZhang,ꢀS.ꢀBetzi,ꢀX.ꢀMorelli,ꢀP.ꢀRoche,ꢀFutureꢀMed.ꢀChem.,ꢀ
ꢀ
7
8
9
wasꢀadded,ꢀunderꢀArꢀatm.,ꢀtoꢀaꢀsolutionꢀofꢀcompoundꢀα−23ꢀ
100ꢀ mg,ꢀ 0.34ꢀ mmol)ꢀ inꢀ anhydrousꢀ THFꢀ (10ꢀ mL)ꢀ andꢀ theꢀ
2
014,ꢀ6,ꢀ1291-1307.ꢀ
S.ꢀ Dandapani,ꢀ L.ꢀ A.ꢀ Marcaurelle,ꢀ Nat.ꢀ Chem.ꢀ Biol.,ꢀ 2010,ꢀ 6,ꢀ
61-863.ꢀ
(a)ꢀF.ꢀLovering,ꢀJ.ꢀBikker,ꢀC.ꢀHumblet,ꢀ J.ꢀMed.ꢀChem.,ꢀ2009,ꢀ
2,ꢀ6752-6756;ꢀ(b)ꢀW.ꢀH.ꢀB.ꢀSauer,ꢀM.ꢀK.ꢀSchwarz,ꢀJ.ꢀChem.ꢀ
(
8
mixtureꢀwasꢀstirredꢀforꢀ48ꢀhꢀatꢀ60ꢀ°C.ꢀWaterꢀwasꢀthenꢀaddedꢀ
andꢀ theꢀ productꢀ wasꢀ extractedꢀ withꢀ CH2Cl2ꢀ (3ꢀtimes).ꢀ Theꢀ
combinedꢀ organicꢀ phasesꢀ wereꢀ driedꢀ overꢀ MgSO4ꢀ andꢀ
concentratedꢀ underꢀ reducedꢀ pressure.ꢀ Theꢀ residueꢀ wasꢀ
purifiedꢀ byꢀ columnꢀ chromatographyꢀ onꢀ silicaꢀ gelꢀ usingꢀ
heptane/EtOAcꢀ8:2ꢀtoꢀ0:10ꢀtoꢀobtain,ꢀasꢀcolourlessꢀoils,ꢀpureꢀ
lactoneꢀ 25ꢀ (54ꢀ mg,ꢀ 57%)ꢀ andꢀ diolꢀ 24ꢀ (47ꢀ mg,ꢀ 44%)ꢀ thatꢀ
spontaneouslyꢀlactonizedꢀinꢀfewꢀhoursꢀinꢀlactoneꢀ26.ꢀLactoneꢀ
5
Inf.ꢀComput.ꢀSci.,ꢀ2003,ꢀ43,ꢀ987-1003.ꢀ
1
0 (a)ꢀS.ꢀL.ꢀSchreiber,ꢀScience,ꢀ2000,ꢀ287,ꢀ1964-1969;ꢀ(b)ꢀD.ꢀR.ꢀ
Spring,ꢀ Org.ꢀ Biomol.ꢀ Chem.,ꢀ 2003,ꢀ 1,ꢀ 3867-3870;ꢀ (c)ꢀ M.ꢀ K.ꢀ
Dow,ꢀ M.ꢀ Fisher,ꢀ T.ꢀ James,ꢀ F.ꢀ Marchetti,ꢀ A.ꢀ Nelson,ꢀ Org.ꢀ
Biomol.ꢀChem.,ꢀ2012,ꢀ10,ꢀ17-28;ꢀ(d)ꢀA.ꢀW.ꢀHung,ꢀA.ꢀRamek,ꢀY.ꢀ
Wang,ꢀT.ꢀKaya,ꢀJ.ꢀA.ꢀWilson,ꢀP.ꢀA.ꢀClemons,ꢀD.ꢀW.ꢀYoung,ꢀProc.ꢀ
Natl.ꢀAcad.ꢀSci.,ꢀ2011,ꢀ108,ꢀ6799-6804;ꢀ(e)ꢀM.ꢀC.ꢀMcLeod,ꢀG.ꢀ
Singh,ꢀ J.ꢀ N.ꢀ Plampinꢀ III,ꢀ D.ꢀ Rane,ꢀ J.ꢀ L.ꢀ Wang,ꢀ V.ꢀ W.ꢀ Day,ꢀ J.ꢀ
Aubé,ꢀ Nat.ꢀ Chem.,ꢀ 2014,ꢀ 6,ꢀ 133-140;ꢀ (f)ꢀ R.ꢀ G.ꢀ Doveston,ꢀ P.ꢀ
Tosatti,ꢀM.ꢀDow,ꢀD.ꢀJ.ꢀFoley,ꢀH.ꢀY.ꢀLi,ꢀA.ꢀJ.ꢀCampbell,ꢀD.ꢀHouse,ꢀ
I.ꢀ Churcher,ꢀ S.ꢀ P.ꢀ Marsden,ꢀ A.ꢀ Nelson,ꢀ Org.ꢀ Biomol.ꢀ Chem.,ꢀ
2
ꢀ
5ꢀwasꢀrecrystallizedꢀinꢀhotꢀEtOAc.ꢀ
1
ꢀ
Diolꢀ24.ꢀ HꢀNMRꢀ(300ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.29ꢀ(dd,ꢀ Jꢀ=ꢀ
.6,ꢀ1.5ꢀHz,ꢀ1H),ꢀ4.07ꢀ(t,ꢀJꢀ=ꢀ10.0ꢀHz,ꢀ1H),ꢀ3.93ꢀ(d,ꢀJꢀ=ꢀ10.0ꢀHz,ꢀ
H),ꢀ3.73ꢀ(s,ꢀ3H),ꢀ3.66ꢀ(s,ꢀ3H),ꢀ3.44-3.32ꢀ(m,ꢀ2H),ꢀ2.97ꢀ(brs,ꢀ1H),ꢀ
.66ꢀ (brs,ꢀ 2ꢀ OH),ꢀ 2.44-2.32ꢀ (m,ꢀ 1H),ꢀ 2.19-2.06ꢀ (m,ꢀ 2H),ꢀ 1.95-
.71ꢀ(m,ꢀ2H),ꢀ1.64-1.57ꢀ(m,ꢀ2H),ꢀ1.49-1.39ꢀ(m,ꢀ1H),ꢀ1.22-1.08ꢀ
6
1
2
1
2
015,ꢀ13,ꢀ859-865;ꢀ(g)ꢀJ.ꢀD.ꢀFirth,ꢀP.ꢀG.ꢀE.ꢀCraven,ꢀM.ꢀLilburn,ꢀ
A.ꢀPahl,ꢀS.ꢀP.ꢀMarsden,ꢀA.ꢀNelson,ꢀChem.ꢀCommun.,ꢀ2016,ꢀ52,ꢀ
837-9840.ꢀ
9
13
(
m,ꢀ 1H);ꢀ Cꢀ NMRꢀ (75ꢀ MHz,ꢀCDCl3,ꢀ 25ꢀ °C):ꢀ δꢀ ꢀ 175.7,ꢀ 165.1,ꢀ 11 (a)ꢀ K.ꢀ Alderꢀ andꢀ G.ꢀ Stein,ꢀ Justusꢀ Liebigsꢀ Ann.ꢀ Chem.,ꢀ 1932,ꢀ
4
96,ꢀ 197-203;ꢀ (b)ꢀ D.ꢀ Valentine,ꢀ N.ꢀ J.ꢀ Turroꢀ Jr.,ꢀ G.ꢀ S.ꢀ
1
2
3
ꢀ
44.7,ꢀ138.5,ꢀ74.9,ꢀ63.5,ꢀ52.5,ꢀ51.6,ꢀ42.1,ꢀ35.0,ꢀ33.7,ꢀ32.6,ꢀ26.4,ꢀ
+
0.4,ꢀ 19.5,ꢀ 17.6;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ C16H23O6ꢀ [M+H] :ꢀ
Hammond,ꢀJ.ꢀAm.ꢀChem.ꢀSoc.,ꢀ1964,ꢀ86,ꢀ5202-5208.ꢀ
2 F.-G.ꢀKlärner,ꢀB.ꢀM.ꢀJ.ꢀDogan,ꢀO.ꢀErmer,ꢀW.ꢀvonꢀE.ꢀDoering,ꢀM.ꢀ
P.ꢀCohen,ꢀAngew.ꢀChem.ꢀInt.ꢀEd.,ꢀ1986,ꢀ25,ꢀ108-110.ꢀ
3 D.ꢀ H.ꢀ Ess,ꢀ A.ꢀ E.ꢀ Hayden,ꢀ F.ꢀ -G.ꢀ Klärner,ꢀ K.ꢀ N.ꢀ Houk,ꢀ J.ꢀ Org.ꢀ
Chem.,ꢀ2008,ꢀ73,ꢀ7586-7592.ꢀ
4 (a)ꢀD.ꢀValentine,ꢀN.ꢀJ.ꢀTurroꢀJr.,ꢀG.ꢀS.ꢀHammond,ꢀJ.ꢀAm.ꢀChem.ꢀ
Soc.,ꢀ1964,ꢀ86,ꢀ5202-5208;ꢀ(b)ꢀD.ꢀJ.ꢀBellville,ꢀD.ꢀD.ꢀWirth,ꢀN.ꢀL.ꢀ
Baud,ꢀ ibid,ꢀ 1981,ꢀ 103,ꢀ 718-720;ꢀ (c)ꢀ S.ꢀ E.ꢀ Nigenda,ꢀ D.ꢀ M.ꢀ
Schleich,ꢀ S.ꢀ C.ꢀ Narang,ꢀ T.ꢀ Keumi,ꢀ J.ꢀ Electrochem.ꢀ Soc:ꢀ
Electrochem.ꢀSci.ꢀTech.,ꢀ1987,ꢀ134,ꢀ2465-2470.ꢀ
1
1
1
11,1489;ꢀfound:ꢀ311.1499.ꢀ
ꢀ
Lactoneꢀ25. HꢀNMRꢀ(300ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.53ꢀ(dd,ꢀJꢀ=ꢀ
1
ꢀ
.9,ꢀ1.5ꢀHz,ꢀ1H),ꢀ4.55ꢀ(d,ꢀ Jꢀ=ꢀ6.0ꢀHz,ꢀ1H),ꢀ4.38ꢀ(s,ꢀ1H),ꢀ3.75ꢀ(s,ꢀ
6
3
2
1
1
1
2
ꢀ
H),ꢀ3.06-3.00ꢀ(m,ꢀ1H),ꢀ2.99-2.96ꢀ(m,ꢀ1H),ꢀ2.25-2.15ꢀ(m,ꢀ1H),ꢀ
.04-1.92ꢀ(m,ꢀ1H),ꢀ1.83-1.72ꢀ(m,ꢀ3H),ꢀ1.66-1.57ꢀ(m,ꢀ2H),ꢀ1.30-
13
.21ꢀ(m,ꢀ2H);ꢀ CꢀNMRꢀ(75ꢀMHz,ꢀCDCl3,ꢀ25ꢀ°C):ꢀδꢀ17.ꢀ90,ꢀ165.1,ꢀ
44.5,ꢀ137.9,ꢀ82.3,ꢀ73.4,ꢀ51.6,ꢀ51.0,ꢀ43.7,ꢀ33.8,ꢀ30.1,ꢀ27.6,ꢀ22.1,ꢀ
+
9.5,ꢀ 16.8;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ C15H22NO5ꢀ [M+NH4] :ꢀ 15 (a)ꢀ J.ꢀ Gagnepain,ꢀ R.ꢀ Méreau,ꢀ D.ꢀ Dejugnac,ꢀ J.ꢀ -M.ꢀ Léger,ꢀ F.ꢀ
Castet,ꢀ D.ꢀ Deffieux,ꢀ L.ꢀ Pouységu,ꢀ S.ꢀ Quideau,ꢀ Tetrahedron,ꢀ
007,ꢀ63,ꢀ6493-6505;ꢀ(b)ꢀJ.ꢀGagnepain,ꢀF.ꢀCastet,ꢀS.ꢀQuideau,ꢀ
Angew.ꢀChem.ꢀInt.ꢀEd.,ꢀ2007,ꢀ46,ꢀ1533-1535.ꢀ
96.1498;ꢀfound:ꢀ296.1496.ꢀ
Lactoneꢀ 26.ꢀ AlCl3ꢀ (159ꢀ mg,ꢀ 1.19ꢀ mmol,ꢀ 4ꢀ eq)ꢀ wasꢀ added,ꢀ
2
underꢀArꢀatm.,ꢀtoꢀaꢀsolutionꢀofꢀcompoundꢀβ−23ꢀ(87ꢀmg,ꢀ0.30ꢀ
mmol)ꢀinꢀanhydrousꢀTHFꢀ(10ꢀmL)ꢀandꢀtheꢀmixtureꢀwasꢀstirredꢀ
1
6 D.ꢀL.ꢀBoger,ꢀM.ꢀPatel,ꢀF.ꢀTakusagawa,ꢀJ.ꢀOrg.ꢀChem.,ꢀ1985,ꢀ50,ꢀ
911-1916.ꢀ
1
forꢀ12ꢀhꢀatꢀ60ꢀ°C.ꢀWaterꢀwasꢀthenꢀaddedꢀandꢀtheꢀproductꢀwasꢀ 17 J.ꢀ Dardenne,ꢀ S.ꢀ Desrat,ꢀ F.ꢀ Guéritte,ꢀ F.ꢀ Roussi,ꢀ Eur.ꢀ J.ꢀ Org.ꢀ
Chem.,ꢀ2013,ꢀ2116-2122.ꢀ
8 H.ꢀD.ꢀZook,ꢀM.ꢀReam,ꢀE.ꢀW.ꢀDelchamps,ꢀJ.ꢀAm.ꢀChem.ꢀSoc.,ꢀ
extractedꢀwithꢀCH2Cl2ꢀ(3ꢀtimes).ꢀTheꢀcombinedꢀorganicꢀphasesꢀ
wereꢀ driedꢀ overꢀ MgSO4ꢀ andꢀ concentratedꢀ underꢀ reducedꢀ
pressure.ꢀTheꢀresidueꢀwasꢀpurifiedꢀbyꢀcolumnꢀchromatographyꢀ
onꢀ silicaꢀ gelꢀ usingꢀ heptane/EtOAcꢀ 10:0ꢀ toꢀ 5:5ꢀ toꢀ obtainꢀ pureꢀ
1
1
1
953,ꢀ75,ꢀ5590-5591.ꢀ
9 Forꢀ someꢀ examplesꢀ ofꢀ additionꢀ ofꢀ enaminesꢀ toꢀ isocyantesꢀ
see:ꢀ(a)ꢀJ.ꢀH.ꢀRigby,ꢀN.ꢀBalasubramanian,ꢀJ.ꢀOrg.ꢀChem.,ꢀ1989,ꢀ
54,ꢀ 224-228;ꢀ (b)ꢀ F.ꢀ Palacios,ꢀ D.ꢀ Aparicio,ꢀ J.ꢀ Garcia,ꢀ
Tetrahedron,ꢀ 1997,ꢀ 53,ꢀ 2931-2940;ꢀ (c)ꢀ F.ꢀ Palacios,ꢀ A.ꢀ M.ꢀ
OchoaꢀdeꢀRetana,ꢀJ.ꢀOyarzabal,ꢀTetrahedron,ꢀ1999,ꢀ55,ꢀ5947-
1
lactoneꢀ26ꢀ(34ꢀmg,ꢀ40%)ꢀasꢀcolourlessꢀoil.ꢀ HꢀNMRꢀ(300ꢀMHz,ꢀ
ꢀ
ꢀ
CDCl3,ꢀ25ꢀ°C):ꢀδꢀ7.53ꢀ(dd,ꢀ Jꢀ=ꢀ6.9,ꢀ1.5ꢀHz,ꢀ1H),ꢀ4.55ꢀ(t,ꢀ Jꢀ=ꢀ5.4ꢀHz,ꢀ
1
2
1
H),ꢀ4.45ꢀ(d,ꢀJꢀ=ꢀ5.4ꢀHz,ꢀ1H),ꢀ3.74ꢀ(s,ꢀ3H),ꢀ 3.00-2.75ꢀ(m,ꢀ 3H),ꢀ
.38-2.26ꢀ(m,ꢀ1H),ꢀ2.24-2.06ꢀ(m,ꢀ2H),ꢀ1.97-1.84ꢀ(m,ꢀ2H),ꢀ1.76-
5964.ꢀ
0 W.ꢀL.ꢀF.ꢀAmarego,ꢀC.ꢀL.ꢀL.ꢀChaiꢀinꢀPurificationꢀofꢀLaboratoryꢀ
2
13
th
Chemicals,ꢀ7 ꢀEd.,ꢀButterworth-Heinemann,ꢀElsevier,ꢀOxford,ꢀ
2013.ꢀ
.50ꢀ(m,ꢀ2H),ꢀ1.28-1.01ꢀ(m,ꢀ2H);ꢀ CꢀNMRꢀ(75ꢀMHz,ꢀCDCl3,ꢀ25ꢀ
°
C):ꢀδꢀ177.9,ꢀ165.5,ꢀ145.8,ꢀ137.8,ꢀ77.3,ꢀ73.6,ꢀ51.6,ꢀ48.1,ꢀ42.9,ꢀ
5.0,ꢀ 34.1,ꢀ 25.5,ꢀ 21.8,ꢀ 20.1,ꢀ 17.0;ꢀ HRMSꢀ (ESI):ꢀ m/zꢀ calcd.ꢀ forꢀ
3
+
C15H22NO5ꢀ[M+NH4] :ꢀ296.1498;ꢀfound:ꢀ296.1509.ꢀ
Notesꢀandꢀreferencesꢀ
1
W.ꢀ R.ꢀ J.ꢀ D.ꢀ Galloway,ꢀ A.ꢀ Isidro-Llobet,ꢀ D.ꢀ R.ꢀ Spring,ꢀ Nat.ꢀ
Commun.,ꢀ2010,ꢀ1:80,ꢀ1-13.ꢀ
2
W.ꢀP.ꢀWalters,ꢀJ.ꢀGreen,ꢀJ.ꢀR.ꢀWeiss,ꢀM.ꢀA.ꢀMurcko,ꢀJ.ꢀMed.ꢀ
Chem.,ꢀ2011,ꢀ54,ꢀ6405-6416.ꢀ
3
4
J.-L.ꢀReymond,ꢀAcc.ꢀChem.ꢀRes.,ꢀ2015,ꢀ48,ꢀ722-730.ꢀ
A.ꢀH.ꢀLipkus,ꢀQ.ꢀYuan,ꢀK.ꢀA.ꢀLucas,ꢀS.ꢀA.ꢀFunk,ꢀW.ꢀF.ꢀBarteltꢀIII,ꢀ
R.ꢀ J.ꢀ Schenck,ꢀ A.ꢀ J.ꢀ Trippe,ꢀ J.ꢀ Org.ꢀ Chem.,ꢀ 2008,ꢀ 73,ꢀ 4443-
4
451.ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ7ꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ