A short route for the synthesis of "sweet" macrocycles via a click-dimerization-ring-closing metathesis approach

Article abstract of DOI:10.1039/b502682b

A facile and flexible approach for the preparation of macrocyclic molecules containing different carbohydrate moieties is presented, employing the reaction cascade: click-dimerization and ring-closing metathesis. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b502682b

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A short route for the synthesis of ‘‘sweet’’ macrocycles via a
click-dimerization–ring-closing metathesis approach{
Simon Do¨rner and Bernhard Westermann*
Received (in Cambridge, UK) 24th February 2005, Accepted 6th April 2005
First published as an Advance Article on the web 21st April 2005
DOI: 10.1039/b502682b
azides by 1,3-dipolar cycloadditions with a dialkyne, ii) ring-
A facile and flexible approach for the preparation of macro-
cyclic molecules containing different carbohydrate moieties is
presented, employing the reaction cascade: click-dimerization
and ring-closing metathesis.
closing metathesis. We reasoned that synthetic operations would
be minimal by starting with a precursor molecule that incorporates
both the azide and the alkene functionality so that the 1,3-dipolar
cycloaddition and the RCM could be carried out in a consecutive
manner without necessity for functionalization after each step.
Additionally, potential problems of stereocontrol are ruled out
while starting from bifunctional carbohydrate units. With this in
mind we examined first the dimerization of anomeric carbohydrate
azides with a dialkyne (Scheme 1).
Carbohydrate containing macrocycles such as cyclic glycolipids
sophorolipid lactone (A) and tricolorin G (B) constitute a class of
molecules with diverse structural characteristics and interesting
biological profiles.1 They contain a variable number of linked
carbohydrate units tied up by a lipophilic aglycon. In an elegant
approach Fu¨rstner and co-workers reported the synthesis of
several cyclic glycolipids and analogues using ring-closing metath-
esis (RCM).2 This methodology was also used to synthesize
structurally related cyclic neoglycoconjugates combining structural
preorganized carbohydrate moieties and lipophilic subunits.
Kirschning et al. synthesized spacer-linked aminoglycoside mimics
to target polynucleotides3 while Murphy et al. fashioned cyclic
multivalent carbohydrate scaffolds.4 All these examples among
others constitute elegant applications of ring-closing metathesis in
macrocycle synthesis.5
The azides 1 and 2 were prepared starting from glucose and
glucosamine according to literature procedures. Azide 3 was
readily prepared from the commercially available neomycin B by
degradation to the corresponding anomeric bromide8 and
subsequent replacement of bromine with an azide residue under
phase transfer conditions.9 We found that after addition of an
aqueous copper(II)acetate–sodium ascorbate solution to the
mixture of the corresponding carbohydrate azide and 1,7-
octadiyne in tert-butanol, the carbohydrate dimers 4–6 could be
isolated in good yields.
Encouraged by these results, we turned our attention to the
synthesis of suitable bifunctional building blocks containing
olefinic and azide groups. For the ring-closing metathesis the
prerequisite olefinic functions are introduced at the anomeric
centre as an O-allyl side chain via a classic Ko¨nigs–Knorr-reaction
furnishing 7, or Keck-allylation leading to the C-glycosidic
compound 8.10 In contrast to the initial dimerization reactions
outlined in Scheme 1 we decided to incorporate the azide
In order to develop a short entry to new sugar-containing
macrocyclic compounds we sought to combine the highly reliable
RCM with another reaction which allows for a facile linkage of
carbohydrate monomers. In this context the Cu-catalyzed
modification of the classic Huisgen-reaction (‘‘click-reaction’’),6
which was successfully employed for the synthesis of glycoconju-
gates recently,7 seemed to be promising. Therefore, we settled on
the following reaction sequence: i) dimerization of carbohydrate
Scheme 1 Carbohydrate dimerization. Reagents and conditions: (a) 1–3
(1 eq.) 0.1 M solution in tBuOH, 1,7-octadiyne (0.5 eq.), sodium ascorbate
(0.4 eq., 0.08 M solution in H2O), Cu(OAc)2 (0.2 eq., 0.04 M solution in
H2O), 12 h, rt.
{ Electronic supplementary information (ESI) available: nmr data and
copies of nmr-spectra of all compounds. See http://www.rsc.org/suppdata/
cc/b5/b502682b/
*bwesterm@ipb-halle.de
2852 | Chem. Commun., 2005, 2852–2854
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Scheme 2 Synthesis of bifunctional building blocks. Reagents and
conditions: (a) i. NaOMe, MeOH, rt; ii. TsCl, pyridine, 0 uC A rt then
Ac2O; iii. NaN3, DMF, 90 uC, 70% (10), 64% (11); (b) 6-bromo-1-hexene,
NaH, THF, rt A reflux, 43%.
Scheme 3 Dimerization of bifunctional carbohydrate building blocks.
For conditions (a) see Scheme 1.
functionality at C-6 of the sugar core rather than the anomeric
centre to allow more flexibility for the heterocycle formation.
Therefore, after deacetylation of 7 and 8, the azide residue was
introduced by tosylation of the primary hydroxy group followed
by substitution with sodium azide. Starting with the literature-
known molecule 911 a hexenyl residue was attached by alkylation
at C-4 of the sugar moiety (Scheme 2).
Scheme 4 Preparation of macrocycles. Reagents and conditions: (a) 14–17 (2 mmolar solution in DCM), Grubbs I catalyst 26 (5 mol%), reflux, 12–24 h,
73–95%; (b) 18–20, MeOH, Pd(OH)2/C/H2, 87–99%; (c) acetyl protected compounds (solution in MeOH), NaOMe, 2 h, 79–99%; (d) NaOH (0.1 M), THF,
12 h, 40%; (e) MeOH, Pd(OH)2/C/H2, 88%.
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Simon Do¨rner and Bernhard Westermann*
With these molecules in hand the stage was set for the click-
dimerization. Except for azide 1312 that provided the dimerized
product in only 79% yield, it was found that by employing the
same reaction conditions as described for 1–3, the reaction of 10,
11 and 12, having primary azide groups at C-6, went to completion
(Scheme 3). This might indicate that steric and electronic effects are
less favorable for the reaction of azides at the anomeric center.
Having successfully finished the assembly of dimeric precursors
14–17, only a few steps had to be effected to finish the synthesis of
the desired macrocyclic compounds. To accomplish the ring-
closing metathesis, the diolefinic molecules were reacted for 12–
24 hours with a 5 mol% loading of Grubbs’ ruthenium catalyst 26.
The ring formation reactions were carried out in a 2 mmolar
dichloromethane solution at 40 uC to facilitate the macrocycliza-
tion and to prevent a competitive homodimerization. These
reactions proceeded smoothly to yield 18–21 (Scheme 4). As
expected, no E/Z-selectivity was observed during the metathesis
leading to a non-separable mixture of both isomers in 73–95%
yield. In order to obtain single compounds for clear characteriza-
tion the double bonds of the products 18–21 were reduced
hydrogenolytically. This task was easily accomplished using
palladium hydroxide on charcoal as a catalyst under a hydrogen
atmosphere. While in the case of molecules 18–20 the reduced
macrocycles had to be deprotected by saponification to provide
22–24, the hydroxyl groups of 21 were unveiled during double
bond reduction in a single operation affording 25 in good yield. By
variation of the length of the olefinic side chain, macrocycles of
different ring sizes and hence lipophilicity were obtained.
Leibniz Institute of Plant Biochemistry, Department of Bioorganic
Chemistry, Weinberg 3, 06120 Halle (Saale), Germany.
E-mail: bwesterm@ipb-halle.de; Fax: +49 345 5582 1309;
Tel: +49 345 5582 1340
Notes and references
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Diversity, 2005, 9, 171.
2 A. Fu¨rstner, Eur. J. Org. Chem., 2004, 943; A. Fu¨rstner and T. Mu¨ller,
J. Org. Chem., 1998, 63, 424; A. Fu¨rstner and T. Mu¨ller, J. Am. Chem.
Soc., 1999, 121, 7814.
3 G. W. Chen and A. Kirschning, Chem. Eur. J., 2002, 8, 2717;
J. Jaunzems, B. Oelze and A. Kirschning, Org. Biomol. Chem., 2004, 2,
3448; A. Kirschning, G. W. Chen, J. Jaunzems, M. Jesberger,
M. Kalesse and M. Lindner, Tetrahedron, 2004, 60, 3505.
4 T. Velasco-Torrijos and P. V. Murphy, Org. Lett., 2004, 6, 3961.
5 M. A. Leeuwenburgh, G. A. van der Marel and H. S. Overkleeft, Curr.
Opin. Chem. Biol., 2003, 7, 757; G. T. Fan, T. S. Hus, C. C. Lin and
C. C. Lin, Tetrahedron Lett., 2000, 41, 6593.
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2001, 40, 2004; H. C. Kolb and K. B. Sharpless, Drug Discovery Today,
2003, 8, 1128; C. W. Tornoe, C. Christensen and M. Meldal, J. Org.
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transfer conditions for the substitution of anomeric halogens with
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In summary, we presented a short route for the synthesis of
sugar-containing macrocycles by an amalgamation of click-
reactions and RCM. Employing different precursors, this cascade
transformation constitutes a powerful approach to generate
molecular complexity. A large number of potential sugar
precursors for the assembly of compound libraries following this
strategy can be found in literature. While azide groups are found in
large number in sugar chemistry as surrogates for amine functions,
olefins occur as part of protecting or activating groups.
S. D. appreciates the support by the Studienstiftung des
deutschen Volkes (Ph.D.-grant).
12 C. Rosenbohm, D. Van den Berghe, A. Vlietinck and J. Wengel,
Tetrahedron, 2001, 57, 6277.
2854 | Chem. Commun., 2005, 2852–2854
This journal is ß The Royal Society of Chemistry 2005