Synthesis and conformational preferences of cyclic unnatural di- and tripeptides containing an L-valine unit: Part 2

Article abstract of DOI:10.1016/j.tetasy.2005.10.030

Stereoselective syntheses of non-proteinogenic di- 14a,b, 15a,b and 16a,b and tripeptides 14c, 15c and 16c containing an L-valine unit and a cyclic unnatural α-amino acid have been accomplished starting from the L-valine derived chiral synthon 1. The conf

Full text of DOI:10.1016/j.tetasy.2005.10.030

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3785–3794
Synthesis and conformational preferences of cyclic unnatural
di- and tripeptides containing an L-valine unit: Part 2I
Daniele Balducci,a Enrico Emer,a Fabio Piccinelli,a Gianni Porzi,a,*
Maurizio Recanatinib and Sergio Sandria,*
a
`
Dipartimento di Chimica ‘G.Ciamician’, Universita di Bologna, Via Selmi 2, 40126 Bologna, Italy
`
Dipartimento di Scienze Farmaceutiche, Universita di Bologna, Via Belmeloro 6, 40126 Bologna, Italy
b
Received 18 July 2005; revised 4 October 2005; accepted 20 October 2005
Abstract—Stereoselective syntheses of non-proteinogenic di- 14a,b, 15a,b and 16a,b and tripeptides 14c, 15c and 16c containing an
L-valine unit and a cyclic unnatural a-amino acid have been accomplished starting from the L-valine derived chiral synthon 1. The
1
conformational preferences of these unnatural peptides were investigated by H NMR and IR spectroscopies and by molecular
modelling calculations. X-ray analysis of pseudopeptides 15a and 15b is also reported.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
synthon 1, a monolactim ether easily obtained from
L-valine.
In a preceding paper,1 we described a stereoselective
approach to a series of unusual dipeptides containing
the L-valine unit. Our interest in this field is because
peptidomimetic structures could exhibit therapeutic
effects similar to natural peptides with the advantage
of metabolic stability.2 In addition, non-proteinogenic
dipeptides could be useful building blocks for preparing
higher peptides or components to use as starting materi-
als in the organic synthesis.
2. Synthesis
As previously reported, the stereoselective synthesis
followed makes use of the chiral synthon 1, (6S)-1-ben-
zyl-5-ethoxy-3,6-dihydro-6-isopropyl-pyrazin-2-one,3
a
monolactim ether easily obtained starting from L-valine
(Scheme 1). The cyclic unnatural dipeptides 2, 3 and 4,
obtained in good overall yield as previously reported,1
were converted into the corresponding acetamides 5, 6
and 7. After hydrolysis of the ester group, the carboxylic
acid function was activated by conversion of intermedi-
ates 8, 9 and 10 into pentafluorophenylester 11, 12 and
13 derivatives, respectively. Finally, the activated esters
were converted into the respective pseudodipeptides,
14a,b, 15a,b and 16a,b, by treatment with cyclohexyl-
amine or benzylamine and the pseudotripeptides 14c,
15c and 16c by reaction with L-valine methylester. The
final products were all obtained in good overall yields.
Thus, in connection with our interest in these structural
derivatives, we undertook the synthesis of new pseudo-
peptide derivatives 14–16 containing L-valine and a cyc-
lic non-proteinogenic a-amino acid (proline derived). To
determine if these unnatural peptide analogues behave
as a scaffold, giving rise to conformationally constrained
cyclic structures through the formation of intramole-
cular hydrogen bonds, studies were performed by
1H NMR and IR spectroscopies and by molecular mod-
elling calculations.1,3–6
The strategy followed to accomplish the asymmetric
synthesis of these pseudopeptide derivatives is that
previously acquired on the stereoselective approach to
analogous substrates,1,3–5 that is starting from the chiral
1
3. H NMR and IR studies
To determine the structural features of the unnatural
peptides 14–16, we performed conformational investi-
1
gations by both H NMR and IR spectroscopies3–7 as
q Ref. 1 is considered to be Part 1.
*
Corresponding authors. E-mail: gianni.porzi@unibo.it
well as by molecular modelling studies. Essentially,
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.030

3786
D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 3785–3794
OEt
N
N
PhH2C
O
1
O
O
O
N
N
N
NH3Cl
H
NH3Cl
NH3Cl
COOEt
i
COOEt
i
COOEt
2
4
3
i
O
O
O
N
N
N
R
O
NH
O
NH
O
NH
H
R
R
5 R = COOEt
8 R = COOH
11 R = CO2Pfp
6 R = COOEt
9 R = COOH
12 R = CO2Pfp
7 R = COOEt
10 R = COOH
13 R = CO2Pfp
ii
ii
ii
iii
iii
iii
iv
iv
iv
O
O
O
N
N
N
NH1
NH1
NH1
H
O
O
O
O
O
O
H2
N
H2
N
H2
N
R
R
R
15a-c
R = a) -C6H11; b) -CH2-C6H5; c) (S)-CH(i-C3H7)CO2Me
16a-c
14a-c
Scheme 1. Reagents and conditions: (i) CH3COCl/Et3N in CH2Cl2; (ii) 2 M NaOH in EtOH, 2 h at rt; (iii) pentafluorophenyl trifluoroacetate
(CF3CO2Pfp) in CH2Cl2, Py; (iv) R–NH2 in DMF.
information on the intramolecular hydrogen bonds exis-
tence was derived from the chemical shift value (dNH),
the magnitude of temperature coefficient (DdNH/DT)
and solvent titration studies by adding up to 20% of
DMSO, a strongly competitive solvent in hydrogen
bond formation. Participation in hydrogen bonding
can be further confirmed by a broad band in the range
3300–3350 cmꢀ1 for the infrared stretching absorption
of the amidic NH, taking into account that a sharp band
higher than 3400 cmꢀ1 is attributable to hydrogen-bond-
free NH groups. In Table 1 are listed the meaningful 1H
NMR and IR data of substrates investigated in dilute
solutions and for clarity their amide protons are labelled
as H1 and H2 (see Scheme 1).
From the spectroscopic data in Table 1, it can be
inferred that in all pseudopeptides studied, the H1
proton does not form hydrogen bonds because the
chemical shifts are <7 ppm and the signals undergo a
significant downfield shift (1.3–2 ppm) upon addition
of 20% DMSO. Further support for this deduction
comes from the IR spectra that show sharp bands at
m > 3400 cmꢀ1, that is in the region characteristic of free
NH amide absorbance.
Conversely, the spectroscopic data allowed us to
conclude that most probably the H2 proton in some
substrates is involved in an intramolecular hydrogen
bond. Although the chemical shift of H2 in pseudopep-

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 3785–3794
Table 1. Meaningful H NMR and IR data of pseudopeptides 14–16
3787
1
dNH (ppm) (in 2 mM
dNH (ppm) (in 2 mM
DdNH/DT(ppb/ꢁC)
IR (cmꢀ1) (2 mM CHCl3)
CDCl3)
CDCl3/DMSO 4:1)
(in CDCl3)
H1
H2
H1
H2
H1
H2
14a
15a
16a
14b
15b
16b
14c
15c
16c
5.96
6.10
6.16
5.91
6.01
5.99
6.08
6.11
6.26
6.34
6.36
6.63
7.05
6.71
7.28
7.03
6.96
7.47
7.96
7.40
8.03
7.76
7.40
7.86
7.73
7.67
7.60
6.55
6.64
6.92
7.48
7.49
7.73
6.88
7.30
7.49
2.0
1.7
3.6
2.9
2.2
2.6
2.5
2.4
2.9
0.9
1.2
1.6
2.9
1.1
1.4
1.0
0.2
2.1
3436 (sharp) 3369 (broad)
3431 (sharp) 3305 (broad)
3432 (sharp) 3356 (broad)
3434 (sharp) 3363 (broad)
3461 (shoulder) 3425 (sharp)
3437 (sharp) 3349 (broad)
3430 (sharp) 3290 (shoulder)
3449 (shoulder) 3429 (sharp)
3422 (sharp) 3315 (broad)
tides 14a, 15a and 16a is below 7 ppm, the small change
in dNH2 after addition of 20% DMSO (0.21–0.28 ppm)
and the small value of the temperature coefficient (0.9–
1.6 ppb/ꢁC) are in agreement with the participation of
H2 in an intramolecular hydrogen bonding state. Such
a conjecture is supported by the IR spectra that show
broad bands in the range 3305–3369 cmꢀ1 in compara-
ble intensity with the sharp bands at higher m values, that
is in the range 3431–3436 cmꢀ1 (Table 1). Thus, it is rea-
sonable to infer that most probably, in pseudopeptides
14a, 15a and 16a, H2 is involved in an intramolecular
hydrogen bond although the chemical shifts are in the
range 6.34–6.63 ppm. We believe that the dNH2 value
below 7 ppm, registered for these pseudopeptides, could
be due to the shielding effect induced by the nearby
cyclohexane ring.
forms hydrogen bonds weaker than those in 14a, 15a
and 16a.
Conversely, the spectroscopic parameters reported in
Table 1 for 15b, dNH2 ¼ 6:71 ppm, an appreciable down-
shift of ꢁ0.8 ppm upon addition of 20% DMSO, a small
temperature coefficient (1.1 ppb/ꢁC) and the absence of
a broad band around 3310 cmꢀ1, typical of a hydrogen
bonding state, are consistent with H2 does not partici-
pate in an intramolecular hydrogen bond.
In pseudopeptide 15c, the 1H NMR data do not allow us
to assert if the H2 proton is or not engaged in an intra-
molecular hydrogen bond. However, because the IR
spectrum shows only a sharp band at 3429 cmꢀ1, typical
of a free amidic NH (with a shoulder at 3449 cmꢀ1), we
hypothesize that the H2 probably does not form a
hydrogen bond.
Also in substrates 14b and 16b, we believe that H2 is
engaged in an intramolecular hydrogen bond because
dNH2 values are greater than 7 ppm and the IR spectra
show a consistent broad band attributable to the hydro-
gen bonded amidic NH. Nevertheless, the solvent titra-
tion value (a downshift of ꢁ0.44 ppm) suggests that the
added solvent (DMSO) competes with the carbonyl
oxygen in the intramolecular hydrogen bonding forma-
tion. So, probably in pseudopeptides 14b and 16b H2
In the case of pseudopeptides 14c and 16c, we infer that
the H2 proton is involved in hydrogen bond because the
dNH2 remains unchanged on adding 20% DMSO, or is
rather shifted upfield as for 14c, the temperature coeffi-
cients are small and the IR spectra show a broad shoul-
der at 3290 and a broad band at 3310 cmꢀ1, respectively,
attributable to amidic NH in hydrogen bonding states.
Figure 1. Molecular structure of (a) 15a and (b) 15b.

3788
D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 3785–3794
4. X-ray analysis
The two compounds 15a and 15b differ only for the sub-
stituent bonded to N(2) (cyclohexyl and benzyl, respec-
tively) and adopt the same conformation in the solid
state.
The inner part of compounds 15a and 15b consists of a
five-membered ring [C(1)–C(2)–C(4)–C(5)–N(1)] in an
envelope conformation with the flap occupied by C(4),
˚
which is placed 0.508(4) A out of the average plane
described by C(1)–C(2)–C(5)–N(1) in compound 15a
˚
[0.486(2) A in compound 15b] (Fig. 1a and b).
The molecules possess three amidic functional groups:
one tertiary (central) and two secondary ones. The two
secondary groups O(1)–C(6)–N(2)–H(2N) and O(3)–
C(19)–N(3)–H(3N) are almost perpendicular to each
other. The spatial arrangement of the amido groups
does not allow formation of intramolecular hydrogen
bonds in the solid state. Interestingly, the orientations
of the secondary amido groups in each molecules give
rise to four intermolecular hydrogen bonds: two by
using the amidic protons [H(2N) and H(3N)] and two
by using the oxygens [O(1) and O(3)].
Furthermore, each hydrogen bond is only established
with another molecule and as a consequence, each
molecule is connected through hydrogen bonds to four
distinct molecules. This kind of intermolecular interac-
tions produces, in both molecular structures, a peculiar
structural motif that consists of a complex 3D network
made of macrocycles containing six molecules linked
to each other through six hydrogen bonds (Fig. 2a and b).
Since the two molecules crystallize with a similar crystal
packing only that of molecule 15b is shown (Fig. 3).
The strength of the N(2)–H(2N)ꢂ ꢂ ꢂO(3) hydrogen bond
is slightly different in the two molecules being weaker
˚
in 15a [N(2)–H(2N), 0.861(3) A, N(2)–H(2N)ꢂ ꢂ ꢂO(3),
˚
147.25(7)ꢁ, H(2N)ꢂ ꢂ ꢂO(3) 2.348(6) A for 15a and N(2)–
Figure 2. Structural motif in the crystal structure of (a) 15a and (b)
15b.
˚
H(2N), 0.967(3) A, N(2)–H(2N)ꢂ ꢂ ꢂO(3), 163.87(4)ꢁ,
˚
H(2N)ꢂ ꢂ ꢂO(3) 1.977(2) A for 15b] presumably because
of small differences in the crystal. The two remaining
intermolecular interactions are almost identical [N(3)–
and those within 50 kJ/mol from the global minimum
were then minimized through a molecular mechanics
force field approach simulating the CHCl3 solvation
environment (see experimental section 7.8). The com-
pounds 14b and 16b produced 72 and 49 conformations,
respectively, whereas compound 15c generated 57 con-
formations. By inspection of the minimized conforma-
tions, it can be inferred that all the three molecules are
able to form an intramolecular hydrogen bond using
the H2 proton. In no case does the H1 proton seems to
be involved in a hydrogen bond. From the conforma-
tional analysis, it appears that pseudopeptides 14b and
16b behave in a similar manner, both forming a hydro-
gen bond in their minimum energy conformation. In the
case of 14b, it is a seven-membered hydrogen bond,
while a ten-membered H-bond is detected in the global
minimum of 16b. However, for both molecules, several
conformations displaying hydrogen bonds via seven-
˚
H(3N), 0.904(5) A, N(3)–H(3N)ꢂ ꢂ ꢂO(1), 166.42(9)ꢁ,
˚
H(3N)ꢂ ꢂ ꢂO(1) 2.231(9) A for 15a and N(3)–H(3N),
˚
˚
0.903(2) A, N(3)–H(3N)ꢂ ꢂꢂO(1), 175.38(6)ꢁ, H(3N)ꢂ ꢂꢂO(1)
2.145(3) A for 15b].
5. Molecular modelling
In an attempt to obtain some clues to the interpretation
of the spectroscopic data regarding the pseudopeptides
described above, we carried out a molecular modelling
conformational analysis. Particularly, we studied 14b,
16b and 15c, not only as representative compounds of
the set, but also because the conclusions about their
intramolecular H-bonding profile seemed not com-
pletely unequivocal. For each molecule, conformations
were generated by means of the Monte Carlo method,

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 3785–3794
3789
Figure 3. Crystal packing of 15b (view down the a axis).
Table 2. Energetic and geometric parameters of the lowest energy hydrogen-bonded conformations of pseudopeptides 14b, 16b and 15c
Molecule
Energy (kJ/mol)
DE (kcal/mol)
Hydrogen bond geometry
˚
Cycle members
O–H Distance (A)
O–H–N Angle (ꢁ)
14b
16b
15c
Conf. 1a
Conf. 4
84.642
85.064
0.24
0.21
0.74
7
10
1.810
2.398
92.71
105.90
Conf. 1a
Conf. 3
45.114
45.982
10
7
2.192
1.881
105.53
90.79
Conf. 1a
Conf. 2
194.01
197.12
0
7
—
1.820
—
95.85
a Lowest energy conformation.
or ten-membered rings are present within a few kJ/mol
from the minimum.
structures are interesting because they could exhibit
therapeutic effects similar to natural peptides with the
advantage of a metabolic stability.
The pseudopeptide 15c does not show a hydrogen bond
in its global minimum, but a conformation containing a
seven-membered hydrogen bond is accessible within
3 kJ/mol. For this molecule, no conformation forming
a ten-membered hydrogen bond was found.
Interestingly, X-ray analysis performed on 15a and 15b
showed that the amide groups do not form intramole-
cular hydrogen bonds, but rather each molecule is
connected through intermolecular hydrogen bonds to
four distinct molecules giving rise to a complex tridi-
mensional network consisting of macrocycles containing
six molecules linked to each other through hydrogen
bonds.
In Table 2, the energetic and geometric parameters of
some representative conformations of 14b, 16b and 15c
are reported; the same conformations of the three mole-
cules are shown in Figure 4a–f.
Nevertheless, X-ray structural information, that is the
existence of intermolecular hydrogen bonds, is only
apparently in disagreement with the spectroscopic data
showing the H2 involved in an intramolecular hydrogen
bond. In fact, the molecular geometry deduced by X-ray
analysis concerns the compound in the crystalline state,
while the spectroscopic measurements are performed on
sufficiently diluted solution where the intermolecular
hydrogen bonds are broken. As a consequence, the sin-
gle molecule of 15a can adopt such a geometry (evi-
dently not allowed in the crystal packing), which
6. Conclusion
We have accomplished the synthesis of new enantio-
merically pure unnatural peptides containing L-valine
and a cyclic non-proteinogenic a-amino acid, that is a
proline derived. The approach, carried out by starting
from L-valine, might also represent a new and simple
synthetic path to more complex pseudopeptides with
potential biological activities. In fact, peptidomimetic

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D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 3785–3794
Figure 4. Representative conformations of pseudopeptides 14b (a, b), 16b (c, d) and 15c (e, f). Structures shown in (a), (c), and (e) represent the
minimum energy conformation of 14b, 16b and 15c, respectively. Structures shown in (b), (d) and (f) represent the closest hydrogen-bonded
conformation.
makes possible the formation of an intramolecular
hydrogen bond through H2. Conversely, in the case of
15b the spectroscopic data, obtained in dilute solution,
suggested that the single molecule forms neither inter-
nor intramolecular hydrogen bonds.
Chemical shifts are reported in parts per million relative
to CDCl3 and the coupling constants (J) are in hertz. IR
spectra were recorded on a Nicolet 210 spectrometer.
Optical rotation values were measured at 25 ꢁC on a
Perkin–Elmer 343 polarimeter. Dry THF was distilled
from sodium benzophenone ketyl. Chromatographic
separations were performed with silica gel 60 (230–400
mesh).
In reasonable agreement with the spectroscopic data,
conformational analysis shows that both pseudodipep-
tides 14b and 16b form a hydrogen bond in their mini-
mum energy conformations, giving rise to a seven- or
a ten-membered ring, respectively. Conversely, pseudo-
tripeptide 15c shows a seven-membered hydrogen bond
structure, which lies 3 kJ/mol higher than the global
minimum.
Synthesis and spectroscopic data of compounds 1–4
have been previously reported.1
7.2. Acylation of 2–4
Acetyl chloride (0.55 mL, 7.5 mmol) was added to a stir-
red solution of 2, 3 or 4 (5 mmol) and triethylamine
(2.1 mL, 15 mmol) in CH2Cl2 (20 mL) cooled at 0–
5 ꢁC. After about 2 h, 2 M HCl (5 mL) was added and
the reaction product extracted by ethyl acetate. The
organic solution was dried on Na2SO4 and the solvent
completely evaporated under vacuum. The residue was
7. Experimental
7.1. General information
1H and 13C NMR spectra were recorded on a Gemini
spectrometer at 300 MHz using CDCl3 as the solvent.

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 3785–3794
3791
then submitted to purification by silica gel chromatogra-
phy eluting with hexane/ethyl acetate and the product
was isolated in good yield as an oil.
J = 8.8); 7.8–8.2 (s, OH). 13C NMR d: 18.1, 19.0, 21.1,
22.5, 31.1, 44.6, 52.7, 55.9, 66.5, 109.0, 141.2, 171.3,
171.6, 175.4. [a]D = +5.6 (c 0.5, CHCl3). Anal. Calcd
for C14H22N2O4: C, 59.56; H, 7.85; N, 9.92. Found: C,
59.35; H, 7.87; N, 9.95.
7.2.1. (20S,2R)-1-(20-Acetylamino-30-methyl-butyryl)-2-
methyl-4-methylene-pyrrolidine-2-carboxylic acid ethyl
ester, 5. It was obtained starting from 2 in 80% yield.
1H NMR d: 0.92 (d, 3H, J = 6.6); 0.97 (d, 3H,
J = 6.6); 1.21 (t, 3H, J = 6.8); 1.54 (s, 3H); 1.98 (m,
1H); 2.00 (s, 3H); 2.52 (dd, 1H, J = 1.4, 15.4); 2.89 (d,
1H, J = 15.4); 4.15 (m, 2H); 4.23 (d, 1H, J = 14.2);
4.56 (d, 1H, J = 14.2); 4.56 (dd, 1H, J = 7, 9.2); 5.07
(m, 2H); 6.22 (d, 1H, J = 9.2). 13C NMR d: 13.7, 17.6,
18.9, 20.9, 22.6, 31.0, 44.4, 52.1, 55.3, 60.7, 65.8, 108.4,
141.3, 169.8, 170.3, 172.5. [a]D = +2.8 (c 0.5, CHCl3).
Anal. Calcd for C16H26N2O4: C, 61.91; H, 8.44; N,
9.03. Found: C, 62.11; H, 8.42; N, 9.01.
7.3.2. (20S,2S)-1-(20-Acetylamino-30-methyl-butyryl)-2-
methyl-4-methylene-pyrrolidine-2-carboxylic acid, 9. It
was obtained pure in 95% yield starting from 6. 1H
NMR d: 0.91 (d, 3H, J = 6.6); 0.98 (d, 3H, J = 6.6);
1.5 (s, 3H); 2.0 (s, 3H); 2.08 (m, 1H); 2.48 (d, 1H,
J = 14.6); 3.03 (d, 1H, J = 14.6); 3.08–3.50 (s, OH);
4.33 (d, 1H, J = 14); 4.44–4.53 (m, 2H); 5.09 (m, 2H);
6.51 (d, 1H, J = 9). 13C NMR d: 18.9, 20.4, 22.7, 31.0,
44.9, 52.2, 55.9, 66.3, 109.4, 141.0, 171.0, 171.2, 176.3.
[a]D = ꢀ33.7 (c 0.2, CHCl3). Anal. Calcd for
C14H22N2O4: C, 59.56; H, 7.85; N, 9.92. Found: C,
59.84; H, 7.82; N, 9.88.
7.2.2. (20S,2S)-1-(20-Acetylamino-30-methyl-butyryl)-2-
methyl-4-methylene-pyrrolidine-2-carboxylic acid ethyl
ester, 6. It was obtained starting from 3 in 82% yield.
1H NMR d: 0.92 (d, 3H, J = 6.6); 1.0 (d, 3H, J = 6.6);
1.23 (t, 3H, J = 7.4); 1.46 (s, 3H); 1.97 (s, 3H); 2.03
(m, 1H); 2.43 (d, 1H, J = 14.8); 2.88 (d, 1H, J = 14.8);
4.15 (m, 2H); 4.32 (br s, 2H); 4.48 (dd, 1H, J = 7, 9.2);
5.06 (m, 2H); 6.2 (d, 1H, J = 9.2). 13C NMR d: 13.2,
17.7, 18.0, 19.6, 21.5, 29.8, 43.9, 51.0, 55.6, 60.1, 65.0,
108.2, 141.0, 169.8, 170.2, 171.5. [a]D = ꢀ35.5 (c 0.9,
CHCl3). Anal. Calcd for C16H26N2O4: C, 61.91; H,
8.44; N, 9.03. Found: C, 61.82; H, 8.46; N, 9.05.
7.3.3. (20S,2R)-1-(20-Acetylamino-30-methyl-butyryl)-4-
methylene-pyrrolidine-2-carboxylic acid, 10. It was
obtained in 90% yield starting from 7. 1H NMR d:
0.97 (d, 6H, J = 7); 1.97 (s, 3H); 2.03 (m, 1H); 2.75–
3.05 (m, 2H); 4.31 (d, 1H, J = 14.4); 4.5–4.7 (m, 3H);
5.12 (m, 2H); 5.36–5.68 (s, OH); 7.11 (d, 1H, J = 9.2).
13C NMR d: 17.9, 19.2, 22.2, 30.9, 35.2, 51.5, 55.7,
58.6, 109.1, 141.4, 171.5, 171.9, 173,3. The product
was not isolated in sufficiently pure form to measure
the specific rotation.
7.4. Activation of the carboxylic function
7.2.3. (20S,2R)-1-(20-Acetylamino-30-methyl-butyryl)-4-
methylene-pyrrolidine-2-carboxylic acid ethyl ester,
7. It was obtained starting from 4 in 78% yield. H
NMR d: 0.93 (d, 3H, J = 7); 0.97 (d, 3H, J = 7); 1.24
(t, 3H, J = 7.2); 2.02 (s, 3H); 2.04 (m, 1H); 2.65 (m,
1H); 2.96 (m, 1H); 4.18 (q, 2H, J = 7.2); 4.29 (d, 1H,
J = 14.2); 4.46 (d, 1H, J = 14.2); 4.55–4.7 (m, 2H);
5.05 (m, 2H); 6.3 (d, 1H, J = 8.8). 13C NMR d: 13.9,
17.6, 19.3, 22.9, 31.1, 35.2, 51.1, 55.3, 58.5, 61.0, 108.9,
141.7, 169.9, 171.1. The product was not isolated in suf-
ficiently pure form to measure the specific rotation.
To a stirred solution of 8, 9 or 10 (5 mmol) in dry
CH2Cl2 (10 mL) at 0 ꢁC, pyridine (1.2 mL, 15 mmol)
was added followed by pentafluorophenyl trifluoroace-
tate (1.3 mL, 7.5 mmol). After removing from the cool-
ing bath, the reaction was stirred at rt for about 10 h
and monitored by TLC. When the reaction was com-
plete, CH2Cl2 (10 mL) was added and the organic solu-
tion washed with water. The organic extract was then
dried over CaCl2 and evaporated to dryness in vacuo.
The crude reaction product was purified by silica gel
chromatography eluting with hexane/ethyl acetate and
the product was obtained in good yield as a wax.
1
7.3. Hydrolysis of 5–7
NaOH (2 M, 10 mmol, 5 mL) was added to a stirred
solution of 5, 6 or 7 (5 mmol) in ethanol at rt and the
reaction was monitored by TLC. After 2 h, ethanol
was evaporated under vacuum and the residue solution
extracted with ethyl acetate. The aqueous solution was
acidified to pH = 2–3 with diluted HCl and then
extracted with ethyl acetate. The organic solution was
dried and the solvent completely evaporated in vacuo.
The product was isolated in semisolid state in good
yield.
7.4.1. (20S,2R)-1-(20-Acetylamino-30-methyl-butyryl)-2-
methyl-4-methylene-pyrrolidine-2-carboxylic acid penta-
fluorophenyl ester, 11. It was obtained in 90% yield
1
starting from 8. H NMR d: 0.99 (d, 3H, J = 6); 1.03
(d, 3H, J = 6); 1.7 (s, 3H); 2.04 (s, 3H); 2.08 (m, 1H);
2.75 (d, 1H, J = 15.6); 3.18 (d, 1H, J = 15.6); 4.35 (d,
1H, J = 13.8); 4.62 (dd, 1H, J = 7.5, 9.3); 4.69 (d, 1H,
J = 13.8); 5.19 (m, 2H); 6.14 (d, 1H, J = 9.3). 13C
NMR d: 17.8, 19.0, 21.2, 22.8, 31.3, 44.1, 52.0, 55.3,
65.8, 109.7, 125 (m), 140 (m), 140.6, 168.7, 170.1,
170.7. [a]D = ꢀ6.9 (c 1.0, CHCl3). Anal. Calcd for
C20H21F5N2O4: C, 53.57; H, 4.72; N, 6.25. Found: C,
53.82; H, 4.71; N, 6.23.
7.3.1. (20S,2R)-1-(20-Acetylamino-30-methyl-butyryl)-2-
methyl-4-methylene-pyrrolidine-2-carboxylic acid, 8. It
was obtained pure in 90% yield starting from 5. 1H
NMR d: 0.95 (d, 6H, J = 6.6); 1.56 (s, 3H); 1.99 (s,
3H); 2.06 (m, 1H); 2.54 (d, 1H, J = 15.4); 3.0 (d, 1H,
J = 15.4); 4.26 (d, 1H, J = 14); 4.52 (t, 1H, J = 8.4);
4.65 (d, 1H, J = 14); 5.09 (m, 2H); 7.43 (d, 1H,
7.4.2. (20S,2S)-1-(20-Acetylamino-30-methyl-butyryl)-2-
methyl-4-methylene-pyrrolidine-2-carboxylic acid penta-
fluorophenyl ester, 12. It was obtained in 88% yield
1
starting from 9. H NMR d: 0.96 (d, 3H, J = 6); 1.03

3792
D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 3785–3794
(d, 3H, J = 6); 1.57 (s, 3H); 2.03 (s, 3H); 2.07 (m, 1H);
2.68 (d, 1H, J = 15); 3.17 (d, 1H, J = 15); 4.36–4.61
(m, 3H); 5.2 (m, 2H); 6.12 (d, 1H, J = 8.4). 13C NMR
d: 18.3, 18.4, 20.2, 22.1, 30.5, 44.4, 51.5, 56.7, 65.5,
109.7, 125 (m), 139 (m); 140.6, 168.5, 170.6, 171.6.
[a]D = ꢀ38.7 (c 0.4, CHCl3). Anal. Calcd for
C20H21F5N2O4: C, 53.57; H, 4.72; N, 6.25. Found: C,
53.48; H, 4.73; N, 6.24.
171.4, 172.0, 173.0. [a]D = +4.9 (c 1, CHCl3). Anal.
Calcd for C21H29N3O3: C, 67.9; H, 7.87; N, 11.31.
Found: C, 68.2; H, 7.84; N, 11.27.
7.5.3.
(2S,20S,200R)-2-{[1-(20-Acetylamino-30-methyl-
butyryl)-200-methyl-400-methylene-pyrrolidine-200-carbonyl]-
amino}-3-methyl-butyric acid methyl ester, 14c. It was
obtained as an oil in 60% yield by reacting 11 with L-
valine methylester. 1H NMR d: 0.9 (d, 3H, J = 6.6);
0.97 (d, 3H, J = 6.6); 1.03 (d, 6H, J = 6.6); 1.71 (s,
3H); 1.99 (s, 3H); 2.07 (m, 1H); 2.15 (m, 1H); 2.52 (d,
1H, J = 15.9); 3.10 (d, 1H, J = 15.9); 3.69 (s, 3H); 4.32
(d, 1H, J = 13.8); 4.35 (t, 1H, J = 8.1); 4.46 (dd, 1H,
J = 5.1, 8.4); 4.61 (d, 1H, J = 13.8); 5.07 (m, 2H); 6.16
(d, 1H, J = 6.9); 7.0 (d, 1H, J = 8.7). 13C NMR d:
17.7, 18.5, 18.7, 21.5, 22.4, 30.3, 45.3, 51.6, 52.9, 57.1,
57.5, 68.0, 108.6, 140.5, 170.7, 171.2, 172.0, 172.7.
[a]D = +3.7 (c 0.9, CHCl3). Anal. Calcd for
C20H33N3O5: C, 60.74; H, 8.41; N, 10.62. Found: C,
61.02; H, 8.39; N, 10.6.
7.4.3. (20S,2R)-1-(20-Acetylamino-30-methyl-butyryl)-4-
methylene-pyrrolidine-2-carboxylic acid pentafluorophen-
yl ester, 13. It was obtained in 85% yield starting
1
from 10. H NMR d: 0.97 (d, 3H, J = 6.6); 1.01 (d, 3H,
J = 6.6); 2.0 (s, 3H); 2.04 (m, 1H); 2.9 (m, 1H); 3.17
(m, 1H); 4.34 (d, 1H, J = 15.4); 4.58 (d, 1H, J = 15.4);
4.65 (dd, 1H, J = 7.4, 8.8); 4.91 (dd, 1H, J = 3.4, 9.4);
5.18 (m, 2H); 6.31 (d, 1H, J = 8.8). 13C NMR d: 17.6,
18.8, 22.0, 30.6, 35.0, 51.0, 55.6, 57.9, 109.4, 140.7,
124.4 (m), 139 (m), 167.0, 170.3, 171.8. The product
was not isolated in sufficiently pure form to measure
the specific rotation.
7.5.4. (20S,2S)-1-(20-Acetylamino-30-methyl-butyryl)-2-
methyl-4-methylene-pyrrolidine-2-carboxylic acid cyclo-
hexylamide, 15a. It was obtained pure as a solid in 62%
7.5. Pseudopeptides 14a–c, 15a–c and 16a–c
1
To a stirred solution of activated esters 11, 12 or 13
(0.6 mmol) in dry CH2Cl2 (6 mL) cyclohexylamine, ben-
zylamine or L-valine methylester (0.12 mmol) was added
under an inert atmosphere and the reaction monitored
by TLC. After about 1 h CH2Cl2 (6 mL) was added
and the organic solution washed with dilute HCl and
then water. The organic extract was dried over CaCl2
and evaporated to dryness in vacuo in a water bath at
about 50 ꢁC. The crude reaction product was purified
by the silica gel chromatography eluting with hexane/
ethyl acetate.
yield by reacting 12 with cyclohexylamine. H NMR d:
0.98 (d, 3H, J = 6.9); 1.04 (d, 3H, J = 6.9); 1.10–1.98
(m, 10H); 1.6 (s, 3H); 2.03 (s, 3H); 2.05 (m, 1H); 2.42
(d, 1H, J = 15); 3.2 (d, 1H, J = 15); 3.75 (m, 1H); 4.3
(d, 1H, J = 13); 4.5 (d, 1H, J = 13); 4.58 (dd, 1H,
J = 6.6, 8.7); 5.1 (m, 2H); 6.08 (d, 1H, J = 8.4); 6.4 (d,
1H, J = 7.8). 13C NMR d: 17.9, 19.3, 21.4, 22.8, 24.6,
25.4, 30.9, 32.69, 32.72, 44.9, 48.2, 52.8, 56.1, 68.2,
108.5, 141.1, 170.1, 171.5, 171.6. [a]D = ꢀ59.7 (c 0.3,
CHCl3). Mp 167.5–168.5 ꢁC. Anal. Calcd for
C20H33N3O3: C, 66.08; H, 9.15; N, 11.56. Found: C,
66.15; H, 9.12; N, 11.53.
7.5.1. (20S,2R)-1-(20-Acetylamino-30-methyl-butyryl)-2-
methyl-4-methylene-pyrrolidine-2-carboxylic acid cyclo-
hexylamide, 14a. It was obtained as an oil in 60% yield
7.5.5. (20S,2S)-1-(20-Acetylamino-30-methyl-butyryl)-2-
methyl-4-methylene-pyrrolidine-2-carboxylic acid ben-
zylamide, 15b. It was obtained pure as an oil in 60%
yield by reacting 12 with benzylamine. 1H NMR d:
0.89 (d, 3H, J = 6.9); 0.96 (d, 3H, J = 6.9); 1.63 (s,
3H); 2.01 (m, 1H); 2.05 (s, 3H); 2.47 (dd, 1H, J = 1.5,
15.9); 3.23 (d, 1H, J = 15.9); 4.32 (d, 1H, J = 13.8);
4.52 (m, 4H); 5.01 (m, 2H); 6.23 (d, 1H, J = 8.7); 6.72
(t, 1H, J = 5.1); 7.33 (m, 5H). 13C NMR d: 17.7, 19.1,
21.1, 22.8, 30.8, 43.7, 45.0, 52.7, 56.0, 67.9, 108.7,
127.2, 127.5, 128.4, 138.0, 141.0, 170.1, 171.4, 172.5.
[a]D = ꢀ39.6 (c 0.6, CHCl3). Mp 158.5–159.5 ꢁC. Anal.
Calcd for C21H29N3O3: C, 67.9; H, 7.87; N, 11.31.
Found: C, 67.79; H, 7.89; N, 11.34.
1
by reacting 11 with cyclohexylamine. H NMR d: 1.05
(d, 3H, J = 6.9); 1.07 (d, 3H, J = 6.9); 1.10–1.95 (m,
10H); 1.67 (s, 3H); 2.03 (m, 1H); 2.05 (s, 3H); 2.55 (d,
1H, J = 15.6); 2.96 (d, 1H, J = 15.6); 3.7 (m, 1H); 4.12
(dd, 1H, J = 6.6, 8.7); 4.26 (d, 1H, J = 13.5); 4.75 (d,
1H, J = 13.5); 5.09 (m, 2H); 6.07 (d, 1H, J = 6.6); 6.39
(d, 1H, J = 8.4). 13C NMR d: 18.5, 19.2, 21.6, 22.3,
24.7, 25.4, 29.9, 32.3, 46.4, 48.3, 53.1, 58.3, 68.2, 108.3,
140.9, 171.3, 171.7. [a]D = +6.9 (c 1, CHCl3). Anal.
Calcd for C20H33N3O3: C, 66.08; H, 9.15; N, 11.56.
Found: C, 65.85; H, 9.17; N, 11.6.
7.5.2. (20S,2R)-1-(20-Acetylamino-30-methyl-butyryl)-2-
methyl-4-methylene-pyrrolidine-2-carboxylic acid benzyl-
amide, 14b. It was obtained as an oil in 63% yield
7.5.6.
(2S,20S,200S)-2-{[1-(20-Acetylamino-30-methyl-
butyryl)-200-methyl-400-methylene-pyrrolidine-200-carbonyl]-
amino}-3-methyl-butyric acid methyl ester, 15c. It was
obtained pure as an oil in 65% yield by reacting 12 with
1
by reacting 11 with benzylamine. H NMR d: 1.02 (d,
3H, J = 7); 1.03 (d, 3H, J = 7); 1.67 (s, 3H); 1.76 (s,
3H); 2.05 (m, 1H); 2.62 (d, 1H, J = 15.8); 3.03 (d, 1H,
J = 15.8); 4.06 (dd, 1H, J = 7, 9.2); 4.24 (dd, 1H,
J = 4.8, 15); 4.31 (d, 1H, J = 14.6); 4.60 (dd, 1H, J =
7, 15); 4.76 (d, 1H, J = 14.6); 5.07 (m, 2H); 6.07
(d, 1H, J = 4.8); 7.09 (m, 1H); 7.28 (m, 5ArH). 13C
NMR d: 18.8, 19.1, 22.1, 22.2, 30.3, 43.4, 46.4, 53.3,
58.2, 68.6, 108.8, 126.8, 127.4, 128.2, 138.8, 140.8,
1
L-valine methylester. H NMR d: 0.92 (d, 3H, J = 6.9);
0.94 (d, 3H, J = 6.9); 0.96 (d, 3H, J = 6.9); 1.03 (d,
9H, J = 6.9); 1.66 (s, 3H); 2.03 (s, 3H); 2.08 (m, 1H);
2.18 (m, 1H); 2.45 (d, 1H, J = 15); 3.18 (d, 1H,
J = 15); 3.72 (s, 3H); 4.30 (d, 1H, J = 13); 4.56 (m,
3H); 5.06 (m, 2H); 6.24 (d, 1H, J = 9.2); 6.96 (d, 1H,
J = 8.4). 13C NMR d: 17.6, 17.8, 18.9, 19.5, 21.5, 23.2,

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 3785–3794
3793
31.1, 31.3, 45.1, 52.0, 52.9, 55.8, 57.5, 68.2, 108.8, 141.1,
170.0, 171.3, 172.3, 172.6. [a]D = ꢀ54.4 (c 0.6, CHCl3).
Anal. Calcd for C20H33N3O5: C, 60.74; H, 8.41; N,
10.62. Found: C, 60.55; H, 8.43; N, 10.65.
for all non-hydrogen atoms yielded R1 = 0.0427 and
wR2 = 0.1271 for [I > 2r(I)] and R1 = 0.0535 and
wR2 = 0.1337 for all intensity data. All hydrogen atoms
were added in calculated position except the amidic
hydrogens that were located in the Fourier map. Good-
ness-of-fit = 1.085. CCDC number is 278479.
7.5.7. (20S,2R)-1-(20-Acetylamino-30-methyl-butyryl)-4-
methylene-pyrrolidine-2-carboxylic acid cyclohexylamide,
16a. It was obtained pure as a wax in 60% yield by
7.7. Crystallographic data of 15b
1
reacting 13 with cyclohexylamine. H NMR d: 0.96 (d,
3H, J = 6.9); 1.01 (d, 3H, J = 6.9); 1.16–1.95 (m,
10H); 2.04 (s, 3H); 2.01 (m, 1H); 2.7–3.0 (m, 2H); 3.68
(m, 1H); 4.17 (dd, 1H, J = 7.2, 9); 4.3 (d, 1H,
J = 14.4); 4.6 (d, 1H, J = 14.4); 4.75 (dd, 1H, J = 1.8,
8.4); 5.14 (m, 2H); 6.5 (d, 1H, J = 6.6); 6.5 (d, 1H,
J = 8.1). 13C NMR d: 18.9, 19.1, 22.7, 24.9, 25.5, 29.9,
32.5, 32.7, 36.0, 48.3, 51.3, 57.8, 60.1, 108.9, 142.1,
169.3, 171.5, 171.7. [a]D = +53.2 (c 1, CHCl3). Anal.
Calcd for C19H31N3O3: C, 65.3; H, 8.94; N, 12.02.
Found: C, 65.58; H, 8.92; N, 11.98.
Single crystal X-ray diffraction data: C21H29N3O3, Fw
371.47, colourless parallelepiped, size: 0.50 · 0.30 ·
0.20 mm, Orthorhombic, space group P212121, a =
˚
˚
˚
10.6448(7) A, b = 11.8037(8) A, c = 16.9260(11) A,
3
˚
V = 2126.7(2) A , theta range for data collection 2.10–
28.65ꢁ, Z = 4, F(000) = 800, Dx = 1.160 Mg/m3,
l = 0.078mmꢀ1, data collected on a Bruker APEX II
˚
CCD diffractometer (Mo-Ka radiation, k = 0.71073 A)
at 100(2) K, total of 17,283 reflections, of which 5008
unique [R(int) = 0.0196]. Empirical absorption correction
was applied, initial structure model by direct methods.
Anisotropic full-matrix least-squares refinement on F2
for all non-hydrogen atoms yielded R1 = 0.0315 and
wR2 = 0.0825 for [I > 2r(I)] and R1 = 0.0342 and
wR2 = 0.0838 for all intensity data. All hydrogen atoms
were added in calculated position except the amidic
hydrogens that were located in the Fourier map. Good-
ness-of-fit = 1.052. CCDC number is 278478.
7.5.8. (20S,2R)-1-(20-Acetylamino-30-methyl-butyryl)-4-
methylene-pyrrolidine-2-carboxylic acid benzylamide,
16b. It was obtained pure as an oil in 65% yield by
reacting 13 with benzylamine. 1H NMR d: 1.02 (d,
3H, J = 7); 1.04 (d, 3H, J = 7); 1.68 (s, 3H); 2.03 (m,
1H); 2.75–3.05 (m, 2H); 4.13 (dd, 1H, J = 6.2, 9.2);
4.20–4.34 (m, 2H); 4.6 (m, 2H); 4.87 (dd, 1H, J = 3.6,
6.8); 5.14 (m, 2H); 6.46 (d, 1H, J = 6.2); 7.3 (m,
5ArH); 7.39 (t, 1H, J = 5.6). 13C NMR d: 18.9, 21.9,
29.7, 36.0, 43.1, 51.4, 58.2, 60.3, 109.6, 126.9, 127.1,
128.2, 137.9, 141.4, 171.0, 172.0, 172.7. [a]D = +50.1 (c
1.8, CHCl3). Anal. Calcd for C20H27N3O3: C, 67.2; H,
7.61; N, 11.76. Found: C, 67.53; H, 7.59; N, 11.73.
7.8. Computational method
All the calculations were performed using the Macro-
Model Version 5.59 package. The initial structure of
each compound was energy minimized with the MMFF8
force field by means of the Conjugate Gradient algo-
(2S,20S,200R)-2-{[1-(20-Acetylamino-30-methyl-
rithm using a derivative convergence of 0.1 kJ/(A mol),
˚
7.5.9.
butyryl)-400-methylene-pyrrolidine-200-carbonyl]-amino}-3-
methyl-butyric acid methyl ester, 16c. It was obtained
pure as an oil in 60% yield by reacting 13 with L-valine
along with the GB/SA10 continuum solvation model
for chloroform. Conformational searches were carried
out using internal coordinate Metropolis Monte Carlo
simulations at the reference temperature of 300 K. For
each compound a total of 15000 conformations were
sampled, and then they were energy minimized accord-
ing to the above mentioned criteria. All of the confor-
mations within about 50 kJ/mol above the global
minimum were kept.
1
methylester. H NMR d: 0.89 (d, 3H, J = 6.9); 0.96 (d,
3H, J = 6.9); 1.00 (d, 3H, J = 6.9); 1.02 (d, 3H,
J = 6.9); 2.03 (s, 3H); 2.17 (m, 2H); 2.70 (m, 1H); 3.12
(d, 1H, J = 15); 3.69 (s, 3H); 4.31 (s, 2H); 4.47 (m,
2H); 4.91 (d, 1H, J = 9); 5.12 (m, 2H); 6.47 (d, 1H,
J = 8.4); 7.44 (d, 1H, J = 8.7). 13C NMR d: 17.7, 18.3,
19.1, 19.4, 22.8, 30.5, 30.6, 33.6, 51.1, 51.9, 56.5, 57.4,
59.1, 108.8, 142.3, 170.4, 171.7, 172.4. [a]D = +8.7 (c
0.6, CHCl3). Anal. Calcd for C19H31N3O5: C, 59.82;
H, 8.19; N, 11.02. Found: C, 59.93; H, 8.17; N, 10.98.
Acknowledgements
Thanks are due to the University of Bologna for finan-
cial support (ÔRicerca Fondamentale OrientataÕ, ex
60%).
7.6. Crystallographic data of 15a
Single crystal X-ray diffraction data: C20H33N3O3, Fw
363.49, colourless parallelepiped, size: 0.45 · 0.32 ·
0.25 mm, Orthorhombic, space group P212121, a =
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˚
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