Cyclopeptoids: A novel class of phase-transfer catalysts

Article abstract of DOI:10.1039/c2ob26764k

The synthesis, complexation properties and catalytic activities under phase-transfer (PT) conditions of differently substituted cyclohexapeptoids are reported. Association constants, for small cationic alkali, and catalytic performances, in a model nucleophilic substitution, are comparable to those of representative crown ethers. Noteworthy, the N-[2-(2-methoxyethoxy)ethyl] side chain derivative presents a catalytic efficiency comparable to that of crypt-222, and higher than some commonly used quaternary ammonium salts and crown ethers. Moreover its association constant for Na⁺ complexation proved to be higher when compared with dicyclohexyl-18-crown-6. The synthesized cyclohexapeptoids represent the first example of these peptidomimetics in PT catalysis, anticipating interesting applications in biphasic PT methodology. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2ob26764k

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PAPER
Cyclopeptoids: a novel class of phase-transfer catalysts†
Giorgio Della Sala,* Brunello Nardone, Francesco De Riccardis and Irene Izzo*
Received 7th September 2012, Accepted 16th October 2012
DOI: 10.1039/c2ob26764k
The synthesis, complexation properties and catalytic activities under phase-transfer (PT) conditions of
differently substituted cyclohexapeptoids are reported. Association constants, for small cationic alkali, and
catalytic performances, in a model nucleophilic substitution, are comparable to those of representative
crown ethers. Noteworthy, the N-[2-(2-methoxyethoxy)ethyl] side chain derivative presents a catalytic
efficiency comparable to that of crypt-222, and higher than some commonly used quaternary ammonium
salts and crown ethers. Moreover its association constant for Na+ complexation proved to be higher when
compared with dicyclohexyl-18-crown-6. The synthesized cyclohexapeptoids represent the first example
of these peptidomimetics in PT catalysis, anticipating interesting applications in biphasic PT
methodology.
Introduction
Today phase-transfer catalysis (PTC) is recognized as a versatile
methodology for organic synthesis in both industry and acade-
mia, because of its general application, efficiency, mild and
environment-friendly reaction conditions.1 Moreover continuing
efforts towards the design of new, synthetically versatile cata-
lysts, especially in asymmetric synthesis, are currently being
made.2 Peptoids are an archetypal example of peptidomimetics,
which have shown unique structural, chemical and physical
Fig. 1 Structures of the cyclopeptoids examined in our studies.
properties.3
Taking inspiration from the natural cyclopeptides, recently, we
studied alkali metal ions complexation4 and cation transport
across a phospholipid membrane5 for N-benzyloxyethyl glycine
cyclic oligopeptoids of various sizes, reporting the first metallo-
peptoid X-ray structure to be solved.4 The complex association
constants, Ka, for the alkali metal ion–host complexes were
determined by picrate extraction techniques in H2O–CHCl3, as
described by Cram and co-workers.6 In particular, the hexacyclo
peptoid 1 (Fig. 1) showed a good degree of selectivity for the
smaller cations, with a peak for Na+.4
synthesis, and their well-known metal ion affinities prompted us
to investigate the use of cyclopeptoids in the field of PTC.
In this contribution we report the syntheses, binding affinities
and catalytic abilities of cyclohexapeptoids 2–6 (Fig. 1) in a
biphasic nucleophilic substitution reaction and in comparison
with well known phase-transfer catalysts.
Results and discussion
Despite the wide use of peptides and synthetic analogues in
catalysis,7 to the best of our knowledge, to date, peptoid oligo-
mers of N-substituted glycines have been scarcely explored for
catalytic applications and only one example has been reported in
the literature.8 In this context, the easy access to highly diverse
peptoids side chains and backbones, the high-yield solid-phase
Design and synthesis of the new catalysts
The design of an efficient phase transfer catalyst can be a very
difficult task since a number of factors are simultaneously
involved, often counteracting each other in determining the reac-
tion rate in a two-phase system. Although these factors depend
on the experimental conditions and on the kind of reaction, some
of them are of general importance for the catalytic efficiency.
The lipophilicity of the catalyst, the extraction selectivity, the
cation–anion separation within an ion pair and the solvation of
the anion must be carefully evaluated to obtain the best results.9
Similarly to crown ethers, cyclopeptoids are neutral ligands,
lacking unwanted, potentially competitive, extraneous anions in
Dipartimento di Chimica e Biologia, Università degli Studi di Salerno,
via Ponte don Melillo, 84084 Fisciano (SA), Italy.
E-mail: izzo@unisa.it, gdsala@unisa.it; Fax: (+39)089969603;
Tel: (+39)089969560, (+39)089969554
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26764k
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Determination of association constants by Cram’s method
the reaction medium. On the other hand this fact entails uncer-
tainty about the nature of the actual catalyst formed from the
ligand–cation complex.
Efficient metal complexation is an important requirement for PT
catalysts. Table 1 reports the association constants (Ka), as well
In order to assess the potential of cyclopeptoids as PT cata-
lysts, a series of structurally different cyclohexapeptoids, differ-
ing in the nature of the N-alkyl side chain, have been prepared
taking advantage of the efficient sub-monomer synthetic
method.10 Side chains were designed to guarantee optimal lipo-
philicity (benzyl and n-hexyl appendages) or cation affinity
(methoxyethyl and methoxyethoxyethyl pendant groups). The
elaboration of the linear precursors, performed on a 2-chlorotrityl
resin through a two step construction of the N-alkyl glycine, is
shown in Scheme 1.
as −ΔG° and RCHCl values, that have been determined for the
3
complexation of 2–6 to Li+, Na+ and K+ (in H2O–CHCl3, fol-
lowing Cram’s method),6 in comparison with the dicyclohexyl-
18-crown-6 and 15-crown-5 (14 and 16, Fig. 3), excellent com-
plexing agents6,12 and very efficient PT catalysts.13 While the
18-crown-6 derivatives are known to show high affinity for
potassium, 15-crown-5 has been found to be selective for
sodium.7,14
The acylation reaction, using the bromoacetic acid, was fol-
lowed by a displacement step using the appropriate primary
amine. After the completion of synthesis the oligomers were
cleaved from the resin using a 1 : 4 solution of hexafluoroisopro-
panol (HFIP)–CH2Cl2. Head-to-tail macrocyclizations of the
linear N-substituted oligoglycines 7–11 proceeded smoothly
giving, under high dilution conditions (3.0 × 10−3 M) and in the
presence of the efficient coupling agent O-(7-azabenzotriazol-1-
yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU),
the cyclic peptoids 2–6.11
Table 1 Parameters for association between hosts and picrate salts in
CHCl3 at 25 °C
Complexing
Entry agent
a
M+ RCHCl3 Ka × 10−4/M−1 −ΔG°/kcal mol−1
1
2
2b
3
Li+
Na+ 0.22
0.13
63
120
7.9
8.3
3
4
5
Li+
0.24
170
260
31
8.5
8.8
7.5
Na+ 0.32
K+
0.12
6
7
8
5
6
Li+
0.07
27
250
5.1
7.4
8.7
6.4
In order to evaluate the use of preformed complexes in the
phase-transfer reactions, it was decided to prepare the sodium
hexafluorophosphate adducts 12 and 13 shown in Fig. 2 (from
neutral 2 and 5, respectively).
Na+ 0.32
K+
0.03
9
10
11
Li+
0.38
490
1500
590
9.1
9.8
9.2
Na+ 0.55
K+
0.48
12
13
14
14c
16
Li+
0.053
19.2
234
0.809 20 000
7.20
8.68
11.32
Na+ 0.308
K+
15
16
17
Li+ <0.01
Na+ 0.49
<3
884
23
—
9.5
7.3
K+
0.10
a [Guest]/[Host] in CHCl3 layer at equilibrium obtained by direct
measurement, or calculated by difference from measurement made on
aqueous phase. b For compound 2 it was not possible to determine the
association constant with the potassium picrate for the formation of a
precipitate (probably an insoluble complex with the salt). c See ref. 6.
Scheme 1 Sub-monomer approach for the synthesis of oligomers
7–11. DIPEA = N,N diisopropylethylamine; DIC = N,N′-diisopropyl
carbodiimide; (a) bromoacetic acid, DIPEA; (b) RNH2 (10 equiv.); (c)
bromoacetic acid, DIC; (d) HFIP–CH2Cl2 (1 : 4).
Fig. 3 Crown ethers and other complexing agents discussed in this
Fig. 2 Complexed cyclopeptoids.
article.
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The synthesized cyclopeptoids exhibited a good degree of
selectivity towards Na+, as previously observed for 14 (6 being
the most efficient). In particular, the macrocycle 6 showed a Ka
value for Na+ higher than that determined for 15-crown-5 (16)
and more than six times greater than that calculated for dicyclo-
hexyl-18-crown-6 (14).
It is noteworthy to mention that while all the commercially
available PT catalysts (14–19) were more efficient in the pres-
ence of potassium thiocyanate, with almost all the new cyclohex-
apeptoids the reaction proved to be faster with sodium
thiocyanate. An exception was cyclopeptoid 2, both in the free
and complexed form (entries 2 and 7, respectively). Interestingly,
the catalysts in the complexed form (12 and 13, entries 7 and 8)
were shown to be less efficient than those in the free form (2 and
5). All the uncomplexed cyclopeptoids proved to be more effec-
tive catalysts than the known poly(ethylene glycol) 19. The most
active cyclopeptoids, 3, 5 and 6, exhibited activities comparable
with the crown ethers. To our delight, macrocycle 6, containing
N-[2-(2-methoxyethoxy)ethyl] side chains, showed, in the reac-
tion with NaSCN, higher efficiency than crown ethers, and an
activity comparable to that observed for cryptand 17, the best
one among the screened catalysts. A high activity, albeit lower,
was achieved also with KSCN as the reagent.
As previously pointed out, the design of an efficient catalyst
and the rationalization of the experimental results are intrinsi-
cally difficult tasks. Anyhow, some general considerations can
be drawn from the observed experimental data. The poor per-
formance of the complexed catalysts 12 and 13 could be attribu-
ted to the low solubility of such compounds in the reaction
solvent. This observation also comes from the comparison of
reactions carried out with the macrocycles 2–6. The better solu-
bility for the compounds 3–6 relative to the products 2, 12 and
13, achieved with the introduction of a more lipophilic N-alkyl
chain, led to reduced reaction times. The solubility in chloroform
is not the only parameter to be taken into account. The very
soluble compound 4, indeed, proved to be less active than 3, 5
and 6, probably due to the presence of the bulky silyl group.
More complex is the interpretation of the data obtained for the
N-benzyl glycine hexacyclopeptoid both in free and complexed
form (2 and 12) which showed an opposite trend to that of the
other macrocycles. In fact, shorter reaction times and a higher
conversion were observed using potassium thiocyanate. Unfortu-
nately, for the macrocycle 2 it was not possible to determine the
Ka for K+, in order to compare it with those estimated for the
other ions. However, Ka values for Na+ were found to be lower
than that of the other macrocycles, which might explain the
poorer activity of this catalyst. Indeed, the data determined by
Cram’s method support the results observed in catalysis since
compound 6, which shows the greatest Ka values, proved to be
the best catalyst.
Catalytic activities and comparison with other phase transfer
catalysts
In order to assess the ability of the cyclopeptoids as PT catalysts,
the substitution reaction of p-nitrobenzyl bromide, in a liquid–
liquid two phase system, using sodium or potassium thiocyanate,
was chosen. These phase-transfer reactions were found to obey
pseudo-first order kinetics. Moreover, the observed rates of the
reaction were proportional to the amount of the catalyst and the
process was found to take place in the organic layer.13,15
All reactions were carried out in a CHCl3–H2O two-phase
system, with 5 mol% of catalyst loading. The reactions were
monitored chromatographically in order to evaluate the time
required for total conversion. All the reactions were stopped
within 24 hours and the percentage of conversion was measured
by 1H-NMR. Table 2 depicts the activities of the synthesized
cyclohexapeptoids compared to some commonly used commer-
cially available PT catalysts, namely dicyclohexyl-18-crown-6
(14), 18-crown-6 (15), 15-crown-5 (16), crypt-222 (17), tetra-
butylammonium bromide (18), poly(ethylene glycol) (average
Mn 300, 19) (Fig. 3).
As can be seen from the comparison with the uncatalyzed
reaction (entry 1), all the new compounds (2–6 and 12–13,
entries 2–8) catalyzed the substitution reaction.
Table 2 SN2 reaction with NaSCN and KSCN catalyzed by
cyclopeptoids and common PT catalystsa
NaSCN
Time
KSCN
Conversion
(%)
Time
(h)
Conversion
(%)
Entry Catalyst (h)
1
2
3
4
5
6
7
8
—
2
3
4
5
24
24
4.5
12
8
2.5
24
24
6.5
24
8
2
10
95
>99
>99
>99
>99
55
24
13
24
24
24
7.5
24
24
3
7.5
1
1
4.5
24
5
>99
53
71
91
>99
79
30
>99
>99
>99
>99
>99
85
Conclusions
6
12
13
14
15
16
17
18
19
In conclusion, this paper highlights the potential of the cyclopep-
toids as phase transfer catalysts, proving their applicability in the
case of the nucleophilic substitution reaction of p-nitrobenzyl
bromide with thiocyanate salts, in a two-phase liquid–liquid
system. Notably, the macrocycle 6 containing N-[2-(2-methoxy-
ethoxy)ethyl] side chains showed Ka values for Na+ greater than
that reported for the efficient complexing agents dicyclohexyl-
18-crown-6 (14) and 15-crown-5 (16). Moreover, 6 exhibited
high catalytic activity in the reaction with NaSCN, comparable
to that evaluated for cryptand 17 and higher than those displayed
by commonly used crown ethers and the tetrabutylammonium
78
9
>99
>99
>99
>99
>99
81
10
11
12
13
14
4.5
24
a All the reactions were carried out using a 0.25 M solution of
p-nitrobenzyl bromide in CHCl3 (0.4 mL, 0.10 mmol), a 0.75 M
aqueous solution of NaSCN or KSCN (0.2 mL, 0.15 mmol) and catalyst
(0.005 mmol).
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bromide. Good activity was also achieved in the reaction with
KSCN.
3.9 mmol) on a shaker platform for 60 min at room temperature,
followed by washing with dry CH2Cl2 (6 mL) and then with
DMF (3 × 6 mL). To the bromoacetylated resin was added a
DMF solution of the desired amine (1 M, 6 mL). All the amines
are commercially available except for the methoxyethoxymethyl
amine, which was prepared through a rapid two step sequence,
as described in the literature.16 The mixture was left on a shaker
platform for 30 min at room temperature, then the resin was
washed with DMF (3 × 3 mL). Subsequent bromoacetylation
reactions were accomplished by reacting the aminated oligomer
with a solution of bromoacetic acid (1.08 g, 7.80 mmol) in DMF
(6 mL) and of DIC (1.3 mL, 8.40 mmol) for 40 min at room
temperature. The filtered resin was washed with DMF (3 ×
6 mL) and treated again with the amine under the same con-
ditions reported above. This cycle of reactions was iterated until
the target oligomer was obtained. The cleavage was performed
by treating twice the resin, previously washed with CH2Cl2 (3 ×
6 mL), with a solution of HFIP in CH2Cl2 (20% v/v, 8 mL) on a
shaker platform at room temperature for 30 min and 5 min,
respectively. The resin was then filtered away and the combined
filtrates were concentrated in vacuo. The final products were dis-
solved in 50% acetonitrile in HPLC grade water and analyzed by
RP-HPLC [purity >95% for oligomers 7–9, 65% for oligomers
10–11; conditions: 5 → 100% B in 30 min for oligomers 7–10,
25 → 100% B in 50 min for oligomer 11 (A, 0.1% TFA in
water, B, 0.1% TFA in acetonitrile); flow: 1 mL min−1, 220 nm].
The linear oligomers were subjected to the cyclization reaction
without further purification with the exception of 11 which was
purified by semipreparative RP-HPLC [conditions: 25%–100%
B in 50 min (A, 0.1% TFA in water, B, 0.1% TFA in aceto-
nitrile); flow: 2 mL min−1, 220 nm].
The present contribution represents the first example of the
use of cyclopeptoids in PTC. Considering the enormous poten-
tial of peptoids in the exploration of chemical space, we firmly
believe in further developments of these systems in liquid–solid
two-phase reactions, and especially in the asymmetric phase-
transfer catalysis. Studies in this regard are currently in progress.
Experimental
General information
Reactions involving air or moisture sensitive reagents were
carried out under nitrogen atmosphere using freshly distilled sol-
vents. Toluene and dichloromethane were distilled from calcium
hydride under nitrogen. Glassware was flame-dried (0.05 Torr)
prior to use. When necessary, compounds were dried in vacuo
over P2O5, by azeotropic removal of water with toluene under
reduced pressure. Starting materials and reagents purchased from
commercial suppliers were generally used without purification.
Reactions were monitored by TLC on silica gel plates (0.25 mm)
and visualized by UV light or by spraying with ninhydrin solu-
tions and drying with iodine. Flash chromatography was per-
formed on Silica Gel 60 (particle size: 0.040–0.063 mm) and the
solvents employed were of analytical grade. HPLC analysis was
performed on C18 reversed-phase analytical and semipreparative
columns (Waters, Bondapak, 10 μm, 125 Å, 3.9 mm × 300 mm
and 7.8 × 300 mm, respectively) using a Modular HPLC System
JASCO LC-NET II/ADC equipped with a JASCO Model
PU-2089 Plus Pump and a JASCO MD-2010 Plus UV-vis
multiple wavelength detector set at 220 nm.
8: 61% (crude residue); ES-MS: 865.9 m/z [M + H]+; tR:
20.3 min;
Yields refer to chromatographically and spectroscopically (1H
and 13C NMR) pure materials. The NMR spectra were recorded
on a Bruker DRX 400 (1H at 400.13 MHz, 13C at 100.03 MHz).
Chemical shifts (δ) are reported in ppm relative to the residual
solvent peak (CHCl3, δ = 7.26; 13CDCl3, δ = 77.0; CD2HCN:
δ = 1.94; 13CD3CN: δ = 1.39) and the multiplicity of each signal
is designated by the following abbreviations: s, singlet; d,
doublet; t, triplet; q, quartet; quint, quintuplet; m, multiplet; bs,
broad singlet. Coupling constants (J) are quoted in hertz. High
resolution ESI-MS spectra were performed on a Q-Star Applied
Biosystem mass spectrometer. ESI-MS analysis in positive ion
mode was performed using a Finnigan LCQ Deca ion trap mass
spectrometer (ThermoFinnigan, San Josè, CA, USA) and the
mass spectra were acquired and processed using the Xcalibur
software provided by Thermo Finnigan.
9: 76% (crude residue); ES-MS: 1477.7 m/z [M + H]+; tR:
26.4 min;
10: 65% (crude residue); ES-MS: 709.1 m/z [M + H]+; tR:
10.4 min;
11: 69% (purified by RP-HPLC); ES-MS: 973.5 m/z
[M + H]+; tR: 7.8 min.
General procedure for the cyclization reactions: synthesis of
compounds 2–611
A solution of the linear peptoids (7–11) (0.36 mmol), previously
co-evaporated three times with toluene, was prepared under
nitrogen in dry DMF (12 mL). The mixture was added dropwise
by a syringe pump in 2 h to a stirred solution of HATU (548 mg,
1.44 mmol) and DIPEA (389 μL, 2.23 mmol) in dry DMF
(110 mL) at room temperature in anhydrous atmosphere. After
12 h the resulting mixture was concentrated in vacuo, diluted
with CH2Cl2 (80 mL) and a solution of HCl (0.5 M, 40 mL).
The mixture was extracted with CH2Cl2 (2 × 80 mL) and the
combined organic phases were washed with water (120 mL),
dried over anhydrous MgSO4, filtered and concentrated in vacuo.
The cyclic products were dissolved in 50% acetonitrile in HPLC
grade water and analyzed by RP-HPLC [purity >95% for oligo-
mers 2–6, conditions: 5%–100% B in 30 min for cycles 2–5,
25%–100% B in 50 min for cycle 6 (A, 0.1% TFA in water, B,
General procedure for sub-monomer solid-phase synthesis of the
linear peptoids 7–1111
Linear peptoid oligomers 7–11 were synthesized using a sub-
monomer solid-phase approach. In a typical synthesis 2-chloro-
trityl chloride resin (2,α-dichlorobenzhydryl-polystyrene cross-
linked with 1% DVB; 100–200 mesh; 1.3 mmol g−1, 0.60 g,
0.78 mmol) was swelled in dry CH2Cl2 (6 mL) for 45 min and
washed twice with dry DMF (6 mL). The first sub-monomer was
attached onto the resin by adding bromoacetic acid (173 mg,
1.25 mmol) in dry CH2Cl2 (3 mL) and DIPEA (680 μL,
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0.1% TFA in acetonitrile); flow: 1 mL min−1, 220 nm]. The
crude residues 2, 3 and 5 were purified by precipitation in aceto-
nitrile–water 1 : 1 and 5 and 6 by RP-HPLC on a C18 reversed-
phase semi-preparative column, tR: 18.0 min and tR: 15.4 min,
respectively, conditions: 5%–100% B in 30 min for compound
5, 25%–100% B in 50 min for compound 6 [(A, 0.1% TFA in
water, B, 0.1% TFA in acetonitrile); flow: 2 mL min−1, 220 nm].
3: 37%; white amorphous solid; HR-ESI MS: m/z 869.6809
(bs), 59.1 (bs), 58.9 (bs), 58.6 (bs), 58.2 (bs), 53.4 (bs), 52.5
(bs), 52.3 (bs), 50.9 (bs), 50.7 (bs), 50.4 (bs), 50.3 (bs), 50.2
(bs), 49.9 (bs), 49.1 (bs), 48.7 (bs), 48.4 (bs), 48.3 (bs), 48.0
(bs), 47.6 (bs), 47.4 (bs), 47.0 (bs), 46.8 (bs), 46.6 (bs), 45.9
(bs), 45.5 (bs), 43.3 (bs).
6: 42%, by HPLC; yellow oil; HR-ESI MS: m/z 955.5449
[M + H]+ (calcd for C42H79N6O18 955.5455); ES-MS 955.5
+
m/z [M + H+]; tR: 10.6 min; 1H-NMR: (400 MHz, CDCl3,
mixture of rotamers) δ: 4.94–3.32 (m, 42 H, COCH2N,
OCH2CH2O–, OCH2CH2O, NCH2CH2O–, NCH2CH2O, OCH3
overlapped); 13C-NMR: (100 MHz, CDCl3, mixture of rotamers)
δ: 172.6, 172.3, 171.3, 170.9, 170.7, 170.5, 170.1, 169.7, 169.4,
169.0, 168.9, 168.4, 168.3, 168.0, 71.8, 71.8, 70.4, 70.3, 70.2,
70.1, 69.8, 69.7, 69.4, 69.2, 69.0, 68.8, 68.7, 68.5, 68.0, 67.8,
67.4, 58.9, 52.4, 51.0, 50.3, 49.5, 49.3, 48.8, 48.1, 47.3, 46.3.
+
[M + Na]+(calcd for C48H90N6NaO6 869.6814); ES-MS: 869.7
m/z [M + Na]+, tR: 23.2 min; 1H-NMR: (400 MHz, CDCl3,
mixture of rotamers) δ: 4.73–3.76 (m, 12 H, COCH2N),
3.58–2.70 (m, 12 H, NCH2(CH2)4CH3), 2.05–1.20 (m, 48 H,
NCH2(CH2)4CH3), 0.89–0.83 (bs, 18 H, NCH2(CH2)4CH3);
13C-NMR: (100 MHz, CDCl3, mixture of rotamers) δ: 171. 8 (bs),
171.5 (bs), 171.0 (bs), 170.5 (bs), 170.3 (bs), 170.2 (bs), 169.9
(bs), 169.5 (bs), 169.2 (bs), 169.1 (bs), 168.8 (bs), 168.6 (bs),
168.4 (bs), 168.3 (bs), 168.2 (bs), 168.0 (bs), 167.6 (bs), 167.4
(bs), 167.3 (bs), 166.8 (bs), 166.7 (bs), 166.4 (bs), 166.3 (bs),
51.5 (bs), 51.1 (bs), 50.9 (bs), 50.4 (bs), 50.0 (bs), 49.7 (bs),
49.5 (bs), 49.3 (bs), 49.0 (bs), 48.8 (bs), 48.7 (bs), 48.6 (bs),
48.3 (bs), 48.2 (bs), 47.9 (bs), 47.7 (bs), 47.5 (bs), 47.3 (bs),
47.1 (bs), 46.8 (bs), 46.6 (bs), 46.3 (bs), 46.0 (bs), 43.3 (bs),
32.7 (bs), 31.6 (bs), 31.5 (bs), 30.1 (bs), 30.0 (bs), 29.9 (bs),
29.7 (bs), 29.4 (bs), 29.1 (bs), 29.0 (bs), 28.9 (bs), 28.7 (bs),
28.5 (bs), 28.1 (bs), 28.0 (bs), 27.7 (bs), 27.6 (bs), 27.5 (bs),
27.3 (bs), 27.2 (bs), 27.0 (bs), 26.9 (bs), 26.5 (bs), 22.6 (s),
14.0 (s).
General procedure for the synthesis of complexed cyclopeptoids
12 and 13
To a solution of cyclopeptoid 2 or 5 (0.034 mmol) in CH2Cl2 :
MeOH (9 : 1) sodium hexafluorophosphate (5.6 mg,
0.034 mmol) was added. The mixture was stirred overnight and
then concentrated in vacuo.
12: quant.; white amorphous solid; ES-MS: 883.9 m/z
1
[M + H+], 905.4 [M + Na+]; H-NMR: (400 MHz, CD3CN) δ:
7.37–7.26 (m, 30 H, Ar), 4.86 (d, 6 H, J = 16.8 Hz, CHHAr),
4.72 (d, 6 H, J = 16.3 Hz, NCHHCO), 4.41 (d, 6 H, J =
16.8 Hz, CHHAr), 3.72 (d, J = 16.3 Hz, 6 H, NCHHCO);
13C-NMR: (100 MHz, CD3CN) δ: 171.7, 136.8, 129.8 (×3),
128.9, 128.7, 53.2, 50.8.
4: 51%; white amorphous solid; HR-ESI MS: m/z 1481.6911
+
[M + Na]+ (calcd for C87H102N6NaO9Si3 1481.6908); ES-MS
1481.7 m/z [M + Na+]; tR: 28.2 min; 1H-NMR: (400 MHz,
CDCl3, mixture of rotamers) δ: 7.68–6.89 (m, 45 H, Ar),
5.36–5.24, 4.75–2.71 (m, 30 H, COCH2N, NCH2CH2O–,
NCH2CH2O), 1.25–0.82 (m, 27 H, SiC(CH3)3; 13C-NMR:
(100 MHz, CDCl3, mixture of rotamers) δ: 171. 8 (bs), 171.3
(bs), 170.4 (bs), 170.2 (bs), 170.1 (bs), 169.7 (bs), 169.5 (bs),
169.1 (bs), 168.9 (bs), 168.6 (bs), 168.1 (bs), 167.8 (bs), 167.7
(bs), 167.6 (bs), 167.2 (bs), 167.0 (bs), 137.1 (bs), 136.7 (bs),
135.4 (bs), 134.7 (bs), 133.5 (bs), 133.0 (bs), 132.8 (bs), 129.9
(bs), 129.8 (bs), 129.6 (bs), 129.0 (bs), 128.6 (bs), 128.3 (bs),
127.9 (bs), 127.7 (bs), 127.2 (bs), 126.9 (bs), 126.8 (bs), 125.3
(bs), 82.8–79.7 (bs), 63.3 (bs), 62.9 (bs), 62.6 (bs), 62.3 (bs),
62.0 (bs), 61.7 (bs), 61.3 (bs), 61.0 (bs), 60.6 (bs), 53.2 (bs),
52.6 (bs), 51.8 (bs), 51.5 (bs), 51.1 (bs), 50.8 (bs), 50.5 (bs),
50.0 (bs), 49.7 (bs), 49.1 (bs), 48.3 (bs), 48.1 (bs), 47.7 (bs),
47.4 (bs), 47.0 (bs), 46.6 (bs), 46.2 (bs), 32.0 (bs), 31.6 (bs),
31.4 (bs), 31.2 (bs), 30.9 (bs), 30.6 (bs), 29.7 (bs), 26.9 (bs).
5: 29%, by HPLC; white amorphous solid; HR-ESI MS: m/z
13: quant.; white amorphous solid; ES-MS 713.7 m/z
1
[M + Na+]; H-NMR: (400 MHz, CD3CN) δ: 4.69 (d, 6 H, J =
16.7 Hz, NCHHCO), 3.84 (d, 6 H, J = 16.7 Hz, NCHHCO),
3.59–3.33 (m, 24 H, NCH2CH2O and NCH2CH2O), 3.34 (s,
18 H, OCH3); 13C-NMR: (100 MHz, CD3CN) δ: 170.6, 71.0,
59.1, 50.5, 49.6.
Determination of binding affinities for compounds 2, 3, 5, 6 and
16
Association constants Ka were calculated from the equation Ka =
Ke/Kd, according to methodology reported by Cram and co-
workers.6 Kd values, which represent the distribution constants
of the picrate salts between water and CHCl3, were previously
determined by Cram,6 while Ke values were calculated following
the “ultraviolet method” reported by Cram and coworkers.6 All
ultraviolet (UV) measurements were made on a Varian Cary 50
UV-Vis Spectrophotometer at 380 nm at 24–26 °C, using spec-
trophotometric grade solvents. The picrate salts were prepared
according to literature procedures,17 and dried under high
vacuum before use. Aqueous solutions were prepared that were
0.0150 M in the picrate of Li+, Na+, K+. Aliquots of these solu-
tions (250 μL of Li+, Na+, K+) were introduced in six Eppendorf
vials, and to each of these, 250 μL of a 0.015 M solution of the
host in CHCl3 was added. The vials were capped (in order to
prevent evaporation) and mixed thoroughly, using a Vortex
“Maxi Mixer”, for 5 minutes and then centrifuged (1000 rpm).
Aliquots of 50 μL of each aqueous phase were diluted with
+
691.3869 [M + H]+ (calcd for C30H55N6O12 691.3872);
ES-MS: 691.8 m/z [M + H+], 713.7 m/z [M + Na+]; tR:
1
11.8 min; H-NMR: (400 MHz, CDCl3, mixture of rotamers) δ:
10.1 (CF3COOH), 4.92–3.86 (m, 12 H, COCH2N), 3.86–2.80
(m, 42 H, NCH2CH2O–, NCH2CH2O, OCH3 overlapped);
13C-NMR: (100 MHz, CDCl3, mixture of rotamers) δ: 171. 5
(bs), 171.0 (bs), 170.6 (bs), 170.1 (bs), 170.0 (bs), 169.8 (bs),
169.7 (bs), 169.5 (bs), 169.3 (bs), 169.1 (bs), 168.9 (bs), 168.7
(bs), 168.2 (bs), 168.1 (bs), 158.7 (q, J = 40 Hz, CF3COOH),
115.0 (q, J = 285 Hz, CF3COOH), 71.7 (bs), 71.5 (bs), 71.4
(bs), 71.3 (bs), 71.0 (bs), 70.8 (bs), 70.6 (bs), 70.2 (bs), 70.0
(bs), 69.8 (bs), 69.6 (bs), 69.3 (bs), 69.1 (bs), 68.8 (bs), 68.7
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem.

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4 N. Maulucci, I. Izzo, G. Bifulco, A. Aliberti, D. Comegna, C. Gaeta,
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CH3CN up to 5.0 mL. Successively 200 μL of these solutions
were diluted with CH3CN up to 1.0 mL. Aliquots of 100 μL of
each organic phase were also diluted with CH3CN up to 5.0 mL.
Successively 200 μL of the latter solutions were diluted with
CH3CN up to 1.0 mL. The absorbance of each sample was then
measured against the appropriate blank solution at 372 nm at
25 °C. R, Ke, Ka and ΔG° were thus calculated in the proper
way.6
General procedure for the substitution reaction using 2–6, 13,
14 and commercially available PTC catalysts 14–19
To a solution of p-nitrobenzyl bromide (21.5 mg, 0.10 mmol) in
CHCl3 (0.25 M, 0.200 mL), containing 5 mol% of the catalyst, a
0.75 M aqueous solution of thiocyanate salt (0.15 mmol) was
added and the resulting mixture was stirred for up to 24 hours in
total. The reaction was monitored by TLC at intervals of
30 minutes. The mixture was filtered through a short-path silica
gel column and removal of the solvent in vacuo afforded a
6 K. E. Koenig, G. M. Lein, P. Stuckler, T. Kaneda and D. J. Cram, J. Am.
Chem. Soc., 1979, 101, 3553–3566.
7 For some recent reviews see: (a) H. Wennemers, Chem. Commun., 2011,
47, 12036–12041; (b) M. Freund and S. B. Tsogoeva, Peptides for Asym-
metric Catalysis, in Catalytic Methods in Asymmetric Synthesis:
Advanced Materials, Techniques, and Applications, ed. M. Gruttadauria
and F. Giacalone, John Wiley & Sons, Inc., Hoboken, NJ, USA, 2011,
pp. 529–578; (c) R. P. Megens and G. Roelfes, Chem.–Eur. J., 2011, 17,
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1
residue that was analyzed by H-NMR to determine the % of
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8 G. Maayan, M. D. Ward and K. Kirshenbaum, Proc. Natl. Acad.
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10 R. N. Zuckermann, J. M. Kerr, S. B. H. Kent and W. H. Moos, J. Am.
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Acknowledgements
11 Synthesis and characterization of compounds 7 and 2 are reported in:
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Bioorg. Med. Chem., 2010, 18, 2010–2018.
12 Y. Takeda, T. Namisaki and S. Fujiwara, Bull. Chem. Soc. Jpn., 1984, 57,
1055–1057.
We acknowledge financial support from the University of
Salerno. We thank Miss Serena Monaco and Miss Laura
Malzone for valuable experimental work and Dr Patrizia Iannece
for MS.
13 P. E. Stott, J. S. Bradshaw and W. W. Parish, J. Am. Chem. Soc., 1980,
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15 C. M. Starks and R. M. Oweres, J. Am. Chem. Soc., 1973, 95, 3613–
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Notes and references
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of Phase-Transfer Catalysis, ed. Y. Sasson and R. Neumann, Blackie
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Org. Biomol. Chem.
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