Synthesis of Functional Amino Acids Bearing 1,3-Dithiane Modification

JournalofChinesePharmaceuticalSciences
195
http://www.jcps.ac.cn
Note
Synthesisoffunctionalaminoacidsbearing1,3dithianemodification
YingYang,ChaoWang*
DepartmentofMedicinalChemistry,SchoolofPharmaceuticalSciences,PekingUniversityHealthScienceCenter,
Beijing100191,China
Abstract:Twoprotectedsingleaminoacidchelates,NFmocN,Ndi((2,2dimethyl1,3dithian5yl)methyl)Llysine(7)and
NFmocN(2,2dimethyl1,3dithian5yl)methyl,NBocLlysine(9),weresynthesizedbymodifyingthesidechainoflysine
with1,3dithianethroughdirectreductiveNalkylationprotocol.Theseaminoacidshavepotentialusesinpeptidechemistry.
Keywords: Aminoacidchelate1,3DithianeReductiveNalkylation
CLCnumber:R916
Documentcode:A
ArticleID:10031057(2011)219504
1.Introduction
(A)
Radiolabeled peptides can be used to target a

variety of disease tissues through interaction with
specific cell receptors[1]. Introduction of an entity
that allows facile labeling with medically useful
radionuclidessuchas99mTcfordiagnosisand186/188Re
for targeted therapy is desirable. The general
approaches for the linking of metal cations to a
readily prepared peptide are through the use of
bifunctionalchelatestoformmetalchelatingagent
peptide complex. However, the limitations of this
strategy for peptide labeling are its poor residue
selectivity and potentially significant alteration of
thepeptidesstructureandreceptorbindingaffinity.
Inviewoftheneedforbetterlabelingstrategyand
the importance of the thiolate ligands in coordina
tion with heavy metals to form stable complex, we
designedanovelaminoacidchelatethatwasprepared
frommodifiedaminoacidanalogues.Theprotected
thiols in a 1,3dithiane structure as the potential
chelating functionality were introduced to the side
chainoflysineforeffectivecoordinationwith99mTc
(Fig.1).Weanticipatedsuchaminoacidchelatecan
beusedinpeptidesynthesisandthisspecificresidue
canbeincorporatedintoanypositionalongapeptide
sequence.
w
w
c
j
.
w
a
.
s
p
(B)
(CH2)n C AA1-AA2-AA3........AAn-1-AAn-OH
O Tc
S
S
(C)
n
c
c.
H-AA1-AA2-AA3........AAn-1-AAn-OH
HS
AAC=
HS
SH
N
(CH2)4
N
H
SH
H-AAC-AA2-AA3........AAn-1-AAn-OH
H-AA1-AAC-AA3........AAn-1-AAn-OH
H-AA1-AA2-AAC........AAn-1-AAn-OH
H-AA1-AA2-AA3........AAC-AAn-OH
H-AA1-AA2-AA3........AAn-1-AAC-OH
Figure 1. Schematic representation of labeling peptide with 99mTc:

(A) The sequence of a bioactive peptide (B) An example of a
bifunctional chelatelinkingradioactive metalcationto thepeptide
(C) Amino acid chelate modified peptide for labeling with 99mTc.
AAC=aminoacidchelate.
In our earlier experiments, two protected amino

acid chelators, NFmocO((S,Sdiacetamidomethyl)
3,3dithioether)isobutyl Ltyrosine and NFmoc
O((S,Sisopropylidene)3,3dithioether)isobutyl
Ltyrosine were synthesized from NFmoctyrosine
methyl ester with the hydroxyl components by

Mitsunobureaction[2].Thoseaminoacidshavebeen
used in peptide synthesis by solution method or by
solidphasemethod.Theprotectionofthesulfhydryl
groupcouldberemovedbydeprotectingprocedures
Receiveddate:20101107.
*
Correspondingauthor.Tel.:861082805049
Email:chaowang@bjmu.edu.cn
commonly used in peptide chemistry, and the 1,3
doi:10.5246/jcps.2011.02.025
of1,2dithiolanes.
dithiolsunitscanbeeasilyregeneratedviatheform
Copyright 2011 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University
196
Y.Yang etal./JournalofChinesePharmaceuticalSciences20(2011)195198
The purpose of this study was to develop a new
SH SH
moiety in one amino acid residue. The reactions

used in the preparation of such specific functional
single amino acid chelate that has multithiolate
OH
OH
aminoacidsareshowninScheme1.
S
2.Resultsanddiscussion
OH
NH2
Inourexperiment,weattemptedtopreparealdehyde
(4) with these procedures and the results showed
that the reductive method using Weinreb amide
O
6
affordedcorrespondingaldehydesatisfactorily.
reactioninorganicpreparation.Inthecaseofamino
acids, the reductive alkylation with aldehydes is
n
c
c.
(CH2)4
OH
Fmoc N
H
alkylationofaminoacidswithafreeacidfunctionality
arerare.Inourexperiments,therequireddialkylated
product (7) and the monoalkylated product (8)
were obtained in one pot under mild condition.
Compounds7and8wereisolatedin20%and46%
yield,respectively,bysilicacolumnchromatography.
Theiminogroup of monoalkyl derivative(8)was
protected by the Boc group, which can be used for
peptidesynthesisbytheFmocstrategy.
AbdelMagid et al[4] have recently demonstrated
thatNaBH(OAc)3 canbeusedeffectivelyasamild
reagentinthereductiveaminationofaldehydesand
ketones with shorter reaction time and excellent
yields.Thismethodwasconfirmedinourexperiment,
because the efficiency of NaBH(OAc)3 was much
higherthanthatofNaBH3CNorNaBH4.
The finalaim of ourresearches istosynthesizea
series of bioactive peptides that contain the key
structural feature of multithiols in one amino acid
residue,andthatresiduecanbeincorporatedintoany
a
.
s
p
(CH2)4
Fmoc N
H
OH
O
8 R=H
9 R=Boc
Scheme 1. Reagents and conditions: (a) CH3COCH3 , BF3/Et2O,

CHCl3,0C,50%(b)CH3NHOCH3,TBTU,DMF,56%(c)LiAlH4,
THF, 0 C, 100% (d) DMP, CH 2Cl2, 50% (e) NaBH(OAc) 3,
THF,20%(7),46%(8)(f)NaHCO3/H2O,Boc2O,70%.TBTU =2
(1HBenzotriazole1yl)1,1,3,3tetramethyluronium tetrafluoroborate
DMP=DessMartinperiodinaneFmoc=9Fluorenylmethoxycarbonyl
Boc= tbutyloxycarbonyl.
c
j
.
w
generally performed after protecting the carboxyl

groupasanester.Thereportsthatdetailthereductive
Reductiveaminationofaldehydesisaveryuseful
99m
OH
Fmoc N
H
H
4
alcohols.Italsocanbesynthesizedfromcarboxylic
acids via Weinreb amides under mild conditions[3].
Aldehydes are often prepared by oxidation of
w
w
3.Experimental
Meltingpointsweremeasuredusingamicroscope
hotstageapparatusandareuncorrected.NMRandMS
spectroscopicdatawereobtainedontheBruker500
and ZQ2000 instruments, respectively. Elemental
analyses were performed on a PE2400 elemental
analyzer. All reactions were monitored by TLC
usingprecoatedplatesofsilicagel60F254 (Merck).
3.1. 3Mercapto2(mercaptomethyl)propoinic
acid(1)
It was prepared according to the literature proce
dure[6].
3.2.2,2Dimethyl1,3dithiane5carboxylicacid(2)
Toawellstirredsolutionof1(1.9g,12.5mmol)
in CHCl3 (15 mL), acetone (1.45 g, 25 mmol) and
[5]
position ofa peptidesequence for Tclabeling .

The amino acid chelates synthesized in the present
BF3/ethylether(0.76mL)wereaddedat0C .The
reaction mixture was stirred at room temperature
reportcouldhavepotentialusesinpeptidechemistry.
overnight. It was washed with saturated aqueous
197
NaHCO3 (33mL)and water(33mL),dried over
oil(0.41g,>100%),whichwasdirectlyusedfornext
anhydrous Na2SO4 and concentrated in vacuo to
stagepreparationwithoutfurtherpurification. 1HNMR
giveacrudeproduct,whichwasrecrystallizedfrom
(500 MHz, CDCl3) : 1.72 (s, 3H), 1.73 (s, 3H),
ethyletherpetroleumethertoaffordawhiteneedle
2.73 (m, 1H), 3.08 (dd, 2H, J1 8.6 Hz, J2 14.6 Hz),
crystal(0.92g,50%).Mp131132CESIMS:m/z
3.15(dd,2H,J13.3Hz,J214.6Hz),9.79(s,1H).
+ 1
193 (M+H) , 215 (M+Na) H NMR (500 MHz,
MethodB:Toawellstirredsolutionof5(0.04g,
CDCl3):1.67(s,3H),1.81(s,3H),2.90(m,1H),
0.225mmol)inCH2Cl2,NaHCO3(0.113g,1.35mmol)
3.06(dd,2H,J 13.2Hz,J 214.8Hz),3.20(dd,2H,
andDMP(0.143g,0.338mmol)wereaddedatroom
J 1 10.1Hz, J214.8Hz).
temperature.Themixturewasstirredforanother2h
3.3. 2,2Dimethyl1,3dithiane5carboxylic acid

methoxymethylamide(3)
until5 wasdisappeared.ThenCH2Cl2 (15 mL)was

added,andthereactionwasquenchedwithNa2S2O3
(0.235g,1.35mmol).Themixturewaswashedwith
n
c
c.
5% NaHCO3 (25 mL) and water (33 mL), dried
in DMF (20 mL), N, Odimethylhydroxylamine
over anhydrous Na2SO4 and concentrated in vacuo
hydrochloride (0.92 g, 9.36 mmol) and N, N
to giveayellow oil, whichisused directlywithout
diisopropylethylamine(2.57mL,1.94g,1.5mmol)
were added. The reaction mixture was stirred for
30 min at room temperature, then TBTU (3.37 g,
c
j
.
w
10.4 mmol) was added. The reaction mixture was

stirred for 3 h, TLC showed the reaction was
completed. The reaction mixture was poured into

water and NaCl was added, and the mixture was
w
w
a
.
s
p
furtherpurification.
3.5.2,2Dimethyl1,3dithiane5methanol(5)
It was obtained as a a white crystal according to
thepreviousreport[2].
3.6.NFmocLlysine(6)
extracted using EtOAc (310 mL). The organic

layer was washed with water (33 mL), dried over
anhydrousNa2SO4 andconcentratedinvacuotogive
It was obtained as a white crystal in 50% yield

accordingtotheliteraturemethod[7,8].
awhitesolid,which was purifiedbycrystallization
3.7. NFmocN, Ndi((2,2dimethyl1,3dithian
from ethyl ether to afford a white crystal (1.0 g,
5yl)methyl)Llysine (7) and NFmocN(2,2
56%).Mp6465CESIMS:m/z236(M+H) ,258
(M+Na)+,274(M+K)+1HNMR(500MHz,CDCl3)
dimethyl1,3dithian5yl)methylLlysine(8)
:1.62(s,3H),1.89(s,3H),2.76(dd,2H,J12.5Hz,
J2 14.5 Hz), 3.16 (m, 1H), 3.22 (s, 3H), 3.28 (dd,
in THF (7 mL), compound 6 (0.458, 0.95 mmol)
2H,J111.8Hz,J213.4Hz),3.76(s,3H).
wasaddedatroomtemperature.Itwasstirredfor
3.4.2,2Dimethyl1,3dithiane5carbaldehyde(4)
30 min, and NaBH(OAc)3 (0.5 g, 2.38 mmol) was

added.Thereactionmixturewasstirredfor3hat
MethodA:Toawellstirredsolutionof3(0.45g,
room temperature until the reagent disappeared
1.9 mmol) in THF (10 mL), LiAlH4 (0.095 g,
(thereaction was monitoredby TLC).Thereaction
2.47 mmol) was added at 0 C. The reaction was
mixture was poured into water and stirred. The
quenched by 10% KHSO4 after 1.5 h stirring, then
mixturewasfiltrated,andtheprecipitatewaspurified
the mixture was filtered. The filtrate was extracted
by column chromatography (CHCl3MeOHHOAc
using CH2Cl2 (310 mL). The organic layer was
EtOAcpetroleum ether, 20:1:0.4:2:2) to get the
washedwithwater(33mL),driedoveranhydrous
product 7 asawhitesolid(0.09g,20%)andproduct 8
Na2SO4 andconcentratedinvacuotogiveayellow
(0.2g,46%)asawhitesolid.
198
[]20
Compound7,mp106107C.+1.43(MeOH
D
20
whitesolid(0.07g,70%).Mp7778C[]D 0.70
c1.0) ESIMS: m/z 688(M+H)+1HNMR (500MHz,
(MeOH c1.0)HRESIMS:m/z629.26945(M+H)+,
CDCl3):1.29(m,2H),1.42(m,2H),1.54(m,1H),
calcd. 629.27136, 651.25303 (M+Na)+ found
1.67 (s, 6H), 1.68 (s, 6H), 1.97 (m, 1H), 2.15 (m,
651.253301HNMR(500MHz,CDCl3):1.29(m,
2H),2.632.77(m,8H),2.84(m,2H),3.02(m,4H),
2H),1.41(m,2H),1.48(s,9H),1.60(m,1H),1.68
3.04(m,1H),4.25(m,2H),4.48(m,1H),7.33(t,2H,
(s, 3H), 1.75 (s, 3H), 1.96 (m, 1H), 2.13 (m, 1H),
J6.5Hz),7.41(t,2H,J6.5Hz),7.65(m,2H),7.78
3.22(m,2H),3.32(m,2H),4.26(m,1H),4.43(m,
(d,2H, J 7Hz).Anal.calcd.for C35H48N2O4S2H2O: C,
3H), 7.34(t, 2H,J7.5Hz), 7.42 (t, 2H,J 7.5 Hz),
59.46 H, 7.13 N, 3.96. Found: C, 59.65 H, 7.24
7.63(m,2H),7.78(d,2H, J8Hz).
N,3.58.
Compound 8, mp 192193 C ESIMS: m/z 529
(M+H)+.Itisuseddirectlyinthenextpreparation.
3.8. NFmocN(2,2dimethyl1,3dithian5yl)
methyl,NBocLlysine(9)
References
n
c
c.
[1]Fischman,A.J.Babich,J.W.Strauss,H.W.J.Nucl.Med.
1993, 34,22532260.
[2] Sun, Y. Li, X.Q. Meng, Y.P. Wang, C. Syn. Commun.
a
.
s
p
2008, 38,33033310.
To a flask, compound 8 (0.084 g, 0.159 mmol),

water (5 mL), NaHCO3 (0.38 g, 0.454 mmol) and
[3] Marielle, P. Catherine, P. Laurent, G. Annie, H.
Boc2O(0.643g,0.295mmol)wereaddedinsequence.
Martinez,J.FehrentzJ.A.React.Funct.Polym.1999,41,
c
j
.
w
The mixture was stirred at room temperature and
255261.
becameclear20 minlater.The mixture wasstirred
[4]AbdelMagid,A.F.Carson,K.G.Harris,B.C.Maryanoff,
foranother1hatroomtemperature.ThenthepHof
C.A.Shah,R.D. J.Org.Chem.1996, 61,38493862.
themixturewasadjustedto2with5%KHSO4.The
[5]Liu,S.Edwards,D.S. Chem.Rev. 1999, 99,22352268.
mixturewasextractedwithEtOAc(310 mL).The
[6] Singh, R. Whitesides, G.M. J. Am. Chem. Soc. 1990,
w
w
organic layer was washed with water (33 mL),
112,11901197.
dried over anhydrous Na2SO4 and concentrated in
[7] Leman, L.J. Weinberger, D.A. Huang, Z,Z. Wilcoxen,
vacuo to give a yellow oil, which was purified by
K.M. Ghadiri,M.R.J.Am.Chem.Soc.2007,129,2959
column chromatography (EtOAcpetroleum ether
2966.
HOAc, 5:1:0.4) to get the desired product as a
[8]Haldar,D.Tetrahedron. 2008, 64,186190.
, *
, 100191
: N1,3, N
FmocN, Ndi((2,2dimethyl1,3dithian5yl)methyl)Llysine (7) NFmocN((2,2dimethyl1,3dithian5yl)methyl, N
BocLlysine(9)
: 1,3 N

Synthesis of Functional Amino Acids Bearing 1,3-Dithiane Modification

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JournalofChinesePharmaceuticalSciences

Radiolabeled peptides can be used to target a

Figure 1. Schematic representation of labeling peptide with 99mTc:

In our earlier experiments, two protected amino

methyl ester with the hydroxyl components by

commonly used in peptide chemistry, and the 1,3

The purpose of this study was to develop a new

moiety in one amino acid residue. The reactions

single amino acid chelate that has multithiolate

Scheme 1. Reagents and conditions: (a) CH3COCH3 , BF3/Et2O,

generally performed after protecting the carboxyl

Aldehydes are often prepared by oxidation of

position ofa peptidesequence for Tclabeling .

overnight. It was washed with saturated aqueous

NaHCO3 (33mL)and water(33mL),dried over

anhydrous Na2SO4 and concentrated in vacuo to

(500 MHz, CDCl3) : 1.72 (s, 3H), 1.73 (s, 3H),

193 (M+H) , 215 (M+Na) H NMR (500 MHz,

3.06(dd,2H,J 13.2Hz,J 214.8Hz),3.20(dd,2H,

3.3. 2,2Dimethyl1,3dithiane5carboxylic acid

until5 wasdisappeared.ThenCH2Cl2 (15 mL)was

5% NaHCO3 (25 mL) and water (33 mL), dried

in DMF (20 mL), N, Odimethylhydroxylamine

over anhydrous Na2SO4 and concentrated in vacuo

hydrochloride (0.92 g, 9.36 mmol) and N, N

to giveayellow oil, whichisused directlywithout

10.4 mmol) was added. The reaction mixture was

completed. The reaction mixture was poured into

extracted using EtOAc (310 mL). The organic

It was obtained as a white crystal in 50% yield

awhitesolid,which was purifiedbycrystallization

3.7. NFmocN, Ndi((2,2dimethyl1,3dithian

from ethyl ether to afford a white crystal (1.0 g,

5yl)methyl)Llysine (7) and NFmocN(2,2

in THF (7 mL), compound 6 (0.458, 0.95 mmol)

30 min, and NaBH(OAc)3 (0.5 g, 2.38 mmol) was

room temperature until the reagent disappeared

1.9 mmol) in THF (10 mL), LiAlH4 (0.095 g,

(thereaction was monitoredby TLC).Thereaction

2.47 mmol) was added at 0 C. The reaction was

mixture was poured into water and stirred. The

quenched by 10% KHSO4 after 1.5 h stirring, then

the mixture was filtered. The filtrate was extracted

by column chromatography (CHCl3MeOHHOAc

using CH2Cl2 (310 mL). The organic layer was

EtOAcpetroleum ether, 20:1:0.4:2:2) to get the

c1.0) ESIMS: m/z 688(M+H)+1HNMR (500MHz,

calcd. 629.27136, 651.25303 (M+Na)+ found

(d,2H, J 7Hz).Anal.calcd.for C35H48N2O4S2H2O: C,

3H), 7.34(t, 2H,J7.5Hz), 7.42 (t, 2H,J 7.5 Hz),

59.46 H, 7.13 N, 3.96. Found: C, 59.65 H, 7.24

[2] Sun, Y. Li, X.Q. Meng, Y.P. Wang, C. Syn. Commun.

To a flask, compound 8 (0.084 g, 0.159 mmol),

[3] Marielle, P. Catherine, P. Laurent, G. Annie, H.

The mixture was stirred at room temperature and

becameclear20 minlater.The mixture wasstirred

C.A.Shah,R.D. J.Org.Chem.1996, 61,38493862.

[5]Liu,S.Edwards,D.S. Chem.Rev. 1999, 99,22352268.

[6] Singh, R. Whitesides, G.M. J. Am. Chem. Soc. 1990,

organic layer was washed with water (33 mL),

dried over anhydrous Na2SO4 and concentrated in

[7] Leman, L.J. Weinberger, D.A. Huang, Z,Z. Wilcoxen,