Conformational behaviour of peptides containing a 2- pyrrolidinemethanesulfonic acid (2PyMS) residue

Article abstract of DOI:10.1039/c2ob27058g

The conformational behaviour of model peptides containing a 2-pyrrolidinemethanesulfonic acid (2PyMS) residue was studied in both the crystalline state and in solution using X-ray, NMR and IR experiments. It was found that in crystals dipeptide PhC(O)-2PyMS-Phe-NHiPr adopted -turn conformation, which was not stabilized by an intramolecular hydrogen bond and could be classified as a type IV -turn. In the crystalline state tripeptide PhC(O)-Ala-2PyMS-Phe-NHiPr existed as an α-turn with uncommon cis-conformation of the amide bond formed by the pyrrolidine nitrogen atom of the 2PyMS residue, for which no close analogue can be envisaged among the tight turns identified so far. Although the tendency to adopt folded conformations was only partially retained in solution, 2-PyMS could be considered as a promising structural unit for the design of foldamers and peptidomimetics with unusual conformational properties.

Full text of DOI:10.1039/c2ob27058g

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Conformational behaviour of peptides containing
2-pyrrolidinemethanesulfonic acid residue (2PyMS)
Oleksandr O. Grygorenko,*a,b Sergey Zhersh,a,b Bohdan V. Oliinyk,a Oleg V. Shishkin,c and
Andrey A. Tolmacheva,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Conformational behaviour of model peptides containing 2-pyrrolidinemethanesulfonic acid residue
(2PyMS) was studied in both crystalline state and in solution using X-Ray, NMR and IR experiments. It
was found that in crystals dipeptide PhC(O)–2PyMS–Phe–NHiPr adopted β-turn conformation, which
10 was not stabilized by intramolecular hydrogen bond and could be classified as a type IV β-turn. In the
crystalline state tripeptide PhC(O)–Ala–2PyMS–Phe–NHiPr existed as an α-turn with uncommon
cis-conformation of the amide bond formed by the pyrrolidine nitrogen atom of the 2PyMS residue, for
which no close analogue can be envisaged among the tight turns identified so far. Although the tendency
to adopt folded conformations was only partially retained in solution, 2-PyMS could be considered as a
15 promising structural unit for the design of foldamers and peptidomimetics with unusual conformational
properties.
acids are much more promising. In particular, peptides derived
from (S)-2-pyrrolidinemethanesulfonic acid (2) were evaluated as
45 endomorphin-2 and morphiceptin analogues,13 fibrillogenesis
peptide inhibitors;14 they were also used in the design of chiral
ligands for enantioselective catalysis.15
Introduction
Structural modification of peptide backbones is a valuable
approach to the design of peptidomimetics, peptide models and
20 other molecules of both biological relevance and theoretical
interest.1 Sulfonamide is one of the possible surrogates used for
the replacement of the peptide bond. It was introduced by
Liskamp et al. as a transition-state analogue of the hydrolysis of
the amide bond nearly 20 years ago.2 A number of studies on the
25 use of “sulfopeptides” in the design of biologically active
compounds were reported since then. The nearest analogues of
the peptides, sulfonamido-α-peptides, have found limited
application due to the low stability of α-aminosulfonic acids and
their derivatives.3 On the contrary, sulfonamido-β-peptides have
30 attracted much interest, in particular, for the design of potential
tools for tumor imaging and/or radionuclide therapy,4 PPI
inhibitors,5 chemotactic peptides,6 HIV-1 non-nucleoside reverse
transcriptase inhibitors,7 factor Xa inhibitors,8 inhibitors of
leukocyte adhesion,9 and scaffolds for MC4 pharmacophoric
35 groups.10
O
O
S
S
OH
H2N
OH
N
H
O
O
1
2
Whereas biological properties of sulfonamide peptides have
50 aroused considerable interest, their conformational behavior has
attracted much less attention. To the best of our knowledge, all of
these studies dealt with the taurine-derived peptides.16 Conforma-
tional preferences of peptides containing residue of 2 (for which
we propose an abbreviation “2PyMS”) were beyond the scope of
55 investigation to date.
In this work, we report an experimental study on the
conformational properties of the model peptides containing
residues of (S)-2-pyrrolidinemethanesulfonic acid and
phenylalanine. These peptides can be considered as analogues of
60 the Pro–Phe sequence, which attracted much attention as a target
for the replacement studies in the last decade.17
It should be noted that most of these studies employed derivatives
of the simplest β-aminosulfonic acid – taurine (1). It was shown,
however, that peptides containing sulfonamide moiety
demonstrated considerable flexibility,11 whereas limitation of this
40 property has been widely considered as desirable for both
biological and conformational studies.12 From this point of view,
derivatives of the conformationally restricted β-aminosulfonic
Results and discussion
Synthesis
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Model peptides 3 (PhC(O)–2PyMS–Phe–NHiPr) and 4 (PhC(O)–
cell of 3 contains six equal molecules (Figure 1), whereas in the
Ala–2PyMS–Phe–NHiPr) were prepared from (S)-2-pyrrolidine-
methanesulfonyl chloride derivative 518 using standard coupling
procedures (Scheme 1). Reaction of 5 and (S)-phenylalanine
isopropylamide 6 in the presence of ethyl diisopropylamine 30 summarized in the Table 1.
(DIPEA) gave dipeptide 7 in 50% yield. Upon deprotection of 7
by catalytic hydrogenation, amine 8 was obtained quantitatively.
Reaction of 8 with benzoyl chloride in the presence of
triethylamine gave dipeptide 3 (53%). Coupling of 8 with (S)-N-
case of 4 two molecules with quite similar conformations are
observed in a unit cell (the root-mean-square deviation (RMSD)
value is 0.192 Ǻ) (Figure 2). The lattice parameters of 3 and 4 are
View Article Online
5
10 benzoylalanine was accompanied by partial epimerisation.
Therefore, reaction with the corresponding Boc derivative in the
presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDC) and 1-hydroxybenzotriazole (HOBt) was used instead,
followed by the change of the protective group to give tripeptide
15 4.
H2N
H
N
Ph
NH
O
O
S
DIPEA
50%
Ph
S
O
Cl
O
+
N
N
O
NH
O
Cbz
Cbz
7
6
5
H2, Pd-C
100%
O
H
N
H
Ph
NH
Ph
NH
O
N
PhC(O)Cl
S
S
O
O
O
N
H
Et3N
53%
N
O
8
Ph
O
3
Boc-Ala-H
67%
N
EDC, HOBt
O
O
N
1. HCl
O
O
HN
BocHN
S
S
2. PhC(O)Cl
DIPEA
O
O
Ph
HN
HN
O
Fig. 2 ORTEP diagram of the compound 4: (a) molecule A; (b) molecule
52%
Ph
Ph
B. Thermal ellipsoids are shown at 20% probability level
N
O
N
O
H
H
Conformation of the 2PyMS – Phe backbone in molecules 3 and
35 4 is rather similar (Table 1, see also Figure 3 for the definition of
torsion angles). The pyrrolidine ring restricts ϕi+1 value to –
67.7(3) – –77.4(4)°, which corresponds to the folded gauche– (–
sc) conformation. On the contrary, values of θi+1 and ψi+1 angles
(150.0(3) – 172.1(2)° and –159.2(2) – –178.8(3)°, respectively)
40 are characteristic for the extended trans (ap) conformation.
Conformation of the Phe residues (as well as the Ala residue in
the molecule of 4) corresponds to the β region of the
Ramachandran plot (ϕ = –75.3(4)° – –106.9(3)°; ψ = 122.0(3)° –
147.5(3)°).19
4
9
Scheme 1 Synthesis of model peptides 3 and 4
Conformation: X-Ray diffraction data
45 Normally, such combinations of ψ and θ angles allow one to
expect the extended conformation of the peptide molecule,20
taking into account that values close to 180° are more common
for ω angles. In the case of 3 and 4, situation is different due to
the intrinsic properties of the sulfonamide bond.11, 21 Values of
50 ωi+2 are 63.0(4) – 80.0(2)° (gauche+ (+sc) conformation). It
reflects anti orientation of the nitrogen lone pair and the S–C
bond. This situation is most frequently encountered in the crystal
structures of sulfonamide derivatives.16, 22 Moreover, the less
common cis configuration23 is observed for the amide bond
55 formed by the pyrrolidine nitrogen atom in the molecule of 4
(ωi+1 = –11.2(6) – –12.0(6)°). This is the major difference in the
20 Fig. 1 ORTEP diagram of the compound 3. Thermal ellipsoids are shown
at 20% probability level
Crystals of 3 and 4 for the X-ray diffraction studies were obtained
by slow evaporation of their solution in Hexanes – EtOAc. Both 3
and 4 crystallize in non-centrosymmetric space groups; that
25 indicates presence of the single enantiomers in the crystals. Unit
2
|
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conformations of the peptide backbones of 3 and 4: in the case of
3, the corresponding amide bond (as well as all the other amide 30 atoms of the benzoyl moiety, Ala and Phe residues, and the iPr
pseudotorsion angle Cαi–1 – Cαi – Cαi+2 – Cαi+3, formed by the Cα
bonds in the molecules of 3 and 4) has trans configuration (ωi,
fragment in the molecule of 4 is –66.4° (conformer A) and –64.8°
ωi+1, and ωi+3 = ±172.1(2)° – ±180.0(3)°).
(conformer B). The turn conformation in the molecule of 4 is
stabilized by the intramolecular hydrogen bond C=Oi–1 ← NHi+3
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(H…O 2.01 Ǻ; N–H…O 152° (conformer A) and H…O 2.03 Ǻ;
35 N–H…O 152° (conformer B)) (Figure 2). Additional stabilization
is provided by the contact between C=O group of the benzoyl
moiety and CH2 unit of the 2PyMS residue (H…O 2.44 Ǻ; C–
H…O 160° Ǻ (conformer A) and H…O 2.39 Ǻ; C–H…O 165°
(conformer B)).
40 The amide nitrogen atoms in the molecules of 3 and 4 have planar
configuration (deviation from the planarity is less than 0.1°). In
the case of the sulfonamide nitrogen atoms, a more pronounced
pyramidalization is observed (sums of the angles centered at them
are 342° – 355°), which is typical for sulfonamide
45 derivatives.11, 21
5
Fig. 3 Definition of the backbone and side chain torsion angles in the
model dipeptides (compound 4 is given as an example)
Some remarkable differences are found in conformations of the
side chains of the amino acid residues in the molecules of 3 and
4. In particular, the pyrrolidine ring in the molecule of 3 adopts
twisted conformation with deviations of C-3 and C-4 atoms from
50 the mean-square plane formed by the rest of the ring of 0.33 Å
and –0.26 Å, respectively. In the case of 4, this five-membered
ring is found in an envelope conformation; C-3 atom deviates
from the mean-square plane formed by the other ring atoms by
–0.53 Å (conformer А) and 0.59 Å (conformer B). In both cases,
55 down puckering of the pyrrolidine ring is observed (Table 2).28
Conformations of the side chain of the Phe residue are completely
different for both investigated model peptides. In the case of 3,
the phenyl substituent adopts gauche– (–sc) orientation with
Table 1 Backbone torsion angles (deg) in the molecules of 3 and 4
Angle
Angle definition
4 (A)
4 (B)
3
C19–N4–C21–C2
C18–C19–N4–C21
N1–C18–C19–N4
C4–N1–C6–C7 (3),
C4–N1–C18–C19 (4)
C6–N1–C4–C5 (3),
C18–N1–C4–C5 (4)
N1–C4–C5–S1
–
–
–
–172.2(3) –173.2(3)
ωi
ϕi
ψi
–75.3(4)
147.5(3)
–76.0(4)
147.2(3)
–12.0(6)
–174.8(3) –11.2(6)
ωi+1
–67.7(3)
–77.4(4)
–75.8(4)
ϕi+1
172.1(2)
–159.2(2) 177.6(3)
150.0(3)
154.0(3)
178.8(3)
63.0(4)
θi+1
ψi+1
ωi+2
C4–C5–S1–N2
C5–S1–N2–C13 (3),
C5–S1–N2–C6 (4)
S1–N2–C13–C21 (3),
S1–N2–C6–C7 (4)
N2–C13–C21–N3 (3),
N2–C6–C7–N3 (4)
C13–C21–N3–C22 (3),
C6–C7–N3–C8 (4)
C24–C22–N3–C21 (3),
S1–N2–C6–C7 (4)
80.0(2)
–88.8(3)
144.8(2)
180.0(3)
63.6(3)
respect to the Cα–N bond of the peptide backbone (χ1
=
–99.3(3) –106.9(3)
122.0(3) 124.2(4)
178.2(3) –177.1(3)
ϕi+2
ψt+2
ωi+3
ϕi+3
i+2
60 –62.8(3)°), whereas in the molecule of 4 the value of χ1 angle
i+2
is –171.0(3)° (molecule A) or –170.9(3)° (molecule B), which
corresponds to trans (ap) conformation.
Table 2 Pyrrolidine ring puckering in the molecules of 3 and 428b
–66.9(4) –146.3(4) –149.9(4)
Parameter
4 (A)
4 (B)
3
Combinations of the backbone torsion angles discussed above
Degree of puckering
Polar angle, deg
0.52
92.6
0.54
78.5
0.49
76.6
10 result in folded conformations of both 3 and 4, which can be
classified as tight turns. The key criteria for such an assignment is
the distance between Cα atoms of the ending residues, which
should be within 7 Ǻ limit.24 In the case of 3, distance between
It might be also noted that molecules of 3 and 4 differ in relative
65 orientation of the isopropyl substituents. The extrapolated torsion
angle ϕi+3 is –66.9(4)° in the case of 3, whereas for 4,
corresponding values are –146.3(4)° (conformer A) and
–149.9(4)° (conformer B) (Table 1).
In the crystal lattice the molecules of 3 are linked by the
70 intermolecular hydrogen bonds formed by Phe C=O group and
iPrNH unit of the next molecule ((x–y+1, x+1, z–1/6); H…O
2.18 Å; N–H…O 164°), Phe NH unit and SO2 fragment of the
next molecule ((y–1, –x+y, z+1/6); H…O 2.22 Å; N–H…O
153°), as well as CH2 unit of the 2PyMS residue and benzoyl
75 C=O group of the next molecule ((y–1, –x+y, 1/6+z); H…O 2.39
Å; C–H…O 160°), which results in the formation of chains along
the c axis (Figure 4a). Neighboring molecules in the chain are
turned by 120°, so that their sulfur atoms form a spiral
(Figure 4b).
the ipso-C of the phenyl ring (Cα ) and the CH of the isopropyl
i
15 fragment (Cαi+3) is 5.706 Ǻ, which clearly indicates presence of
the β turn. Since no intramolecular hydrogen bond is present in
the molecule, this conformation can be classified as type IV
(miscellaneous) β turn.24, 25 The pseudo dihedral angle formed by
the four consecutive Cα atoms in the molecule of 3 is 9.7°;
20 analogous geometry, i. e. linking protein chains approaching from
almost anti-parallel directions, is found for the type II β turn.26
In the molecule of 4 distance between the Cα atoms of the ending
residues (Cαi–1 – Cαi+3) is 5.206 Ǻ for the conformer A and
5.181 Ǻ for the conformer B, which is characteristic for an α
25 turn. In this case, no close analogue can be envisaged among the
tight turns identified so far: the only reported α turn, which has
cis-configuration of the central residue (type I-αC turn) has too
distinct values of other backbone torsion angles.24, 27 The
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Fig. 4 Packing of the molecules of 3 in crystals viewed along: (a) b axis; (b) c axis
Fig. 5 Packing of the molecules of 4 in crystals viewed along b axis
5
In the crystals molecules A and B of 4 form dimers, connected by 25 (Figure 6).
intermolecular hydrogen bonds formed by Phe NH unit of the
molecule A and Phe C=O group of the molecule B (H…O
1.96 Ǻ; N–H…O 163°), as well as CH2 unit of the 2PyMS
residue of the molecule B and Phe C=O group of the molecule A
10 (H…O 2.38 Ǻ; C–H…O 158°) (Figure 5). These dimers are
linked by weak intermolecular hydrogen bonds formed by Ala
NH unit of the molecule B and SO2 fragment of the molecule A
from the next dimer ((x, y, z–1); H…O 2.43 Ǻ; N–H…O 163°)
into chains running along the c axis, which are further held
15 together via a number of weak intermolecular contacts.
Conformation: solution studies
Conformation of the peptides 3 and 4 in solution was studied
using NMR and IR experiments. It was found that in CDCl3 as a
solvent both 3 and 4 existed as single rotamers around the amide
20 bonds, showing only one set of signals in 1H and 13C NMR
spectra.
Fig. 6 Chemical shift dependence of the NH resonances of 3 and 4 as a
function of DMSO-d6 concentration (% v/v) in CDCl3. Peptide
concentrations 0.062 M (3) and 0.054 M (4)
Addition of DMSO-d6 to the CDCl3 solution of 3 resulted in the
significant shift of both Phe and iPr NH signals to the higher field
(by 0.84 and 0.99 p. p. m. at 10% v/v DMSO-d6, respectively)
30 In the case of 4, accessibility of the NH protons to the solvent
decreased in the series: Phe NH >> iPr NH > Ala NH; at 10% v/v
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DMSO-d6 the signals were shifted by 0.87, 0.49 and 0.31,
respectively. All these results show that the NH protons of 3 and 45 opinion, the main reason behind the differences in the
different from that found in the crystals) is observed. In our
4 are not involved into strong intramolecular hydrogen bonding,
and the conformation of 4, observed in crystalline state, is not
preserved in solution.
conformational behaviour of 4 observed in solid state and in
solution is that cis configuration of the amide bond, found in the
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5
crystals of 4, is thermodynamically unfavourable; therefore,
3
Analysis of the Phe NH – CαH JHH coupling constants using
stabilisation provided by the intramolecular hydrogen bond is not
modified Karplus equation shows that in the case of 3, the Phe 50 enough to retain the α turn conformation in solution. This can be
N–H and Cα–H bonds are almost antiperiplanar (estimated
dihedral angle H–N–Cα–H value is 151°), which is consistent
10 with the conformation observed in crystals (where the
corresponding dihedral angle value is 174.5°). In the case of 4,
corresponding constant is less informative as the Karplus
equation has two roots for the value of J observed (Table 3).
tuned by stabilisation of the conformer containing cis amide
bond, in particular by introducing bulky substitutent at C-5
position of the 2PyMS residue, as it was described for proline
derivatives.32
Table 3 Analysis of the Phe NH – CαH coupling constants in 3 and 4
O
S
N
O
H
Ph
N
3JHH, Hz
N
Molecular fragment
∠ H–N–Cα–H, °
Strong NOE
Weak NOE
O
O
O
H
Calculateda
X-Ray data
H
N
H
8.3
7.3
151
143 or 3
174.5
144.9
Phe NH – CαH of 3
Phe NH – CαH of 4
55
15 aValues of the dihedral angles were calculated using modified Karplus
Fig. 8 Significant correlations observed in NOESY spectrum of 4
equation (J = 6.98 cos2θ – 1.38 cosθ + 1.72) updated from29
(CDCl3 solution)
The most significant correlations observed in the NOESY
spectrum of 3 are shown in the Figure 7. Strong correlation
between ortho-protons of the benzoyl substituent and 5-CH2
20 group of 2PyMS, as well as iPrNH and protons of the Phe
CHCH2 fragment, characterize trans conformations of both amide
bonds in the molecule of 3. Correlations between CαH of the Phe
residue and the protons of the 2PyMS CHCH2 fragment are
characteristic for gauche (and not trans) conformation of the
25 sulfonamide bond. Finally, a weak correlation between ortho-
protons of the benzoyl substituent and methyl groups of the
isopropyl substituent shows that at least some considerable
population of the folded conformation is observed.
IR spectra of both 3 and 4 in CHCl3 showed three bands in the
NH stretching region, which can be assigned to free and
60 hydrogen-bonded C(O)NH and SO2NH (Table 4). Since relative
intensities of the bands observed at ~3350 cm–1 and ~3190 cm–1
diminished upon dilution of the solutions (Figure 9), hydrogen
bonds formed by the corresponding NH fragments were
intermolecular. These data are in accordance with results of the
65 NMR experiments discussed above. The bands at 1670 cm-1 (3)
and 1662 cm-1 (4) in the Amide I region are characteristic for
turn-type conformations,32 which is also consistent with NMR
data.
Table 3 Main absorption bands in IR spectra of 3 and 4 (CHCl3, 30 mM
70 (3) and 20 mM (4))
Bands, cm–1
Assignmenta
O
S
N
H
3
4
Ph
N
Strong NOE
Weak NOE
O
O
O
3423
3419
H
ν(NH)
free C(O)NH
N
H
3346
3186
3365
3186
ν(NH)
hydrogen-bonded C(O)NH
and free SO2NH
ν(NH)
30
Fig. 7 Significant correlations observed in NOESY spectrum of 3
hydrogen-bonded SO2NH
Amide I
(CDCl3 solution)
1670
1622
1616
1338
1327
1313
1151
1134
1662
1654
1637
1338
1325
1313
1153
1148
1136
A similar pattern of the correlations is observed in the NOESY
spectrum of 4 (Figure 8). In particular, correlations between
ortho-protons of the benzoyl group and Ala NH,30 Ala CH(CH3)
νas(SO2)
νs(SO2)
35 fragment and 5-CH2 group of 2PyMS residue, as well as iPrNH
and protons of the Phe CHCH2 fragment are characteristic for
trans configuration of the corresponding amide bonds. As in the
case of 3, correlations between Phe CαH and NH with protons of
the 2PyMS CHCH2 fragment are characteristic for gauche (and
40 not trans) conformation of the sulfonamide bond. Correlations
between ortho-protons of the benzoyl substituent and Ala NH
with protons of the isopropyl fragment show that at least some
considerable population of the folded conformations (which are
aThe band assignment was done using the literature data for analogous
systems.31, 32
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instrument. HRMS were obtained using LTQ Orbitrap mass
45 spectrometer.
N-((((2S)-1-benzyloxycarbonylpyrrolidin-2-
yl)methyl)sulfonyl)-L-phenylalanine isopropylamide (7)
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Amine 6 (11.0 g, 53 mmol) was dissolved in CH2Cl2 (200 mL),
and DIPEA (12.9 g, 0.1 mol) was added. The mixture was cooled
50 to 0 °C, and compound 5 (16.9 g, 53 mmol) in CH2Cl2 (100 mL)
was added dropwise upon stirring. The resulting mixture was
stirred at 0 °C for 30 min and at rt for 1 h, then washed with
saturated aq NaHCO3 (100 mL), 1 M aq KHSO4 (100 mL), brine
(100 mL), dried over Na2SO4 and evaporated in vacuo. The
55 residue was purified by column chromatography (Hexanes –
EtOAc (3 : 2) as eluent) to give 7 (7.13 g, 50%) as white
amorphous solid. [α]D –1.2 (с 1.42, MeOH). 1H NMR (CDCl3), δ
(major rotamer) 7.22–7.39 (m, 10H), 5.92 (d, J = 6.0 Hz, 1H),
5.53 (d, J = 8.3 Hz, 1H), 5.13 (s, 2H), 5.04–5.22 (m, 1H), 4.30 (br
60 s, 1H), 3.77–4.00 (m, 2H), 3.37–3.41 (m, 3H), 3.22 (dd,
J = 12.7 Hz and 5.3 Hz, 1H), 3.11 (dd, J = 12.7 Hz and 7.2 Hz,
1H), 2.97 (br s, 1H), 2.71 (dd, J = 13.1 Hz and 8.7 Hz, 1H), 1.82–
1.92 (m, 2H), 1.06 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H).
13C NMR (CDCl3), δ (major rotamer) 169.6, 154.9, 136.64,
65 136.55, 129.8, 128.8, 128.6, 128.2, 127.9, 127.2, 67.1, 58.8, 55.4,
53.8, 46.2, 41.7, 39.5, 30.4, 23.6, 22.4, 22.3. Anal. calcld. for
C25H33N3O5S C 61.58, H 6.82, N 8.62, S 6.58. Found C 61.75,
H 6.57, N 8.64, S 6.31. MS (APCI) m/z 488 (MH+); negative
mode: 486 (M–H+). HRMS (ESI) m/z calcld. for C25H33N3O5SNa
70 510.2033. Found 510.2031.
Fig. 9 NH stretching region of IR spectra of 3 and 4 (CHCl3)
Analysis of ν(SO2) regions (~1300 cm-1 and ~1150 cm-1) of the
IR spectra revealed that several conformational states are
observed in solution for both 3 and 4. This effect cannot be solely
attributed to the formation of intermolecular hydrogen bonds, as
the number of peaks in the above referenced regions is not
affected by the dilution of the solutions. We assign existence of
multiple ν(SO2) bands to relatively high rotational barrier around
5
10 the sulphonamide bonds (30–40 kJ/mol),33 which is observable
on IR spectroscopy timescale, but not on NMR.
Conclusions
The residue of (S)-2-pyrrolidinemethanesulfonic acid (2PyMS) is
capable of inducing folded structures when introduced into model
15 peptides. In particular, peptides PhC(O)–2PyMS–Phe–NHiPr and
PhC(O)–Ala–2PyMS–Phe–NHiPr adopt β- and α-turn
conformations in crystalline state, respectively. Folded
conformations were only partially observed in solution, with no
intramolecular hydrogen bonding retained. The intrinsic
20 conformational properties of 2PyMS can be attributed to the
conformational restriction provided by the pyrrolidine ring, as
well as propensity of the sulphonamide bond to adopt gauche
conformation. These features stabilize conformations with folded
arrangement of those parts of the peptide backbone, which are
25 defined by ϕ and ω torsion angles (ϕ ~ –70°, ω ~ 70°).
N-(((2S)-pyrrolidin-2-ylmethyl)sulfonyl)-L-phenylalanine
isopropylamide (8)
Compound 7 (13.0 g, 26.7 mmol) was dissolved in MeOH
(200 mL), and 10% Pd-C (2 g) was added. A slow steam of
75 hydrogen was bubbled through the mixture at rt upon stirring
until the starting material disappeared (monitored by TLC). The
catalyst was filtered off, and the filtrate was evaporated to
dryness to give 8 (9.4 g, 100%) as white amorphous solid. The
product was pure enough to be used in the next steps without any
80 additional purification. An analytical sample was prepared by
column chromatography (Hexanes – EtOAc (2 : 3) as eluent).
Experimental section
1
[α]D –6.4 (с 0.38, MeOH). H NMR (CDCl3), δ 7.25–7.31 (m,
General
4H), 7.20–7.24 (m, 1H), 6.47 (d, J = 7.8 Hz, 1H), 5.32 (br s, 2H),
4.18 (t, J = 7.2 Hz, 1H), 3.91–4.00 (m, 1H), 3.51–3.57 (m, 1H),
85 3.13 (dd, J = 14.0 Hz and 6.4 Hz, 1H), 2.99–3.05 (m, 2H), 2.97 (t,
J = 7.0 Hz, 2H), 2.88 (dd, J = 14.0 Hz and 3.1 Hz, 1H), 1.89–1.96
(m, 1H), 1.73–1.82 (m, 1H), 1.64–1.74 (m, 1H), 1.35–1.42 (m,
1H), 1.09 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H). 13C NMR
(CDCl3), δ 170.2, 136.8, 129.7, 128.7, 127.1, 58.7, 56.8, 53.9,
90 46.0, 41.7, 39.3, 31.2, 24.4, 22.5, 22.3. Anal. calcld. for
C17H27N3O3S C 57.76, H 7.70, N 11.89, S 9.07. Found C 57.63,
H 7.96, N 12.02, S 8.80. MS (APCI) m/z 354 (MH+); negative
mode: 352 (M–H+). HRMS (ESI) m/z calcld. for C17H27N3O3SH
354.1846. Found 354.1848.
The solvents were purified according to the standard procedures.
Compounds 518 and 634 were prepared according to the methods
30 reported in literature. All other starting materials were purchased
from Acros, Merck, Fluka, and UkrOrgSyntez. Analytical TLC
was performed using Polychrom SI F254 plates. Column
chromatography was performed using Kieselgel Merck 60 (230–
400 mesh) as the stationary phase. 1H, 13C, and all 2D NMR
35 spectra were recorded on a Bruker 170 Avance 500 spectrometer
(at 499.9 MHz for Protons and 124.9 MHz for Carbon-13).
Chemical shifts are reported in ppm downfield from TMS (1H,
13C) as an internal standard. IR spectra were obtained on Perkin
Elmer BX II FT-IR spectrometer. νmax (cm-1) values in IR spectra 95 N-((((2S)-1-benzoylpyrrolidin-2-yl)methyl)sulfonyl)-L-
phenylalanine isopropylamide (3)
40 are given for the main absorption bands. Elemental analyses were
performed at the Laboratory of Organic Analysis, Department of
Chemistry, Kyiv National Taras Shevchenko University. Mass
spectra were recorded on an Agilent 1100 LCMSD SL
8 (0.97 g, 2.7 mmol) was dissolved in CH2Cl2 (50 mL), and Et3N
(0.5 g, 4.9 mmol) was added. The mixture was cooled to 0 °C,
and benzoyl chloride (0.38 g, 2.7 mmol) was added dropwise.
6
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Journal Name, [year], [vol], 00–00
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Page 7 of 9
Organic & Biomolecular Chemistry
N-((((2S)-1-(N-benzoyl-L-alanyl)pyrrolidin-2-
60 yl)methyl)sulfonyl)-L-phenylalanine isopropylamide (4)
The resulting mixture was stirred at rt for 2 h, then washed with
1 M aq KHSO4 (15 mL), brine (15 mL), dried over Na2SO4 and
evaporated in vacuo. The residue was purified by column
chromatography (Hexanes – EtOAc (1 : 1) as eluent) to give 3
(0.65 g, 53%) as white crystals. Mp 135–137 °C (Hexanes –
EtOAc). [α]D –37.7 (с 0.27, MeOH). IR (CHCl3, cm–1): 3423,
3346, 3186 (ν(NH)); 1670, 1622, 1616 (Amide I); 1338, 1327,
Compound 9 (1.00 g, 1.9 mmol) was dissolved in 10% HCl in
dioxane (10 mL). The resulting mixture was stirred for 2 h and
View Article Online
5
evaporated to dryness. CH2Cl2 (50 mL) and DIPEA (0.65 g,
5.0 mmol) were added to the residue, and the mixture was stirred
65 for 30 min, then cooled to –10 °C, and benzoyl chloride (0.27 g,
1.9 mmol) was added dropwise. The mixture was warmed to rt
upon stirring over 1 h, then poured into H2O (200 mL). The
organic phase was separated, washed with 1 M KHSO4 (50 mL),
brine (50 mL), dried over Na2SO4 and evaporated in vacuo. The
70 residue recrystallized from Hexanes – EtOAc to give 4 (0.52 g,
52%) as grayish crystals. Mp 148 – 149 °C (Hexanes – EtOAc).
[α]D –50.9 (с 0.62, MeOH). IR (CHCl3, cm–1): 3419, 3365, 3186
(ν(NH)); 1662, 1654, 1637 (Amide I); 1338, 1325, 1313
(νas(SO2)); 1153, 1148, 1136 (νs(SO2)). 1H NMR (CDCl3), δ 7.79
75 (d, J = 7.0 Hz, 2H, 2′-C6H5 of PhC(O)), 7.43 (t, J = 7.0 Hz, 1H,
4′-C6H5 of PhC(O)), 7.33–7.37 (m, 3H, 3′-C6H5 of PhC(O) and
Ala NH), 7.18–7.20 (m, 4H, Phe 2′- and 3′-C6H5), 7.12–7.16 (m,
1H, Phe 4′-C6H5), 6.30 (d, J = 7.3 Hz, 1H, Phe NH), 6.13 (d,
J = 6.0 Hz, 1H, iPrNH), 4.85 (quint, J = 6.0 Hz, 1H, Ala CαH),
80 4.18 (br s, 2PyMS CαH), 4.02 (q, J = 6.4 Hz, Phe CαH), 3.84–
3.90 (m, 1H, CH(CH3)2), 3.50 (br s, 1H, 2PyMS 5-CHH), 3.38–
3.43 (m, 1H, 2PyMS 5-CHH), 3.09–3.16 (m, 2H, 2PyMS
CαHCHH and Phe CαHCHH), 2.97 (dd, J = 13.1 Hz and 7.4 Hz,
1H, Phe CαHCHH), 2.60 (dd, J = 13.0 Hz and 6.0 Hz, 1H,
85 2PyMS CαHCHH), 1.77–1.88 (m, 4H, 2PyMS 3- and 4-CH2),
1.34 (d, J = 5.7 Hz, 3H, Ala CH3), 0.98 (d, J = 5.7 Hz, 3H, CH3
of iPr), 0.90 (d, J = 5.7 Hz, 3H, CH3 of iPr). 13C NMR (CDCl3), δ
171.7 (C=O), 169.6 (C=O), 166.5 (C=O), 136.8 (1′-C of C6H5),
133.9 (1′-C of C6H5), 131.9 (4′-CH of PhC(O)), 129.7 (2′- or 3′-
90 CH of Phe C6H5), 128.8 (2′- or 3′-CH of Phe C6H5), 128.6 (3′-CH
of PhC(O)), 127.3 (2′-CH of PhC(O)), 127.2 (4′-CH of Phe
C6H5), 59.2 (Phe CαH), 55.0 (2PyMS CαHCH2), 53.2 (2PyMS
CαHCH2), 47.5 (Ala CαH), 46.3 (2PyMS 5-CH2), 41.7 (CH of
iPr), 39.4 (Phe CαHCH2), 30.2 (2PyMS 3- or 4-CH2), 23.8
95 (2PyMS 3- or 4-CH2), 22.5 (CH3 of iPr), 22.4 (CH3 of iPr), 17.8
(Ala CH3). Anal. calcld. for C27H36N4O5S C 61.34, H 6.86,
N 10.60, S 6.06. Found C 61.29, H 7.00, N 10.51, S 5.84. MS
(APCI) m/z 529 (MH+); negative mode: 527 (M–H+). HRMS
(ESI) m/z calcld. for C27H36N4O5SNa 551.2299. Found 551.2299.
1
1313 (νas(SO2)); 1151, 1134 (νs(SO2)). H NMR (CDCl3), δ 7.42
(d, J = 7.1 Hz, 2H, 2´-CH of PhC(O)), 7.31–7.38 (m, 3H, 3´-and
10 4´-CH of PhC(O)), 7.18–7.22 (m, 4H, Phe 2´-and 3´-C6H5), 7.13
(t, J = 6.9 Hz, 1H, Phe 4´-C6H5), 6.19 (d, J = 6.8 Hz, 1H, iPrNH),
5.94 (d, J = 8.3 Hz, 1H, Phe NH), 4.58 (br s, 1H, 2PyMS CαH),
4.08 (q, J = 7.1 Hz, 1H, Phe CαH), 3.92 (oct, J = 6.6 Hz, 1H, CH
of iPr), 3.45 (dd, J = 13.6 Hz and 3.2 Hz, 1H, 2PyMS CαHCHH),
15 3.30–3.39 (m, 2H, 2PyMS 5-CH2), 3.04–3.12 (m, 2H, Phe
CαHCH2), 2.66 (dd, J = 13.6 Hz and 8.4 Hz, 1H, 2PyMS
CαHCHH), 2.12–2.20 (m, 1H, 2PyMS 3-CHH), 1.89–1.96 (m,
1H, 2PyMS 3-CHH), 1.77–1.84 (m, 1H, 2PyMS 4-CHH), 1.67–
1.76 (m, 1H, 2PyMS 4-CHH), 0.98 (d, J = 6.6 Hz, 1H, CH3 of
20 iPr), 0.91 (d, J = 6.6 Hz, 1H, CH3 of iPr). 13C NMR (CDCl3), δ
170.4 (C=O), 169.6 (C=O), 136.7 (1´-C of C6H5), 136.6 (1´-C of
C6H5), 130.4 (4´-CH of PhC(O)), 130.0 (2´- or 3´-CH of Phe),
128.8 (2´- or 3´-CH of Phe), 128.5 (3´-CH of PhC(O)), 127.3 (2´-
CH of PhC(O)), 127.1 (4´-CH of Phe), 59.1 (Phe CαH), 55.1
25 (2PyMS CαHCH2), 53.4 (2PyMS CαH), 49.9 (2PyMS 5-CH2),
41.8 (CH of iPr), 39.4 (Phe CαHCH2), 30.6 (2PyMS 3-CH2), 24.9
(2PyMS 4-CH2), 22.5 (CH3 of iPr), 22.3 (CH3 of iPr). Anal.
calcld. for C24H31N3O4S C 63.00, H 6.83, N 9.18, S 7.01. Found
C 62.75, H 6.68, N 8.99, S 7.07. MS (APCI) m/z 458 (MH+);
30 negative mode: 456 (M–H+). HRMS (ESI) m/z calcld. for
C24H31N3O4SNa 480.1927. Found 480.1928.
N-((((2S)-1-(N-tert-butyloxycarbonyl-L-alanyl)pyrrolidin-2-
yl)methyl)sulfonyl)-L-phenylalanine isopropylamide (9)
Compound 8 (1.00 g, 2.8 mmol), HOBt (0.40 g, 3.0 mmol), and
35 DIPEA (0.77 g, 6.0 mmol) were dissolved in DMF (100 mL).
The mixture was cooled to –10 °C, and EDC (0.47 g, 3.0 mmol)
was added. The resulting mixture was stirred at –10 °C for 1 h,
then warmed to rt over 2 h, poured into H2O (300 mL) and
extracted with EtOAc (3×50 mL). The combined organic extracts
40 were washed with 1 M aq KHSO4 (50 mL), saturated aq NaHCO3
(50 mL), brine (50 mL), dried over Na2SO4 and evaporated in
vacuo. The residue was purified by column chromatography
(Hexanes – EtOAc (3 : 2) as eluent) to give 9 (1.00 g, 67%) as
yellowish amorphous solid. [α]D –26.3 (с 1.14, MeOH). 1H NMR
45 (CDCl3), δ 7.28–7.31 (m, 4H), 7.22–7.25 (m, 1H), 6.33 (d,
J = 7.3 Hz, 1H), 6.06 (d, J = 7.8 Hz, 1H), 5.52 (d, J = 7.5 Hz,
1H), 4.41 (quint, J = 6.6 Hz, 1H), 4.12–4.18 (m, 1H), 4.06–4.10
(m, 1H), 3.98–4.05 (m, 1H), 3.59–3.63 (m, 1H), 3.35–3.42 (m,
2H), 3.22 (dd, J = 13.2 Hz and 6.6 Hz, 1H), 3.10 (dd, J = 13.2 Hz
50 and 7.0 Hz, 1H), 2.63 (dd, J = 13.5 Hz and 8.4 Hz, 1H), 1.91–
2.00 (m, 4H), 1.46 (s, 9H), 1.28 (d, J = 6.6 Hz, 3H), 1.10 (d,
J = 6.2 Hz, 3H), 1.04 (d, J = 6.2 Hz, 3H). 13C NMR (CDCl3), δ
171.8, 169.4, 155.2, 136.8, 129.8, 128.7, 127.0, 79.8, 59.0, 54.0,
53.4, 48.1, 46.3, 41.7, 39.4, 29.8, 28.5, 23.8, 22.4, 22.4, 18.3.
55 Anal. calcld. for C25H40N4O6S C 57.23, H 7.68, N 10.68, S 6.11.
Found C 57.01, H 7.73, N 10.80, S 5.92. MS (APCI) m/z 425
(MH+ – CO2 – C4H8); negative mode: 523 (M–H+). HRMS (ESI)
m/z calcld. for C25H40N4O6SNa 547.2561. Found 547.2560.
100 X-Ray diffraction studies
Crystals of 3 and 4 for X-ray diffraction studies were obtained by
slow evaporation of their solution in Hexanes – EtOAc.
The colorless crystals of 3 (C24H31N3O4S) are hexagonal. At
293 K, a = b = 12.342(1) Å, c = 28.361(5) Å, V = 3741.1(8) Ǻ3,
105 Mr = 457.58, Z = 6, space group P65, dcalc = 1.219 g/сm3,
µ(MoKα) = 0.163 mm-1, F(000) = 1464.
The colorless crystals of 4 (C27H36N4O5S) are triclinic. At 293 K,
a = 8.9964(4) Å, b = 11.1739(4) Å, c = 14.3314(6) Å,
α = 98.212(3)°, β = 97.800(4)°, γ = 91.098(4)°, V = 1411.6(1) Ǻ3,
110 Mr = 528.66, Z = 2, space group P1, dcalc = 1.244 g/сm3,
µ(MoKα) = 0.157 mm-1, F(000) = 564.
Intensities of 18252 reflections (7218 independent, Rint=0.072)
for 3 and 13651 reflections (10282 independent, Rint=0.023) for 4
were measured on an Xcalibur 3 diffractometer (graphite
115 monochromated MoKα radiation, CCD-detector, ω scanning,
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Organic & Biomolecular Chemistry
Page 8 of 9
G.; Masi, A.; Paradisi, M. P.; Sansone, A.; Spisani, S. Bioorg. Med.
Chem. 2006, 14, 2642–2652.
2Θmax = 60°).
The structure was solved by direct method using SHELXTL
package.35 Positions of hydrogen atoms were located from
electron density difference maps and refined using riding model
with Uiso = nUeq (n = 1.5 for methyl groups and 1.2 for other
hydrogen atoms), except the atoms involved into the N–H...О
hydrogen bonds which were refined using isotropic model. In the
case of 4, restriction was applied to the bond lengths of
C(12)…C(17) aromatic ring (1.38 Ǻ). Full-matrix least-squares
7
8
Piscitelli, F.; Coluccia, A.; Brancale, A.; La Regina, G.; Sansone A,
Giordano, C; Balzarini, J.; Maga, G.; Zanoli, S.; Samuele, A.; Cirilli,
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65
70
75
80
85
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Chem. 2009, 52, 1922–1934.
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Diallo, H.; Kelly, H. A.; King, N. P.; Kleanthous, S.; Mason, A. M.;
Mordaunt, J. E.; Patel, C.; Pateman, A. J.; Senger, S.; Shah, G. P.;
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714.
10 refinement against F2 in anisotropic approximation for non-
hydrogen atoms was converged to wR2=0.086 for 7189
reflections (R1 = 0.053 for 3338 reflections with F > 4σ(F),
S = 0.885) in the case of 3, and wR2=0.138 for 10181 reflections
(R1 = 0.053 for 5727 reflections with F > 4σ(F), S = 0.932) in the
15 case of 4.
Final atomic coordinates, geometrical parameters and
crystallographic data have been deposited with the Cambridge
Crystallographic Data Centre, 11 Union Road, Cambridge, CB2
9
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(E-mail:
deposit@ccdc.cam.ac.uk;
fax:
20 +44 1223 336033) and are available on request quoting the
deposition numbers 901480 (3) and 901481 (4).
Acknowledgements
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