Novel synthesis of carbohydrate fused α-amino γ-lactams and glycopeptides by NIS mediated ring opening of donor-acceptor substituted cyclopropanes

Article abstract of DOI:10.1016/j.carres.2014.02.022

α-Amino γ-lactams have been synthesized from carbohydrate derived cyclopropanecarboxylates using N-iodosuccinimide (NIS) and NaN ₃. Cyclopropane ring opening with NIS and NaN₃ in different solvents has been studied. Reductive cyclization of the intermediate di-azides leads to the carbohydrate fused α-amino γ-lactam and γ-lactams. Additionally, the methodology has been successfully extended to the synthesis of a glycopeptide.

Full text of DOI:10.1016/j.carres.2014.02.022

Carbohydrate Research 390 (2014) 1–8
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Novel synthesis of carbohydrate fused a-amino c-lactams and
glycopeptides by NIS mediated ring opening of donor–acceptor
substituted cyclopropanes
⇑
Gade Kishore, Vibha Gautam, Srinivasan Chandrasekaran
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Amino c-lactams have been synthesized from carbohydrate derived cyclopropanecarboxylates using
Received 13 December 2013
Received in revised form 19 February 2014
Accepted 22 February 2014
Available online 4 March 2014
N-iodosuccinimide (NIS) and NaN3. Cyclopropane ring opening with NIS and NaN3 in different solvents
has been studied. Reductive cyclization of the intermediate di-azides leads to the carbohydrate fused
a-amino
c-lactam and c-lactams. Additionally, the methodology has been successfully extended to the
synthesis of a glycopeptide.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Donor–acceptor cyclopropane
Ring opening
c
-Lactam
Glycopeptide
N-Iodosuccinimide
Reductive cyclization
c
-Lactam is a key unit in numerous natural products and many
synthetic analogues exhibit diverse biological activities.1–3 Due to
the development of antibiotic resistance, -lactams are being used
as bioisosteres to the most popular b-lactam antibiotics.4–6
-Ami-
no -lactam (Freidinger–Veber lactam) bridged peptides are more
active agonists to lutropin-releasing hormone than parent peptide
analogues.7
-Cycloserine and (+)-HA-966 are antagonists at the
glycine site of N-methyl-
-aspartate (NMDA) receptors (Fig. 1).8
-Amino
c
-lactams are very similar to polyhydroxylated heterocycles like
carbohydrate fused pyrazolidin-3-one, isoxazolidin-5-one and pyr-
rolidine conjugates which are useful in studying the inhibition of
glycosidases.18,19
c
a
c
Only a few reports have been published on the synthesis of car-
bohydrate fused c-lactams. Calvo-Mateo et al. reported the forma-
D
tion of carbohydrate fused c-lactam as a side product in very low
D
yield (8%) during the synthesis of sugar amino acids.20 Pachamuthu
a
c
-lactam bears a close resemblance to
D
-cycloserine9
et al. utilized Michael addition of dimethyl malonate to tri-O-alkyl
and (+)-1-hydroxy-3-aminopyrrolidine-2-one (HA-966).10
glycal to achieve the synthesis of carbohydrate fused c
-lactams.21
The binding ability of striatal dopamine receptor agonists can
Yin and Linker have isolated a carbohydrate fused c-lactam during
potentially be enhanced by insertion of the
ety into peptide mimetics.11
-Amino -lactam derivatives exhibit
antiamensic properties at a low concentration (1 mg/Kg) when
a-amino
c
-lactam moi-
a study on the synthesis of the carbohydrate fused lactones.22
In continuation of our studies on the synthesis of carbohydrate
a
c
fused c
-lactones,23 herein, we disclose a flexible protocol for the
studied in mice.12
a-Amino
c
-lactam derivatives also moderately
synthesis of carbohydrate fused a-amino c-lactam by ring opening
inhibit the N-acyl-homoserine mediated bacterial signalling13
of carbohydrate derived donor–acceptor cyclopropanes.24–27 The
significant advantage of this method is that carbohydrate fused
and act as anti-inflammatory agents in vivo.14 Moreover, carbohy-
drate fused
GABAA receptor ligands in pharmacological studies.15 Carbohy-
drate fused amino -lactams are the derivatives of C-linked
glyco-amino-acids which are very stable, resistant to enzymatic
deglycosylation16 and have become very crucial synthons in the
development of anticancer vaccines.17 The carbohydrate fused
c
-lactams and lactones have been shown to be good
a
a
-amino
-amino
c
-lactam derivatives are readily converted easily into
c-lactam-bridged glycopeptide conjugates, subsequently.
a
c
We commenced our synthetic approach from the cyclopropanation
of tri-O-(tert-butyldimethylsilyl)- -glucal 1 using methyl diazoace-
tate and 2 mol% of Rh2(OAc)4 to give methyl exo- -1,2-cyclopropan-
D
a
ecarboxylate 2a (Scheme 1).28,29 When cyclopropanecarboxylate 2a
was treated with NIS and NaN3 in CH3CN, (rt, 12 h), it gave the cor-
responding iodo-azide 3a in very good yield (82%) with high
diastereoselectivity.
⇑
Corresponding author. Tel.: +91 80 22932404; fax: +91 80 23600529.
E-mail address: scn@orgchem.iisc.ernet.in (S. Chandrasekaran).
http://dx.doi.org/10.1016/j.carres.2014.02.022
0008-6215/Ó 2014 Elsevier Ltd. All rights reserved.

2
G. Kishore et al. / Carbohydrate Research 390 (2014) 1–8
via reductive intramolecular cyclization.30,31 After standardization
of the reaction protocol for glucose fused -amino -lactam 5a,
this general methodology was extended to the synthesis of differ-
ent carbohydrate fused -amino -lactam derivatives and the re-
sults are summarized in Table 1.
Starting from cyclopropanecarboxylates 2b–2e, di-azides 4b–4e
were synthesized via iodo-azides 3b–3e in very good yield
(70–90%) using NaN3 in DMF.32 Further reduction of di-azides
O
NH
N
NH
OH
H2N
H2N
a
c
H2N
D-Cycloserine
-amino -lactam and its analogues.
O
O
O
a
c
Agl
(+)-HA-966
Figure 1. Structure of
a
c
4b–4e with Zn/AcOH provided the corresponding
a
-amino
The iodo-azide 3a was then converted to di-azide 4a in excel-
lent yield (94%) by treatment with NaN3 in DMF. The di-azide 4a
c-lactam derivatives 5b–5e respectively in moderate to good yield
(40–66%).
on reduction with Zn/AcOH afforded
a-amino c-lactam 5a (66%)
OTBS
OTBS
O
TBSO
TBSO
O
OTBS
O
MDA, Rh2(OAc)4
CH2Cl2, 0 °C, 4 h
59%
NIS, NaN3, CH3CN,
4Å mol. sieves, rt, 12 h
82%
TBSO
TBSO
N3
COOCH3
TBSO
TBSO
O
I
O
1
2a
3a
OTBS
O
OTBS
TBSO
NaN3, DMF
rt, 24 h
94%
O
Zn, AcOH:THF
TBSO
TBSO
N3
COOCH3
TBSO
rt, 3 h
66%
H2N
NH
N3
O
4a
5a
MDA: Methyl diazoacetate
Scheme 1. Synthesis of carbohydrate fused
a-amino c-lactam 5a.
Table 1
Synthesis of carbohydrate fused
a
-amino
c
-lactam derivatives
Iodo-azide
OTBS
Entry
Cyclopropane
Di-azide
Agl
OTBS
OTBS
O
OTBS
O
TBSO
TBSO
O
O
TBSO
TBSO
TBSO
TBSO
TBSO
TBSO
N3
N3
COOCH3
COOCH3
H2N
NH
N3
I
1
O
O
O
3a
(82%)
4a
(94%)
2a
OBn
OBn
OBn
OBn
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
O
O
O
N3
COOCH3
N3
COOCH3
H2N
NH
N3
I
2
3
4
5
O
O
O
3b
(70%)
4b
(90%)
2b
5b
(56%)
O
O
O
O
O
O
O
N3
COOCH3
N3
NH
O
O
O
O
O
O
O
COOCH3
N3
H
BnO
BnO
BnO
H
NH2
O
BnO
H
I
2c
5c (48%)
3c (75%)
OTBS
4c (70%)
OTBS
OTBS
O
OTBS
O
BnO
BnO
O
O
BnO
BnO
BnO
N3
COOCH3
N3
BnO
BnO
BnO
COOCH3
H2N
NH
NH
I
N3
O
O
O
3d
(71%)
4d
(85%)
5d
(59%)
OBn
2d
OBn
OBn
OBn
O
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
N3
COOCH3
N3
COOCH3
H2N
O
I
N3
O
O
∗
3e
(78%)
2e
4e
(86%)
5e
(40%)
⁄ 10% of 2e was recovered.

G. Kishore et al. / Carbohydrate Research 390 (2014) 1–8
3
OBn
O
OTBS
O
OBn
OTBS
BnO
BnO
NIS, NaN3, CH3CN,
NaN3, DMF
TBSO
TBSO
O
Zn,
O
BnO
BnO
N3
COOEt
TBSO
TBSO
N3
COOCH3
4Å mol sieves, rt, 12 h
70%
rt, 24 h
84%
AcOH, THF
H2N
NH
5a
I
3f
O
N3
O
O
2f
†
4a
OBn
OBn
O
BnO
BnO
O
Zn, AcOH:THF
BnO
BnO
N3
COOEt
rt, 8 h
30%
OTBS
O
OTBS
O
H2N
NH
N3
O
TBSO
TBSO
TBSO
TBSO
NH2
COOCH3
4f
9% of 2f was recovered
5e
H2N
O
NH2
H2N
†
O
4aβ
Scheme 4. Plausible mechanism for the synthesis of
4aα
Scheme 2. Synthesis of
2f.
a
-amino
c
-lactam 5e from ethyl cyclopropanecarboxylate
a
-amino
c
-lactam 5a.
Zn, AcOH:THF
The mechanism proposed for the formation of
a
-amino c-lac-
OBn
OBn
rt, 48 h, 34%
tam 5a from di-azide 4a is presented in Scheme 4. In the first step,
both azide groups are reduced to the corresponding amines in the
presence of Zn/AcOH. Due to the anomeric effect40 the equilibrium
A
O
O
BnO
BnO
BnO
N3
COOCH3
BnO
B
NH
I
Zn, NH4Cl, EtOH
rt, 12 h, 30%
a
shifts from 4ab to 4a and lactamization then occurs via internal
O
nucleophilic substitution of the methyl ester by the anomeric
3e
6
amine group to give the carbohydrate fused
(Scheme 4).
a-amino c-lactam 5a
Scheme 3. Synthesis of carbohydrate fused
c
-lactam 6.
The cis geometry of
a-amino c-lactam 5d was determined by
analysis of 1H NMR and NOESY experiments (Supplementary info).
When a-amino c-lactam 5e was synthesized from cyclopropane
The observed coupling constant 3JH
for the anomeric proton
a—Hb
ethyl ester 2f, the yield in the reductive cyclization of 4f was 30%;
this is lower than that obtained in the reduction of the methyl ester
of the corresponding glucose derivative 4e (Scheme 2). The poor
yield reflects the lower reactivity of the ethyl ester derivative 4f
compared to the methyl ester 4e towards lactamization.
(Ha) was found to be 5.5 Hz confirming the presence of a cis-bicy-
clic system. The analysis of NOE cross peaks between Ha–Hb, Ha–Hg
À
Á
and Hb–Hd together with the coupling constant 3JH
for the
a—Hb
ring junction confirmed that all four protons are cis to each other
(Fig. 2).
In order to improve the yield of glucose fused a-amino c-lactam
It has been reported that glycopeptide conjugates act as potent
d-opioid receptor agonists after transforming into glycopeptides
from glycosylamines.41 Herein, we have shown the utility of our car-
5e, various conditions of reductive cyclization of di-azide 4e were
studied. Reductive cyclization of 4e with Lindlar catalyst,33 Zn acti-
vated by trimethylsilyl chloride (TMSCl),34 Zn(Cu) in AcOH, Mg/
MeOH,35 or In/NH4Cl36 failed to furnish
a-amino c-lactam 5e.
bohydrate fused
-lactam-bridged glycopeptide conjugates in a single-step with
high efficiency (Scheme 5).42,43 When gluco
-amino -lactam 5a
was coupled with N-protected dipeptide Boc-Val-Ala-OH in the
-amino
-Amino
-lactam-bridged glycopeptides
a-amino c-lactams in the synthesis of a-amino
Reduction of 4e with PPh3/THF/H2O (Staudinger conditions),37
c
Zn/NH4Cl38 or Zn/AcOH under ultra-sonication gave a mixture of
a
c
products, and from which
a-amino c-lactam 5e was isolated in
presence of EDCꢀHCl and HOBt, it furnished the
a
poor yields (<30%). Nevertheless, after extensive screening, Zn/
AcOH was identified to be superior to other reducing systems stud-
ied for the reductive cyclization step. We also attempted the
one-pot synthesis of di-azide 4e by treating the cyclopropanecarb-
oxylate 2e with NIS and NaN3 in different solvents. When 2e was
reacted with an excess of NaN3 (4 equiv) and NIS (2.5 equiv) in
CH3CN or CH2Cl2, iodo-azide 3e was obtained in good yield. When
the reaction was performed in DMF, THF or DMSO, only the starting
material 2e was recovered with no observable side reactions. No
trace of iodo-azide 3e or di-azide 4e was detected in the crude reac-
tion mixture either by 1H NMR or mass spectrometry.
c
-lactam-bridged glycopeptide 7 in very good yield (75%). a
c-lactam derivatives and a-amino c
Hd
OR'
4
Hb
O
Hg Ha
RO
RO
2
1
3
H2N
NH
O
We also synthesized the carbohydrate fused
c-lactam 6 in a
5d
(R= Bn, R'= TBS)
single-step from the iodo-azide 3e by reductive cyclization
(Scheme 3). When iodo-azide 3e was treated with Zn/AcOH,
Figure 2. NOESY correlation of -amino-
a
c
-lactam 5d.
c-lactam 6 was isolated in poor yield (34%) even after reaction time
was increased to 48 h from 12 h (deiodination occurs under
Zn/AcOH conditions).39 Since reduction of iodo-azide 3e gave the
OTBS
O
c
-lactam 6 in poor yield (34%) under Zn/AcOH conditions, reduc-
tion of 3e was carried out with Zn/NH4Cl (Scheme 3, route B).38
This method also provided -lactam 6 in low yield (30%) but in
shorter time (12 h). However, neither method A nor method B
furnished the -lactam 6 in good yield.
OTBS
O
TBSO
TBSO
EDC·HCl, HOBt,
TBSO
TBSO
c
Boc-Val-Ala-OH
HN
CH3CN, rt, 10 h
NH
O
H2N
75%
NH
O
N
H
c
O
O
NHBoc
5a
7
The yield of 3e is 75% and 52% in CH3CN and CH2Cl2, respectively. 10% of starting
material 2e was recovered in both the solvents.
Scheme 5. Synthesis of glycopeptide conjugate 7 of
a
-amino
c
-lactam 5a.

4
G. Kishore et al. / Carbohydrate Research 390 (2014) 1–8
can be implemented as drugs directed at the central nervous system
since the carbohydrate moiety could increase the lipophilicity and
render them permeable to the blood–brain barrier.44
1.2.1. 3,4,6-Tri-O-(tert-butyldimethylsilyl)-2-deoxy-2-C-
carbmethoxyiodomethyl-b- -glucopyranosyl azide (3a)
D
The iodo-azide 3a was synthesized using the procedure re-
ported in Section 1.2 and the crude product was purified by col-
umn chromatography on silica gel (230–400 mesh) using 10% of
In summary, a stereoselective synthesis of carbohydrate fused
a-amino c-lactams has been developed involving the ring opening
of cyclopropanecarboxylates. After screening, CH3CN was shown to
be a better solvent for the ring opening with NIS and NaN3 and this
methodology has been applied to other benzyl and silyl ether pro-
ethyl acetate and petroleum ether. Yield: 82%; Gummy; ½a D25
ꢂ
ꢁ132.5 (c 0.5, CHCl3); Rf = 0.6 (hexanes/EtOAc, 9:1); IR (neat):
1736, 1099,2106 cmꢁ1 1H NMR (400 MHz, CDCl3): d 4.92 (d, 1H,
;
tected carbohydrate derivatives. Carbohydrate fused
were also synthesized using this methodology. We also demon-
strated the synthesis of an -amino -lactam-bridged glycopeptide
-amino -lactam 5a.
c
-lactams
J = 4.56 Hz), 4.66 (d, 1H J = 12.16 Hz), 4.25 (s, 1H), 4.03–3.99 (m,
1H), 3.90 (d, 1H, J = 2.9 Hz), 3.83–3.78 (m, 5H), 2.28 (dd, 1H,
J = 4.56, 4.00 Hz), 0.92–0.89 (m, 27H, 3 ꢃ (CH3)3C), 0.22–0.06 (m,
18H, 3 ꢃ (CH3)2Si); 13C NMR (100 MHz, CDCl3): d 171.1 (C@O),
85.2 (C-1), 81.67, 73.3, 68.9, 63.6, 53.0 (C-2), 47.99 (C-7), 25.9,
25.8, 24.4, 18.3, 17.9, 17.8, ꢁ4.0, ꢁ4.2, ꢁ4.6, ꢁ4.9, ꢁ5.3, ꢁ5.4;
a
c
conjugate 7 from carbohydrate fused
a
c
1. Experimental section
HRMS (ESI-QTOF) m/z: Calcd for
C
27H56IN3O6Si3 [M+Na]+
752.2419; Found 752.2418.
All reactions were carried out in an oven-dried apparatus using
dry solvents under anhydrous conditions, unless otherwise noted.
All the solvents used for the reaction were dried following the
prescribed method over 4 Å molecular sieves or other appropriate
drying agents.45 Chromatography was performed using silica gel
(230ꢁ400 mesh) with indicated solvents. All reactions were
monitored by thin-layer chromatography on 0.25 mm silica plates
(F-254) visualized under UV light and developed using sulphuric
acid or vanillin solution. Optical rotation of compounds has been
recorded on ‘JASCO digital polarimeter: Model DIP-370’. NMR spec-
tra were recorded on a 400 MHz NMR spectrometer ‘Bruker Avance
400’ and chemical shifts are cited with respect to tetramethylsilane
as internal (1H and 13C). HRMS was recorded on ‘MicroMass ESI-
TOF’ by electron spray ionization method.
1.2.2. 3,4,6-Tri-O-benzyl-2-deoxy-2-C-carbmethoxyiodomethyl-
b-D
-galactopyranosyl azide (3b)
The iodo-azide 3b was synthesized using the procedure re-
ported in Section 1.2 and the crude product was purified by col-
umn chromatography on silica gel (230ꢁ400 mesh) using 20% of
ethyl acetate and petroleum ether. Yield: 70%; Gummy; ½a D25
ꢂ
7.52
(c 0.92, CHCl3); Rf = 0.6 (hexanes/EtOAc, 4:1); IR (neat): 2116,
1744, 1247, 1100 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.36–7.26
;
(m, 15H, Ar-H), 4.98–4.95 (m, 1H), 4.82 (d, 1H, J = 11.48 Hz, OBn),
4.68–4.63 (m, 2H, OBn), 4.54–4.45 (m, 4H), 3.97 (s, 1H), 3.68–
3.61 (m, 4H), 3.42 (s, 3H, COOMe), 2.33–2.27 (m, 1H, H-2); 13C
NMR (100 MHz, CDCl3): d 167.3 (C@O), 138.4, 137.7, 136.8,
128.4, 128.2, 128.1, 127.9, 127.8, 127.6, 90.8 (C-1), 81.2, 75.6,
74.4, 73.6, 72.2, 71.1, 68.4, 53.3, 44.5; HRMS (ESI-QTOF) m/z: Calcd
for C30H32IN3O6 [M+Na]+ 680.1234; Found 680.1273.
1.1. Synthesis of cyclopropanecarboxylate 2a
To a stirred suspension of tri-O-tert-butyldimehtylsilyl D-glucal
1.2.3. 3-O-Benzyl-5,6-O-isopropylidine-2-deoxy-2-C-
carbmethoxyiodomethyl-b-D-mannofuranosyl azide (3c)
1 (3 g, 6.0 mmol) and Rh2(OAc)4 (27 mg, 0.06 mmol) in anhydrous
dichloromethane (5 mL), methyl diazoacetate (1.2 g, 12.0 mmol) in
dichloromethane (35 mL) was added drop wise over a period of
2 h. After cessation of the nitrogen evolution (5 min), the reaction
mixture was concentrated in vacuo and the remaining residue
was purified by column chromatography on silica gel (230–
400 mesh) using 2% of EtoAc in petroleum ether to obtain the
cyclopropanecarboxylate 1a (1.4 g). Tri-O-tert-butyldimehtylsilyl
The iodo-azide 3c was synthesized using the procedure re-
ported in Section 1.2 and the crude product was purified by col-
umn chromatography on silica gel (230ꢁ400 mesh) using 15%
ethyl acetate and petroleum ether. Yield: 75%; Gummy; Rf = 0.5
(hexanes/EtOAc, 4:1); ½a D25
ꢁ5 (c 1, CHCl3); IR (neat): 2120, 1723,
ꢂ
738 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.41–7.29 (m, 5H, Ar-H),
;
5.03 (d, 1H, J = 2.29 Hz, H-1), 4.71 (d, 1H, J = 11.73 Hz, OBn), 4.63
(d, 1H, J = 11.73 Hz, OBn), 4.45 (q, 1H, J = 6.39 Hz), 4.22 (d, 1H,
J = 10.25 Hz), 4.18–4.11 (m, 3H), 4.02 (dd, 1H, J = 8.6, 6.2 Hz), 3.77
(s, 3H, COOMe), 2.94 (dt, 1H, J = 10.24, 1.86 Hz, H-2), 1.43 (s, 3H,
(CH3)2C), 1.37 (s, 3H, (CH3)2C); 13C NMR (100 MHz, CDCl3): d
170.1 (C@O), 137.5, 128. 3, 127.9, 127.8, 109.1 (C-1), 92.5, 83.3,
82.1, 73.1, 71.6, 66.9, 56.1 (C-2), 53.3 (C-7), 26.7, 25.4; HRMS
(ESI-QTOF) m/z: Calcd for C19H24IN3O6 [M+Na]+ 540.0604; Found
540.0607.
D
-glucal (0.9 g) was also recovered from the reaction mixture.
Yield: 58%; Gummy; ½a D25
ꢂ
37.0 (c 2, CHCl3); Rf = 0.6 (hexanes/EtOAc,
9:1); IR (neat): 2929, 1719, 1443, 1072, 834 cmꢁ1
;
1H NMR
(400 MHz, CDCl3): d 3.99–3.94 (m, 2H, H-6, H-60), 3.81 (dd, 1H,
J = 1.3, 7.2 Hz), 3.70 (d, 1H, J = 3.4 Hz), 3.67 (s, 3H), 3.60–3.57 (m,
2H), 2.27 (dd, 1H, J = 1.60, 6.08 Hz, H-2), 1.68 (t, 1H, J = 6.68 Hz,
H-7), 0.92–0.91 (m, 27H, 3 ꢃ (CH3)3C), 0.12–0.06 (m, 18H,
3 ꢃ (CH3)2Si); 13C NMR (100 MHz, CDCl3): d 172.7 (C@O), 78.8 (C-
1), 71.0, 66.3, 62.3, 55.5 (C-2), 51.6 (C-7), 27.2, 26.2, 25.9, 25.7,
24.8, 18.3, 17.83, 17.79, ꢁ4.7, ꢁ4.8, ꢁ4.9, ꢁ5.0, ꢁ5.27, ꢁ5.34;
HRMS (ESI-QTOF) m/z: Calcd for C27H56O6Si3 [M+Na]+ 583.3282;
Found 583.3290.
1.2.4. 3,4-Di-O-benzyl-6-(tert-butyldimethylsilyl)-2-C-
carbmethoxyiodomethyl-2-deoxy-b-D-glucopyranosyl azide
(3d)
The iodo-azide 3d was synthesized using the procedure re-
ported in Section 1.2 and the crude product was purified by col-
umn chromatography on silica gel (230ꢁ400 mesh) using 15% of
1.2. General procedure for the synthesis of iodo-azides
To a solution of cyclopropane carboxylate (1 mmol) and NaN3
(2.5 mmol) in CH3CN (7 mL), N-iodosuccinimide (2.5 mmol) and
4 Å molecular sieves were added under argon atmosphere. The
reaction mixture was stirred for 12 h at room temperature. After
removal of CH3CN under vacuum, the reaction mixture was diluted
with CH2Cl2 (20 mL). The reaction mixture was treated with satu-
rated Na2S2O3 solution and then the organic layer was separated
and dried over anhydrous Na2SO4 and the crude product was
purified.
ethyl acetate and petroleum ether. Yield: 71%; Gummy; ½a D25
ꢂ
ꢁ10.18 (c 4.5, CHCl3); Rf = 0.7 (hexanes/EtOAc, 4:1); IR (neat):
2118, 1749, 1253, 1093 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.31–
;
7.25 (m, 10H, Ar-H), 4.97 (d, 1H, J = 10.44 Hz, OBn), 4.90–4.89 (m,
1H, OBn), 4.78–4.75 (m, 3H), 4.65 (d, 1H, J = 8.9 Hz), 3.94–3.87
(m, 3H), 3.82–3.77 (m, 1H), 3.43 (s, 1H), 3.36 (s, 3H, COOMe),
1.78–1.73 (m, 1H, H-2), 0.93 (s, 9H, (CH3)3C), 0.12–0.07 (m, 6H,
(CH3)2Si); 13C NMR (100 MHz, CDCl3): d 167.2 (C@O), 137.9,

G. Kishore et al. / Carbohydrate Research 390 (2014) 1–8
5
137.8, 128.5, 128.1, 127.9, 127.7, 89.9 (C-1), 81.4, 79.1, 77.98,
74.98, 74.8, 61.6, 53.6 (C-7), 49.8 (C-2), 28.6, 25.8, 18.3, 0.97,
1.3.2. 3,4,6-Tri-O-benzyl-2-deoxy-2-C-
carbmethoxyazidomethyl-b- -galactopyranosyl azide (4b)
D
ꢁ5.1, ꢁ5.4; HRMS (ESI-QTOF) m/z: Calcd for
C
29H40IN3O6Si
The di-azide 4b was synthesized using the procedure reported
in Section 1.3 and the crude product was purified by column chro-
matography on silica gel (230ꢁ400 mesh) using 20% of ethyl ace-
[M+Na]+ 704.1629; Found 704.1629.
1.2.5. 3,4,6-Tri-O-benzyl-2-deoxy-2-C-carbmethoxyiodomethyl-
tate and petroleum ether. Yield: 90%; Gummy; ½a D25
ꢂ
77.52 (c 0.8,
b-
D
-glucopyranosyl azide (3e)32
CHCl3); Rf = 0.5 (hexanes/EtOAc, 4:1); IR (neat): 2110, 1747, 1214,
The iodo-azide 3e was synthesized using the procedure re-
1104 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.40–7.29 (m, 15H, Ar-
;
ported in Section 1.2 and the crude product was purified by col-
H), 4.89 (d, 1H, J = 11.6 Hz), 4.71 (d, 1H, J = 11.6 Hz), 4.64–4.58
(m, 3H), 4.46 (d, 2H, J = 4.40 Hz), 4.39 (d, 1H, J = 11.6 Hz, H-2),
3.99 (s, 1H), 3.79 (s, 3H, COOMe), 3.61–3.60 (m, 3H), 3.47 (dd,
1H, J = 11.08, 2.12 Hz), 2.71 (t, 1H, J = 10.28 Hz, H-7); 13C NMR
(100 MHz, CDCl3): d 170.4 (C@O), 138.2, 137.6, 136.97, 128.74,
128.66, 128.44, 128.37, 128.27, 128.1, 128.0, 127.92, 127.88,
127.7, 86.9, 77.2, 75.4, 74.5, 73.6, 71.4, 70.0, 68.3, 58.4, 52.6, 43.4
umn chromatography on silica gel (230ꢁ400 mesh) using 20% of
ethyl acetate and petroleum ether. Yield: 78%; Gummy; ½a D25
ꢁ50
ꢂ
(c 1, CHCl3); Rf = 0.6 (hexanes/EtOAc, 4:1); IR (neat): 2117, 1747,
1455, 1361, 1250 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.38–7.10
;
(m, 15H, Ar-H), 4.97–4.92 (m, 2H), 4.78–4.67 (m, 4H), 4.6 (d, 1H,
J = 4.3 Hz), 4.57 (d, 1H, J = 5.92 Hz), 3.93–3.88 (m, 1H), 3.83–3.75
(m, 3H), 3.58 (d, 1H, J = 9.2 Hz), 3.34 (s, 3H), 1.87–1.83 (m, 1H, H-
2); 13C NMR (100 MHz, CDCl3): d 167.1 (C@O), 137.9, 137.8,
137.5, 128.4, 128.4, 127.8, 127.7, 127.6, 127.4, 90.4 (C-1), 81.4,
79.3, 77.2, 74.84, 74.80, 73.5, 68.01, 53.5, 49.6 (C-2); HRMS (ESI-
QTOF) m/z: Calcd for C30H32IN3O6 [M+Na]+ 680.1233; Found
680.1241.
(C-2); HRMS (ESI-QTOF) m/z: Calcd for
595.2281; Found 595.2288.
C
30H32N6O6 [M+Na]+
1.3.3. 3-O-Benzyl-2-C-carbmethoxyazidomethyl-2-deoxy-5,6-
isopropylidine-b- -mannofuranosyl azide (4c)
D
The di-azide 4c was synthesized using the procedure reported
in Section 1.3 and the crude product was purified by column chro-
matography on silica gel (230ꢁ400 mesh) using 15% of ethyl ace-
1.2.6. 3,4,6-Tri-O-benzyl-2-deoxy-2-C-carbethoxyiodomethyl-b-
D
-glucopyranosyl azide (3f)
tate and petroleum ether. Yield: 70%; Gummy; ½a D25
ꢁ26.29 (c
ꢂ
The iodo-azide 3f was synthesized using the procedure reported
in Section 1.2 and the crude product was purified by column chro-
1.3, CHCl3); Rf = 0.4 (hexanes/EtOAc, 85:15); IR (neat): 2156,
2109, 1754, 1586, 1439, 1244, 1069 cmꢁ1 1H NMR (400 MHz,
;
matography on silica gel (230ꢁ400 mesh) using 20% of ethyl ace-
CDCl3): d 7.38–7.32 (m, 5H, Ar-H), 5.19 (d, 1H, J = 3.96 Hz, H-1),
4.67 (d, 1H, J = 11.5 Hz, OBn), 4.54 (d, 1H, J = 11.5 Hz, OBn), 4.45–
4.40 (m, 1H), 4.17–4.11 (m, 2H), 4.05–3.97 (m, 3H), 3.78 (s, 3H,
COOMe), 2.66–2.62 (m, 1H, H-7), 1.44 (s, 3H, (CH3)2C), 1.39 (s,
3H, (CH3)2C); 13C NMR (100 MHz, CDCl3): d 168.8 (C@O), 137.4,
128.4, 128.0, 109.3 (C-1), 90.9, 82.1, 79.0, 77.2, 73.2, 72.3, 67.0,
60.3, 53.0, 52.4 (C-2), 26.7, 25.5; HRMS (ESI-QTOF) m/z: Calcd for
tate and petroleum ether. Yield: 70%; Gummy; ½a D25
ꢁ1.28 (c 1,
ꢂ
CHCl3); Rf = 0.6 (hexanes/EtOAc, 4:1); IR (neat): 2114, 1740, 1616,
1134, 1111 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.36–7.07 (m,
;
15H, Ar-H), 4.95–4.92 (m, 2H), 4.81–4.66 (m, 4H), 4.59 (d, 1H,
J = 4.28 Hz), 4.56 (d, 1H, J = 2.16 Hz), 3.89–3.75 (m, 6H), 3.57 (d,
1H, J = 9.60 Hz), 1.86 (t, 1H, J = 9.58 Hz, H-2), 1.05 (t, 3H,
J = 7.14 Hz); 13C NMR (100 MHz, CDCl3): d 166.6 (C@O), 138.0,
137.7, 137.5, 128.43, 128.42, 128.0, 127.9, 127.7, 127.4, 90.5 (C-
1), 81.5, 79.3, 74.8, 74.7, 73.6, 68.0, 62.8, 49.5 (C-2), 29.3, 13.8;
HRMS (ESI-QTOF) m/z: Calcd for C31H34IN3O6 [M+Na]+ 694.1390;
Found 694.1389.
C
19H24N6O6 [M+Na]+ 455.1655; Found 455.1653.
1.3.4. 3,4-Di-O-benzyl-6-(tert-butyldimethylsilyl)-2-C-
carbmethoxyazidomethyl-2-deoxy-b-D-glucopyranosyl azide
(4d)
The di-azide 4d was synthesized using the procedure reported
in Section 1.3 and the crude product was purified by column chro-
matography on silica gel (230ꢁ400 mesh) using 15% of ethyl ace-
1.3. General procedure for the synthesis of di-azides
To a stirred solution of iodo-azide (1 mmol) in dry DMF (5 mL)
was added NaN3 (2 mmol) and the reaction mixture was stirred for
24 h at room temperature. DMF was removed under vacuum and
the crude product was extracted with CH2Cl2 (20 mL). The organic
layer was washed with water (10 mL), dried over anhydrous Na2-
SO4 and filtered. The filtrate was concentrated and the crude prod-
uct was purified.
tate and petroleum ether. Yield: 85%; Gummy; ½a D25
ꢂ
54.31 (c 2.15,
CHCl3); Rf = 0.6 (hexanes/EtOAc, 85:15); IR (neat): 2112, 1752,
1455, 1254 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.38–7.30 (m,
;
10H, Ar-H), 4.97 (d, 1H, J = 11.4 Hz, OBn), 4.82 (q, 2H, J = 10.6 Hz),
4.64 (d, 1H, J = 11.6 Hz), 4.54 (d, 1H, J = 9.3 Hz), 4.35 (s, 1H),
3.94–3.87 (m, 2H), 3.81 (s, 3H), 3.77–3.72 (m, 1H), 3.66–3.58 (m,
1H), 3.31 (d, 1H, J = 9.44 Hz), 2.21 (t, 1H, J = 10.1 Hz, H-7), 0.92 (s,
9H, 1 ꢃ (CH3)3C), 0.09 (s, 6H, 1 ꢃ (CH3)2Si); 13C NMR (100 MHz,
CDCl3): d 170.1 (C@O), 137.99, 137.7, 128.6, 128.5, 128.2, 127.8,
86.1 (C-1), 78.9, 78.2, 77.9, 75.3, 74.7, 61.6, 58.4, 52. 8, 48.3 (C-
2), 25.8, 18.3, ꢁ5.1, ꢁ5.4; HRMS (ESI-QTOF) m/z: Calcd for C29H40-
N6O6Si [M+Na]+ 619.2676; Found 619.2674.
1.3.1. 3,4,6-Tri-O-(tert-butyldimethylsilyl)-2-deoxy-2-C-
carbmethoxyazidomethyl-b-D-glucopyranosyl azide (4a)
The di-azide 4a was synthesized using the procedure reported
in Section 1.3 and the crude product was purified by column chro-
matography on silica gel (230ꢁ400 mesh) using 10% of ethyl ace-
tate and petroleum ether. Yield: 94%; Gummy; ½a D25
ꢂ
ꢁ2.68 (c
1.3.5. 3,4,6-Tri-O-benzyl-2-deoxy-2-C-
carbmethoxyazidomethyl-b-D-glucopyranosyl azide (4e)
1.55, CHCl3); Rf = 0.6 (hexanes/EtOAc, 9:1); IR (neat): 2109, 1750,
1468, 1256 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 5.01 (d, 1H,
The di-azide 4e was synthesized using the procedure reported
in Section 1.3 and the crude product was purified by column chro-
matography on silica gel (230ꢁ400 mesh) using 20% of ethyl ace-
J = 7.2 Hz, H-1), 4.36 (d, 1H, J = 6.2 Hz), 3.97 (dd, 1H, J = 6.34,
10.26 Hz), 3.86–3.76 (m, 6H), 3.66 (q, 1H, J = 4.72 Hz), 2.20 (q,
1H, J = 6.2 Hz, H-2), 0.90–0.89 (m, 27H, 3 ꢃ (CH3)3C), 0.14–0.11
(m, 12H, 2 ꢃ (CH3)2Si), 0.07–0.06 (m, 6H, 1 ꢃ (CH3)2Si); 13C NMR
(100 MHz, CDCl3): d 169.7 (C@O), 85.5 (C-1), 80.3, 72.1, 70.6,
63.2, 60.6, 52.7, 48.1 (C-2), 25.8, 18.3, 18.05, 17.99, ꢁ3.5, ꢁ3.7,
ꢁ3.9, ꢁ4.2, ꢁ5.5, ꢁ5.4; HRMS (ESI-QTOF) m/z: Calcd for C27H56N6-
O6Si3 [M+Na]+ 667.3467; Found 667.3463.
tate and petroleum ether. Yield: 86%; Gummy; ½a D25
ꢂ
65.71 (c 2.5,
CHCl3,); Rf = 0.55 (hexanes/EtOAc, 4:1); IR (neat): 2112, 1747,
1119, 1089 cmꢁ1 1H NMR (400 MHz, CDCl3): d 7.39–7.20 (m,
;
15H, Ar-H), 4.96 (d, 1H, J = 11.52 Hz, OBn), 4.81 (d, 1H,
J = 10.84 Hz, OBn), 4.67–4.62 (m, 4H), 4.55 (d, 1H, J = 11.98 Hz),
4.34 (s, 1H), 3.79–3.70 (m, 6H), 3.60 (t, 1H, J = 9.8 Hz), 3.48 (d,

6
G. Kishore et al. / Carbohydrate Research 390 (2014) 1–8
1H, J = 8.92 Hz), 2.29–2.24 (m, 1H, H-7); 13C NMR (100 MHz,
CDCl3): d 170.1 (C@O), 137.8, 137.65, 137.59, 128.6, 128.5, 128.4,
128.1, 127.8, 126.1, 86.8 (C-1), 79.1, 78.4, 75.1, 74.8, 73.5, 68.1,
58.3, 52.7 (C-7), 48.1 (C-2); HRMS (ESI-QTOF) m/z: Calcd for
(C-1), 76.0, 74.4, 73.5, 71.5, 70.7, 70.6, 68.9, 54.6, 41.8; HRMS
(ESI-QTOF) m/z: Calcd for C29H32N2O5 [M+Na]+ 511.2209; Found
511.2201.
C
30H32N6O6 [M+Na]+ 595.2281; Found 595.2281.
1.4.3. (3S)-3-Amino-(3-O-benzyl-1,2-dideoxy-5,6-
isopropylidine-b-
D
-mannofuranoso)[2,3-b]-pyrrolidin-2-one
1.3.6. 3,4,6-Tri-O-benzyl-2-deoxy-2-C-carbethoxyazidomethyl-
(5c)
b-D
-glucopyranosyl azide (4f)
The a-amino c-lactam 5c was synthesized using the procedure
The di-azide 4f was synthesized using the procedure reported in
Section 1.3 and the crude product was purified by column chroma-
reported in Section 1.4 and the crude product was purified by col-
umn chromatography on amine-pretreatment silica gel (0.5 mL of
Et3N for 50 g of silica gel) using 3% of CHCl3 and MeOH. Yield:
tography on silica gel (230ꢁ400 mesh) using 20% of ethyl acetate
and petroleum ether. Yield: 84%; Gummy; ½a D25
ꢂ
73.08 (c 1.8,
48%; Gummy; ½a 2D5
ꢂ
ꢁ5.16 (c 1, CHCl3); Rf = 0.5 (CHCl3/MeOH,
CHCl3); Rf = 0.5 (hexanes/EtOAc, 4:1); IR (neat): 2109, 1742, 1132,
97:3); IR (neat): 1704, 1655, 1375, 1028 cmꢁ1 1H NMR
;
1118 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 7.38–7.20 (m, 15H Ar-
(400 MHz, CDCl3): d 7.36–7.30 (m, 5H, Ar-H), 6.29 (br s, 1H,
NH), 5.63 (d, 1H, J = 6.2 Hz, H-1), 4.61 (s, 2H), 4.49 (d, 1H,
J = 4.40 Hz), 4.43 (q, 1H, J = 6.31 Hz), 4.08 (dd, 1H, J = 6.31,
8.47 Hz), 3.97–3.93 (m, J = 5.96, 8.47 Hz, 1H), 3.86 (dd, 1H,
J = 3.60, 6.56 Hz), 3.74 (d, 1H, J = 10.24 Hz), 3.15 (dd, 1H,
J = 6.26, 10.2 Hz, H-2), 1.43 (s, 3H, (CH3)2C), 1.37 (s, 3H,
H), 4.96 (d, 1H, J = 11.5 Hz), 4.81 (d, 1H, J = 10.85 Hz), 4.65–4.61
(m, 4H), 4.57–4.54 (m, 1H), 4.32 (s, 1H), 4.26 (q, 2H, J = 7.1 Hz),
3.75–3.71 (m, 3H), 3.63–3.58 (m, 1H), 3.48 (d, 1H, J = 9.6 Hz),
2.30–2.25 (m, 1H, H-2), 1.32 (t, 3H, J = 7.06 Hz, H-2); 13C NMR
(100 MHz, CDCl3): d 169.5 (C@O), 137.8, 137.6, 137.6, 128.6,
128.5, 128.4, 128.2, 127.8, 86.8 (C-1), 79.1, 78.4, 77.1, 75.2, 74.8,
73.5, 68.1, 62.2, 58.3, 48.1 (C-2), 13.9; HRMS (ESI-QTOF) m/z: Calcd
for C31H34N6O6 [M+Na]+ 609.2438; Found 609.2438.
(CH3)2C); 13C NMR (100 MHz, CDCl3):
d 176.6 (C=O), 137.9,
128.6, 128.4, 127.8, 108.9 (C-1), 86.7, 80.8, 78.3, 72.9, 71.9, 66.9,
51.1, 50.5 (C-2), 26.6, 25.3; HRMS (ESI-QTOF) m/z: Calcd for C18-
H24N2O5[M+Na]+ 371.1583; Found 371.1584.
1.4. General procedure for the synthesis of carbohydrate fused
a-amino
c
-lactam
1.4.4. (3S)-3-Amino-[3,4-di-O-benzyl-6-(tert-
butyldimethylsilyl)-1,2-dideoxy]-a-D-glucopyranoso][2,3-b]-
To a stirred solution of di-azide (1 mmol) in 10 mL of AcOH/THF
pyrrolidin-2-one (5d)
(1:1), Zn dust (1 mmol) was added and the reaction was stirred for
12 h at room temperature (25 °C). After completion of the reaction,
Zn was removed by filtration. Then solvent was removed under
vacuum followed by dilution with 20 mL of ethyl acetate. The or-
ganic layer was thoroughly washed with NaHCO3 solution. It was
separated and dried over anhydrous Na2SO4. The filtrate was con-
centrated and the crude product was purified.
The a-amino c-lactam 5d was synthesized using the procedure
reported in Section 1.4 and the crude product was purified by col-
umn chromatography on amine-pretreatment silica gel (0.5 mL of
Et3N for 50 g of silica gel) using 5% of CHCl3 and MeOH. Yield:
59%; Gummy; ½a 2D5
ꢂ
34.32 (c 1.6, CHCl3); Rf = 0.6 (CHCl3/MeOH,
95:5); IR (neat): 1718, 1457, 1257, 1102, 1074 cmꢁ1
;
1H NMR
(400 MHz, CDCl3): d 7.35–7.28 (m, 10H, Ar-H), 5.89 (bs, 1H, NH),
5.42 (d, 1H, J = 5.89 Hz, H-1), 4.86 (s, 2H, OBn), 4.79–4.72 (m, 2H,
OBn), 4.01–3.97 (m, 1H, H-3), 3.89 (dd, 1H, J = 3.75, 11.2 Hz, H-6),
3.80–3.74 (m, 3H, H-60, H-4, H-7), 3.64–3.62 (m, 1H, H-5), 2.82–
2.76 (m, 1H, H-2), 0.91 (s, 9H, 1 ꢃ (CH3)3C), 0.07–0.06 (m, 6H,
1 ꢃ (CH3)2Si); 13C NMR (100 MHz, CDCl3): d 176.5 (C@O), 138.74,
138.1, 128.44, 128.40, 127.8, 127.7, 127.6, 127.5, 80.7 (C-1), 77.2
(C-4), 74.1 (OBn), 73.3 (OBn), 73.1 (C-5), 62.6 (C-6), 54.6 (C-7),
45.7 (C-2), 25.9, 18.3, ꢁ5.2, ꢁ5.4; HRMS (ESI-QTOF) m/z: Calcd
for C28H40N2O5Si [M+Na]+ 535.2604; Found 535.2606.
1.4.1. (3S)-3-Amino-[3,4,6-tri-O-(tert-butyldimethylsilyl)-1,2-
dideoxy-
a
-
D
-glucopyranoso][2,3-b]-pyrrolidin-2-one (5a)
-lactam 5a was synthesized using the procedure
The -amino
a
c
reported in Section 1.4 and the crude product was purified by col-
umn chromatography on amine-pretreatment silica gel (0.5 mL of
Et3N for 50 g of silica gel) using 1% of CHCl3 and MeOH. Yield:
66%; Gummy; ½a 2D5
ꢂ
8.89 (c 1.34, CHCl3); Rf = 0.6 (CHCl3/MeOH,
99:1); IR (neat): 2929, 1715, 1467, 1085 cmꢁ1
;
1H NMR
(400 MHz, CDCl3): d 6.19 (s, 1H, NH), 5.44 (d, J = 7.4 Hz, 1H, H-
1), 4.21 (s, 1H), 3.77–3.73 (m, 3H), 3.54–3.48 (m, 2H), 2.83–2.78
(m, 1H, H-2), 0.88 (s, 27H, 3 ꢃ (CH3)3C), 0.12–0.05 (m, 18H,
3 ꢃ (CH3)2Si); 13C NMR (100 MHz, CDCl3): d 178.2 (C@O), 79.2
(C-1), 74.5, 69.3, 68.8, 64.1, 52.5, 41.99, 25.96, 25.89, 25.7, 18.4,
18.0, 17.9, ꢁ3.6, ꢁ4.3, ꢁ4.5, ꢁ4.76, ꢁ4.79, ꢁ5.2, ꢁ5.3; HRMS
(ESI-QTOF) m/z: Calcd for C26H56N2O5Si3 [M+H]+ 561.3575; Found
561.3580.
1.4.5. (3S)-3-Amino-(3,4,6-tri-O-benzyl-1,2-dideoxy-
glucopyranoso)[2,3-b]-pyrrolidin-2-one (5e)
a-D-
The a-amino c-lactam 5e was synthesized using the procedure
reported in Section 1.4 and the crude product was purified by col-
umn chromatography on amine-pretreatment silica gel (0.5 mL of
Et3N for 50 g of silica gel) using 5% of CHCl3 and MeOH. Yield:
40%; Gummy; ½a 2D5
ꢂ
33.34 (c 1.15, CHCl3); Rf = 0.5 (CHCl3/MeOH,
95:5); IR (neat): 1719, 1454, 1099, 1070, 736 cmꢁ1
;
1H NMR
1.4.2. (3S)-3-Amino-(3,4,6-tri-O-benzyl-1,2-dideoxy-
galactopyranoso)[2,3-b]-pyrrolidin-2-one (5b)
a
-
D
-
(400 MHz, CDCl3): d 7.32–7.16 (m, 15H, Ar-H), 5.88 (s, 1H, NH),
5.43 (d, J = 5.94 Hz, 1H, H-1), 4.84 (s, 2H), 4.73 (d, 1H,
J = 11.16 Hz, OBn), 4.59–4.51 (m, 4H), 3.97–3.94 (m, 1H), 3.76–
3.60 (m, 7H), 2.84–2.79 (m, 1H); 13C NMR (100 MHz, CDCl3): d
176.4 (C@O), 138.7, 137.7, 128.39, 128.37, 127.8, 127.8, 127.7,
127.5, 127.4, 80.7 (C-1), 77.5, 74.0, 73.5, 73.2, 71.6, 69.1, 54.6,
45.5 (C-1); HRMS (ESI-QTOF) m/z: Calcd for C29H32N2O5 [M+Na]+
511.2209; Found 511.2209.
The a-amino c-lactam 5b was synthesized using the procedure
reported in Section 1.4 and the crude product was purified by col-
umn chromatography on amine-pretreatment silica gel (0.5 mL of
Et3N for 50 g of silica gel) using 5% of CHCl3 and MeOH. Yield:
56%; Gummy; ½a 2D5
ꢂ
85.04 (c 1, CHCl3); Rf = 0.5 (CHCl3/MeOH,
95:5); IR (neat): 1713, 1519, 1100 cmꢁ1
;
1H NMR (400 MHz,
CDCl3): d 7.36–7.29 (m, 15H, Ar-H), 5.84 (s, 1H, NH), 5.41 (d, 1H,
J = 5.40 Hz, H-1), 4.90 (d, 1H, J = 11.53 Hz, OBn), 4.74 (d, 1H,
J = 10.76 Hz, OBn), 4.62–4.57 (m, 2H), 4.52–4.42 (m, 2H), 4.01 (s,
1H), 3.89–3.77 (m, 3H), 3.60–3.50 (m, 2H), 2.97–2.91 (m, 1H, H-
2); 13C NMR (100 MHz, CDCl3): d 176.4 (C@O), 138.3, 137.7,
128.5, 128.4, 128.3, 128.0, 127.86, 127.81, 127.74, 127.70, 80.6
1.5. Procedure for the synthesis of
1.5.1. Method A using Zn/AcOH
To a stirred solution of iodo-azide 3e (1 mmol) in 10 mL of
AcOH/THF (1:1) Zn dust (1 mmol) was added and the reaction
c-lactam (6)

G. Kishore et al. / Carbohydrate Research 390 (2014) 1–8
7
was stirred for 48 h at room temperature (25 °C). After completion
Acknowledgements
of the reaction, Zn was removed by filtration. Then solvent was
removed under vacuum followed by dilution with 20 mL of ethyl
acetate. The organic layer was thoroughly washed with NaHCO3
solution. It was separated and dried over anhydrous Na2SO4. The
filtrate was concentrated and the crude product was purified by
column chromatography on silica gel using hexanes/EtOAc to fur-
G.K. thanks the UGC, New Delhi for a Senior Research Fellow-
ship, V.G. thanks the Department of Science and Technology
(DST), New Delhi for a fellowship under the Women Scientists
Programme and S.C.N. thanks the DST for the award of a J.C. Bose
National Fellowship and the JNCASR, Jakkur for the Hindustan
Lever Professorship.
nish the c-lactam.
1.5.2. Method B using Zn/NH4Cl
Supplementary data
To a stirred solution of iodo-azide 3e (1 mmol) and NH4Cl
(2 mmol) in 10 mL of EtOH, Zn dust (2 mmol) was added and the
reaction was stirred for 12 h at room temperature (25 °C). After
completion of the reaction, Zn was removed by filtration. Then
the solvent was removed under vacuum followed by dilution with
20 mL of ethyl acetate. The organic layer was thoroughly washed
with NaHCO3 solution. It was separated and dried over anhydrous
Na2SO4. The filtrate was concentrated and the crude product was
purified by column chromatography using hexanes/EtOAc to fur-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2014.
02.022.
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ꢂ
82.44 (c
1, CHCl3); Rf = 0.85 (hexanes/EtOAc, 1:1); IR (neat): 3317, 2922,
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(m, 2H), 3.61–3.58 (m, 2H), 2.80–2.77 (m, 1H), 2.54 (dd, 1H,
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To
a stirred solution of a-amino c-lactam 2a (25 mg,
0.04 mmol) in CH3CN (5 mL), diisopropylethylamine (0.03 mL,
0.13 mmol) and Boc-valinylalanine (17 mg, 0.06 mmol) were
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1.6.1. Glucopeptide (7)
Yield: 75%; Gummy; ½a D25
ꢁ28.30 (c 0.8, CHCl3); Rf = 0.5 (CHCl3/
ꢂ
MeOH, 95:5); IR (neat): 3313, 1685, 1702, 1709, 1254, 1093,
836 cmꢁ1 1H NMR (400 MHz, CDCl3): d 6.74 (d, 1H, J = 6.3 Hz),
;
6.23 (d, 1H, J = 7.7 Hz), 6.03 (s, 1H), 5.62 (d, 1H, J = 7.7 Hz), 5.12
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1.45 (s, 9H), 0.97–0.95 (m, 9H), 0.91–0.89 (m, 27H), 0.19–0.18
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28.3, 26.3, 26.0, 25.7, 19.2, 18.6, 18.4, 17.9, 17.6, ꢁ3.8, ꢁ4.5,
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