Diversity oriented synthesis of novel haloglycolipids potentially useful for crystallization of integral membrane proteins

Article abstract of DOI:10.1039/c3ob42308e

A series of novel haloglycolipids were synthesized based on Cu(i) catalyzed Huisgen's [3 + 2] cycloaddition reaction of diversely functionalized azides and alkynes, using a mixture of N-bromosuccinimide and Cu(i) halide as the halogen source. Since halogen atoms, like bromine and iodine, with a very high scattering power facilitate the solving of crystal structures, the title haloglycolipids could prove to be invaluable in structure-based drug design involving membrane proteins as targets. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ob42308e

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Diversity oriented synthesis of novel
haloglycolipids potentially useful for
Cite this: DOI: 10.1039/c3ob42308e
crystallization of integral membrane proteins†
Laxminarayan Sahoo,* Anadi Singhamahapatra and Duraikkannu Loganathan‡
A series of novel haloglycolipids were synthesized based on Cu(I) catalyzed Huisgen’s [3 + 2] cycloaddition
reaction of diversely functionalized azides and alkynes, using a mixture of N-bromosuccinimide and Cu(I)
halide as the halogen source. Since halogen atoms, like bromine and iodine, with a very high scattering
power facilitate the solving of crystal structures, the title haloglycolipids could prove to be invaluable in
structure-based drug design involving membrane proteins as targets.
Received 19th November 2013,
Accepted 3rd February 2014
DOI: 10.1039/c3ob42308e
www.rsc.org/obc
activities of the protein in a desirable way.4,5 In the literature,
there are a few examples of the rapid development of drug
Introduction
Integral membrane proteins (IMPs), which play important molecules which were initiated and accelerated by an X-ray
roles in many biological processes, have emerged to be con- structural study of the target membrane protein.6 However,
siderably important in recent years in the area of drug progress in this area of research is still hindered by the
design.1,2 Considering the diverse biological activities of mem- difficulties in protein extraction in an active form, solubil-
brane proteins, including their role as a membrane receptor isation and subsequent crystallization, as the proteins may be
relaying signals between a cells’ internal and external environ- denatured upon extraction from the cell membrane. In the lit-
ment, acting as transport proteins to move molecules and ions erature, there are reports on different chemical, biochemical
across the membrane, mediating the interaction with other and biophysical studies on membrane proteins, such as rho-
cells and extracellular elements like bacteria or viruses, a dopsin or bacteriorhodopsin, to understand their sequence–
thorough knowledge of the three dimensional structure of structure–activity correlation, useful in medical science. These
various membrane proteins will help the design and synthesis studies include the use of site-specific mutagenesis and spec-
of drug candidates with complementary structures and specific troscopic methods to understand the interaction of the protein
medical applications. Understanding the correlation between with the chromophore and correlate that with the structure
the structure and function of these integral membrane pro- and biological activities of the membrane protein.7–9 Consider-
teins (IMPs) in their native form is a key step in this regard.3 ing the sensitivity of the protein structure to some of the
This emphasizes the importance of high resolution structural experimental conditions (e.g. the light stability of rhodopsin)
information of integral membrane proteins (IMPs) at the mole- light-stable pigments were also developed for structural
cular level, using X-ray crystallography. Crystal structures of studies on membrane proteins.10 However, all these
membrane proteins give information about the three dimen- approaches suffer from the lack of structurally diverse com-
sional arrangement of the active functional groups in the pounds useful for the crystallization of membrane proteins
protein, which not only gives practical evidence of the modes without affecting their native structure. The use of a suitable
of the different biological activities of the protein, but also detergent or surfactant, which extracts the protein from the
helps to design drug candidate molecules with complementary cell membrane without denaturation, will be a consequential
structures and the potential ability to enhance or inhibit the approach for this purpose. Among all the synthetic surfactants
reported in the literature, a limited number of detergents,
such as n-octyl glucoside and n-dodecyl maltoside, which are
mimics of the cell membrane, have seen encouraging results
in this area.11,12 Depending on their chemical structure, deter-
gents have different types of interactions (preferably non-
covalent interactions) with the membrane protein, which act
as a decisive factor in the solubilisation and crystallization
process. Thus, the choice of the detergent is critical for retain-
Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036,
India. E-mail: laxminarayanchem@gmail.com; Fax: +91-44-22570509;
Tel: +91-44-22575221, +91-9380820326
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of selected compounds. See DOI: 10.1039/c3ob42308e
‡Deceased on 9th February, 2013.
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ing the function of the membrane proteins, as well as for a
successful crystallization. Only a limited number of detergents
Results and discussion
are commercially available and these are also expensive for The initial reaction was performed by reacting 2,3,4,6-tetra-O-
large scale applications. So, there is a need for the synthesis of acetyl-β-D-glucopyranosyl azide (0.5 mmol) with n-octyl propar-
novel, structurally diverse glycolipids, that can be employed for gyl ether (0.55 mmol) in the presence of CuBr (0.55 mmol)
membrane protein crystallization.
and NBS (0.55 mmol) in dry acetonitrile, taking diisopropyl-
Diversity oriented synthesis is the strategy for the synthesis ethylamine (1 mmol) as the base. The 1H NMR spectrum of
of a library of molecules from simple starting materials, by a the crude product, after an aqueous work up, showed a
common methodology.13 This is a method for quick access to mixture of two components in the ratio 7 : 3. The crude
a large number of molecules with a systematic structural diver- product was purified by column chromatography, to separate
sity. The Cu(I) catalyzed Huisgen’s [3 + 2] cycloaddition reac- the two components. The minor component obtained was
tion has found remarkable applications in the synthesis of found to be 1-N-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-
structurally diverse and biologically active molecules, i.e. in (n-octyloxymethyl)-1,2,3-triazole (12)14 which was confirmed by
diversity oriented synthesis.14 This is one of the most versatile comparing the NMR data with that reported in the literature.
methods for the synthesis of a required compound with a high The major component was found to be the corresponding
1
yield and high selectivity along with a high degree of purity. 5-bromotriazole derivative (13). The H NMR spectrum of the
Based on the versatility of this reaction, the first report on a compound showed the absence of a triazole proton. In the
triazole linked glycolipid was reported from our laboratory, 13C NMR spectrum, the C-5 carbon of triazole showed a high
taking sugar azides and n-alkyl propargyl ethers in the pres- field shift by 12 ppm, compared to C-5 protonated derivative,
ence of Cu(I).15 The efficiency and versatility of this methodo- attributed to the heavy atom effect of bromine, which appeared
logy, we reasoned, could be exploited for synthesizing a new at δ = 111.9 ppm. The formation of the compound was further
class of halogen containing glycolipids, by reacting an aryl-Cu(I) confirmed by ESI-MS HRMS spectroscopy, which showed the
intermediate, generated in situ, with a mixture of a Cu(I) presence of an [M + Na]+ peak corresponding to the 5-bromo-
halide and N-bromosuccinimide, which is a source of a triazole containing glycolipid.
halogen atom.16 Halogen atoms, such as bromine and iodine,
After the successful synthesis of the 5-bromotriazole linked
termed heavy atoms, containing a large number of electrons glycolipid, the corresponding 5-iodotriazole linked glycolipid
with a very high scattering power, have found tremendous was synthesized using the same methodology, except for using
applications in solving crystal structures.17 Among the CuI in place of CuBr. The crude reaction mixture showed the
different methods reported in the literature for the synthesis presence of two compounds in the ratio 24 : 1. After purifi-
of halotriazoles,18,19 the method using NBS-Cu(I)X (X = Br and cation, the major component was found to be the 5-iodotria-
I)18 was found to be the most efficient method. Accordingly, in zole containing haloglycolipid (15), which was confirmed by
1
the present work, a library of halogen containing glycolipids the absence of a triazole proton in the H NMR spectrum and
have been synthesized by the reaction of different sugar the heavy atom effect of iodine (the C-5 carbon was shifted to
derived azides and alkynes with varieties of long chain alkynes 80 ppm, compared to the 125 ppm in 12) in the 13C NMR spec-
and azides, respectively, in the presence of NBS-Cu(I)X trum. The identity of the compound was further confirmed by
(X = Br and I), classified into six different types (Fig. 1). This high resolution ESI-MS spectroscopy, which showed only one
is the first report on glycolipids containing heavy halogen peak, corresponding to the iodotriazole containing glycolipid.
atoms. These novel glycolipids have diversely functionalized The absence of a peak corresponding to the bromine contain-
5-halotriazole rings, which are stable under various hydrolytic ing glycolipid confirmed the mechanism reported earlier for
conditions.
the synthesis of iodotriazole.18
Fig. 1 5-Halotriazole linked glycolipids with systematic variation in the constituent azide and alkyne molecules used for synthesis.
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After the successful synthesis of the bromo and iodoglyco- cation by column chromatography, the alkyl propiolamides
lipids derived from 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl were taken for a click reaction, by reacting with 2,3,4,6-tetra-O-
azide and n-octyl propargyl ether, the method was extended acetyl-β-D-glucopyranosyl azide and N-(2,3,4,6-tetra-O-acetyl)-
to another n-alkyl propargyl ether i.e. n-dodecyl propargyl β-D-glucopyranosyl azidoacetamide21 (0.5 mmol) to furnish
ether, which was synthesized following a literature proce- eight different haloglycolipids. The products (19–26) were
dure.20 The identities of the compounds (14 and 16) syn- obtained with improved yields and were confirmed by various
thesized were confirmed by NMR and ESI-MS HRMS data spectroscopic techniques. In some cases, the compound was
(Scheme 1).
purified by a simple recrystallization, having small amount of
The method of synthesizing structurally diverse haloglyco- succinimide as the byproduct, without any trace of the corre-
lipids using the [3 + 2] cycloaddition reaction was extended sponding C-5 protonated glycolipid (Scheme 2).
to N-(2,3,4,6-tetra-O-acetyl-β-D-glycopyranosyl) azidoacetamide
After successfully synthesizing both the ether and amide
(0.5 mmol), taken as the azide part, with n-octyl propargyl linked halogen containing glycolipids, by the reaction of azide
ether as the alkyne. The product (17) was obtained with good functionalized sugars and alkyne functionalized alkyl chains,
yield and was characterized based on various spectroscopic the methodology was extended to an alkyne functionalized
data, such as NMR and ESI-MS.
sugar and azide functionalized alkyl chain. N-(2,3,4,6-tetra-O-
The 5-iodotriazole containing glycolipid (16) (0.25 mmol), acetyl)-β-D-glucopyranosyl propiolamide was chosen as the
synthesized by the reaction of 2,3,4,6-tetra-O-acetyl-β-D-gluco- alkyne containing sugar, along with four different azide con-
pyranosyl azide and n-dodecyl propargyl ether, was taken for taining alkyl chains i.e. n-octyl(8)/decyl(9) azide23 and n-octyl
de-O-acetylation, using a catalytic amount of NaOMe in metha- (10)/dodecyl(11) azidoacetamide. The propiolamide derivative
nol at 0 °C. The formation of the product (18) was confirmed was synthesized by DCC coupling reaction of 2,3,4,6-tetra-O-
by 1H and 13C NMR spectroscopy and ESI-MS HRMS. Thus, acetyl-β-D-glucopyranosyl amine and propiolic acid. During
unlike the alkyl bromo/iodo compounds, which are unstable the course of this reaction, a similar report was published for
under basic conditions, the 5-iodotriazoles synthesized by the the synthesis of N-(2,3,4,6-tetra-O-acetyl)-β-D-glucopyranosyl
above method are stable under the de-O-acetylation reaction propiolamide.22 The click reaction between N-(2,3,4,6-tetra-
conditions.
O-acetyl)-β-D-glucopyranosyl propiolamide (0.5 mmol) with
To explore the versatility of the novel method for the syn- n-alkyl azides and azidoacetamides (0.55 mmol) in the pres-
thesis of halogen containing glycolipids, the methodology was ence of Cu(I) halide (0.55 mmol) and N-bromosuccinimide
extended to other alkyne functionalized n-alkyl chains, such as (0.55 mmol) furnished seven novel haloglycolipids (27–33),
n-alkyl propiolamides, to add diversity in the alkyne part, in with good to excellent yields, with diverse structures (Scheme 3).
which the ether functionality was replaced by an amide group.
Using the Cu(I) catalyzed [3 + 2] cycloaddition reaction of
n-Alkyl propiolamides were synthesized by a DCC coupling of an azide and alkyne, followed by an in situ electrophilic
n-alkyl amine with propiolic acid in dry DCM. After purifi- addition of a halonium ion, twenty per-O-acetylated 5-halotri-
Scheme 1 Synthesis of 5-halotriazole from the reaction of per-O-acetylated glucopyranosyl azide and azidoacetamide with n-alkyl propargyl
ether.
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Scheme 2 Synthesis of 5-halotriazole from the reaction of per-O-acetylated glucopyranosyl azide and azidoacetamide with n-alkyl propiolamides.
Scheme 3 Synthesis of 5-halotriazole from per-O-acetylated glucopyranosyl propiolamide.
azole linked glycolipids were synthesized. The structural diver- part constant, the alkyl part was connected to the triazole ring,
sity of all the glycolipids is depicted in Fig. 2 and these are using an ether and amide linkage, respectively. For the com-
listed in Table 1. Except for having different halogens pounds III and IV the long chain alkyl is attached to the tria-
(bromine or iodine), different lengths of the alkyl chain (n = 7, zole by an amide or ether linkage, while keeping the sugar
9, 11) and the glucose fragment being acetylated or free, all connected by an amide in both cases. Compounds V and VI
these molecules can be broadly classified in six different have a different type of connectivity, compared to the other
classes of molecules, depending on the functional groups next four classes of molecules. In both these cases, the sugars are
to the 5-halotriazole. In the case of I and II, keeping the sugar attached to the C-5 of the triazole with an amide linkage, while
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Fig. 2 Diversity in structure of various haloglycolipids.
Table 1 Synthesis of 5-halotriazole linked glycolipids
S. no.
1
Azide
Alkyne
X
Yield (%)
75
Br
2
3
4
5
I
85
70
85
74
Br
I
Br
6
7
8
Br
78
85
75
I
Br
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Table 1 (Contd.)
S. no.
Azide
Alkyne
X
I
Yield (%)
84
9
10
11
12
13
14
15
16
Br
71
81
70
81
70
75
80
I
Br
I
Br
I
Br
17
18
19
20
I
84
69
72
81
Br
I
I
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the alkyl chains have different linkages, as they are derived
from long chain azides and azidoacetamides.
Spectral data for compound 6: yield 0.45 g (50%, 90% pure),
syrup, 1H NMR (400 MHz, CDCl3): δ 6.11 (bs, 1H, NH),
3.31–3.26 (q, 2H, –NH–CH2−), 2.78 (s, 1H, alkyne –CH),
1.54–1.49 (m, 2H, –NHCH2CH2), 1.29–1.27 (m, 10H, 5 × CH2),
0.88 (t, 3H, –CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 152.1
(NHCO), 77.4, 72.9, 39.9, 31.7, 29.1, 26.8, 22.6, 14.0 ppm;
Summary and conclusion
The position of the 5-halotriazole rings and the functional ESI-MS HRMS: experimental 182.1548 for [M + H]+ calculated
groups connecting the sugar and long chain alkyl fragment to 182.1545 for C11H20NO.
the triazole ring varies in these glycolipids, diversifying their
Spectral data for compound 7: yield 0.55 g (50%, 90% pure),
physical characteristics such as the solubility, dipole moment, white solid, M. P. 144–147 °C, 1H NMR (400 MHz, CDCl3):
non-covalent interactions (H-bond and halogen bond) etc. δ 5.89 (bs, 1H, NH), 3.32–3.27 (q, 2H, –NH–CH2−), 2.76 (s, 1H,
Because of their structural diversity, as well as the heavy atom alkyne –CH), 1.55–1.49 (m, 2H, –NHCH2CH2), 1.29–1.25
effect of the halogen atoms, these haloglycolipids can be (m, 18H, 9 × CH2), 0.88 (t, 3H, –CH3) ppm; 13C NMR (100 MHz,
potentially useful for the crystallization of integral membrane CDCl3): δ 152.1 (NHCO), 79.2, 72.9, 39.9, 31.9, 29.6, 29.5 (×2),
proteins and other biomedical applications. The methodology 29.3, 29.2, 29.1, 26.8, 22.6, 14.1 ppm; ESI-MS HRMS:
can be extended to other sugar derivatives, as well as long experimental 238.2179 for [M + H]+ calculated 238.2171 for
chain alkyl derivatives, justifying the versatility and novelty of C15H28NO.
the methodology.
Synthesis of n-alkyl azides/azidoacetamides (8–11). The
n-alkyl azides were synthesized following a literature proce-
dure.19 For the synthesis of n-alkyl azidoacetamides, chloro-
acetyl chloride (0.6 mL, 7.5 mmol) was added dropwise to a
solution of n-alkyl amine (5 mmol) in dry DCM (15 mL) at
0 °C. The reaction mixture was stirred at room temperature for
Experimental section
General methods
The reaction mixtures were stirred magnetically, unless other- 24 h. After the reaction was complete, the reaction mixture was
wise stated. The products were characterized by NMR spec- washed several times with water. The organic layer was concen-
troscopy and ESI-MS. All the solvents used were distilled prior trated to dryness and taken to the next step without any purifi-
to use. Acetonitrile was initially refluxed over P2O5 and stored cation. To the chloroacetamido derivative (5 mmol) taken in
over 4 Å molecular sieves. Column chromatography was per- 5 mL of acetone, was added an aqueous solution of NaN3
formed using silica gel (100–200 mesh) using a mixture of (1.5 g, 25 mmol) and the reaction mixture was refluxed at
1
ethyl acetate and hexane as the eluent. The H and 13C NMR 60 °C for 24 h to give the azidoacetamide derivative, in a near
spectra were recorded at 400 and 100 MHz, respectively. The quantitative yield. The product formed was used in the next
coupling constants are reported in Hertz.
reaction without any further purification.
Synthesis of N-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)pro-
Spectral data for compound 10: yield 0.96 g (90%), syrup,
piolamide (3).22 2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl azide 1H NMR (400 MHz, CDCl3): δ 6.50 (bs, 1H, NH), 3.96 (s, 2H,
(373 mg, 1 mmol) was reduced to the corresponding amine by NHCOCH2−), 3.30–3.25 (q, 2H, –NH–CH2−), 1.54–1.49 (m, 2H,
treating with 5 mol% of Pd/C in the presence of H2 gas, in dry –NHCH2CH2), 1.29–1.27 (m, 10H, 5 × CH2), 0.88 (t, 3H, –CH3)
DCM. The amine formed was added to a stirred solution of ppm; 13C NMR (100 MHz, CDCl3): δ 166.5 (NHCO), 52.6, 39.5,
DCC (230 mg, 1.1 mmol) and propiolic acid (0.7 mL, 31.7, 29.4, 29.2, 29.1, 26.8, 22.6, 14.0 ppm; ESI-MS HRMS:
1.1 mmol) in dry DCM at 0 °C. The reaction mixture was experimental 235.1535 for [M + Na]+ calculated 235.1535 for
allowed to come to room temperature. The progress of the C10H20N4ONa.
reaction was monitored by TLC. After the reaction was com-
Spectral data for compound 11: yield 1.3 g (90%), white
plete, the reaction mixture was diluted with DCM, filtered and solid, M. P. 47–50 °C, 1H NMR (400 MHz, CDCl3): δ 6.31
evaporated to dryness. The crude reaction mixture was purified (bs, 1H, NH), 3.98 (s, 2H, NHCOCH2−), 3.30–3.25 (q, 2H,
by column chromatography. The NMR spectrum of the –NH–CH2−), 1.54–1.49 (m, 2H, –NHCH2CH2), 1.29–1.24 (m,
product was compared with the literature reported value.
18H, 9 × CH2), 0.88 (t, 3H, –CH3) ppm; 13C NMR (100 MHz,
Synthesis of n-alkyl propargyl ethers (4, 5). The n-alkyl pro- CDCl3): δ 166.3 (NHCO), 52.8, 39.5, 31.9, 29.6, 29.5 (×2), 29.4,
pargyl ethers were prepared by following
procedure.16
a
literature 29.3, 29.2, 26.8, 14.1 ppm; ESI-MS HRMS: experimental
291.2172 for [M + Na]+ calculated 291.2161 for C14H28N4ONa.
Synthesis of n-alkyl propiolamides (6, 7). To a stirred solu-
General procedure for [3 + 2] cycloaddition reactions. The
tion of DCC (1.1 g, 5.5 mmol) in dry DCM, propiolic acid selectively functionalized azide (0.5 mmol) was reacted with an
(350 mg, 5.5 mmol) was added dropwise at 0 °C. The solution alkyne (0.6 mmol) in the presence of NBS (110 mg, 0.6 mmol),
was stirred at that temperature for 30 minutes and n-alkyl Cu(I)X (0.6 mmol) (X = Br, I) and DIEA (1.25 mL, 1 mmol) in
amine (5 mmol) was slowly added to this. The reaction was dry CH3CN (5 mL). The progress of the reaction was monitored
continued for 24 h. After that, the reaction mixture was filtered by TLC. After the reaction was complete, the reaction mixture
and concentrated to dryness. The crude product was purified by was evaporated to dryness and ethyl acetate was added.
column chromatography to give the analytically pure product.
The organic layer was washed several times with water and
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evaporated to dryness. The crude product obtained was puri- experimental 746.2147 for [M + Na]+ calculated 746.2126 for
fied by column chromatography (hexane–ethyl acetate).
Data for lipid 13: yield 0.23 (75%), grey solid,
C29H46N3O10NaI.
g
Data for 17: yield 0.5 g (74%), syrup, [α]D: 12.4° (c = 0.5,
M. P. 84–87 °C, [α]D: −4.1° (c = 1.1, CHCl3); 1H NMR (400 MHz, CHCl3) H NMR (400 MHz, CDCl3): δ 6.87 (d, 1H, J = 9.2 Hz,
CDCl3): δ 5.96 (t, 1H, J = 9.6 Hz, H-2), 5.80 (d, 1H, J = 10.0 Hz, NH), 5.23–5.13 (m, 2H, H-1, H-2), 5.08–4.92 (m, 3H, H-3 &
H-1), 5.42 (t, 1H, J = 9.6 Hz, H-3), 5.28 (t, 1H, J = 9.6 Hz, H-4), –NHCOCH2−), 4.80 (t, J = 9.6 Hz, H-4), 4.52 (s, 2H, –OCH2−),
4.56 (s, 2H, –CH2−O) 4.28–4.24 (dd, 1H, H-6a), 4.20–4.17 (dd, 4.24–4.20 (dd, 1H, H-6a), 4.03–4.00 (dd, 1H, H-6b), 3.76–3.72
1H, H-6b), 4.00–3.97 (m, 1H, H-5) 3.52–3.48 (t, 2H, O–CH2−), (m, 1H, H-5), 3.46–3.43 (t, 2H, –O–CH2CH2−), 2.01, 1.96 (×2),
1
2.08, 2.04, 1.87 (3 × s, 12H, 4 × –COCH3), 1.61–1.56 (m, 2H, 1.93 (4
× s, 12H, 4 × –COCH3), 1.55–1.48 (m, 2H,
–OCH2CH2), 1.34–1.26 (m, 10H, 5 × CH2), 0.87 (t, 3H, –CH3) –O–CH2CH2−), 1.25–1.19 (m, 10H, 5 × –CH2−), 0.82–0.78 (t,
ppm; 13C NMR (100 MHz, CDCl3): δ 170.5, 170.2, 169.2, 168.5 3H, –CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 169.8, 169.6,
(4 × –COCH3), 144.4, 111.9 (BrCvC), 84.8 (C-1), 74.9, 73.1, 168.8, 168.5, 163.8, 143.1, 111.7 (vC–Br), 77.3 (C-1), 72.7, 71.5,
71.0, 69.1, 67.5, 62.6, 61.5, 31.8, 29.5, 29.4, 29.2, 26.0, 69.9, 69.3, 66.9, 61.9, 60.5, 50.3, 30.7, 28.5, 28.3, 28.2, 25.0,
22.6, 20.6, 20.5, 20.2, 14.1 (CH3) ppm; ESI-MS HRMS: experi- 21.6, 19.7, 19.6, 19.5, 13.0 (CH2–CH3) ppm; ESI-MS HRMS
mental 642.1637 for [M + Na]+ calculated 642.1638 for experimental 677.2056 for [M + H]+ calculated 677.2033 for
C25H38N3O10NaBr.
C27H42N4O11Br.
Data for 14: yield 0.23 g (70%), white solid, M. P. 78–80 °C,
Data for 18: yield 0.12 g (quantitative), syrup, [α]D: −13.9°
[α]D: −22.7° (c = 0.2, CHCl3), 1H NMR (400 MHz, CDCl3): δ 5.96 (c = 0.2, M), 1H NMR (400 MHz, CD3OD): δ 5.55 (d, 1H, J =
(t, 1H, J = 9.6 Hz, H-2), 5.80 (d, 1H, J = 9.6 Hz, H-1), 5.42 (t, 1H, 9.2 Hz, H-1), 4.57 (s, 2H, –O–CH2), 4.36 (t, 1H, J = 9.2 Hz, H-2),
J = 9.6 Hz, H-3), 5.28 (t, 1H, J = 9.6 Hz, H-4), 4.56 (s, 2H, 3.92–3.88 (dd, 1H, H-4), 3.74–3.70 (dd, 1H, H-5), 3.62–3.57
O–CH2), 4.28–4.24 (dd, 1H, H-6a), 4.21–4.18 (dd, 1H, H-6b), (m, 2H, H-6a & H-3), 3.55–3.52 (m, 3H, H-6b & O–CH2−CH2)
4.00–3.98 (m, 1H, H-5), 3.51–3.48 (t, 2H, O–CH2−CH2), 2.08, 1.61–1.56 (m, 2H, –O–CH2−CH2−), 1.30 (bs, 18H, 9 × –CH2−),
2.07, 2.04, 1.87 (4 × s, 12H, 4 × –COCH3), 1.61–1.57 (m, 2H, 0.92 (t, 3H, –CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 149.6,
O–CH2−CH2−), 1.29–1.25 (m, 18H, 9 × –CH2−), 0.87 (t, 3H, 89.6 (C-1), 85.7 (vC–I), 81.2, 78.7, 72.9, 71.7, 70.9, 64.4, 62.4,
–CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 170.5, 170.2, 169.2, 33.0, 30.8, 30.7, 30.6 (×2), 30.5, 27.5, 23.7, 14.4 ppm; ESI-MS
168.4, (4 × COCH3), 144.4, 111.9 (vC–Br), 84.8 (C-1), 74.9, HRMS experimental 578.1727 for [M
+
Na]+ calculated
73.1, 71.0, 69.1, 67.5, 62.6, 61.5, 31.9, 29.6, 29.5, 29.4, 29.3, 578.1703 for C21H38N3O6NaI.
26.0, 22.6, 20.6, 20.5, 20.2, 14.1 ppm; ESI-MS HRMS experi-
Data for 19: yield 0.24 g (78%), syrup, [α]D: −2.0° (c = 0.5,
mental 676.2433 for [M
C29H47N3O10Br.
+
H]+ calculated 676.2445 for CHCl3), 1H NMR (400 MHz, CDCl3): δ 7.20 (t, 1H, NH), 6.03
(t, 1H, J = 9.6 Hz, H-2), 5.82 (d, 1H, J = 9.2 Hz, H-1), 5.44 (t, 1H,
Data for 15: yield 0.28
g
(85%), white solid, J = 9.2 Hz, H-3), 5.30 (t, 1H, J = 9.6 Hz, H-4), 4.28–4.25 (dd, 1H,
M. P. 131–134 °C, [α]D: −12.1° (c = 0.2, CHCl3), 1H NMR H-6a) 4.20–4.17 (dd, 1H, H-6b), 4.07–4.03 (m, 1H, H-5),
(400 MHz, CDCl3): δ 6.01 (t, 1H, J = 9.6 Hz, H-2), 5.80 (d, 1H, 3.45–3.40 (t, 2H, NHCH2−), 2.07, 2.05, 1.89 (3s, 12H, 4 ×
J = 9.6 Hz, H-1), 5.43 (t, 1H, J = 9.6 Hz, H-3), 5.29 (t, 1H, J = –COCH3), 1.62–1.59 (m, 2H, NHCH2CH2−), 1.37–1.24 (m, 10H,
9.6 Hz, H-4), 4.60–4.53 (ABq, 2H, O–CH2), 4.29–4.24 (dd, 1H, 5 × –CH2−), 0.89–0.86 (t, 3H, –CH3) ppm; 13C NMR (100 MHz,
H-6a), 4.21–4.18 (dd, 1H, H-6b), 4.03–3.98 (m, 1H, H-5), CDCl3): δ 170.5, 170.2, 169.2, 168.4, 158.6, 139.6, 114.7
3.51–3.48 (t, 2H, J = 6.8 Hz, O–CH2–CH2), 2.08, 2.07, 2.04, 1.87 (vC–Br), 84.0, 75.0, 73.1, 69.2, 67.4, 61.4, 39.2, 31.7, 29.5, 29.2,
(4 × s, 12H, 4 × –COCH3), 1.62–1.56 (m, 2H, O–CH2−CH2−), 29.1, 26.9, 22.6, 20.6, 20.5, 20.2, 14.0 (CH2–CH3) ppm; ESI-MS
1.36–1.26 (m, 10H, 5 × –CH2−), 0.87 (t, 3H, J = 6.8 Hz, –CH3) HRMS experimental 655.1575 for [M
+
Na]+ calculated
ppm; 13C NMR (100 MHz, CDCl3): δ 170.5, 170.2, 169.2, 168.4, 655.1591 for C25H37N4O10NaBr.
(4 × COCH3), 149.4, 85.7 (C-1), 80.0 (vC–I), 74.9, 73.2, 71.0,
Data for 20: yield 0.25 g (75%), white solid, M. P. 120–122 °C,
69.4, 67.6, 63.5, 61.5, 31.8, 29.5, 29.4, 29.2, 26.1, 22.6, 20.7, [α]D: −13.6° (c = 1.0, CHCl3), 1H NMR (400 MHz, CDCl3): δ 7.19
20.5, 20.3, 14.1 ppm; ESI-MS HRMS experimental 690.1465 for (t, 1H, J = 9.6 Hz, NHCH2), 6.04 (t, 1H, J = 9.6 Hz, H-2), 5.81
[M + Na]+ calculated 690.1500 for C25H38N3O10NaI.
(d, 1H, J = 9.6 Hz, H-1), 5.43 (t, 1H, J = 9.6 Hz, H-3), 5.30 (t, 1H,
Data for 16: yield 0.3 g (85%), white solid, M. P. 78–80 °C, J = 9.6 Hz, H-4), 4.29–4.25 (dd, 1H, H-6a), 4.20–4.16 (dd, 1H,
[α]D: −13.98° (c = 0.2, CHCl3), 1H NMR (400 MHz, CDCl3): H-6b), 4.04–4.00 (m, 1H, H-5), 3.45–3.40 (q, 2H, NHCH2), 2.08,
δ 6.02 (t, 1H, J = 9.6 Hz, H-2), 5.79 (d, 1H, J = 9.2 Hz, H-1), 5.43 2.05, 1.88 (3s, 12H, 4 × COCH3), 1.61–1.57 (m, 2H, NH–
(t, 1H, J = 9.6 Hz, H-3), 5.29 (t, 1H, J = 9.6 Hz, H-4), 4.60–4.53 CH2−CH2−), 1.25 (m, 18H, 9 × –CH2−), 0.88 (t, 3H, –CH3) ppm;
(ABq, 2H, –O–CH2), 4.29–4.24 (dd, 1H, H-6a), 4.21–4.18 (dd, 13C NMR (100 MHz, CDCl3): δ 170.6, 170.3, 169.3, 168.5
1H, H-6b), 4.02–4.00 (m, 1H, H-5), 3.52–3.48 (t, 2H, O–CH2– (4 × COCH3), 158.7 (NHCO), 139.7, 114.8 (vC–Br), 84.1 (C-1),
CH2), 2.09, 2.08, 2.05, 1.87 (4 × s, 12H, 4 × –COCH3), 1.62–1.59 75.1, 73.2, 69.3, 67.5, 61.5, 39.3, 32.0, 29.7, 29.6, 29.4, 29.3,
(m, 2H, –O–CH2−CH2−), 1.39–1.22 (m, 18H, 9 × –CH2−), 0.88 27.0, 22.7, 20.7, 20.6, 20.4, 14.2 ppm; ESI-MS HRMS experi-
(t, 3H, –CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 170.6, 170.3, mental 711.2219 for [M + Na]+ calculated 711.2217 for
169.3, 168.5, (4 × COCH3), 149.4, 85.7 (C-1), 80.2 (vC–I), 74.9, C29H45N4O10NaBr.
73.2, 71.0, 69.4, 67.6, 63.6, 61.6, 32.0, 29.7, 29.6, 29.5,
Data for 21: yield 0.29 g (85%, 95% pure), white solid,
29.4, 26.1, 22.7, 20.8, 20.6, 20.4, 14.2 ppm; ESI-MS HRMS M. P. 131–134 °C, [α]D: −13.3° (c = 0.8, CHCl3), 1H NMR
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(400 MHz, CDCl3): δ 7.23 (t, 1H, NH), 6.09 (t, 1H, J = 9.6 Hz, 5.29 (t, 1H, J = 9.6 Hz, H-3), 5.26–5.02 (m, 4H, H-1, H-4,
H-2), 5.83 (d, J = 9.6 Hz, H-1), 5.44 (t, J = 9.6 Hz, H-3), 5.30 (t, COCH2), 4.83 (t, 1H, J = 9.6 Hz, H-2), 4.32–4.28 (dd, 1H, H-6a),
J = 9.6 Hz, H-4), 4.33–4.25 (dd, 1H, H-6a), 4.20–4.17 (dd, 1H, 4.10–4.07 (dd, 1H, H-6b), 3.83–3.81 (m, 1H, H-5), 3.46–3.41 (q,
H-6b), 4.07–4.03 (m, 1H, H-5), 3.45–3.40 (t, 2H, NCH2−), 2.07, 2H, NHCH2), 2.09, 2.03, 2.00, (3s, 12H, 4 × COCH3), 1.64–1.58
2.04, 1.87 (3s, 12H,
4 × –COCH3), 1.62–1.59 (m, 2H, (m, 2H, NH–CH2−CH2−), 1.37–1.25 (m, 10H, 5 × –CH2−), 0.87
NCH2CH2−), 1.37–1.24 (m, 10H, 5 × –CH2−), 0.89–0.86 (t, 3H, (t, 3H, J = 6.4 Hz, –CH3) ppm; 13C NMR (100 MHz, CDCl3):
–CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 170.5, 170.3, 169.3, δ 171.3, 170.7, 169.9, 169.6 (4 × COCH3), 164.6, 159.1 (2 ×
168.4, 159.0, 143.4, 85.4 (C-1), 82.2 (vC–I), 75.1, 73.3, 69.5, NHCO), 143.8, 82.7 (vC–I), 78.5 (C-1), 73.8, 72.4, 70.5, 68.1,
67.6, 61.6, 39.4, 31.8, 29.7, 29.6, 29.3, 29.2, 27.0, 22.7, 61.6, 53.0, 39.4, 31.9, 29.8, 29.6, 29.4, 29.3, 27.0, 22.7, 20.9,
20.7, 20.6, 20.3, 14.1 (CH2–CH3) ppm; ESI-MS HRMS experi- 20.8, 20.6, 14.1 ppm; ESI-MS HRMS experimental 760.1656 for
mental 703.1443 for [M + Na]+ calculated 703.1452 for [M + Na]+ calculated 760.1667 for C27H40N5O11NaI.
C25H37N4O10NaI.
Data for 26: yield 0.32 g (81%), white solid, M. P. 122–124 °C,
Data for 22: yield 0.31 g (84%), white solid, M. P. 155–158 °C, [α]D: +15.1° (c = 0.5, CHCl3), 1H NMR (400 MHz, CDCl3): δ 7.25
[α]D: −20.6° (c = 0.7, CHCl3), 1H NMR (400 MHz, CDCl3): δ 7.30 (t, 1H, CONHCH2), 6.78 (bs, 1H, NH–), 5.29 (t, 1H, J = 9.6 Hz,
(t, 1H, NH), 6.11 (t, 1H, J = 9.6 Hz, H-2), 5.87 (d, 1H, J = 9.2 Hz, H-1), 5.25–5.02 (m, 4H, H-2, H-4 & –NHCOCH2−), 4.84 (t, 1H,
H-1), 5.47 (t, 1H, J = 9.6 Hz, H-3), 5.32 (t, 1H, J = 9.6 Hz, H-4), J = 8.8 Hz, H-3), 4.33–4.29 (dd, 1H, H-6a), 4.10–4.06 (dd, 1H,
4.32–4.27 (dd, 1H, H-6a), 4.21–4.17 (dd, 1H, H-6b), 4.11–4.07 H-6b), 3.84–3.80 (m, 1H, H-5), 3.46–3.41 (q, 2H, CONHCH2−),
(m, 1H, H-5), 3.45–3.42 (q, 2H, NH–CH2−), 2.08, 2.05, 1.88 (3s, 2.09, 2.03 (×2), 2.00 (4 × s, 12H, 4 × –COCH3), 1.65–1.58
12H, 4 × –COCH3), 1.63–1.59 (m, 2H, NH–CH2CH2−), 1.36–1.25 (m, 2H, NCH2CH2−), 1.38–1.25 (m, 18H, 9 × –CH2−), 0.89–0.86
(m, 18H, 9 × –CH2−), 0.89–0.86 (t, 3H, –CH3) ppm; 13C NMR (t, 3H, –CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 171.1, 170.7,
(100 MHz, CDCl3): δ 170.5, 170.2, 169.2, 168.3, 158.9, 143.3, 169.9, 169.6, 164.7, 159.1, 143.8, 82.8, 78.5, 73.8, 72.4, 70.5,
85.2 (C-1), 82.4, 74.9, 73.2, 69.3, 67.5, 61.5, 39.3, 31.8, 29.6, 68.0, 61.6, 53.0, 39.4, 32.0, 29.7, 29.6, 29.5, 29.4, 27.0, 22.8,
29.5, 29.3, 29.2, 26.9, 22.6, 20.7, 20.5, 20.3, 14.1 (CH2–CH3) 20.9, 20.8, 20.7, 20.6, 14.1 (CH2–CH3) ppm; ESI-MS HRMS
ppm; ESI-MS HRMS experimental 759.2076 for [M + Na]+ calcu- experimental 794.2461 for [M + H]+ calculated 794.2473 for
lated 759.2078 for C29H45N4O10NaI.
C31H49N5O11I.
Data for 23: yield 0.24 g (71%), white solid, charred beyond
Data for 27: yield 0.22 g (70%), white solid, M. P. 68–72 °C,
1
175 °C, [α]D: +4.0° (c = 0.5, CHCl3), 1H NMR (400 MHz, CDCl3): [α]D: −1.1° (c = 0.4, CHCl3), H NMR (400 MHz, CDCl3): δ 7.94
δ 7.20 (t, 1H, J = 6 Hz, NHCH2), 6.85 (d, 1H, J = 8.8 Hz, NHCO), (d, 1H, J = 9.2 Hz, NH), 5.45 (t, 1H, J = 9.6 Hz, H-1), 5.35 (t, 1H,
5.32 (t, 1H, J = 9.2 Hz, H-3), 5.27–5.02 (m, 4H, H-1, H-4, J = 9.6 Hz, H-2), 5.13 (t, 2H, J = 10.4 Hz, H-3, H-4), 4.42 (t, 2H,
COCH2), 4.85 (t, 1H, J = 9.6 Hz, H-2), 4.32–4.28 (dd, 1H, H-6a), –NH–CH2−), 4.31–4.27 (dd, 1H, H-6a), 4.13–4.09 (dd, 1H,
4.10–4.07 (dd, 1H, H-6b), 3.84–3.81 (m, 1H, H-5), 3.47–3.42 (q, H-6b), 3.88–3.86 (m, 1H, H-5), 2.08, 2.04, 2.03, 2.01 (4 × s, 12H,
2H, NHCH2), 2.09, 2.03, 2.00 (3s, 12H, 4 × COCH3), 1.65–1.59 4 × –COCH3), 1.92–1.91 (m, 2H, NCH2CH2−), 1.33–1.26 (m,
(m, 2H, NH–CH2−CH2−), 1.38–1.27 (m, 10H, 5 × –CH2−), 0.88 10H, 5 × –CH2−), 0.88 (t, 3H, –CH3) ppm; 13C NMR (100 MHz,
(t, 3H, –CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 171.2, 170.6, CDCl3): δ 170.7, 170.3, 170.0, 169.5, 159.7 (4 × –COCH3), 137.8,
169.8, 169.5 (4 × COCH3), 164.3, 158.7 (2 × NHCO), 139.7, 114.3, 77.8 (C-1), 73.6, 73.0, 70.2, 68.1, 61.6, 49.4, 31.6, 29.6,
114.8 (vC–Br), 78.4 (C-1), 73.8, 72.3, 70.4, 68.0, 61.5, 51.3, 29.3, 29.0, 28.8, 26.3, 22.6, 20.7, 20.6, 14.0 (CH2–CH3) ppm;
39.2, 31.7, 29.5, 29.3, 29.2, 26.9, 22.6, 20.8, 20.7, 20.6, 20.5, ESI-MS HRMS experimental 655.1572 for [M + Na]+ calculated
14.1 ppm; ESI-MS HRMS experimental 712.1821 for [M + Na]+ 655.1591 for C25H37N4O10NaBr.
calculated 712.1805 for C27H40N5O11NaBr.
Data for 28: yield 0.26 g (80%), syrup, [α]D: +1.0° (c = 0.2,
1
Data for 24: yield 0.26 g (70%), white solid, M. P. 77–81 °C, CHCl3), H NMR (400 MHz, CDCl3): δ 7.85 (d, 1H, J = 9.6 Hz,
[α]D: +9.74° (c = 0.2, CHCl3), 1H NMR (400 MHz, CDCl3): δ 7.13 NH), 5.43 (t, 1H, J = 9.6 Hz, H-1), 5.35 (t, 1H, J = 9.6 Hz, H-3),
(t, 1H, CONHCH2), 6.78 (d, 1H, J = 8.8 Hz, NHCOCH2), 5.22 5.15–5.09 (m, 2H, H-2, H-4), 4.37 (t, 2H, J = 7.2 Hz, N–CH2−),
(t, 1H, J = 9.6 Hz, H-3), 5.16–4.90 (m, 4H, H-1, H-4 & 4.31–4.27 (dd, 1H, H-6a), 4.13–4.09 (dd, 1H, H-6b), 3.88–3.85
–NHCOCH2−), 4.77 (t, 1H, J = 9.6 Hz, H-2), 4.25–4.21 (dd, 1H, (m, 1H, H-5), 2.08, 2.04, 2.03, 2.01 (4 × s, 12H, 4 × –COCH3),
H-6a), 4.03–4.00 (dd, 1H, H-6b), 3.77–3.74 (m, 1H, H-5), 1.92–1.88 (m, 2H, NCH2CH2−), 1.32–1.25 (m, 14H, 7 × –CH2−),
3.39–3.34 (q, 2H, CONHCH2−), 2.02, 1.96, 1.93 (3s, 12H, 0.88 (t, 3H, J = 6.8 Hz, –CH3) ppm; 13C NMR (100 MHz, CDCl3):
4 × –COCH3), 1.58–1.51 (m, 2H, NCH2CH2−), 1.34–1.18 (m, δ 170.7, 170.3, 170.0, 169.5, (4 × –COCH3), 159.7 (NHCO),
18H, 9 × –CH2−), 0.80 (t, 3H, –CH3) ppm; 13C NMR (100 MHz, 137.8, 114.2 (–BrCC–), 77.8 (C-1), 73.6, 73.0, 70.2, 68.1, 61.6,
CDCl3): δ 170.2, 169.6, 168.7, 168.5, 163.2, 157.7, 138.7, 113.7, 49.4, 31.8, 29.5, 29.4, 29.3, 29.2, 28.9, 26.3, 22.6, 20.7, 20.6,
77.4, 72.7, 71.3, 69.4, 66.9, 60.4, 50.3, 38.2, 30.8, 28.6, 28.5, 14.1 (CH2–CH3) ppm; ESI-MS HRMS experimental 683.1921 for
28.3, 28.2, 25.9, 21.6, 19.7, 19.6, 13.1 (CH2–CH3) ppm; ESI-MS [M + Na]+ calculated 683.1904 for C27H41N4O10NaBr.
HRMS experimental 768.2423 for [M
768.2431 for C31H48N5O11NaBr.
+
Na]+ calculated
Data for 29: yield 0.25 g (75%), white solid, M. P. 54–58 °C,
[α]D: +6.6° (c = 0.1, CHCl3), H NMR (400 MHz, CDCl3): δ 7.86
1
Data for 25: yield 0.27 g (81%), white solid, M. P. 115–118 °C, (d, 1H, J = 9.6 Hz, NH), 5.38 (t, 1H, J = 9.6 Hz, H-1), 5.28 (t, 1H,
1
[α]D: +9.6° (c = 0.5, CHCl3), H NMR (400 MHz, CDCl3): δ 7.23 J = 9.6 Hz, H-3), 5.06 (t, 2H, J = 9.6 Hz, H-2 & H-4), 4.34 (t, 2H,
(t, 1H, J = 6 Hz, NHCH2), 6.73 (d, 1H, J = 8.8 Hz, NHCO), J = 7.2 Hz, N–CH2−), 4.24–4.20 (dd, 1H, H-6a), 4.05–4.02 (dd,
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1H, H-6b), 3.81–3.78 (m, 1H, H-5), 2.01, 1.97, 1.96, 1.93 (4 × s, 3.89–3.85 (m, 1H, H-5), 3.29–3.24 (q, 2H, N–CH2−), 2.09, 2.05,
12H, 4 × –COCH3), 1.85–1.82 (m, 2H, NCH2CH2−), 1.26–1.19 2.04, 2.03 (4 × s, 12H, 4 × –COCH3), 1.50–1.46 (m, 2H,
(m, 10H, 5 × –CH2−), 0.80 (t, 3H, J = 6.8 Hz, –CH3) ppm; NCH2CH2−), 1.24 (bs, 18H, 9 × –CH2−), 0.87 (t, 3H, J = 6.8 Hz,
13C NMR (100 MHz, CDCl3): δ 170.7, 170.3, 170.1, 169.5, (4 × – –CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 170.8, 170.6, 170.1,
COCH3), 160.1 (NHCO), 141.7, 81.9 (–ICv), 77.9 (C-1), 73.6, 169.6 (4 × –COCH3), 163.4, 159.6 (2 × NHCO), 142.5, 84.2
73.1, 70.3, 68.2, 61.7, 50.9, 31.7, 29.8, 29.0, 28.9, 26.3, (–ICC–), 78.0 (C-1), 73.7, 72.9, 70.3, 68.1, 61.6, 53.2, 40.1, 32.0,
22.6, 20.8, 20.6, 14.1 (CH2–CH3) ppm; ESI-MS HRMS experi- 29.7, 29.6, 29.5, 29.4, 29.2, 26.8, 22.7, 20.8, 20.7, 14.2 ppm;
mental 703.1476 for [M + Na]+ calculated 703.1452 for ESI-MS HRMS experimental 794.2474 for [M + H]+ calculated
C25H37N4O10NaI.
794.2473 for C31H49N5O11I.
Data for 30: yield 0.3 g (84%), white solid, M. P. 58–62 °C,
1
[α]D: −6.0° (c = 0.2, CHCl3), H NMR (400 MHz, CDCl3): δ 7.90
(d, 1H, J = 9.6 Hz, NH), 5.43 (t, 1H, J = 9.6 Hz, H-1), 5.35 (t, 1H,
J = 9.6 Hz, H-3), 5.16–5.10 (m, 2H, H-2, H-4), 4.43–4.39 (t, 2H,
Acknowledgements
J = 7.2 Hz, N–CH2−), 4.31–4.27 (dd, 1H, H-6a), 4.13–4.09 (dd, The authors are thankful to the Indian Institute of Technology,
1H, H-6b), 3.87–3.85 (m, 1H, H-5), 2.08, 2.04, 2.03, 2.01(4 × s, Madras for the instrumental facilities. LNS is thankful to UGC,
12H, 4 × –COCH3), 1.93–1.89 (m, 2H, NCH2CH2−), 1.39–1.13 New Delhi and AS thanks CSIR, New Delhi for research fellow-
(m, 14H, 7 × –CH2−), 0.87 (t, 3H, –CH3) ppm; 13C NMR ships. The authors are thankful to Prof. S. Sankararaman,
(100 MHz, CDCl3): δ 170.7, 170.3, 170.0, 169.5, (4 × –COCH3), Department of Chemistry, Indian Institute of Technology
160.1 (NHCO), 141.6, 81.9 (–ICC−), 77.8 (C-1), 73.6, 73.0, 70.2, Madras and Dr Satyanarayan Sahoo, Department of Chemistry,
68.1, 61.6, 50.8, 31.8, 29.7, 29.6, 29.4, 29.3, 29.2, 28.9, Berhampur University, for their valuable input during the
26.3, 22.6, 20.7, 20.6, 14.1 (–CH3) ppm; ESI-MS HRMS experi- manuscript preparation.
mental 731.1785 for [M + Na]+ calculated 731.1765 for
C27H41N4O10NaI.
Data for 31: yield 0.24 g (69%), sticky solid, M. P. not deter-
References
mined, [α]D: +3.9° (c = 0.2, CHCl3), 1H NMR (400 MHz, CDCl3):
δ 7.88 (d, 1H, J = 9.6 Hz, NH), 5.86 (bs, 1H, NH), 5.44 (t, 1H, J =
9.6 Hz, H-1), 5.36 (t, 1H, J = 9.6 Hz, H-3), 5.15–5.08 (m, 2H,
H-2, H-4), 4.31–4.27 (dd, 1H, H-6a), 4.14–4.11 (dd, 1H, H-6b),
3.89–3.85 (m, 1H, H-5), 3.29–3.24 (m, 2H, N–CH2−), 2.08, 2.04,
2.03, 2.02 (4 × s, 12H, 4 × –COCH3), 1.49 (m, 2H, NCH2CH2−),
1.26 (bs, 10H, 5 × –CH2−), 0.87 (t, 3H, –CH3) ppm; 13C NMR
(100 MHz, CDCl3): δ 170.6, 170.5, 170.0, 169.5, (4 × –COCH3),
163.2, 159.2 (2 × NHCO), 138.4, 116.1 (–BrCC–), 77.8 (C-1), 73.7,
72.9, 70.3, 68.1, 61.6, 51.5, 40.1, 31.7, 29.3, 29.1, 26.7,
22.6, 20.7, 20.6, 14.0 (CH2–CH3) ppm; ESI-MS HRMS experi-
mental 712.1826 for [M + Na]+ calculated 712.1805 for
C27H40N5O11NaBr.
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Data for 32: yield 0.3 g (72%), white solid, M. P. 178–180 °C,
1
[α]D: 12.6° (c = 0.9, CHCl3), H NMR (400 MHz, CDCl3): δ 7.95
(d, 1H, J = 9.6 Hz, NH), 5.78 (t, 1H, J = 9.6 Hz, NH), 5.44 (t, 1H,
J = 9.6 Hz, H-1), 5.36 (t, 1H, J = 9.6 Hz, H-3), 5.16–5.12 (m, 2H,
H-2, H-4), 4.32–4.27 (dd, 1H, H-6a), 4.14–4.10 (dd, 1H, H-6b),
3.89–3.86 (m, 1H, H-5), 3.29–3.24 (q, 2H, N–CH2−), 2.09, 2.05,
2.04, 2.03 (4 × s, 12H, 4 × –COCH3), 1.49–1.47 (m, 2H,
NCH2CH2−), 1.26 (bs, 10H, 5 × –CH2−), 0.87 (t, 3H, J = 6.8 Hz, 10 J. F. Resek, S. Bhattacharya and H. G. Khorana, J. Org.
–CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 170.8, 170.6, 170.1,
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169.6, (4 × –COCH3), 163.5, 159.7 (2 × NHCO), 142.5, 84.3 11 W. T. Bass and T. M. Bricker, Anal. Biochem., 1988, 171,
(–ICC–), 78.0 (C-1), 73.7, 73.0, 70.3, 68.1, 61.7, 53.2, 40.1, 31.8, 330.
29.4 29.2, 26.8, 22.7, 20.8, 20.7, 14.2 (CH2–CH3) ppm; ESI-MS 12 J. A. Lundbaek, P. Birn, A. J. Hansen, R. Søgaard, C. Nielsen,
HRMS experimental 738.1859 for [M + H]+ calculated 738.1847
for C27H41N5O11I.
J. Girshman, M. J. Bruno, S. E. Tape, J. Egebjerg,
D. V. Greathouse, G. L. Mattice, R. E. Koeppe II and
O. S. Andersen, J. Gen. Physiol., 2004, 123, 599.
Data for 33: yield 0.32 g (81%), white solid, M. P. 165–167 °C,
[α]D: −17.8° (c = 0.3, CHCl3), 1H NMR (400 MHz, CDCl3): δ 7.93 13 S. L. Schreiber and M. D. Burke, Angew. Chem., Int. Ed.,
(d, 1H, J = 9.2 Hz, NH), 5.63 (t, 1H, J = 9.6 Hz, NH), 5.44 (t, 1H,
2004, 43, 46.
J = 9.6 Hz, H-1), 5.36 (t, 1H, J = 9.6 Hz, H-3), 5.16–5.09 (m, 2H, 14 V. V. Rostovtsev, L. G. Green, V. V. Fokin and B. K. Sharpless,
H-2, H-4), 4.32–4.28 (dd, 1H, H-6a), 4.14–4.10 (dd, 1H, H-6b),
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