Synthesis of glycotriazololipids and observations on their self-assembly properties

Article abstract of DOI:10.1016/j.carres.2015.04.008

Abstract Various carbohydrate-anchored triazole-linked lipids prepared by solvent-free mechanochemical azide-alkyne click reaction, on analysis by TEM, have been found to spontaneously self-assemble in solvents leading to structures of interesting physicochemical attributes. Interestingly, analogous compounds based on different sugars (e.g., d-glucose, and d-galactose, as also d-lactose) assemble in patterns distinctly different from each other thus reiterating the fact that the structure of the sugar as well as that of the lipid are important factors that determine the size and shape of the supramolecular assembly formed. Besides, the molecular self-assembly was also found to be solvent-as well as temperature-dependent.

Full text of DOI:10.1016/j.carres.2015.04.008

Accepted Manuscript
Synthesis of glycotriazololipids and observations on their self-assembly properties
Mohit Tyagi, K.P. Ravindranathan Kartha
PII:
S0008-6215(15)00121-4
10.1016/j.carres.2015.04.008
CAR 6983
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 3 January 2015
Revised Date: 30 March 2015
Accepted Date: 8 April 2015
Please cite this article as: Tyagi M, Ravindranathan Kartha KP, Synthesis of glycotriazololipids
and observations on their self-assembly properties, Carbohydrate Research (2015), doi: 10.1016/
j.carres.2015.04.008.
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ACCEPTED MANUSCRIPT
Synthesis of glycotriazololipids and observations on their self-assembly properties
Mohit Tyagi, K. P. Ravindranathan Kartha*

ACCEPTED MANUSCRIPT
Synthesis of glycotriazololipids and observations on their self-
assembly properties
Mohit Tyagi and K. P. Ravindranathan Kartha*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research,
Punjab, India
*
Fax: 91-172-2214692; E-mail: rkartha@niper.ac.in
Abstract- Various carbohydrate-anchored triazole-linked lipids prepared by solvent-free
mechanochemical azide-alkyne click reaction, on analysis by TEM, have been found to spontaneously
self-assemble in solvents leading to structures of interesting physicochemical attributes. Interestingly,
analogous compounds based on different sugars (e.g. D-glucose, and D-galactose, as also D-lactose)
assemble in patterns distinctly different from each other thus reiterating the fact that the structure of the
sugar as well as that of the lipid are important factors that determine the size and shape of the
supramolecular assembly formed. Besides, the molecular self-assembly was also found to be solvent- as
well as temperature-dependent.
Keywords: Environment-dependent molecular assembly, CTSAMs, mechanochemical click reaction,
nano bioorganomaterials.
1
. Introduction
The concept of molecular assembly, a process in which molecules, by way of contiguous non-covalent
interactions between them, spontaneously come together to form structurally defined assemblages is
1
highly inspired by nature which has examples of well-organized structures in abundance. The
2
organization of α-linked glucans into a complex starch granule, the self-assembly of the coat protein
3
,4
around the RNA (single strand) to form the tobacco mosaic virus capsid and the lipid bilayer, an
1

ACCEPTED MANUSCRIPT
integral part of a cell membrane can, for instance, serve as three typical kinds of classic examples of how
stable structures can be formed through a network of non-covalent interactions. Nature’s numerous such
examples have indeed been fascinating as well as challenging to chemists and have been central to
generating novel molecules and structures possessing interesting physicochemical attributes for serving as
materials for new and emerging applications. Indeed the concept has found diverse innovative
5
6-8
9-
applications in making valuable materials composed of organic, inorganic and/or mixed constituents
1
3
(metal-organic framework, MOF). These materials have been explored for their applications in drug
1
4,15
16-18
19
20-22
delivery,
gene delivery,
electronics, nanofabrication,
etc. The pioneering applications of such
self-assembling chemical entities in various new fields has triggered intensified search for new materials
with interesting attributes. Click chemistry (azide-alkyne) has emerged as a powerful tool for accessing
2
3,24
complex tricky molecules valuable as materials.
In addition to enabling making new materials, click
2
5-29
chemistry is also quite well explored for making biologically important chemical entities
by virtue of
the pharmacophoric features of the triazole moiety. Click chemistry has also received huge attention in
the field of supramolecular chemistry because of the abilities of the triazole moiety to show various non-
3
0-35
covalent interactions.
In carbohydrate chemistry it has been widely applied in making
3
6-40
41-45
46-51
52,53
glycodendrimers,
glycomacrocycles,
multivalent inhibitors,
pseudo-oligosaccharides,
5
4,55
56,57
58-60
61
62-64
glycopolymers,
carbohydrate-protein conjugates
reported for the preparation of triazole-linked compounds under mechanochemical CuAAC reaction.
glycopeptides,
glycomimetics,
glycorotaxanes, cyclodextrin analogues,
6
5-67
etc. Recently, various solvent-free and green methods have also been
6
8-70
Although the self-assembling behavior of glycolipids owe much to their amphiphilic structural
characteristics that can be considered as at the root of their ability to organize into biomembrane-
7
1,72
assemblies,
they can also exist in various nano forms such as rods, sheets, vesicular aggregates, etc.
depending upon their structural parameters such as the configuration of the glycosidic linkage (α or β),
2

ACCEPTED MANUSCRIPT
7
3-80
nature of the substituents (their lipophilic/lipophobic nature), etc.
the potential that various ampiphilic molecules hold for nanotube formation.
isolated changes such as a mere change in the stereochemistry of the glycosidic bond or the like can lead
Shimizu et al. has recently reviewed
8
1,82
Most interestingly, even
7
5,80,83,84
to a diversification of their self-assembling characteristics.
Because of the self-assembling
features of these molecules they were further demonstrated for their applications in making uniformly
sized metal nanowires, drug encapsulation, nanoparticle synthesis, surfactants, imaging, ion-channels,
8
5-92
toxin mimics, etc.
Recently, certain triazole-linked glycolipids were reported along with their
9
3
physicochemical characterization and potential application in bio-related surfactants. Oriol et. al. also
studied the self-assembling behavior of various disaccharide-based triazole-linked glycoamphiphiles and
9
4,95
have shown the importance of the polar head group and the lipid chain in the self-assembly process.
Introduction of aromatic residues (for example, azobenzene moiety) in the lipid component could also
influence the self-assembly pattern of these molecules and have also shown their important application as
9
6
light sensitive materials.
Multivalent carbohydrate derivatives such as 1 having more than one hexose residue anchored on
to a phenyl ring via a triazole moiety have recently been shown to spontaneously self-assemble yielding
nano-structured materials possessing interesting physicochemical properties including ability to form gel
9
7
as well as possessing moderate antimicrobial activity (Fig 1). A structure-dependent binding potency for
the manno-analogues of the above compounds for their binding with Concanavalin A has also been
98
demonstrated in the past. In view of these observations, we wish to report molecules simpler in
architecture but that would essentially retain the self-assembling characteristics of 1. This must also make
their preparation easier. These considerations led us to explore the possibilities with the sugar-linked
triazoles of structure 2 in which the triazole residue is flanked by a sugar moiety on the one side and a
long-chain lipid moiety on the other (Fig 1). The lipid moiety by virtue of being able to form micellar (or
3

ACCEPTED MANUSCRIPT
other) structures through association should allow the molecule to self-assemble in solution. The presence
of hydroxyl groups on the sugar residue that allows introduction of fatty alkanoyl groups through ester
linkages, must also provide platform for the molecule to organize. A few of such molecules have already
9
3
been shown to have applications as bio-surfactants and importantly, have also been evaluated for their
9
9
cytotoxicity profile . Therefore a study on the effect of the nature of the lipid chain and the polar head
group on their self-assembly seemed in context. Therefore a small set of carbohydrate-based triazole-
linked lipids were prepared under solvent-free ball-milling conditions and were investigated for their self-
assembling properties by TEM. Compound 2, required for the synthesis of the glycolipids presented in
this work, could be sourced conveniently from the desired propargyl glycoside 3 and the appropriate
1
00
azide 4 (Fig 1) through solvent-free mechanochemical click reaction optimized in our laboratory.
N
N
OR
N
O
N
OR
O
N
OR
OR
RO
RO
O
N
OR
O
RO
N
N
N
N
N
N
O
OR
OR
O
O
1
O
RO
RO
RO
OR
OR
OR
R = Hexanoyl/Dodecanoyl
N
N
O
N
Lip
id
2
O
O
N
3
3
4
Figure 1. Proposed potentially self-assembling glycolipids
2. Results and Discussion
2
.1 Synthesis of carbohydrate-based triazole-linked lipids
Three different propargyl glycosides, two monosaccharide-derived (5 and 6) and one disaccharide-
derived (7), were chosen as examples for 3, while compounds 8, 9 and 10 served as the model azide
4

ACCEPTED MANUSCRIPT
counterpart (examples for 4) for the desired click reaction. The propargyl glycosides 5, 6 and 7 were
synthesised under solvent-free conditions by grinding in a planetary ball mill using ZnCO as the
3
1
01
promoter. The lipophilic azides on the other hand were prepared by the conventional nucleophilic
1
02-104
substitution of their corresponding bromo-/tosylate derivatives by azide (Fig 2).
Figure 2. Structures of various clickable alkynes and azides synthesized and used in the work
The azides 8, 9 and 10 and the propargyl glycosides 5, 6, and 7 once in hand were allowed to react
under solvent-free mechanochemical click reaction conditions to give the desired products 11a, 12, 13,
9
9
1
1b, and 11c, respectively, in nearly quantitative yields. Subsequent Zemplen’s removal of the acetate-
protection on the sugar residues in them yielded the sugar-anchored triazole-linked lipid derivatives 14a,
5, 16, 14b, and 14c (Scheme 1).
1
5

ACCEPTED MANUSCRIPT
Scheme 1. Synthesis of sugar-based triazole-linked lipids
2
.2 Investigations on the self-assembly of carbohydrate-based triazole-linked lipids
Based on our recent observations on the self-assembling properties of certain triazole-linked sugars
9
7
having hydrophobic attachments, glycolipid 14a was subjected to examination under TEM to look for
patterns typical of self-assembled materials. Thus, a sample of 14a (20 mg) was taken up in water (2 ml at
3
0 °C) and after applying on to a copper grid was allowed to dry and was loaded on to the TEM for
examination. Indeed, structural patterns characteristic of self-assembled molecules large enough to be
observed under TEM could be clearly observed (Fig 3a). The assemblages were very uniformly shaped
and in the form of discrete, tiny capsules/rods ranging in size from 150-230 nm in diameter and 450-550
nm in length. Interestingly when the sample solution was prepared at 50 °C prior to the TEM
examination, the supramolecular assembly obtained was a network of long (contiguous) tubular
formations (diameter in the range of 100-200 nm, Fig 3b). Clearly, warming the aqueous solution appears
6

ACCEPTED MANUSCRIPT
to allow the molecules to further organize in a thermodynamically driven self-assembly-process to form
highly ordered elongated tubular structures as seen in Fig 3b. The hydrogel formed by the maltose-based
9
5
glycoamphiphile of Oriol et. al. also formed a network similar to those formed by the glucose-based
4a (at 50 °C ) noted above although their analogous compounds bearing shorter aliphatic chain or one
having an appended azobenzene moiety gave rise to structures wherein the individual strands of the
1
9
4,96
network existed in helical/twisted ribbon forms.
Likewise, a mannose-based triazole-containing
neoglycolipid-derived hydrogel prepared by Khiar and coworkers has also been reported to form a
1
05
network-structure constituted of an assembly of nanotubes. Again, when the sample was prepared in
hexane at 30 °C prior to examination under TEM the molecules did organize much like in the aqueous
environment with a majority of the rods formed remaining clustered (Fig 3c), although some extended
rods were also visible in the sample.
Magnification: x1100
Magnification: x1100
Magnification: x1100
a: A solution of 14a in H
2
O at 30 °C was used for
b: A solution of 14a in H
2
O at 50 °C was used for TEM.
c: A solution of 14a in hexane at 30 °C was used for TEM.
Assembles into rods that tend to form clusteres.
sampling for TEM.Assembles into discrete rods,
approx.150-230 nm (dia) X 450-550 nm (length)
Assembles into contiguous criss-crossing tubular (dia, 100-
200 nm; length, infinite) pattern giving rise to a network
structure
Figure 3. TEM images showing the self-assembling properties of carbohydrate-based triazole-linked lipid
4a. 20 mg of 14a in 2 ml water/hexanes was used for TEM. For a larger image please see Supplementary
Information.
1
7

ACCEPTED MANUSCRIPT
With a view to obtaining experimental evidence for the role of the triazole residue in 14a, glucoside
analogues 22 and 23 devoid of the triazole residues were synthesized from 20 and 21 respectively,
obtained from the corresponding glycosyl bromides under mechanochemical grinding in a planetary ball
1
01
mill using ZnCO (Scheme 2). Analysis of these compounds by TEM revealed that they did not show
3
Scheme 2. Synthesis of sugar-linked lipids devoid of triazolyl moiety
any patterns typical of self-assembled structures sufficient in size to be visible by TEM. This clearly
demonstrated the influence of the triazole moiety in the formation of organized molecular assembly (large
enough to be visible under TEM) in the case of 14a, obviously through various intermolecular H-bonding
as well as π-π interactions. Experimental evidence for the role of the carbohydrate moiety was
subsequently gathered. Thus the triazole-linked lipid 17 devoid of any carbohydrate residue was also
synthesized (Scheme 1) and was subjected to analysis by TEM. Compound 17, as to be expected, was
completely insoluble in water and therefore for its analysis by TEM a solution in hexane had to be used
for the sample application. It was observed that the triazolyl alkane 17 did also assemble into organized
structures, but unlike 14a, in flake-like arrangement (Fig. 4a). Moreover, under these conditions
a: Magnification: x330
b: Magnification: x800
c: Magnification: x1100
d: Magnification: x1100
e: Magnification: x2500
A solution of 17 in hexane at 30 °C A solution of 15 in H
2
O at 30 °C was used for TEM. Assembles into A solution of 16 in MeOH-H
2
O at 30 °C was used for TEM. Assembles
was used for TEM. The material
assembles into discrete flakes.
helical nano-threads of diameter 25-100 nm.
into spherical jelly particles with dense centre (dia 300-1000 nm) and
lighter outer sphere (dia 2-4 ꢀm).
8

ACCEPTED MANUSCRIPT
Figure 4. TEM Images of compounds 15, 16 and 17. 20 mg of the compound in 2 ml water was used for
TEM in all the cases. For a larger image please see Supplementary Information.
compound 19 (Scheme 1) which is devoid of the hydroxyl functionality did not generate self-assembled
structures, as revealed by TEM, large enough to be observed. This lends support to the need for having a
hydrophilic residue, such as the sugar residue in 14a, in the structural architecture in order for it to exhibit
effective self-assembly characteristics. Other compounds analogous to 14a prepared for study by TEM
were those obtained by changing the sugar moiety on the one hand (15 and 16) and the alkyl substituent
on the triazole residue (14b and 14c) on the other (Scheme 1). The galactoside 15 when investigated by
TEM under the same conditions as for 14a, revealed its existence in the form of twine threads of
diameter, 25-100 nm (Fig 4b and c), a pattern different from that of 14a. As all the structural parameters
other than the componental sugars are the same in both the cases, the differences seen in the patterns must
clearly be attributable to the difference in the sugar structure. As the only difference in the sugar structure
involved being that they are epimeric at C-4, the differences observed in the organizational patterns must
be attributable to this factor. This is not surprising because the configurational differences at C-4 of the
hexoses has been observed to lead to different molecular packing behaviour and hence different crystal
73,81
structures, for instance in the case of glycolipids.
Moreover, triazole-linked selfassembling
9
7
97
98
neoglycoconjugates based on mono- (for example, hexoses such as glucose, galactose and mannose )
9
4
95,96
and disaccharides (such as cellobiose and maltose
) have already been reported to yield composites
made up of nanotubes/ribbons with/without twists/turns on selfassembly. Different alditol-based head
groups attached to fatty alkyl chains are also known to form supramolecular assemblies of varying
8
3
structures. The extended polyhydroxylic moiety in the form of a disaccharide in 16 (as opposed to the
monosaccharide moieties in 14a and 15) must also be expected to contribute to the generation of
9

ACCEPTED MANUSCRIPT
organized structures significantly different from those of the above. Thus, the lactoside 16 prepared in
water containing traces of MeOH (to overcome the solubility problem) indeed were spherical particles
with dense central portion and a lighter more diffused outer sphere typically forming a matrix (Fig. 4d
and e). Interestingly, the aqueous (methanolic) solution was a hydrogel thick enough to be held back at
the bottom of the vial even on inverting it (Fig.5).
Compound 16 (10 mg) was mixed with H O (1 ml)
2
containing traces of MeOH. The clear hydrogel formed
was thick enough to be held back in the vial even on
turning it upside down.
Figure 5. Hydrogel formed by compound 16
Thus the effect of the structure/molecular size of the triazole-linked glycolipids on the structure of the
organized particles formed in solution became clearly evident. The 14a-analogues prepared in one case
with a truncated alkyl chain (14b, bearing an octyl group) and in another having unsaturation in the chain
(14c, bearing a farnesyl residue) were also subjected to TEM examination as in the foregoing cases.
Interestingly, 14b did not form any structural pattern observable under TEM in spite of its expected
surfactant-like properties in aqueous solutions, thereby demonstrating the requirement of an extended
fatty alkyl chain in forming large-enough structures. The farnesylated triazole derivative 14c on the other
hand did form discrete organized particles (Fig. 6) similar to that of 14a though more compact and of
smaller dimensions (62-68 nm wide and 325-350 nm long). The structural differences in 14a and 14c
have been in the respective lipid moieties, the alkyl chain of 14a while being sixteen carbon-long and
linear, and that of 14c being fourteen carbon-long but also branched and bearing three double bonds along
the chain, the differences must arise mainly from the unsaturation in the alkyl chain of the lipid moiety. It
1
0

ACCEPTED MANUSCRIPT
appears that the unsaturation (the sp2 carbons) allows the chain to organize more tightly. Thus the effect
of size (length) as well as nature of the lipid moiety on the respective self-assembled structures the
compounds can produce could also be successfully demonstrated.
Compound 14c assembling in water at 30 °C into discrete rods,
approx. 62-68 nm wide and 325-350 nm long. Magnification: X1700
Figure 6. TEM image showing the self-assembling properties of the triazole-linked lipid 14c. 20 mg of
1
4c in 2 ml water was used for TEM. For a larger image please see Supplementary Information.
. Experimental
3
3
.1 General
All reagents and chemicals were purchased from Aldrich Chemical Co (Milwaukee, WI, USA). Farnesol
precursor for the preparation of farnesyl azide 10) obtained was a mixture of isomers. Reactions were
(
monitored by TLC, which was performed on 0.2 mm Merck pre-coated silica gel 60 F254 aluminium
sheets. Compounds were detected by dipping the TLC plates in an ethanolic solution of sulphuric acid
(5% v/v)/phosphomolybdic acid (5% w/v) and thereafter heating them. Melting points were recorded on a
Büchi melting point apparatus. Specific rotations were obtained on Rudolph Research Autopol IV
polarimeter at 20 °C. IR spectra were recorded on a Nicolet FT-IR Impact 410 instrument either as neat or
1
13
KBr pellets. H and C NMR spectra were referenced to the internal standard tetramethylsilane, in the
respective deuterated solvents. Coupling constants (J) are reported in Hertz. High resolution mass spectra
(HRMS) were recorded on a Bruker Maxis spectrometer and the low resolution mass spectra were
9
3
93
recorded on MALDI (Bruker Daltonics, Ultraflex TOF/TOF) Spectrometer. Compounds 11a, 11b,
9
3
93
106
107
106
107
1
4a, 14b, 20,
21,
22,
23,
are previously reported in the literature, therefore their
1
1

ACCEPTED MANUSCRIPT
1
13
characterisation data is shown in the supporting information along with scanned H & C NMR of other
compounds.
1
01
3
.2 Solvent-free mechanochemical O-glycosylation
Typical procedure: Preparation of propargyl 2,3,4,6-tetra-O-acetyl-β-
D
-glucopyranoside (5):
Acetobromoglucose (5a, 4.11 g, 10 mmol), propargyl alcohol (1.12 g, 20 mmol) and ZnCO (1.18 g, 15
3
mmol) were allowed to mix in a stainless steel (SS) jar (capacity, 50 mL) containing 10 SS balls (10 mm
o.d.) for about 3 h (or until the reaction was complete by TLC, depending upon the glycosyl bromide
chosen, that is, 5a/6a/7a) in a planetary ball mill (Retsch PM-100, Retsch GmbH, Germany) at 600 rpm.
To the reaction mixture was added EtOAc and the mixture was filtered through a Celite-bed. The residue
was washed with EtOAc and the combined filtrate and washings were concentrated to dryness under
reduced pressure and was purified by column chromatography to yield analytically pure 5 (3 g, 77%).
3
.3 General procedure for the synthesis of glycotriazololipids by planetary ball-milling: The azide
and the alkyne (1 mol equiv) were taken in a stainless steel (SS) jar (capacity, 50 mL) containing SS balls
10 of 10 mm o.d.), and sodium ascorbate (0.4 mol equiv) was added to it followed by the addition of
CuSO (0.2 mol equiv). The reaction mixture was then ground in a planetary ball mill (Retsch PM-100,
(
4
Retsch GmbH, Germany) at 500 rpm. After completion of the reaction the mixture was dissolved in
CH Cl :MeOH (1:1) and was purified by column chromatography (EtOAc:Hex) to yield analytically pure
2
2
product. Compound 11a was prepared at 5 g scale (from 5 g of the glucoside derivative 5). The reaction
time optimized for the preparation of 11a was 4.5 h at the 5 g scale reaction and 6 h at the 1.5 g scale
reaction. The reactions for the preparation of all other glycotriazololipids (from 6/7/8/18) were at 1.5 g
scale using a reaction time of 6 h and had been complete (by TLC) in all cases.
3
.4 Characterization of compounds:
1
2

ACCEPTED MANUSCRIPT
1
-Farnesyl-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxymethyl)-1H-1,2,3-triazole (11c)
1
.8 g, Yield 74%; colourless syrup; [α] -30.4 (c = 0.2, CHCl ); δ (400 MHz, CDCl ); 7.49 (1H, s, CH
D
3
H
3
Triazole), 5.42 (1H, t, J 7.0 Hz, NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ), 5.19 (1H, t, J 9.4
2
3
2 2
3
2 2
3 2
Hz, H-3), 5.09 (3H, m, H-4, 2H of NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ), 5.00 (1H, dd, J
2
3
2 2
3
2 2
3 2
8
.0
Hz,
J
9.2
Hz,
H-2),
4.94
(2H,
d,
J
7.2
Hz,
2H
of
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ), 4.91 (1H, d, J 12.6 Hz, 1H of OCH Triazole),
2
3
2 2
3
2 2
3 2
2
4
2
.79 (1H, d, J 12.6 Hz, 1H of OCH Triazole), 4.68 (1H, d, J 7.9 Hz, H-1), 4.27 (1H, dd, J 4.7 Hz, J 12.3
Hz, H-6a), 4.14 (1H, dd, J 2.2 Hz, J 12.2 Hz, H-6b), 3.73 (1H, m, H-5), 2.18 (4H, m, 4H of
NCH
2
CHC(CH
3
)(CH
2
)
2
CHC(CH
3
)(CH
2
)
2
CHC(CH
3
)
2
), 2.09, 2.02 (6H, s, 2xOCOCH
3
), 2.04 (3H, s, 3H
s, 1H of
of
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ),
2.08 (1H,
2
3
2 2
3
2 2
3 2
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ), 1.99, 1.96 (6H, s, 2xOCOCH ), 1.81 (3H, s, 3H of
2
3
2 2
3
2 2
3 2
3
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ),
1.67
1.61
1.61
(3H,
(3H,
(3H,
s,
3H
3H
3H
of
of
of
2
3
2 2
3
2 2
3 2
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ),
s,
s,
2
3
2 2
3
2 2
3 2
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ),
2
3
2 2
3
2 2
3 2
NCH
2
CHC(CH
3
)(CH
2
)
2
CHC(CH
3
)(CH
2
)
2
CHC(CH
3
)
2
); δ
C
(100 MHz, CDCl
3
); 170.10, 170.61, 170.15,
1
1
6
2
5
69.41, 169.29, 144.04, 143.43, 143.18, 136.44, 136.32, 131.69, 131.44, 124.10, 124.05, 123.76, 122.90,
22.10, 117.71, 117.57, 99.73, 77.40, 77.08, 76.77, 72.79, 71.85, 71.22, 70.08, 68.47, 68.30, 62.88, 61.83,
0.34, 53.83, 47.76, 39.66, 32.34, 32.12, 31.90, 30.87, 29.24, 26.59, 26.54, 26.28, 26.03, 25.65, 23.43,
3.39, 23.35, 20.99, 20.55, 17.66; IR (Neat) νmax 2934, 1757, 1438, 1376, 1226, 1165, 1044, 906, 749,
+
+
99; HRMS: m/z calculated for C H N O : 633.3261, 656.3153 [M +Na] Found 656.3148 [M +Na] .
3
2
47
3
10
1
-Hexadecyl-4-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxymethyl)-1H-1,2,3-triazole (12)
1
3

ACCEPTED MANUSCRIPT
2
7
.2 g, Yield 89%; colourless solid; mp 98.9-99.7 °C; [α]
D 3 H 3
-43.5 (c = 0.2, CHCl ); δ (400 MHz, CDCl );
.52 (1H, s, CH Triazole), 5.38 (1H, d, J 2.0 Hz, H-4), 5.20 (1H, t, J 8.3 Hz, H-2), 5.00 (1H, dd, J 3.2 Hz,
J 10.4 Hz, H-3), 4.95 (1H, d, J 11.0 Hz, 1H of OCH Triazole), 4.80 (1H, d, J 11.0 Hz, 1H of OCH
2
2
Triazole), 4.65 (1H, d, J 7.9 Hz, H-1), 4.32 (2H, t, J 6.9 Hz, 2H of NCH (CH ) CH ), 4.14 (1H, m, H-
2
2 14
3
6
a), 3.95 (1H, t, J 6.4 Hz, H-6b), 3.23 (1H, t, J 6.9 Hz, H-5), 2.13, 2.03, 1.96, 1.95 (12H, s, 4xOCOCH3),
.80 (2H, m, NCH CH (CH ) CH ), 1.23 (26H, m, of NCH CH (CH ) CH ), 0.85 (3H, t, J 6.3 Hz, 3H
1
2
2
2 13
3
2
2
2 13
3
of NCH
2
(CH
2
)
14CH
3
C 3
); δ (100 MHz, CDCl ); 170.38, 170.20, 170.04, 169.50, 100.39, 70.81, 70.80,
6
2
3
8
8.78, 67.97, 67.06, 62.93, 61.27, 51.44, 50.47, 31.88, 30.27, 29.64, 29.61, 29.59, 29.57, 29.50, 29.45,
9.36, 29.32, 29.12, 28.97, 28.80, 26.68, 26.47, 22.65, 20.71, 20.65, 20.61, 20.52; IR (Neat) νmax 3481,
143, 2924, 2853, 2096, 1752, 1646, 1551, 1465, 1438, 1370, 1226, 1171, 1133, 1077, 1050, 955, 903,
+
01, 740, 721; HRMS: m/z calculated for C H N O : 653.3887, 676.3780 [M +Na] Found 676.3781
3
3
55
3
10
+
[
M +Na] .
1
-Hexadecyl-4-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl-(1→4)-2,3,6-tri-O-acetyl-β-D-
glucopyranosyloxymethyl)-1H-1,2,3-triazole (13)
1
7
.7 g, Yield 85%; colourless solid; mp 91.8-92.6 °C; [α]
D 3 H 3
-20.4 (c = 0.2, CHCl ); δ (400 MHz, CDCl );
.48 (1H, s, CH Triazole), 5.34 (1H, d, J 2.9 Hz, H-4), 5.19 (1H, t, J 9.0 Hz, H-3’), 5.09 (1H, dd, J 7.9
Hz, J 6.3 Hz, H-2), 4.92 (2H, m, H-3, H-2’), 4.90 (1H, d, J 12.6 Hz, OCH Triazole), 4.90 (1H, d, J 12.6
2
Hz, OCH Triazole), 4.63 (1H, d, J 7.9 Hz, H-1’), 4.67 (2H, m, H-1, H-6a’), 4.33 (2H, t, J 7.3 Hz, 2H of
2
NCH (CH ) CH ), 4.09 (3H, m, H-6a, H-6b’, H-5’), 3.85 (1H, t, J 7.0 Hz, H-6b), 3.78 (1H, t, J 9.2 Hz,
2
2 14
3
H-4’), 3.63 (1H, m, H-5), 2.15, 2.13, 2.05, 2.03, 2.01, 1.98, 1.96 (21H, s, 7xOCOCH ), 1.87 (2H, m,
3
NCH
2
2
CH
2
(CH
2
)
13CH
3
), 1.25 (26H, m, NCH
2 2 2 3
CH (CH )13CH ), 0.82 (3H, t, J 6.4 Hz, 3H of
NCH
(CH
2
)14CH
3
); δ
C
(100 MHz, CDCl ); 170.36, 170.15, 170.08, 169.72, 169.66, 169.03, 144.04,
3
1
4

ACCEPTED MANUSCRIPT
1
3
22.48, 101.03, 99.67, 72.78, 72.74, 71.59, 70.98, 70.70, 69.10, 66.62, 63.06, 61.85, 60.81, 50.42, 31.92,
0.32, 29.68, 29.65, 29.60, 29.53, 29.39, 29.35, 29.01, 26.52, 22.68, 20.89, 20.79, 20.70, 20.63, 20.51; IR
(Neat) νmax 2925, 2852, 2721, 1751, 1435, 1369, 1223, 1078, 1039, 1027, 902, 749; HRMS: m/z
+
+
calculated for C H N O : 941.4733, 964.4625 [M+Na] Found 964.4715 [M+Na] .
4
5
71
3
18
1
-Farnesyl-4-(β-D-glucopyranosyloxymethyl)-1H-1,2,3-triazole (14c)
.3 g, Yield 100%; Colourless syrup; [α] -12.4 (c = 0.2, MeOH); δ
CHC(CH )(CH CHC(CH
)(CH CHC(CH ), 5.00 (2H, d, J 7.3 Hz, 2H of
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ), 4.95 (1H, d, J 12.4 Hz, 1H of OCH Triazole),
1
D
H
(400 MHz, MeOD); 7.90 (1H, s,
)(CH CHC(CH ), 5.09
CH Triazole), 5.47 (1H, t, J 7.2 Hz, 1H of NCH
2
3
2
)
2
3
2
)
2
3 2
)
(
2H, m, 2H of NCH CHC(CH )(CH CHC(CH
2
3
2
)
2
3
2
)
2
3 2
)
2
3
2 2
3
2 2
3 2
2
4
3
,
.76 (1H, d, J 12.4 Hz, 1H of OCH Triazole), 4.38 (1H, d, J 7.7 Hz , H-1), 3.88 (1H, d, J 11.2 Hz, H-6a),
2
.66 (1H, dd, J 5.2 Hz, J 11.8 Hz, H-6b), 3.34 (1H, m, H-3), 3.29 (2H, m, H-4, H-5), 3.21 (1H, t, J 8.3 Hz
H-2), 2.25 (1H, m, 2H of NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ), 2.17 (2H, m, 2H of
2
3
2 2
3
2 2
3 2
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ),
2.07
(2H,
(2H,
(3H,
m,
m,
2H
2H
of
of
of
s,
2
2
2
3
3
3
2 2
3
3
3
2 2
3 2
NCH
NCH
CHC(CH
CHC(CH
)(CH
2
2
)
2
CHC(CH
CHC(CH
)(CH
2
2
)
2
CHC(CH
3
3
)
2
2
),
),
1.99
)(CH
)
2
)(CH
)
2
CHC(CH
)
1.81
s,
3H
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ),
1.65
(3H,
(3H,
(3H,
2
3
2 2
3
2 2
3 2
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ),
1.62
1.59
s,
2
3
2 2
3
2 2
3 2
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ),
s,
2
3
2 2
3
2 2
3 2
NCH CHC(CH )(CH ) CHC(CH )(CH ) CHC(CH ) ),); δ (100 MHz, MeOD); 144.19, 143.19, 143.02,
2
3
2 2
3
2 2
3 2
C
1
7
2
35.79, 135.67, 131.10, 130.83, 123.96, 123.91, 123.50, 123.22, 117.75, 117.70, 102.25, 76.65, 76.58,
3.63, 70.24, 61.53, 61.40, 39.43, 31.86, 31.54, 31.46, 26.29, 26.23, 25.91, 25.85, 24.56, 24.51, 22.27,
2.23, 16.40, 14.75; IR (Neat) νmax 3399, 2927, 2509, 2242, 2137, 2073, 1938, 1664, 1450, 1378, 1219,
1
5

ACCEPTED MANUSCRIPT
1
39 3 6
119, 1086, 1040, 1027, 975, 823, 774; HRMS: m/z calculated for C24H N O : 465.2839, 488.2731 [M
+
+
+
Na] Found 488.2735 [M +Na] .
1
-Hexadecyl-4-(β-D-galactopyranosyloxymethyl)-1H-1,2,3-triazole (15)
.6 g, Yield 100%; colourless solid; mp 65-66.5 °C ; [α] -43.3 (c = 0.2, MeOH); δ (400 MHz, MeOD);
1
D
H
7
.9 (1H, s, CH Triazole), 4.93-4.78 (2H, m, OCH Triazole), 4.36-4.28 (3H, m, 2H of NCH (CH ) CH
2 2 2 14 3
&
H-1), 3.78-3.66 (3H, m, H-6a, H-6b, H-4), 3.52-3.40 (3H, m, H-3, H-2, H-5), 1.85 (2H, m,
CH (CH ), 1.23 (26H, m, of NCH CH (CH ), 0.84 (3H, m, 3H of OCH (CH );
(100 MHz, MeOD); 106.77, 79.38, 77.44, 72.86, 65.56, 65.12, 35.60, 33.83, 33.30, 33.18, 33.09,
2.99, 32.63, 30.01, 26.26, 16.97; IR (Neat) νmax 3695, 3680, 3663, 2922, 2864, 2844, 2076, 1560, 1454,
NCH
2
2
2
)
13CH
3
2
2
2
)
13CH
3
2
2 3
)14CH
δ
C
3
1
5
+
412, 1054, 1032, 1016; HRMS: m/z calculated for C H N O : 485.3465, 508.3357 [M +Na] Found
2
5
47
3
6
+
08.3355 [M +Na] .
1
-Hexadecyl-4-(β-
.2 g, Yield 100%; colourless solid; mp 63.4-64.5 °C; δ
O:MeOD; δ (100 MHz, D O:MeOD); Weak signal because of gelation in D
2
D
-galactopyranosyl-(1→4)-β-
D
-glucopyranosyloxymethyl)-1H-1,2,3-triazole (16)
(400 MHz, D O:MeOD); Weak signal because
O:MeOD;
1
H
2
of gelation in D
2
C
2
IR (Neat) νmax 3430, 2918, 2851, 2531, 2237, 2074, 1591, 1434, 1348, 1295, 1207, 1151, 1131, 1115,
+
1
038, 1000, 983, 969, 774. HRMS:. m/z calculated for C H N O : 647.3993, 670.3885 [M +Na]
31 57 3 11
+
Found 670.3877 [M +Na] .
1
1
4
-Hexadecyl-4-hydroxymethyl-1H-1,2,3-triazole (17)
.6 g, Yield 92%; colourless solid; mp 79.5-80.4 °C ; δ
H
(400 MHz, CDCl
3
); 7.51 (1H, s, CH Triazole),
.79 (2H, s, 2H of CH
2
OH), 4.42 (1H, t, J 7.2 Hz, 1H of NCH
2
(CH ), 4.43 (1H, t, J 7.2 Hz, 1H of
2 3
)14CH
1
6

ACCEPTED MANUSCRIPT
NCH
2
(CH
2
)
14CH
3
), 1.91 (2H, m, NCH
2
CH
2
(CH
2
)13CH
3
2 2 2 3
), 1.25 (26H, m, of NCH CH (CH )13CH ), 0.72
(
3H, t, J 6.7 Hz, 3H of NCH (CH ) CH ); δ (100 MHz, CDCl ); 185.23, 147.79, 124.93, 121.46, 56.57,
2
2 14
3
C
3
5
2
7
+
0.83, 50.42, 31.92, 30.30, 30.09, 26.67, 29.65, 29.59, 29.51, 29.47, 29.38, 29.35, 29.00, 28.90, 26.50,
6.37, 22.69, 14.11; IR (Neat) νmax 3378, 2953, 2918, 2846, 1687, 1461, 1275, 1260, 1145, 1056, 997,
+
64, 749; HRMS: m/z calculated for C H N O: 323.2937, 346.2829 [M +Na] Found 346.2825 [M
1
9
37
3
+
Na] .
1
2
4
-Octyl-4-hexyl-1H-1,2,3-triazole (19)
.3 g, Yield 93%; colourless solid; mp 39.5-40.4 °C; δ
.15 (2H, m, 2H of NCH CH (CH ) CH ), 2.53 (2H, m, 2H of CCH CH (CH ) CH ), 1.72 (2H, m, 2H of
H
3
(400 MHz, CDCl ); 7.19 (1H, s, CH Triazole),
2
2
2 5
3
2
2
2 3
3
NCH CH (CH ) CH ), 1.50 (2H, m, 2H of CCH CH (CH ) CH ), 1.14 (16H, m, 6H of
2
2
2 5
3
2
2
2 3
3
CCH CH (CH ) CH , 10H of NCH CH (CH ) CH ), 0.55 (6H, s, 3H of CCH CH (CH ) CH , 3H of
2
2
2 3
3
2
2
2 5
3
2
2
2 3
3
NCH CH (CH ) CH ); δ (100 MHz, CDCl ); 148.04, 120.36, 49.91, 31.54, 31.43, 31.26, 30.37, 30.20,
2
2
2 5
3
C
3
3
2
1
7
2
0.01, 29.53, 29.32, 29.15, 28.89, 28.81, 28.76, 26.48, 26.33, 26.14, 25.80, 25.55, 23.80, 22.56, 22.42,
2.39, 22.24; IR (Neat) νmax 3123, 3074, 2954, 2923, 2849, 2411, 2269, 1694, 1554, 1469, 1435, 1377,
329, 1308, 1265, 1212, 1181, 1154, 1127, 1107, 1061, 1048, 1030, 1006, 986, 936, 889, 851, 789, 752,
+
20, 678, 655, 501, 477; HRMS: m/z calculated for C H N : 265.2518, 288.2410 [M +Na] Found
1
6
31
3
+
88.2411 [M +Na] .
3
.5 TEM analysis: Philips TECNAI electron microscope was used for taking transmission micrographs
at 120 Kv accelerating voltage. Compounds were taken up in solvents (hexane, heptane, etc as mentioned
in the manuscript) and aliquots were applied onto copper grids coated with carbon film (Quantifoil on 200
1
7

ACCEPTED MANUSCRIPT
square mesh copper grid of hole-shape R 2/2) and after allowing to dry was mounted on the microscope
for recording the micrographs.
Acknowledgements: MT thanks the Council of Scientific and Industrial Research (CSIR), New Delhi for
scholarship.
4
. Conclusions
This work reports application of click chemistry in making carbohydrate-based triazole-containing self-
assembling materials of a variety of structures. The diversification of the structure using different sugar
residues and lipid moieties in the molecules reported has led to the generation of a variety of
supramolecular structures useful for application as templates. For instance, while the glucose-based
molecule formed rods, the galactose-linked compound formed helical nanotubes and the lactose-based
compound yielded rather spherical particles upon self-assembly. The nature of the lipid moiety also was
important in defining the size and the shape of the assemblages obtained. Thus, in conclusion, the study
of the glycotriazololipids of various structural attributes described in this work has enabled demonstration
of the importance of individual structural motifs [namely, the structure of the sugar, the presence of the
triazole unit, the nature (saturated/unsaturated) and the length of the alkyl chain of the lipid moiety] of
these interesting and versatile biomolecules in their ability to form supramolecular structures of different
shapes and dimensions. This not only has reiterated the currently available literature on glycolipids of
varied structures and their self-assembly, but has also been helpful in indicating that designing molecules
with pre-determined (pre-defined) supramolecular structures (useful in applications as templates) which
they would yield/adopt upon allowing to organize/self-assemble in solution, is possible. However,
rationalization of the self-assembly properties by molecular modelling and quantum chemical calculations
that need to follow could become a prerequisite for a fruitful realization of this.
1
8

ACCEPTED MANUSCRIPT
5
1
2
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1
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01. Tyagi, M.; Khurana, D.; Kartha, K. P. R. Carbohydr. Res., 2013, 379, 55-59.
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1
1
03. Vollrath, S. B. L.; Fürniss, D.; Schepers, U.; Bräse, S. Org. Biomol. Chem., 2013, 11, 8197-8201.
04. Caution! Azides are known to be explosive under various conditions such as heating, shock
treatments, storage in pure form, etc because of the nitrogen-releasing tendency. For this reason all azides
were prepared just before they were to be used for the CuAAC reaction and were not retained for storage
at
http://www.ehs.ucsb.edu/units/labsfty/labrsc/factsheets/Azides_FS26.pdf.
05. Assali, M.; Cid, J.-J.; Fernandez, I.; Khiar, N. Chem. Mater., 2013, 25, 4250−4261.
any
time.
For
manual
handling
and
safety
concerns
on
azides
see:
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1
06. Noller, C. R.; Rockwell, W. C. J. Am. Chem. Soc., 1938, 60, 2076-2077.
07. Weber, N.; Benning, H. Chem. Phys. Lipids, 1982, 31, 325-329.
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Figures and Schemes:
N
N
OR
N
N
O
N
OR
O
N
OR
OR
RO
RO
O
N
OR
O
RO
N
N
N
N
N
O
OR
OR
O
O
1
O
RO
RO
RO
OR
OR
OR
R = Hexanoyl/Dodecanoyl
N
N
O
N
Lip
id
2
O
O
N
3
3
4
Figure 1. Proposed potentially self-assembling glycolipids
RO
AcO
OAc
O
N
3
O
n
AcO
8
, n = 14
9, n = 6
5
6
7
, R = Ac, equatorial
, R = Ac, axial
, R = Ac Galp-β-, equatorial
4
N3
10
Figure 2. Structures of various clickable alkynes and azides synthesized and used in the work
2
7

ACCEPTED MANUSCRIPT
R'
N
N
R'
N
RO
HO
OH
O
RO
AcO
OAc
O
RO
AcO
OAc
O
N
N
a
N
b
O
R'N
3
O
O
OH
AcO
, 6, 7
AcO
1
4a, 15, 16, 14b, 14c
11a, 12, 13, 11b, 11c
5
OH
HO
N
3
a
a
N
N
n
n
N
8
, n = 14
1
7, n = 14
N3
n2
N
N
n1
n1
= 6
n2
8, n = 4
N
9
, n
1
1
2
1
1 2
9, n = 6, n = 4
5
, R = Ac, equatorial -OR; 6, R = Ac, axial -OR; 7, R = Ac Galp-β-, equatorial -
4
OR; 11a, R = Ac, equatorial -OR, R' = C16H33; 11b, R = Ac, equatorial -OR, R'
=
C
C
8
H
17; 11c, R = Ac, equatorial -OR, R' = farnesyl; 12, R = Ac, axial -OR, R' =
33; 13, R = Ac 33; 14a, R = H,
Galp-β-, equatorial -OR, R' = C16
equatorial -OR, R' = C H ; 14b, R = H, equatorial -OR, R' = C H17; 14c, R =
16
H
4
H
1
6
33
8
H, equatorial -OR, R' = farnesyl; 15, R = H, axial -OR, R' = C16
H
33; 16, R =
Galp-β-, equatorial -OR, R' = C16
H
33
Reagents and conditions:
a.
CuSO .5H O (0.4
mol
equiv),
4
2
sodium ascorbate (0.8 mol equiv), 600 rpm, rt, 2 h, 84-92% ; b. NaOMe/MeOH,
Ice-bath, 30 min, 100%
Scheme 1. Synthesis of sugar-based triazole-linked lipids
Magnification: x1100
a: A solution of 14a in H O at 30 °C was used for
sampling for TEM.Assembles into rods, approx.150-230 Assembles into contiguous criss-crossing tubular (dia, 100-
Magnification: x1100
Magnification: x1100
2
b: A solution of 14a in H O at 50 °C was used for TEM.
2
c: A solution of 14a in hexane at 30 °C was used for TEM.
Assembles into rods that tend to form clusteres.
nm (dia) X 450-550 nm (length)
200 nm; length, infinite) pattern giving rise to a network
structure
Figure 3. TEM images showing the self-assembling properties of carbohydrate-based triazole-linked lipid
4a. For a larger image please see Supplementary Information.
1
2
8