Amphiphilic analogues of peptidoamines with perfluorinated side chains. Synthesis and preliminary investigations of their surfactant and complexing abilities

Article abstract of DOI:10.1016/S0022-1139(00)00381-X

A new synthetic pathway for preparing perfluorinated β-alanines is described. 2-Perfluoroalkyl-ethanols are oxidized, dehydrofluorinated, substituted with an azide group and finally hydrogenated with excellent yields. The C-perfluoroalkylated β-alanines o

Full text of DOI:10.1016/S0022-1139(00)00381-X

Journal of Fluorine Chemistry 107 (2001) 375±386
Amphiphilic analogues of peptidoamines with
per¯uorinated side chains
Synthesis and preliminary investigations of
their surfactant and complexing abilities
a
a
b
a
È
Sedat Cosgun , Mehmet Ozer , Faouzia Hamdoune , Christine Gerardin ,
Sylvie Thiebauta, Bernard Henrya, Jacques Amosa,
a
Ludwig Rodehuser , Claude Selve
a,*
È
Faculte des Sciences, Laboratoire de Chimie Physique Organique et Colloõdale, Universite Henri Poincare, Nancy I,
a
Â
È
Â
Â
UMR CNRS-UHP No. 7565, BP 239, F-54506 Vandoeuvre les Nancy Cedex, France
Â
b
 Â
Departement de Chimie, Faculte des Sciences et Techniques, Universite Abdelmalek Essaadi, BP 416, Tanger, Morocco
Received 3 April 2000; accepted 5 May 2000
Abstract
A new synthetic pathway for preparing per¯uorinated b-alanines is described. 2-Per¯uoroalkyl-ethanols are oxidized, dehydro-
¯uorinated, substituted with an azide group and ®nally hydrogenated with excellent yields. The C-per¯uoroalkylated b-alanines obtained in
this way are subsequently used as hydrophobic moieties for the synthesis of amphiphilic lipo-peptides and lipo-peptidoamines. The choice
of the peptidoamine structure is justi®ed by the anti-oxidative and complexing properties of natural analogues such as carcinine and
carnosine. Measurements of the surface tension of aqueous solutions of the compounds synthesized reveal their surfactant properties.
Potentiometric and spectroscopic investigations give evidence for their good ability to complex copper(II) ions in solution. # 2001 Elsevier
Science B.V. All rights reserved.
Keywords: Per¯uoroalkyl-b-alanine; Per¯uoroalkyl-peptidoamine; Surfactants; Critical concentration; Complexation
1. Introduction
tecting substances certain metal complexes of pseudopep-
tides of the peptidoamine type are known for their
anti-oxidative action [8,9]. We have shown previously
[10] that lipo-oligopeptide structures are surface active.
The peptidoamines containing an imidazol moiety stem-
ming from histidine or histamine structures [11±13], in
particular carcinine [14] and carnosine [15,16] seemed to
us the most promising. The structures of these two dipep-
tides are shown in Scheme 1.
Both contain the b-alanine moiety linked via a peptide
bond either to histidine (in carnosine) or to histamine (in
carcinine). We have described ef®cient syntheses of b-
per¯uoroalkyl-b-alanines previously [17]. These com-
pounds may be used as hydrophobic junction modules in
modular synthetic pathways [18,19]. In this paper we
describe the preparation of carnosine and carcinine analo-
gues starting from b-per¯uoroalkyl-b-alanines, and the
investigation of some of their physico-chemical properties.
The new compounds are surfactants and good ligands for
divalent cations such as copper(II).
Many biological applications use ¯uorinated organic
compounds and chemical research in this ®eld gives rise
to numerous publications [1,2]. The surfactants pertaining to
this family are of particular interest for the preparation of
¯uids capable to transport respiratory gases [3±5]. However,
the high concentrations of oxygen supplied by these solu-
tions may lead to the formation of toxic derivatives (per-
oxides, free radicals) [6] in amounts such that the natural
defense mechanisms of the organism can no longer cope
with them [7].
We have, therefore, attempted to solve this dif®culty by
synthesizing molecules bearing a per¯uorinated hydropho-
bic chain which exhibit simultaneously surfactant and
potentially anti-oxidative properties. Among the bio-pro-
* Corresponding author. Tel.: ‡33-3-83-91-23-60;
fax: ‡33-3-83-91-25-32.
E-mail address: claude.selve@lesoc.uhp-nancy.fr (C. Selve).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 3 8 1 - X

376
S. Cosgun et al. / Journal of Fluorine Chemistry 107 (2001) 375±386
Table 1
Yields of coupling reactions with three different activation agentsa
Compound
n
R1
R2
Yield (%)
BOP
DCC
Mixed
anhydrides
Z-3AA5-Me
Z-3AA7-Me
Z-3AA9-Me
Z-2A5
5
7
9
5
7
9
5
7
CH3
CH3
CO2Me
CO2Me
CO2Me
H
80
80
60
75
70
75
65
60
75
65
55
55
45
50
40
40
45
40
25
40
30
±
Scheme 1. Structures of carnosine and carcinine.
CH3
CH2-Im
CH2-Im
CH2-Im
Z-2A7
Z-2A9
H
2. Results and discussion
H
Z-1B5-Me
Z-1B7Me
CH2-Im CO2Me
CH2-Im CO2Me
±
2.1. Syntheses
±
a Structure of the products:
We have prepared three series of compounds (Schemes 2
and 3). They are amphiphilic pseudopeptide analogues of the
lipo-oligopeptide (series 3AAn) or the lipo-peptidoamine
type (series 1Bn and 2An). The latter derive either from
carnosine (series 1Bn) or from carcinine (series 2An). They
contain a hydrophobic per¯uoroalkyl chain of n carbon
atoms, which is attached to the peptidoamine via a C±C
bond (Scheme 2).
.
these reactions yield the series of lipo-pseudopeptides
3AAn. The activation via mixed anhydrides proves to be
less ef®cient than the other methods. For the reaction with
histidine (series 1Bn) or with histamine (series 2An), we
have, therefore, chosen BOP or DCC as coupling agents. For
all these syntheses, the puri®cation of the products is rather
dif®cult so that the yields of pure products do not exceed 50±
75% (Table 1).
The hydrogenolysis of the above intermediates with a Pd/
C catalyst leads to the unprotected compounds 3AAn, 1Bn
et 2An (Table 2) via the removal of the benzyloxy-carbonyl
group Z from the terminal amino group (Scheme 4). In this
way, we readily obtain the amphiphilic analogues of carci-
nine (series 2An).
While the hydrogenolysis yields the carcinine analogues
immediately by removing the only protecting group on the
amine function, the other series of products (3AAn and 1Bn)
still bear an ester group on the carboxyl function. It may be
hydrolyzed under usual basic conditions (Scheme 5) to yield
the series of lipopeptide surfactants (3AAn) and that of the
RFn-carnosine type (1Bn). The results are summarized in
Table 3.
The syntheses described above have satisfactory yields
and the methods used should allow an easy scaling up of the
preparations. We have prepared a derivative of carnosine
(1B5) as well as two lipo-oligopeptides 3AA5 and 3AA7 in
suf®cient quantity (several grams) to investigate the surface
The synthesis of these compounds has been achieved the
following reaction pathways indicated in Scheme 3, starting
from commercially available 2-per¯uoroalkyl-ethanols 4. In
previous publications, we had described the ®rst steps
leading to compounds 8 [17] and the subsequent preparation
of the b-per¯uoroalkyl-b-alanines derived from intermedi-
ates similar to 9 [20]. In this paper, we complete the
description of the syntheses with the preparation of the
N-protected-b-per¯uoroalkyl-b-alanines 10. The latter have
been used to prepare the desired surfactants in a further step.
For all compounds of structure 10, derivatives protected
by the benzyloxycarbonyl group Z on the nitrogen atoms
have been synthesized in order to prepare the series of
single-chain surfactants following classical methods
[21,22]. In order to optimize the experimental conditions
for the coupling reaction, we have started with the con-
densation of alanine methyl ester, a non-functional
aminoacid derivative, on the surfactant precursors. We have
used different activators for these couplings which are
classically employed in peptide syntheses: dicyclohexylcar-
bodiimide (DCC) [21,22]; mixed anhydrides in combination
with isopropenyl chloroformate [22,23], and benzo-triazo-
lyl-oxy-tris(dimethylamino)-phosphonium hexa¯uoropho-
sphate (BOP) [24,25]. After the usual deprotection steps,
Scheme 2. Structures of amphiphilic lipo-oligopeptides, analogues of carnosine and carcinine. Single-chain surfactants.

S. Cosgun et al. / Journal of Fluorine Chemistry 107 (2001) 375±386
377
Scheme 3. Synthesis of amphiphilic perfluoroalkyl-pseudopeptides.
Table 2
Hydrogenolytic removal of the N-carbobenzyloxy group Za
activity of these compounds and the ability of surfactant 1B5
to complex the divalent copper ion.
Compound
n
R1
R2
Yield (%)
3AA5-Me
3AA7-Me
3AA9-Me
2A5b
5
7
9
5
7
9
5
7
CH3
CO2CH3
CO2CH3
CO2CH3
H
78
75
58
80
85
50
65
75
3. Preliminary studies of physico-chemical properties
CH3
CH3
CH2-Imc
CH2-Imc
CH2-Imc
CH2-Imc
CH2-Imc
3.1. Surface activity
2A7b
H
2A9b
H
We have measured the surface tension g of aqueous
solutions of the compounds mentioned above at different
concentrations C. The curves g ˆ f (log C) are shown in
Fig. 1.
1B5-Me
1B7-Me
CO2CH3
CO2CH3
a Structures of products 2AAn Me; 1An, 1Bn-Me:
The intersection of the linearly decreasing and the hor-
izontal branch of each curve yields immediately the value of
the CMC and the minimal surface tension gCMC. The inter-
secting solid lines shown in Fig. 1 are the result of a linear
b RFn-carcinine.
c Im ˆ imidazole.
.
Scheme 4. Hydrogenolysis of protecting groups.

378
S. Cosgun et al. / Journal of Fluorine Chemistry 107 (2001) 375±386
Scheme 5. Hydrolysis of protecting groups.
Table 3
Results of the hydrolysis of the methyl ester groupa
Compound
n
R0
R1
R2
Analogue
Yield (%)
3AA5H
3AA7H
3AA9H
1B5Hb
1B7Hb
5
7
9
5
7
H
H
H
H
H
CH3
CH3
CO2H
CO2H
CO2H
CO2H
CO2H
±
80
85
55
75
80
±
CH3
±
CH2-Im
CH2-Im
RF5-carnosine
RF7-carnosine
a Structure of the products:
b RFn-carnosine.
.
regression calculation based on the corresponding experi-
mental values.
Table 4 summarizes the results of these measurements.
For comparison, we have included the values obtained by
other authors [10,19,26,27] for compounds with structures
similar to the above surfactants. It may be noticed that the
products are rather water soluble and their gCMC-values
range from 16 to 19 mN/m [27,28]. For these non-ionic
per¯uoro-lipo-peptides the addition of two CF2 groups leads
to a decrease of the CMC by a factor of about 10. In a similar
way, the increase in chain length by one CF2 group in the
non-ionic surfactants synthesized by Achilefu and cowor-
kers [26,29] lowers the CMC by a factor of 3. The properties
of the new compounds compare favorably with these obser-
vations. The decrease of the CMC between the per¯uoro-
lipo-peptides 3AA5 and 3AA7 is also of the order of 10. The
derivative 1B5 bears the same hydrophobic chain as 3AA5
(Scheme 6) and the two compounds could, therefore, be
g
CMC-values of the per¯uorinated amphiphilic products
synthesized in this work are very close to those usually
found for this type of compounds.
The surfactants prepared by Hamdoune and coworkers
[10,27] represent a series of non-ionic lipo-oligopeptide
amphiphiles bearing a per¯uorinated alkyl chain. These
^
Fig. 1. Surface tension measurements for surfactants 1B5-HCl ( ), 3AA5 ( ), and 3AA7 ( ).

S. Cosgun et al. / Journal of Fluorine Chemistry 107 (2001) 375±386
379
Table 4
Minimal surface tension (gCMC) and critical micelle concentration (CMC) for aqueous solutions of derivatives 3AA5, 3AA7, and 1B5-HCl as well as of
analogous compounds reported in the literature
Compound
gCMC Æ 1 mN/m
CMC Â 104 m/l
Factora
Reference
1B5-HCl: RF5-carnosine, HCl
3AAC5 C5Ala-Ala
19
19
16
29.5
This work
This work
This work
ꢀ3
10
3AAC7 C7Ala-Ala
1.2
ꢀ10
F(CF2)6-CH2-(OC2H4)4-OH
F(CF2)7-CH2-(OC2H4)4-OH
F(CF2)6-CH2-(OC2H4)4-OCH3
F(CF2)7-CH2-(OC2H4)4-OCH3
18
17
18
17
1.17
0.41
1.15
0.39
[26]
[26]
[26]
[25]
ꢀ3
ꢀ3
F(CF2)6-CH2-C(O)-Gly-Sar-GlyNH2
F(CF2)8-CH2-C(O)-Gly-Sar-GlyNH2
17
16
15
[10,27]
[10,27]
ꢀ10
ꢀ5
1.3
FC6N3PC (Scheme 7)
FC6NH3PC (Scheme 7)
23
25
7.6
38
[19]
[19]
a For explanations see the text.
FC6N3PC on one hand and the cationic surfactant
FC6NH3PC on the other (Scheme 7), prepared and studied
by Papadopoulos and coworkers [19,32]. The two surfac-
tants bear identical hydrophobic tails but, due to the
additional charge on the latter, their CMC-values differ
1
4
4
by a factor of ca. 5 (7:6 Â 10 and 38 Â 10 mol l
,
respectively).
The above results show clearly that the new products
synthesized are indeed, as expected, typical surfactants. The
comparison with analogous molecules reveal a classical
behavior both for their surface activity and for their critical
micelle concentrations.
Scheme 6. Chemical structure of surfactants 3AA5 and 1B5.
We had also suggested that the presence of a peptidoa-
mine moiety in these compounds might be favorable for the
complexation of metal ions such as Cu2‡ [33] unless their
coordinating ability of the carnosine subunit be reduced by
the strong electron-withdrawing effect of the per¯uoro-alkyl
side chain. A preliminary investigation described below
reveals that the complexing capacity for copper ions of the
peptidoamine group in our surfactants is largely preserved.
expected to behave similarly. In fact, while the gCMC-values
are indeed very close to each other, the CMC-values are in
favor of 1B5 by a factor of 3.
Although the hydrophobic tails of the two compounds are
identical, the hydrophilic parts differ signi®cantly. The
alanine moiety in 3AA5 is replaced by a histidine substituent
in 1B5. It is well known that the hydrophilic character of
histidine is more pronounced than that of alanine [30,31].
The higher CMC-value observed for 1B5 is, therefore, not
surprising. Moreover, the imidazole ring is protonated by an
equivalent of HCl. Compared to the zwitterion 3AA5, an
additional charge is situated on the hydrophilic part which,
due to repulsion effects, is unfavorable to aggregation and
delays the formation of micelles.
3.2. Complexation of Cu(II)
The pK-values and complexing properties of compound
1B5 the structure of which is shown in Scheme 8,
have been investigated by acid±base titrations and UV±
VIS spectroscopy.
Another analogy may be established between the surfac-
tants of this work and the zwitterionic per¯uoro-lysolecithin
The titration curves obtained for different metal-to-ligand
ratios in the system Cu(II)- ``C5F11 Ð carnosine'' (1B5) are
Scheme 7. Structure of lyso-lecithin analogues [19].

380
S. Cosgun et al. / Journal of Fluorine Chemistry 107 (2001) 375±386
Table 5
pK-values for free 1B5 and literature values for carnosine
This work
Gajda [35]
Sovago [36]
Brookes [37]
pKCOOH
pKN3
1.24
6.11
9.81
2.66
6.77
9.38
2.53
6.84
9.30
2.60
6.83
9.46
Scheme 8. Structure of ``C5F11-carnosine'' 1B5, showing the numbering
of imidazole nitrogen atoms.
0
pKN
shown in Fig. 2. They give evidence for the complexing
ability of the surfactant molecule. Curve a corresponds to the
titration of 1B5 without copper; it displays two in¯ection
points related to the neutralization of the two weak acid
functions of the compound (deprotonation of the imidazo-
lium nitrogen followed by deprotonation of the terminal
nitrogen atom, the carboxyl proton being neutralized at the
beginning of the titration). Curve b corresponds to a solution
containing copper and the ligand in a 1:2 ratio, and curve c to
a similar solution but with a copper-to-ligand ratio of 1.
The shift of curves b and c is in agreement with a strong
co-ordination of compound 1B5 to the Cu2‡ ion.
The pK-values of the different protonated sites of the free
ligand have been extracted from the titration curves by using
the PSEQUAD software developed by Zekany [34]. They
are listed in Table 5 (second column). For comparison those
reported in previous literature for unsubstituted carnosine
are also included in the table.
The results from the titration experiments combined with
those of complementary UV±VIS investigations are in
agreement with a structure of the copper complex schema-
tically shown below. At pH values above 7.5, the titration
data show that three nitrogen binding sites are available for
co-ordination to copper and the maximum in the electronic
spectra of the copper ion, situated at ꢀ620 nm suggests,
according to Billo [38], that three nitrogen atoms are
engaged in the ®rst co-ordination sphere of the metal ion
Scheme 9.
Since the ligand 1B5 binds ef®ciently to copper(II),
similar types of complexes can be predicted for other
divalent transition ions such as Ni2‡ and Co2‡. A more
detailed investigation of the structure and the stability of the
complex compounds containing the new surfactants
described above is under way.
In spite of the electron-withdrawing character of the
per¯uoroalkyl chain, supposed to increase the acidity of
the amino group in the a-position (N0H2), a decrease in
acidity is actually observed, whereas the other protonated
sites become more acid as expected. This observation may
be explained by local variations of the pK-values of the
titrated functions when the molecules are engaged in micel-
lar structures.
4. Experimental section
4.1. Syntheses
4.1.1. Experimental protocols
All solvents were reagent grade and used without
further puri®cation. The progress of reactions and the
purity of products were evaluated on thin layer silica gel
Fig. 2. Titration curves of the system Cu2‡-1B5 with 0.1 M NaOH starting from 5 ml of 8:9  10 M 1B5 and (a) 0; (b) 2, and (c) 4.25 ml of 9:9  10
M
3
3
Cu(ClO4)2 solutions.

S. Cosgun et al. / Journal of Fluorine Chemistry 107 (2001) 375±386
381
1
Spectroscopic characteristics: IR n[N3]: 2158 cm
;
1
n[C(O)]: 1724 cm 1; n[C=C]: 1654 cm
.
NMR (CDCl3) [1H] for A ˆ Me, d ˆ 3:75 ppm (OCH3, s,
3H) and for A ˆ Et, d ˆ 1:10 ppm (CH3, t, 3H, 3JH ˆ
8:0 Hz); d ˆ 4:20 ppm (OCH2, q, 2H, 3JH ˆ 8:0 Hz); b:
d ˆ 6:00 ppm (s, 1H). [19F] a: d ˆ 81:40 ppm (t, 3F,
3J ˆ 14:5 Hz); b: d ˆ 126:75 ppm (m, 2F); g: d ˆ
123:10 ppm (m); d: d ˆ 122:40 ppm (m, 2F); e:
Scheme 9. Schematic structure of the copper(II) Ð ``RF5-carnosine''
(1B5) complex.
3
d ˆ 115:00 ppm (t, 2F, JF ˆ 14:5 Hz).
Microanalyses for 9-7-Me: Calcd. for C11H4F15N3O2
(M ˆ 495:15): C% 26.68, H% 0.81, N% 8.49, F% 57.55;
Found C% 26.97, H% 0.91, N% 8.34, F% 58.10. For 9-7-Et:
Calcd. for C12H6F15N3O2 (M ˆ 509:17): C% 28.31, H%
1.19, N% 8.25, F% 55.97; Found C% 28.81, H% 1.27, N%
8.42, F% 56.12.
chromatographic (TLC) plates (Merck, Kieselgel 60 F254
)
with eluents ethyl-acetate/hexane or chloroform/methanol.
Puri®cation is carried out by ¯ash silica gel column chro-
matography with the same eluents. Melting points were
determined with an electronic apparatus (Electrothermal)
and have not been corrected. The proton 1H and ¯uorine 19
F
NMR spectra were recorded on a Bruker AM 400 or AC 250
spectrometer. The chemical shifts d are reported in parts per
million (d in ppm) down®eld from internal tetramethylsilane
(TMS) or CFCL3, respectively. The IR spectra were
recorded on a Perkin-Elmer 580D or 1600 FTIR spectro-
meter. The elemental analyses were carried out at the
``Centre de microanalyses du CNRS, Vernaison, France''.
They agree with the proposed structures, their values are
shown below for several compounds. Mass spectra were
enregistred on Fisons TRIO 1000 apparatus.
4.2.2. Preparation of Z-b-perfluoroalkyl-b-alanines of type
10
General procedure for 3-per¯uoroalkyl-3-(N-benzyloxy-
carbonyl)-amino-propanoic acids 10-n (RF-Z-b-Ala-OH).
Hydrogenation of compounds of type 9: to a solution of
the appropriate ``azide'' 9 (20 mmol) in 50 ml of methanol
and 10 ml of ethyl acetate, in a stainless steel hydrogenation
bomb of approximately 250 ml capacity, are added 10 ml of
an aqueous suspension of Raney nickel. The mixture is
stirred under 80 bars of hydrogen at 808C for 12 h. After
a renewal of hydrogen gas, the reaction is continued under
the same conditions for 18 h. After ®ltration the solvent is
evaporated under reduced pressure. The crude residue is
puri®ed by ¯ash chromatography (eluent: AcOEt/hexane
1:1) Table 7.
4.2. Syntheses of surfactants 2An, 1Bn, and 3AAn
4.2.1. Preparation of ``azides'' of type 9
General procedure for methyl-3-per¯uoroalkyl-3-azido-
prop-2-enoate 9n-Me and ethyl-3-per¯uoroalkyl-3-azido-
prop-2-enoate 9-n-Et. To a solution of the appropriate ester
8 (15 mmol) [17] in 80 ml of formamide, are added 10
equivalents of sodium azide. The mixture is stirred at room
temperature for 16 h. Water (50 ml) is added and the mixture
is extracted with ether (3 Â 75 ml). The ether phases are
washed with water (2 Â 30 ml) and dried over magnesium
sulfate; the solvent is evaporated under reduced pressure and
the crude residue puri®ed by ¯ash chromatography (eluent:
AcOEt/hexane 1:1) Table 6.
Spectroscopic characteristics: IR: n[NH2], 3400±
1
3250 cm
.
NMR (CDCl3) [1H] for A ˆ Me, d ˆ 3:64 ppm (OCH3, s,
3H) and for A ˆ Et, d ˆ 1:24 ppm (CH3, t, 3H,3JH ˆ
8:0 Hz); d ˆ 4:24 ppm (OCH2, q, 2H, 3JH ˆ 8:0 Hz); c:
2
3
d ˆ 2:85 ppm (dd, 2H, J ˆ 16:0 Hz and J ˆ 8:0 Hz); d:
d ˆ 5:15 ppm (m, 1H); e: d ˆ 6:30 ppm (m, 2H). [19F] a:
d ˆ 79 ppm (t, 3F, 3J ˆ 10 Hz); b: d ˆ 126 to
121 ppm; g: d ˆ 118 ppm (m, 2 or 4F); d: d ˆ 112 ppm.
Products 9-n-A (A ˆ Me or Et)
4.2.2.1. Amine protection. To a stirred dispersion of the
above perfluoroalkyl-b-alanine ester (10 mmol) in 35 ml of
an aqueous solution of sodium hydrogen carbonate (1N),
Table 6
Properties of compounds 9
Compound
Aspect
MM (g/mol)
mp (8C)
nD20
Rf (AcOEt/hexane)
Yield (%)
9-5-Me
9-7-Me
9-9-Me
9-5-Et
9-7-Et
9-9-Et
Oil
395.13
495.15
595.16
409.15
509.17
609.19
±
±
1.321
1.354
±
0.87
0.85
0.72
0.83
0.80
0.52
78
75
75
80
80
73
Oil
Solid
Oil
46
±
1.369
1.376
±
Oil
±
Solid
52

382
S. Cosgun et al. / Journal of Fluorine Chemistry 107 (2001) 375±386
Table 7
Spectroscopic characteristics: IR n[OH]: 3100 at
1
1
Properties of hydrogenated compounds
3400 cm
;
n[NH]: 3321 cm
;
n[C=O carbamate]:
1
1681 cm 1; n[C=O acid]: 1712 cm
.
NMR (CD3COCD3) [1H]; b: d ˆ 2:65 ppm (dd, 1H,
2J ˆ 16:0 Hz, 3J ˆ 12:0 Hz) and d ˆ 2:85 ppm (dd, 1H;
2J ˆ 16:0 Hz, J ˆ 4:0 Hz); c: d ˆ 4:10 ppm (m, 1H); e:
3
d ˆ 5:14 ppm (s, 2H); f: d ˆ 7:28 ppm (m, 5H); d:
d ˆ 9:30 ppm (m, 1H) a: d ˆ 10:45 ppm (s, 1H). [19F] a:
d ˆ 81.40 ppm (t, 3F, 3J ˆ 9.5 Hz); b: d ˆ 126:40 ppm
at d ˆ 122:40 ppm (m, 4F); g: d ˆ 117:15 ppm (m, 2F);
d: d ˆ 111:00 ppm (m, 2F).
Compound
MM (g/mol)
Rf (AcOEt)
Yield (%)
C5F11CH(NH2)CH2CO2Me 371.16
C7F15CH(NH2)CH2CO2Me 471.17
C9F19CH(NH2)CH2CO2Me 571.19
0.30
0.34
0.41
0.33
0.35
0.44
70
75
55
82
80
60
C5F11CH(NH2)CH2CO2Et
C7F15CH(NH2)CH2CO2Et
C9F19CH(NH2)CH2CO2Et
385.17
485.19
585.20
Microanalyses for 10-5: Calcd. for C16H12F11NO4
(M ˆ 491:26): C% 39.12, H% 2.46, N% 2.85, F% 42.54;
Found C% 39.63, H% 2.70, N% 3.28, F% 43.10.
benzyl-chloroformate (1.1 equivalent) is added dropwise at
58C. The mixture is stirred for 16 h at room temperature. The
solid is filtered off and washed with hexane (2 Â 10 ml)
4.2.3. ``Peptide-coupling'' methods for the synthesis of
1Bn, 2An and 3AAn
Table 8.
1
Spectroscopic characteristics: IR n[NH], 3321 cm
;
;
4.2.3.1. BOP activation method. The appropriate
perfluoroalkyl-Z-b-alanine (10 mmol) is dissolved in
acetonitrile (50 ml) and 3 equivalents of triethylamine, 1
equivalent of BOP and 1 equivalent of appropriate amino-
acid ester are added. The mixture is stirred at room
temperature for 4 h. The precipitate is filtered off and
washed with hexane (2 Â 30 ml), dissolved in ethyl
acetate (50 ml), washed with 20 ml of 2N aqueous HCl,
20 ml of a saturated aqueous solution of NaHCO3 and 20 ml
of brine. The organic phase is dried over magnesium sulfate,
the solvent is evaporated under reduced pressure and the
crude residue purified by flash chromatography (MeOH/
AcOEt 20/80) (see Table 1).
1
n[C=O carbamate], 1711 cm 1; n[C=O ester], 1733 cm
1
n[C±F]: 1300±1100 cm
.
NMR CD3COCD3 [1H] for A ˆ Me, d ˆ 3:25 ppm
(OCH3, s, 3H) and for A ˆ Et, d ˆ 1:25 ppm (CH3, t,
3H,3JH ˆ 8:0 Hz); d ˆ 4:15 ppm (q, 2H, J ˆ 8:0 Hz); b:
3
d ˆ 2:65 ppm (dd, 1H, 2J ˆ 16:0 Hz, 3J ˆ 8:0 Hz); c:
d ˆ 4:90 at 5.10 ppm (m, 1H); d: d ˆ 5:45 ppm (d, 1H,
2J ˆ 8:0 Hz); e: d ˆ 5:15 ppm (s, 2H); f: d ˆ 7:10 at
7.40 ppm (m, 5H). [19F] a: d ˆ 82:40 ppm (t, 3F,
3J ˆ 10:0 Hz); b: d ˆ 127:70 to 122.90 ppm (m); g:
d ˆ 119:50 ppm (m, 2F); d: d ˆ 112:00 ppm (m, 2F).
4.2.2.2. Ester hydrolysis. To a solution of 8 mmol of the
above protected ester in 10 ml of methanol are added 5
equivalents of a 2N sodium hydroxide solution in methanol/
water (90/10). The mixture is stirred at room temperature for
3 h. The solvent is evaporated under reduced pressure. The
crude product is dissolved in ethyl acetate (100 ml) and then
added to 100 ml of 2N HCl. The aqueous phase is extracted
with ethyl acetate (2 Â 100 ml). The organic phase is dried
over magnesium sulfate and the solvent is evaporated under
reduced pressure. The crude residue is purified by flash
chromatography (AcOEt/hexane 1:1) Table 9.
4.2.3.2. DCC activation method. The appropriate
perfluoroalkyl-Z-b-alanine (10 mmol) is dissolved in
dichloromethane (50 ml) and
2 equivalents of tri-
ethylamine, 1 equivalent of dicyclohexylcarbodiimide and
1 equivalent of the appropriate amino-acid ester are added.
The mixture is stirred at room temperature for 18 h. The
precipitate is filtered off, washed with hexane (2 Â 30 ml),
dissolved in ethyl acetate (50 ml), washed with 20 ml of 2N
HCl, 20 ml of a saturated aqueous solution of NaHCO3 and
20 ml of brine. The organic phase is dried over magnesium
Table 8
Properties of Z-protected compounds
Compound
MM (g/mol)
Rf (AcOEt)
mp (8C)
Yield (%)
C5F11CH(NH-Z)CH2CO2Me
C7F15CH(NH-Z)CH2CO2Me
C9F19CH(NH-Z)CH2CO2Me
C5F11CH(NH-Z)CH2CO2Et
C7F15CH(NH-Z)CH2CO2Et
C9F19CH(NH-Z)CH2CO2Et
505.28
605.30
705.32
519.31
619.34
719.35
0.58
0.55
0.49
0.58
0.53
0.47
74
78
87
79
81
93
85
82
65
84
80
62

S. Cosgun et al. / Journal of Fluorine Chemistry 107 (2001) 375±386
383
Table 9
Characteristics of compounds of type 10
Compound
MM (g/mol)
Rf (AcOEt)
mp (8C)
Yield (%)
10-5: C5F11CH(NH-Z)CH2CO2H
10-7: C7F15CH(NH-Z)CH2CO2H
10-9: C9F19CH(NH-Z)CH2CO2H
491.26
591.27
691.29
0.68
0.66
0.61
131
138
151
85
82
65
sulfate; the solvent is evaporated under reduced pressure and
the crude residue purified by flash chromatography (MeOH/
AcOEt 20/80) see Table 1).
4.2.3.3. Mixed anhydride method. The appropriate
perfluoroalkyl-Z-b-alanine (10 mmol) is dissolved in
tetrahydrofuran (20 ml) and 1.1 equivalents of iso-
propenyl or isobutyl chloroformate are added rapidly at
28C. The mixture is stirred for 5 min 1 equivalent of
Spectral characteristics: IR n[NH]: 3370 cm 1: n[C=O
amides]: 1643 cm 1; n[C=O carbamate]: 1715 cm 1; n[C-
1
F]: 1100±1300 cm
.
appropriate amino-acid ester,
3
equivalents of
NMR (CD3OD) [1H] a: d ˆ 7:60 ppm (s, 1H); b:
d ˆ 7:85 ppm (s, 1H); c: d ˆ 2:80 ppm (m, 2H); d: d ˆ
2:90 ppm (m, 2H); f:d ˆ 2:50 ppm (m, 2H); h: d ˆ
5:28 ppm (m, 2H); g: d ˆ 4:60 ppm (m, 1H); i:
d ˆ 7:23 ppm (m, 5H). [19F] a: d ˆ 82:39 ppm (t, 3F,
3J ˆ 10:0 Hz); b: d ˆ 127:70 to 122.90 ppm (m,); g:
d ˆ 119:50 ppm (m, 2F); d: d ˆ 112:00 ppm (m, 2F).
Microanalyses for Z-2A-5: Calcd. for C21H19F11N4O3
(M ˆ 584:38): C% 43.16, H% 3.28, N% 9.59, F% 35.76;
Found C% 43.47, H% 3.47, N% 9.78, F% 36.10; for Z-2A-7
Calcd. for C23H19F15N4O3 (M ˆ 684:40): C% 40.36, H%
2.80, N% 8.19, F% 41.64; Found C% 40.65, H% 3.12, N%
8.55, F% 42.12.
triethylamine are added and the mixture is stirred at 28C
for another 3 h. The solvent is evaporated under reduced
pressure. The residue is dissolved in ethyl acetate (50 ml),
washed with 20 ml of 2N HCl, 20 ml of a saturated aqueous
solution of NaHCO3 and 20 ml of brine. The organic phase
is dried over magnesium sulfate, the solvent is evaporated
under reduced pressure and the crude residue purified by
flash chromatography (MeOH/AcOEt 20/80) (see Table 1).
For products Z-3AA-n-Me (with n ˆ 5, 7, 9) (see
Table 1).
For products Z-1B-n-Me (RF-Z-b-Ala-HisOMe; RF-Z-
carnosine-OMe) (with n ˆ 5, 7, 9) (see Table 1).
1
Spectroscopic characteristics: IR n[NH]: 3390 cm
;
1
n[C=O amides]: 1653 cm
;
n[C=O carbamate]:
1711 cm 1; n[C=O ester]: 1734 cm 1; n[C±F]: 1100±
1
1300 cm
.
1
NMR (CD3OD) [1H] a: d ˆ 1:12 ppm (M, 3H); b:
d ˆ 3:85 ppm (s, 1H); d: d ˆ 2:45 ppm (dd, 2H); e: d ˆ
3:6 ppm (s, 3H); f: d ˆ 5:05 ppm (m, 1H); g: d ˆ 5:25 ppm
(m, 2H); h: d ˆ 7:20 ppm (m, 5H). [19F] a: d ˆ
81:50 ppm (t, 3F, 3J ˆ 10:0 Hz); b: d ˆ 126:80 at
122.90 ppm (m); g: d ˆ 118:50 ppm (m, 2F); d: d ˆ
110:00 ppm (m, 2F).
Microanalyses for Z-3AA-5-Me: Calcd. for C20H19-
F11N2O3 (M ˆ 576:36): C% 41.68, H% 3.32, N% 4.86,
F% 36.26; Found: C% 41.86, H% 3.37, N% 4.88, F%
37.04; for Z-3AA-7-Me Calcd. for C22H19F15N2O3
(M ˆ 676:37): C% 39.07, H% 2.83, N% 4.14, F% 42.13;
Found C% 39.55, H% 2.92, N% 4.18, F% 42.21.
For products: Z-2A-n (RF-Z-carcinine with n ˆ 5, 7, 9)
(see Table 1).
Spectral characteristics: IR n[NH]: 2928±3390 cm
:
1
n[C=O amides]: 1653 cm
;
n[C=O carbamate]:
1
1712 cm 1; n[C±F]: 1100±1300 cm
.
NMR (CD3OD) [1H] a: d ˆ 7:40 ppm (s, 1H); b: d ˆ
8:25 ppm (s, 1H); c: d ˆ 2:70 ppm (m, 2H); d:
d ˆ 3:35 ppm (s, 1H); e: dˆ3.30 ppm (m, 3H); f: d ˆ
2:65 ppm (m, 2H); g: d ˆ 5:10 ppm (m, 1H); h: d ˆ
5:10 ppm (s, 2H); i: d ˆ 7:40 ppm (m, 5H). [19F] a:
d ˆ 77:80 ppm (t, 3F, 3J ˆ 10 Hz); b: d ˆ 124:0 to
122.2 ppm (m); g: d ˆ 118:5 ppm (m, 2F); a:
d ˆ 114:10 ppm (m, 2F).
Microanalyses for Z-1B-5-Me: Calcd. for C23H21F11-
N4O5 (M ˆ 642:42): C% 43.00, H% 3.29, N% 8.72, F%
32.53; Found C% 43.24, H% 3.46, N% 8.94, F% 32.81;
for Z-1B-7-Me Calcd. for C25H21F15N4O5 (M ˆ 742:44):

384
S. Cosgun et al. / Journal of Fluorine Chemistry 107 (2001) 375±386
C% 40.44, H% 2.85, N% 7.55, F% 38.38; Found C% 40.85,
H% 2.98, N% 7.52, F% 41.02.
ppm, (m, 2F); g: d ˆ 119.45 ppm, (m, 4F); d:
d ˆ 114.65 ppm, (m, 2F).
Microanalyses for 2A5 [3-per¯uoropentyl-b-alanyl-hista-
mine] Calcd. for C13H13F11N4O (M ˆ 450:25): C% 34.68,
H% 2.91, N% 12.44, F% 46.41; Found C% 34.87, H% 3.17,
N% 12.64, F% 46.10; for 2A7 [3-per¯uoroheptyl-b-alanyl-
histamine] Calcd. for C15H13F15N4O(M ˆ 550:27): C%
32.74, H% 2.38, N% 10.18, F% 51.79; Found C% 32.16,
H% 2.42, N% 10.69, F% 51.14.
4.2.4. Hydrogenolysis and hydrolysis of protecting groups
4.2.4.1. Hydrogenolysis. Preparation of the products: 2An:
RF-Carcinine; 1BnMe: RF-carnosine-OMe and 3AA-nMe
(with n ˆ 5, 7, 9) (see Table 2). Hydrogenation of
compounds Z3AA-nMe; Z2A-n and Z1B-nMe: to
a
solution of the appropriate Z-compound (5 mmol) in
50 ml of methanol, placed in stainless steel
The products 1B-nMe [RF-b alanyl-histidine-OMe ˆ
RF-carnosine-OMe] 1B-5Me [methyl-3-per¯uoropentyl-b-
alanine histidinate] and 1B-7Me [methyl-3-per¯uoroheptyl-
b-alanine histidinate].
a
hydrogenation bomb of approximately 150 ml capacity, is
added 0.1 g of Pd/C. The mixture is stirred at room
temperature for 2 h under 30 bars of hydrogen. After the
renewal of hydrogen gas, the reaction is continued under the
same conditions for 4 h. After filtration, the solvent is
evaporated under reduced pressure. The crude residue is
purified by flash chromatography (AcOEt/hexane 80/20)).
All products are white solids Table 10.
Spectroscopic characteristics: IR n[NH]: 2928±
Microanalyses for 3AA-5Me [methyl-3-per¯uoropentyl-
alaninate]
1
3389 cm 1: n[C=O amide]: 1653±1712 cm
.
b-alanyl
Calcd.
for
C12H13F11N2O3
NMR (CD3OD) [1H] a: d ˆ 7:60 ppm, (s, 1H); b:
d ˆ 7:85 ppm, (s, 1H); c: d ˆ 2:80 ppm, (m, 2H); d:
d ˆ 3:05 ppm, (m); e: d ˆ 3:65 ppm, (s, 3H); f: d ˆ
2:80 ppm, (m, 2H); g: d ˆ 4:60 ppm, (m, 1H); j: d ˆ
6:25 ppm, (m, 2H). [19F] a: d ˆ 78:90 ppm, (t, 3F,
1J ˆ 10:0 Hz); b: d ˆ 124 ppm, (m, 2F); g: d ˆ
119:45 ppm, (m, 4F); d: d ˆ 114:65 ppm, (m, 2F).
Microanalyses for 1B7Me [methyl-3-per¯uoroheptyl-
b-alanyl-histidinate] Calcd. for C17H15F15N4O3 (M ˆ
608:31): C% 33.57, H% 2.49, N% 9.21, F% 46.85; Found
C% 33.74, H% 2.67, N% 9.34, F% 47.24.
(M ˆ 442:23): C% 32.59, H% 2.96, N% 6.33, F% 47.26;
Found C% 32.67, H% 3.17, N% 6.50, F% 48.08; for
3AA-7Me [methyl-3-per¯uoroheptyl-b-alanyl alaninate]
Calcd. for C14H13F15N2O3(M ˆ 542:24): C% 31.01, H%
2.42, N% 5.17, F% 52.55; Found C% 31.97, H% 2.68, N%
4.95, F% 53.14.
The products 2A-n [RF-b alanyl-histidine ˆ RF-carci-
nine]
4.2.4.2. Hydrolysis. Preparation of the products: 1B-n: RF-
carnosine (with n ˆ 5, 7, 9) (see Table 3).
Spectroscopic characteristics: IR n[NH]: 2928±
1
3389 cm 1; n[CO amide]: 1653 cm
.
4.2.4.2.1. Hydrolysis of esters. To a solution of 5 mmol of
the appropriate ester 1B-nMe in 20 ml of dioxane, are added
2.5 equivalents of a 1N aqueous solution of sodium
hydroxide. The mixture is stirred at room temperature for
3 h. The solvent is evaporated under reduced pressure. The
crude product is dissolved in ethyl acetate (100 ml), and
NMR (CD3OD) [1H] a: d ˆ 7:60 ppm, (s, 1H); b: d ˆ
7:85 ppm, (s, 1H); c: d ˆ 2:80 ppm, (m, 2H); d:
d ˆ 3.05 ppm, (m, 2H); e: d ˆ 2:85 ppm, (m, 2H); f ˆ g:
d ˆ 5:10 ppm, (m); h: d ˆ 3:25 ppm, (m, 2H). [19F] a:
d ˆ 78:90 ppm, (t, 3F), 3J ˆ 9.5 Hz; b: d ˆ 123.90
Table 10
Compounds obtained by saponification
Code
Compounda
MM
Rfa
mp (8C)
Yield (%)
3AA-5Me
3AA-7Me
3AA-9Me
2A-5
C5F11CH(NH2)CH2C(O)NHCH(CH3)CO2CH3
C7F15CH(NH2)CH2C(O)NHCH(CH3)CO2CH3
C9F19CH(NH2)CH2C(O)NHCH(CH3)CO2CH3
C5F11CH(NH2)CH2C(O)NHCH2CH2-Im
442.23
542.24
642.26
450.25
550.27
650.29
508.29
608.31
0.57
0.55
0.52
0.45
0.45
0.47
0.48
0.45
147
152
163
167
172
177
182
197
85
80
57
78
75
45
75
73
2A-7
2A-9
C7F15CH(NH2)CH2C(O)NHCH2CH2-Im
C9F19CH(NH2)CH2C(O)NHCH2CH2-Im
1B-5Me
1B-7Me
C5F11CH(NH2)CH2C(O)NHCH(CO2CH3)CH2-Im
C7F15CH(NH2)CH2C(O)NHCH(CO2CH3)CH2-Im
a Eluent: AcOEt/hexane 70/30; Im ˆ imidazole.

S. Cosgun et al. / Journal of Fluorine Chemistry 107 (2001) 375±386
385
acidified with 1N aqueous HCl to pH 1. The aqueous
phase is extracted with ethyl acetate (2 Â 100 ml). The
organic phase is dried over magnesium sulfate and the
solvent is evaporated under reduced pressure; the crude
residue is purified by flash chromatography (AcOEt/
hexane 1:1) and recristallized from hexane/ether or from
chloroform.
The products 1B-n [RF-b alanyl-histidine ˆ RF-carno-
sine]: 1B-5 [3-per¯uoropentyl-b-alanyl-histidine] and 1B-
7 [3-per¯uoroheptyl-b-alanyl-histidine] are white solids.
4.2.5.2. Potentiometry. The protonation and coordination
equilibria have been investigated by potentiometric
titrations in aqueous solution at a constant ionic strength
of 0.1 mol/l (NaClO4) and T ˆ 298 Æ 1 K under argon
atmosphere by using an automatic titration apparatus
including a Dosimat 665 autoburette (Metrohm), an Orion
710A precision digital pH-meter and an Orion 9103SC
combined glass electrode. pK-values have been calculated
from 4 independent titrations (ca. 100 data points each) by
means of the PSEQUAD software [34].
4.2.5.3. UV±VIS spectrophotometry. The UV±VIS
absorption spectra have been recorded on a Varian Cary
3E UV±VIS spectrophotometer. The ligand-to-metal ratio
varied from 0 to 2.
1B-5 ˆ RF5-carnosine [C5F11CH(NH2)CH2C(O)NHCH-
CO2HCH2-Im; MM ˆ 494:26]; Rf (AcOEt/hexane 70/30)
0.48; mpꢁꢂC† ˆ 182; Yield: 75%. 1B-7 ˆ RF7-carnosine
[C7F15CH(NH2)CH2C(O)NHCHCO2HCH2-Im;
MM ˆ 594:28]; Rf (AcOEt/hexane 70/30) 0.45; mpꢁꢂC† ˆ
197; Yield: 73%.
Acknowledgements
We wish to thank Eliane Eppiger for her valuable tech-
nical assistance with the NMR measurements, as well as
Dr. A. Lantz and Dr. P. Durual (Atochem Society) for
supplying us with the ¯uorinated material. We are grateful
Spectroscopic characteristics: IR n[COOH]: 3450±
1
1
 Â
to Dr. M.-J. Stebe for many useful discussions.
3120 cm
;
n[N±H]: 3290±3215 cm
;
n[CO acide]:
1711 cm 1; n[CO amide]: 1690.
NMR (CD3OD) [1H] a: d ˆ 7:80 ppm, (s, 1H); b:
d ˆ 8:10 ppm, (s, 1H); c: d ˆ 2:80 ppm, (m, 2H); d: d ˆ
3:45 ppm, (m, 1H); e: d ˆ 2:50 ppm, (m, 2H); f and i:
d ˆ 5:10 ppm, (m, 2H); g: d ˆ 10:25 ppm, (m, 1H); h:
d ˆ 6:3 ppm, (m, 2H). [19F] a: d ˆ 82:39 ppm (t, 3F),
3J ˆ 10:0 Hz); b: d ˆ 127:70 ppm at 122.90 ppm (m); g:
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