Novel peptide mimetics based on N-Protected amino acids derived from isomannide as potential inhibitors of NS3 serine protease of hepatitis C virus

Article abstract of DOI:10.2174/157017812800233787

Abstract: Hepatitis C virus (HCV) is among the most important flaviviruses. It has a serine protease which is important for viral replication and this enzyme constitutes a suitable target for new anti-retroviral drugs. Herein we disclose a series of amide and ester peptide mimetic inhibitors of serine proteases, all of them obtained via coupling reactions of isomannide derivatives with N-protected amino acids. The arginine derivative 19 showed 45% of inhibition of NS3/4A serine protease at 100 μM and molecular modeling studies had shown that 19 interacted with the active site of this enzyme.

Full text of DOI:10.2174/157017812800233787

Letters in Organic Chemistry, 2012, 9, 239-249
239
Novel Peptide Mimetics Based on N-protected Amino Acids Derived from
Isomannide as Potential Inhibitors of NS3 Serine Protease of Hepatitis C
Virus
Thalita G. Barrosa,b, Bruna C. Zorzanellia,b, Sergio Pinheirob, Monique A. de Britoa,
Amílcar Tanuric, Emmerson C.B. da Costad, Ronaldo S. Mohana-Borgesd, Carlos R. Rodriguese,
Alessandra T.M. Souzab,e, Vitor F. Ferreirab and Estela M.F. Muri*,a
aFaculdade de Farmácia, Universidade Federal Fluminense, Rua Mario Viana 523, Santa Rosa, 24241-000 Niterói, RJ,
Brazil; bInstituto de Química, Universidade Federal Fluminense, Niterói, RJ, Brazil; cLaboratório de Virologia
Molecular, Instituto de Biologia, Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro,
RJ, Brazil; dLaboratório de Genômica Estrutural, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do
e
Rio de Janeiro, Rio de Janeiro, RJ, Brazil; ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de
Janeiro, Rio de Janeiro, RJ, Brazil
Received October 14, 2011: Revised February 01 2012: Accepted February 01, 2012
Abstract: Hepatitis C virus (HCV) is among the most important flaviviruses. It has a serine protease which is important
for viral replication and this enzyme constitutes a suitable target for new anti-retroviral drugs. Herein we disclose a series
of amide and ester peptide mimetic inhibitors of serine proteases, all of them obtained via coupling reactions of
isomannide derivatives with N-protected amino acids. The arginine derivative 19 showed 45% of inhibition of NS3/4A
serine protease at 100 µM and molecular modeling studies had shown that 19 interacted with the active site of this
enzyme.
Keywords: HCV, isomannide, peptide mimetic, serine protease.
INTRODUCTION
enzymatic degradation and, moreover, the gastrointestinal
tract provides an additional barrier. If a peptide drug
manages to pass these barriers, enzymatic digestion in the
blood stream will occur, resulting in a very low half-life
[12]. Studies on the development of peptide mimetic
inhibitors have demonstrated the importance of the peptide
approach in drug research in order to overcome the low
bioavailability of peptide drugs [13-15]. Indeed, in the last
decade the development of peptide mimetic-based inhibitors
of NS3 pro with activity against both HCV and Dengue virus
have enjoyed a surge in popularity [16-26].
The most important flavivirues known are the Hepatitis C
virus (HCV), the West Nile virus (WNV) and the Dengue
virus (DENV). More than 170 million people worldwide are
affected by HCV and this infection is associated with liver
cirrhosis and hepatocellular carcinoma [1, 2]. The current
therapeutic for HCV based on alpha interferon and the
nucleoside analog ribavirin is effective in only 50% of the
patients and is limited by the adverse effects of both agents
[3].
This flavivirus presents a non structural NS3 serine
Compounds possessing a fused-bicycle structure, such as
Darunavir (TCM-114) [27] and VX-950 [28], represent an
effort toward the design and development of new drugs. On
the other hand, as the diversity of carbohydrate-based
templates has been and can be further exploited in the
preparation of carbohydrate-based peptide mimetics [29-31],
we envisaged the isomannide (1) rigid scaffold as an
important moiety in the structure of compounds that can be
used as protease inhibitors.
protease (NS3 pro) which has in its active site
a
characteristic catalytic triad His, Asp and Ser [4-6]. The NS3
pro activity is essential for viral replication and maturation of
infectious virions, representing an attractive target for the
development of chemotherapeutic approaches for the
treatment of flaviviruses [7, 8]. In fact, new inhibitors of
HCV NS3 protease are in clinical trials [9]. Among them, the
clinical candidate BILN-2061 was shown to be effective in
reducing HCV viral load but was abandoned due to
cardiotoxicity in animal studies [10].
Isomannide itself is a kind of U-shaped structure so
forcing a kind of β-sheet structure in a given compound.
Inversion of configuration on the hydroxy group leads to a
kind of W-shaped conformation forcing a quasi linear
structure. These easy structural manipulations are of great
importance in designing new compounds, in particular
peptide mimetic compounds [27].
Peptides interact with NS3 pro and have received high
interest due to their activity and specificity. However, there
are some limitations associated with peptide drugs, the
greatest one being the low bioavailability upon oral
administration [11]. The drugs can undergo a pre-systemic
We have employed 1 as the core unity of the peptide
mimetic compounds, rationalizing its use as a structural
analog of cyclic rigid dipeptides and a C2 symmetry
providing a rigid scaffold [32-34]. In this context we have
*Address correspondence to this author at the Departamento de Tecnologia
Farmacêutica/MTC Faculdade de Farmácia Universidade Federal Flumi-
nense–UFF Rua Mário Viana 523, Santa Rosa/Niterói/RJ; Cep: 24241-000;
Tel:(21) 2629 9578/2629 9588; E-mail: estelamuri@yahoo.com.br
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

240 Letters in Organic Chemistry, 2012, Vol. 9, No. 4
Barros et al.
H
H
O
H
O
HO
O
HO
BnO
O
H
O
H
i
ii
O
OH
OTs
OTs
H
3
2
1
iii
ii
H
H
O
H
BnO
O
BnO
BnO
O
H
O
H
iv
O
OH
O
NH2
N3
H
6
5
4
Scheme 1. i) TsCl, pyridine, CH2Cl2, r. t., overnight, 40%. ii) BnCl, TBAB, 50% NaOH, CH2Cl2, r. t., overnight, 75% (for 2) or 45% (for 6).
iii) NaN3, [bmim]+[BF4]-, r. t., overnight, 73%. iv) H2 (2.75 bar), 5% Pd-C, EtOH, 5 h, 100%.
Table 1. Structures and Yields of Amides (7-19) and Esters (20-28)
H
H
O
BnO
BnO
O
O
H
O
DCC, DMAP, CH2Cl2, r. t.
X
X
Y
O
Y-COOH (29-42)
H
5: X =
6: X =
7-19: X =
NH2
OH
NH
O
20-28: X =
Y-COOH (29-42)
#
7
Yield (%)
#
Yield (%)
Y
N-Boc- L-Pro (29)
31
20
50
N
Boc
Pri
N-Boc-L-Val (30)
8
40
21
60
NHBoc
BnO
N-Boc-O-Benzyl-L-Ser (31)
N-Boc-L-Met (32)
9
46
63
67
22
23
24
53
75
75
NHBoc
MeS
10
11
NHBoc
Trp
N-Boc-L-Trp (33)
NHBoc
Bn
N
N-Cbz-Pro-Phe (34)
N-Cbz-D-Pro (35)
12
13
97
63
25
26
46
63
H
N
O
Cbz
N
Cbz

Novel Peptide Mimetics Based on N-protected Amino Acids
Letters in Organic Chemistry, 2012, Vol. 9, No. 4
241
(Table 1). Contd…..
Yield (%)
Y-COOH (29-42)
#
Yield (%)
#
Y
CbzHN
N- -Boc-N -Cbz-L-Lys (36)
14
64
27
52
NHBoc
N
N-Boc imTosyl-L-His (37)
15
16
63
80
N
NHBoc
Ts
Bn
O
CbzHN
Pri
N-Cbz-Val-Phe (38)
N
H
OH
N-Boc-L-IsoSer (39)
N-Boc-L-Thr (40)
17
18
50
56
BocHN
OH
NHBoc
H
N
CbzHN
N-α-Boc-N-ω-di-Cbz-L-Arg (41)
N-Boc-L-Asp-benzyl ester (42)
19
88
2
NCbz
NHBoc
BnO2C
28
NHBoc
found that some synthetic peptide mimetics derived from 1
presented activity against HCV [32, 33] and appears to
interact with the desired target as shown by computational
studies [34, 35]. Indeed, the docking of diester-based peptide
mimetics derived from 1 into the active site of NS3 showed
that one oxygen atom of the bicycle group at P1’ position
interacts with a Gly residue via hydrogen bond. In spite of
their cytotoxicities, in diamide-based peptide mimetic series
derived from 1 the amino acids residues at position P1
interacts via hydrogen bond with Ser135 in the catalytic site
of NS3 [34, 35]. In order to direct our research program
toward new peptide mimetic antiviral compounds, we
present a series of N-protected amino acids derived from 1.
The biological data on the inhibition of NS3 as well as the
modeling studies on the interaction of the best active
compound 19 with this enzyme are also shown.
with sodium azide performed in [bmim]+[BF4]- yielded the
azido derivative 4 with inversion of configuration [38].
Reduction of 4 with H2/Pd-C gave the amino derivative 5,
the starting material for the production of the amide
derivatives [39]. Monobenzylate isomannide 6, the starting
material for formation of the ester derivatives, was obtained
from 1 [37].
Among the peptide-coupling reagents, DCC has attracted
attention because it shows at least reasonable performance,
besides being relatively cheap and the reactional by products
are generally insoluble in most organic solvents [40, 41]. So
we decided to use DCC reagent for coupling reactions of
amine derivative 5 and monobenzylate isomannide 6 with
different commercially available N-protected amino acids
29-42 (Table 1). Using a standard protocol it was made
possible to reach the corresponding amides 7-19 and esters
20-28 in moderate to good yields.
RESULTS AND DISCUSSION
Chemistry
Biology
Inhibitory effect of peptide mimetics (in vitro)
The first step of our synthesis is the transformation of the
readily available isomannide (1) into its monotosyl
derivative 2 using tosyl chloride in pyridine (Scheme 1).
Compound 2 was alkylated with benzyl chloride in 50%
aqueous NaOH under phase-transfer conditions affording the
O-benzylated product 3 [35-37]. The SN2-type reaction of 3
In our preliminary studies we identified a lead peptide
mimetic compound as inhibitor of HCV-1b replicon in Huh-
7 cell culture [32]. The scaffold of this lead compound was
used to design the new peptide mimetics 7-19 and 20-28,

242 Letters in Organic Chemistry, 2012, Vol. 9, No. 4
Barros et al.
which were diluted in DMSO. The standard inhibitor Ac-
DE-Dif-E-Cha-C (AnaSpec, CA, USA) was diluted in water.
Experimental section. Inhibitory studies of the NS3/4A
protease were performed using different concentrations of
compound 19 (Fig. 2A). The results showed that the
compound 19 is unable to inhibit 100% of the proteolytic
activity at that high concentration gave a maximum
inhibition of 50% of initial activity. Interestingly, compound
19 at a low concentration yielded 2.5 fold increase in the
proteolytic activity of NS3/4A protease enzyme. This
activation effect at low concentration was already observed
with certain protease inhibitors recently described in the
literature [42]. To confirm whether the NS3/4A protease
enzyme (commercially available) could be fully inhibited,
the dose-response of enzyme was evaluated using the Ac-
DE-Dif-Cha-E-C inhibitor (AnaSpec, CA, USA). Various
concentrations of the inhibitor were tested in four replicates
each, and the inhibitory effect was observed in the range of
concentrations tested (IC50 = 0.8 ± 0.3 µM; Fig. 2B).
The inhibitory effect of peptide mimetic compounds 7-19
and 20-28 on substrate cleavage by NS3/4A protease was
investigated. In Fig. (1), the percentage of substrate cleavage
in the presence of 7-19 and 20-28 as well as of the standard
inhibitor was determined as residual activity using the
control sample in the absence of inhibitor compounds as
reference. The arginine derivative 19 was shown to inhibit
45% of the NS3/4A protease activity at 100 µM, whereas
other compounds such as 16, 17 and 18 showed only ~15-
40% inhibition at the same concentration.
Molecular Modeling
In order to investigate the binding mode of the most
active peptide mimetic compound 19, we docked it into
NS3/4A serine protease using Autodock 4.0 program
running on a Windows based PC [43]. The 3D structure of
the ligand was built and optimized with the semi-
empirical AM1 Hamiltonian with the molecular modeling
program Spartan’06 (Wavefunction, Inc.). NS3/4A serine
protease crystal structure was obtained from Protein Data
Bank (PDB ID: 2OC0) [44].
Briefly the compound 19 was embedded in the NS3/4A
protease active site represented by the cubic grid box of
60x60x60ų with a spacing of 0.375Å. Docking studies were
carried out using the empirical free energy function and the
Lamarckian genetic algorithm applying a standard protocol,
with an initial population of 150 randomly placed individuals
and a maximum number of 2.5 × 106 energy evaluations. A
total of 50 independent docking runs were carried out for the
most active compound 19. To evaluate the accuracy of
AutoDock 4.0 as an appropriate docking tool for the present
Fig. (1). Inhibitory effect of NS3/4A protease. Bar 1 (B1): no
inhibitor control. Bars 2 to 23: compounds 7 to 28. Bar 24 (B24):
Ac-DE-Dif-Cha-E-C inhibitor. Bar 25 (B25): without inhibitor and
NS3/4A protease.
To measure the dose-response activity of 19, the
proteolytic activity assay was carried out at different
inhibitor concentrations using the protocol described in the
Fig. (2). Inhibition of the proteolytic activity by the compound 19 (a) Inhibitory activity of 19 against the NS3/4A protease. Inset, it is
showing the residual activity of NS3/4A protease at low concentration (0.78, 15.6 and 31.2µM) of 19, and (b) inhibitory activity of Ac-DE-
Dif-E-Cha-C against the NS3/4A protease. Each point represents the mean of four replicates independent in different concentrations of
inhibitors (0.08, 0.16, 0.31, 0.63, 1.25, 2.5, 5.0, and 10.0µM).

Novel Peptide Mimetics Based on N-protected Amino Acids
Letters in Organic Chemistry, 2012, Vol. 9, No. 4
243
Fig. (3). (a) Schematic figure of the important interactions between compound 19 and NS3/4A protease, including hydrogen bonds and
hydrophobic interactions with specific residues. (b) Compound 19 (in green) bound to NS3/4A protease (NS3 is colored in pink and NS4A
cofactor is colored in yellow).
work, we performed a re-docking of the native co-
crystallized ligand (SCh491762) into NS3/4A protease
binding site.
EXPERIMENTAL
General Procedures
All solvents were purchased as reagent grade, dried using
standard conditions and stored over molecular sieves.
Purification of products was carried out using silica gel flash
chromatography (Whatman 60, 230-400 mesh). NMR
analyses were carried out on a Varian Unity Plus-300
spectrometer. Melting points were obtained on a Thomas
Hoover capillary melting point apparatus and are
uncorrected. High-resolution mass spectra (HRMS) were
performed on a Waters Micromass Q-Tof Micromass
spectrometer equipped with a lock spray source. The IR
spectra were obtained on a Perkin-Elmer spectrometer model
Spectrum One in liquid film or KBr pellets. Optical rotation
measurements were determined on a Perkin-Elmer 341 LC
polarimeter.
In order to analyze the binding mode of compound 19,
our most active peptide mimetic inhibitor, docking studies
were performed (Fig. 3). Docking of 19 revealed that this
compound is placed in S1 pocket, a hydrophobic surface
consisting of Ile132, Leu135, Lys136, Gly137, Ser138,
Ser139, Phe154 and Ala157 residues [44]. In fact, the
docking complex of 19-NS3/4A protease showed that the
arginine moiety interacts with Ile132, Leu135, Lys136,
Gly137, Ser139 and Phe154 residues from the hydrophobic
S1 pocket of NS3/4A and also with Gln41, His57, Ala156
residues. Additionally, six hydrogen bonds were observed in
the complex with Gln41, His57, Arg155 and Ala157 with
distances between 2.65Å and 3.17Å. These six hydrogen
bonds are obtained from these amino acid residues with the
arginine portion of the molecule as well as the isomannide
ring. This moiety shows also a hydrogen bond with Gln41.
These interactions may contribute to the stabilization and
maintenance of 19 into NS3/4A protease active site.
1,4:3,6-dianhydro-mono(4-methylbenzenesulfonate)-D-
mannitol (2)
To a solution of 1 (1.0 g, 6.85 mmol) and pyridine (1.10
mL) in CH2Cl2 (10 mL) was added TsCl (1.49 g, 7.81 mmol)
o
at 0 C. The mixture was stirred at r. t. overnight and diluted
CONCLUSIONS
with CH2Cl2 (20 mL). The solution was washed with H2O,
1M HCl, brine and dried (Na2SO4). The product was
recrystallized (EtOAc-i-PrOH) affording a white solid (0.822
g, 40%), mp 103-104°C. IR (KBr) νmax (cm-1): 3526, 2933,
New isomannide-based peptide mimetics 7-28
possessing amide and ester groups were easily prepared in
high purities employing a general and suitable protocol for
larger library of compounds that can be potentially useful
against Hepatitis C or other flaviviruses. The most active
compound of the series, the arginine derivative 19, has
shown some inhibitory effect on HCV NS3/4A serine
protease at 100µM. The docking studies showed a good
interaction of arginine and isomannide moieties of 19 into
the active site of NS3 serine protease.
1
2866, 1596, 1359, 1189, 1173, 1050, 1019, 818, 663. H
NMR (300 MHz, CDCl3): 7.84 (d, J = 8.1Hz, 2H), 7.34 (d, J
= 8.1Hz, 2H), 4.91 (dd, J = 6.6Hz, J = 5.5Hz, 1H), 4.42 (t, J
= 5.1Hz, 1H), 4.49 (t, J = 4.8Hz, 1H), 4.29-4.25 (m, 1H),
4.04-3.95 (m, 2H), 3.79 (t, J = 7.8Hz, 1H), 3.55 (dd, J =
7.2Hz, J = 1.8Hz, 1H), 2.46 (s, 3H).

244 Letters in Organic Chemistry, 2012, Vol. 9, No. 4
Barros et al.
1,4:3,6-dianhydro-5-O-(phenylmethyl)-2-(4-methylbenzen-
esulfonate)-D-mannitol (3)
CH2Cl2 and the combined organic extracts were dried
(Na2SO4). The product was purified by column
chromatography on SiO2 (EtOAc-hexane 1/ 4) affording a
white solid (7.27 g, 45%), mp 93ºC. IR (KBr) νmax (cm-1):
3459, 3404, 2920, 2865, 1459, 1419, 1329, 1266, 1200,
To a mixture of 2 (10 g, 33.3 mmol), aq 50% KOH and
TBAB (0.322 g, 1 mmol) in CH2Cl2 (80 mL) was added
BnCl (6.54 g, 38.2 mmol). After stirring overnight, the
mixture was diluted with water (10 mL) and the organic
layer was separated. The aqueous layer was extracted with
CH2Cl2 and the combined organic extracts were dried
(Na2SO4). The product was purified by column
chromatography on SiO2 (EtOAc-hexane 5/ 95) affording a
1
1118, 1068, 1021, 820. H NMR (300 MHz, CDCl3): 7.36-
7.27 (m, 5H), 4.79 (d, J = 12.0Hz, 1H), 4.58 (d, J = 12.0Hz,
1H), 4.57-4.53 (m, 1H), 4.48 (t, J = 5.1 Hz, 1H), 4.27 (br,
1H), 4.11-3.95 (m, 3H), 3.76-3.68 (m, 2H), 2.82 (br, 1H).
13C NMR (75.4 MHz, CDCl3, ppm): 137.5, 128.4, 127.9,
127.8, 81.7, 80.6, 78.9, 74.7, 72.5, 72.2, 71.3.
20
colorless oil (9.75 g, 75%) [α]D +98 (c 0.1, DMSO). IR
(film) νmax (cm-1): 3063, 2977, 2950, 2879, 1598, 1454,
1
General Procedure for Amide (7-19) and Ester (20-28)
Compounds
1366, 1190, 1178, 1141, 1027, 853. H NMR (300 MHz,
CDCl3): 7.81 (d, J = 8.4Hz, 2H), 7.35-7.32 (m, 7H), 4.91-
4.89 (m, 1H), 4.69 (d, J = 12.0Hz, 1H), 4.50 (d, J = 12.0Hz,
1H), 4.47 (t, J = 2.1Hz, 2H), 4.04-3.79 (m, 4H), 3.62 (t, J =
8.4Hz, 1H), 2.44 (s, 3H).
To a solution of the amino derivative 5 or the benzyl-
isomannide 6 (1.27 mmol) in CH2Cl2 (10 mL) at 0ºC was
added the appropriate N-protected amino acid (1.27 mmol),
DCC (1.27 mmol) and DMAP (0.12 mmol). The mixture
was stirred for 12 hours at room temperature after which it
was filtered and evaporated under reduced pressure. The
product was purified either by recrystallization or by flash
chromatography on silica gel using hexane and ethyl acetate
mixture as eluent.
1,4:3,6-dianhydro-2-azido-2-deoxy-5-O-(phenylmethyl)-D-
glucitol (4)
A mixture of 3 (1.86 g, 4.77 mmol), [bmim]+[BF4]-
o
(previously dried under vacuum at 90 C) (4.8 mL, 23.85
o
mmol) and NaN3 (0.93 g, 14.3 mmol) was heated at 120 C
overnight. Water was added and the aqueous layer was
extracted with ethyl ether. The product was purified by flash
column chromatography on SiO2 (EtOAc-hexane 5/ 95) to
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(N-t-butoxycarbonyl-
L-proline)-D-glucitol (7)
20
give a pale yellow oil (0.908 g, 73%) [α]D +92 (c 0.1,
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-Boc- L-Pro (29)
(0.273 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 3/ 7). The reaction
DMSO). IR (film) νmax (cm-1): 3063, 3031, 2946, 2878, 2102,
1
1455, 1320, 1256, 1135, 1100, 1083, 1021, 739. H NMR
(300 MHz, CDCl3): 7.36-7.26 (m, 5H), 4.75 (d, J = 11.7Hz,
1H), 4.66 (t, J = 4.5Hz, 1H), 4.54 (d, J = 11.7Hz, 1H), 4.48
(d, J = 4.2Hz, 1H), 4.15-4.00 (m, 4H), 3.86 (dd, J = 6.3Hz, J
= 2.7Hz, 1H), 3.66 (t, J = 7.8Hz, 1H). 13C NMR (75.4 MHz,
CDCl3): 137.4, 128.3, 127.8, 127.7, 86.4, 80.5, 78.8, 72.6,
72.4, 70.7, 66.2. HRMS (FAB): Calcd. for C13H15N3O3Na
[M + H+]: 284.1011. Found: 284.1025.
20
produced a colorless oil (0.172 g, 31%). [α]D +91 (c 0.1,
DMSO). IR (film) νmax (cm-1): 3055, 2986, 1684, 1604, 1423,
1
1159, 987, 896, 741. H NMR (300 MHz): 7.40-7.25 (m,
5H), 4.77-4.74 (m, 1H), 4.66 (t, J = 4.8 Hz, 1H), 4.57 (d, J =
11.4 Hz, 1H), 4.41-4.40 (m, 1H), 4.25-4.24 (m, 1H), 4.16-
4.12 (m, 2H), 4.10-4.01 (m, 1H), 3.87-3.82 (m, 1H), 2.21-
1.92 (m, 2H), 1.92-1.86 (m, 2H), 1.41 (s, 9H). 13C NMR
(75.4 MHz, CDCl3): 175.7, 155.9, 139.4, 129.4, 129.0, 128.8,
88.4, 81.9, 81.4, 80.7, 74.0, 73.5, 71.7, 61.4, 58.5, 32.6, 28.7,
25.4, 24.7. HRMS (FAB): Calcd. for C23H32N2O6Na [M+]:
455.2158. Found: 455.2164.
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-D-
glucitol (5)
To a solution of azide 4 (0.870 g, 3.33 mmol) in EtOH
(25 mL) was added 5% Pd-C (0.33 mmol) and the mixture
was hydrogenated under 2.75 bar for 5 hours. The mixture
was filtered under XAD-4 and washed with EtOH affording
20
the product as a colorless oil (0.783 g, 100%) [α]D +104 (c
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(N-t-butoxycarbonyl-
L-valine)-D-glucitol (8)
0.1, DMSO). IR (KBr) νmax (cm-1): 3360, 2876, 1605, 1455,
1
1369, 1209, 1065, 1017, 751, 700. H NMR (300 MHz,
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-Boc-L-Val (30)
(0.276 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by recrystallization in
ethyl ether. The reaction produced a white solid (0.223 g,
CDCl3): 7.37-7.35 (m, 5H), 4.76 (d, J = 11.4Hz, 1H), 4.68 (t,
J = 4.2Hz, 1H), 4.54 (d, J = 12.0Hz, 1H), 4.27 (d, J = 4.2Hz,
1H), 4.06-4.02 (m, 1H), 3.85 (dd, J = 6.3Hz, J = 2.4Hz, 1H),
3.76 (d, J = 9.3Hz, 1H), 3.64 (t, J = 7.8Hz, 1H), 3.53 (d, J =
4.2Hz, 1H), 3.45 (s, 1H). 13C NMR (75.4 MHz, CDCl3):
137.9, 128.6, 128.0, 127.8, 90.0, 80.1, 79.4, 76.3, 72.6, 70.5,
58.8. HRMS (FAB): Calcd. for C13H17NO3Na [M + H+]:
236.1287. Found: 236.1284.
20
40%), mp 102-103ºC. [α]D +67 (c 0.1, DMSO). IR (KBr)
ν
max (cm-1): 3335, 2968, 2934, 2879, 1687, 1654, 1529, 1461,
1
1368, 1299, 1250, 1169, 1092, 1052, 1018, 738. H NMR
(300 MHz, CDCl3): 7.38-7.24 (m, 5H), 6.23 (br, 1H), 5.01
(br, 1H), 4.76 (d, J = 11.7Hz, 1H), 4.60-4.53 (m, 2H), 4.42
(q, J = 3.9Hz, 2H), 4.08-4.02 (m, 2H), 3.88-3.81 (m, 3H),
3.69-3.63 (m, 1H), 2.15-2.09 (m, 1H), 1.44 (s, 9H), 0.95 (d, J
= 6.9Hz, 3H), 0.91 (d, J = 6.9 Hz, 3H). 13C NMR (75.4 MHz,
CDCl3): 171.4, 155.9, 137.6, 128.4, 127.9, 127.8, 86.9, 80.3,
80.2, 80.0, 79.0, 72.5, 70.8, 59.9, 56.8, 30.6, 28.2, 19.3, 17.8.
1,4:3,6-dianhydro-5-O-(phenylmethyl)-2-hydroxy-D-
mannitol (6)
To a mixture of 1 (10 g, 68.5 mmol), aq 50% KOH and
TBAB (0.622 g, 2.057 mmol) in CH2Cl2 (160 mL) was
added BnCl (13.45 g, 78.6 mmol). After stirring overnight,
the mixture was diluted with water (22 mL) and the organic
layer was separated. The aqueous layer was extracted with

Novel Peptide Mimetics Based on N-protected Amino Acids
Letters in Organic Chemistry, 2012, Vol. 9, No. 4
245
HRMS (FAB): Calcd. for C29H35N3O6Na [M+]: 544.2424.
Found: 544.2408.
HRMS (FAB): Calcd. for C23H34N2O6Na [M+]: 457.22315.
Found: 457.2324.
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(N-carbobenzyloxy-L-
proline-L-phenylalanine) D-glucitol (12)
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(N-t-butoxycarbonyl-
O-benzyl-L-serine)-D-glucitol (9)
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-Cbz-Pro-Phe (34)
(0.503 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained byg flash
chromatography on SiO2 (EtOAc-hexane 1/ 1). The reaction
produced a white solid (0.761 g, 97%), mp 141-143oC.
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-Boc-O-Benzyl- L-
Ser (31) (0,374 g, 1.27 mmol) were allowed to react as
described above. The pure product was obtained by
recrystallization in ethyl ether. The reaction produced a
white solid (0.302 g, 46%), mp 116-117ºC. [α]D20 +57 (c 0.1,
DMSO). IR (KBr) νmax (cm-1): 3289, 2968, 2974, 2873,
1690, 1650, 1553, 1511, 1299, 1310, 1243, 1168, 1133,
20
[α]D -15 (c 0.1, CH2Cl2). IR (KBr) νmax (cm-1): 3279, 3069,
2949, 2878, 1704, 1649, 1554, 1448, 1415, 1355, 1247,
1
1
1093, 1023, 914, 743. H NMR (300 MHz, CDCl3): 7.27-
1049, 864, 742. H NMR (300 MHz, CDCl3): 7.35-7.27 (m,
7.02 (m, 15H), 6.61 (br, 1H), 6.29 (br, 1H), 5.06-4.90 (m,
2H), 4.66 (d, J = 12.0Hz, 2H), 4.45 (d, J = 12.0Hz, 2H),
4.31-4.27 (m, 2H), 4.18-4.15 (m, 1H), 3.99-3.91 (m, 2H),
3.78-3.72 (m, 2H), 3.56 (t, J = 8.1Hz, 1H), 3.44-3.30 (m,
3H), 3.10-3.03 (m, 1H), 1.93-1.60 (m, 4H). 13C NMR (75.4
MHz, CDCl3): 171.2, 170.2, 155.9, 137.6, 136.4, 135.9,
129.0, 128.6, 128.5, 128.3, 128.2, 127.7, 127.0, 86.8, 80.1,
79.0, 73.4, 72.3, 70.4, 67.5, 61.2, 57.0, 53.4, 47.0, 37.3, 29.3,
24.3. HRMS (FAB): Calcd. for C35H39N3O7Na [M+]:
636.2686. Found: 636.2697.
10H), 4.73 (d, J = 12.0 Hz, 1H), 4.54-4.45 (m, 3H), 4.40-
4.38 (m, 2H), 4.32-4.31 (m, 1H), 4.23-4.21 (m, 1H), 4.05-
3.95 (m, 2H), 3.91-3.81 (m, 3H), 3.67-3.57 (m, 1H), 3.64
(dd, J = 7.5, 8.7 Hz, 1H), 3.61-3.54 (m, 1H), 1.44 (s, 9H).
13C NMR (75.4 MHz, CDCl3): 169.9, 155.7, 137.6, 137.3,
128.5, 128.4, 128.0, 127.9, 127.8, 86.8, 80.4, 80.1, 79.1,
73.5, 73.2, 72.4, 70.7, 69.8, 56.8, 51.9, 28.2. HRMS (FAB):
Calcd. for C28H36N2O7Na [M+]: 535.2420. Found: 535.2400.
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(N-t-butoxycarbonyl-
L-methionine)-D-glucitol (10)
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(N-carbobenzyloxy-D-
proline)-D-glucitol (13).
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-Boc-L-Met (32)
(0.316 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 3/ 7). The reaction
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-Cbz-D-Pro (35)
(0.316 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 1/ 1). The reaction
20
produced a white solid (0.377 g, 63%), mp 91-93ºC. [α]D
+34 (c 0.1, CH2Cl2). IR (KBr) νmax (cm-1): 3297, 2974, 2931,
20
produced a white solid (0.377 g, 63%), mp. 89-90ºC. [α]D
2873, 1660, 1650, 1530, 1452, 1368, 1249, 1168, 1092, 860,
+94 (c 0.1, CH2Cl2). IR (KBr) νmax (cm-1): 3345, 3034, 2974,
2926, 2873, 1679, 1531, 1451, 1421, 1356, 1253, 1208,
1122, 1091, 952, 866, 758. H NMR (300 MHz, CDCl3):
1
742. H NMR (300 MHz, CDCl3): 7.35-7.30 (m, 5H), 6.55
(br, 1H), 5.16 (br, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.59-4.52
(m, 2H), 4.42-4.38 (m, 2H), 4.24-4.17 (m, 1H), 4.08-4.02 (m
2H), 3.87-3.82 (m, 2H), 3.67 (dd, J = 7.5Hz, J = 9.0 Hz, 1H),
2.55-2.52 (m, 2H), 2.10 (s, 3H), 2.06-2.03 (m, 2H), 1.44 (s,
9H). 13C NMR (75.4 MHz, CDCl3): 171.3, 155.6, 137.6,
128.4, 127.8, 127.8, 86.9, 80.4, 80.2, 73.2, 72.4, 70.8, 56.8,
53.4, 31.2, 30.2, 28.2, 15.2. HRMS (FAB): Calcd. for
C23H32N2O6NaS [M+]: 489.2035. Found: 489.2038.
1
7.36-7.26 (m, 6H), 5.15-5.13 (m, 2H), 4.75 (d, J = 11.7Hz,
1H), 4.56 (d, J = 12.0Hz, 1H), 4.30-4.26 (m, 2H), 4.00-3.91
(m, 2H), 3.85-3.80 (m, 2H), 3.66-3.62 (m, 1H), 3.61-3.44
(m, 4H), 2.34-1.85 (m, 4H). 13C NMR (75 MHz, CDCl3):
171.1, 156.5. 137.6, 136.4, 128.5, 128.4, 128.1, 127.8, 86.9,
80.1, 78.9, 73.4, 72.4, 70.6, 67.3, 60.2, 56.8, 47.0, 27.9, 24.6.
HRMS (FAB): Calcd. for C26H30N2O6Na [M+]: 489.2002.
Found: 489.2011.
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(N-t-butoxycarbonyl-
L-triptophan)-D-glucitol (11)
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(Nα-t-butoxycarbonyl-
Nε-carbobenzyloxy-L-lysine)-D-glucitol (14)
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-Boc-L-Trp (33)
(0.386 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained byg flash
chromatography on SiO2 (EtOAc-hexane 1/ 1). The reaction
produced a white solid (0.448 g, 67%), mp 161-162ºC.
[α]D20 +44 (c 0.1, CH2Cl2). IR (KBr) νmax (cm-1): 3321, 2974,
2933, 2881, 1685, 1646, 1523, 1455, 1366, 1250, 1169,
1095, 1018, 863, 743. 1H NMR (300 MHz, CDCl3): 8.24 (br,
1H), 7.64 (d, J = 7.8 Hz, 1H), 7.36-7.29 (m, 6H), 7.19-7.07
(m, 3H), 5.70 (br, 1H), 5.29 (br, 1H), 4.48 (q, J = 12.0 Hz,
1H), 4.39-4.36 (m, 1H), 4.23-4.21 (m, 1H), 3.84-3.65 (m,
5H), 3.55-3.49 (m 3H), 3.29 (dd, J = 14.4Hz, J = 5.7Hz, 1H),
3.10 (dd, J = 14.4Hz, J = 8.4Hz, 1H), 1.44 (s, 9H). 13C NMR
(75.4 MHz, CDCl3): 171.4, 155.4, 137.6, 136.1, 128.4, 127.9,
127.7, 127.3, 123.2, 122.2, 119.7, 118.9, 111.2, 110.6, 86.3,
80.1, 79.6, 79.0, 72.6, 72.3, 70.4, 56.4, 55.6, 28.6, 28.3.
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-α-Boc-Nε-Cbz-L-
Lys (36) (0.483 g, 1.27 mmol) were allowed to react as
described above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 3/ 7). The reaction
20
produced a white solid (0.490 g, 64%), mp. 62-63ºC. [α]D
+23 (c 0.1, CH2Cl2). IR (KBr) νmax (cm-1): 3360, 2972, 2937,
2879, 1694, 1659, 1459, 1366, 1254, 1168, 1087, 1015, 908,
749. H NMR (300 MHz, CDCl3): 7.34-7.30 (m, 10H), 6.55
1
(br, 1H), 5.29 (s, 2H), 5.09-5.02 (m, 1H), 4.75 (d, J =
11.7Hz, 1H), 4.58 (t, J = 4.5Hz, 1H), 4.51 (d, 1H, J = 12Hz),
4.41-4.36 (m, 2H), 4.07-4.00 (m, 2H), 3.86-3.81 (m, 2H),
3.65 (dd, J = 8.7Hz, J = 7.5Hz, 1H), 3.17 (q, J = 6.0 Hz, 2H),
1.84-1.82 (m, 2H), 1.64-1.50 (m, 2H), 1.43 (s, 9H), 1.39-
1.34 (m, 2H). 13C NMR (75.4 MHz, CDCl3): 172.0, 156.6,

246 Letters in Organic Chemistry, 2012, Vol. 9, No. 4
Barros et al.
155.8, 137.6, 136.5, 128.4, 128.3, 128.0, 127.9, 127.8, 86.9,
80.2, 80.1, 79.0, 73.2, 72.4, 70.7, 66.6, 56.8, 54.3, 40.1, 31.5,
29.4, 28.2, 22.4. HRMS (FAB): Calcd. for C32H43N3O8Na
[M+]: 620.2948. Found: 620.2958.
(d, J = 12.0Hz, 1H), 4.43-4.41 (m, 2H), 4.17 (br, 1H), 4.11-
4.02 (m, 2H), 3.88-3.81 (m, 2H), 3.70-3.64 (m, 1H), 3.61-
3.44 (m, 2H), 1.74 (br, 1H), 1.43 (s, 9H). 13C NMR (75.4
MHz, CDCl3): 171.8, 158.9, 137.6, 128.4, 127.8, 87.0, 80.7,
80.3, 79.0, 73.6, 73.4, 72.4, 70.7, 56.5, 44.7, 28.2. HRMS
(FAB): Calcd. for C21H30N2O7Na [M+]: 445.1951. Found:
445.1947.
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(Nα-t-butoxycarbonyl-
N -tosil-L-histidine)-D-glucitol (15)
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-Boc imTosyl-L-
His (37) (0.519 g, 1.27 mmol) were allowed to react as
described above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 2/ 3). The reaction
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(N-t-butoxycarbonyl-
L-threonine)-D-glucitol (18)
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-Boc-L-Thr (40)
(0.262 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 3/ 7). The reaction
20
produced a white solid (0.505 g, 63%), mp. 91-93ºC. [α]D
+55 (c 0.1, CH2Cl2). IR (KBr) νmax (cm-1): 3290, 3073, 2974,
2934, 2879, 1661, 1527, 1376, 1300, 1248, 1174, 1088, 814,
1
20
744. H NMR (300 MHz, CDCl3): 7.93 (s, 1H), 7.81 (d, J =
produced a colorless oil (0.305 g, 56%). [α]D +6 (c 0.1,
8.4Hz, 2H), 7.35-7.29 (m, 7H), 7.08 (s, 1H), 6.77 (br, 1H),
5.87 (br, 1H), 4.71 (d, J = 11.7Hz, 1H), 4.55 (d, J = 11.7Hz,
1H), 4.46 (t, J = 4.5Hz, 1H), 4.34-4.23 (m, 3H), 4.04 (q, J =
6.9Hz, 1H), 3.92-3.80 (m, 2H), 3.65-3.59 (m, 2H), 3.04 (dd,
J = 14.7Hz, J = 5.1Hz, 1H), 2.85 (dd, J = 14.7Hz, J = 6.3Hz,
1H), 2.42 (s, 3H), 1.42 (s, 9H). 13C NMR (75.4 MHz,
CDCl3): 170.8, 155.4, 146.4, 140.4, 137.6, 134.5, 130.4,
128.3, 127.8, 127.3, 114.9, 86.7, 81.7, 80.1, 79.1, 72.9, 72.4,
70.7, 56.6, 53.9, 30.4, 28.2, 21.6. HRMS (FAB): Calcd. for
C31H38N4O8NaS [M+]: 649.2308. Found 649.2321.
CH2Cl2). IR (film) νmax (cm-1): 3944, 3755, 3691, 3056,
2987, 1682, 1604, 1424, 1265, 1159, 986, 896, 742. 1H NMR
(300 MHz, CDCl3): 7.35-7.29 (m, 5H), 6.92 (br, 1H), 5.51
(br, 1H), 4.73 (d, J = 12.0Hz, 1H), 4.63-4.61 (m, 1H), 4.56
(d, J = 12.0Hz, 1H), 4.43-4.35 (m, 3H), 4.08-4.04 (m, 2H),
4.00 (dd, J = 8.1Hz, J = 2.1 Hz, 1H), 3.88-3.81 (m, 2H), 3.67
(dd, J = 9.0Hz, J = 7.5 Hz, 1H), 1.46 (s, 9H), 1.17 (d, J =
6.3Hz, 3H). 13C NMR (75.4 MHz, CDCl3): 171.2, 156.6,
137.6, 128.4, 127.9, 127.8, 86.9, 80.5, 80.3, 78.9, 73.2, 72.4,
70.5, 66.6, 58.2, 56.9, 28.2, 18.3. HRMS (FAB): Calcd. for
C22H32N2O7Na [M+]: 459.2107. Found: 459.2085.
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(N-carbobenzyloxy-
valine-phenylalanine)-D-glucitol (16)
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(Nα-t-butoxycarbonyl-
Nδ,Nω-di-carbobenzyl oxy-L-arginine)-D-glucitol (19)
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-Cbz-Val-Phe (38)
(0.505 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 3/ 7). The reaction
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-α-Boc-Nω-di-
Cbz-L-Arg (41) (0.670 g, 1.27 mmol) were allowed to react
as described above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 3/ 7). The reaction
20
produced a white solid (0.630 g, 80%), mp. 81-83ºC. [α]D
+26 (c 0.1, CH2Cl2). IR (KBr) νmax (cm-1): 3290, 3066, 2962,
1708, 1646, 1544, 1393, 1241, 1132, 1091, 1023, 914, 741.
1H NMR (300 MHz, CDCl3): 7.33-7.12 (m, 15H), 6.77 (br,
1H), 5.59-5.57 (m, 1H), 5.12-5.01 (m, 2H), 4.80 (q, J =
7.8Hz, 1H), 4.65 (dd, J = 12.0, J = 4.5Hz, 1H), 4.45-4.38 (m,
1H), 4.32-4.27 (m, 2H), 4.01-3.80 (m, 3H), 3.77-3.70 (m,
2H), 3.66-3.57 (m, 1H), 3.10-2.98 (m, 2H), 2.11-1.95 (m,
1H), 0.91 (d, J = 6.6Hz, 3H), 0.84 (d, J = 6.6Hz, 3H). 13C
NMR (75.4 MHz, CDCl3): 171.6, 170.5, 156.6, 137.8, 136.3,
136.2, 129.4, 129.3, 128.5, 128.4, 128.3, 128.1, 127.7, 126.9,
126.7, 87.0, 80.3, 78.9, 72.9, 72.2, 70.8, 67.1, 60.7, 56.6,
53.7, 39.2, 31.2, 19.3, 18.1. HRMS (FAB): Calcd. for
C35H41N7O7Na [M+]: 638.2842. Found: 638.2862.
produced a white solid (0.838 g, 88%), mp. 81-83ºC. [α]D
20
+34 (c 0.1, CH2Cl2). IR (KBr) νmax (cm-1): 3387, 3328, 2929,
2857, 1717, 1656, 1615, 1510, 1451, 1376, 1252, 1093, 744.
1H NMR (300 MHz, CDCl3): 9.42 (br, 1H), 7.43-7.29 (m,
15H), 6.68 (br, 1H), 5.64 (br, 1H), 5.29 (s, 2H), 5.24 (s, 2H),
5.19-5.10 (m, 2H), 4.73 (d, J = 12.0Hz, 1H), 4.52 (d, J =
12.0Hz, 1H), 4.33-4.20 (m, 3H), 3.96-3.90 (m, 2H), 3.78 (dd,
J = 9.0, J = 7.5 Hz, 1H), 3.63-3.57 (m, 1H), 1.94-1.70 (m,
2H), 1.68-1.58 (m, 4H), 1.43 (s, 9H). 13C NMR (75.4 MHz,
CDCl3): 171.8, 163.4, 160.7, 155.8, 155.6, 137.7, 136.6,
134.5, 128.8, 128.7, 128.5, 128.4, 128.3, 127.9, 127.8, 127.7,
86.9, 80.0, 79.9, 78.9, 72.9, 72.3, 70.4, 68.9, 67.0, 56.9, 49.0,
43.9, 28.4, 25.5, 24.7. HRMS (FAB): Calcd. for
C40H49N5O10Na [M+]: 782.3377. Found: 782.3405.
1,4:3,6-dianhydro-5-O-(benzyl)-2-N-(N-t-butoxycarbonyl-
L-isoserine)-D-glucitol (17)
1,4:3,6-dianhydro-5-O-(benzyl)-2-O-(N-t-butoxycarbonyl-
L-proline)-D-mannitol (20)
1,4:3,6-dianhydro-2-amino-2-deoxy-5-O-(phenylmethyl)-
D-glucitol (5) (0.300 g, 1.27 mmol) and N-Boc-L-IsoSer (39)
(0.260 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 1/ 4). The reaction
produced a white solid (0.271 g, 50%), mp. 133-134ºC.
1,4:3,6-dianhydro-5-O-(phenylmethyl)-2-hydroxy-D-
mannitol (6) (0.300 g, 1.27 mmol) and the N-Boc- L-Pro (29)
(0.273 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 1/ 4). The reaction
20
20
[α]D +4.0 (c 0.1, CH2Cl2). IR (KBr) νmax (cm-1): 3398,
produced a colorless oil (0.278 g, 50%). [α]D +91 (c 0.1,
3315, 2975, 2936, 2889, 1708, 1640, 1547, 1515, 1399,
DMSO). IR (film) νmax (cm-1): 2974, 2880, 1746, 1697, 1454,
1
1
1325, 1256, 1171, 1110, 1043, 882, 731. H NMR (300
1398, 1261, 1128, 1090, 1028, 885, 819. H NMR (300
MHz, CDCl3): 7.36-7.18 (m, 5H), 5.37 (br, 1H), 5.20 (br,
1H), 4.77 (d, J = 12.0Hz, 1H), 4.64 (t, J = 4.5Hz, 1H), 4.53
MHz, CDCl3): 7.30-7.21 (m, 5H), 5.06-4.95 (m, 1H), 4.76-
4.68 (m, 2H), 4.57 (s, 1H), 4.53-4.46 (m, 1H), 4.39-4.30 (m,

Novel Peptide Mimetics Based on N-protected Amino Acids
Letters in Organic Chemistry, 2012, Vol. 9, No. 4
247
1H), 4.07-3.99 (m, 1H), 3.95-3.84 (m, 2H), 3.51-3.35 (m,
75.0, 72.5, 71.1, 70.4, 52.8, 32.0, 29.7, 28.2, 15.4. HRMS
(FAB): Calcd. for C22H33NO7NaS [M+]: 490.1875. Found:
490.1895.
2H), 2.23-2.19 (m, 2H), 2.04-1.86 (m, 2H), 1.40 (s, 9H). 13
C
NMR (75.4 MHz, CDCl3): 172.5, 153.7, 137.5, 128.4, 127.9,
80.6, 80.4, 79.9, 78.8, 74.3, 72.5, 70.8, 70.5, 59.0, 46.5, 30.9,
28.3, 24.2. HRMS (FAB): Calcd. for C23H31NO7Na [M+]:
456.1998. Found: 456.2009.
1,4:3,6-dianhydro-5-O-(benzyl)-2-O-(N-t-butoxycarbonyl-
L-triptophan)-D-mannitol (24)
1,4:3,6-dianhydro-5-O-(phenylmethyl)-2-hydroxy-D-
mannitol (6) (0.300 g, 1.27 mmol) and the N-Boc-L-Trp (33)
(0.386 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 15/ 85). The
reaction produced a colorless oil (0.500 g, 75%). [α]D20 +114
(c 0.1, CH2Cl2). IR (film) νmax (cm-1): 3344, 2974, 2933,
2876, 1740, 1706, 1500, 1455, 1366, 1247, 1166, 1068,
1,4:3,6-dianhydro-5-O-(benzyl)-2-O-(N-t-butoxycarbonyl-
L-valine)-D-mannitol (21)
1,4:3,6-dianhydro-5-O-(phenylmethyl)-2-hydroxy-D-
mannitol (6) (0.300 g, 1.27 mmol) and the N-Boc-L-Val (30)
(0.276 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 3/ 7). The reaction
20
1
produced a colorless oil (0.335 g, 60%). [α]D +107 (c 0.1,
1023, 858, 743. H NMR (300 MHz, CDCl3): 7.56 (d, J =
DMSO). IR (film) νmax (cm-1): 3350, 2970, 2880, 1713, 1502,
8.1Hz, 1H), 7.35-7.25 (m, 7H), 7.17-7.02 (m, 2H), 4.99 (q, J
= 5.7Hz, 1H), 4.75-4.46 (m, 5H), 4.13-4.01 (m, 1H), 3.90-
3.85 (m, 2H), 3.80-3.67 (m, 1H), 3.58 (t, J = 8.4Hz, 1H),
3.31-3.9 (m, 2H), 1.42 (s, 9H). 13C NMR (75.4 MHz,
CDCl3): 171.7, 155.0, 137.5, 135.9, 128.4, 127.9, 127.6,
127.5, 122.9, 121.9, 119.4, 118.6, 111.1, 110.0, 81.7, 80.6,
80.5, 80.2, 79.7, 78.6, 74.9, 72.5, 60.3, 54.3, 28.2. HRMS
(FAB): Calcd. for C29H34N2O7Na [M+]: 545.2264. Found:
545.2283.
1
1461, 1367, 1251, 1161, 1090, 1023, 866, 740. H NMR
(300 MHz, CDCl3): 7.40-7.25 (m, 5H), 5.14 (q, J = 6.0Hz,
1H), 5.01-4.98 (m, 1H), 4.76-4.68 (m, 2H), 4.58 (s, 1H),
4.49 (t, J = 4.8Hz, 1H), 4.31-4.26 (m, 1H), 4.13-4.00 (m,
2H), 3.95-3.90 (m, 2H), 3.62 (t, J = 8.5 Hz, 1H), 1.44 (s,
9H), 0.98 (d, J = 6.9Hz, 3H), 0.90 (d, J = 6.9Hz, 3H). 13C
NMR (75.4 MHz, CDCl3): 171.7, 155.5, 137.5, 128.4, 127.9,
80.5, 80.3, 79.7, 78.7, 74.8, 72.5, 71.0, 70.5, 58.5, 31.2, 28.3,
18.9, 17.4. HRMS (FAB): Calcd. for C23H33NO7Na [M+]:
458.2155. Found: 458.2163.
1,4:3,6-diahydro-5-O-(benzyl)-2-O-(N-carbobenzyloxy-L-
proline-L-phenylalanine)-D-mannitol (25)
1,4:3,6-dianhydro-5-O-(benzyl)-2-O-(N-t-butoxycarbonyl-
O-benzyl-L-serine)-D-mannitol (22)
1,4:3,6-dianhydro-5-O-(phenylmethyl)-2-hydroxy-D-
mannitol (6) (0.300 g, 1.27 mmol) and the N-Cbz-Pro-Phe
(34) (0.503 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 3/ 7). The reaction
1,4:3,6-dianhydro-5-O-(phenylmethyl)-2-hydroxy-D-
mannitol (6) (0.300 g, 1.27 mmol) and the N-Boc-O-Benzyl-
L-Ser (31) (0.374 g, 1.27 mmol) were allowed to react as
described above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 1/ 4). The reaction
20
produced a colorless oil (0.407 g, 46%). [α]D +53 (c 0.1,
CH2Cl2). IR (film) νmax (cm-1): 3413, 3316, 3060, 2952,
20
produced a colorless oil (0.348 g, 53%). [α]D +92 (c 0.1,
2881, 1744, 1694, 1524, 1448, 1416, 1355, 1200, 1122,
DMSO). IR (film) νmax (cm-1): 3328, 2974, 2928, 2876, 1749,
1029, 918, 738. H NMR (300 MHz, CDCl3): 7.40-7.00 (m,
1
1
1713, 1499, 1363, 1245, 1166, 1098, 1028, 859, 742. H
15H), 5.12-5.09 (m, 2H), 4.90 (q, J = 7.2Hz, 1H), 4.75-4.72
(m, 2H), 4.54-4.46 (m, 2H), 4.35-4.29 (m, 1H), 4.07-3.90
(m, 4H), 3.70-3.60 (m, 1H), 3.49-3.38 (m, 3H), 3.20-3.02
(m, 2H), 1.90-1.65 (m, 4H). 13C NMR (75.4 MHz, CDCl3):
171.0, 170.7, 155.9, 137.4, 136.3, 135.9, 129.2, 128.4, 127.8,
126.9, 126.8, 80.3, 80.1, 78.6, 74.9, 72.4, 70.9, 70.7, 70.4,
67.2, 60.1, 53.0, 46.7, 37.7, 27.7, 23.3. HRMS (FAB): Calcd.
for C35H38N2O8Na [M+]: 637.2526. Found: 637.2542.
NMR (300 MHz, CDCl3): 7.36-7.27 (m, 10H), 5.43-5.40 (m,
1H) 5.13 (q, J = 5.7Hz, 1H), 4.74-4.70 (m, 2H), 4.57-4.43
(m, 4H), 4.04-3.88 (m, 5H), 3.86-3.60 (m, 1H), 3.51-3.46
(m, 1H), 1.44 (s, 9H). 13C NMR (75.4 MHz, CDCl3): 170.1,
155.3, 137.5, 137.4, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6,
80.5, 80.3, 79.9, 78.7, 75.1, 73.2, 72.5, 71.0, 70.4, 69.8, 53.9,
28.3. HRMS (FAB): Calcd. for C28H35NO8Na [M+]:
536.2260. Found: 536.2278.
1,4:3,6-dianhydro-5-O-(benzyl)-2-O-(N-carbobenzyloxy-D-
proline)-D-mannitol (26)
1,4:3,6-dianhydro-5-O-(benzyl)-2-O-(N-t-butoxycarbonyl-
L-methionine)-D-mannitol (23)
1,4:3,6-dianhydro-5-O-(phenylmethyl)-2-hydroxy-D-
mannitol (6) (0.300 g, 1.27 mmol) and the N-Cbz-D-Pro (35)
(0.316 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 3/ 7). The reaction
1,4:3,6-dianhydro-5-O-(phenylmethyl)-2-hydroxy-D-
mannitol (6) (0.300 g, 1.27 mmol) and the N-Boc-L-Met (32)
(0.316 g, 1.27 mmol) were allowed to react as described
above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 1/ 4). The reaction
20
produced a white solid (0.377 g, 63%), mp. 71-72ºC. [α]D
20
produced a colorless oil (0.449 g, 75%). [α]D +116 (c 0.1,
+158 (c 0.1, CH2Cl2). IR (KBr) νmax (cm-1): 3405, 2964,
2869, 1739, 1708, 1465, 1411, 1351, 1197, 1124, 1071, 880,
746. 1H NMR (300 MHz, CDCl3): 7.36-7.29 (m, 10H), 5.18-
5.07 (m, 1H), 4.98 (q, J = 5.7Hz, 1H), 4.79-4.64 (m, 2H),
4.54 (dd, J = 11.7Hz, J = 2.4 Hz, 1H), 4.49-4.42 (m, 1H),
4.38 (dd, J = 8.4Hz, J = 3.9 Hz, 1H), 4.06-3.89 (m, 2H),
3.88-3.80 (m, 2H), 3.70-3.45 (m, 4H), 2.19-1.96 (m, 2H),
1.94-1.68 (m, 2H). 13C NMR (75.4 MHz, CDCl3): 172.3,
160.1, 137.5, 136.6, 128.5, 128.4, 128.3, 127.9, 127.8, 127.7,
CH2Cl2). IR (film) νmax (cm-1): 3339, 2974, 2923, 2876,
1710, 1509, 1450, 1366, 1253, 1166, 1069, 1028, 864, 743.
1H NMR (300 MHz, CDCl3): 7.36-7.32 (m, 5H), 5.13 (q, J =
5.7Hz, 2H), 4.76-4.69 (m, 2H), 4.59 (s, 1H), 4.49-4.46 (m,
1H), 4.07-4.04 (m, 3H), 3.95-3.90 (m, 1H), 3.60 (t, J =
8.5Hz, 1H), 2.57-2.51 (m, 2H), 2.10-2.05 (m, 2H), 2.08 (s,
3H), 1.44 (s, 9H). 13C NMR (75.4 MHz, CDCl3): 171.5,
155.1, 137.4, 128.4, 127.9, 127.8, 80.5, 80.3, 79.9, 78.6,

248 Letters in Organic Chemistry, 2012, Vol. 9, No. 4
Barros et al.
80.6, 80.2, 78.6, 74.5, 72.5, 71.4, 70.1, 66.9, 58.8, 46.4, 30.8,
23.4. HRMS (FAB): Calcd. for C26H29NO7Na [M+]:
490.1842. Found: 490.1824.
from progress curves using the linear regression method. The
SigmaPlot v.10.0 software was used to calculate the kinetics
data.
1,4:3,6-dianhidro-5-O-(benzyl)-2-O-(Nα-t-butoxycarbonyl-
Nε-carbobenzyloxy-L-lisine)-D-mannitol (27)
CONFLICT OF INTEREST
Declared none.
1,4:3,6-dianhydro-5-O-(phenylmethyl)-2-hydroxy-D-
mannitol (6) (0.300 g, 1.27 mmol) and the N-α-Boc-Nε-Cbz-
L-Lys (36) (0.483 g, 1.27 mmol) were allowed to react as
described above. The pure product was obtained by flash
chromatography on SiO2 (EtOAc-hexane 1/ 4). The reaction
ACKNOWLEDGEMENTS
Authors thank to CNPq, CAPES, FAPERJ and FINEP
for the financial support and for individual research
fellowship. We thank to John S. Williamson and Paulo
Carvalho (University of Mississippi) for HRMS.
20
produced a colorless oil (0.398 g, 52%). [α]D +79 (c 0.1,
CH2Cl2). IR (film) νmax (cm-1): 3344, 3033, 2938, 2874,
1710, 1522, 1455, 1366, 1255, 1165, 1091, 1024, 859, 737.
1H NMR (300 MHz, CDCl3): 7.35-7.27 (m, 10H), 5.15-5.08
(m, 2H), 4.89 (br, 1H), 4.74-4.68 (m, 2H), 4.57 (d, J =
11.7Hz, 1H), 4.47-4.44 (m, 1H), 4.32 (br, 1H), 4.03-3.89 (m,
4H), 3.60 (t, J = 8.4Hz, 1H), 3.18 (q, J = 6.3Hz, 2H), 1.90-
1.81 (m, 2H), 1.66-1.52 (m, 2H), 1.50 (s, 9H), 1.48-1.42 (m,
2H). 13C NMR (75.4 MHz, CDCl3): 171.9, 156.4, 155.3,
137.5, 136.5, 128.5, 128.4, 128.0, 127.9, 127.8, 127.7, 80.5,
80.2, 79.8, 78.6, 74.8, 72.5, 71.0, 70.4, 66.5, 53.3, 40.5, 32.2,
29.9, 28.2, 22.2. HRMS (FAB): Calcd. for C32H42N2O9Na
[M+]: 621.2788. Found: 621.2784.
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20
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