Synthesis and electrochemical properties of tetrathiafulvalene derived amino acids and peptides

Article abstract of DOI:10.1039/a800759d

A synthetic route to a tetrathiafulvalene (TTF) derived aspartic acid derivative 18, with suitable orthogonal protecting groups has been developed. The aspartic acid derivative 18 can be used in the synthesis of peptides, as exemplified by the synthesis of di-, tri- and tetra-peptides 21-23. Preliminary electrochemical studies of these novel peptides indicate that they may well undergo conformational reorganisation upon oxidation of the TTF moieties.

Full text of DOI:10.1039/a800759d

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Synthesis and electrochemical properties of tetrathiafulvalene derived
amino acids and peptides
Susan Booth, Emma N. K. Wallace, Kavita Singhal, Philip N. Bartlett and
Jeremy D. Kilburn*
Department of Chemistry, University of Southampton, Highfield, Southampton, UK SO17 1BJ
A synthetic route to a tetrathiafulvalene (TTF) derived aspartic acid derivative 18, with suitable
orthogonal protecting groups has been developed. The aspartic acid derivative 18 can be used in the
synthesis of peptides, as exemplified by the synthesis of di-, tri- and tetra-peptides 21–23. Preliminary
electrochemical studies of these novel peptides indicate that they may well undergo conformational
reorganisation upon oxidation of the TTF moieties.
residues,7 but as far as we are aware no such studies using TTF
derived amino acids have been reported.
Introduction
Organic π-donors based on tetrathiafulvalene (TTF) deriv-
atives and their cation radical salts have been the subject of
numerous studies due to their ability to form charge transfer
compounds, and their potential as molecular conductors and
superconductors.1 Most of the interesting properties of these
materials are, however, exhibited by single crystals and this
places limitations on their practical application. Polymeric
TTFs are a potential solution to this problem, but most of the
polymers reported to date2 show low conductivity, reflecting
the difficulty in preparing materials with control over the stack-
ing interactions of the individual TTF units. Recently consider-
able attention has also been focused on the incorporation of
TTF units into supramolecular architectures and several of
these multiple TTF systems have shown interesting electro-
chemical properties.3 We reasoned that conducting materials
might be prepared by the incorporation of unnatural TTF bear-
ing amino acids into a polypeptide predicted to form regular
secondary structural motifs, where the role of the peptide
backbone in such materials would be to control the spatial
arrangement of the TTF units.4 For example, in a β-sheet struc-
ture layering of the sheets involves interleaving of the amino
acid side chain residues perpendicular to the sheet, giving a
separation of the side chain residues of approximately 0.36 nm
along the axis of an individual peptide strand with slight
variations depending on substituent effects, and similar close
packing between adjacent peptide strands in the sheet. In
one-dimensional organic metals, based upon TTF derivatives,
the TTF units are generally observed to arrange themselves in
segregated stacks and the separation of TTF units is typically in
the range of 0.345–0.365 nm.5 A β-sheet structure constructed
from TTF amino acids could thus provide sheets of extremely
tightly ordered TTF molecules with separation ideal for con-
ductivity, after partial oxidation of the TTF units. Interaction
between the sheets, and thus the conductivity orthogonal to the
plane, might, however, be limited. Alternatively incorporation
of TTF bearing amino acids into an α-helical structure might
allow the alignment of the TTF units into a conducting stack
on one face of the helix6 or even a helical arrangement of con-
ducting TTF units giving rise to a molecular solenoid! The
packing of the individual helical units in the solid state, and
hence the degree of interaction between TTF units on adjacent
helices, would be influenced by the substitution pattern of the
TTF units on the peptide backbone. In addition to the possibil-
ity of generating new conducting materials, there has been con-
siderable interest in studying electron transfer processes in
proteins, which has been modelled by synthetic peptides derived
from amino acids bearing electroactive groups in the side chain
In order to prepare peptides incorporating TTF derived
amino acids we set out to establish synthetic routes to suitable,
orthogonally protected amino acid derivatives. In this paper we
report the synthesis of such unnatural TTF bearing amino
acids and their incorporation into small peptide structures. Pre-
liminary electrochemical studies on these new materials are also
reported and indicate that on oxidation of the TTF units the
higher oligomers may undergo conformational reorganisation
in solution, presumably in response to interactions between the
oxidised TTF units.
Results and discussion
Synthesis
TTF amino acids derived from aspartic and glutamic acid were
chosen because of the ability of these amino acids to promote
β-sheet formation8 and the potential ease of attachment of
TTF derivatives to the side-chain carboxylates via an ester link-
age. In order to provide orthogonal protecting groups which
would be compatible with the potentially acid-sensitive TTF
units, we chose to use fluoren-9-ylmethoxycarbonyl (Fmoc) as
the amine protecting group, with the carboxylic acid protected
as its 2-phenylpropan-2-yl ester, which requires only weak acid
for its cleavage.9 Protection of the carboxylic acid as its tert-
butyl ester was avoided because of the strongly acidic condi-
tions required for its removal. Suitably protected aspartic acid
and glutamic acid derivatives 8 and 9 were prepared in four
steps (Scheme 1). Initial formation of the allyl esters 1 and 2
following the method of Belshaw et al.,10 Fmoc protection of
the amino group under standard conditions,11 and reaction of
the resulting acids 3 and 4 with 2-phenylpropan-2-yl 2,2,2-
trichloroacetimidate 5,9 prepared in one step by the reaction
of the sodium salt of 2-phenylpropan-2-ol with trichloro-
acetamide, afforded the fully protected derivatives 6 and 7.
Palladium(0) catalysed deallylation released the acid side chains
to give 8 and 9 respectively.
A series of TTF-alcohols were prepared with a view to link-
ing them to the amino acid derivatives 8 and 9. Although both
alcohols 10 and 11 could be prepared, essentially following
literature methods,12 the overall yields were disappointing.
Instead we found that TTF-alcohol 15 could be prepared more
readily, and on a large scale, from bis(cyanoethylthio) protected
TTF 13 (Scheme 2), described by Becher and co-workers.13 TTF
13 was prepared in four steps, in good overall yield from Zn-
(dmit)2(NBu4)2 12, itself prepared on a large scale by the sodium
metal reduction of carbon disulfide in the presence of DMF.14
J. Chem. Soc., Perkin Trans. 1, 1998
1467

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S
S
S
S
ClH3N
CO2H
S
S
S
S
S
S
S
H2N
CO2H
Me3SiCl
OH
OH
( )n
O
O
allyl alcohol
S
( )n
CO2Me
HO2C
11
10
1 n = 1, 88%
2 n = 2, 71%
n = 1, aspartic acid
n = 2, glutamic acid
2–
(Bu4N+)2
S
S
S
S
S
S
S
S
S
S
Zn
9% Na2CO3 (aq)
dioxane
Fmoc ONSu
12
NH
FmocHN
CO2CMe2Ph
FmocHN
CO2H
4 steps
(ref. 13)
Me
O
CCl3
Ph
CH2Cl2
( )n
( )n
O
O
Me
O
5
S
S
S
S
O
CN
CN
3 n = 1, 87%
4 n = 2, 84%
6 n = 1, 97%
7 n = 2, 96%
S
S
S
S
13
Pd(PPh3)4
N-methylmorpholine
CH2Cl2, AcOH
(i) CsOH•H2O
or Me4NOH
(ii) MeI
FmocHN
HO2C
CO2CMe2Ph
( )n
S
S
S
S
S
S
S
CN
8 n = 1, 82%
9 n = 2, 80%
SMe
Scheme 1
14 94%
Treatment of 13 with one equivalent of either caesium hydroxide
monohydrate or a solution of tetramethylammonium hydroxide
in methanol gave the corresponding monothiolate, which was
quenched with methyl iodide to give the previously described13
TTF derivative 14. Treatment with a further equivalent of base,
followed by quenching with 2-bromoethanol, then gave TTF-
alcohol 15 in 89% yield.
Coupling of amino acids 8 and 9 with TTF-alcohol 15 was
best achieved using Mitsunobu conditions15 [diisopropyl azodi-
carboxylate (DIAD), PPh3] which gave the TTF derived amino
acids 18 and 16 in 76 and 41% yield, respectively (Scheme 3).
Fmoc-Deprotection of 16 and 18 was attempted using a 20%
solution of piperidine in THF. Deprotection of glutamic acid
derivative 16, under these conditions, resulted in immediate
formation of pyroglutamate derivative 17, with loss of TTF-
alcohol 15. In the case of aspartic acid derivative 18, however,
Fmoc-deprotection occurred smoothly to afford TTF-amine 19
in 92% yield. Treatment of 18 with 1% TFA in dichloromethane
gave the corresponding TTF-acid 20 in 87% yield.9
(i) CsOH•H2O
or Me4NOH
(ii) BrCH2CH2OH
S
S
S
S
S
S
OH
S
SMe
15 89%
Scheme 2
trolled oxidation with iodine, led to crude products which could
not be purified or recrystallised for conductivity measurements
or further studies.
Electrochemical studies
The electrochemistry of the TTF amino acid 18, dipeptide 21,
tripeptide 22 and tetrapeptide 23 were examined using cyclic
voltammetry at a macroscopic platinum electrode and at plat-
inum microelectrodes. The voltammetry for the TTF amino
acid 18 in acetonitrile showed two reversible one electron redox
processes corresponding to the expected oxidation to the TTFϩ
radical cation and to the TTF2ϩ dication [Fig. 1(a)]. This
behaviour is identical to that found for unsubstituted TTF
except that the redox potentials for the two reactions are shifted
anodic by 153 and 47 mV respectively (Table 1), as would be
expected for a tetrathioalkyl substituted TTF.16 At a micro-
electrode (Fig. 2) the TTF amino acid 18 again showed two
reversible one electron waves (as judged by the Tomes criteria17)
as expected. From the limiting currents at the microelectrode a
diffusion coefficient of 1 × 10Ϫ5 cm2 sϪ1 was obtained, 20% less
than the corresponding value for TTF18 and consistent with the
increased molecular volume of the TTF amino acid 18 over the
parent compound.
Having successfully developed a route to a TTF bearing
amino acid derivative, and having established that the orthog-
onal protecting groups could be selectively removed, we used
these derivatives in the synthesis of a series of di-, tri- and tetra-
peptides. Thus, TTF-amine 19 was coupled with TTF-acid 20,
using pyBOP and DIPEA, to afford the dipeptide 21 in 87%
yield (Scheme 4). Treatment of dipeptide 21 with 1% TFA in
dichloromethane gave the corresponding acid which could
again be coupled with TTF-amine 19 using tris(pyrrolidinyl)-
benzotriazolyloxyphosphonium hexafluorophosphate (pyBOP)
and DIPEA to give tripeptide 22 in 88% yield. Repeating the
cycle of acid deprotection (1% TFA in dichloromethane), fol-
lowed by coupling with TTF-amine 19 (pyBOP, DIPEA) gave
tetrapeptide 23 in 85% yield. All the peptides were characterised
1
unambiguously by H and 13C NMR spectroscopy, mass spec-
trometry, and, with the exception of the tetrapeptide, by micro-
analysis. Unfortunately at this stage we have been unable to
prepare crystalline samples of these materials suitable for X-ray
crystallographic studies, and preliminary attempts to prepare
solid-state charge transfer salts of these compounds, by con-
In contrast the voltammetry of the di-, tri- and tetra-peptides
21, 22 and 23, showed a number of significant differences from
the nearly ideally electrochemically reversible behaviour shown
1468
J. Chem. Soc., Perkin Trans. 1, 1998

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9
+
15
O
PriO2CN=NCO2Pr i
PPh3, THF
FmocHN
CO2CMe2Ph
N
H
O
O
FmocHN
CO2CMe2Ph
PyBOP
DIPEA, DMF
O
O
19 + 20
S 3
3′ S 4′
S
S
4
S
MeS
S
SMe
S
S
S
S
O
O
2
2′
5
MeS
S
S
5′
1
1′
S
16 41%
20% piperidine
in THF
S
S
S
S
S
S
S
S
H
N
O
CO2CMe2Ph
21 87%
17
(i) 1% TFA
in CH2Cl2
(ii) 19, PyBOP,
8 + 15
DIPEA, DMF
PriO2CN=NCO2Pri
PPh3, THF
O
O
FmocHN
CO2CMe2Ph
N
H
O
N
n
H
O
FmocHN
CO2CMe2Ph
O
O
O
S
S
S
S
S
S
S
O
O
MeS
O
18 76%
SMe
S
MeS
S
SMe
S
S
S
S
S
S
S
S
20% piperidine
in THF
S
S
S
S
S
S
S
H2N
CO2CMe2Ph
O
1% TFA
in CH2Cl2
S
S
S
S
S
S
S
S
S
S
S
MeS
(i) 1% TFA
in CH2Cl2
(ii) 19, PyBOP,
DIPEA, DMF
O
22 n = 1 88%
23 n = 2 85%
19 92%
Scheme 4
FmocHN
CO2H
O
macroscopic electrode also showed clear broadening of the first
redox wave corresponding to the oxidation of the TTF groups
to the TTFϩ radical cation but no corresponding broadening of
the second wave corresponding to oxidation to the TTF2ϩ di-
cation (Table 1) indicating that the broadening is not due to iR
drop. This broadening is independent of the sweep rate over the
range 10 to 100 mV sϪ1. In addition, on going from the mono-
mer to the di-, tri- and tetra-peptides the mid peak potentials for
the second oxidation shift to more anodic potentials (Table 1).
Examination of the dependence of the peak currents for both
the first and second redox processes on the square root of the
sweep rate (not shown) revealed that, whereas for the mono-
meric TTF amino acid 18 there is a linear relationship as
expected for an electrochemically reversible reaction, there
was increasing deviation from linearity for the di-, tri- and
tetra-peptides indicating the presence of an associated chemical
reaction accompanying the electron transfer process. Similar
deviations from the behaviour expected for a simple sequential
electrochemical reaction were evident in the voltammetry for
the four species recorded at a microelectrode [Fig. 2(a)–(d)]
where the first wave became broader on going from the mono-
mer to the di-, tri- and tetra-peptide. In contrast to the cyclic
voltammetry at the macroscopic electrode, however, the limiting
S
S
S
S
S
S
S
MeS
O
20 87%
Scheme 3
Table 1 Cyclic voltammetric data (mid peak potential, E1/2, and
peak separation, ∆Ep) for TTF amino acid oligomers. Experimental
conditions are given in Fig. 1.
First wave
Second wave
E1/2/mV vs.
∆Ep/
mV
E1/2/mV vs.
∆Ep/
mV
Compound
Agϩ/Ag
Agϩ/Ag
TTF
Ϫ20
133
123
140
128
70
85
100
130
130
358
405
433
453
458
65
70
65
70
65
TTF amino acid 18
Dipeptide 21
Tripeptide 22
Tetrapeptide 23
by the monomer. First we note that the peak currents increase
as expected as the number of redox centres attached to the
molecule increases [Fig. 1(b)–(d)]. The cyclic voltammetry at a
J. Chem. Soc., Perkin Trans. 1, 1998
1469

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Fig. 2 Voltammograms recorded at 50 mV sϪ1 at platinum microdisc
electrodes for (a) 1 mmol dmϪ3 TTF amino acid 18 in acetonitrile at a
13 µm radius electrode, (b) 1 mmol dmϪ3 dipeptide 21 in acetonitrile–
dichloromethane (4:1) at a 2.7 µm radius electrode, (c) 1 mmol dmϪ3
tripeptide 22 in acetonitrile–dichloromethane (1:1) at a 2.7 µm
radius electrode, (d) 1 mmol dmϪ3 tetrapeptide 23 in acetonitrile–
dichloromethane (7:3) at a 2.7 µm radius electrode. In all cases the
background electrolyte was 0.1 mol dmϪ3 tetraethylammonium tetra-
fluoroborate. Thecurrents(i)arenormalisedwithrespecttotheelectrode
radius (a) to aid direct comparison.
Fig. 1 Cyclic voltammograms at a macroscopic platinum electrode
recorded at 20 mV sϪ1 for (a) 1 mmol dmϪ3 TTF amino acid 18
in acetonitrile, (b) 1 mmol dmϪ3 dipeptide 21 in acetonitrile–di-
chloromethane (4:1), (c) 1 mmol dmϪ3 tripeptide 22 in acetonitrile–
dichloromethane (1:1), (d) 1 mmol dmϪ3 tetrapeptide 23 in aceto-
nitrile–dichloromethane (7:3). In all cases the background electrolyte
was 0.1 mol dmϪ3 tetraethylammonium tetrafluoroborate.
macroscopic electrodes and at the microelectrode could be
explained in terms of a structural reorganisation which is fast
on the cyclic voltammetry timescale but which is too slow
to occur effectively on the timescale of the microelectrode
measurement (<~100 sϪ1) where the enhanced rate of mass
transport at the microdisc means that the TTF species can
diffuse away from the electrode before completing the conform-
ational reorganisation.
In conclusion we have developed a synthetic route to a TTF
derived aspartic acid derivative, with suitable orthogonal pro-
tection to allow this derivative to be used in the synthesis of
peptides, as exemplified by the synthesis of a di-, tri- and tetra-
peptide. Although we have not been able to prepare character-
isable charge transfer salts of these compounds, preliminary
electrochemical studies of these materials do indicate that
they may well undergo conformational reorganisation upon
oxidation of the TTF moieties. Further studies on the electro-
chemical properties of these materials, and the synthesis of
larger peptide structures incorporating the TTF derived amino
acid, which may lead to new conducting materials are underway.
current associated with the second redox reaction at the micro-
electrode also decreased with increasing molecular size. Studies
of the effect of a 10-fold change in the concentration of the
monomer and the di-, tri- and tetra-peptides showed the
expected change in the magnitude of the currents, but no
changes in the peak potentials or peak separation, clearly indi-
cating that the particular effects seen for the di-, tri- and tetra-
peptides arise from intramolecular interactions between the
TTF groups, and not from intermolecular interactions or
effects of adsorption onto the electrode surface.
These systematic changes, on going from the monomer to the
dimer, trimer and tetramer, are consistent with the occurrence
of interactions between the TTF moieties within the oligomers.
A similar broadening of the first redox wave, in this case
accompanied by a sharpening of the second redox wave, has
been reported by Kuo et al.19 in studies of TTF immobilised
at an electrode surface, and more recently by Bryce and co-
workers20 in a study of the electrochemistry of a TTF
dendrimer. In this latter work the changes in the peak widths
for the two redox processes were only observed in thin layer
voltammetry and not in conventional cyclic voltammetry
studies. This difference can be rationalised in terms of the time-
scales of the two measurements. Thus if structural reorganis-
ation of the system, following oxidation to TTFϩ, is slow on the
timescale of the experiment then the TTF units will behave as
non-interacting redox centres. However if there is time during
the measurement for structural reorganisation to bring the
TTFϩ groups into a stacked configuration then interaction
between the centres will be evident in the voltammetry for both
redox process. In the case of the TTF dendrimer the results are
consistent with a structural reorganisation which is slow on the
cyclic voltammetric timescale (<~1 sϪ1). In our studies the differ-
ence which we observe between the cyclic voltammetry at
Experimental
Melting points were recorded on a Gallenkamp melting point
apparatus (MF-370). Infrared spectra were recorded on a
1
Perkin-Elmer 1600 spectrophotometer. H NMR Spectra were
recorded on a JEOL FX90Q (90 MHz) and a JEOL JNM-GX
270 (270 MHz) instrument; chemical shifts are given in ppm
relative to SiMe4 and J values are given in Hz. 13C NMR
Spectra were recorded on a JEOL JNM-GX 270 and a Bruker
AC 300 instrument. Mass spectra were obtained on a VG
Analytical, 70/250/SE, normal geometry double focussing mass
spectrometer.
Electrochemical measurements were carried out in aceto-
nitrile (Aldrich HPLC grade, freshly distilled and dried over
calcium chloride) or mixtures of acetonitrile and dichloro-
methane (Fisons), depending on the solubilities of the
1470
J. Chem. Soc., Perkin Trans. 1, 1998

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compounds. In all cases 0.1  tetraethylammonium tetra-
fluoroborate (Fluka >99%) was used as the background
electrolyte.
to a stirred solution of 3 (1.00 g, 2.53 mmol) in dichloro-
methane (30 cm3). Stirring was continued at room temperature
overnight. Solvent was evaporated under reduced pressure, the
residue diluted with a small amount of dichloromethane and
insoluble trichloroacetamidate removed by filtration. Chrom-
atography on silica gel with diethyl ether–light petroleum (bp
40–60 ЊC) (3:7, v/v) afforded 6 as a clear, colourless oil (1.26 g,
97%); νmax(film)/cmϪ1 3420m, 3065m, 3030m, 2985m, 2945m,
1735s, 1585w, 1505s, 1450m, 1380m, 1340m, 1270m, 1210s;
δH(300 MHz, CDCl3) 7.78 (d, J 7.7, 2 H), 7.60 (d, J 7.4, 2 H),
7.43–7.25 (complex m, 9 H), 5.91 (ddt, J 17.1, 10.3, 5.8, 1 H),
5.83 (d, J 8.4, 1 H), 5.35 (dd, J 17.1, 1.5, 1 H), 5.27 (dd, J 10.3,
1.5, 1 H), 4.69–4.57 (complex m, 3 H), 4.41 (dd, J 10.6, 7.0,
1 H), 4.37 (dd, J 10.6, 7.0, 1 H), 4.23 (t, J 7.0, 1 H), 3.11 (dd,
J 16.9, 4.4, 1 H), 2.92 (dd, J 16.9, 4.8, 1 H), 1.82 (s, 3 H), 1.80
(s, 3 H); δC(75.5 MHz, CDCl3) 170.7 (CO), 169.2 (CO), 156.1
(CO), 145.0 (C), 143.9 (C), 141.4 (C), 131.8 (CH), 128.5 (CH),
127.9 (CH), 127.5 (CH), 127.2 (CH), 125.3 (CH), 124.5 (CH),
120.2 (CH), 119.0 (CH2), 84.0 (C), 67.4 (CH2), 65.9 (CH2), 51.1
(CH), 47.3 (CH), 36.9 (CH2), 28.6 (CH3), 28.2 (CH3); LRMS
(FAB) m/z 513 (Mϩ, 1%), 119 (100).
Cyclic voltammetry experiments at macroscopic platinum
electrodes were carried out using a conventional three electrode
system with a platinum gauze counter and either Ag/0.1 
AgNO3/acetonitrile or Ag/0.01  AgNO3/acetonitrile reference
electrodes (all potential values have been corrected to the same
standard value for Ag/0.1  AgNO3/acetonitrile). For micro-
electrode measurements a two electrode system was used with
the Ag/AgNO3 electrode as the combined counter and reference
electrode. All platinum working electrodes were polished with
slurries of 1 and 0.3 µm alumina before each experiment.
β-Allyl hydrogen -aspartate 1 and γ-allyl hydrogen -gluta-
mate 2 were prepared according to the method of Belshaw et al.9
â-Allyl hydrogen N-(fluoren-9-ylmethoxycarbonyl)-L-aspartate 3
N-(Fluoren-9-ylmethoxycarbonyl)succinimide (4.14 g, 12.28
mmol) in dioxane (25 cm3) was added to a stirred solution of
1 (3.00 g, 14.32 mmol) and 9% aqueous sodium carbonate (25
cm3). Stirring at room temperature was continued overnight.
The reaction mixture was diluted with water (250 cm3) and
washed with ethyl acetate (3 × 250 cm3). The aqueous phase
was acidified with concentrated hydrochloric acid and extracted
with ethyl acetate (2 × 250 cm3). The organic phase was dried
(MgSO4) and concentrated under reduced pressure. Chrom-
atography on silica gel with dichloromethane–methanol (19:1,
v/v) as eluent afforded 3 as a white solid (4.91 g, 87%), mp 105–
107 ЊC [from ethyl acetate–light petroleum (bp 40–60 ЊC)];
δH(300 MHz, CDCl3) 8.84 (br s, 1 H), 7.77 (d, J 7.4, 2 H), 7.61
(d, J 7.4, 1.1, 2 H), 7.41 (t, J 7.4, 2 H), 7.32 (dt, J 7.4, 1.1, 2 H),
5.98–5.85 (m, 2 H), 5.34 (d, J 17.3, 1 H), 5.27 (d, J 10.3, 1 H),
4.74 (dt, J 8.5, 4.4, 1 H), 4.64 (d, J 5.5, 2 H), 4.46 (dd, J 10.7,
7.4, 1 H), 4.38 (dd, J 10.7, 7.4, 1 H), 4.24 (t, J 7.4, 1 H), 3.14 (dd,
J 17.6, 4.4, 1 H), 2.95 (dd, J 17.6, 4.4, 1 H); δC(75.5 MHz,
CDCl3) 175.7 (CO), 171.0 (CO), 156.3 (CO), 143.8 (C), 141.5
(C), 131.6 (CH), 127.9 (CH), 127.3 (CH), 125.3 (CH), 120.2
(CH), 119.1 (CH2), 67.6 (CH2), 66.1 (CH2), 50.3 (CH), 47.2
(CH), 36.5 (CH2); LRMS (FAB) m/z 396 (MHϩ, 18%) (Found:
C, 66.75; H, 5.49; N, 3.53. C22H21NO6 requires C, 66.82; H,
5.36; N, 3.54%).
á-(2-Phenylpropan-2-yl) ã-allyl N-(fluoren-9-ylmethoxycarb-
onyl)-L-glutamate 7
2-Phenylpropan-2-yl 2,2,2-trichloroacetimidate8
5 (7.51 g,
26.77 mmol; 26 cm3 of a 0.96  solution in cyclohexane)
was added to a stirred solution of 4 (5.47 g, 13.39 mmol) in
dichloromethane (100 cm3). Stirring was continued at room
temperature overnight. The trichloroacetamide side-product
was removed by filtration and the filtrate concentrated in vacuo.
Chromatography on silica gel with diethyl ether–light petrol-
eum (bp 40–60 ЊC) (3:7 v/v) afforded 7 as a clear, colourless oil
(6.78 g, 96%); νmax(film)/cmϪ1 3065m, 2980m, 2945m, 2360w,
2255w, 1955w, 1730s, 1620s, 1450s, 1340m; δH(270 MHz,
CDCl3) 7.76 (d, J 7.3, 2 H), 7.59 (d, J 7.5, 2 H), 7.43–7.31 (m, 9
H), 5.94 (ddt, J 17.2, 10.8, 5.8, 1 H), 5.39 (br, 1 H), 5.34 (dq,
J 17.2, 1.5, 1.5, 1 H), 5.26 (dq, J 10.8, 1.5, 1.5, 1 H), 4.61
(dt, J 5.8, 1.5, 2 H), 4.44–4.37 (m, 3 H), 4.21 (t, J 7.0, 1 H),
2.49–2.35 (m, 3 H), 2.01 (m, 1 H), 1.83 (s, 3 H), 1.81 (s, 3 H);
δC(75.5 MHz, CDCl3) 172.7 (CO), 170.7 (CO), 156.2 (CO),
145.0 (C), 143.9 (C), 141.5 (C), 132.2 (CH), 128.6 (CH), 127.9
(CH), 127.6 (CH), 127.3 (CH), 125.3 (CH), 124.5 (CH), 120.2
(CH), 118.6 (CH2), 83.8 (C), 67.2 (CH2), 65.6 (CH2), 53.9 (CH),
47.3 (CH), 30.3 (CH2), 28.8 (CH3), 28.4 (CH3), 27.9 (CH3);
LRMS (FAB) m/z 1077 (2 Mϩ ϩ Na, 15%), 550 (Mϩ ϩ Na,
100).
ã-Allyl hydrogen N-(fluoren-9-ylmethoxycarbonyl)-L-glutamate 4
N-(Fluoren-9-ylmethoxycarbonyl)succinimide (6.03 g, 17.9
mmol) in dioxane (50 cm3) was added to a stirred solution of 2
(5.00 g, 22.4 mmol) and 9% aqueous sodium carbonate (45 cm3)
cooled to 0 ЊC. The reaction mixture was allowed to warm to
room temperature and stirring at this temperature continued
overnight. Water (250 cm3) was added and the aqueous mixture
was washed with ethyl acetate (2 × 250 cm3). The aqueous
phase was acidified with concentrated hydrochloric acid
and extracted with diethyl ether (2 × 250 cm3). The organic
phase was dried (MgSO4) and concentrated in vacuo. Chrom-
atography on silica gel with dichloromethane–methanol–glacial
acetic acid (94:5:1, v/v) as eluent afforded 4 as a white solid
(7.69 g, 84%); δH(300 MHz, CDCl3) 8.82 (br s, 1 H), 7.76 (d,
J 7.4, 2 H), 7.60 (d, J 7.4, 2 H), 7.42 (t, J 7.4, 2 H), 7.32 (t, J 7.4,
2 H), 5.88 (ddt, J 17.1, 10.7, 5.8, 1 H), 5.69 (d, J 8.1, 1 H), 5.32
(d, J 17.1, 1 H), 5.24 (d, J 10.1, 1 H), 4.70–4.35 (m, 5 H), 4.22 (t,
J 7.1, 1 H), 2.60–2.40 (m, 3 H), 2.11 (m, 1 H); δC(75.5 MHz,
CDCl3) 175.8 (CO), 172.9 (CO), 156.4 (CO), 143.8 (C), 141.5
(C), 132.1 (CH), 127.9 (CH), 127.3 (CH), 125.3 (CH), 120.2
(CH), 118.7 (CH2), 67.4 (CH2), 65.7 (CH2), 53.4 (CH), 47.3
(CH), 30.4 (CH2), 27.4 (CH2) (Found: C, 67.25; H, 5.72; N,
3.65. C23H23NO6 requires C, 67.47; H, 5.66; N, 3.42%).
á-(2-Phenylpropan-2-yl) hydrogen N-(fluoren-9-ylmethoxycarb-
onyl)-L-aspartate 8
Palladium tetrakis(triphenylphosphine) (324 mg, 0.28 mmol)
was added to a degassed solution of 6 (1.44 g, 2.80 mmol) in
chloroform–glacial acetic acid–N-methylmorpholine (37:2:1,
v/v) (80 cm3) under a nitrogen atmosphere. Stirring at room
temperature under nitrogen was continued overnight, solvent
was evaporated under reduced pressure, the residue diluted with
dichloromethane (100 cm3) and washed with 1  hydrochloric
acid (3 × 100 cm3). The organic phase was dried (MgSO4) and
concentrated in vacuo. Chromatography on silica gel with
dichloromethane–methanol (39:1, v/v) as eluent afforded 8 as a
pale yellow viscous oil (1.09 g, 82%); νmax(film)/cmϪ1 3330br m,
3025m, 2975m, 2360w, 1715s, 1515s, 1450m; δH(300 MHz,
CDCl3) 7.76 (d, J 7.4, 2 H), 7.59 (d, J 7.4, 2 H), 7.42–7.28
(complex m, 9 H), 5.79 (d, J 8.1, 1 H), 4.65 (dt, J 8.1, 4.1, 1 H),
4.42 (dd, J 10.3, 7.0, 1 H), 4.36 (dd, J 10.3, 7.0, 1 H), 4.22 (t,
J 7.0, 1 H), 3.14 (dd, J 17.5, 4.1, 1 H), 2.95 (dd, J 17.5, 4.1, 1 H),
1.81 (s, 3 H), 1.79 (s, 3 H); δC(75.5 MHz, CDCl3) 176.1 (CO),
169.1 (CO), 156.2 (CO), 144.9 (C), 143.9 (C), 141.4 (C), 128.5
(CH), 127.9 (CH), 127.6 (CH), 127.3 (CH), 125.3 (CH), 124.5
(CH), 120.2 (CH), 84.2 (C), 67.5 (CH2), 51.0 (CH), 47.3 (CH),
36.7 (CH2), 28.6 (CH3), 28.1 (CH3); LRMS (FAB) m/z 473 (Mϩ,
á-(2-Phenylpropan-2-yl) â-allyl N-(fluoren-9-ylmethoxycarb-
onyl)-L-aspartate 6
2-Phenylpropan-2-yl 2,2,2-trichloroacetimidate8 5 (1.42 g, 5.06
mmol; 5.3 cm3 of a 0.96  solution in cyclohexane) was added
J. Chem. Soc., Perkin Trans. 1, 1998
1471

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2%), 179 (100) (Found: C, 70.91; H, 5.73; N, 2.74. C28H27NO6
requires C, 71.02; H, 5.75; N, 2.96%).
under reduced pressure. Chromatography on silica gel with
dichloromethane–light petroleum (bp 40–60 ЊC) (4:1, v/v) as
eluent afforded 16 (88 mg, 41%) as an orange foam; νmax(film)/
cmϪ1 3350m, 2010–2925w, 1730s, 1515m, 1445m, 1265m,
1210m; δH(300 MHz, CDCl3) 7.69 (d, J 7.4, 2 H), 7.51 (d, J 7.4,
2 H), 7.38–7.19 (complex m, 9 H), 5.31 (br, 1 H), 4.39–4.28
(complex m, 3 H), 4.24–4.09 (complex m, 3 H), 3.21 (s, 4 H),
2.96 (t, J 6.7, 2 H), 2.51–2.16 (complex m, 6 H), 2.00 (m, 1 H),
á-(2-Phenylpropan-2-yl) hydrogen N-(fluoren-9-ylmethoxycarb-
onyl)-L-glutamate 9
Palladium tetrakistriphenylphosphine (1.37 g, 1.18 mmol) was
added to a degassed solution of 7 (6.25 g, 11.84 mmol) in
chloroform–glacial acetic acid–N-methylmorpholine (37:2:1,
v/v) (360 cm3) under a nitrogen atmosphere. Stirring at room
temperature under nitrogen was continued overnight, solvent
was evaporated under reduced pressure, the residue diluted with
dichloromethane (250 cm3) and washed with 1  hydrochloric
acid (3 × 250 cm3). The organic phase was dried (MgSO4) and
concentrated in vacuo. Chromatography on silica gel with a
solvent gradient of diethyl ether–light petroleum (bp 40–
60 ЊC)–glacial acetic acid (50:49:1, v/v) up to diethyl ether–
glacial acetic acid (99:1, v/v) afforded 9 as a clear, colourless
viscous oil (4.62 g, 80%); νmax(film)/cmϪ1 3335br m, 3020m,
2980m, 2360w, 1720s, 1515s, 1450m, 1340m, 1215s; δH(270
MHz, CDCl3) 7.76 (d, J 7.5, 2 H), 7.58 (d, J 7.3, 2 H), 7.42–7.30
(m, H-2, 9 H), 5.44 (d, J 8.1, 1 H), 4.41–4.38 (m, 3 H), 4.22 (t,
J 7.0, 1 H), 2.51–2.25 (m, 3 H), 2.00 (m, 1 H), 1.81 (s, 3 H), 1.80
(s, 3 H); δC(75.5 MHz, CDCl3) 178.3 (CO), 170.6 (CO), 156.3
(CO), 144.9 (C), 143.9 (C), 141.5 (C), 128.6 (CH), 127.9 (CH),
127.6 (CH), 127.3 (CH), 125.3 (CH), 124.5 (CH), 120.2 (CH),
83.9 (C), 67.3 (CH2), 53.7 (CH), 47.3 (CH), 30.1 (CH2), 28.7
(CH3), 28.4 (CH3), 27.8 (CH2); LRMS (FAB) m/z 487 (Mϩ,
7%), 179 (100) (Found: C, 71.23; H, 6.03; N, 2.75. C29H29NO6
requires C, 71.44; H, 6.00; N, 2.87%).
1.76 (s, 3 H), 1.75 (s, 3 H); δC
(75.5 MHz, CDCl3) 172.6 (CO),
170.5 (CO), 156.1 (CO), 145.0 (C), 143.9 (C), 141.5 (C), 132.7
(C), 128.6 (CH), 127.9 (CH), 127.6 (CH), 127.3 (CH), 125.3
(CH), 124.5 (CH), 123.1 (C), 120.2 (CH), 114.1 (C), 83.8 (C),
67.3 (CH2
), 63.2 (CH ), 53.8 (CH), 47.4 (CH), 34.6 (CH ), 30.4
2
2
(CH2), 28.7 (CH3), 28.4 (CH3), 19.3 (CH3); LRMS m/z (FAB)
885 (Mϩ, 42%), 119 (100) (Found: Mϩ, 885.0506. C40H39NO6S8
requires Mϩ, 885.0543).
á-(2-Phenylpropan-2-yl) â-[4Ј,5Ј-ethylenedithio-5-(methylthio)-
tetrathiafulvalen-4-ylthioethyl] N-(fluoren-9-ylmethoxycarb-
onyl)-L-aspartate 1816
Diisopropyl azodicarboxylate (64 mg, 0.32 mmol) in dry THF
(2 cm3) was added via a syringe to a solution of 8 (100 mg, 0.21
mmol), 15 (88 mg, 0.21 mmol) and triphenylphosphine (83 mg,
0.32 mmol) in dry THF (5 cm3) under a nitrogen atmosphere.
Stirring at room temperature was continued overnight. THF
was evaporated in vacuo. Chromatography on silica gel with
ethyl acetate–light petroleum (bp 40–60 ЊC) (9:16, v/v) as elu-
ent afforded 18 as an orange foam (139 mg, 76%); νmax(CH2Cl2)/
cmϪ1 3415w, 2930w, 2360w, 1730s, 1505m, 1340w, 1210m;
δH(300 MHz, CDCl3) 7.85 (d, J 7.4, 2 H), 7.70 (d, J 7.4, 2 H),
7.44–7.21 (complex m, 9 H), 4.66 (m, 1 H), 4.37 ( d, J 6.6, 2 H),
4.30 (t, J 6.6, 2 H), 4.25 (t, J 6.6, 1 H), 3.39 (s, 4 H), 3.10 (t,
J 6.6, 2 H), 2.96 (m, 2 H), 2.46 (s, 3 H), 1.76 (s, 6 H); δC(75.5
MHz, CD3COCD3) 170.6 (CO), 169.7 (CO), 156.6 (CO), 146.3
(C), 144.8 (C), 141.8 (C), 133.7 (C), 133.6 (C), 129.7 (C), 129.5
(C), 128.8 (CH), 128.3 (CH), 127.8 (CH), 127.6 (CH), 125.9
(CH), 125.1 (CH), 120.6 (CH), 83.5 (C), 67.2 (CH2), 63.7 (CH2),
52.0 (CH), 47.8 (CH), 37.0 (CH2), 30.6 (CH2), 28.6 (CH3), 19.0
(CH3); LRMS (FAB) m/z 871 (Mϩ, 100%) (Found: C, 52.84;
H, 4.28; N, 1.79. C39H37NO6S8 requires C, 53.24; H, 4.28; N,
1.61%).
4,5-Ethylenedithio-4Ј-methylthio-5Ј-(2-hydroxyethylthio)-
tetrathiafulvalene 15†
Following the procedure of Becher et al.13 a degassed solution
of tetramethylammonium hydroxide (450 mg, 2.08 cm3 of a
25% solution by wt. of tetramethylammonium hydroxide in
methanol, 4.94 mmol) was added dropwise to a degassed solu-
tion of 4,5-ethylenedithio-4Ј-methylthio-5Ј-(2-cyanoethylthio)-
tetrathiafulvalene 14 (1.91 g, 4.49 mmol) in dry THF (50 cm3).
Stirring at room temperature was continued for 1 h after which
time a degassed solution of 2-bromoethanol (617 mg, 4.94
mmol) in dry THF (5 cm3) was added in one portion. Stirring
at room temperature was continued overnight. Solvent was
evaporated under reduced pressure and the residue partitioned
between water and dichloromethane. The organic phase was
dried (MgSO4) and concentrated in vacuo. Chromatography on
silica gel with ethyl acetate–light petroleum (bp 40–60 ЊC)
(1:1, v/v) afforded 15 as a red–brown solid (1.66 g, 89%);
νmax(CH2Cl2)/cmϪ1 3605br m, 3045w, 2925w, 2875w, 1810w,
1730w, 1415m, 1385w, 1285m, 1055s; δH(270 MHz, CDCl3) 3.85
(br, 2 H), 3.30 (s, 4 H), 2.94 (t, J 7.0, 2 H), 2.45 (s, 3 H); δC(75.5
MHz, CDCl3) 133.6 (C), 122.7 (C), 114.1 (C), 114.0 (C), 60.1
(C), 39.4 (CH2), 30.4 (CH2), 19.5 (CH2) (Found: C, 31.70; H,
2.89. C11H12OS8 requires C, 31.70; H, 2.90%).
á-(2-Phenylpropan-2-yl) â-[4Ј,5Ј-ethylenedithio-5-(methylthio)-
tetrathiafulvalen-4-ylthioethyl] L-aspartate 1917
The protected amino acid 18 (756 mg, 0.868 mmol) was
stirred at room temperature under a nitrogen atmosphere in a
piperidine–THF (1:20, v/v) solution (20 cm3) for 3 min. Solvent
was evaporated under reduced pressure. Chromatography on
silica gel with dichloromethane–methanol (99:1, v/v) as eluent
afforded 19 as an orange oil (520 mg, 92%); δH(300 MHz,
CDCl3) 7.36–7.25 (complex m, 5 H), 4.27 (t, J 6.6, 2 H), 3.81
(dd, J 7.3, 5.0, 1 H), 3.32 (s, 4 H), 3.00 (t, J 6.6, 2 H), 2.85 (dd,
J 16.2, 5.0, 1 H), 2.70 (dd, J 16.2, 7.3, 1 H), 2.43 (s, 3 H), 1.80
(s, 3 H), 1.79 (s, 3 H); δC(75.5 MHz, CDCl3) 172.7 (CO), 171.1
(CO), 145.3 (C), 128.5 (CH), 127.4 (CH), 124.4 (CH), 82.9 (C),
63.2 (CH2), 51.9 (CH), 39.2 (CH2), 34.5 (CH2), 30.4 (CH2),
28.7 (CH3), 28.6 (CH3), 19.4 (CH3) [Found (FAB-MS): MHϩ,
649.9756. C24H27NO4S8 requires MH, 649.9784].
á-(2-Phenylpropan-2-yl) ã-[4Ј,5Ј-ethylenedithio-5-(methylthio)-
tetrathiafulvalen-4-ylthioethyl] N-(fluoren-9-ylmethoxycarb-
onyl)-L-glutamate 1616
Diisopropyl azodicarboxylate (73 mg, 0.36 mmol) in dry THF
(2 cm3) was added dropwise to a solution of 9 (117 mg, 0.24
mmol), 15 (100 mg, 0.24 mmol) and triphenylphosphine (95
mg, 0.36 mmol) in dry THF (5 cm3) cooled to 0 ЊC under a
nitrogen atmosphere. Stirring at room temperature was con-
tinued for 48 h. THF was evaporated in vacuo, the residue
diluted with dichloromethane (50 cm3) and the solution washed
with saturated aqueous sodium hydrogen carbonate (2 × 50
cm3). The organic phase was dried (MgSO4) and concentrated
â-[4Ј,5Ј-Ethylenedithio-5-(methylthio)tetrathiafulvalen-4-ylthio-
ethyl]hydrogenN-(fluoren-9-ylmethoxycarbonyl)-L-aspartate208
The protected amino acid 18 (100 mg, 0.115 mmol) was stirred
in a solution of trifluoroacetic acid–dichloromethane (1:99,
v/v) (50 cm3) for 5 min. 10% Aqueous sodium hydrogen
carbonate (50 cm3) was added and the mixture extracted
with dichloromethane (2 × 50 cm3). The organic phase was
dried (MgSO4) and concentrated under reduced pressure.
Chromatography on silica gel with dichloromethane–
methanol–acetic acid (95:4:1, v/v) as eluent afforded 20 as an
orange oil (76 mg, 87%); νmax(CH2Cl2)/cmϪ1 3515br m, 2545w,
† The numbering system used for these TTF compounds is shown for
compound 16 in Scheme 3.
1472
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
2360w, 1730s, 1510w; δH(300 MHz, CD3COCD3) 7.83 (d, J 7.4,
2 H), 7.69 (d, J 7.4, 2 H), 7.40 (t, J 7.4, 2 H), 7.31 (t, J 7.4, 2 H),
6.81 (d, J 8.8, 1 H), 4.69 (dt, J 8.8, 6.4, 1 H), 4.36 (d, J 7.4, 2 H),
4.31–4.22 (complex m, 3 H), 3.34 (s, 4 H), 3.10 (t, J 6.4, 2 H),
2.97 (m, J 5.1, 2 H), 2.46 (s, 3 H); δC(75.5 MHz, CD3COCD3)
172.3 (CO), 170.8 (CO), 156.7 (CO), 144.8 (C), 141.8 (C), 133.5
(C), 128.4 (CH), 127.8 (CH), 126.0 (CH), 123.4 (C), 120.7 (CH),
114.2 (C), 108.1 (C), 67.2 (CH2), 63.7 (CH2), 51.3 (CH), 47.8
(CH), 37.0 (CH2), 30.7 (CH2), 19.2 (CH3); LRMS m/z (ESϩ) 776
(Mϩ ϩ Na, 25%), 753 (Mϩ, 30) [Found (ESϩ): Mϩ, 752.9642.
C30H27NO6S8 requires Mϩ, 752.9604].
(br), 51.3, 49.4, 47.0, 36.0, 35.6, 34.3, 34.1, 31.4, 30.2, 28.4, 28.2,
19.1; LRMS m/z (ESϩ) 1896 (Mϩ, 28%) (isotopic substitution
pattern was in accordance with C69H67N3O12S24) (Found: C,
73.39; H, 6.10; N, 3.52. C69H67N3O12S24 requires C, 73.32; H,
5.97; N, 3.72%).
Tetrapeptide 23
Tripeptide 22 (95 mg, 0.05 mmol) was stirred in a solution of
trifluoroacetic acid–dichloromethane (1:99, v/v) (10 cm3) for
30 min. The reaction mixture was diluted with dichloro-
methane (50 cm3) and washed with saturated aqueous sodium
hydrogen carbonate (50 cm3). The sodium salt of the tripeptide
acid formed an insoluble brown gum in the aqueous phase
which was acidified with 1  aqueous HCl and the free acid
was extracted into dichloromethane. The organic phases were
combined, dried (MgSO4) and concentrated in vacuo to give the
tripeptide acid which was used directly in the next reaction.
Thus the tripeptide acid (89 mg, 0.05 mmol), amine 19 (33 mg,
0.05 mmol) and pyBOP (31 mg, 0.06 mmol) were dissolved in
dry DMF (5 cm3). DIPEA (9 mg, 0.06 mmol) in DMF (1 cm3)
was added dropwise. Stirring at room temperature under nitro-
gen was continued overnight. The reaction mixture was poured
into water and washed with dichloromethane (50 cm3). The
organic phase was dried (MgSO4) and concentrated in vacuo
and the resultant oil was triturated with methanol to remove
any remaining DMF. Chromatography on silica gel with
dichloromethane–acetonitrile (95:5, v/v) as eluent afforded 23
as an orange glass (102 mg, 85%); νmax(CH2Cl2)/cmϪ1 2925w,
1730s, 1685s, 1500s, 1450w, 1415w, 1390w, 1355w, 1290m;
δH(270 MHz, CD3COCD3) 7.70 (d, J 7.3, 2 H), 7.54 (d, J 6.8, 2
H), 7.35–7.26 (complex m, 9 H), 4.79–4.58 (br, 3 H), 4.44 (br, 1
H), 4.32 (m, 2 H), 4.09 (br, 9 H), 3.26 (s, 16 H), 2.84–2.78 (br m,
16 H), 2.61 (s, 12 H), 1.69 (s, 6 H); δC(75.5 MHz, CDCl3) 171.5,
171.4, 171.2, 170.7, 170.3, 169.9, 169.6, 168.5, 156.2, 145.1,
143.8, 141.5, 132.8, 132.6, 128.5, 128.0, 127.3, 125.3, 124.5,
120.2, 118.1, 116.8, 83.8, 67.6, 63.9 (br), 51.3, 50.1, 49.6, 47.3,
36.3, 35.7, 30.5, 28.6, 28.4, 19.6 (br); LRMS m/z (FAB) 2409
(Mϩ) (isotopic substitution pattern was in accordance with
C84H82N4O15S32).
Dipeptide 21
DIPEA (36 mg, 0.277 mmol) in dry DMF (1 cm3) was added
dropwise to a solution of 19 (150 mg, 0.231 mmol), 20 (174 mg,
0.231 mmol) and pyBOP (144 mg, 0.277 mmol) in dry DMF (10
cm3). Stirring at room temperature was continued overnight
under a nitrogen atmosphere. The reaction mixture was diluted
with dichloromethane (100 cm3) and the organic phase washed
with water to remove DMF. The organic phase was dried
(MgSO4) and concentrated in vacuo. Chromatography on silica
gel with dichloromethane–methanol (99:1, v/v) as eluent
afforded 21 as an orange foam (279 mg, 87%); νmax(CH2Cl2)/
cmϪ1 3740m, 3415w, 3045w, 2930w, 1735s, 1685w, 1450m,
1415w, 1390w, 1355w, 1265m, 1215m; δH(300 MHz, CDCl3)
7.71 (d, J 7.7, 2 H), 7.54 (d, J 7.0, 2 H), 7.38–7.10 (complex m, 9
H), 5.96 (d, J 5.9, 1 H), 4.76 (m, 1 H), 4.59 (m, 1 H), 4.33 (m, 2
H), 4.20 (complex m, 5 H), 3.22 (s, 8 H), 3.03–2.65 (complex m,
8 H), 2.36 (s, 3 H), 2.33 (s, 3 H), 1.72 (s, 6 H); δC(75.5 MHz,
CDCl3) 171.2 (CO), 170.3 (CO), 170.1 (CO), 168.4 (CO), 155.9
(CO), 144.8 (C), 143.7 (C), 141.3 (C), 133.4 (CO), 133.1 (CO),
129.2 (CO), 129.1 (CO), 128.4 (CH), 127.8 (CH), 127.4 (CH),
127.2 (CH), 125.3 (CH), 124.4 (CH), 122.2 (C), 120.1 (CH),
113.9 (C), 113.2 (C), 109.9 (C), 83.9 (C), 67.4 (CH2), 63.3 (CH2),
51.0 (CH), 49.4 (CH), 47.1 (CH), 36.3 (CH2), 36.1 (CH2), 34.2
(CH2), 30.3 (CH2), 28.4 (CH3), 28.3 (CH3), 19.2 (CH3); LRMS
(FAB) m/z 1386 (M ϩ 2, 9%), 119 (100) (Found: C, 46.94; H,
3.77; N, 1.86. C54H52N2O9S16 requires C, 46.79; H, 3.78; N,
2.02%).
Tripeptide 22
Acknowledgements
Dipeptide 21 (300 mg, 0.217 mmol) was stirred in a solution of
trifluoroacetic acid–dichloromethane (1:99, v/v) (40 cm3) for
1 h. 10% Aqueous sodium hydrogen carbonate (50 cm3) was
added and the mixture extracted with dichloromethane (2 × 50
cm3). The sodium salt of the dipeptide acid was seen as an
insoluble brown gum in the aqueous phase. The aqueous phase
was acidified with aqueous 1  HCl and the free acid extracted
into dichloromethane. The organic phases were combined,
dried (MgSO4) and concentrated under reduced pressure.
Chromatography on silica gel with dichloromethane–methanol
(98:2, v/v) as eluent afforded the dipeptide acid as an orange
glass (210 mg, 77%) which was used directly in the next reac-
tion. Thus DIPEA (13 mg, 0.104 mmol) in dry DMF (1 cm3)
was added dropwise to a solution of the dipeptide acid (110 mg,
0.0869 mmol), amine 19 (56 mg, 0.0869 mmol) and pyBOP (54
mg, 0.104 mmol) in dry DMF (10 cm3). Stirring at room tem-
perature under nitrogen was continued overnight. The reaction
mixture was poured into water and the resultant solid filtered,
dissolved in dichloromethane, dried (MgSO4) and concentrated
in vacuo. Chromatography on silica gel with dichloromethane–
methanol (99:1, v/v) as eluent afforded 22 as an orange glass
(146 mg, 88%); νmax(CH2Cl2)/cmϪ1 2930w, 2400w, 1730s, 1680m,
1495s, 1355w, 1290m; δH(270 MHz, CD3COCD3) 7.71 (d, J 7.3,
2 H), 7.55 (d, J 6.7, 2 H), 7.48–7.15 (complex m, 9 H), 6.75 (d,
J 5.7, 1/3 H), 4.77 (br, 2 H), 4.50 (br, 1 H), 4.32 (m, 2 H), 4.18
(br, 7 H), 3.28 (s, 12 H), 2.91–2.78 (br m, 21 H), 1.69 (s, 6 H);
δC(75.5 MHz, CDCl3) 171.1, 170.3, 170.1, 169.6, 168.4, 156.1,
144.8, 143.7, 141.2, 133.0, 132.7, 128.3, 127.8, 127.1, 125.1,
124.3, 122.4, 122.2, 120.0, 113.8, 113.7, 113.2, 83.5, 67.3, 63.2
We thank the EPSRC for funding this work (GR/H23427)
and Dr S. V. Kelkar for preliminary work on the synthesis of
compounds 10 and 11.
References
1 F. Wudl, D. Wobschall and E. J. Hufnagel, J. Am. Chem. Soc., 1972,
94, 671; J. Ferraris, D. O. Cowan, V. V. Walatka and J. H. Perlstein,
ibid., 1972, 94, 3372; J. M. Williams, A. J. Schultz, U. Geiser, K. D.
Carlson, A. Kini, H. H. Wang, W.-K. Kwok, M.-H. Whangbo and
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Paper 8/00759D
Received 28th January 1998
Accepted 27th February 1998
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