Short synthesis of diamide-linked sucrose macrocycles

Article abstract of DOI:10.1021/ol301993d

A convenient route to macrocyclic diamide-linked macrocyclic derivatives with a sucrose scaffold is presented. Reaction of sucrose based amines (o- and m-) with acid dichlorides afforded the monomeric macrocycles in excellent yields, while reaction of the p-amines also provided dimeric products.

Full text of DOI:10.1021/ol301993d

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Short Synthesis of Diamide-Linked
Sucrose Macrocycles
Mykhaylo A. Potopnyk, Piotr Cmoch, and Szawomir Jarosz*
Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
slawomir.jarosz@icho.edu.pl
Received July 18, 2012
ABSTRACT
A convenient route to macrocyclic diamide-linked macrocyclic derivatives with a sucrose scaffold is presented. Reaction of sucrose based
amines (o- and m-) with acid dichlorides afforded the monomeric macrocycles in excellent yields, while reaction of the p-amines also provided
dimeric products.
Carbohydrates are convenient and easily accessible
starting platforms for the preparation of chiral macrocyc-
lic receptors.1 Such macrocyclic derivatives based upon
sugar scaffolds have been extensively used as chiral cata-
lysts in asymmetric synthesis (asymmetric epoxidation
of chalcones,2 Michael addition,2c,e,3 and Darzens reac-
tions2c,e,g,3c,4). They have also been investigated as fluo-
rescent molecular sensors for cations5 and anions.6
Recently we have demonstrated the synthesis of such
receptors with a sucrose scaffold. The C-6 and C-60 posi-
tions in 10,2,3,30,4,40-hexa-O-benzylsucrose (1)7 were con-
nected via a bridge providing a range of macrocyclic
derivatives (2aꢀc).8 Macrocyclic derivatives with higher
symmetry (e.g., 3)9 are also available (Figure 1). Com-
pounds of type 2 showed significant enantioselectivity in
the complexation of an R-phenylethylammonium cation.8c
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r
10.1021/ol301993d
XXXX American Chemical Society

Scheme 1. Synthesis of Dimesylate 7
Figure 1. Macrocyclic receptors containing a sucrose scaffold.
In this paper we report on the synthesis of sucrose-
derived macrocyclic derivatives containing isophthalic
and 2,6-pyridinedicarbonate amide groupings. Macrocyc-
lic compounds with such aromatic platforms play an
important role in supramolecular chemistry,10 as receptors
for anions,11 ion pairs,12 zwitterions (e.g., dopamine12c),
(10) Davis, F.; Higson, S. Macrocycles: construction, chemistry, and
nanotechnology application; John Wiley & Sons, Ltd.: 2011.
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Bisson, A. P.; Anslyn, E. V. J. Chem. Soc., Perkin Trans. 2 1999, 1111–
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Santos, S. M.; Felix, V.; Beer, P. D. Chem.;Eur. J. 2008, 14, 2248–2263.
Scheme 2. Synthesis of Sucrose-Based Macrocyclic Diamides
ꢀ
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and amino acid derivatives.13 The anion-complexing prop-
erties of these amides have been exploited in the templated
syntheses of catenane,14 rotaxane,14a,15 and pseudorotaxane16
systems.
Macrocyclic diamides are usually synthesized from iso-
phthalic and 2,6-pyridinedicarboxylic acids (or isophtha-
loyl and 2,6-pyridinedicarbonyl dichlorides) in combina-
tion with other building blocks, suchaspolyethylene glycol
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B
Org. Lett., Vol. XX, No. XX, XXXX

Figure 2. Macrocyclic diamides 13aꢀe and 14aꢀe.
(PEG) reagents,14b,c,15b,d,fꢀh,j chiral 1,2-diamines,13 calix-
[4]arenes,11c,12b,14a,15c and calix[4]diquinones.12d,14d,15i
Our synthesis of sucrose-based macrocyclic derivatives of
this type was initiated from 10,2,3,30,4,40-hexa-O-methylsu-
crose (4). These protecting groups were selected because
they are stable to a range of conditions (e.g., catalytic
hydrogenation). Moreover, the NMR spectra of the com-
plex macrocyclic products might be simpler than those of
their per-O-benzyl analogs. Therefore we reasoned that
application of hexa-O-methylsucrose (4) inthemodel synth-
esis of macrocyclic diamides would be preferable in com-
parison to 10,2,3,30,4,40-hexa-O-benzylsucrose (1).
Per-O-methylation of either 5 or 6 with methyl iodide
followed by deprotection of the 6,60-hydroxyl groups
afforded the diol 4 in good overall yield (Scheme 1).
This diol 4 was converted into the mesylate 7 which was
then applied as starting material for the preparation of the
target macrocycles. Its condensation with 2 equiv of the
proper nitro-phenol 8aꢀc (o-, m-, p- respectively) provided
the expected 6,60-di-O-nitrophenyl-10,2,3,30,4,40-hexa-O-
methylsucroses 9aꢀc in 85ꢀ90% yields.
Hydrogenation of these intermediates afforded the re-
spective diamines 10aꢀc in excellent (91ꢀ96%) yield
(Scheme 2). These diamines were used for the prepara-
tion of the macrocyclic bis-amides under high dilution
conditions.
Synthon 4 was prepared for the first time by Sachinvala
et al. in a rather long and tedious synthesis from free
sucrose.17 We offer now an alternative and more conve-
nient method for the preparation of 4 from either 6,60-
ditrityl18 or 6,60-disilyl19 sucroses (5 and 6 respectively).
Condensation ofo-diamine 10a withisophthaloyl or 2,6-
pyridinedicarbonyl dichlorides (11 and 12 respectively)
afforded the expected macrocyclic derivatives 13a or 14a
in 77% and 78% yields (Figure 2). These excellent yields of
cyclization can be explained by assuming that there is good
preorganization of the molecule substrate.
(17) Sachinvala, N. D.; Niemczura, W. P.; Litt, M. H. Carbohydr.
Res. 1991, 218, 237–245.
(18) (a) Lewandowski, B.; Listkowski, A.; Petrova, K.; Jarosz, S.
Reaction of the m-diamine 10b with reagent 11 or 12
proceeded analogously, although the corresponding di-
amides 13b and 14b were formed in lower yields (57% and
62% respectively).
Condensation of the p-diamine 10c with acid dichloride
11 or 12 under the same conditions was, however, more
complex. The expected monomeric product 13c was
formed in low yield (18%) in the reaction with 11, and
the main one consisted of a mixture of two isomeric dimers
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9243. (c) Gouy, M.-H.; Danel, M.; Gayral, M.; Bouchu, A.; Queneau,
Y. Carbohydr. Res. 2007, 342, 2303–2308. (d) Barros, M. T.; Petrova,
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Org. Lett., Vol. XX, No. XX, XXXX
C

with C2-symmetry (13d/13e) obtained in 62% overall
yield. Reaction of 10c with dichloride 12 proceeded analo-
gously affording the monomeric product 14c (23%) and a
1:1 mixture of the dimeric products 14d/14e (54%;
Figure 2).
number of steps, making this an efficient synthesis of such
macrocycles.
The presence of sucrose and isophthalic or 2,6-pyridi-
nedicarbonate amide in these scaffolds makes them pro-
mising receptors.
Although these dimers could not be isolated in pure
form, the proportions of 13d:13e and 14d:14e were esti-
mated as 1:1 based on integration of aromatic signals in the
1H NMR spectrum.
The relative orientations of the amino groups in the
energetically accessible conformations of substrates 10aꢀc
define the direction of macrolactamization. For com-
pound 10c, conformations of the monoamide where the
second amine is close to the remaining acid chloride must
have low populations, reducing the probability of forma-
tion of dilactams 13c and 14c; thus, 2:2-cyclization be-
comes dominant.
It is worth pointing out that the sucrose p-diamine (10c)
upon reaction with an acid dichloride (11 or 12) afforded
only small amounts of the desired monomer; the main
products were dimers (with C2-symmetry) which could be
distinguished by NMR.
Acknowledgment. The support from Grant POIG.01.
01.02-14-102/09 (partly financed by the European Union
within the European Regional Development Fund) is
acknowledged. This paper is dedicated to Professor Marek
Chmielewski on the occasion of his 70th birthday.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
In conclusion, the work presented herein describes
the synthesis of macrocyclic diamides 13ꢀ14 contain-
ing the sucrose subunit. The starting material for the
macrocyclization is prepared in a relatively small
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX