Easy access to constrained peptidomimetics and 2,2-disubstituted azetidines by the unexpected reactivity profile of α-lithiated N-Boc-azetidines

Article abstract of DOI:10.1039/c5cc06323j

The reactivity profile of lithiated N-Boc-2-arylazetidines has been investigated filling a gap in the chemistry of this class of four-membered heterocycles. Two unexpected and unprecedented results have been observed: an "ortho-effect" accounting for the regioselective functionalization of the azetidine ring, and self-condensation leading to new and interesting azetidine-based peptidomimetics.

Full text of DOI:10.1039/c5cc06323j

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Capitanelli, A. Pierro, G. Romanazzi, G. J. Clarkson, L. Degennaro and R. LUISI, Chem. Commun., 2015,
DOI: 10.1039/C5CC06323J.
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Page 1 of 5
Pleaseꢀd Co hꢀ ne omt ꢀ Ca do j mu smt ꢀmarginsꢀ
View Article Online
DOI: 10.1039/C5CC06323J
JournalꢀNameꢀ
COMMUNICATIONꢀ
ꢀ
Easyꢀaccessꢀtoꢀconstrainedꢀpeptidomimeticsꢀandꢀ2,2-disubstitutedꢀ
azetidinesꢀ byꢀ unexpectedꢀ reactivityꢀ profileꢀ ofꢀ α-lithiatedꢀ N-Boc-
azetidinesꢀꢀ
Receivedꢀ00thꢀJanuaryꢀ20xx,ꢀ
Acceptedꢀ00thꢀJanuaryꢀ20xxꢀ
a
a
a
b
c
DOI:ꢀ10.1039/x0xx00000xꢀ
GiovannaꢀParisi, ꢀEmanuelaꢀCapitanelli, ꢀAntonellaꢀPierro, ꢀGiuseppeꢀRomanazzi, ꢀGuyꢀJ.ꢀClarkson ꢀ
ꢀ
a
a
LeonardoꢀDegennaro,* ꢀandꢀRenzoꢀLuisi* ꢀ
www.rsc.org/ꢀ
TheꢀreactivityꢀprofileꢀofꢀlithiatedꢀN-Boc-2-arylazetidinesꢀhasꢀbeenꢀ azetidines,ꢀ aꢀ switchꢀ inꢀ regioselectivityꢀ isꢀ observedꢀ andꢀ α-
investigatedꢀ fillingꢀ aꢀ gapꢀ inꢀ theꢀ chemistryꢀ ofꢀ thisꢀ kindꢀ ofꢀ four- lithiationꢀ occurs.ꢀ Nevertheless,ꢀ inꢀ aꢀ preliminaryꢀ investigationꢀ
memberedꢀ heterocycles.ꢀ Twoꢀ unexpectedꢀ andꢀ unprecedentedꢀ weꢀfoundꢀthatꢀN-Boc-2-phenylazetidineꢀcouldꢀbeꢀlithiatedꢀandꢀ
resultsꢀ haveꢀ beenꢀ observed:ꢀ anꢀ “ortho-effect”ꢀ accountingꢀ forꢀ aꢀ trappedꢀ atꢀ theꢀ α-positionꢀ withꢀ lowꢀ yieldsꢀ andꢀ onlyꢀ underꢀ
7
regioselectiveꢀ functionalizationꢀ ofꢀ theꢀ azetidineꢀ ring,ꢀ andꢀ aꢀ self- internalꢀquenchingꢀconditions. ꢀRecently,ꢀHodgsonꢀreportedꢀonꢀ
condensationꢀ leadingꢀ toꢀ newꢀ andꢀ interestingꢀ azetidine-basedꢀ theꢀ elegantꢀ useꢀ ofꢀ otherꢀ N-activatingꢀ groupsꢀ suchꢀ asꢀ N-tert-
peptidomimetics.ꢀꢀ
butoxythiocarbonylꢀ(Botc)ꢀandꢀN-thiopivaloylꢀforꢀsuccessfulꢀα-
8
lithiation/trappingꢀ ofꢀ unsubstitutedꢀ azetidines. ꢀ Inꢀ suchꢀ
Saturatedꢀ nitrogen-bearingꢀ heterocyclesꢀ areꢀ anꢀ importantꢀ
classꢀ ofꢀ compoundsꢀ withꢀ widespreadꢀ diffusionꢀ inꢀ severalꢀ
naturalꢀ products,ꢀ marketedꢀ drugsꢀ andꢀ bioactiveꢀ molecules.ꢀ
Withꢀanꢀeyeꢀonꢀfour-memberedꢀheterocycles,ꢀazetidinesꢀhaveꢀ
receivedꢀmuchꢀlessꢀattentionꢀwithꢀrespectꢀtoꢀhigherꢀandꢀlowerꢀ
reports,ꢀ emergedꢀ theꢀ factꢀ thatꢀ theꢀ readilyꢀ installedꢀ tert-
butoxycarbonylꢀ (Boc)ꢀ groupꢀ isꢀ unsuitableꢀ forꢀ effectiveꢀ
lithiation/trappingꢀ sequencesꢀ onꢀ unsubstitutedꢀ azetidine,ꢀ
2
whileꢀ itꢀ isꢀ theꢀ groupꢀ ofꢀ choiceꢀ inꢀ theꢀ Csp -α-lithiationꢀ ofꢀ
ꢀ9
azetines. ꢀ
1
N-bearingꢀ homologues. ꢀ Theꢀ chemistryꢀ ofꢀ thisꢀ kindꢀ ofꢀ
heterocycleꢀisꢀemergingꢀasꢀanꢀactiveꢀresearchꢀarea,ꢀbecauseꢀofꢀ
theꢀ importanceꢀ ofꢀ azetidinesꢀ inꢀ catalysis,ꢀ stereoselectiveꢀ
2
synthesisꢀ andꢀ medicinalꢀ chemistry. ꢀ Recentꢀ examplesꢀ are,ꢀ
Inꢀ Schemeꢀ 1ꢀ areꢀ collectedꢀ theꢀ observedꢀ reactivities,ꢀ towardsꢀ
lithiatingꢀagents,ꢀofꢀlowerꢀandꢀhigherꢀhomologuesꢀN-Boc-2-arylꢀ
heterocyclesꢀ (aziridines,ꢀ pyrrolidinesꢀ andꢀ piperidines).ꢀ Inꢀ allꢀ
cases,ꢀtheꢀN-Bocꢀgroupꢀactsꢀasꢀactivatingꢀgroupꢀallowingꢀforꢀα-
lithiation.ꢀ Nevertheless,ꢀ aziridinesꢀ undergoꢀ aꢀ fastꢀ N-Cꢀ
amongꢀ others,ꢀ entriesꢀ toꢀ chiralꢀ highlyꢀ functionalizedꢀ
azetidines,ꢀringꢀopeningꢀreactionsꢀandꢀsynthesisꢀofꢀaminoꢀacidsꢀ
3
incorporatingꢀ theꢀ azetidineꢀ nucleus. ꢀ Owingꢀ toꢀ structuralꢀ
10
migration ꢀwhileꢀα-lithiatedꢀpyrrolidinesꢀandꢀpiperidinesꢀcanꢀ
11
beꢀeffectivelyꢀfunctionalized. ꢀ
ꢀ
rigidityꢀbroughtꢀbyꢀthisꢀheterocycle,ꢀandꢀtheꢀcapacityꢀtoꢀalterꢀ
4
pharmacologicalꢀproperties, ꢀitꢀisꢀnotꢀsurprisingꢀthatꢀsomeꢀofꢀ
theꢀ recentlyꢀ marketedꢀ drugsꢀ (Azelnidipine,ꢀ Melagatran,ꢀ
5
Exanta)ꢀ containꢀ theꢀ azetidineꢀ ring. ꢀ Ourꢀ interestꢀ inꢀ theꢀ
developmentꢀ ofꢀ aꢀ divergentꢀ synthesisꢀ ofꢀ functionalizedꢀ
azetidines,ꢀ byꢀ lithiation/electrophileꢀ trappingꢀ sequence,ꢀ
promptedꢀ usꢀ toꢀ discloseꢀ theꢀ ortho-directingꢀ abilityꢀ ofꢀ theꢀ
6
azetidineꢀ ring. ꢀ Inꢀ N-alkylꢀ 2-arylꢀ azetidines,ꢀ theꢀ loneꢀ pairꢀ
availabilityꢀ allowedꢀ forꢀ aꢀ multipleꢀ andꢀ site-selectiveꢀ
functionalizationꢀ ofꢀ theꢀ aromaticꢀ ring.ꢀ However,ꢀ whenꢀ suchꢀ
loneꢀpairꢀavailabilityꢀwasꢀmissing,ꢀasꢀinꢀtheꢀcaseꢀofꢀN-Bocꢀ2-arylꢀ
ꢀ
Schemeꢀ1.ꢀReactivityꢀobservedꢀinꢀN-Bocꢀ2-arylꢀheterocyclesꢀ
ꢀ
Beingꢀ azetidinesꢀ aꢀ missingꢀ linkꢀ inꢀ thisꢀ reactivityꢀ scenario,ꢀ weꢀ
decidedꢀ toꢀ investigateꢀ furtherꢀ theꢀ α-lithiationꢀ ofꢀ N-Boc-2-
arylazetidinesꢀwithꢀtheꢀaimꢀtoꢀunderstandꢀtheꢀreasonꢀofꢀsuchꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ1ꢀꢀ
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COMMUNICATIONꢀ
JournalꢀNameꢀ
differentꢀ behavior.ꢀ Weꢀ reportꢀ hereinꢀ ourꢀ findingsꢀ aboutꢀ thisꢀ arylazetidines.ꢀ
study.ꢀꢀ
Deuteration,ꢀ
carbonylationꢀofꢀlithiatedꢀdimersꢀoccurredꢀwithꢀgoodꢀyieldsꢀbutꢀ
hydroxyalkylationꢀ
andꢀ
View Article Online
DOI: 10.1039/C5CC06323J
WeꢀbeganꢀtheꢀstudyꢀreinvestigatingꢀtheꢀreactivityꢀofꢀN-Boc-2- modestꢀ diastereoselectivityꢀ usingꢀ MeOD,ꢀ acetoneꢀ andꢀ Boc2Oꢀ
phenylazetidineꢀ 1aꢀ startingꢀ fromꢀ previousꢀ observations,ꢀ asꢀ electrophiles.ꢀ However,ꢀ inꢀ mostꢀ casesꢀ mixturesꢀ ofꢀ
leadingꢀ toꢀ α-functionalizedꢀ azetidinesꢀ 2a,bꢀ underꢀ inꢀ situꢀ diastereomericꢀ dimersꢀ3ꢀ andꢀ diast-3ꢀ wereꢀ separableꢀ byꢀ flashꢀ
7
quenchꢀconditions, ꢀandꢀrunningꢀtheꢀlithiationꢀreactionsꢀunderꢀ chromatographyꢀ (Schemeꢀ 3).ꢀ Onꢀ theꢀ otherꢀ hand,ꢀ theꢀ
externalꢀquenchꢀconditionsꢀ(Schemeꢀ2).ꢀUnderꢀinꢀsituꢀquenchꢀ characterizationꢀ ofꢀ suchꢀ dimericꢀ azetidinesꢀ wasꢀ aꢀ demandingꢀ
conditions,ꢀ theꢀ baseꢀ isꢀ addedꢀ toꢀ aꢀ precooledꢀ solutionꢀ ofꢀ theꢀ taskꢀbecauseꢀofꢀtheirꢀlowꢀsolubilityꢀandꢀdueꢀtoꢀpoorlyꢀresolvedꢀ
azetidineꢀ andꢀ theꢀ electrophile;ꢀ whileꢀ underꢀ externalꢀ quenchꢀ NMRꢀspectraꢀforꢀtheꢀpresenceꢀofꢀrotamers.ꢀHowever,ꢀtheꢀuseꢀ
conditions,ꢀtheꢀelectrophileꢀisꢀadded,ꢀafterꢀaꢀdefiniteꢀamountꢀ ofꢀ homoꢀ andꢀ heterocorrelationꢀ 2Dꢀ NMRꢀ experimentsꢀ andꢀ
ofꢀ time,ꢀ toꢀ aꢀ cooledꢀ solutionꢀ ofꢀ theꢀ putativeꢀ lithiatedꢀ HRMSꢀ analysesꢀ wereꢀ mandatoryꢀ toꢀ supportꢀ theꢀ proposedꢀ
intermediateꢀ generatedꢀ byꢀ addingꢀ theꢀ baseꢀ toꢀ theꢀ azetidine.ꢀ structuresꢀ(seeꢀESI).ꢀInꢀtheꢀcaseꢀofꢀ3bꢀandꢀdiast-3b,ꢀpreparedꢀ
Severalꢀ reactionꢀ parametersꢀ asꢀ temperature,ꢀ concentration,ꢀ byꢀ trappingꢀ withꢀ acetone,ꢀ X-rayꢀ analysisꢀ confirmedꢀ theirꢀ
solvents,ꢀ ligandsꢀ andꢀ lithiatingꢀ agentsꢀ wereꢀ carefullyꢀ varied.ꢀ structureꢀ andꢀ relativeꢀ stereochemistry.ꢀ Theꢀ Xꢀ rayꢀ structuresꢀ
Theꢀ deuterationꢀ reactionꢀ wasꢀ evaluated.ꢀ Afterꢀ anꢀ extensiveꢀ revealedꢀdifferentꢀpackingꢀandꢀtorsionꢀanglesꢀforꢀ3bꢀandꢀdiast-
experimentalꢀ investigation,ꢀ weꢀ foundꢀ asꢀ optimalꢀ reactionꢀ 3b,ꢀ andꢀ suchꢀ informationꢀ usedꢀ toꢀ assignꢀ theꢀ relativeꢀ
‡,§
conditions,ꢀforꢀaꢀcompleteꢀconversionꢀofꢀ1a,ꢀtheꢀuseꢀofꢀs-BuLiꢀ configurationꢀtoꢀdiastereoisomericꢀpairsꢀ(seeꢀESI).ꢀ ꢀꢀ
(
3ꢀequiv)ꢀasꢀtheꢀlithiatingꢀagentsꢀinꢀTHFꢀatꢀ-98ꢀ°Cꢀforꢀ5ꢀminutesꢀ
atꢀ0.05ꢀMꢀconcentration.ꢀAnꢀunexpectedꢀself-condensationꢀofꢀ
aꢀ wasꢀ observed,ꢀ underꢀ suchꢀ reactionꢀ conditions,ꢀ leadingꢀ toꢀ
ꢀ
Boc
N
Boc
N
Boc
N
s-BuLi
98 °C
5 min.
Boc
N
Ar
Ar
-
Ar
E+
1
+
N
Ar
N
N
-
98 °C
Li 30 min
O
ꢀ
THF
O
O
Ar
E
diastereomericꢀdimersꢀ3a-Dꢀandꢀdiast-3a-Dꢀ(Schemeꢀ2).
Ar
Ar
E
1
a: Ar = Ph
3a-h
Major
diast-3a-h
Minor
ꢀ
1b: Ar = 4-PhC H4
6
1
c: Ar = 4-ClC6H4
1) n-HexLi
) E+
Boc
N
2
R1
E
E = SiMe2Ph (38%) E+ = ClSiMe Ph
2
-MeTHF, -98 °C
2
Boc
N
Boc
N
R
+
Ph2COH (30%)
E
= Ph C=O
2
N
Ph
in situ quench
Ph
Ph
N
2
a,b
Preliminary observations
N
N
O
R2
Me
Me
OH
O
Me
Me
OH
R
O
Boc
Ph
constrained
dipeptide
Ph
N
3b
diast-3b
Ph
a
5% ; dr 70/30
+
b
7
E
= acetone
1
a
Boc
N
Boc
Cl
Cl
D
Boc
N
Boc
N
Boc
Ph
N
Ph
Boc
N
external quench
) s-BuLi (3 equiv)
Ph
N
Ph
N
+
N
8
>
0 % yield
98% D
dr 3a-D/diast-3a-D: 70:30
N
N
1
O
O
N
N
O
O
O
Ot-Bu
a
O
Ot-Bu
O
D
THF, -98 °C, 5 min
) MeOD
Ph
D
Ph
D
Ph
Ph
2
3a-D
diast-3a-D
ꢀ
O
3
c
diast-3c
Schemeꢀ2.ꢀLithiationꢀofꢀN-Bocꢀ2-phenylazetidineꢀ1aꢀunderꢀexternalꢀ
quenchꢀconditionsꢀ
ꢀ
5% ; dr 60/40b
E+ = (Boc)2O
Cl
Cl
b
diast-3d
5
3d
a
8
0% ; dr 65/35
E+ = MeOD
Cl
Cl
Cl
Cl
Boc
Boc
N
Boc
Boc
N
Theꢀuseꢀofꢀotherꢀlithiatingꢀagentsꢀ(n-HexLi,ꢀn-BuLi,ꢀLDA,ꢀLTMP)ꢀ
asꢀ wellꢀ asꢀ differentꢀ reactionꢀ mediumꢀ (THF,ꢀ 2-MeTHF,ꢀ
toluene/tmeda,ꢀ Et2O/tmeda)ꢀ furnishedꢀ unreactedꢀ startingꢀ
materialꢀ orꢀ complexꢀ reactionꢀ mixturesꢀ dependingꢀ onꢀ
concentration,ꢀreactionꢀtime,ꢀandꢀtemperature.ꢀInꢀfact,ꢀhigherꢀ
concentrationsꢀ(>0.05ꢀM),ꢀlongerꢀreactionꢀtimesꢀ(>5ꢀmin)ꢀandꢀ
temperaturesꢀ aboveꢀ -98ꢀ °Cꢀ returnedꢀ onlyꢀ complexꢀ reactionꢀ
mixtures.ꢀ Theꢀ expectedꢀ α-deuteratedꢀ azetidineꢀ (1a-D)ꢀ wasꢀ
observedꢀinꢀtraceꢀamountꢀduringꢀtheꢀoptimizationꢀstudyꢀwhileꢀ
theꢀN-Cꢀmigrationꢀproductꢀneverꢀwasꢀobserved.ꢀꢀ
N
N
N
N
N
N
Me
Me
OH
O
Ot-Bu
O
Ot-Bu
O
Me
Me
OH
O
O
O
Cl
3
f
Cl
b
diast-3f
Cl
3
e
Cl
diast-3e
63%a,c; dr 60/40
+
a
b
8
0% ; dr 70/30
E
+
E
= (Boc)2O
= acetone
N
Boc
Ph
N
Boc
Ph
N
Boc
O
Ph
O
Ph
O
N
N
N
HO
Me
D
HO
Me
Ph
Me
diast-3h
b
78% ; dr 75/25
Ph
Me
3
g
3h
a
7
7%a,d
E+ = MeOD
E
+
= acetone
ꢀ
Schemeꢀ 3.ꢀ Scopeꢀ ofꢀ theꢀ lithiation/dimerization/electrophileꢀ trappingꢀ
sequence.ꢀ Overallꢀ yieldꢀ forꢀ isolatedꢀ products.ꢀ Diastereomericꢀ ratioꢀ
Dimericꢀazetidinesꢀ3a-Dꢀandꢀdiast-3a-Dꢀrepresent,ꢀtoꢀtheꢀbestꢀ
ofꢀourꢀknowledge,ꢀtheꢀfirstꢀexampleꢀofꢀself-condensationꢀofꢀaꢀ
a
b
c
calculatedꢀ onꢀ theꢀ weightꢀ ofꢀ isolatedꢀ products.ꢀ Inseparableꢀ mixture.ꢀ
d
Bocꢀ stabilizedꢀ α-lithiatedꢀ amine.ꢀ Interestingly,ꢀ suchꢀ dimers,ꢀ Onlyꢀ3gꢀwasꢀisolated.ꢀꢀ
easilyꢀ separableꢀ byꢀ flashꢀ chromatography,ꢀ showꢀ peculiarꢀ
structuresꢀ resemblingꢀ toꢀ constrainedꢀ peptidomimeticsꢀ whichꢀ Interestingly,ꢀtheꢀintroductionꢀofꢀaꢀtert-butoxycarbonylꢀunit,ꢀasꢀ
ꢀ
12,13
areꢀimportantꢀscaffoldsꢀinꢀmedicinalꢀchemistry.
ꢀ
inꢀ theꢀ caseꢀ ofꢀ 3c,fꢀ andꢀ diast-3c,f,ꢀ providesꢀ aꢀ constrainedꢀ
Inꢀ orderꢀ toꢀ verifyꢀ theꢀ applicabilityꢀ ofꢀ thisꢀ dipeptideꢀwithꢀpotentialꢀuseꢀinꢀmedicinalꢀchemistryꢀprogramsꢀ
14
lithiation/dimerization/electrophileꢀtrappingꢀstrategyꢀtoꢀaccessꢀ andꢀhavingꢀprotectedꢀN-ꢀandꢀC-terminals. ꢀꢀ
azetidine-basedꢀpeptidomimetics,ꢀweꢀexploredꢀtheꢀscopeꢀusingꢀ Anotherꢀsurprisingꢀandꢀunexpectedꢀresultꢀwasꢀobtainedꢀwhenꢀ
readilyꢀavailableꢀN-Boc-2-arylazetinesꢀ1a-cꢀandꢀrepresentativeꢀ N-Boc-2-(o-tolyl)azetidineꢀ
1dꢀ
wasꢀ
subjectedꢀ
toꢀ
electrophilesꢀ (Schemeꢀ 3).ꢀ Weꢀ wereꢀ gladꢀ toꢀ observeꢀ thatꢀ thisꢀ lithiation/deuterationꢀsequenceꢀunderꢀtheꢀconditionsꢀusedꢀforꢀ
self-condensationꢀ takesꢀ placeꢀ alsoꢀ withꢀ otherꢀ α-lithiatedꢀ 2- azetidinesꢀ 1a-c.ꢀ Inꢀ strikingꢀ contrastꢀ toꢀ 1a-c,ꢀ azetidineꢀ 1dꢀ didꢀ
2
ꢀ|ꢀJ.ꢀName.,ꢀ2012,ꢀ00,ꢀ1-3ꢀ
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notꢀ undergoꢀ anyꢀ self-condensationꢀ andꢀ theꢀ correspondingꢀ Whenꢀ (R)-1aꢀ wasꢀ lithiatedꢀ underꢀ optimizedVꢀiewcoAnrtidclietOionnlinse,ꢀ
deuteratedꢀazetidinesꢀ4aꢀwasꢀobtainedꢀwithꢀ50%ꢀofꢀdeuteriumꢀ quenchingꢀwithꢀMeODꢀgaveꢀhighlyꢀenant iDo Oe In: 1r 0i c. 1h 0 e3 d9 ꢀ/ dC e5 Cu Ct e0 r6 a3 t2 e3 dJ ꢀ
content.ꢀ Fullꢀ conversionꢀ 1dà4aꢀ wasꢀ obtainedꢀ runningꢀ theꢀ dimersꢀ (R,S)-3a-Dꢀ (erꢀ 85:15)ꢀ andꢀ (R,R)-diast-3a-Dꢀ (erꢀ 98:2)ꢀ inꢀ
lithiation/deuterationꢀreactionꢀwithꢀs-BuLiꢀ(2.5ꢀequiv)ꢀinꢀTHFꢀatꢀ 70:30ꢀdiastereomericꢀratioꢀrespectivelyꢀ(Schemeꢀ5).ꢀThisꢀresultꢀ
1
78ꢀ°Cꢀforꢀ10ꢀmin.ꢀ HꢀNMRꢀofꢀtheꢀreactionꢀcrudeꢀdidꢀnotꢀshowꢀ demonstratesꢀ thatꢀ thisꢀ strategyꢀ couldꢀ beꢀ suitableꢀ forꢀ theꢀ
-
anyꢀ signꢀ ofꢀ decomposition.ꢀ Itꢀ isꢀ worthꢀ mentioningꢀ thatꢀ preparationꢀofꢀchiralꢀazetidine-basedꢀdipeptides. ꢀꢀ
§§
azetidinesꢀ1a-cꢀundergoꢀfullꢀdecompositionꢀatꢀ-78ꢀ°C.ꢀHowever,ꢀ
lithiatedꢀ azetidineꢀ 1d-Liꢀ wasꢀ foundꢀ chemicallyꢀ stableꢀ andꢀ
smoothlyꢀreactedꢀwithꢀelectrophilesꢀleadingꢀ2,2-disubstitutedꢀ
azetidinesꢀ4b-dꢀ(Schemeꢀ4).ꢀꢀ
ꢀ
Boc
N
Ph
(R)
s-BuLi
N
(
R)
O
Ph
H
Boc
N
Boc
N
Boc
N
s-BuLi
2.5 equiv)
E+
HD (R)-1a
Li
E
(
s-BuLi
THF
-
3
78 °C
0 min
THF
Boc
Boc
Ph
-98 °C
Boc
Boc
N
-78 °C
Me
N
(S)-1a-Li
Me
Me
5 min.
N
N
Ph
Ph
10 min.
Li
1
d
Chemically stable!
d-Li
4a-d
t-Bu
SC
N
N
Ph
1
O
O
(
R)-1a
er: 98:2
Ph Li
Ph Li
(R)-1a-Li
Boc
N
Boc
N
BocO
Boc OH
N
MeOD
D
Me
Ph
Ph
N
O
Boc
N
Boc
N
*
Boc
H
N
Ph
Ph
(R)
N
D
Boc
Ph
(
R)
Me
Me
Me
N
+
N
(R)
Me
Ph
O
(S)
O
4
a
4b
4c
4d
87%
E+ = (Boc)2O
not observed
Ph
D
Ph
D
>
94% D
E+ = MeOD
96%
E+ = MeI
75%
E+ = acetone
3a-D
SC = self-condensation
HD = homochiral dimerization
diast-3a-D
er: 98:2
>95% D
er: 85:15
95% D
>
NHPg
COOPg
Boc
Me
*
N
s-BuLi
O
R
THF
Boc
Li
Boc
-78 °C
N
N
H+
N
10 min.
(R)-1a
1
d
+
(R)-1a
Me
E
Phe - analogs
not observed
ꢀ
1
d
Schemeꢀ4.ꢀEffectiveꢀtrappingꢀofꢀα-lithiatedꢀN-Bocꢀazetidineꢀ
ꢀ
Schemeꢀ 5.ꢀ Stereochemicalꢀ investigationꢀ onꢀ theꢀ self-condensationꢀ ofꢀ
Thisꢀ is,ꢀ inꢀ ourꢀ opinion,ꢀ aꢀ remarkableꢀ resultꢀ forꢀ twoꢀ mainꢀ
reasons.ꢀFirst,ꢀitꢀdemonstratesꢀaꢀsurprisingꢀ“ortho-effect”ꢀableꢀ
toꢀ switchꢀ theꢀ reactivityꢀ ofꢀ α-lithiatedꢀ N-Bocꢀ azetidinesꢀ
preventingꢀ self-condensation.ꢀ Second,ꢀ itꢀ givesꢀ theꢀ possibilityꢀ
forꢀ accessingꢀ toꢀ 2,2-disubstitutedꢀ azetidinesꢀ andꢀ constrainedꢀ
aminoacidsꢀ asꢀ inꢀ theꢀ caseꢀ ofꢀ 4dꢀ whichꢀ canꢀ beꢀ consideredꢀ aꢀ
(
R)-1aꢀandꢀattemptꢀtoꢀdemonstrateꢀtheꢀSCꢀpathway.ꢀ
Attemptsꢀtoꢀquenchꢀ(MeOD)ꢀtheꢀreactionꢀatꢀshorterꢀreactionꢀ
timesꢀ (5,ꢀ 30ꢀ sec.,ꢀ 1ꢀ min)ꢀ resultedꢀ inꢀ largeꢀ amountsꢀ ofꢀ
unreactedꢀ startingꢀ material.ꢀ Theꢀ slightꢀ erosionꢀ observedꢀ inꢀ
(R,S)-3a-Dꢀ(erꢀ85:15)ꢀcouldꢀbeꢀtheꢀresultꢀofꢀaꢀpropensityꢀofꢀ(R)-
1a-Liꢀ toꢀ racemizeꢀ underꢀ theꢀ reactionꢀ conditionsꢀ asꢀ seenꢀ inꢀ
15
cyclicꢀanalogꢀofꢀphenylalaninesꢀ(seeꢀSchemeꢀ4). ꢀꢀ
Weꢀ ascribeꢀ theꢀ chemicalꢀ stabilityꢀ ofꢀ 1d-Li,ꢀ andꢀ itsꢀ lowꢀ
propensityꢀ toꢀ undergoꢀ self-condensation,ꢀ toꢀ aꢀ preferentialꢀ
16
relatedꢀ systems. ꢀ Itꢀ isꢀ likelyꢀ thatꢀ theꢀ rateꢀ ofꢀ racemizationꢀ isꢀ
similarꢀtoꢀtheꢀrateꢀofꢀself-condensation.ꢀInꢀorderꢀtoꢀsupportꢀtheꢀ
hypothesisꢀ ofꢀ SCꢀ ofꢀ lithiatedꢀ species,ꢀ azetidineꢀ 1d,ꢀ whichꢀ
doesn’tꢀ dimerize,ꢀ wasꢀ lithiatedꢀ andꢀ reactedꢀ withꢀ (R)-1a.ꢀ
QuenchingꢀwithꢀMeOHꢀreturnedꢀ1aꢀandꢀunreactedꢀ(R)-1a.ꢀNoꢀ
evidenceꢀ forꢀ crossꢀ self-condensationꢀ ꢀ wereꢀ found.ꢀ Next,ꢀ theꢀ
equilibriumꢀbetweenꢀlithiatedꢀdimersꢀ3a-Liꢀandꢀdiast-3a-Liꢀwasꢀ
demonstratedꢀ withꢀ theꢀ experimentꢀ reportedꢀ inꢀ Schemeꢀ 6.ꢀ
Whenꢀ3aꢀ(drꢀ>95:5)ꢀandꢀ diast-3aꢀ(drꢀ>95:5)ꢀwhereꢀsubjectedꢀ
separatelyꢀtoꢀlithiationꢀreactionꢀusingꢀs-BuLiꢀ(2ꢀequiv)ꢀinꢀTHFꢀatꢀ
conformationꢀ
reactivity/preferentialꢀ conformationꢀ relationshipꢀ hasꢀ beenꢀ
ofꢀ
theꢀ
o-tolylꢀ
substituent.ꢀ
Suchꢀ
6
observedꢀ inꢀ otherꢀ similarꢀ systems. ꢀ Byꢀ aꢀ conformationalꢀ
analysisꢀ andꢀ DFTꢀ calculationsꢀ weꢀ foundꢀ thatꢀ theꢀ mostꢀ stableꢀ
conformerꢀsetsꢀtheꢀo-methylꢀgroupꢀsynꢀtoꢀtheꢀα-protonꢀofꢀtheꢀ
azetidineꢀ ringꢀ (seeꢀ ESI).ꢀ Thisꢀ suggestsꢀ thatꢀ theꢀ methylꢀ groupꢀ
actsꢀasꢀaꢀshieldꢀhamperingꢀself-condensation.ꢀꢀ
Next,ꢀ withꢀ theꢀ aimꢀ toꢀ getꢀ someꢀ mechanisticꢀ insightsꢀ forꢀ theꢀ
processesꢀ describedꢀ above,ꢀ weꢀ runꢀ aꢀ stereochemicalꢀ
investigationꢀ performingꢀ theꢀ lithiation/dimerization/ꢀ
deuterationꢀsequenceꢀonꢀchiralꢀnon-racemicꢀazetidineꢀ(R)-1a.ꢀ
AsꢀreportedꢀinꢀSchemeꢀ5,ꢀtwoꢀpossibilitiesꢀcouldꢀbeꢀenvisagedꢀ
forꢀ theꢀ dimerization:ꢀ a)ꢀ aꢀ twoꢀ stepsꢀ sequenceꢀ (reportedꢀ asꢀ
homochiralꢀdimerization,ꢀHD),ꢀinvolvingꢀtheꢀreactionꢀofꢀ(R)-1a-
Liꢀwithꢀitsꢀneutralꢀprecursor,ꢀandꢀleadingꢀtoꢀdiast-3aꢀwhichꢀisꢀ
furtherꢀdeprotonated;ꢀb)ꢀaꢀsingleꢀstepꢀdimerizationꢀofꢀ(R)-1a-Liꢀ
-
98ꢀ°Cꢀforꢀ5ꢀmin,ꢀmixturesꢀofꢀdiastereomericꢀdimersꢀ3a-Dꢀandꢀ
diast-3a-DꢀformedꢀuponꢀquenchingꢀwithꢀMeOD.ꢀTheꢀsenseꢀofꢀ
stereoinductionꢀwasꢀtheꢀsameꢀinꢀbothꢀexperimentsꢀbeingꢀ3a-Dꢀ
theꢀfavoredꢀstereoisomerꢀjustꢀasꢀseenꢀinꢀtheꢀself-condensationꢀ
ofꢀ1a.ꢀ
Evenꢀ thoughꢀ theꢀ HDꢀ pathwayꢀ cannotꢀ beꢀ ruledꢀ out,ꢀ ourꢀ
preliminaryꢀ evidenceꢀ supportꢀ theꢀ hypothesisꢀ ofꢀ aꢀ SCꢀ ofꢀ α-
lithiatedꢀ N-Bocꢀ azetidines,ꢀ followedꢀ byꢀ theꢀ epimerizationꢀ ofꢀ
theꢀcorrespondingꢀlithiatedꢀdimers.ꢀ
(
reportedꢀasꢀself-condensation,ꢀSC),ꢀgivingꢀdirectlyꢀtheꢀlithiatedꢀ
dimer.ꢀInꢀbothꢀpathways,ꢀweꢀassumedꢀanꢀequilibriumꢀbetweenꢀ
theꢀlithiatedꢀdimers.ꢀ
Thisꢀjournalꢀisꢀ©ꢀTheꢀRoyalꢀSocietyꢀofꢀChemistryꢀ20xxꢀ
J.ꢀName.,ꢀ2013,ꢀ00,ꢀ1-3ꢀ|ꢀ3ꢀ
Pleaseꢀdoꢀnotꢀadjustꢀmarginsꢀ

Pleaseꢀd Co hꢀ ne omt ꢀ Ca do j mu smt ꢀmarginsꢀ
Page 4 of 5
COMMUNICATIONꢀ
JournalꢀNameꢀ
Biomol.ꢀChem,ꢀ2012,ꢀ2326.ꢀc)ꢀM.ꢀK.ꢀGhorai,ꢀD.ꢀSVhieuwkAlart,icꢀKle.OꢀDnalinse,ꢀ
J.ꢀOrg.ꢀChem.,ꢀ2009,ꢀ74,ꢀ7013.ꢀd)ꢀM.ꢀK.ꢀGhorai,ꢀA.ꢀKumar,ꢀD.ꢀ
DOI: 10.1039/C5CC06323J
P.ꢀTiwari,ꢀJ.ꢀOrg.ꢀChem.,ꢀ2010,ꢀ75,ꢀ137.ꢀ
4
5
. a)ꢀJ.ꢀSlade,ꢀJ.ꢀBajwa,ꢀH.ꢀLiu,ꢀD.ꢀParker,ꢀJ.ꢀVivelo,ꢀG.-P.ꢀChen,ꢀJ.ꢀ
Calienni,ꢀE.ꢀVillhauer,ꢀK.ꢀPrasad,ꢀO.ꢀRepicꢀandꢀT.ꢀJ.ꢀBlacklock,ꢀ
Org.ꢀProcessꢀRes.ꢀDev.,ꢀ2007,ꢀ11,ꢀ825.ꢀꢀ
. a)ꢀ Ericksson,ꢀ B.ꢀ I.;ꢀ Carlsson,ꢀ S.;ꢀ Halvarsson,ꢀ M.;ꢀ Risberg,ꢀ B.;ꢀ
Mattsson,ꢀ C.ꢀ Thromb.ꢀ Haemostasisꢀ 1997,ꢀ 78,ꢀ 1404.ꢀ b)ꢀ
AstraZeneca;ꢀPCTꢀInt.ꢀAppl.ꢀWOꢀ00/41716,ꢀ2000.ꢀc)ꢀY.ꢀYagil,ꢀ
M.ꢀ Miyamoto,ꢀ L.ꢀ Frasier,ꢀ K.ꢀ Oizumiꢀ andꢀ H.ꢀ Koike,ꢀ Am.ꢀ J.ꢀ
Hypertens.,ꢀ1994,ꢀ7,ꢀ637.ꢀ
6
7
8
. M.ꢀ Zenzola,ꢀ L.ꢀ Degennaro,ꢀ P.ꢀ Trinchera,ꢀ L.ꢀ Carroccia,ꢀ A.ꢀ
Giovine,ꢀG.ꢀRomanazzi,ꢀP.ꢀMastrorilli,ꢀR.ꢀRizzi,ꢀL.ꢀPisanoꢀandꢀR.ꢀ
Luisi,ꢀChem-Eur.ꢀJ.,ꢀ2014,ꢀ20,ꢀ12190.ꢀ
. L.ꢀ Degennaro,ꢀ M.ꢀ Zenzola,ꢀ P.ꢀ Trinchera,ꢀ L.ꢀ Carroccia,ꢀ A.ꢀ
Giovine,ꢀ G.ꢀ Romanazzi,ꢀ A.ꢀ Falcicchioꢀ andꢀ R.ꢀ Luisi,ꢀ Chemicalꢀ
Communications,ꢀ2014,ꢀ50,ꢀ1698.ꢀ
. a)ꢀD.ꢀM.ꢀHodgson,ꢀC.ꢀL.ꢀMortimer,ꢀJ.ꢀM.ꢀMcKennaꢀOrg.ꢀLett.,ꢀ
2015,ꢀ 17,ꢀ 330.ꢀ b)ꢀ D.ꢀ M.ꢀ Hodgson,ꢀ C.ꢀ I.ꢀ Pearson,ꢀ A.ꢀ L.ꢀ
ThompsonꢀJ.ꢀOrg.ꢀChem.,ꢀ2013,ꢀ78,ꢀ1098.ꢀc)ꢀD.ꢀM.ꢀHodgson,ꢀJ.ꢀ
Kloesges,.ꢀAngew.ꢀChem.ꢀInt.ꢀEd.ꢀ2010,ꢀ49,ꢀ2900.ꢀꢀ
Schemeꢀ6.ꢀEvidenceꢀforꢀepimerizationꢀofꢀlithiatedꢀdimersꢀ
Inꢀ conclusion,ꢀ thisꢀ investigationꢀ demonstratesꢀ thatꢀ N-Boc-2-
arylazetidinesꢀ canꢀ beꢀ regioselectivelyꢀ α-lithiated.ꢀ Theꢀ
correspondingꢀ lithiatedꢀ intermediatesꢀ displayꢀ aꢀ reactivityꢀ
dependentꢀ onꢀ theꢀ substituentꢀ ofꢀ theꢀ aromaticꢀ ring.ꢀ Self-
condensationꢀ toꢀ newꢀ constrainedꢀ azetidine-basedꢀ
peptimomimeticsꢀoccursꢀwhenꢀtheꢀaromaticꢀringꢀlackꢀanꢀorthoꢀ
substituent.ꢀ Inꢀ strikingꢀ contrast,ꢀ theꢀ presenceꢀ ofꢀ theꢀ ortho-
substituentꢀ hampersꢀ theꢀ self-condensationꢀ allowingꢀ theꢀ
preparationꢀ ofꢀ 2,2-disubstitutedꢀ azetidines.ꢀ Furtherꢀ
investigationꢀareꢀunderwayꢀinꢀorderꢀtoꢀexpandꢀtheꢀapplicabilityꢀ
ofꢀthisꢀmethodologyꢀandꢀgetꢀfurtherꢀmechanisticꢀinsights.ꢀꢀ
9
1
. D.ꢀM.ꢀHodgson,ꢀC.ꢀI.ꢀPearson,ꢀM.ꢀKazmi,ꢀOrg.ꢀLett.,ꢀ2014,ꢀ16,ꢀ
8
56.ꢀꢀ
0. a)ꢀB.ꢀMusio,ꢀG.ꢀJ.ꢀClarkson,ꢀM.ꢀShipman,ꢀS.ꢀFlorioꢀandꢀR.ꢀLuisi,ꢀ
OrgꢀLett,ꢀ2009,ꢀ11,ꢀ325.ꢀb)ꢀD.ꢀM.ꢀHodgson,ꢀX.ꢀZu,ꢀBeilsteinꢀJ.ꢀ
Org.ꢀ Chem.,ꢀ 2010,ꢀ 6,ꢀ 978.ꢀ c)ꢀ L.ꢀ Degennaro,ꢀ P.ꢀ Trinchera,ꢀ R.ꢀ
LuisiꢀChem.ꢀRev.ꢀ114,ꢀ7881.ꢀꢀ
1. a)ꢀL.ꢀDegennaro,ꢀB.ꢀMusio,ꢀR.ꢀLuisi,ꢀinꢀLithiumꢀCompoundsꢀinꢀ
OrganicꢀSynthesis:ꢀFromꢀFundamentalsꢀtoꢀApplications,ꢀeds.ꢀ
R.ꢀ Luisi,ꢀ V.ꢀ Capriati,ꢀ WILEYꢀ VCH,ꢀ Weinheimꢀ 2014,ꢀ ch.ꢀ 7,ꢀ ppꢀ
191-224.ꢀꢀ
1
Weꢀ thankꢀ Nationalꢀ Projectꢀ “FIRBꢀ -ꢀ Futuroꢀ inꢀ Ricerca”ꢀ (code:ꢀ 12. Strictlyꢀrelatedꢀoxetane-containingꢀtripeptidesꢀhaveꢀrecentlyꢀ
CINECAꢀ RBFR083M5N);ꢀ Regionalꢀ projectꢀ “Retiꢀ diꢀ Laboratoriꢀ
Pubbliciꢀ diꢀ Ricerca"ꢀ (Project.ꢀ Codeꢀ 20).ꢀ Laboratorioꢀ SISTEMA,ꢀ
beenꢀreported,ꢀseeꢀN.ꢀH.ꢀPowell,ꢀG.ꢀJ.ꢀClarkson,ꢀR.ꢀNotman,ꢀP.ꢀ
Raubo,ꢀN.ꢀG.ꢀMartin,ꢀM.ꢀShipman,ꢀChemicalꢀCommunications,ꢀ
2
014,ꢀ50ꢀ8797.ꢀꢀ
(
Codeꢀ PONa300369)ꢀ financedꢀ byꢀ Italianꢀ Miur.ꢀ Weꢀ thankꢀ
1
3. a)ꢀ A.ꢀ Žukauskaitė,ꢀ A.ꢀ Moretto,ꢀ C.ꢀ Peggion,ꢀ M.ꢀ Deꢀ Zotti,ꢀ A.ꢀ
Šačkus,ꢀ F.ꢀ Formaggio,ꢀ N.ꢀ Deꢀ Kimpe,ꢀ S.ꢀ Mangelinckxꢀ Eur.ꢀ J.ꢀ
Org.ꢀChem.,ꢀ2014,ꢀ2312.ꢀb)ꢀY.ꢀZhang,ꢀR.ꢀM.ꢀMalamakal,ꢀD.ꢀM.ꢀ
Marinaꢀ Zenzolaꢀ andꢀ Lauraꢀ Carrocciaꢀ forꢀ theirꢀ contributionꢀ inꢀ
theꢀpreparationꢀofꢀsomeꢀchemicalsꢀusedꢀinꢀthisꢀwork.ꢀꢀ
Chenoweth,ꢀ
Angew.ꢀ
Chem.ꢀ
Int.ꢀ
Ed.ꢀ
2015,ꢀ
DOI:ꢀ10.1002/anie.201504459.ꢀ c)ꢀ A.ꢀ Altmayer-Henzien,ꢀ V.ꢀ
Declerck,ꢀJ.ꢀFarjon,ꢀD.ꢀMerlet,ꢀR.ꢀGuillot,ꢀD.ꢀJ.ꢀAitken,ꢀAngew.ꢀ
Chem.ꢀInt.ꢀEd.ꢀ2015,ꢀDOI:ꢀ10.1002/anie.201504126.ꢀꢀ
Notesꢀandꢀreferencesꢀ
‡
§
ꢀꢀ Crystalꢀdataꢀforꢀ3bꢀandꢀdiast-3b:ꢀCCDCꢀ1412576-1412577.ꢀ
ꢀꢀ Theꢀrelativeꢀstereochemistryꢀwasꢀassignedꢀbyꢀanalogyꢀtoꢀ3bꢀ 14. a)ꢀB.ꢀF.ꢀFisher,ꢀL.ꢀGuo,ꢀB.ꢀS.ꢀDolinar,ꢀI.ꢀA.ꢀGuzei,ꢀS.ꢀH.ꢀGellmanꢀ
andꢀdiast-3bꢀforꢀwhichꢀXꢀrayꢀanalysesꢀwereꢀavailable.ꢀSeeꢀESIꢀ
§ꢀꢀWeꢀ assumeꢀ thatꢀ lithiatedꢀ azetidineꢀ (R)-1a-Liꢀ reactsꢀ withꢀ
retentionꢀofꢀconfigurationꢀjustꢀasꢀlithiatedꢀN-Bocꢀpyrrolidinesꢀ
andꢀpiperidines,ꢀseeꢀrefs.ꢀ10,ꢀ14.ꢀ
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Maynard,ꢀA.ꢀM.ꢀAlmeida,ꢀL.ꢀGuo,ꢀI.ꢀA.ꢀGuzei,ꢀL.ꢀC.ꢀSpencer,ꢀS.ꢀ
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M.ꢀ E.ꢀ Rabaglia,ꢀ M.ꢀ P.ꢀ Keller,ꢀ A.ꢀ D.ꢀ Attie,ꢀ A.ꢀ Saghatelian,ꢀ A.ꢀ
Bisello,ꢀS.ꢀH.ꢀGellmanꢀJ.ꢀAm.ꢀChem.ꢀSoc.,ꢀ2014,ꢀ136,ꢀ12848.ꢀꢀ
§
1
2
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