Novel mixed-heteroatom macrocycles via templating: A new protocol

Article abstract of DOI:10.1016/j.tetlet.2013.01.025

A series of novel thiadiaza and triaza crown ether attached galactose- and glucose-based glycolipids is synthesized, applying a new strategy. The key step is the formation of α-chloroacetamido precursors (14 and 21) from selectively protected bis(cyanomethyl)-glycolipids (13 and 19) in two steps. The cyclization reaction furnishes good yields in relatively short times in aqueous ethanol or acetonitrile. To generalize this method, macrocycles 3 and 25 are reported as well. Attempts to use the traditional synthetic approaches for cyclization failed to provide reasonable yields.

Full text of DOI:10.1016/j.tetlet.2013.01.025

Tetrahedron Letters 54 (2013) 1534–1537
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Novel mixed-heteroatom macrocycles via templating: a new protocol
Karem J. Sabah a,b, , Rauzah Hashim a
⇑
a Chemistry Department, Faculty of Science, University of Malaya, Lembah Pantiai, 50603 Kuala Lumpur, Malaysia
b Chemistry Department, College of Science, University of Kufa, 54001 Najaf, Iraq
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel thiadiaza and triaza crown ether attached galactose- and glucose-based glycolipids is
Received 18 August 2012
Revised 16 December 2012
Accepted 8 January 2013
Available online 16 January 2013
synthesized, applying a new strategy. The key step is the formation of
a-chloroacetamido precursors
(14 and 21) from selectively protected bis(cyanomethyl)-glycolipids (13 and 19) in two steps. The cycli-
zation reaction furnishes good yields in relatively short times in aqueous ethanol or acetonitrile. To gen-
eralize this method, macrocycles 3 and 25 are reported as well. Attempts to use the traditional synthetic
approaches for cyclization failed to provide reasonable yields.
Keywords:
Macrocycle
Ó 2013 Elsevier Ltd. All rights reserved.
Glycolipid
Thia-crown ether
Aza-crown ether
Templating
Complex carbohydrates are involved in recognition events of
many biological processes, mostly by the interaction between the
proteins and the carbohydrate moiety of glycoconjugates.1 Gener-
ally the terminal carbohydrate head-group is responsible for the
attachment to the protein receptor.2 Since glycolipids are essential
components of cell membranes, several synthetic analogues have
been produced in order to understand the self-organizing properties
with respect to their structures.3 Although there are numerous mod-
ified carbohydrates with macrocycles, most of these were based on
simple glycosides, that is, methyl or phenyl glycosides.4 These com-
poundshave been suggested to participate in various tasks including
molecular recognition,5 extraction of either metal cations6 or organ-
ic molecules,7 asymmetric catalysis,8 and chiral separation.9 Fur-
thermore, sugar-attached crown ethers with long alkyl chains on
the 4,6-hydroxyl groups of the methyl glycoside have been synthe-
sized to study aggregation10 and molecular recognition features.11
We previously reported a novel class of glycosidic alkyl chain
glycolipids containing crown ethers and studied their self-assem-
bly in water.12 These crown ethers attached to the sugar head-
group played a crucial role in self-assembly by shifting the assem-
bly of the parent glycolipids from lamellar to more curved struc-
tures, that is, hexagonal and cubic phases.13 Interestingly, among
all the liquid crystal phases, the cubic phases appeared most prom-
ising as candidates to use in protein crystallization.14 Indeed,
mixed N, O, S donor macrocycles represent an interesting category
of compounds. They exhibit high affinities toward soft metal cat-
ions,15 act as chemosensors16 and as models for the active sites
of some enzymes.17 However, owing to the difficulties in forming
the macrocycles on the sugar, the synthesis has so far been limited
to oxa-,18 aza-,19 diaza-,20 and thia-crown ethers.21
As a part of our ongoing program to develop new protocols to
synthesize novel macrocycles and to study their applications, we
report here an effective general strategy for preparing mixed-het-
eroatom macrocycles.
A mixed-heteroatom 15-crown-5 can be synthesized using var-
ious techniques. Among these methods, the high dilution approach
is commonly used, which is inconvenient due to tedious simulta-
neous addition of the starting materials to a large quantity of sol-
vent.22 Another approach reported by Tabushi23 used slightly more
concentrated conditions. This method had disadvantages too, as it
required a dry solvent and a long reaction time (7 days). For exam-
ple, the synthesis of thiadiaza-crown 3 under these conditions gave
only a 21% yield of the expected product (Scheme 1).24
Attempts to synthesize macrocycles 6 and 7 from precursor 4
applying high dilution conditions, gave only 14% and 11% yields,
respectively (Scheme 2).
Instead, we designed the intermediates 14, 21, and 24 in such a
way as to achieve the following advantages: (1) increased reactiv-
ity of the precursor, that is, an
a-chlorocarbonyl derivative, (2)
reduction of the cost of the synthesis (i.e., by omitting dry sol-
vents), (3) increased chance of sodium templating assisted by the
oxygen of the carbonyl compound, and (4) a significantly short-
ened reaction time.
To construct the macrocyclic backbones 6 and 7 (Scheme 3), we
started by synthesizing the glycolipid 11, as the major b-anomer, in
three steps starting from galactose.25 Selective protection of the
⇑
Corresponding author. Tel.: +60 037 967 4009; fax: +60 037 9674193.
E-mail address: karemchemist@gmail.com (K.J. Sabah).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.025

K. J. Sabah, R. Hashim / Tetrahedron Letters 54 (2013) 1534–1537
1535
Scheme 1. Synthesis of macrocycle 3.
Figure 1. Modeling of the transition state upon cyclization.
tonitrile under strongly basic conditions [NaH in DMF or NaOH un-
der phase-transfer catalysis (PTC)]. We found that NaH gave a
lower yield compared to PTC. Reduction of the nitrile group was
successfully achieved in 86% yield by using LiAlH4 in THF to furnish
the diamine 4. Although the conversion of the amino groups of 4
into chloroacetamides could be carried out with chloroacetyl chlo-
ride, the formation of side products made this reaction undesirable.
Therefore, chloroacetic anhydride was used instead. The latter pro-
cess required only extraction with water to obtain 14 in 87% yield
and sufficient purity.
Scheme 2. Synthesis of macrocycles 6 and 7 from diamine 4.
4,6-hydroxyl groups was achieved by benzylidenation to afford 12
as the pure b-anomer in an overall yield of 49% based on galactose
8. Compound 13 was obtained by treatment of 12 with bromoace-
The highly reactive intermediate 14 was treated with anhy-
drous sodium sulfide in absolute ethanol under reflux conditions
for 12 h. This gave macrocycle 6 in 50% yield. Increasing the
reaction time to 72 h did not improve the yield. On the other hand,
absolute ethanol played a poor role in solvation of sodium to tem-
plate the cyclization. Notably, replacing anhydrous Na2S with its
hydrated analogue in absolute ethanol increased the yield up to
70%. Based on this observation we decided to apply greener condi-
tions by utilizing aqueous ethanol in differing ratios. Interestingly,
we found that 10% water content in the ethanol and 1.5 equiv of
sodium sulfide gave an excellent yield (85%) of the product. Since
no organic side product was observed by TLC, simple extraction
was performed to remove other impurities, that is, unreacted so-
dium sulfide and inorganic salts. Thus, purification by column
chromatography could be omitted. After installation of sulfur in
the glycolipid–macrocycle, the alternative reaction of intermediate
14 with benzylamine in acetonitrile in the presence of sodium car-
bonate was performed to furnish the triaza-macrocycle 7 in 58%
yield.
The good yields obtained using this approach can be explained
in terms of the templating effect. While O-2 of the sugar ring is too
far away to interact with sodium, templating was possible by three
of the oxygen atoms, O-3 of the sugar ring and the oxygens of the
carbonyl groups. On the other hand, the nitrogen and sulfur did not
contribute to the templating as they are soft ligands. This assump-
tion was supported by preliminary results of modeling of the tran-
sition state upon cyclization, which revealed that the energy of the
system dropped from +500 to À4 kJ/mol in the presence of Na+
(Fig. 1).
Similarly, macrocycles 22 and 23 were synthesized applying the
same strategy (Scheme 4). Benzylidene derivative 18 was prepared
from glucose pentaacetate as reported previously.12 Subsequently,
Scheme 3. Synthesis of macrocycles
6 and 7 incorporating a galactose-based
glycolipid at the 2,3-positions. Reagents: (i) Ac2O2, AcONa, (ii) C12H25OH, BF3ÁEt2O,
(iii) MeOH, MeONa, (iv) PhCH(OMe)2, TsOHÁH2O, (v) BrCH2CN, NaOH, Bu4NHSO4,
(vi) LiAlH4, THF, (vii) (ClCH2CO)2O, (viii) Na2SÁ9H2O, aq EtOH, (ix) BnNH2, MeCN,
Na2CO3.
Full modeling studies (using Avogadro 1.0.3 free software) will be published at a
later date along with self-assembly studies.

1536
K. J. Sabah, R. Hashim / Tetrahedron Letters 54 (2013) 1534–1537
CH2Cl
4.5
4.4
4.3
4.2
4.1
4.0
3.9
3.8
3.7
3.6
3.5
3.4
3.3
3.2
3.1
3.0
2.9
CH2S
4.6
4.5
4.4
4.3
4.2
4.1
4.0
3.9
3.8
3.7
3.6
3.5
3.4
3.3
3.2
3.1
ppm
Figure 2. 1H NMR spectra of (a) compound 21, (b) macrocycle 22.
Scheme 4. Synthesis of macrocycles 22 and 23 incorporating glucose-based
glycolipids at the 2,3-positions. Reagents: (i) C12H25OH, BF3ÁEt2O, (ii) MeOH,
MeONa, (iii) PhCH(OMe)2, TsOHÁH2O, (iv) BrCH2CN, Bu4NHSO4, (v) LiAlH4, THF, (vi)
(ClCH2CO)2O, (vii) Na2SÁ9H2O, aq EtOH, (viii) BnNH2, MeCN, Na2CO3.
applied a new strategy based on nucleophilic substitution of highly
reactive species with strong nucleophiles. In addition, applying
aqueous solvent assisted the solvation of sodium, and therefore,
it could be acting as a template during cyclization of the macrocy-
cles. Furthermore, most of the starting materials used in this ap-
proach were extremely reactive, which gave good overall yields
and, as a result, reduced the number of column chromatographic
purification steps.
the reaction of 18 with bromoacetonitrile, followed by reduction
with LiAlH4 produced the diamine 20 as a white solid in good yield.
Conversion of 20 into bis-chloroacetamide 21 using chloroacetic
anhydride occurred in 85% yield. Finally, the cyclization of 21 with
either Na2SÁ9H2O, in aqueous ethanol or benzylamine in acetoni-
trile, produced the macrocycles 22 and 23, respectively.
Another two examples (3 and 25) involved a non-sugar precur-
sor 2426 to synthesize the desired macrocycles (Scheme 5). The
yields were consistent with the sugar macrocycle analogues.
The formation of the macrocycles could be easily detected by
NMR spectroscopy, since the chemical shifts of the CH2Cl group
in both the proton and carbon NMR spectra appeared downfield
in the spectra compared to CH2S and CH2NBn.27 For example, the
chemical shift of the CH2Cl protons in compound 21 is 4.02 ppm,
and after conversion into macrocycle 22 the corresponding CH2S
protons resonate at 3.20 ppm (Fig. 2). In addition, the 13C NMR
spectrum showed that the carbon bearing the chlorine which ap-
peared at 42 ppm was shifted to 37 ppm in the corresponding
macrocycle.
Acknowledgment
This work was supported by the University of Malaya (Grant
UM.C/625/1/HIR/MOHE/SC/11).
Supplementary data
Supplementary data (experimental procedures and copies of 1H
and 13C NMR spectra) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.025. These data include MOL files and InChiKeys of the most
important compounds described in this article.
In summary, we have demonstrated the successful synthesis of
novel mixed-heteroatom macrocycles in high yields. The method
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