Synthesis and crystal structure of cis-4-azido-L-proline methyl ester hydrochloride

Article abstract of DOI:10.3184/030823409X12555437784172

The key precursor for the synthesis of novel influenza neuraminidase inhibitors, cis-4-azido-L-proline methyl ester hydrochloride (C6H ₁₁ClN₄O₂, Mr = 206.63), was prepared as white needle-shaped crystals and its structure was elucidated by single-crystal X-ray diffraction. In the crystal structure, molecules are linked through intermolecular hydrogen bonds, forming layers perpendicular to the bc plane.

Full text of DOI:10.3184/030823409X12555437784172

6
68ꢀ RESEARCH PAPER
NOVEMBER,ꢀ668–670ꢀ
JOURNALꢀOFꢀCHEMICALꢀRESEARCHꢀ2009
Synthesis and crystal structure of cis-4-azido-L-proline methyl ester
hydrochloride
a
b
a
Jianzhi Gong , Yanqing Gong and Wenfang Xu *
a
School of Pharmaceutical Sciences, Shandong University, Ji'nan 250012, P.R.China
bState key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, P.R.China
Theꢀkeyꢀprecursorꢀforꢀtheꢀsynthesisꢀofꢀnovelꢀinfluenzaꢀneuraminidaseꢀinhibitors,ꢀcis-4-azido-L-prolineꢀmethylꢀesterꢀ
hydrochlorideꢀ (C H ClN O ,ꢀ Mrꢀ =ꢀ 206.63),ꢀ wasꢀ preparedꢀ asꢀ whiteꢀ needle-shapedꢀ crystalsꢀ andꢀ itsꢀ structureꢀ wasꢀ
6
11
4
2
elucidatedꢀbyꢀsingle-crystalꢀX-rayꢀdiffraction.ꢀInꢀtheꢀcrystalꢀstructure,ꢀmoleculesꢀareꢀlinkedꢀthroughꢀintermolecularꢀ
hydrogenꢀbonds,ꢀformingꢀlayersꢀperpendicularꢀtoꢀtheꢀbcꢀplane.
Keywords: pyrrolidine,ꢀsynthesis,ꢀcrystalꢀstructure,ꢀhydrogenꢀbonds
Theꢀ collagenꢀ tripleꢀ helixꢀ isꢀ aꢀuniqueꢀstructuralꢀ motifꢀfoundꢀ
inꢀ proteins,ꢀ withꢀ aꢀ characteristicꢀ repeatꢀ ofꢀ Gly-X-Y,ꢀ where
O
O
OH
OH
X andꢀYꢀ areꢀ oftenꢀ L-prolineꢀ (Pro,ꢀ 1)ꢀ andꢀ trans-4-hydroxy-
L-prolineꢀ (Hyp,ꢀ 2)ꢀ residues,ꢀ respectively. ꢀ Hypꢀ isꢀ producedꢀ
1
HN
HN
byꢀ hydroxylationꢀ ofꢀ itsꢀ precursorꢀ Proꢀ in situꢀ afterꢀ proteinꢀ
synthesisꢀ inꢀ theꢀ body.ꢀ Itꢀ permitsꢀ theꢀ sharpꢀ twistingꢀ ofꢀ theꢀ
collagenꢀhelixꢀandꢀhelpsꢀprovideꢀstabilityꢀtoꢀtheꢀtripleꢀhelicalꢀ
structureꢀ ofꢀ collagen.ꢀ However,ꢀ theꢀ mechanismꢀ byꢀ whichꢀ
stabilisationꢀisꢀachievedꢀneedsꢀfurtherꢀdiscussion.2
OH
1
2
,3
Fig. 1ꢀ Chemicalꢀ structuresꢀ ofꢀ L-prolineꢀ (Pro)ꢀ andꢀ trans-4-
Theseꢀtwoꢀcyclicꢀaminoꢀacidsꢀhaveꢀbeenꢀusedꢀtoꢀgoodꢀeffectꢀ
inꢀtheꢀdesignꢀofꢀpeptidesꢀandꢀpeptidomimeticsꢀwithꢀdefinedꢀ
hydroxy-L-prolineꢀ(Hyp).
4,5
conformation. ꢀInꢀpreviousꢀworkꢀfromꢀourꢀlaboratory,ꢀHypꢀ
hadꢀbeenꢀusedꢀtoꢀprepareꢀaꢀseriesꢀofꢀpyrrolidineꢀderivativesꢀ
materialsꢀ wereꢀ purchasedꢀ fromꢀ commercialꢀ suppliers.ꢀ Anhydrousꢀ
reactionsꢀwereꢀcarriedꢀoutꢀinꢀoven-driedꢀglasswareꢀunderꢀaꢀnitrogenꢀ
atmosphere.ꢀAllꢀreactionsꢀwereꢀmonitoredꢀbyꢀTLCꢀonꢀ25.4ꢀ×ꢀ76.2ꢀmmꢀ
silicaꢀgelꢀplatesꢀ(GF-254)ꢀandꢀvisualisedꢀwithꢀiodineꢀvapour.ꢀSpecificꢀ
rotationꢀwereꢀdeterminedꢀonꢀaꢀGYROMAT-HPꢀhigh-precisionꢀdigitalꢀ
automaticꢀ polarimeterꢀ (Kernchen,ꢀ Germany).ꢀ Meltingꢀ pointsꢀ wereꢀ
determinedꢀ onꢀ anꢀ electrothermalꢀ meltingꢀ pointꢀ apparatusꢀ andꢀ areꢀ
uncorrected.ꢀ HꢀNMRꢀspectraꢀwereꢀdeterminedꢀonꢀaꢀBrukerꢀAvanceꢀ
300ꢀspectrometerꢀinꢀD OꢀorꢀCDCl ꢀusingꢀTMSꢀasꢀanꢀinternalꢀstandard.ꢀ
IRꢀspectraꢀwereꢀmeasuredꢀonꢀaꢀnicoletꢀnexusꢀ470ꢀFT-IRꢀspectrometerꢀ
usingꢀsmearꢀKBrꢀcrystalꢀorꢀKBrꢀplate.ꢀESI-MSꢀwereꢀdeterminedꢀonꢀ
anꢀAPIꢀ4000ꢀspectrometer.ꢀElementalꢀanalysisꢀforꢀcompoundsꢀwereꢀ
performedꢀusingꢀanꢀelementarꢀvarioꢀELꢀIIIꢀCNꢀanalyserꢀ(Germany).
6
-10
asꢀ inhibitorsꢀ targetingꢀ matrixꢀ metalloproteinaseꢀ (MMP),
ꢀ
11
inducibleꢀ nitricꢀ oxideꢀ synthaseꢀ (iNOS) ꢀ andꢀ influenzaꢀ
neuraminidaseꢀ(NA).12
Theꢀpresentꢀworkꢀisꢀpartꢀofꢀourꢀresearchꢀinvolvingꢀaꢀseriesꢀ
ofꢀnovelꢀpyrrolidineꢀderivativesꢀwhichꢀcanꢀbeꢀmoreꢀpotentꢀNAꢀ
inhibitors.ꢀ cis-4-Azido-L-prolineꢀ methylꢀ esterꢀ hydrochloride,ꢀ
aꢀ keyꢀ intermediateꢀ thatꢀ canꢀ beꢀ modifiedꢀ further,ꢀ wereꢀ
preparedꢀ via theꢀ sequenceꢀ ofꢀ esterification,ꢀ Boc-protection,ꢀ
mesylation,ꢀ azidationꢀ andꢀ removalꢀ ofꢀ protectingꢀ groupꢀ byꢀ
usingꢀenantiomericallyꢀpureꢀtrans-4-hydroxy-L-prolineꢀasꢀtheꢀ
startingꢀmaterialsꢀ(Schemeꢀ1).ꢀTheꢀpreparationꢀandꢀapplicationꢀ
1
2
3
Synthetic procedure
ofꢀtheꢀtitleꢀcompoundꢀwereꢀinvolvedꢀinꢀmanyꢀreferencesꢀandꢀ
Synthesis of trans-4-hydroxy-L-proline methyl ester hydrochloride
(3):ꢀ Preparedꢀ fromꢀ compoundꢀ 2ꢀ asꢀ describedꢀ byꢀ Mckillopꢀ et al. ꢀ
2
1
patents.13-20ꢀHowever,ꢀtheꢀcleavageꢀofꢀtheꢀBoc-protectingꢀgroupꢀ
2
0
Whiteꢀneedles (79.50%);ꢀ[a] –25.3°(cꢀ4,ꢀH O);ꢀm.p.ꢀ160–164ꢀ°Cꢀ
Dꢀ
2
ofꢀ6ꢀwithꢀtrifluroaceticꢀacidꢀ(TFA)ꢀgaveꢀtheꢀproductꢀasꢀaꢀyellowꢀ
2
2
(
lit. ꢀm.p.ꢀ156–160ꢀ°C).
oil,ꢀ whichꢀ isꢀ notꢀ convenientꢀ toꢀ storeꢀ orꢀ handle.1
3,19,20
ꢀ Twoꢀ
Synthesis of N-Boc-trans-4-hydroxy-L-proline methyl ester (4):ꢀ
Preparedꢀfromꢀcompoundꢀ3ꢀasꢀdescribedꢀbyꢀAbrahamꢀet al. ꢀtoꢀgiveꢀ
aꢀcolourless,ꢀviscousꢀoil.ꢀThisꢀoilꢀcouldꢀbeꢀcrystallisedꢀafterꢀstandingꢀ
groupsꢀremovedꢀBocꢀusingꢀHClꢀinꢀethylꢀacetateꢀorꢀdixoaneꢀwithꢀ
quantitiveꢀyield,ꢀbutꢀnoꢀspectralꢀdataꢀwereꢀprovided.1 ꢀHere,ꢀ
theꢀsyntheticꢀstepsꢀleadingꢀtoꢀ6ꢀandꢀ7ꢀwereꢀimprovedꢀandꢀallꢀtheꢀ
productsꢀwereꢀobtainedꢀasꢀcrystalsꢀfromꢀsuitableꢀsolventꢀexceptꢀ
forꢀcompoundꢀ6.ꢀTheꢀcrystalꢀstructureꢀofꢀ7ꢀisꢀalsoꢀreported.
13
4,18
2
5
atꢀroomꢀtemperatureꢀ(100.0%).ꢀ[a] ꢀ–75.9°(cꢀ1,ꢀCH OH);ꢀm.p.ꢀ93–
D
3
1
3
28
9
4ꢀ°Cꢀ[Ref. ꢀ[a] ꢀ–75.2°(cꢀ1,ꢀCH OH),ꢀ97–98ꢀ°C].
D 3
Synthesis of N-Boc-trans-4-methanesulfonyloxy-L-proline methyl
ester (5): Preparedꢀ fromꢀ compoundꢀ 4ꢀ asꢀ describedꢀ byꢀAbrahamꢀ et
1
3
25
al. ꢀasꢀwhiteꢀgranularꢀparticleꢀ(87.11%):ꢀ[a] ꢀ–54.2°(cꢀ2,ꢀCHCl );ꢀ
D
3
Experimental
13
25
m.p.ꢀ85–86ꢀ°Cꢀ(lit. ꢀ[a] ꢀ–52.3°ꢀ(cꢀ1.6,ꢀCHCl ),ꢀ85–86ꢀ°C).
D
3
Theꢀstartingꢀmaterialꢀ2ꢀisꢀaꢀwhiteꢀcrystallineꢀpowderꢀwithꢀm.p.ꢀ274–
Synthesis of N-Boc-cis-4-azido-L-proline methyl ester (6):ꢀ
75ꢀ°Cꢀ (dec.),ꢀ [a]20 –75.1°ꢀ (cꢀ 4,ꢀ H O),ꢀ purchasedꢀ fromꢀ Jinzhouꢀ
Mesylateꢀ5 (26.80ꢀg,ꢀ82.88ꢀmmol,ꢀ323.36ꢀgꢀmol )ꢀandꢀsodiumꢀazidoꢀ
-1
2
Dꢀ
2
-
1
JirongꢀAminoꢀAcidꢀCo.ꢀLtd,ꢀChina.ꢀUnlessꢀotherwiseꢀspecified,ꢀotherꢀ
(NaN ,ꢀ10.78ꢀg,ꢀ165.82ꢀmmol,ꢀ65.01ꢀgꢀmol ,ꢀ2ꢀequiv.)ꢀwereꢀstirredꢀ
3
O
O
O
O
O
O
O
O
OH
O
O
O
Boc
Boc
Boc
HN
a
Cl H N
b
N
c
N
d
N
e
Cl H N
2
2
OH
OH
OH
OMs
N3
N3
2
3
4
5
6
7
Scheme 1ꢀ Synthesisꢀofꢀtheꢀkeyꢀprecursorꢀ7.ꢀReagentsꢀandꢀconditions:ꢀ(a)ꢀAcetylꢀchloride,ꢀCH OH;ꢀ(b)ꢀ(Boc) O,ꢀTEA,ꢀDCM;ꢀ
3
2
(
c)ꢀMsCl,ꢀPyr,ꢀDCM,ꢀ0 ꢀ° C;ꢀ(d)ꢀNaN ,ꢀDMF,ꢀ55 ꢀ° C;ꢀ(e)ꢀHCl/EtOAc.
3
*
ꢀCorrespondent.ꢀE-mail:ꢀxuwenf@sdu.edu.cn
PAPER:ꢀJC090715

JOURNALꢀOFꢀCHEMICALꢀRESEARCHꢀ2009ꢀ 669
inꢀ dryꢀ DMFꢀ (30ꢀ mL)ꢀ atꢀ 55–60ꢀ°Cꢀ overnight.ꢀTheꢀ reactionꢀ mixtureꢀ
wasꢀ cooledꢀ toꢀ roomꢀ temperatureꢀ andꢀ thenꢀ partitionedꢀ betweenꢀ iceꢀ
waterꢀ andꢀ EtOAcꢀ (100ꢀ mL).ꢀ Theꢀ organicꢀ layerꢀ wasꢀ washedꢀ withꢀ
X-ray diffraction analysis
Crystalsꢀ suitableꢀ forꢀ singleꢀ crystalꢀ X-rayꢀ diffractionꢀ wereꢀ grownꢀ
fromꢀ anꢀ ethanolꢀ solution.ꢀ Theꢀ dataꢀ wereꢀ collectedꢀ onꢀ aꢀ Brukerꢀ
SMARTꢀ CCDꢀ area-detectorꢀ diffractometerꢀ atꢀ roomꢀ temperatureꢀ
usingꢀ graphite-monochromatedꢀ MoKaꢀ radiationꢀ (lꢀ =ꢀ 0.71073Å)ꢀ
byꢀ wꢀ scanꢀ modeꢀ withinꢀ theꢀ angularꢀ rangeꢀ 2.14–30.17.ꢀTheꢀ detailsꢀ
ofꢀtheꢀcrystallographicꢀdataꢀareꢀgivenꢀinꢀTableꢀ1.ꢀTheꢀstructureꢀwasꢀ
solvedꢀbyꢀdirectꢀmethodsꢀandꢀallꢀofꢀtheꢀnon-Hꢀatomsꢀwereꢀrefinedꢀ
brine,ꢀdriedꢀwithꢀanhydrousꢀMgSO ,ꢀandꢀevaporatedꢀtoꢀgiveꢀaꢀpaleꢀ
4
yellowꢀoilꢀ(24.12ꢀg,ꢀcrudeꢀ>100%),ꢀwhichꢀwasꢀsuitableꢀforꢀtheꢀnextꢀ
2
5
13
25
step.ꢀ[a] ꢀ–35.6°(cꢀ3,ꢀCHCl )ꢀ[lit. ꢀ[a] ꢀ–36.6°ꢀ(cꢀ2.8,ꢀCHCl )];ꢀ
D
3
D
3
1
HꢀNMRꢀ(CDCl )ꢀdꢀ1.42,ꢀ1.48ꢀ[s,ꢀ9H,ꢀC(CH ) ];ꢀ2.14–2.21,ꢀ2.40–
.54ꢀ(m,ꢀ2H,ꢀ3-CH ),ꢀ3.76ꢀ(s,ꢀ3H,ꢀOCH ),ꢀ3.44–3.52,ꢀ3.67–3.74ꢀ(m,ꢀ
H,ꢀ 5-H),ꢀ 4.14–4.19ꢀ (m,ꢀ 1H,ꢀ 2-H),ꢀ 4.31–4.35,ꢀ 4.41–4.45ꢀ (m,ꢀ 1H,ꢀ
-H);ꢀIRꢀ(KBr,ꢀcm ):ꢀ2978,ꢀ2105,ꢀ1703,ꢀ1399,ꢀ1262,ꢀ1204;ꢀESI-MS,ꢀ
3
3 3
2
2
4
2
3
2
againstꢀF ꢀbyꢀfull-matrixꢀleast-squaresꢀmethodsꢀusingꢀtheꢀSHELXTLꢀ
-1
23
program. ꢀ Theꢀ aminoꢀ groupꢀ hydrogenꢀ atomsꢀ wereꢀ locatedꢀ fromꢀ
+
m/zꢀCalcdꢀforꢀC H N O ꢀ[Mꢀ+ꢀH] ꢀ271.1.ꢀFound:ꢀ271.1
aꢀ differenceꢀ Fourierꢀ mapꢀ andꢀ refinedꢀ withꢀ isotropicꢀ temperatureꢀ
factors.ꢀAllꢀ otherꢀ Hꢀ atomsꢀ wereꢀ placedꢀ inꢀ geometricallyꢀ idealisedꢀ
positionsꢀandꢀconstrainedꢀtoꢀrideꢀonꢀtheirꢀparentꢀatoms.ꢀNoꢀabsorptionꢀ
correctionꢀwasꢀapplied.ꢀCCDCꢀ731637ꢀcontainsꢀtheꢀsupplementaryꢀ
crystallographicꢀdataꢀforꢀthisꢀpaper.ꢀTheꢀdataꢀcanꢀbeꢀobtainedꢀfreeꢀofꢀ
chargeꢀfromꢀtheꢀCambridgeꢀCrystallographicꢀDataꢀCentreꢀviaꢀwww.
ccdc.cam.ac.uk/data_request.cif.
11
18
4
4
Synthesis of cis-4-azido-L-proline methyl ester hydrochloride (7):
-1
Azideꢀ 6ꢀ (24.12ꢀ g,ꢀ 89.24ꢀ mmol,ꢀ 270.29ꢀ gꢀ mol )ꢀ wasꢀ dissolvedꢀ inꢀ
EtOAcꢀ(20ꢀmL),ꢀcooledꢀinꢀice,ꢀandꢀthenꢀtreatedꢀwithꢀ3ꢀNꢀHCl/EtOAcꢀ
(100ꢀmL).ꢀAfterꢀtheꢀmixtureꢀwasꢀstirredꢀforꢀ30ꢀmin,ꢀtheꢀsolventꢀwasꢀ
filtrated,ꢀ theꢀ precipitateꢀ washedꢀ withꢀ EtOAcꢀ andꢀ thenꢀ driedꢀ underꢀ
highꢀvacuumꢀtoꢀgiveꢀtheꢀfinalꢀcompoundꢀasꢀaꢀwhiteꢀsolidꢀthatꢀcouldꢀ
beꢀcrystallisedꢀfromꢀethanolꢀasꢀwhiteꢀneedle-shapedꢀcrystalsꢀ(12.93ꢀg,ꢀ
0.12%).ꢀ [a]25 ꢀ 33.1°(cꢀ 1,ꢀ H O);ꢀ m.p.ꢀ 153–155ꢀ°C;ꢀ Hꢀ NMRꢀ
1
7
Discussion
D
2
(
CDCl )ꢀ dꢀ 1.75ꢀ (brꢀ s,ꢀ 1H,ꢀ 1-NH),ꢀ 2.48–2.53,ꢀ 2.64–2.72ꢀ (m,ꢀ 2H,ꢀ
Figureꢀ2ꢀgivesꢀaꢀperspectiveꢀviewꢀofꢀtheꢀmolecularꢀstructureꢀofꢀtheꢀ
titleꢀ compoundꢀ withꢀ theꢀ atomicꢀ labellingꢀ system.ꢀ Selectedꢀ bondꢀ
lengthsꢀ andꢀ anglesꢀ areꢀ listedꢀ inꢀ Tableꢀ 2.ꢀ Theꢀ skeletonꢀ ofꢀ theꢀ titleꢀ
compoundꢀconsistsꢀofꢀaꢀpyrrolidiniumꢀring,ꢀaꢀmethoxycarbonylꢀgroupꢀ
andꢀanꢀazideꢀgroup.ꢀAllꢀtheꢀbondꢀlengthsꢀandꢀanglesꢀareꢀwithinꢀnormalꢀ
ranges.ꢀTheꢀ2-methoxycarbonylꢀgroupꢀandꢀ4-azidoꢀgroupꢀareꢀatꢀtheꢀ
sameꢀsideꢀofꢀtheꢀpyrrolidiniumꢀring.ꢀTheꢀtorsionꢀanglesꢀofꢀN2–C2–
C3–C4,C2–C3–C4–C5ꢀ andꢀ C2–N2–N3–N4ꢀ areꢀ 75.2(2)°,ꢀ –84.5(2)°ꢀ
andꢀ–170(3)°,ꢀrespectively.ꢀInꢀtheꢀcrystalꢀstructure,ꢀN1,ꢀCl(x,y,z)ꢀandꢀ
3
3
1
2
+
-CH ),ꢀ3.57–3.74,ꢀ(m,ꢀ2H,ꢀ5-CH ),ꢀ3.90ꢀ(s,ꢀ3H,ꢀOCH ),ꢀ4.47ꢀ(m,ꢀ
2
2
3
-
1
H,ꢀ2-H),ꢀ4.70–4.72ꢀ(m,ꢀ1H,ꢀ4-H);ꢀIRꢀ(KBr,ꢀcm ):ꢀ3339,ꢀ2945,ꢀ2876,ꢀ
105,ꢀ1681,ꢀ1434,ꢀ1324,ꢀ1258;ꢀESI-MSꢀm/zꢀCalcdꢀforꢀC H N O ꢀ[Mꢀ
6
10
4
2
+
ꢀH] ꢀ171.2.ꢀFound:ꢀ171.3;ꢀAnal.ꢀCalcdꢀforꢀC H ClN O (206.63),ꢀ
6
11
4
2ꢀ
C,ꢀ34.88;ꢀH,ꢀ5.37;ꢀN,ꢀ27.11;ꢀFound:ꢀC,ꢀ34.86;ꢀH,ꢀ5.39;ꢀN,ꢀ27.13%.
Table 1ꢀ Crystalꢀdataꢀandꢀrefinementꢀparametersꢀ
Molecularꢀformulaꢀ
Molecularꢀweightꢀ
Temperatureꢀ(K)ꢀ
Wavelengthꢀ
Crystalꢀsystemꢀ
Spaceꢀgroupꢀ
a/Åꢀ
C H N O Cl
6 11 4 2
206.64
298(2)
0.71073ꢀÅ
Orthorhombic
P2 2 2
1
1 1
5.335(1)
b/Åꢀ
12.218(2)
15.169(3)
988.8(3)
c/Åꢀ
3
V/Å ꢀ
Z
4
-3
Dcalc(gꢀcm )ꢀ
1.388
Crystalꢀsizeꢀ(mm)ꢀ
Crystalꢀcolourꢀ
Reflectionsꢀcollected/uniqueꢀ
Indexꢀrangesꢀ(h,k,l)ꢀ
Thetaꢀrangesꢀforꢀdataꢀcollectionꢀ
Absorptionꢀcoefficientꢀ(cm )ꢀ
F(000)ꢀ
0.20ꢀ×ꢀ0.20ꢀ×ꢀ0.15
Colourless
4319/2412ꢀ[Rintꢀ=ꢀ0.0179]
–7,6;ꢀ–17,10;ꢀ–10,20
2.14–30.17
0.363
-
1
Fig. 2ꢀ Theꢀ molecularꢀ structureꢀ withꢀ theꢀ atom-numberingꢀ
scheme.ꢀ Displacementꢀ ellipsoidsꢀ areꢀ drawnꢀ atꢀ 30%ꢀ probabilityꢀ
level.
432
No.ꢀofꢀobservedꢀdata,ꢀI>2σ(I)ꢀ
No.ꢀofꢀvariablesꢀ
2412
126
No.ꢀofꢀrestraintsꢀ
0
2
GoodnessꢀofꢀfitꢀonꢀF ꢀ
1.062
a
R ,wR [I≥2σ(I)] ꢀ
0.0375,ꢀ0.0885
0.0472,ꢀ0.0953
0.157,ꢀ–0.164
731637
1
2
a
R ,wR ꢀ(allꢀdata) ꢀ
1
2
Largestꢀdiffꢀpeakꢀandꢀholeꢀ
CCDCꢀdepositꢀno.ꢀ
a
R ꢀ=ꢀΣ||F |-|F ||/Σ|F |,wR ꢀ=ꢀ[Σw(FO2-FC ) /Σw(FO ) ] ,wꢀ=ꢀ1/[σ2
2 2
2 2 1/2
1
O
C
O
2
2
2
2
2
(
FO )ꢀ+ꢀ(0.0459P) ꢀ+ꢀ0.0437P]ꢀwhereꢀPꢀ=ꢀ(FO ꢀ+ꢀ2FC )/3.
Table 2ꢀ Selectedꢀbondꢀlengthsꢀ(Å)ꢀandꢀanglesꢀ(°)ꢀforꢀtheꢀtitleꢀ
compound
N1–C4ꢀ
N1–C1ꢀ
N2–C2ꢀ
N2–N3ꢀ
N3–N4ꢀ
O1–C5ꢀ
O2–C5ꢀ
O2–C6ꢀ
1.498(3)ꢀ
1.500(2)ꢀ
1.492(3)ꢀ
1.219(3)ꢀ
1.110(3)ꢀ
1.198(2)ꢀ
1.326(2)ꢀ
1.441(3)ꢀ
C4–N1–C1ꢀ
C3–C2–C1ꢀ
N2–C2–C3ꢀ
N3–N2–C2ꢀ
N4–N3–N2ꢀ
O1–C5–O2ꢀ
O1–C5–C4ꢀ
O2–C5–C4ꢀ
108.62(15)
103.60(17)
112.1(2)
114.7(2)
173.0(3)
125.56(19)
123.92(17)
110.50(17)
Fig. 3ꢀ Packingꢀ diagram.ꢀ Hydrogenꢀ bondsꢀ areꢀ shownꢀ asꢀ
dashedꢀlines.
Table 3ꢀ Geometricalꢀparametersꢀforꢀhydrogenꢀbondsꢀforꢀtheꢀtitleꢀcompound
Hydrogenꢀbondsꢀ
D–H(Å)ꢀ
H…A(Å)ꢀ
D…A(Å)ꢀ
D–H…A(°)
N1–HN1A…O1ꢀ
N1–HN1A…Cl1ꢀ
0.86(2)ꢀ
0.86(2)ꢀ
0.97(3)ꢀ
2.34(2)ꢀ
2.39(2)ꢀ
2.21(3)ꢀ
2.746(2)ꢀ
3.17(2)ꢀ
3.11(2)ꢀ
109.0(16)
150.3(18)
154(2)
a
N1–HN1B…Cl1 ꢀ
aX +ꢀ1,y,z.
PAPER:ꢀJC090715

6
70ꢀ JOURNALꢀOFꢀCHEMICALꢀRESEARCHꢀ2009
Cl(xꢀ+ꢀ1,y,z)ꢀformꢀstrongꢀintermolecularꢀN–H…Clꢀhydrogenꢀbondsꢀ
Tableꢀ3).ꢀTheꢀserialꢀhydrogenꢀbondsꢀformꢀlayersꢀperpendicularꢀtoꢀbcꢀ
planeꢀ(Fig.ꢀ3),ꢀwhichꢀisꢀvitalꢀforꢀtheꢀstabilityꢀofꢀtheꢀcrystalꢀstructure.
ꢀ 6ꢀ Y.L.ꢀLiꢀandꢀW.F.ꢀXu,ꢀBioorg. Med. Chem.,ꢀ2004, 12,ꢀ5171.
ꢀ 7ꢀ L.ꢀZhang,ꢀJ.ꢀZhang,ꢀH.ꢀFang,ꢀQ.ꢀWangꢀandꢀW.F.ꢀXu,ꢀBioorg. Med. Chem.,ꢀ
(
2
006,ꢀ14,ꢀ8286.
ꢀ
ꢀ
8ꢀ X.C.ꢀ Cheng,ꢀ Q.ꢀ Wang,ꢀ H.ꢀ Fang,ꢀ W.ꢀ Tangꢀ andꢀ W.F.ꢀ Xu,ꢀ Eur. J. Med.
Chem.,ꢀ2008,ꢀ43,ꢀ2130.
9ꢀ X.C.ꢀ Cheng,ꢀ Q.ꢀ Wang,ꢀ H.ꢀ Fang,ꢀ W.ꢀ Tangꢀ andꢀ W.F.ꢀ Xu,ꢀ Bioorg. Med.
Chem.,ꢀ2008,ꢀ16,ꢀ5398.
Conclusions
Inꢀ summary,ꢀ usingꢀ enantiomericallyꢀ pureꢀ trans-4-hydroxy-
L-prolineꢀ asꢀ theꢀ startingꢀ material,ꢀ weꢀ preparedꢀ cis-4-azido-
L-prolineꢀ methylꢀ esterꢀ hydrochlorideꢀ asꢀ whiteꢀ needle-
shapedꢀcrystalsꢀwithꢀtotalꢀyieldꢀaboutꢀ50%,ꢀwhoseꢀchemicalꢀ
ꢀ10ꢀ X.C.ꢀ Cheng,ꢀ Q.ꢀ Wang,ꢀ H.ꢀ Fang,ꢀ W.ꢀ Tangꢀ andꢀ W.F.ꢀ Xu,ꢀ Bioorg. Med.
Chem.,ꢀ2008,ꢀ16,ꢀ7932.
ꢀ11ꢀ F.Z.ꢀLiu,ꢀH.ꢀFang,ꢀH.W.ꢀZhu,ꢀQ.ꢀWang,ꢀY.ꢀYangꢀandꢀW.F.ꢀXu,ꢀBioorg.
Med. Chem.,ꢀ2008,ꢀ16,ꢀ578.
1
structureꢀ wasꢀ confirmedꢀ byꢀ Hꢀ NMR,ꢀ IR,ꢀ ESI-MSꢀ andꢀ
ꢀ12ꢀ J.ꢀZhang,ꢀQ.ꢀWang,ꢀH.ꢀFang,ꢀW.ꢀXu,ꢀA.ꢀLiuꢀandꢀG.ꢀDu,ꢀBioorg. Med.
elementalꢀ analysis.ꢀAllꢀ theꢀ reactionsꢀ wereꢀ processedꢀ underꢀ
mildꢀconditionsꢀandꢀtheꢀfinalꢀcompoundꢀshouldꢀbeꢀopticallyꢀ
pureꢀdeducedꢀfromꢀtheꢀdeterminationꢀofꢀspecificꢀrotationꢀandꢀ
elucidationꢀofꢀitsꢀcrystalꢀstructure.ꢀThisꢀkeyꢀprecursorꢀcouldꢀ
beꢀ usedꢀ forꢀ theꢀ synthesisꢀ ofꢀ novelꢀ influenzaꢀ neuraminidaseꢀ
inhibitors,ꢀandꢀmanyꢀotherꢀpharmaceuticalꢀintermediates.
WeꢀthankꢀtheꢀNationalꢀNaturalꢀScienceꢀFoundationꢀofꢀChinaꢀ
Chem.,ꢀ2007, 15,ꢀ2749.
ꢀ
13ꢀ D.J.ꢀAbraham,ꢀM.ꢀMokotoff,ꢀL.ꢀShehꢀandꢀJ.E.ꢀSimmons,ꢀJ. Med. Chem.,ꢀ
983,ꢀ26,ꢀ549.
14ꢀ L.L.ꢀKlein,ꢀL.ꢀLi,ꢀH.J.ꢀChen,ꢀC.B.ꢀCurty,ꢀD.A.ꢀDeGoey,ꢀD.J.ꢀGrampovnik,ꢀ
1
ꢀ
C.L.ꢀ Leone,ꢀ S.A.ꢀ Thomas,ꢀ C.M.ꢀ Yeung,ꢀ K.W.ꢀ Funk,ꢀ V.ꢀ Kishore,ꢀ
E.O.ꢀ Lundell,ꢀ D.ꢀ Wodka,ꢀ J.A.ꢀ Meulbroek,ꢀ J.D.ꢀ Alder,ꢀ A.M.ꢀ Nilius,ꢀ
P.A.ꢀLarteyeꢀandꢀJ.J.ꢀPlattner,ꢀTotalꢀBioorg. Med. Chem.,ꢀ2000,ꢀ8,ꢀ1677.
ꢀ
15ꢀ T.ꢀBaer,ꢀT.ꢀMartin,ꢀJ.ꢀStadlwieser,ꢀS.L.ꢀWollin,ꢀK.ꢀZech,ꢀC.P.ꢀSommerhoffꢀ
andꢀW.R.ꢀUlrich,ꢀPCT Int. Appl.,ꢀWOꢀ2002060895,ꢀ2002.
(grantꢀNo.ꢀ36072541)ꢀforꢀfinancialꢀsupport.
ꢀ
16ꢀ T.ꢀBaer,ꢀJ.ꢀStadlwieser,ꢀS.L.ꢀWollin,ꢀK.ꢀZech,ꢀC.P.ꢀSommerhoff,ꢀT.ꢀMartinꢀ
andꢀW.R.ꢀUlrich,ꢀPCT Int. Appl.,ꢀWOꢀ2002102771,ꢀ2002.
ꢀ17ꢀ T.ꢀMartinꢀandꢀW.R.ꢀUlrich,ꢀPCT Int. Appl.,ꢀWOꢀ2004012731,ꢀ2004.
ꢀ18ꢀ L.S.ꢀ Sonntag,ꢀ S.ꢀ Ivan,ꢀ M.ꢀ Langer,ꢀ M.M.ꢀ Conzaꢀ andꢀ H.ꢀ Wennemers,ꢀ
Synlett,ꢀ2004,ꢀ7,ꢀ1270.
Received 16 July 2009; accepted 10 October 2009
Paper 09/0715 doi: 10.3184/030823409X12555437784172
Published online: 16 November 2009
ꢀ
19ꢀ U.ꢀSirion,ꢀH.J.ꢀKim,ꢀJ.H.ꢀLee,ꢀJ.W.ꢀSeo,ꢀB.S.ꢀLee,ꢀS.J.ꢀLee,ꢀS.J.ꢀOhꢀandꢀ
D.Y.ꢀChi,ꢀTetrahedron Lett.,ꢀ2007,ꢀ48,ꢀ3953.
ꢀ20ꢀ B.ꢀHan,ꢀH.ꢀKnust,ꢀM.ꢀNettekoven,ꢀH.ꢀRatniꢀandꢀX.ꢀWu,ꢀPCT Int. Appl.,ꢀ
WOꢀ2008148689,ꢀ2008.
References
ꢀ
1ꢀ J.ꢀBaumꢀandꢀB.ꢀBrodsky,ꢀMechanisms of protein folding,ꢀ2ndꢀedn,ꢀOxfordꢀ
UniversityꢀPress,ꢀOxford, 2000, ppꢀ330-351.
ꢀ21ꢀ A.ꢀ Mckillop,ꢀ R.J.K.ꢀ Taylor,ꢀ R.J.ꢀ Watsonꢀ andꢀ N.ꢀ Lewis,ꢀ Synthesis,ꢀ
1
994,ꢀ31.
ꢀ
ꢀ
2ꢀ C.L.ꢀJenkinsꢀandꢀR.T.ꢀRaines,ꢀNat. Prod. Rep., 2002,ꢀ19,ꢀ49.
3ꢀ R.ꢀBerisio,ꢀL.ꢀVitagliano,ꢀL.ꢀMazzarellaꢀandꢀA.ꢀZagari,ꢀProtein Pept. Lett.,
ꢀ22ꢀ U.ꢀ Jordis,ꢀ F.ꢀ Sauterꢀ andꢀ S.M.ꢀ Siddiqi,ꢀ Indian J. Chem. Sec. B,ꢀ 1989,
28B,ꢀ294.
2
002,ꢀ9,ꢀ107.
ꢀ
ꢀ
4ꢀ G.ꢀTuchschererꢀandꢀM.ꢀMutter,ꢀChimia, 2001,ꢀ55,ꢀ306.
5ꢀ J.D.ꢀFisk,ꢀD.R.ꢀPowellꢀandꢀS.H.ꢀGellman,ꢀJ. Am. Chem. Soc., 2000,ꢀ122,ꢀ5443.
ꢀ23ꢀ G.M.ꢀ Sheldrick,ꢀ SHELXTLꢀ V5.1ꢀ Software Reference Manual,ꢀ Brukerꢀ
AXS,Inc.,ꢀMadison,ꢀWisconsin.
PAPER:ꢀJC090715