Amino-acid templated assembly of sucrose-derived macrocycles

Article abstract of DOI:10.1021/ol100749m

C₂-Symmetrical chiral macrocyles containing two sucrose units were prepared by an amino acid templated macrocyclization reaction between appropriate sucrose-based linear precursors and ethylenediamine.

Full text of DOI:10.1021/ol100749m

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2532-2535
Amino-Acid Templated Assembly of
Sucrose-Derived Macrocycles
Bartosz Lewandowski and Slawomir Jarosz*
Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
sljar@icho.edu.pl
Received March 31, 2010
ABSTRACT
C2-Symmetrical chiral macrocyles containing two sucrose units were prepared by an amino acid templated macrocyclization reaction between
appropriate sucrose-based linear precursors and ethylenediamine.
The ongoing quest for efficient and cheap synthetic methods
that lead to large-sized rings is motivated by a wide variety
of possible applications of natural and synthetic macrocyclic
molecules (in medicine, material and supramolecular chem-
istry, and many others).1 The classical high-dilution technique
developed by Ziegler,2 although still being applied especially
in the synthesis of complex supramolecular assemblies, has
two major limitations. Usually it does not provide the
products in high yields and it is also very time-consuming.
On the other hand, high-pressure techniques,3 which require
a special apparatus, impede the monitoring and control of
the reaction. A more convenient methodology lays in metal-
templated synthesis of crown ethers,4 and there is increasing
growth in the number of different templating methods
available. This allows a wide variety of macrocycles to be
obtained, possessing diverse structures and properties, it
being devoid of the limitations mentioned above. Besides
metal-templated macrocyclizations,5 a considerable number
of other synthetic approaches, which take advantage of
nonmetallic templates, have also been discovered and studied.
The most common methodologies utilize π-stacking, π-donor/
π-acceptor interactions, and hydrogen bonding6 as the
(1) (a) Breinbauer, R.; Vetter, I. R.; Waldmann, H. Angew. Chem., Int.
Ed. 2002, 41, 2878–2881. (b) Kessler, H. Angew. Chem., Int. Ed. Engl.
1982, 21, 512–516. (c) Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. K.
Nat. ReV. 2008, 7, 608. (d) Lehn, J.-M. Supramolecular Chemistry: Concepts
and PerspectiVes; Wiley-VCH: Weinheim, 1995. (e) Supramolecular
Chemistry; Vogtle, F., Ed.; Wiley & Sons: Chichester, 1991.
(2) Ziegler, K.; Eberle, H.; Ohlinger, H. Liebigs Ann Chim. 1933, 504,
94–130.
(3) Pietraszkiewicz, M.; Salan˜ski, P.; Jurczak, J. J. Chem. Soc., Chem.
Commun. 1983, 1184–1185.
(4) Template Synthesis of Macrocyclic Compounds; Gerbeleu, N. V.,
Arion, V. B., Burgess, J., Eds.; Wiley-VCH: Weinheim, 1999.
(5) Busch, D. H.; Vance, A. L.; Kolchinski, G. In ComprehensiVe
Supramolecular Chemistry; Lehn, J.-M., Ed.; Elsevier Science: New York,
1996; Vol. 9, pp 1-42.
10.1021/ol100749m  2010 American Chemical Society
Published on Web 05/04/2010

templating motifs, and therefore, the molecules applied as
templates are typically simple aromatic compounds, transi-
tion-metal complexes, amides, esters, and other simple
hydrogen-bond acceptors and donors. So far, there have been
no precedents for the application of amino acid derivatives
or other simple biomolecules as templates for construction
of macrocyclic skeleta.
In recent years, we have devoted considerable effort to
the synthesis of chiral macrocycles based on the sucrose
molecule. We have succeeded in preparing a series of crown7
and aza-crown ether analogues8,9 starting from the partially
protected derivative 1′,2,3,3′,4,4′-hexa-O-benzylsucrose (1).10
Such macrocycles containing nitrogen atoms in the ring (e.g.,
2 and 3) are promising chiral receptors for primary amine
hydrochlorides (Figure 1).11 Given our involvement in the
catalyzed alkyne-azide cycloaddition (AAC)12 of activated
sucrose derivative 5 was used as the key macrocycle-forming
step (Figure 1).13 However, the product 6, obtained from two
molecules of 4, did not show sufficient stability and, therefore,
could not be applied as a macrocyclic receptor.
We changed, therefore, our approach to such symmetric
targets and decided to connect two sucrose molecules via a
dialkyne linker (8 and 11), which was obtained from catechol
(7) or lutidine (9) according to the synthetic routes shown
in Scheme 1. This linker might react efficiently with two
Scheme 1. Synthesis of Dialkyne Linkers
molecules of sucrose that were functionalized with an azide
at one of the terminal positions.
The Cu-AAC reaction between the linker 8 and sucrose
derivative 4 was carried out in acetonitrile with CuI as the
catalyst and diisopropylethylamine as the base (the most effective
conditions applied in the cyclization of 5). It afforded the desired
product 12 containing two sucrose units (Scheme 2).
These conditions could not, however, be applied for the
efficient preparation of another C2-symmetrical derivative
14, which was obtained in very low yield. This resulted
probably from the fact that copper cation was complexed
by the pyridine unit of the linker, as well as that of the
product formed, which effectively decreased the yield of the
reaction. The unwanted formation of the complex was
suppressed by applying the conditions of the CuAAC reaction
first reported by Sharpless.14 This invoved both the linker
and the azide being dispersed in a 1:1 water-t-BuOH
mixture containing copper sulfate and sodium ascorbate.
These conditions proved to be ideal and allowed the desired
Figure 1. Synthesis of macrocyclic receptors containing a sucrose
unit.
synthesis and application of “simple” sucrose-based crown-ether
analogues, we became also interested in exploring C2-sym-
metrical receptors that contain two sucrose units. The Cu(I)-
(6) For comprehensive review, see: ComprehensiVe Supramolecular
Chemistry; Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Vogtle, F.,
Eds.; Pergamon: Oxford, 1996; Vol. 11.
(7) Brzuszkiewicz, A.; Ciunik, Z.; Jarosz, S.; Lewandowski, B.; List-
kowski, A. Tetrahedron 2005, 61, 8485–8492.
(12) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004–2007. (b) Tornoe, C. M.; Christensen, C.; Meldal, M.
J. Org. Chem. 2002, 67, 3057–3064.
(8) Jarosz, S.; Lewandowski, B. Carbohydr. Res. 2008, 5, 965–969
.
(9) Queneau, Y.; Jarosz, S.; Lewandowski, B.; Fitremann, J. AdV.
Carbohydr. Chem. Biochem. 2007, 61, 217–292
(10) Jarosz, S.; Listkowski, A. J. Carbohydr. Chem. 2003, 22, 753–
(13) Jarosz, S.; Lewandowski, B.; Listkowski, A. Synthesis 2008, 913–
917.
.
(14) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (b) Chan, T. R.; Hilgraf, R.;
Sharpless, K. B.; Fokin, V. V. Org. Lett. 2004, 6, 2853–2855.
763.
(11) Jarosz, S.; Lewandowski, B. Chem. Commun. 2008, 6399–6341.
Org. Lett., Vol. 12, No. 11, 2010
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Scheme 2
.
Cu(I)-AAC Assembly of Derivatives Containing
Scheme 3. Amino Acid Templated Macrocyclization
Two Sucrose Units
Unfortunately, the product 16 was obtained in very low yield
(5%) and, moreover, proved to be quite unstable, decompos-
ing within a few hours. The same reaction performed with
dimesylate 15 did not afford any products. Therefore, we
decided to find a template which would preorganize the
reagents in solution and facilitate formation of the target
macrocycle. Unfortunately, neither metal cations nor simple
organic molecules (aromatic compounds and hydrogen bond
donors and acceptors) were effective as templates. Finally,
application of phenylglycine methyl ester hydrochloride
allowed us to obtain the desired macrocycle 17 in 20% yield
(Scheme 3).15 What was even more impressive and surpris-
ing, only the L- enantiomer of the amino acid derivative
proved to act efficiently as a template in this reaction.
D-Methylphenylglycinate hydrochloride had almost no effect
on formation of the product. This result prompted us to apply
the chiral salt in the reaction between 13 and ethylenedi-
amine. To our satisfaction the yield of 16 increased from
product 14 to be obtained in high yield (80%, Scheme 2).
Mesylation of the hydroxyl groups in 12 and 14 led
quantitatively to dimesylates 13 and 15.
Macrocyclization was then performed using various di-
amines and diols (varying their chain length and rigidity).
Ethylenediamine proved to be the best reagent to obtain the
macrocycle in the reaction with dimesylate 13 (Scheme 3).
(15) The dimesylate 15 or 16 (0.1 mmol) was dissolved in acetonitrile
(10 mL). Na2CO3 (500 mg), phenylglycine methyl ester hydrochloride HCl
(25 mg) and ethylenediamine (0.02 mL) were added. The mixture was
refluxed for 48 h. After being cooled to rt, the mixture was partitioned
between water (5 mL) and ethyl acetate (15 mL), the layers were separated,
the organic layer was dried and concentrated, and the product was isolated
bycolumnchromatography(toluene-methanol15:1for16ortoluene-methanol
12:1 then 5:1 for 17).
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Org. Lett., Vol. 12, No. 11, 2010

5% to 25%, once again proving the ability of the amino acid
derivative to template formation of the large ring product
(Scheme 3). The structure of the macrocyclic sucrose
derivative 16 was unambiguously confirmed by the MS, 1H,
13C, 15N, and 2D NMR spectra.
cation. Although the ester oxygen atom is a weak hydrogen
bond acceptor and primary amines are weak hydrogen bond
donors, the interaction of the two in the template and
ethylenediamine brings all three molecules in close proxim-
ity, so the reaction of dimesylate with diamine can occur to
provide the desired product. The importance of the ester
motif is clearly proven by the lack of templating ability of
phenylethylamine hydrochloride. The lack of templating
effect for the D-enantiomer of the amino acid derivative is
most likely due to steric reasons (the repulsion between the
phenyl group and the OBn substituent in position 1′ of the
disaccharide skeleton).
The proposed mechanism of the templated process is
presented in Figure 2.
To our knowledge, this is the first example of an amino-
acid templated macrocyclization reaction. This result opens
interesting perspectives in the area of supramolecular chem-
istry and catalysis. A more precise study of the reaction, its
scope, and its mechanism may provide interesting informa-
tion for the development of new methodologies for large-
ring molecule synthesis, even in a stereoselective fashion,
as well as in the area of mechanically interlocked molecules
(rotaxanes, catenanes etc.). In conclusion, a novel synthetic
route toward sucrose-based C2-symmetrical macrocycles has
been developed. Application of an L-phenylglycine derivative
as a template was crucial for the efficient formation of the
large ring product. This approach is the first reported example
of an amino acid templated reaction leading to a product of
high added value. Further comprehensive study of the scope
and limitations of this reaction may lead to the development
of more general methodologies for amino acid templated
organic reactions.
Figure 2
lectivity).
. Proposed templation mechanism (origin of enantiose-
Supporting Information Available: Details on the syn-
thesis and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The triazole nitrogen atoms (known to be good hydrogen
bond acceptors)16 form a hydrogen bond with the ammonium
(16) Angelo, N. G.; Arora, P. S. J. Am. Chem. Soc. 2005, 127, 17134–
17135.
OL100749M
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