Synthesis of Hybrid Peptidomimetics and Neoglycoconjugates Employing Click Protocol: Dual utility of Poc-group for inserting carbamate-triazole units into peptide backbone

Article abstract of DOI:10.1007/s10989-010-9228-6

Synthesis of new types of peptidomimetics and glycosylated amino acids possessing 1,2,3-triazole and carbamate moieties is described. Poc-protected amino acid esters/1-amino sugars were subjected to Cu(I) catalyzed [2+3]cycloaddition with desired azides u

Full text of DOI:10.1007/s10989-010-9228-6

Int J Pept Res Ther (2010) 16:267–275
DOI 10.1007/s10989-010-9228-6
Synthesis of Hybrid Peptidomimetics and Neoglycoconjugates
Employing Click Protocol: Dual Utility of Poc-Group for Inserting
Carbamate-Triazole Units into Peptide Backbone
•
Hosahalli P. Hemantha Ravi S. Lamani
•
Vommina V. Sureshbabu
Accepted: 29 July 2010 / Published online: 11 August 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Synthesis of new types of peptidomimetics and
glycosylated amino acids possessing 1,2,3-triazole and
carbamate moieties is described. Poc-protected amino acid
esters/1-amino sugars were subjected to Cu(I) catalyzed
[2?3]cycloaddition with desired azides under click proto-
col to obtain novel peptide and carbohydrate mimetics. The
reaction is rapid, efficient and all the products are isolated
in good yield and excellent purity.
prepared by replacing the amide bond with urethane moiety
have been observed to be active against HIV-I proteases
and also screened for binding to monoclonal antibodies
(Cho et al. 1993, 1998). Ureidopeptides such as HIV-I Tat
derived oligourea have been synthesized and found to bind
with high affinity to the trans-activation responsive region
of TAR-RNA (Wang et al. 1997). Recently, a pseudopep-
tide containing no amide bond but alternate ester and urea
moieties in the backbone have been synthesized and their
structural aspects were studied (Hartwig et al. 2010).
Similarly, the synthesis of unnatural oligocarbohydrates by
replacing native linkages with pseudo-glycosidic bonds is
also an emerging field of study (Dondoni et al. 2001).
1,3-Dipolar cycloaddition reactions leading to 5-mem-
bered rings have been one of the key tools in synthetic
organic chemistry whose present status can be attributed to
the pioneering works of Huisgen (1963a, b). The chemistry
of 1,2,3-triazoles accessible through 1,3-dipolar cycload-
dition of azides and alkynes is considered as cream of the
crop among Huisgen’s contributions in this area (Huisgen
1984). However, the thermal conditions employed in these
experiments lead to mixture of regioisomers which was a
serious limitation. Interesting discovery of Cu(I) catalyzed
azide-alkyne cycloaddition by Meldal and Sharpless inde-
pendently to construct 1,2,3-triazoles has gained tremen-
dous interest among synthetic and biological chemists
(Tornoe et al. 2002; Rostovtsev et al. 2002; Kolb and
Sharpless 2003). Due to its exceptional chemo-selectivity,
mild reaction conditions, the click chemistry has cemented
a place of its own in discovering new molecules as drug
candidates and also in library synthesis (Kolb et al. 2001;
Tornoe et al. 2004). A diverse range of substrates starting
from simple organic molecules (Krasinski et al. 2005) to
peptides (Bock et al. 2007), carbohydrates (Dedola et al.
2007; Wilkinson et al. 2006), and nucleic acids are
Keywords Peptidomimetics Á Click chemistry Á
Poc-group Á 1,2,3-triazole Á Carbamate Á Hybrid mimetics
Introduction
The synthesis of peptidomimetics (Nielson 2004; Vagner
et al. 2008) by the replacement of native amide bond with
unnatural bio-potent tethers is a fruitful endeavor in
drug discovery (Seebach and Gardiner 2008; Sewald and
Jakubke 2002). In the past, a wide variety of backbone-
modified peptides such as azapeptides, phosphopeptides,
ureidopeptides, carbamates, and heterocycle embedded
peptides (Fig. 1) have been reported (Gellman 1998;
Videnov et al. 1996; Goodman et al. 2003; May and Abell
2002; Phillips et al. 2000; You and Kelly 2004). The
pharmacological potency of some of these tether-possess-
ing peptidomimetics is found to be higher than that of the
natural peptides. For example, the peptidyl carbamates,
H. P. Hemantha Á R. S. Lamani Á V. V. Sureshbabu (&)
Peptide Research Laboratory, Department of Studies in
Chemistry, Central College Campus, Bangalore University,
Dr. B. R. Ambedkar Veedhi, Bangalore 560 001, India
e-mail: sureshbabuvommina@rediffmail.com;
hariccb@hotmail.com; hariccb@gmail.com
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Int J Pept Res Ther (2010) 16:267–275
O
R
O
O
R
H
H
N
N
HN
N
O
N
Ph
H
Ph
N
MeO
O
R
O
N
O
O
native peptide
CF3
S
N
N
N
N
O
N
O
R
O
R
N
R
H
OH
N
H
H
H
H
HO
OH
O
N
N
N
N
O
N
Fokin et al.,
Fokin et al.,
H
O
R
O
R
O
R
R
OH
O
ureido peptide
peptidyl carbamate
OH
HO
H
O
O
O
N
O
N
N
HO
R
OH
OH
R
R
O
R
O
R
O
N
H
H
N
O
O
Nilsson et al.,
N
N
N
O
H
H
O
O
O
R
O
Fig. 2 Selected examples of triazole-carbamate bearing biologically
active compounds
pseudopeptide with no amide bond
depsi peptide
Ph
N
N
R
R
N
O
O
O
was described by Wang and co-workers (Liu et al. 2007).
In addition, aryl-1,2,3-triazole-4,5-dimethanol-4,5-bis(iso-
propylcarbamates) have also been synthesized as potential
antineoplastic agents (Lalezari et al. 1990). While Berg-
meier et al., synthesized nonactic acid libraries containing
the foresaid moieties (Luesse et al. 2008), Nilsson has
reported multivalent lactose derivatives as selective gal-
actin-1 inhibitors (Tejler et al. 2006). Thus, from these
studies it is quite apparent that triazole and carbamate units
have played significant role in enriching pharmacokinetics
of various classes of molecules. On the other hand, design
of short peptide based drugs by inserting one or more
artificial tethers have brought interesting results and thus
offer further prospectives (Bock et al. 2007; Cho et al.
1993). Based on the fact that triazole and carbamate
functionalities individually have been employed as non
amidic linkages in peptidomimetic synthesis, we envi-
sioned that a hybrid peptide stitched using both these
functionalities would result in interesting results. In the
present study, we report a facile synthesis of such hybrid
mimetics employing a click reaction between appropriate
azide and alkyne derivatives. The protocol is also extended
to prepare neoglycosylated amino acids and neoglyco-
conjugates linked through 1,2,3-triazole-carbamate moiety.
Such functional integration may offer better insight into
structure–activity relationships.
N
N
N
N
H
N
N
H
H
R
O
HN
N
H
oxazoline linked peptide
imidazole linked peptide
tetrazole bearing peptide
Fig. 1 Selected examples among various peptide backbone modifi-
cations
employed, into which 1,2,3-triazole moiety is inserted to
prepare a wide variety of molecular architectures. Several
members of 1,2,3-triazole family have shown interesting
biological properties such as anti-bacterial, anti-HIV-I
protease inhibition (Brik et al. 2005). Thus, Cu(I) catalyzed
1,2,3-triazole synthesis has been employed for the con-
struction of macrocycles, polymers, dendrimers, supra-
molecular assemblies and many more (Gil et al. 2007). In
peptide chemistry, 1,2,3-triazoles are employed in the
synthesis of b-turn mimetics (Angell and Burgess 2005),
cyclic peptides (Bock et al. 2006), pseudo-peptides,
a-helical coils (Horne et al. 2004), glyco-clusters, folda-
mers (Angelo and Arora 2005; Kuijpers et al. 2004) and
Nanotubes (Horne et al. 2003). On the other hand, carba-
mate functionality is also well known for its vital role in
several bioactive molecules (Cho et al. 1993). Many linear
and cyclic oligocarbamates have been tested for binding to
the integrin GP IIb/IIIa and several others of this class have
been screened for inhibitory activity against porcine pan-
creatic elastase, trypsin, chymotrypsin and also against
HIV proteases (Moran et al. 1995).
Propargyloxycarbonyl (Poc) group has been introduced
recently as protecting group for alcohols, amines and car-
boxylic acids (Ramesh and Chandrasekaran 2005).
Chandrasekaran et al. reported the protection of carboxylic
acids as prop-2-ynyl esters and demonstrated their selective
cleavage under mild conditions using tetrathiomolybdate
(Ilankumaran et al. 1996). The Poc group is also employed
for masking amine functionality in amino acids, peptides,
and hydroxy groups of sugar units (Sridhar and Chandr-
asekaran 2002). We envisioned that Poc group along with
masking the amine functionality, can also serve as useful
monomeric building block for a cycloaddition reaction
with a substituted azide owing to the presence of alkyne
Our interest in the synthesis of structurally diverse
classes of peptidomimetics and neoglyco-conjugates
(Sureshbabu et al. 2006, 2008a, 2009; Hemantha and
Sureshbabu 2009) prompted us to design a simple route for
the insertion of both 1,2,3-triazole and carbamate moieties
in the molecular backbone (Fig. 2). It has been reported by
Fokin’s group that molecules bearing 1,2,3-triazole and
carbamate groups serve as HIV-I protease inhibitors
(Whiting et al. 2006a, b). A similar category of linear
multifunctional polyethylene glycol containing molecules
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Int J Pept Res Ther (2010) 16:267–275
269
group leading to the formation of 1,2,3-triazole. Chandr-
asekaran and co-workers prepared few peptide derivatives
bearing Lys, the x-amino group of which was functional-
ized with Poc group and subjected to click reaction with
glycosyl azides to insert a triazole linkage (Chakrabarty
et al. 2009). However, a meticulous study on the dual
utility of Poc functionality facilitating the insertion of
carbamate-triazole units between either two amino acids or
amino acid–glucose units to obtain the corresponding
peptidomimetics and glyco-conjugates is yet to be
demonstrated.
146, 158, 158.2, 173.1. ESI–MS: m/z calcd for
C34H37N5O6: 611.6; found: 612.3 [M?H].
5b: Solid, mp 146°C, 1H NMR (300 MHz, CDCl3):
d = 1.32 (3H, d, J = 3.9 Hz), 1.41–1.63 (4H, m),
3.22–3.41 (2H, m), 3.81(1H, m), 3.66 (3H, s), 4.09–4.21
(4H, m), 4.33–4.46 (3H, m), 5.12 (2H, s), 6.59 (1H, br),
7.26–7.81 (m, 9H); 13C NMR (100 MHz, CDCl3): d =
16.9, 23.8, 27.2, 46.9, 49.6, 51.1, 51.4, 55.0, 57.5, 60.9,
66.4, 120.2, 126.3, 126.5, 127.7, 127.9, 132.9, 142.1, 145,
159, 159.3, 172.9. HRMS: m/z calcd for C28H31N5NaO6:
556.2172; found: 556.2180 [M?Na].
5c: Solid, mp 150°C, 1H NMR (300 MHz, CDCl3):
d = 2.88 (2H, J = 4.5 Hz), 3.66 (3H, s), 3.79–3.82 (4H,
m), 4.18 (1H, m), 5.21 (2H, s), 5.92–6.11 (2H, br),
7.29–7.54 (11H, m); 13C NMR (100 MHz, CDCl3):
d = 38.6, 46.4, 52.9, 54.5, 57.3, 60.2, 68.2, 120.4, 126.4,
126.6, 127.7, 127.8, 128.5, 129.2, 138.1, 141.6, 142.2,
157.1, 157.3, 174. HRMS: m/z calcd for C24H27N5NaO6:
504.1859; found: 504.1851 [M?Na].
Materials and Methods
Chemicals and Instruments
All solvents were freshly distilled before use. Amino acids
1
were used as received from Sigma–Aldrich Company. H
NMR and 13C NMR were recorded on a Bruker AMX
300 MHz instrument with tetra methyl silane (TMS) as an
internal standard. Mass spectra were recorded on high
resolution mass spectra (HRMS) Q-Tof micro mass spec-
trometer. All the reactions were monitored using TLCs
with precoated silica gel plates purchased from Merck.
Column Chromatography was performed with Merck silica
gel (100–200) at normal atmospheric pressure.
5d: Off white solid, mp 152°C, H NMR (300 MHz,
1
CDCl3): d = 0.88 (6H, d, J = 4.5 Hz), 1.29 (2H, m), 1.63
(1H, m), 3.68 (3H, s), 3.89 (1H, m), 4.01–4.19 (4H, m),
4.40–4.50 (3H, m), 5.01 (1H, br), 5.14 (2H, s), 7.11 (1H,
br), 7.25–7.76 (9H, m). 13C NMR (100 MHz, CDCl3):
d = 22.3, 23.4, 42.1, 47.6, 47.8, 50.1, 58.0, 65.3, 66.8,
120.5, 125.2, 125.4, 125.5, 127.6, 128.2, 141.8, 144.2,
156.3, 156.7, 171.3. IR (Kbr): 2954, 1748, 1714,
1539 cm-1
. HRMS: m/z calcd for C28H33N5NaO6:
Synthesis
558.2329; found: 558.2317 [M?Na].
5e: Solid, mp 137°C, 1H NMR (300 MHz, CDCl3):
d = 0.96 (6H, J = 4.1 Hz), 1.29 (2H, m), 1.59 (1H, m),
2.92 (2H, d, J = 4.5 Hz), 3.62 (3H, m), 3.85–4.39 (4H, m),
4.99 (2H, s), 5.02 (2H, s), 5.21 (1H, br), 6.09 (1H, br),
7.19–7.64 (11H, m), 13C NMR (100 MHz, CDCl3):
d = 19.7, 23, 38.6, 43.9, 44.1, 47.9, 48.8, 58.9, 61.2, 66.9,
119.7, 126.5, 127.1, 127.7, 128.4, 138.2, 141.1, 142.2,
156.7, 156.8, 174.2. HRMS: m/z calcd for C28H35N5NaO6:
560.2485; found: 560.2492 [M?Na].
General Procedure for the Synthesis of 5a–i, 7a–c, 10a–c,
12a–c and 13a–c
A solution of appropriate azide (2 mmol) and Poc-amine (3
or 6 or 9 or 12, 2 mmol) in tert-BuOH/water (15 mL, 8:4)
was treated with CuSO4Á5H2O (0.05 mmol) and sodium
ascorbate (0.5 mmol) at room temperature for 2 h (fol-
lowed through TLC). Excess water (30 mL) was added and
the precipitated product was filtered, washed with water
and dried. A recrystallization with MeOH:CH2Cl2 gave the
product as pure white solid. In the case of reactions
involving Z-amino acid derivatives and sugar components,
the isolation of the product was facilitated by extraction
with ethyl acetate followed by an aqueous wash. Column
purification was done wherever necessary.
5a: White solid, mp 162°C, 1H NMR (300 MHz,
CDCl3): d = 0.91 (6H, d, J = 4.4 Hz), 1.31 (2H, m), 1.59
(1H, m), 2.87 (2H, d, J = 4.3 Hz), 3.64 (3H, s), 3.86 (1H,
m), 4.21–4.25 (3H, m), 4.36–4.44 (3H, m), 5.16 (1H, br),
5.18 (2H, s), 6.31 (1H, br), 7.09 (1H, s), 7.32–7.69
(m,13H); 13C NMR (100 MHz, CDCl3): d = 17.2, 22.3,
32.8, 47.1, 47.8, 51.3, 51.9, 57.1, 58.7, 69.9, 121.1, 126.1,
126.2, 126.6, 127.3, 127.5, 128, 129.3, 141.1, 141.8, 145.1,
5f: Solid, mp. 158°C, 1H NMR (300 MHz, CDCl3):
d = 0.96 (3H, t), 1.06 (3H, d, J = 3.6 Hz), 1.21 (2H, m),
1.30 (1H, m), 3.67 (3H, s), 3.81–4.29 (4H, m), 4.41–4.47
(m, 3H), 4.98 (2H, s), 5.20 (1H, br), 6.22 (1H, br),
7.25–7.71 (14H, m), 13C NMR (100 MHz, CDCl3):
d = 15.8, 16.6, 18.1, 20.2, 46.7, 48.4, 53.2, 54.4, 58.5,
60.3, 69.1, 121.6, 126.4, 126.5, 127.4, 127.9, 128.8, 130.5,
136.6, 136.8, 139.4, 142.6, 156.2, 156.5, 173.1. HRMS:
m/z calcd for C34H37N5NaO6: 634.2642; found: 634.2655
[M?Na].
5g: Solid, mp. 123°C, 1H NMR (300 MHz, CDCl3):
d = 0.96 (3H, t), 1.06 (3H, d, J = 3.9 Hz), 1.26 (2H, m),
1.32 (1H, m), 1.90–2.21 (7H, m), 3.66 (3H, s), 3.79–4.19
(3H, m), 4.22 (2H, d, J = 5.1 Hz), 4.43–4.47 (2H, m), 5.11
(2H, s), 5.31 (1H, br), 6.18 (1H, br), 7.26–7.69 (9H, m).
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13C NMR (100 MHz, CDCl3): d = 12.2, 17.1, 20.4, 21.2,
22.1, 30.2, 33.5, 47.8, 47.9, 53.7, 55.4, 59.1, 63.1, 68.1,
120.5, 127.5, 127.9, 128.4, 129.1, 139.4, 141.7, 144.1,
153.3, 153.6, 173.2. ESI–MS: calcd for C31H39N5O6S:
609.7; found: 610.8 [M?H].
144.1,154.4, 155.2, 157.3, 172.9. HRMS: m/z calcd for
C40H45N9NaO8: 802.3289; found: 802.3299 [M?Na].
10a: Gummy solid, 1H NMR (300 MHz, CDCl3):
d = 0.96 (6H, d, J = 4.1 Hz), 1.30 (3H, d, J = 3.5 Hz),
1.53 (1H, m), 2.89 (2H, d, J = 3.6 Hz), 3.64 (3H, s), 3.78
(1H, m), 3.96–4.09 (3H, m), 4.68–4.94 (4H, m), 5.17 (2H,
s), 5.69–6.01 (3H, br), 7.22–7.54 (14H, m). 13C NMR
(100 MHz, CDCl3): d = 18.1, 18.9, 32.1, 39.6, 47.62,
48.9, 49.3, 52.4, 55.1, 58.8, 59.8, 67.7, 119.7, 126.2, 126.8,
127.4, 128.2, 128.5, 128.5, 129.1, 139.6, 140.2, 142.4,
143.2, 156.4, 156.7, 170.0, 174.2. HRMS: m/z calcd for
C37H42N6NaO7: 705.3013; found: 705.3028 [M?Na].
10b: Gummy solid, 1H NMR (300 MHz, CDCl3):
d = 0.92 (6H, d, J = 4.6 Hz), 1.21 (2H, m), 1.56 (1H, m),
1.87 (3H, s), 1.92–2.31 (4H, m), 3.52 (3H, s), 3.92–3.99
(2H, m), 4.23 (2H, d, J = 4.2 Hz), 5.01 (2H, s), 5.30–5.51
(4H, m), 5.60–5.91 (3H, br), 6.92–7.13 (6H, m). 13C NMR
(100 MHz, CDCl3): d = 18.2, 20.3, 22.0, 32.7, 33.1, 38.2,
42.4, 44.1, 50.7, 51.6, 58.2, 61.7, 66.7, 118.9, 125.4, 126.3,
127.2, 139.2, 140.3, 154.1, 155.3, 170.3, 172.2. IR (KBr):
5h: Solid, mp. 135°C, 1H NMR (300 MHz, CDCl3):
d = 0.96 (6H, d, J = 4.2 Hz), 1.29 (2H, m), 1.34 (3H, d,
J = 3.1 Hz), 1.56 (1H, m), 3.61 (3H, s), 3.90–4.22 (4H,
m), 4.43–4.59 (3H, m), 4.94 (2H, s), 5.26 (1H, br), 6.22
(1H, br), 7.24–7.76 (9H, m), 13C NMR (100 MHz, CDCl3):
d = 17.1, 20.4, 21.2, 22.1, 47.6, 47.8, 53.7, 55.4, 59.1,
63.1, 68.5, 119.6, 126, 127.4, 127.7, 129.5, 140.3, 141.7,
142.5, 155, 155.6, 174.3. HRMS: m/z calcd for
C29H35N5NaO6: 572.2485; found: 572.2499 [M?Na].
5i: White solid, mp. 162°C, 1H NMR (300 MHz,
CDCl3): d = 0.95 (6H, d, J = 4.5 Hz), 1.29 (3H, d,
J = 3.9 Hz), 1.55 (1H, m), 3.61 (3H, s), 3.91–4.26 (4H,
m), 4.51 (3H, m), 5.01 (2H, s), 5.20 (1H, br), 6.20 (1H, br),
7.29–7.68 (9H, m). 13C NMR (100 MHz, CDCl3):
d = 18.1, 32.6, 47.3, 49.1, 53.3, 55.4, 56.6, 59.8, 68.5,
120.1, 126.4, 126.9, 127.3, 129.4, 139.8, 140.6, 142.1,
156.3, 156.8, 173.4. HRMS: m/z calcd for C28H33N5NaO6:
558.2329; found: 558.2338 [M?Na].
2952, 1738, 1690 cm-1
.
HRMS: m/z calcd for
C26H38N6NaO7S: 601.2420; found: 601.2431 [M?Na].
10c: Gummy solid, 1H NMR (300 MHz, CDCl3):
d = 1.29 (3H, d, J = 3.9 Hz), 1.90–2.29 (7H, m), 3.61
(3H, s), 4.06–4.20 (4H, m), 4.29–4.34 (3H, m), 4.71 (1H,
m), 5.29 (2H, s), 5.54–5.62 (br, 3H), 7.11–7.34 (14H, m).
13C NMR (100 MHz, CDCl3): d = 20.2, 21.6, 32.4, 33.6,
47.5, 51.2, 51.6, 54.2, 56.1, 57.7, 59.9, 68.1, 119.9, 126.4,
126.8, 127.2, 128.1, 128.4, 129.6, 129.8, 139.4, 140.1,
142.4, 142.6, 155.3, 155.6, 171.1, 174.3. HRMS: m/z calcd
for C36H40N6NaO7S: 723.2577; found: 723.2593 [M?Na].
12a: Gum; 1H NMR (300 MHz, CDCl3): d = 1.20 (3H,
d, J = 5.2 Hz), 1.92 (12H, s), 3.77 (1H, m), 3.83 (2H, d,
J = 3.8 Hz), 4.21–4.40 (3H, m), 4.55 (2H, d, J = 4.5 Hz),
4.82 (2H, s), 4.91–5.25 (3H, m), 5.66 (2H, m), 6.52 (2H,
br), 7.35–7.81 (9H, m). 13C NMR (100 MHz, CDCl3):
d = 18.9, 20.7, 21.1, 21.2, 44.1, 46.3, 59.1, 62.3, 62.8,
66.8, 68.8, 73.5, 73.8, 77.6, 81.1, 120.1, 126.7, 127.5,
128.2, 128.5, 141.2, 141.8, 143.5, 156.0, 156.7, 170.2. IR:
2970, 1763, 1750, 1731, 1717, 1530 cm-1. HRMS: m/z
calcd for C36H41N5NaO13: 774.2599; found: 774.2680
[M?Na].
12b: 1H NMR (300 MHz, CDCl3): d = 0.96 (6H, d,
J = 4.5 Hz), 2.11 (12H, s), 2.21 (1H, m), 3.52 (1H, m),
4.13 (2H, d, J = 5.0 Hz), 4.32 (2H, d), 4.62–4.81 (4H, m),
5.12 (2H, s), 5.23 (2H, s), 5.42 (1H, m), 6.21 (2H, br),
7.12–7.54 (6H, m). 13C NMR (100 MHz, CDCl3):
d = 18.3, 20.2, 20.3, 32.5, 50.1, 57.2, 61.2, 64.1, 66.7,
68.6, 72.2, 73.4, 77.2, 80.6, 121.5, 127.8, 128.7, 130, 140.3,
142.4, 157.2, 157.4, 171.3. HRMS: m/z calcd for
C31H41N5NaO13: 714.2599; found: 714.2589 [M?Na].
12c: Gum; 1H NMR (300 MHz, CDCl3): d = 2.88 (2H,
d, J = 4.2 Hz), 3.80 (1H, m), 3.82–3.86 (2H, m),
7a: Gum, 1H NMR (300 MHz, CDCl3): d = 0.90 (6H, d,
J = 4.8 Hz), 1.12 (2H, m), 1.56 (1H, m), 1.37 (3H, d,
J = 6.1 Hz), 2.86 (2H, d, J = 4.7 Hz), 3.68 (3H, s),
4.13–4.17 (3H, m), 4.27–4.33 (4H, m), 4.51 (3H, m), 5.06
(2H, s), 5.17 (2H, s), 5.37–5.78 (3H, br), 7.22–7.74 (15H,
m). 13C NMR (100 MHz, CDCl3): d = 17.6, 20.6, 20.8,
21.6, 22.7, 24.6, 37.8, 41.2, 47.1, 52.0, 52.2, 58.1, 62.2, 66.6,
69.0, 119.9, 124.8, 125.0, 126.9, 127.0, 127.7, 128.4, 128.5,
128.7, 129.2, 130.1, 136.6, 141.2, 143.1, 153.7, 155.3,
155.8, 173.6. IR (KBr): 2964, 1741, 1698, 1520 cm-1
.
HRMS: m/z calcd for C42H49N9NaO8: 830.3602; found:
830.3615 [M?Na].
7b: Gum, 1H NMR (300 MHz, CDCl3): d = 0.99 (6H, d,
J = 4.7 Hz), 1.66–2.52 (11H, m), 3.62 (3H, s), 3.91–4.05
(3H, m), 4.11–4.24 (3H, m), 4.30–4.34 (4H, m), 4.97 (2H, s),
5.16 (2H, s), 5.29 (1H, br), 5.46–5.71 (2H, br), 7.24–7.77
(10H, m). 13C NMR (100 MHz, CDCl3): d = 17.6, 18.6,
22.1, 32.1, 32.6, 42.0, 48.0, 48.2, 52.5, 56.4, 56.6, 58.5, 59.1,
60.4, 60.7, 69.2, 121.7, 122.6, 126.1, 126.7, 128.1, 128.9,
139.4, 141.4, 142.4, 143.4, 153.8, 155.6, 156.7, 171.3;
HRMS: m/z calcd for C37H47N9NaO8S: 800.3166; found:
800.3174 [M?Na].
7c: Gum, 1HNMR (300 MHz, CDCl3): d = 0.99 (6H, d,
J = 3.9 Hz), 1.31 (2H, m), 1.54 (1H, m), 3.69 (3H, s),
3.89–4.12 (3H, m), 4.20–4.32 (4H, m), 4.50 (3H, m), 5.09
(2H, s), 5.21 (2H, s), 5.42 (1H, m), 5.63–6.09 (3H, br),
7.26–7.84 (15H, m), 13C NMR (100 MHz, CDCl3):
d = 18.1, 20.1, 32.6, 47.4, 50.6, 51.9, 55.3, 57.1, 58.5,
58.7, 59.9, 60.2, 68.1, 120.5, 121.1, 126.3, 126.4, 127.1,
127.6, 127.9, 128.2, 128.9, 139.6, 142.3, 142.4, 143.9,
123

Int J Pept Res Ther (2010) 16:267–275
271
4.21–4.42 (3H, m), 4.47 (2H, d, J = 3.9 Hz), 4.84 (2H, s),
5.01–5.27 (3H, m), 5.71 (2H, m), 6.62 (2H, br), 7.49–7.78
(34H, m). HRMS: m/z calcd for C62H53N5NaO13:
1098.3538; found: 1098.3553 [M?Na].
13a: Gum; 1H NMR (300 MHz, CDCl3): d = 2.13
(12H, s), 2.17 (12H, s), 2.91 (4H, m), 3.65–3.89 (8H, m),
5.11 (2H, s), 5.32–5.45 (2H, m), 6.31 (br, 1H), 7.16 (1H, s).
HRMS: m/z calcd for C32H42N4NaO20: 825.2290; found:
825.2281 [M?Na].
13b: Gum; 1H NMR (300 MHz, CDCl3): d = 2.07
(12H, s), 4.48–4.59 (4H, m), 4.81–4.93 (4H, m), 5.01–5.11
(4H, m), 5.17 (2H, s), 5.41 (1H, m), 5.62 (1H, m), 6.32
(1H, br), 7.16 (1H, s), 7.23–7.68 (20H, m). 13C NMR
(100 MHz, CDCl3): d = 20.6, 21.3, 63.2, 65.6, 66.2, 70.7,
71.2, 71.4, 72.3, 72.4, 72.6, 75.6, 82.3, 85.6, 121.7, 128.7,
129.2, 131.6, 133.1, 143.2, 155.3, 162.4, 165.2, 165.3,
166.3, 168.6, 170.3. ESI–MS calcd for C52H50N4NaO20:
1073.96; found 1075.01 [M?Na].
13c: Gum; 1H NMR (300 MHz, CDCl3): d = 2.10
(12H, s), 4.38–4.46 (4H, m), 4.81–4.93 (4H, m), 5.00–5.18
(4H, m), 5.20 (2H, s), 5.55 (1H, m), 5.68 (1H, m), 6.82
(1H, br), 7.08 (1H, s), 7.24–7.66 (20H, m).
In the next stage, the cycloaddition of N-protected
amino alkyl azide 4 and Poc-protected amino acid ester 3
was undertaken. Widely employed CuSO4Á5H2O/sodium
ascorbate (Na-AsA) system was used as Cu(I) source in
tert-BuOH/water system (Rostovtsev et al. 2002). In a
typical reaction, a solution of N-Poc-Val-OMe and
N-Fmoc-Phe-w[CH2N3] was treated with catalytic amount
of CuSO4Á5H2O and Na-AsA. The reaction was complete in
about 2 h (as monitored by TLC, Scheme 1, Table 1). On
addition of excess water, the dipeptidomimetic 5a precipi-
tated out which was collected by filtration. In the case of
those that did not precipitate from the reaction mixture,
especially while using Z-protected amino acid derivatives,
the product was isolated through simple work-up (Table 1).
Similar conditions were exercised to prepare a few more
examples (5b–i) employing other amino acid derivatives as
well to afford the products in good yield. The HPLC purity
of the crude samples was found to be 91–92%, which were
further purified through column chromatography to above
99%.
We then turned our attention towards the extension of
dipeptidomimetics 5 from N-terminus to afford tripeptidyl
derivatives. N-Fmoc-protected dipeptidomimetic 5h was
selected as a specimen example. The amine was deprotected
from Fmoc group using diethylamine (DEA)-CH2Cl2 mix-
ture (1:1) and the resulting free amino compound was
reacted with 1 to afford the corresponding Poc-functional-
ized dipeptidomimetic 6a. It was isolated after a usual
work-up and then subjected to click reaction with N-Fmoc-
Phe-w[CH2N3]. This led to the desired tripeptidomimetic 7a
in 75% yield (Scheme 2). Two more trimers 7b and 7c were
also synthesized in a similar manner. As can be expected,
the solubility of the tripeptidyl derivatives 7 possessing two
triazole-carbamate moieties decreased to a noticeable
extent when compared to their precursors.
Results and Discussion
Poc-OPfp 1 was prepared by following the reported pro-
cedure (Bhat et al. 2002). It was then treated with amino
acid esters 2 in the presence of triethyl amine (TEA) for
about an hour to obtain N-Poc-amino acid esters 3 in good
yields after a simple work up (Scheme1). Parallely, the
Nb-protected amino alkyl azides 4 were made starting from
Na-Fmoc/Z-amino acids (Sureshbabu et al. 2009). Briefly,
N-protected amino acid was converted to the correspond-
ing alcohol via the reduction of its mixed anhydride using
moist NaBH4. The resulting b-aminol was then subjected
to Mitsunobu reaction (PPh3/imidazole/I2) to afford the
corresponding iodo derivative which on treatment with
NaN3 in DMF at room temperature furnished the desired
N-Fmoc/Z-amino alkyl azide 4.
It is known that an amino acid on reaction with two-fold
excess of Poc-OPfp 1 undergoes simultaneous amino pro-
tection as well as carboxy group activation (Ramesh et al.
2006; Ramapanicker et al. 2009). This kind of strategy
would give a useful intermediate for click reaction leading
to another class of hybrid molecules containing an amide
bond and one 1,2,3-triazole-carbamate unit. While active
OPfp ester terminal reacts with an amine such as amino
acid ester to give a peptide bond, Poc group participates in
cycloaddition reaction with an azide resulting in the
insertion of 1,2,3-triazole functionality. Towards this end,
Na-Poc-amino acid pentafluorophenyl esters 8 were pre-
pared. In the next stage, Na-Poc-amino acid active esters 8
were treated with amino acid esters to afford Na-Poc-
dipeptide esters 9 and were then subjected to Cu(I) medi-
ated cycloaddition with N-protected-amino alkyl azides 4
to afford corresponding class of 1,2,3-triazole-carbamate-
linked tripeptidomimetics 10 in good yields (Scheme 3).
F
R1
H
O
O
F
F
F
TEA
CH2Cl2
O
N
COOMe
H2N
COOMe
+
O
R1
2
O
3
F
Poc-OPfp, 1
R2
R2
N
N
H
N
N3
O
COOMe
N
Pg-HN
4
Pg-HN
O
R1
CuSO4. 5H2O
Na-AsA
tert-BuOH/ water
5
Pg = Fmoc or Z group
Scheme 1 Synthesis of Na-Poc-amino acid esters
3-triazole-carbamate-linked dipeptidomimetics 5
3 and 1,2,
123

272
Int J Pept Res Ther (2010) 16:267–275
Table 1 List of triazole-carbamate hybrid dipeptidomimetics
S. no.
Entry
Yield (%)
HRMS [M?Na] found/calcd
R2
N
N
N
H
O
N
COOMe
Pg-NH
O
R1
Pg
R1
R2
1
2
3
4
5
6
7
8
9
a
5a
5b
5c
5d
5e
5f
Fmoc
Fmoc
Z
CH2C6H5
CH3
CH(CH3)2
88
80
84
90
88
87
79
92
89
612.3/611.6a
–(CH2)3–
H
556.2180/556.2172
504.1851/504.1859
558.2317/558.2329
560.2492/560.2485
634.2641/634.2642
610.8/609.7a
CH2C6H5
H
Fmoc
Z
CH2CH(CH3)2
CH2CH(CH3)2
C6H5
CH2C6H5
Fmoc
Fmoc
Fmoc
Fmoc
CH(CH3)CH2CH3
CH(CH3)CH2CH3
CH2CH(CH3)2
CH(CH3)2
5g
5h
5i
CH2CH2SCH3
CH3
572.2499/572.2485
558.2338/558.2329
CH3
ESI–MS
N
N
employed as building blocks for constructing correspond-
ing oligomers. In continuation of such studies the utility of
the present protocol was elaborated into the synthesis of
few model glycoconjugates. Thus, the triazole-carbamate
combination was inserted between an amino acid and a
carbohydrate as well as between two sugar units. The
required 1-N-Poc-amino sugars 11, were prepared through
the reaction of Poc-OPfp 1 with 1-amino sugars. Two
monosaccharides-Glu and Gal were selected for this study
whose hydroxy groups were first protected as correspond-
ing acetyl or benzoyl esters followed by the insertion of
amine functionality at the anomeric carbon (Scheme 4)
employing known procedures (Deng et al. 2006). Then a
cycloaddition reaction of 11 with azide 4 afforded neo-
glycosylated amino acids 12 (Table 2). A flash chromato-
graphic purification afforded the desired compounds in
excellent yield and purity as well. Under identical condi-
tions, 1-N-Poc-amino sugars 11 were reacted with 1-azido
sugars to obtain carbamate-1,2,3-triazole tethered neo-
glycoconjugates 13 (Scheme 4). All the compounds were
isolated and adequately characterized.
O
O
R2
N
H
N
4, "click"
1. DEA/CH2Cl2
O
O
COOMe
COOMe
5
N
2. 1, TEA
O
O
N
H
O
O
R1
R1
6
R2
N
N
H
N
FmocNH
R3
N
N
H
N
N
7
7a: R1 =CH2CH(CH3)2; R2 =CH3, R3 =CH2C6H5; 75%
7b: R1 =CH(CH3)2; R2 =CH3, R3 =CH2CH2SCH3; 78 %
7c: R1 =H; R2 =CH3CH(CH3)2; R3 =C6H5; 72 %
Scheme 2 Synthesis of tripeptidomimetics 7 containing two triazole-
carbamate units
Three examples were made in this category and in all the
experiments, consistent yield and purity of the corre-
sponding tripeptidomimetics 10a–c were recorded.
In the final part of this study, the protocol was extended
to synthesize some exemplary neoglycosylated amino acids
and neoglycoconjugates by inserting carbamate-1,2,3-tria-
zole functionality in between a sugar and an amino acid
and also between two sugar units. We previously had
reported urea and thiourea linked neoglycosylated amino
acids (Sureshbabu et al. 2008b, 2010) which can be
R2
Scheme 3 Synthesis of
tripeptidomimetic hybrids 10
R1
O
R1
O
R1
H
H2N
COOMe
N
COOMe
OPfp
1
O
N
O
N
H
H2N
COOH
H
O
R2
O
8
9
O
R1
H
N
COOMe
4, " Click" PgHN
O
N
H
N
N
N
O
R2
R3
10
10a: Pg = Fmoc; R1 = CH3; R2 = CH2C6H5; R3 = CH(CH3)2; 82%
10b: Pg = Z; R1 = CH2CH(CH3)2; R2 = H; R3 = CH2CH2SCH3; 80%
10c: Pg = Fmoc; R1 = CH2CH3SCH3; R2 = CH3; R3 = C6H5; 77%
123

Int J Pept Res Ther (2010) 16:267–275
273
H
Scheme 4 Synthesis of
neoglycoconjugates
O
N
O
1, TEA
R4O
O
NH2
R4O
O
11
R4 = -OAc, -OBz
O
N3
OR4
R4O
R2
N
N
N
N
N
N
O
O
OR4
H
4, Click
Click
H
O
N
O
NHPg
11
N
O
R4O
O
13
O
12
Table 2 List of
Sl.
Neoglycosylated amino acids 12
Yield
(%)
Neoglycoconjugates 13
Yield
(%)
triazole-carbamate tethered
neoglycosylated amino acids
and neoglycocojugates
No
OAc
O
AcO
AcO
OAc
N
N
N
N
N
N
H
H
OAc
OAc
O
AcO
AcO
N
O
O
N
O
HNFmoc
AcO
13a AcO
AcO
O
AcO
1
77
78
80
12a
O
OAc
O
AcO
AcO
OBz
N
N
AcO
AcO
N
H
OAc
O
N
OBz
OBz
N
N
O
H
N
O
N
BzO
O
HNZ
AcO
2
3
72
13b
O
12b
AcO
O
Ph
BzO
BzO
OAc
OBz
O
AcO
O
N
N
N
OBz
O
N
H
H
N
N
69
N
74
N
O
BzO
BzO
O
HNFmoc
AcO
OAc
BzO
13c
BzO
O
12c
O
Indian Institute of Science, Bangalore, India are thanked for spectral
data.
Conclusion
In summary, a facile protocol for the incorporation of a
combination of 1,2,3-triazole-carbamate units into peptide
backbone is developed utilizing Poc chemistry. The
extension of the resulting dipeptidomimetics into trimers
containing two such hybrid units in the backbone is dem-
onstrated. Also, another class of unnatural tripeptides
containing one amide and a 1,2,3-triazole-carbamate unit is
synthesized. In view of the importance of backbone mod-
ified peptides and glycoconjugates, and also the usefulness
of carbamate-triazole linkage, a protocol was developed to
access peptidomimetics exploiting the dual utility of Poc
functionality. The Poc group served as amine protection
while exercising carboxy modification and later as a sub-
strate for click reaction. Further, the two functionalities
have also been inserted between an amino acid and a sugar
component as well as between two sugar units leading to
the generation of respective classes of hybrid glycomics.
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