β-Peptoids: Synthesis of a novel dimer having a fully extended conformation

Article abstract of DOI:10.1007/s00726-012-1275-1

Chiral imines 1a,b, already synthesized in our laboratory, were converted in good yield by reduction into the corresponding N-benzyl-γ-lactams 2a,b. Desilylation followed by oxidation of the hydroxymethyl functionality gave the N-benzyl-β-amino acids 5a,b in good yield and high purity. Starting from compound 6a, the corresponding β-peptoid dimer 8 was prepared, together with its derivatives 9 and 10, these latter displaying conformational restriction about the peptide bond, as evidenced by NMR data.

Full text of DOI:10.1007/s00726-012-1275-1

Amino Acids (2012) 43:2005–2014
DOI 10.1007/s00726-012-1275-1
ORIGINAL ARTICLE
b-Peptoids: synthesis of a novel dimer having a fully extended
conformation
•
Gianluca Martelli Antonella Monsignori
•
•
•
•
Mario Orena Samuele Rinaldi Nicola Castellucci
Claudia Tomasini
Received: 3 November 2011 / Accepted: 14 March 2012 / Published online: 28 March 2012
Ó Springer-Verlag 2012
Abstract Chiral imines 1a,b, already synthesized in our
laboratory, wereconverted in good yield by reductionintothe
corresponding N-benzyl-c-lactams 2a,b. Desilylation fol-
lowed by oxidation of the hydroxymethyl functionality gave
the N-benzyl-b-amino acids 5a,b in good yield and high
purity. Starting from compound 6a, the corresponding
b-peptoid dimer 8 was prepared, together with its derivatives
9 and 10, these latter displaying conformational restriction
about the peptide bond, as evidenced by NMR data.
1998; Wu et al. 2003) and loops (Huang et al. 2006).
Understanding the factors that affect peptoid conformation
is a central topic within this research field, since formation
of helical or threaded loop conformations relies on oligo-
mer sequence, chain length and solvent composition. More
recently, the role of monomer units on peptoid folding has
been evidenced because n - p* and steric interactions
allow the control of s-cis/s-trans isomerism in the mono-
mer (Gorske et al. 2009).
Among peptoids, b-peptoids represent a new class of
synthetic polyamides structurally related to b-peptides in
which the amino acid side chain lies on amide nitrogen in
place of Ca or Cb carbons.
Keywords Peptoid Á Lactam Á Foldamer Á Imines Á
Conformational restrictions
Introduction
O
O
Peptoids, a class of biomimetic polymers displaying poly-
N-substituted glycine backbones, are designed to mimic
peptides and proteins (Simon et al. 1992; Fowler and
Blackwell 2009). In fact, owing to their resistance to pro-
teolysis (Miller et al. 1994) and rapid cellular uptake
(Kwon and Kodadek 2007), they are attractive candidates
for interesting biological applications, in particular as
antibiotics (Olsen et al. 2010; Huang et al. 2012). In
solution, peptoids can form well-defined three-dimensional
folds like helices (Kirshenbaum et al. 1998; Armand et al.
N
R
n
β-Peptoid
Since the introduction of these structures (Hamper et al.
1998), very few reports deal to this class of compounds
(Baldauf et al. 2006; Norgren et al. 2006; Cardoso et al.
2009). The lack of the amidic hydrogen and three rotable
bonds in the backbone can greatly modify the folding
properties of b-peptoids related to b-peptides. Of great
concern is the relationship between b-peptoid sequence and
secondary structure displayed. Thus, it is very important to
have chemically different monomers not only for a deeper
insight of the factors affecting peptoid conformation, but
also to obtain new molecules with interesting biological
activity. The conformational stability of dimers about the
amide bond is generally low, and two conformations gen-
G. Martelli (&) Á A. Monsignori Á M. Orena Á S. Rinaldi
Di.S.V.A.-Chemistry, Polytechnic University of Marche,
Via Brecce Bianche, 60131 Ancona, Italy
e-mail: gmartell@univpm.it
N. Castellucci Á C. Tomasini
Department of Chemistry ‘‘G. Ciamician’’,
Alma Mater Studiorum University of Bologna,
Via Selmi 2, 40126 Bologna, Italy
1
erally take place, as revealed by H NMR spectra, leading
to reduced conformational stability of the final peptoid. We
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G. Martelli et al.
have already reported the preparation of monomers of
foldamers tethered on a pyrrolidin-2-one ring, and stable
secondary structures have been observed, such as 12-helix
and 8-helix (Menegazzo et al. 2006; Galeazzi et al. 2011).
Therefore, the preparation of highly conformationally
restricted monomers for b-peptoids can be of interest, and
we devised that useful starting units can be novel 3-ami-
noalkyl substituted pyrrolidin-2-ones.
chromatography on silica gel, which were then treated with
NH4F in methanol to give the desired alcohols 4a,b used
without any further purification. The next synthetic step
was the oxidation of hydroxymethyl functionality with
TEMPO and NaOCl solution in CH2Cl2 (Anelli et al. 1987)
to give the corresponding acids 5a,b in quantitative yield.
Eventually, treatment of 5a,b with CH2N2 in methanol
afforded N-benzyl-b-amino esters 6a,b, which can be
useful monomers for the synthesis of novel b-peptoids
(Scheme 1).
Results and discussion
According to this project, in an attempt to investigate the
behavior of monomer 6a, we have synthesized the dimer 8
and its derivatives 9 and 10. Thus, compound 6a bearing
the chiral inducer (S)-phenylethyl group underwent selec-
tive deprotection of the amino functionality with TFA in
DCM to give the corresponding ammonium salt 7 in 95 %
yield. The reaction of 7 with the corresponding acid 5a in
DCM in the presence of PyBrop (Coste et al. 1994) and
DIPEA allowed to obtain the dimer 8 in moderate yield.
After removal of the t-Boc group by treatment with TFA in
DCM, the trifluoroacetate 9 was obtained in quantitative
yield and, in the event, the corresponding amino derivative
10 was obtained by treatment with TEA (Scheme 2).
In fact, by inspection of 1H-NMR spectra of com-
pounds 6a, two rotamers have been evidenced, due to
hindered rotation of the t-butoxycarbonyl group, giving
Within a program directed towards the synthesis of isos-
teres of proteinogenic and non-proteinogenic amino acids
(Galeazzi et al. 2005; Crucianelli et al. 2010), we already
reported the synthesis of analogs of (R)-2-methylhomo-
serine and (R)-2-methylaspartic acid by alkylation of chiral
imines 1a,b (Crucianelli et al. 2009) and we devised that
these compounds could be also useful as starting materials
suitable for the preparation of new monomers of b-pep-
toids. Thus, imines 1a,b were reduced with NaBH4 in
methanol to give the corresponding amines 2a,b in good
yield and high purity. The protection of the amino func-
tionality was carried out with di-t-butyl dicarbonate in
CH2Cl2 in the presence of TEA leading to the pyrrolidin-
2-ones 3,4-trans-disubstituted 3a,b in good yield after
Scheme 1 (a) R = C6H5,
(b) R = 4-CH3OC6H4. Reagent
and conditions. (i) NaBH4, dry
CH3OH, (a) R = C6H5, 72 %,
(b) R = 4-CH3OC6H4, 87 %;
(ii) Boc2O, TEA, DCM,
(a) R = C6H5, 91 %,
H
N
Si
N
Si
O
O
i
ii
H
O
N
O
N
(b) R = 4-CH3OC6H4, 73 %;
(iii) NH4F, CH3OH,
(a) R = C6H5, 90 %,
R
R
1
2
(b) R = 4-CH3OC6H4, 90 %;
(iv) TEMPO, NaOCl, DCM,
0 °C, (a) R = C6H5, 98 %,
(b) R = 4-CH3OC6H4, 98 %;
(v) CH2N2, CH3OH, 0 °C,
(a) R = C6H5, 98 %,
O
O
O
O
N
O
Si
N
O
O
OH
(b) R = 4-CH3OC6H4, 98 %
iii
iv
N
N
R
R
4
3
O
O
O
O
O
O
N
N
OH
OCH3
v
O
N
O
N
R
R
6
5
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b-Peptoids
2007
Scheme 2 Reagents and
Ph
CF3COO
conditions. (i) TFA, DCM, 95
%; (ii) 5a, PyBroP, DIPEA,
DCM, 44 %; (iii) TFA, DCM,
96 %; (iv) TEA, DCM, 98 %
t-Boc
N
N
O
H
H
O
N
O
COOMe
Bn
i
ii
Bn
N
COOMe
6a
N
O
N
Ph
Ph
Ph
7
8
Ph
Ph
N
CF3COO
N
O
N
O
H
O
H
H
O
N
N
Bn
COOMe
Bn
N
COOMe
iii
iv
O
N
Ph
O
N
Ph
Ph
Ph
10
9
O
O
O
Ph
N
O
OCH3
N
6a
Ph
CF3COO
O
H
H
Ph
N
O
OCH3
N
7
Ph
1
Fig. 1 Structures of compounds 6a and 7, with part of the corresponding H NMR spectra recorded at 25 °C, 5 mM solution in CDCl3
rise to two different signal patterns for the quartet of the
proton of the chiral inducer and for the peak relative to
N-CH2Ph protons. On the other hand, the ammonium salt
7 shows only one signal pattern for the same kind of
protons (Fig. 1). These findings are significant because the
conformational properties of the monomer unit strongly
affect the secondary structure of the corresponding pep-
toid oligomers.
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2008
G. Martelli et al.
Ph
t-Boc
N
N
O
O
Ph
OCH3
N
O
O
N
Ph
Ph
Ph
CF3COO
N
O
H H
N
O
Ph
OCH3
N
O
O
N
Ph
Ph
Ph
N
O
O
H
N
Ph
OCH3
N
O
O
N
Ph
Ph
1
Fig. 2 Structures of dimers 8–10, with part of H NMR spectra (recorded at 25 °C, 5 mM solution in CDCl3) evidencing the conformational
changes
Thus, having in hands the monomer 6a, we directed our
investigation towards the conformational behavior of the
dimer, with the aim to ascertain whether restricted rotation
about C3–C4 bond in the nearly planar five-membered ring is
able to reduce the conformational freedom at dimer level.
In fact, the 1H-NMR spectra of dimer 8, the corre-
sponding ammonium salt 9 and the free amino derivative
10 has given useful information about this question. The
presence of two rotamers has been evidenced for molecules
8 and 9. On the other hand, when t-butoxycarbonyl group is
removed from 8, leading to the corresponding ammonium
salt 9, spectrum displays narrow signals. Eventually, in the
spectrum of the dimer 10, signals due to a single rotamer
are present, exclusively (Fig. 2). These results show the
importance of steric interactions for the cis/trans isomer-
ism at the amide bond in particular when bulky t-butoxy-
carbonyl group is missing, thus favoring the evidence of a
sole conformer.
To have more information on the in-solution preferred
conformation, 10 was further analyzed by two-dimensional
NMR techniques. gCOSY, gHSQC and gHMBC were used
1
to attribute all the H and 13C chemical shifts, that are
reported in Table 1.
The preferential conformation of 10 was then attributed
by 2D ROESY experiments performed on a 10 mM solu-
tion of 10 in CDCl3 (Fig. 3a). As reported in Fig. 3b, no
cross peaks have been detected between the side chains or
between the two heterocyclic rings. So, we can deduce that
this compound preferentially lies in a fully extended con-
formation, similar to a b-sheet conformation.
Conclusions
We reported the synthesis of novel chiral dimers for the
preparation of b-peptoids exploiting a very simple
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b-Peptoids
2009
Table 1 1H and 13C chemical shifts of all the atoms of 10
insertion of these units into peptoids or mixed peptide–
peptoid sequences could give rise to conformationally
stable structures. The ROESY 2D analysis suggests that the
preferred conformation of the dimer 10 is a fully extended
conformation, useful for the formation of b-sheet layers.
Thus, we think that this work can open a promising path to
rational b-peptoid design, which we are currently pursuing.
13
Ph
12
14
15
N
O
11
16 O
O
17
O
H
N
10
Ph
2
7
8
N
1
3
9
Ph
6
O
N
4
5
Ph
Experimental
Carbon atom number
d C (ppm)
d H (ppm)
1H and 13C NMR spectra were recorded at 25 °C on a
Varian MR 400 spectrometer at 400 MHz for 1H and
100 MHz for 13C, in CDCl3 unless otherwise reported.
Chemical shifts are given as ppm from tetramethylsilane
and coupling constants J are given in Hertz. The proton and
carbon signals were assigned by gCOSY, gHSQC, gHMBC
spectra. 2D spectra were recorded in the phase sensitive
mode and processed using a 90°-shifted, squared sine-bell
apodization. 2D ROESY experiments were recorded with a
200 ms mixing time with a proton spectral width of
4,032.3 Hz.
1
51.6
3.88 (d, J = 14.0 Hz, 1H)
4.01 (d, J = 14.0 Hz, 1H)
4.12 (d, J = 8.0 Hz, 1H)
–
2
3
4
5
6
62.4
171.9
49.5
5.43 (q, J = 7.0 Hz, 1H)
1.47 (d, J = 7.0 Hz, 3H)
2.87 (m, 1H)
16.1
42.6
3.24 (m, 1H)
7
8
9
52.3
170.9
53.3
3.37 (m, 1H)
–
4.57 (d, J = 17.0 Hz, 1H)
4.86 (d, J = 17.0 Hz, 1H)
4.40 (d, J = 9.0 Hz, 1H)
–
Optical rotations were measured on a Perkin Elmer 241
polarimeter at the sodium D line (concentration in
g/100 ml). The purity of the products was determined with
a liquid chromatography Agilent Technologies HP1100
equipped with a Zorbax Eclipse XDB-C8 Agilent and
Technologies column (flow rate 0.5 cm3/min) using a
diode-array UV detector (220 and 254 nm). Acetonitrile
and methanol for HPLC were purchased from a commer-
cial supplier. For every analysis the products (1 mg) were
dissolved in 5 ml of H2O/acetonitrile mixture 1:1 or
methanol. The MSD1100 mass detector was utilized under
the following conditions: mass range 100–2,500 amu,
positive scanning, energy of fragmentor 50 V, drying gas
flow (N2) 10.0 cm3/min, nebulizer pressure 310 kPa, dry-
ing gas temperature 350 °C, capillary voltage 4,500 V.
Elemental analyses (C, H, N) were conducted using a Carlo
10
11
12
13
14
63.5
168.1
49.4
5.52 (q, J = 7.0 Hz, 1H)
1.49 (d, J = 7.0 Hz, 3H)
3.23 (m, 1H)
16.0
45.0
3.28 (m, 1H)
15
16
17
41.0
172.8
52.4
3.47 (m, 2H)
–
3.57 (s, 3H)
methodology, which proceeds with very high yields to the
corresponding dimers. Then, by inspection of the 1H NMR
spectra, we further observed rotamers are missing for both
monomer 7 and dimer 10. This result suggests that
(a)
(b)
Ph
Me
H
H
N
O
Ph
H
H
O
NH
H
H
H
H
O
N
H
O
H
O
Ph
H
H
H
N
H
Me
Ph
Fig. 3 a ROESY 2D spectrum of 10 (10 mM solution in CDCl3, mixing time 200 ms); b NOE enhancements as gathered from the spectrum
123

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G. Martelli et al.
General procedure for the preparation
Erba 1106 elemental analyser, and their results were found
to be in good agreement ( 0.2 %) with the calculated
values. Column chromatography was performed using
Kieselgel 60 Merck.
of t-Boc-protected amines 3a,b
To a solution of amine 2a or 2b (1 mmol) in CH2Cl2 (2 ml)
TEA (1.1 mmol) and di-t-butyl-dicarbonate (1.1 mmol)
were added. After stirring for 3 h, H2O (10 ml), ethyl
acetate (20 ml) and 1 M HCl were added until neutral pH
obtained. The reaction mixture was extracted with ethyl
acetate (2 9 20 ml). The organic residue was dried over
Na2SO4 and concentrated under reduced pressure to give
pure compound 3a,b.
General procedure for the preparation of amines 2a,b
To a solution of imine 1a or 1b (1 mmol) in dry methanol
(3 ml) was added, at 0 °C, NaBH4 (2 mmol) under nitro-
gen atmosphere and the solution was stirred at r.t. for 3 h.
Then the reaction mixture was poured in H2O (10 ml) and
extracted with ethyl acetate (3 9 20 ml). The organic
phase was dried over Na2SO4 and evaporated under reduce
pressure to give a residue purified by silica gel chroma-
tography (cyclohexane:ethyl acetate 70:30) to obtain
compounds 2a,b.
Tert-butyl-benzyl ((3S,4R)-4-(((tert-
butyldimethylsilyl)oxy)methyl)-2-oxo-1-
((S)-1-phenylethyl) pyrrolidin-3-yl)carbamate (3a)
Starting from 2a, compound 3a (0.49 g, 91 % yield) was
obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): d
-0.06 (s, 6H), 0.81 (s, 9H), 1.30 (s, 9H, 30 %), 1.42 (s, 9H,
70 %), 1.49 (d, J = 7.2 Hz, 3H, 70 %), 1.60 (d,
J = 7.2 Hz, 3H, 30 %), 2.30–2.47 (m, 1H), 2.98 (dd,
J = 4.8 Hz, J = 17.0 Hz 2H, 70 %), 3.06 (dd, J = 4.8 Hz,
J = 17.0 Hz 2H, 30 %), 3.22–3.48 (m, 2H), 4.41 (d,
J = 16.0 Hz, 2H, 30 %), 4.55 (d, J = 16.0 Hz, 2H, 70 %),
5.45 (q, J = 7.2 Hz, 1H, 30 %), 5.51 (q, J = 7.2 Hz, 1H,
70 %), 7.10–7.40 (m, 10H, ArH); 13C NMR (100 MHz,
CDCl3): d -6.2, -6.4, 13.6, 15.4, 15.8, 17.4, 20.0, 25.1,
26.2, 27.8, 30.0, 40.9, 41.0, 48.0, 48.7, 51.4, 59.3, 59.4,
60.4, 61.1, 61.7, 79.3, 79.7, 126.3, 126.4, 127.0, 127.4,
127.7, 128.0, 131.1, 138.0, 138.5, 154.2, 154.7, 169.5,
170.0; [a]D = -58.5 (c = 0.5, CHCl3); ESI-MS: m/z =
538.32 [M?], 561.32 [M ? Na]?. Anal. Calcd. for
C31H46N2O4Si: C, 69.10; H, 8.61; N, 5.20; Found: C,
69.11; H, 8.64; N, 5.16.
(3S,4R)-3-(Benzylamino)-4-(((tert-
butyldimethylsilyl)oxy)methyl)-1-((S)-1-
phenylethyl)pyrrolidin-2-one (2a)
Starting from 1a, compound 2a (0.31 g, 72 % yield) was
obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): d
0.02 (s, 6H), 0.85 (s, 9H), 1.51 (d, J = 6.8 Hz, 3H), 1.82
(br, 1H), 2.20 (m, 1H), 2.98 (dd, J = 8.8 Hz, J = 9.6 Hz),
3.07 (dd, J = 8.0 Hz, J = 9.6 Hz, 1H), 3.42 (d,
J = 8.4 Hz, 1H), 3.64 (m, 2H), 3.94 (s, 2H), 5.49 (q,
J = 6.8 Hz, 1H), 7.22–7.37 (m, 10H, ArH); 13C NMR
(100 MHz, CDCl3): d 5.8, 16.4, 18.3, 26.0, 27.1, 42.0,
42.3, 49.0, 52.1, 61.0, 62.8, 127.0, 128.0, 128.1, 128.2,
132.1, 140.3, 173.8; [a]D = -105.0 (c = 0.1, CHCl3).
ESI-MS: m/z = 438.27 [M?], 461.27 [M ? Na]?. Anal.
Calcd. for C26H38N2O2Si: C, 71.19; H, 8.73; N, 6.39;.
Found: C, 71.23; H, 8.75; N, 6.41.
Tert-butyl-benzyl((3S,4R)-4-(((tert-
butyldimethylsilyl)oxy)methyl)-1-((S)-1-(4-methoxyphenyl)
ethyl)-2-oxopyrrolidin-3-yl)carbamate (3b)
(3S,4R)-3-(Benzylamino)-4-(((tert-
butyldimethylsilyl)oxy)methyl)-1-((S)-1-(4methoxyphenyl)
ethyl)pyrrolidin-2-one (2b)
Starting from 2b, compound 3b (0.41 g, 73 % yield) was
obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): d
-0.02 (s, 6H), 0.82 (s, 9H), 1.35 (s, 9H, 35 %), 1.41 (s, 9H,
65 %), 1.43 (m, 3H), 2.40 (m, 1H), 2.93–3.10 (m, 2H),
3.24–3.48 (m, 2H), 3.81 (s, 3H), 4.23 (m, 1H), 4.36–4.68
(m, 2H), 5.38–5.50 (m, 1H), 6.85–6.89 (m, 2H, ArH),
7.22–7.34 (m, 7H, ArH); 13C NMR (100 MHz, CDCl3): d
-6.3, -6.2, 13.5, 15.6, 15.9, 17.5, 20.2, 25.2, 26.2, 27.6,
30.3, 40.8, 41.1, 47.9, 49.0, 51.3, 54.3, 59.4, 59.8, 60.5,
61.2, 61.9, 79.4, 79.7, 113.0, 113.2, 126.5, 126.6, 127.1,
127.6, 127.7, 128.1, 131.2, 138.2, 138.6, 154.4, 154.9,
158.2, 158.5, 169.7, 170.1; [a]D = -79.0 (c = 0.6,
CHCl3); ESI-MS: m/z = 568.33 [M?], 581.33 [M ? Na]?.
Starting from 1b, compound 2b (0.41 g, 87 % yield) was
obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): d
0.03 (s, 6H), 0.87 (s, 9H), 1.50 (d, J = 6.8 Hz, 3H), 2.08
(br, 1H), 2.19 (m, 1H), 3.01 (dd, J = 13.6 Hz,
J = 8.4 Hz), 3.06 (dd, J = 7.6 Hz, J = 9.6 Hz, 1H), 3.42
(d, J = 8.0 Hz, 1H), 3.65 (m, 2H), 3.79 (s, 3H, OCH3),
3.95 (s, 2H), 5.45 (q, J = 6.8 Hz, 1H), 6.87 (d, J = 7.6 Hz,
ArH), 7.22–7.38 (m, 7H, ArH); 13C NMR (100 MHz,
CDCl3): d 5.6, 16.1, 18.1, 25.7, 26.8, 41.8, 42.2, 48.5, 51.8,
55.1, 60.5, 62.7, 113.7, 126.9, 128.1, 128.2, 128.3, 131.9,
140.1, 158.8, 173.6; [a]D = -123.0 (c 0.13, CHCl3). ESI-
MS: m/z = 468.28 [M?], 491.28 [M ? Na]?. Anal. Calcd.
for C27H40N2O3Si: C, 69.19; H, 8.60; N, 5.98. Found: C,
69.23; H, 8.62; N, 5.89.
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b-Peptoids
2011
Anal. Calcd. for C32H48N2O5Si: C, 67.57; H, 8.51; N, 4.92.
Found: C, 67.61; H, 8.54; N, 4.96.
vigorous stirring. After 10 min, 0.35 M NaOCl (7 ml) was
added and the mixture was stirred for 10 min. Then temper-
ature was raised to r.t. and ethyl acetate (20 ml) and 1 M HCl
(10 ml) were added. The reaction mixture was extracted with
ethyl acetate (2 9 20 ml) and the organic phase was dried
over Na2SO4 andconcentrated under reduced pressuretogive
acids 5a,b.
General procedure for the preparation of alcohols 4a,b
To a solution of 3a or 3b (1 mmol) in methanol (3 ml) was
added NH4F (5 mmol). The reaction mixture was refluxed
for 6 h, then was added H2O (10 ml) and extracted with
ethyl acetate (3 9 20 ml). The organic residue was dried
over Na2SO4 and evaporated to give alcohols 4a,b.
(3R,4S)-4-(Benzyl(tert-butoxycarbonyl)amino)-5-oxo-1-
((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid (5a)
tert-Butyl-benzyl ((3S,4R)-4-(hydroxymethyl)-2-oxo-1-((S)-
1-phenylethyl)pyrrolidin-3-yl)car-bamate (4a)
Starting from 4a, compound 5a (0.43 g, 98 % yield) was
1
obtained as a colorless oil. H NMR (400 MHz, CDCl3): d
1.30 (s, 9H, 30 %), 1.42 (s, 9H, 70 %), 1.42–1.54 (m, 3H),
3.04–3.39 (m, 3H), 4.32 (d, J = 16.0 Hz, 1H, 30 %), 4.38 (d,
J = 16.0 Hz, 1H, 70 %), 4.56 (d, J = 8.4 Hz, 1H), 4.70 (d,
J = 16.0 Hz, 1H, 70 %), 4.86 (d, J = 16.0 Hz, 1H, 30 %),
5.42 (q, J = 7.2 Hz, 1H, 30 %), 5.51 (q, J = 7.2 Hz, 1H, 70
%), 7.12–7.40 (m, 10H, ArH), 9.41 (br, 1H); 13C NMR
(100 MHz, CDCl3): d 13.9, 14.9, 15.7, 16.2, 20.6, 20.8, 25.9,
27.7, 27.9, 28.0, 29.5, 41.4, 41.5, 41.6, 49.4, 50.7, 52.2, 60.3,
61.5, 62.3, 65.6, 80.9, 81.2, 127.0, 127.2, 127.4, 127.5, 127.7,
127.9, 128.1, 128.2, 128.3, 128.5, 138.7, 138.8, 154.9, 168.9,
169.5, 171.2, 175.1, 175.8; [a]D = -61.0 (c = 0.1, CHCl3);
ESI-MS: m/z = 438.52 [M?], 461.52 [M ? Na]?. Anal.
Calcd. for C25H30N2O5: C, 68.47; H, 6.90; N, 6.39. Found: C,
68.49; H, 6.92; N, 6.35.
Starting from 3a, compound 4a (0.38 g, 90 % yield) was
obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): d
1.41 (s, 9H), 1.49 (d, J = 7.2 Hz, 3H), 1.94 (m, 1H), 2.30
(br, 1H), 2.78 (dd, J = 8.8 Hz, J = 18.0 Hz, 1H), 2.97 (dd,
J = 8.8 Hz, J = 18.0 Hz, 1H), 3.30 (dd, J = 4.8 Hz,
J = 12.0 Hz, 1H), 3.52 (dd, J = 4.8 Hz, J = 18.0 Hz,
1H), 4.27 (d, J = 16.4 Hz, 1H), 4.78 (m, 1H), 5.51 (q,
J = 7.2 Hz, 1H), 7.17–7.38 (m, 10H, ArH); 13C NMR
(100 MHz, CDCl3): d 16.1, 28.2, 29.7, 40.5, 40.9, 48.9,
49.5, 60.1, 61.1, 81.4, 127.0, 127.2, 127.3, 128.4, 128.6,
139.2, 139.7, 165.9, 165.9; [a]D = -49.3 (c 0.5, CHCl3);
ESI-MS: m/z = 424.24 [M?], 467.24 [M ? Na]?. Anal.
Calcd. for C25H32N2O4: C, 70.73; H, 7.60; N, 6.60. Found:
C, 70.75; H, 7.66; N, 6.56.
(3R,4S)-4-(Benzyl(tert-butoxycarbonyl)amino)-1-((S)-1-(4-
methoxyphenyl)ethyl)-5-oxopyrroli-dine-3-carboxylic acid
(5b)
tert-Butyl-benzyl((3S,4R)-4-(hydroxymethyl)-1-((S)-1-(4-
methoxyphenyl)ethyl)-2-oxopyrrolidin-3-yl)carbamate (4b)
Starting from 3b, compound 4b (0.41 g, 90 % yield) was
1
obtained as a colorless oil. H NMR (400 MHz, CDCl3): d
Starting from 4b, compound 5b (0.46 g, 98 % yield) was
1
obtained as a colorless oil. H NMR (400 MHz, CDCl3): d
1.41 (s, 9H), 1.47 (d, J = 7.2 Hz, 3H), 1.95 (m, 1H), 2.78 (m,
1H), 2.94 (m, 1H), 3.26 (br, 1H), 3.41–3.60 (m, 2H), 4.28 (d,
J = 16.0 Hz, 1H), 4.77–4.86 (m, 2H), 5.47 (q, J = 7.2 Hz,
1H), 6.87 (d, J = 8.8 Hz, 2H, ArH), 7.18–7.37 (m, 7H, ArH);
13C NMR (100 MHz, CDCl3): d 15.9, 27.9, 39.8, 40.8, 48.6,
49.3, 55.0, 60.2, 60.9, 80.8, 113.6, 126.9, 127.0, 127.7, 127.9,
128.1, 131.4, 138.9, 156.2, 158.7, 169.8; [a]D = -64.0
(c = 0.2, CHCl3); ESI-MS: m/z = 454.25 [M?], 477.25
[M ? Na]?. Anal. Calcd. for C26H34N2O5: C, 68.70; H, 7.54;
N, 6.16. Found C, 68.73; H, 7.57; N, 6.14.
1.25–1.50 (m, 12H), 2.92 (m, 1H, 20 %), 3.05 (m,1H, 80 %),
3.10–3.25 (m, 2H, 80 %), 3.30–3.39 (m, 2H, 20 %), 3.86 (s,
3H, 20 %), 3.87 (s, 3H, 80 %), 4.26–4.55 (m, 3H), 4.72 (d,
J = 15.6 Hz, 1H, 80 %), 4.86 (d, J = 15.6 Hz, 1H, 20 %),
5.28–5.43 (m, 1H), 6.86 (d, J = 8.4 Hz, 2H, ArH), 7.18–7.42
(m, 7H, ArH); 13C NMR (100 MHz, CDCl3): d 15.8, 16.3,
17.9, 18.3, 28.1, 29.5, 41.5, 41.8, 48.5, 51.9, 56.0, 56.1, 60.4,
61.6, 62.3, 80.9, 81.2, 117.7, 122.4, 126.3, 126.8, 127.0,
127.2, 127.4, 127.6, 127.8, 128.2, 132.3, 132.6, 137.9, 138.0,
154.2, 154.6, 154.9, 155.2, 169.1, 169.5, 171.2, 171.3;
[a]D = -79.5 (c 0.2, CHCl3); ESI-MS: m/z = 468.23 [M?],
491.23 [M ? Na]?. Anal. Calcd. for C26H32N2O6: C, 66.65;
H, 6.88; N, 5.98. Found: C, 65.70; H, 6.92; N, 5.92.
General procedure for the preparation of carboxylic
acids 5a,b
To a solution containing compound 4a or 4b (1 mmol) in
CH2Cl2 (2 ml) at 0 °C, TEMPO (0.01 mmol), 0.5 M NaBr
(0.2 ml) and 0.35 M NaOCl (7 ml) were added at pH = 8.6
(the pH of the sodium hypochlorite was adjusted at 8.6 just
before use by dissolving 350 mg of solid NaHCO3) under
General procedure for preparation of the methyl esters
6a,b
A solution of acid 5a or 5b (1 mmol) in methanol (3 ml)
was treated at 0 °C with an ethereal solution of CH2N2
123

2012
G. Martelli et al.
1
until nitrogen evolution ceased and the solvent was evap-
orated under reduced pressure to give a residue which was
purified by silica gel chromatography (cycloexane/ethyl
acetate 70:30) affording the esters 6a,b.
white solid. M.p. 42–44 °C. H NMR (400 MHz, CDCl3):
d 1.50 (d, J = 7.2 Hz, 3H), 3.12 (br, 2H), 3.23 (d,
J = 8.8 Hz, 2H), 3.58 (m, 1H), 3.66 (s, 3H), 4.18 (d,
J = 9.2 Hz, 1H), 4.43 (s, 2H), 5.41 (q, J = 7.2 Hz, 1H),
7.25–7.46 (m, 10H, ArH); 13C NMR (100 MHz, CDCl3): d
16.1, 41.6, 49.8, 51.3, 55.2, 60.9, 62.3, 117.3 (q,
J = 282.0 Hz), 127.1, 127.3, 128.2, 128.6, 139.2, 140.1,
160.9 (q, J = 41.3 Hz), 172.3; [a]D = -92.5 (c = 0.1,
CHCl3); ESI-MS: m/z = 466.17 [M?], 489.17 [M ? Na]?.
Anal. Calcd. for C23H25F3N2O5: C, 59.22; H, 5.40; N, 6.01.
Found: C, 59.26; H, 5.45; F, 1.24; N, 5.97.
Methyl (3R,4S)-4-(benzyl(tert-butoxycarbonyl)amino)-5-
oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylate (6a)
Starting from 5a, compound 6a (0.44 g, 98 % yield) was
obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): d
1.30 (s, 9H, 40 %),1.42 (s, 9H, 60 %), 1.45–1.51 (m, 3H),
3.10–3.22 (m, 3H, 40 %), 3.23–3.34 (m, 3H, 60 %), 3.55 (s,
3H), 4.38–4.80 (m, 3H), 5.41 (q, J = 6.8 Hz, 1H, 40 %),
5.50 (q, J = 6.8 Hz, 1H, 60 %), 7.18–7.40 (m, 10H, ArH);
13C NMR (100 MHz, CDCl3): d 15.8, 16.2, 28.0, 28.1,
41.4, 41.8, 49.2, 50.5, 52.2, 52.3, 61.7, 61.9, 62.5, 66.4,
71.4, 80.6, 81.1, 127.0, 127.1, 127.4, 127.5, 127.8, 127.9,
128.1, 128.2, 128.3, 128.4, 137.8, 138.4, 139.0, 139.2,
154.7, 168.4, 168.9, 172.9;[a]D = -108.1 (c = 0.1,
CHCl3); ESI-MS: m/z = 452.23 [M?], 575.23 [M ? Na]?.
Anal. Calcd. for C26H32N2O5: C, 69.01; H, 7.13; N, 6.19.
Found: C, 69.04; H, 7.17; N, 6.17.
General procedure for the synthesis of dimers
8, 9 and 10
To a solution of the acid 5a (1 mmol) and ammonium salt 7
(1.1 mmol) in CH2Cl2 (1 ml), PyBroP (1 mmol) and DI-
PEA (1 mmol) were added at 0 °C under nitrogen atmo-
sphere. After 1 min at 0 °C, the mixture was stirred for
12 h at r.t., then ethyl acetate (20 ml) and 1 M HCl (10 ml)
were added. The reaction mixture was extracted with ethyl
acetate (2 9 20 ml) and the organic phase was washed
with Brine, dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (cycloexane/ethyl acetate 60:40) to give
dimer 8 (0.34 g, 44 %) as a colorless oil. The compound 8
(1 mmol) was then dissolved in CH2Cl2 (2 ml) and treated
with TFA (2.40 mL, 0.5 mL/100 mg). The solution was
stirred for 1 h at r.t. After removal of organics under
reduced pressure, the residue was washed with ethyl ether
to give compound 9 (0.55 g, 96 %) as a white solid. This
ammonium salt was treated with TEA (1 mmol) in CH2Cl2
(2 ml) for 30 min at r.t., then concentrated under reduced
pressure and purified by silica gel chromatography
(cycloexane:ethyl acetate 70:30) to give compound 10
(0.66 g, 98 %) as colorless oil.
Methyl (3R,4S)-4-(benzyl(tert-butoxycarbonyl)amino)-1-
((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyr-rolidine-3-
carboxylate (6b)
Starting from 5b, compound 6b (0.47 g, 98 % yield) was
obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): d
1.28–1.51 (m, 12H), 3.10–3.32 (m, 3H), 3.55 (s, 3H), 3.80
(s, 3H, OCH3, 70 %), 3.89 (s, 3H, OCH3, 30 %), 4.30 (d,
J = 8.8 Hz, 1H, 30 %), 4.42 (d, J = 8.8 Hz, 1H, 70 %),
4.45–4.80 (m, 2H), 5.37 (q, J = 7.2 Hz, 1H, 30 %), 5.46
(q, J = 7.2 Hz, 1H, 70 %), 6.86 (d, J = 7.2 Hz, 2 H, ArH),
7.20–7.40 (m, 7H, ArH); 13C NMR (100 MHz, CDCl3): d
16.0, 16.5, 28.2, 28.3, 41.3, 41.4, 41.5, 41.6, 48.9, 50.1,
52.3, 52.4, 55.2, 56.1, 62.1, 62.8, 65.4, 66.6, 67.8, 71.4,
80.7, 81.2, 113.7, 113.9, 127.1, 127.2, 127.4, 127.5, 127.9,
128.3, 128.8, 131.3, 132.2, 137.9, 138.3, 154.8, 155.0,
158.9, 159.2, 168.4, 168.9, 172.7, 173.1; [a]D = -125.0 (c
0.1, CHCl3); ESI-MS: m/z = 482.24 [M?], 505.24
[M ? Na]?. Anal. Calcd. for C27H34N2O6: C, 67.20; H,
7.10; N, 5.81. Found C, 67.24; H, 7.13; N, 5.77.
Methyl (3R,4S)-4-((3R,4S)-N-benzyl-4-(benzyl(tert-
butoxycarbonyl)amino)-5-oxo-1-((S)-1-phe-
nylethyl)pyrrolidine-3-carboxamido)-5-oxo-1-((S)-1-
phenylethyl)pyrrolidine-3-carboxylate (8)
1H NMR (400 MHz, CDCl3): d 1.34 (s, 9H, 60 %), 1.41 (d,
J = 6.8 Hz, 3 H 40 %), 1.42 (s, 9H, 40 %), 1.46 (d,
J = 6.8 Hz, 3H, 60 %), 1.51 (d, J = 6.8 Hz, 3H, 60 %),
1.53 (d, J = 6.8 Hz, 3H, 40 %), 3.06 (dd, J = 9.6 Hz,
J = 9.2 Hz, 1H), 3.16 (dd, J = 9.6 Hz, J = 9.2 Hz, 1H),
3.27 (m, 2H), 3.50 (m, 1H), 3.62 (s, 3H, 60 %), 3.64 (s, 3H,
40 %), 3.86 (m, 1H), 4.25–4.67 (m, 5H), 5.02 (d,
J = 16 Hz, 1H, 60 %), 5.22 (d, J = 16 Hz, 1H, 40 %),
5.32 (q, J = 6.8 Hz, 1H, 40 %), 5.48 (q, J = 6.8 Hz, 1H,
60 %), 5.56 (m, 1H), 7.20–7.40 (m, 20H, ArH); 13C NMR
(100 MHz, CDCl3): d 15.8, 15.9, 16.6, 22.7, 26.9, 27.9,
(3S,4R)-N-benzyl-4-(methoxycarbonyl)-2-oxo-1-((S)-1-
phenylethyl)pyrrolidin-3-aminium
2,2,2-trifluoroacetate (7)
To a solution of compound 6a (1 mmol) in DCM (2 mL),
TFA (2.40 mL, 0.5 mL/100 mg) was slowly added and the
clear solution was stirred for 1 h at r.t. After removal of
organics under reduced pressure, the residue was washed
with ethyl ether to give compound 7 (0.44 g, 95 %) as a
123

b-Peptoids
2013
28.1, 28.3, 29.3, 29.6, 29.7, 30.3, 31.9, 39.6, 40.1, 41.0,
41.1, 41.4, 41.5, 42.2, 49.1, 49.2, 49.3, 50.7, 52.5, 52.8,
52.9, 53.1, 62.3, 62.6, 63.4, 63.5, 80.3, 80.7, 125.5, 126.2,
126.9, 127.0, 127.1, 127.2, 127.4, 127.6, 127.7, 127.8,
127.9, 128.0, 128.2, 128.3, 128.4, 128.5, 128.6, 128.7,
128.8, 129.0, 135.6, 135.7, 137.9, 138.3, 139.1, 139.3,
139.5, 139.6, 154.4, 154.6, 167.9, 168.0, 168.9, 169.3,
172.8, 172.9, 173.0, 173.2; [a]D = -110.1 (c 0.2, CHCl3);
ESI-MS: m/z = 772.93 [M?], 795.93 [M ? Na]?. Anal.
Calcd. for C46H52N4O7: C, 71.48; H, 6.78; N, 7.25. Found
C, 71.45; H, 6.75; N, 7.27.
129.0, 136.4, 140.2, 140.8, 140.9, 168.1, 170.9, 171.9,
172.8; [a]D = -98.3 (c 0.1, CHCl3); ESI-MS: m/z =
672.33 [M?], 695.33 [M ? Na]?. Anal. Calcd. for
C41H44N4O5: C, 73.19; H, 6.59; N, 8.33. Found C, 73.16;
H, 6.54; N, 8.34.
Acknowledgments We thank Polytechnic University of Marche for
financial support.
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