Synthesis and electrochemical studies of disubstituted ferrocene/dipeptide conjugates with sulfur-containing side chains

Article abstract of DOI:10.1016/j.tet.2010.05.070

A series of 1 1'-disubstituted ferrocenoyl peptides incorporating dipeptide sidearms has been synthesized and studied electrochemically. The target peptides include ferrocene as an electrochemical reporter, sulfur-containing amino acids (L-methionine, S-methyl-L-cysteine, S-trityl-L-cysteine, S-benzhydryl-L- cysteine) as metal binding agents, and amino acids with non-polar side chains (L-alanine, L-valine, L-phenylalanine) as spacers between reporter and metal binding groups. Ferrocene/dipeptide conjugates were prepared using solution phase peptide synthesis methods employing a BOC-protecting group strategy and HBTU- (O-(benzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate) mediated peptide coupling. The electrochemical properties of these 1, 1'-substituted ferrocenoyl peptides have been characterized using cyclic voltammetry. All exhibit fully reversible one electron oxidation steps; forward sweep half wave peaks (E_F), reverse sweep half wave peaks (E_R), peak separations (DE_P) and half wave potentials (E1/2) are reported. Finally, towards the goal of utilizing ferrocenoyl peptides to detect heavy metals in solution, the response of these ferrocene/dipeptide conjugates to metal cations (zinc(II), mercury(II), cadmium(II), lead(II), silver(I)) has been examined. Monitoring changes in the potential of the Fe(II)/Fe(III) redox couple to follow peptide/metal interactions, we have probed the influence of the spacer unit between the redox reporter and the metal-binding amino acid, and shown that these systems respond to mercury(II) more strongly than to other heavy metal ions.

Full text of DOI:10.1016/j.tet.2010.05.070

Tetrahedron 66 (2010) 5653e5659
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and electrochemical studies of disubstituted ferrocene/dipeptide
conjugates with sulfur-containing side chains
,
,
Conor C.G. Scully a b, Peter J. Rutledge a
*
a School of Chemistry F11, The University of Sydney, NSW 2006, Australia
b Centre for Synthesis & Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
A series of 1,10-disubstituted ferrocenoyl peptides incorporating dipeptide sidearms has been synthesized
and studied electrochemically. The target peptides include ferrocene as an electrochemical reporter,
Article history:
Received 7 January 2010
Received in revised form 30 April 2010
Accepted 17 May 2010
sulfur-containing amino acids (
cysteine) as metal binding agents, and amino acids with non-polar side chains (
-phenylalanine) as spacers between reporter and metal binding groups. Ferrocene/dipeptide conjugates
L-methionine, S-methyl-L-cysteine, S-trityl-
L
-cysteine, S-benzhydryl-
L-
L
-alanine, -valine,
L
Available online 24 May 2010
L
were prepared using solution phase peptide synthesis methods employing a BOC-protecting group
strategy and HBTU- (O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexafluorophosphate) medi-
ated peptide coupling. The electrochemical properties of these 1,10-substituted ferrocenoyl peptides have
been characterized using cyclic voltammetry. All exhibit fully reversible one electron oxidation steps;
Keywords:
Amino acids
Peptide synthesis
Bio-organometallic chemistry
Ferrocene
forward sweep half wave peaks (EF), reverse sweep half wave peaks (ER), peak separations (DEP) and half
wave potentials (E1/2) are reported. Finally, towards the goal of utilizing ferrocenoyl peptides to detect
heavy metals in solution, the response of these ferrocene/dipeptide conjugates to metal cations (zinc(II),
mercury(II), cadmium(II), lead(II), silver(I)) has been examined. Monitoring changes in the potential of
the Fe(II)/Fe(III) redox couple to follow peptide/metal interactions, we have probed the influence of the
spacer unit between the redox reporter and the metal-binding amino acid, and shown that these systems
respond to mercury(II) more strongly than to other heavy metal ions.
Mercury
Electrochemistry
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
reported.10e13 Ferrocene conjugates have been used widely as
chemical receptors to probe the behaviour of metal ions in solution,
The rapid proliferation of heavy industry in developed and de-
veloping nations has led to increased levels of pollutants and toxins
in the local and global environment.1 Amongst the most harmful of
these are metal pollutants released by mining, incineration and
manufacturing, and within this class the heavy metals mercury,
cadmium and lead pose a particular threat to the environment due
to their extreme toxicity and wide-spread use.2,3 Plants and animals
have developed natural defence mechanisms in response to ele-
vated levels of these metals in the environment, using proteins rich
in sulfur-containing amino acidsdmetallothioneins and phy-
tochelatinsdto bind and sequester metal ions such as mercury(II)
and cadmium(II).4e6
due in large part to the stable and reproducible redox behaviour of
the ferrocene/ferrocenium redox couple and its resulting electro-
chemical properties.14e18 Ferrocene bioconjugates have received
attention more recently as potential receptors for metal ions, part of
an increasing focus on the bio-organometallic chemistry of
ferrocene.19e23 Several ferrocene/peptide systems have been used
to detect cations in solution (including Li(I), K(I), Cs(I), Mg(II), and
La(III)),17,24,25 however the application of ferrocenoyl peptides to
cation-sensing applications has received only limited attention to
date.
We recently reported the synthesis and metal-binding proper-
ties of simple sulfur-containing ferrocene/amino acid conjugates,
which demonstrated a significantly stronger response to mercury
(II) than other thiophilic metals.23 Our strategy uses sulfur-con-
taining amino acids and peptides based loosely on the metal
binding motif of metallothioneins in conjunction with the iron(II)/
iron(III) redox couple of ferrocene as an electrochemical reporter.
As part of ongoing efforts to utilise amino acid and peptide de-
rivatives for binding and sensing heavy metals, we report here the
synthesis and characterization of more complex 1,10-disubstituted
Given the high toxicity and increasing prevalence of mercury
and its derivatives, significant efforts have been directed towards
the development of methods to detect them in the environment,7e9
and
a variety of sensitive redox-active systems have been
* Corresponding author. Tel.: þ61 2 9351 5020; fax: þ61 2 9351 3329; e-mail
address: p.rutledge@chem.usyd.edu.au (P.J. Rutledge).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.070

5654
C.C.G. Scully, P.J. Rutledge / Tetrahedron 66 (2010) 5653e5659
Figure 1. Ferrocenoyl/dipeptide conjugates 1e8.
ferrocenoyl peptides, using electrochemistry to probe the influence
of a spacer unit between the redox reporter (ferrocene) and the
procedure.26 Protected
ine,27 S-benzhydryl- and S-trityl-
known procedures; -methionine and S-protected L
L
-cysteine derivatives S-methyl-
-cysteine28 were prepared using
-cysteine de-
L-cyste-
L
metal-binding amino acid
(L-methionine and
L
-cysteine de-
L
rivatives). We have synthesised a family of eight ferrocene-linked
dipeptide conjugates 1e8 (Fig. 1) and studied their interactions
with heavy metal cations by cyclic voltammetry, surveying a range
rivatives were converted to their methyl esters in high yields (61%e
quantitative) by reaction with thionyl chloride and methanol.29
L-Alanine, L-valine and L-phenylalanine were converted to the N-
of metal-binding residues (
L
-methionine, S-methyl-
-cysteine and S-benzhydryl- -cysteine) and linkers (
-valine and -phenylalanine). The linker amino acids
L
-cysteine, S-
Boc derivatives in excellent yields (85e99%) following a literature
trityl-
nine,
L
L
L-ala-
procedure.30
L
L
L
-Alaninyl-,
esters were synthesised by coupling N-Boc-
valine or N-Boc- -phenylalanine with -methionine methyl ester,
S-methyl- -cysteine methyl ester, S-benzhydryl- -cysteine methyl
ester or S-trityl- -cysteine methyl ester using O-(benzotriazol-1-
L
-valinyl- and
L
-phenylalaninyl-dipeptide methyl
incorporate non-polar side chains, which should play little or no
direct role in metal binding. However they vary in steric bulk and so
will influence the conformation of the peptide in solution, thereby
influencing the approach of a metal ion and ultimately the selec-
tivity and sensitivity of these systems in binding heavy metals. By
comparing these dipeptide-derived systems to previously reported
single-amino acid derivatives23 the influence of distance between
the metal-binding residue and the redox reporter can also be
characterised. The electrochemical properties of the 1,10-
substituted ferrocenoyl peptides 1e8 have been analyzed using
cyclic voltammetry and the interactions of these compounds with
the heavy metal cations mercury(II), cadmium(II), lead(II), silver(I)
and zinc(II) examined.
L
-alanine, N-Boc-
L-
L
L
L
L
L
yl)-N,N,N0,N0-tetramethyluronium hexafluorophosphate (HBTU)
under standard peptide coupling conditions.31 The resulting
N-Boc-protected dipeptides were deprotected at the N-terminus
in excellent yields (71e94%) by heating for 120 min with p-
toluenesulfonic acid in refluxing DCM.28 Deprotected dipeptides
were coupled to ferrocene-1,10-dicarboxylic acid using HBTU, to
give the desired conjugates 1e8 in moderate to high yield
(41e85%).
2. Results and discussion
2.2. Electrochemistry of 1,10-substituted ferrocenoyl
dipeptide compounds
2.1. Synthesis of ferrocenoyl peptides
All the compounds synthesized exhibit fully reversible one
electron oxidation steps in acetonitrile. The forward sweep half
wave peaks (EF), reverse sweep half wave peaks (ER), peak sepa-
The 1,10-substituted ferrocenoyl peptide targets 1e8 were
obtained from ferrocene-1,10-dicarboxylic acid 9 and 2 equiv of the
corresponding dipeptide (Scheme 1). Ferrocene-1,10-dicarboxylic
acid 9 was synthesized in high yield (75%) following the literature
rations (DEP) and half wave potentials (E1/2) are summarised in
Table 1.
Scheme 1. Synthesis of 1,10-substituted ferrocenoyl peptide targets 1e8 (1 R¼CH3, R0¼CH2CH2SCH3; 2 R¼CH2Ph, R0¼CH2CH2SCH3; 3 R¼CH3, R0¼CH2SCH3; 4 R¼CH2Ph, R0¼CH2SCH3;
5 R¼CH3, R0¼CH2SCPh3; 6 R¼CH2Ph, R0¼CH2SCPh3; 7 R¼CH(CH3)2, R0¼CH2SCHPh2; 8 R¼CH2Ph, R0¼CH2SCHPh2); i. Boc2O, NaOH, t-BuOH/H2O, rt 24 h, 85e99%; ii. SOCl2, MeOH,
reflux 4 h, then rt 16 h, 61e100%; iii. HBTU, TEA, DCM/DMF, rt 16 h, 52e88%; iv. TsOH, DCM, reflux 2 h, 71e94%; v. HBTU, TEA, DCM/DMF, 48 h, 41e85%.

C.C.G. Scully, P.J. Rutledge / Tetrahedron 66 (2010) 5653e5659
5655
event involving the transfer of one electron is 59 mV,33 however
due to uncompensated resistance in the solvent between reference
Table 1
Basic electrochemical properties of 1,10-substituted ferrocenoyl compounds
and working electrodes, actual DEP values may be 10e20 mV above
Compound
EF (mV)
ER (mV)
D
EP (mV)
E1/2(mV)
this theoretical value.34 All of the compounds 1e8 show peak
separations within 12 mV of this theoretical value: Fe(C5H4-CO-Val-
Cys(Bzh)-OMe)2 7 has the smallest peak separation at 64 mV, and
only Fe(C5H4-CO-Phe-Cys(Trt)-OMe)2 6 (71 mV) deviates by more
than 10 mV from the theoretical value.
1
2
3
4
5
6
7
8
820
827
825
837
831
860
827
841
856
868
883
755
760
758
769
765
789
763
773
795
794
807
65
67
67
68
66
71
64
68
61
74
76
788
794
792
803
798
825
795
807
826
831
846
2.3. Metal binding studies
10a
11a
12a
The electrochemical properties of ferrocenoyl peptides 1e8
were tested in the presence of various thiophilic heavy metals to
probe the metal binding properties of these compounds. All re-
spond electrochemically to varying concentrations of mercury(II)
nitrate, with corresponding changes in half wave potentials. Much
lower responses are observed to cadmium(II) nitrate, zinc(II) ni-
trate, sliver(I) nitrate and lead(II) triflate. The electrochemical re-
sponses of compounds 1e6 to these five metals are shown in
Figure 3 and their responses to mercury are detailed in Table 2.
Like the single-residue compounds reported previously23 the
ferrocene/dipeptide conjugates 2e6 show a significantly stronger
response to Hg(II) than to other metals tested. The Phe-S-Trt-Cys
derivative Fe(C5H4-CO-Phe-Cys(Trt)-OMe)2 6 shows the highest
redox potential change of these systems, a shift of 64 mV. The re-
sponse is characterised by a concentration-dependant change in
E1/2, which reaches this upper limit at a mercury(II) concentration
of 51 ppm. Compounds 2e5 show similar redox shifts to the single-
residue compounds within comparable Hg(II) concentration
ranges. In contrast, the response to other metals is much smaller,
with none of them causing a shift greater than 10 mV.
a
Data reported previously,23 included for comparison.
The half wave potentials measured for these compounds are
comparable to ferrocene/peptide conjugates previously repor-
ted.17,23,32 Redox potentials are raised relative to ferrocene itself
(E1/2¼448 mV vs Ag/Agþ),24 since covalently bound amino acids
exert an electron withdrawing effect on the metallocene, thus
making the iron(II) centre more difficult to oxidize. Further to the
electronwithdrawing effect of the amide, the amino acid side chains
also exert theirown influence on the redox potential of the ferrocene
core. The
L-alanine-containing compounds 1, 3 and 5 do not dem-
onstrate as strong a cationic shift as the equivalent
L
-phenylalanine-
containing conjugates 2, 4 and 6, which may be attributable to the
more electron rich nature of the phenylalanine side chain; Metzler-
Nolte and co-workers have previously observed small residue-de-
pendant shifts in the redox potentials of several sulfur-containing
ferrocenoyl peptides.20 The influence of the through-bond distance
between the sulfur and the redox core noted previously with single-
amino acid systems (Fig. 2)23 is also apparent with these dipeptide
conjugates, although it is only slight: compare the redox potentials
of Fe(C5H4-CO-Ala-Met-OMe)2 1 (788 mV) and Fe(C5H4-CO-Ala-Cys
(Me)-OMe)2 3 (792 mV), or Fe(C5H4-CO-Phe-Met-OMe)2 2 (794 mV)
vs Fe(C5H4-CO-Phe-Cys(Me)-OMe)2 4 (803 mV).
Intriguingly the Ala-Met derivative Fe(C5H4-CO-Ala-Met-OMe)2
1 exhibits a much smaller response to mercury(II) than the other
responsive compounds, a shift of only 9 mV up to saturation at
52 ppm Hg(II). The reason for this discrepancy is not clear. The
S-benzhydryl-
mercury (or the other metals tested), a result consistent with that
previously observed for the directly linked S-benzhydryl- -cysteine
L-cysteine analogues 7 and 8 do not respond at all to
All of the conjugates 1e8 have lower half wave potentials than
systems in which sulfur-containing amino acids are appended di-
rectly to the cyclopentadiene ring. For example compare Fe(C5H4-
L
derivative Fe(C5H4-CO-Cys(Bzh)-OMe)2, but also difficult to ex-
plain.23 As noted previously, the corresponding S-benzyl- and
S-tritylcysteine analogues respond to mercury and it is not obvious
why S-benzhydryl derivatives do not display properties in-
termediate between these.
The response to mercury of dipeptide conjugates 2e6 show
similar saturation effects and sensitivity (Fig. 3, Table 2) to those
seen previously for similar systems.23. Saturation is observed at
concentrations of 35e60 ppm mercury(II), beyond which the redox
potential is unchanged by further Hg(II) addition (compare to
53 ppm for the directly-linked Fe(C5H4-CO-Met-OMe)2 10, 40 ppm
CO-Ala-Met-OMe)2 1 (788 mV) and Fe(C5H4-CO-Phe-Met-OMe)2
2
(794 mV) to Fe(C5H4-CO-Met-OMe)2 10 (826 mV);23 Fe(C5H4-CO-
Ala-Cys(Me)-OMe)2
3 (792 mV) and Fe(C5H4-CO-Phe-Cys(Me)-
OMe)2 4 (803 mV) to Fe(C5H4-CO-Cys(Me)-OMe)2 11 (831 mV);23 or
Fe(C5H4-CO-Ala-Cys(Trt)-OMe)2 5 (798 mV) and Fe(C5H4-CO-Phe-
Cys(Trt)-OMe)2
6 (825 mV) to Fe(C5H4-CO-Cys(Trt)-OMe)2 12
(846 mV).23 This observation can be rationalized using similar
electron density arguments.
Peak separations (DEP) evince the reversibility of the redox
event. The theoretical peak separation for a diffusion-limited redox
Figure 2. Ferrocenoyl peptides 10e12 in which the S-bearing amino acid is directly attached to the ferrocene core.

5656
C.C.G. Scully, P.J. Rutledge / Tetrahedron 66 (2010) 5653e5659
Figure 3. Electrochemical response of compounds 1e6 to metal ions mercury(II), cadmium(II), zinc(II), silver(I) and lead(II). The apparent diminution of the generated current as the
concentration of mercury(II) increases is due to the increasing interaction of the ligand with the cation. The peak current is proportional to the diffusion constant for the peptide as
given in the Randles/Sevcik equation: ip¼2.69ꢀ105n3/2AD1/2Cv1/2 (where ip¼peak current (mV); n¼no. of electrons transferred; A¼electrode surface area (cm2); D¼diffusion co-
efficient (cm2 sꢁ1); C¼concentration (mol cmꢁ3);
n
¼scan rate (V sꢁ1)). The diffusion coefficient (D) in turn is inversely related to the molecular weight of the ligand/metal complex,
which increases as the heavy metal cation is bound.

C.C.G. Scully, P.J. Rutledge / Tetrahedron 66 (2010) 5653e5659
5657
Table 2
different result is apparent when comparing 5 and 6 to 12 (S-tri-
tylcysteine series): the sensitivities of both 5 (0.72 mV ppmꢁ1) and
6 (1.25 mV ppmꢁ1) are greater than the directly linked analogue 12
(0.53 mV ppmꢁ1), while the maximum potential shift of 5 (64 mV)
outstrips both 6 (26 mV) and 12 (31 mV). Thus through-bond in-
fluences alone do not account for the changes observed. The S-trityl
group is massively more sterically demanding than the side chains
of methionine and S-methylcysteine; it is plausible that this side
chain is afforded greater conformational freedom when positioned
further from the ferrocene core, which in turn influences its bind-
ing to mercury(II), and the through-space interaction between the
mercury guest and iron reporter.
The influence of the side chain on the spacer amino acid (Phe vs
Ala) is small and difficult to generalise. For the methionine (1 vs 2)
and S-tritylcysteine series (5 vs 6), the Phe-linked compounds show
higher maximum potential shift, higher saturation points and
greater sensitivity than the corresponding Ala-linked compounds.
In the S-methylcysteine series (3 vs 4) there is less difference in the
electrochemical properties of the two compounds, but it is the Ala
derivative 3 that shows a slightly higher maximum potential shift
and saturation point, although its sensitivity is again lower than the
Phe compound 4. Thus there is not a generalisable difference be-
Electrochemical response of ferrocenoyl peptides to Hg(II) in solution
Compound
Max potential
shifta (mV)
Hg(II) saturation
pointb (ppm)
Sensitivityc
(mV ppmꢁ1
)
1
2
3
4
5
6
9
52
61
51
36
36
51
53
40
58
0.17
0.43
0.92
1.03
0.72
1.25
0.89
1.73
0.53
26
47
37
26
64
47
69
31
10d
11d
12d
Compounds 7 and 8 are not shown because no response to mercury was observed
for these compounds.
a
The maximum potential shift is the change in the half wave potential from the
value in the absence of mercury(II) to the point at which the system becomes sat-
urated and no further shift is seen.
b
The Hg(II) saturation point is the concentration of mercury beyond which no
further change in half wave potential is observed.
c
The sensitivity indicates how quickly the half wave potential changes with re-
spect to the concentration of mercury present.
d
Data reported previously,23 included for comparison.
for Fe(C5H4-CO-Cys(Me)-OMe)2 11 and 58 ppm for Fe(C5H4-CO-Cys
(Trt)-OMe)2 12). The sensitivity is a measure of how quickly the
redox potential changes with respect to increasing mercury con-
centration and can be calculated from the slope of the mercury
response. The sensitivities of compounds 1e6 fall in the range
0.15e1.25 mV ppmꢁ1, similar to the values previously observed for
compounds 10e12 (0.50e1.75 mV ppmꢁ1).23
tween the L-alanine and L-phenylalanine spacer units. Although the
side chain of phenylalanine is significantly bulkier than that of al-
anine, there are not sufficient conformational constraints on the
dipeptide chain for this to consistently influence metal binding.
Nonetheless it is evident that introducing a spacer amino acid
between the ferrocene reporter and metal binding group of ferro-
cenoyl peptides with sulfur-containing side chains does influence
the fundamental electrochemical properties of these systems and
subtly alter their response to mercury(II) in solution. Moreover, the
greater responsiveness of such ferrocenoyl peptide systems to
mercury(II) than to other metal cations is also observed for di-
peptide conjugates.
2.4. Conclusions
There are four modes by which the interaction of a guest with
a redox active ligand can affect the redox potential of the li-
gand:14,35 (i) direct coordination between the redox core and the
guest;36 (ii) through-space electrostatic interactions;37 (iii)
through-bond communication;38 (iv) redox perturbation by in-
duced conformational change.39 Given the nature of the guest, li-
gand and redox core used in this study, mode (i) can be discounted
for these systems, and modes (ii) and (iii) should be the most
important.
3. Experimental
3.1. Synthesis of building blocks
3.1.1. General procedure for preparation of dipeptides. N-tert-Buty-
loxycarbonyl-L-Xaa (0.5 mmol) was stirred in DCM (10 mL).
The through-bond distance is increased in the dipeptide con-
jugates 1e6 relative to the single-residue compounds 10e12: any
through-bond electronic perturbation has to traverse an extra three
bonds to reach the redox core. Electron transfer through covalent
bonds is expected to decay exponentially with distance,40 however
the formation of peptide secondary structure provides a means for
electron transfer to bypass covalent interactions.41 Through-space
interactions are harder to evaluate in the absence of structural data
pinpointing the relative positions of iron and mercury in the fer-
rocene/peptide/mercury(II) complexes. (While crystal structures
are known for several of the ferrocene/peptide conjugates them-
selves,23 our attempts to crystallize the Hg(II) complexes of 1e12
have proved unsuccessful). Nonetheless comparing the data sum-
marized in Table 2 allows some conclusions to be drawn regarding
the nature of the mercury/peptide interactions, the factors affecting
the observed changes in redox response, and the influence of the
spacer amino acids.
Comparing 1 and 2 to 10 (methionine series) and 3 and 4 to 11
(S-methylcysteine series), it is evident that for these S-methyl
thioethers introducing a spacer lowers the maximum potential
shift and the sensitivity, but does not influence the Hg(II) saturation
point. This is consistent with the spacer amino acid having moved
the metal binding group further from the electrochemical reporter:
these groups are three bonds further apart, although the change in
through-space distance is harder to evaluate (see above). A
Triethylamine (1.0 mmol) was added followed by O-(benzotriazol-
1-yl)-N,N,N0,N0-tetramethyluronium hexafluorophosphate (HBTU)
(0.5 mmol). This solution was stirred for 15 min after which time L-
Yaa methyl ester (0.5 mmol) was added. The reaction was stirred for
16 h, the solvent evaporated in vacuo and the residue dissolved in
ethyl acetate (50 mL). This solution was washed with brine (10 mL),
saturated aqueous sodium bicarbonate solution (10 mL), water
(10 mL), aqueous hydrochloric acid (1 M, 10 mL), water (10 mL) and
brine (10 mL). The organic extract was dried (MgSO4) and the sol-
vent was evaporated in vacuo to yield an off-white foam. This was
purified by column chromatography (SiO2, EtOAc/hexane 1:1) to
yield N-tert-butyloxycarbonyl-L-Xaa-L-Yaa methyl ester as a white
foam (52e88%). All compounds were fully characterized using NMR
and high resolution mass spectrometry.
3.1.2. General procedure for preparation of ferrocenoyl peptides. Fer-
rocene-1,10-dicarboxylic acid (2.5 mmol) was dissolved in acetonitrile
(10 mL) and triethylamine (5.0 mmol) and stirred while HBTU
(5.0 mmol) was added. Stirring was continued for 15 min before the
dipeptide methyl ester p-toluenesulfonate salt (5.0 mmol) was added
along with additional triethylamine (5.0 mmol) and stirring contin-
ued for 24e48 h. The reaction mixture was diluted with ethyl acetate
(50 mL) to prevent the formation of emulsions and the organic phase
washed with water (50 mL), hydrochloric acid (1 M, 25 mL), water
(50 mL), saturated aqueous sodium bicarbonate solution (25 mL),

5658
C.C.G. Scully, P.J. Rutledge / Tetrahedron 66 (2010) 5653e5659
water(50 mL)andbrine(50 mL), thendried(MgSO4).Thesolventwas
evaporated invacuoto give a brownsolid, which was purified by flash
chromatography (hexane/ether); yields and characterization data
follow below.
2ꢀCH2S), 3.46 (6H, s, 2ꢀCO2CH3), 4.22 (2H, s, br, 2 of Fe(C5H4)2),
4.38 (2H, s, br, 2 of Fe(C5H4)2), 4.60 (2H, s, br, 2 of Fe(C5H4)2),
4.65e4.71 (2H, m, 2ꢀNHCHPHE), 4.73 (2H, s, br, 2 of Fe(C5H4)2),
5.04e5.29 (2H, m, 2ꢀNHCHCYS), 7.22e7.48 (10H, m, 2ꢀC6H5); dC
(100 MHz, CDCl3): 16.3 (2ꢀSCH3), 36.7 (2ꢀCH2S), 38.5
(2ꢀCH2C6H5), 53.3 (2ꢀNHCHPHE), 54.2 (2ꢀCO2CH3), 56.9
(2ꢀNHCHCYS), 71.2, 71.9, 72.4, 73.6 (8ꢀCH of Fe(C5H4)2), 77.2
(2ꢀCipso of Fe(C5H4)2), 128.0, 129.7, 130.8 (10ꢀCH of C6H5), 139.8
(2ꢀCipso of C6H5), 172.9, 173.1, 176.0 (6ꢀC]O); nmax (CHCl3 soln):
3323 (m), 2954 (s), 1745, 1672 (m), 1504 (m), 1209 (w); m/z (ESþ):
853 (100%, [MþNa]þ); HRMS (ESþ): found [MH]þ 831.22096,
C40H47FeN4O8S2 requires 831.21847.
3.1.2.1. Ferrocenoyl-1,10-di-
1. Synthesized from ferrocene-1,10-dicarboxylic acid
0.36 mmol) and -alaninyl- -methionine methyl ester p-toluene-
L
-alaninyl-
L
-methionine methyl ester
(0.10 g,
9
L
L
sulfonate (0.30 g, 0.73 mmol) to give an orange oil (0.15 g, 60%); Rf
0.13 (ether); dH (400 MHz, CDCl3): 1.42 (6H, d, J 7.5 Hz, 2ꢀCHCH3),
2.02e2.30 (4H, m, 2ꢀCH2CH2S), 2.15 (6H, s, 2ꢀSCH3), 2.61e2.69
(4H, m, 2ꢀCH2S), 3.76 (6H, s, 2ꢀCO2CH3), 4.30e4.31 (2H, m, 2 of Fe
(C5H4)2), 4.52e4.53 (2H, m, 2 of Fe(C5H4)2), 4.62e4.66 (2H, m,
2ꢀNHCHALA), 4.70e4.76 (2H, m, 2ꢀNHCHMET), 4.78e4.79 (2H, m, 2
of Fe(C5H4)2), 4.86e4.87 (2H, m, 2 of Fe(C5H4)2), 6.80 (2H, d, J
8.0 Hz, 2ꢀNH), 8.35 (2H, d, J 7.5 Hz, 2ꢀNH); dC (100 MHz, CDCl3):
16.6 (2ꢀSCH3), 17.4 (2ꢀCHCH3), 29.8 (2ꢀCH2CH2S), 36.3 (2ꢀCH2S),
49.4 (2ꢀNHCHALA), 52.3 (2ꢀCO2CH3), 52.9 (2ꢀNHCHMET), 70.6,
70.9, 71.8, 72.1 (8ꢀCH of Fe(C5H4)2), 76.3 (2ꢀCipso of Fe(C5H4)2),
170.6, 171.5, 175.1 (6ꢀC]O); nmax (CHCl3 soln): 3319 (m), 1739, 1677
(m), 1537 (m), 1224 (w); m/z (ESþ): 729 (100%, [MþNa]þ); HRMS
(ESþ): found [MH]þ 707.18518, C30H43FeN4O8S2 requires 707.18717.
3.1.2.5. Ferrocenoyl-1,10-di-
ester 5. Synthesized from ferrocene-1,10-dicarboxylic acid 9 (0.15 g,
0.56 mmol) and -alaninyl-S-trityl- -cysteine methyl ester (0.50 g,
L-alaninyl-S-trityl-L-cysteine methyl
L
L
1.12 mmol) to give an orange solid (0.38 g, 61%); Rf 0.61 (ether); mp
107e110 ꢂC;dH (400 MHz, CDCl3): 1.20 (6H, d, J7.0 Hz,2ꢀCHCH3), 2.59
(2H, dd, HB of ABX, JBA 13.0 Hz, JBX 8.0 Hz, 2ꢀ(1 of CH2S)), 2.72 (1H, dd,
HA of ABX, JAB 13.0 Hz, JAX 5.5 Hz, 2ꢀ(1 of CH2S)), 3.58 (6H, s,
2ꢀCO2CH3), 4.19e4.20 (2H, m, 2 of Fe(C5H4)2), 4.24e4.25 (1H, q, J
7.0 Hz, 2ꢀNHCHALA), 4.35e4.36 (2H, m, 2 of Fe(C5H4)2), 4.48 (2H, dd,
HX of ABX, JXA 5.5 Hz, JXB 8.0 Hz, 2ꢀNHCHCYS), 4.67 (2H, m, 2 of Fe
(C5H4)2)), 4.78e4.79 (2H, m, 2 of Fe(C5H4)2)), 6.04 (2H, d, J 7.0 Hz,
2ꢀNH), 7.12e7.38 (30H, m, 2ꢀ(C6H5)3), 8.15 (2H, d, J 7.0 Hz, NHꢀ2); dC
(100 MHz, CDCl3):15.9(2ꢀCHCH3), 32.4 (2ꢀCH2S), 47.5 (2ꢀNHCHALA),
50.8 (2ꢀCO2CH3), 51.4 (2ꢀNHCHCYS), 66.2 (2ꢀC(C6H5)3), 69.1, 69.9,
70.5, 70.8 (8ꢀCH of Fe(C5H4)2), 74.9 (2ꢀCipso of Fe(C5H4)2),125.9,126.1,
126.7, 127.1, 128.5 (30ꢀCHof C6H5),143.2 (6ꢀCipso of C6H5),169.9,170.1,
173.6 (6ꢀC]O); nmax (CHCl3 soln): 1751,1683 (m),1506 (m),1220 (w);
m/z (ESþ): 1157 (100%, [MþNa]þ); HRMS (ESþ): found [MH]þ
1135.34395, C64H63FeN4O8S2 requires 1135.34367.
3.1.2.2. Ferrocenoyl-1,10-di-
ester 2. Synthesized from ferrocene-1,10-dicarboxylic acid 9 (0.31 g,
1.13 mmol) and -phenylalaninyl- -methionine methyl ester p-tol-
L-phenylalaninyl-L-methionine methyl
L
L
uenesulfonate (1.20 g, 2.48 mmol) to give an orange oil (0.66 g, 60%);
Rf 0.41 (ether); dH (400 MHz, CDCl3): 2.11e2.22 (4H, m, 2ꢀCH2CH2S),
2.16 (6H, s, 2ꢀSCH3), 2.61e2.67 (4H, m, 2ꢀCH2C6H5), 3.13e3.15 (4H,
m, 2ꢀCH2S), 3.58 (6H, s, 2ꢀCO2CH3), 4.31 (2H, s, br, 2 of Fe(C5H4)2),
4.55 (2H, s, br, 2 of Fe(C5H4)2), 4.75e4.82 (2H, m, 2ꢀNHCHPHE), 4.77
(2H, s, br, 2 of Fe(C5H4)2), 4.84 (2H, s, br, 2 of Fe(C5H4)2), 4.92e4.96
(2H, m, 2ꢀNHCHMET), 7.12e7.29 (10H, m, 2ꢀC6H5), 8.72 (2H, d, J
7.0 Hz, 2ꢀNH); dC (100 MHz, CDCl3): 15.5 (2ꢀSCH3), 31.3
(2ꢀCH2CH2S), 37.0 (2ꢀCH2S), 37.9 (2ꢀCH2C6H5), 52.1 (2ꢀNHCHPHE),
52.4 (2ꢀCO2CH3), 53.5 (2ꢀNHCHMET), 69.9, 70.8, 71.2, 71.9 (8ꢀCH of
Fe(C5H4)2), 75.7 (2ꢀCipso of Fe(C5H4)2), 126.7, 128.5, 129.3 (10ꢀCH of
C6H5), 137.6 (2ꢀCipso of C6H5), 170.7, 171.9, 174.1 (6ꢀC]O); nmax
(CHCl3 soln): 3352 (m), 2964 (s),1743,1670 (m),1627,1483 (m),1226
(w); m/z (ESþ): 881 (100%, [MþNa]þ); HRMS (ESþ): found [MH]þ
859.24885, C42H51FeN4O8S2 requires 859.24977.
3.1.2.6. Ferrocenoyl-1,10-di-
methyl ester 6. Synthesized from ferrocene-1,10-dicarboxylic acid 9
(0.06 g, 0.22 mmol) and -phenylalaninyl-S-trityl- -cysteine methyl
L-phenylalaninyl-S-trityl-L-cysteine
L
L
ester p-toluenesulfonate (0.30 g, 0.43 mmol) to yield an orange
solid (0.12 g, 44%); Rf 0.75 (ether); mp 128e133 ꢂC; dH (400 MHz,
CDCl3): 2.27e2.77 (4H, m, 2ꢀCH2C6H5), 3.00e3.22 (4H, m,
2ꢀCH2S), 3.78 (6H, s, 2ꢀCO2CH3), 4.23 (2H, s, br, 2 of Fe(C5H4)2),
4.28e4.31 (2H, m, 2ꢀNHCHPHE), 4.36 (2H, s, br, 2 of Fe(C5H4)2),
4.70e4.74 (2H, m, 2ꢀNHCHCYS), 4.70 (2H, s, br, 2 of Fe(C5H4)2), 4.78
(2H, s, br, 2 of Fe(C5H4)2), 6.38e6.42 (2H, d, J 7.5 Hz, 2ꢀNH),
7.13e7.38 (40H, m, 8ꢀC6H5), 8.41e8.45 (2H, d, J 8.0 Hz, 2ꢀNH); dC
(100 MHz, CDCl3): 32.9 (2ꢀCH2S), 37.2 (2ꢀCH2C6H5), 51.9
(2ꢀNHCHPHE), 52.5 (2ꢀCO2CH3), 53.5 (2ꢀNHCHCYS), 67.2 (2ꢀC
(C6H5)3), 70.0, 70.7, 71.5, 71.8 (8ꢀCH of Fe(C5H4)2), 75.9 (2ꢀCipso of
Fe(C5H4)2), 126.8, 127.0, 128.0, 128.2, 128.6, 129.0, 129.7 (40ꢀCH of
C6H5), 137.7, 144.2 (8ꢀCipso of C6H5), 170.2, 170.4, 173.7 (6ꢀC]O);
nmax (CHCl3 soln): 2962 (s), 1730, 1654 (m), 1217 (w); m/z (ESþ):
1309 (100%, [MþNa]þ); HRMS (ESþ): found [MþNa]þ 1309.38941,
C76H70FeN4NaO8S2 requires 1309.38822.
3.1.2.3. Ferrocenoyl-1,10-di-
ester 3. Synthesized from ferrocene-1,10-dicarboxylic acid 9 (0.04 g,
0.15 mmol) and -alaninyl-S-methyl- -cysteine methyl ester p-tol-
L-alaninyl-S-methyl-L-cysteine methyl
L
L
uenesulfonate (0.12 g, 0.30 mmol) to yield an orange solid (0.11 g,
82%); Rf 0.10 (ether); mp 95e96 ꢂC; dH (400 MHz, CDCl3): 1.44 (6H,
d, J 7.0 Hz, 2ꢀCHCH3), 2.18 (6H, s, 2ꢀSCH3), 3.01e3.11 (4H, m,
2ꢀCH2S), 3.78 (6H, s, 2ꢀCO2CH3), 4.32 (2H, s, br, 2 of Fe(C5H4)2),
4.38 (2H, s, br, 2 of Fe(C5H4)2), 4.70e4.73 (2H, m, 2ꢀNHCHALA), 4.81
(2H, s, br, 2 of Fe(C5H4)2), 4.88 (2H, s, br, 2 of Fe(C5H4)2), 4.89e4.95
(2H, m, 2ꢀNHCHCYS), 6.91 (2H, d, J 7.0 Hz, 2ꢀNH), 8.34 (2H, d, J
7.0 Hz, 2ꢀNH); dC (100 MHz, CDCl3): 16.3 (2ꢀSCH3), 17.0
(2ꢀCHCH3), 30.8 (2ꢀCH2S), 49.1 (2ꢀNHCHALA), 51.9 (2ꢀCO2CH3),
52.7 (2ꢀNHCHCYS), 70.3, 70.9, 71.7, 72.1 (8ꢀCH of Fe(C5H4)2), 75.6
(2ꢀCipso of Fe(C5H4)2), 170.6, 171.2, 174.8 (6ꢀC]O); nmax (CHCl3
soln): 3323 (m), 2954 (s), 1743, 1677 (m), 1512 (m), 1220 (w); m/z
(ESþ): 701 (100%, [MþNa]þ); HRMS (ESþ): found [MþNa]þ
701.13941, C28H38FeN4NaO8S2 requires 701.13782.
3.1.2.7. Ferrocenoyl-1,10-di-
L-valinyl-S-benzhydryl-L-cysteine
methyl ester 7. Synthesized according to the general peptide cou-
pling procedure from ferrocene-1,10-dicarboxylic acid 9 (0.20 g,
0.74 mmol) and
L-valinyl-S-benzhydryl-L-cysteine methyl ester
p-toluenesulfonate (0.92 g, 1.48 mmol) to yield a flaky orange solid
(0.26 g, 41%); Rf 0.30 (ether); mp 99e101 ꢂC; dH (300 MHz, CDCl3):
0.99e1.05 (12H, m, 2ꢀCH(CH3)2), 2.05e2.16 (2H, m, 2ꢀ(CH(CH3)2),
2.82e2.95 (4H, m, 2ꢀCH2S), 3.69 (6H, s, 2ꢀCO2CH3), 4.25 (2H, s, br,
2 of Fe(C5H4)2), 4.28e4.31 (2H, s, br, 2ꢀ(NHCHVAL)), 4.31 (2H, s, br, 2
of Fe(C5H4)2), 4.68 (2H, s, br, 2 of Fe(C5H4)2), 4.76 (2H, m,
2ꢀNHCHCYS), 4.81 (2H, s, br, 2 of Fe(C5H4)2)), 5.33 (2H, s, 2ꢀSCH
(C6H5)2), 7.14e7.47 (20H, m, 2ꢀSCH(C6H5)2); dC (75.4 MHz, CDCl3):
19.6, 19.8 (4ꢀCH(CH3)2), 29.7 (2ꢀCH(CH3)2), 33.8 (2ꢀCH2S), 51.9
3.1.2.4. Ferrocenoyl-1,10-di-
methyl ester 4. Synthesized from ferrocene-1,10-dicarboxylic acid 9
(0.04 g, 0.16 mmol) and -phenylalaninyl-S-methyl- -cysteine
L-phenylalaninyl-S-methyl-L-cysteine
L
L
methyl ester p-toluenesulfonate (0.15 g, 0.32 mmol) to afford an
orange oil (0.07 g, 49%); Rf 0.30 (ether); dH (400 MHz, CDCl3): 2.07
(6H, s, 2ꢀSCH3), 2.71e2.95 (4H, m, 2ꢀCH2C6H5), 2.99e3.20 (4H, m,

C.C.G. Scully, P.J. Rutledge / Tetrahedron 66 (2010) 5653e5659
5659
(2ꢀCO2CH3), 52.4 (2ꢀSCH(C6H5)2), 54.2 (NHCHCYS), 60.3
(NHCHVAL), 70.1, 70.2, 71.2, 71.7 (8ꢀCH of Fe(C5H4)2), 76.3 (2ꢀCipso
of Fe(C5H4)2),127.4,127.5,127.4,128.6,128.7,129.2 (20ꢀCH of C6H5),
140.6, 140.8 (4ꢀCipso of C6H5), 169.9, 171.0, 173.5 (6ꢀC]O); nmax
(CHCl3 soln): 3322, 1745, 1672 (s), 1439 (m), 1200 (s); m/z (ESþ):
1039 (20%, [MH]þ), 1061 (100%, [MþNa]þ); HRMS (ESþ): found
[MH]þ 1039.3469, C56H63FeN4O8S2 requires 1039.3431.
for Research in Third Level Institutions (PRTLI) administered by the
HEA, and in Australia by the University of Sydney.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.05.070.
3.1.2.8. Ferrocenoyl-1,10-di-
teine methyl ester 8. Synthesized from ferrocene-1,10-dicarboxylic
acid 9 (0.2 g, 0.74 mmol) and -phenylalanine-S-benzhydryl- -cys-
L-phenylalaninyl-S-benzhydryl-L-cys-
References and notes
L
L
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teine methyl ester p-toluenesulfonate (0.92 g, 1.48 mmol) to yield
an orange oil (0.39 g, 46%); Rf 0.40 (ether); dH (300 MHz, CDCl3):
2.76e2.90 (4H, m, 2ꢀCH2C6H5), 3.07e3.18 (4H, m, 2ꢀCH2S), 3.52
(6H, s, 2ꢀCO2CH3), 4.21 (2H, s, br, 2 of Fe(C5H4)2), 4.33 (2H, s, br, 2 of
Fe(C5H4)2), 4.68 (2H, s, br, 2 of Fe(C5H4)2), 4.79 (2H, s, br, 2 of Fe
(C5H4)2), 4.72e4.86 (4H, m, 4ꢀ(NHCH)), 5.22 (2H, s, 2ꢀSCH(C6H5)2),
7.14e7.42 (30H, m, 6ꢀC6H5); dC (100 MHz, CDCl3): (75.4 MHz,
CDCl3): 33.5 (CH2S), 37.5 (CH2C6H5), 52.1 (CO2CH3), 52.4 (SCH
(C6H5)2), 54.2 (NHCHCYS), 55.9 (NHCHPHE), 70.1, 70.3, 71.1, 71.9
(8ꢀCH of Fe(C5H4)2), 75.8 (2ꢀCipso of Fe(C5H4)2), 126.7, 127.4, 127.5,
128.3, 128.5, 128.6, 128.7, 129.2 (30ꢀCH of C6H5), 137.6, 140.5, 140.8
(6ꢀCipso of C6H5), 169.5, 170.5, 170.7 (6ꢀC]O); nmax (CHCl3 soln):
3322, 1745, 1673 (s), 1538 (m), 1452 (m), 1222 (s); m/z (ESþ): 1157
(50%, [MþNa]þ); HRMS (ESþ): found [MH]þ 1035.3422, C64H63Fe-
N4O8S2 requires 1035.3431.
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Acknowledgements
We wish to thank Professor Robert O’Neil (UCD) and Dr. Aviva
Levina for help and advice with electrochemistry experiments. This
work was funded in Ireland by University College Dublin and the
Centre for Synthesis and Chemical Biology under the Programme