Sweet (hetero)aromatics: Glycosylated templates for the construction of saccharide mimetics

Article abstract of DOI:10.1039/c1cc13078a

Mono- and diglycosylated aromatics and heteroaromatics may serve as building blocks for the construction of metabolically stable mimetics of oligosaccharides. Methods for their preparation from monosaccharidic precursors by direct C-glycosylation, dipolar cycloaddition or Larock cyclization are described.

Full text of DOI:10.1039/c1cc13078a

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COMMUNICATION
Sweet (hetero)aromatics: glycosylated templates for the construction of
saccharide mimeticswz
Christine Wiebe,ab Claudine Schlemmer,ab Stefan Weckab and Till Opatz*a
Received 25th May 2011, Accepted 23rd June 2011
DOI: 10.1039/c1cc13078a
Mono- and diglycosylated aromatics and heteroaromatics may
serve as building blocks for the construction of metabolically
stable mimetics of oligosaccharides. Methods for their preparation
from monosaccharidic precursors by direct C-glycosylation,
dipolar cycloaddition or Larock cyclization are described.
Structurally defined oligosaccharides play an important role
in the communication between cells in higher organisms.1
Prominent examples are the blood group antigens which allow
the differentiation between erythrocytes of different species
and even different individuals or the sialyl LewisX tetra-
saccharide which is involved in the recruitment of leukocytes
within the inflammatory cascade.2 While the recognition of
cell surface oligosaccharides is a key process in numerous
medical conditions, e.g. psoriasis,3 asthma4 or the reperfusion
syndrome,1d their use as drugs is generally hampered by their
poor pharmacokinetics.5 To improve the metabolic stability
and to retain or even increase the binding affinity to the target
structure, various types of oligosaccharide mimetics have been
developed.5,6 In particular, C-glycosides possess a high stability
against ubiquitous glycosidases and in this respect are privileged
in the field of saccharide mimicry.5,7
Scheme 1 Reagents and conditions: (a) TMSOTf, CH2Cl2, molecular
sieves 4 A, 0 1C, 52%; (b) TMSOTf, CH2Cl2, molecular sieves 4 A,
0 1C, 32%; (c) Pd(OAc)2, MeOH, H2 (1 bar), 25 1C, 43%; (d) NaOMe,
MeOH, 25 1C, quant.
isolated from Melaleucaquinquenervia.13 The high electron
density makes the indole nucleus another suitable template
for direct C-glycosylations.14 1-Glycosylindoles 6 can be
prepared according to Mel’nik et al.15 by reaction of hexoses
with indoline followed by dehydrogenation with DDQ.16 After
peracetylation, BF3-etherate promoted reaction with acetylated
trichloroacetimidate donors furnishes 1,3-diglycosylindoles 8,
9, and 10 (Scheme 2). In the case of fucoside 10, the produced
anomeric mixture could not be separated by column
chromatography.
Among the various methods used for the construction of
C-glycosides, the reaction of suitable glycosyl donors with
electron rich phenols8 permits the straightforward synthesis
of trisaccharide mimetics if the initial glycosylation of the
ortho-position is followed by an O-glycosylation of the phenolic
OH-group. As an example, 2-naphthol can be reacted with the
benzylated galactosyl trichloroacetimidate 19 in the presence
of TMSOTf to furnish the thermodynamically preferred
b-C-glycoside 2.8c,d,10 Subsequent reaction with the acetyl
protected mannosyl trichloroacetimidate 311 furnishes
The sterically more encumbered 2,3-diglycosylindoles may
be viewed as mimetics of trisaccharides possessing a vicinal
substitution pattern. These compounds can be obtained from
2-glycosylindoles like 14,17 the synthesis of which proceeds via
C-glycosylacetylene 12.18 Reaction of the benzylated galactosyl
acetate with tributyl[2-(trimethylsilyl)ethynyl]stannane in the
presence of TMSOTf furnishes the TMS-acetylene, which can
be desilylated with TBAF. Sonogashira-coupling with N-tosyl-
2-iodoaniline and Cu(I)-catalyzed hydroamination yields the
N-tosylatedindole 13.17a Alkaline detosylation followed by
BF3ꢀOEt2-promoted reaction of the resulting glycosylindole
1415 with acetylated trichloroacetimidates of D-mannose19
furnishes the b-C-mannoside 15 (Scheme 3).
O,C-digylcoside 4, albeit in only 28% yield (Scheme 1).12
A
similar glycosylation pattern is found in a natural product
a Institute for Organic Chemistry, University of Mainz,
Duesbergweg 10-14, 55128 Mainz, Germany.
E-mail: opatz@uni-mainz.de; Fax: +49 6131 3922338;
Tel: +49 6131 3924443
b Department of Chemistry, University of Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
w This article is part of the ChemComm ‘Glycochemistry and glycobiol-
ogy’ web themed issue.
C-Fucosylation of 14 using donor 720 gives significantly
higher yields but results in the formation of both anomers in
equal amounts (data not shown).
z Electronic supplementary information (ESI) available: Experimental
procedures, compound characterization, and NMR spectra. See DOI:
10.1039/c1cc13078a
c
9212 Chem. Commun., 2011, 47, 9212–9214
This journal is The Royal Society of Chemistry 2011

Scheme 4 Reagents and conditions: (a) 2-iodoaniline, AcOH, EtOH,
100 1C, 31%; (b) AllOH, AcCl, 70 1C - 40 1C; (c) BnBr, NaH, DMF;
(d) Ir(COD)(PPh2CH3)2, H2, THF; (e) I2, NaHCO3, THF/H2O (4 : 1);
(f) Ac2O, pyridine, DMAP, 49% over 5 steps; (g) Bu3SnCRCSiMe3,
TMSOTf, CH2Cl2, molecular sieves 4 A; (h) Pd(OAc)2, PPh3, Et3N,
DMF, 60 1C, 66%.
Scheme 2 Reagents and conditions: (a) indoline, EtOH, 40 1C, quant.;
(b) Ac2O, pyridine, 95%; (c) DDQ, dioxane, 25 1C, 94%; (d) indoline,
EtOH, 40 1C, 82%; (e) DDQ, dioxane, 25 1C, 97%; (f) Ac2O, pyridine,
25 1C, 92%; (g) BF3ꢀOEt2, CH2Cl2, ꢁ60 1C - 0 1C, molecular sieves
4 A, 55% (a); (h) BF3ꢀOEt2, CH2Cl2, ꢁ60 1C - 0 1C, molecular sieves
4 A, 33% (b); (i) BF3ꢀOEt2, CH2Cl2, ꢁ15 1C - 8 1C, molecular sieves 4 A,
44% (a/b = 1:1.7).
In contrast, extension of compounds of type 18 by one
carbonyl group furnishes substrates for the Larock cyclization
which turned out to proceed in high yield if iodine was used
as the electrophile.23 Reaction of glycosylamine 20 with
Scheme 3 Reagents and conditions: (a) Bu3SnCRCSiMe3, TMSOTf,
CH2Cl2, molecular sieves 4 A; (b) TBAF, THF/H2O, 25 1C, 32% over
2 steps; (c) N-tosyl-2-iodoaniline, Pd(OAc)2, PPh3, Et3N, DMF, 60 1C;
(d) CuI, Et3N, DMF, 60 1C, 78% over 2 steps; (e) KOH, MeOH,
THF, 25 1C, 82%; (f) 3, BF3ꢀOEt2, CH2Cl2, ꢁ15 1C - 25 1C,
molecular sieves 4 A, 23% (a).
In analogy to the synthesis of tosylindole 13, the preparation of
1,2-diglycosylated indoles should be possible by coupling of
alkynes of type 12 to N-glycosyl 2-iodoanilines.21 Indeed, the
Sonogashira reaction between these components provides
ethynylanilines such as 18 in high yield which can already be
viewed as trisaccharide mimetics. However, their cyclization to
19 with soft electrophiles or various coinage metal complexes
has not been achieved so far (Scheme 4).22
Scheme 5 Reagents and conditions: (a) 2-iodobenzoyl chloride,
N-ethylmorpholine, THF, 0 1C, 90%; (b) 17, Pd(PPh3)2Cl2, CuI,
Et3N, DMF, 80 1C, 60%; (c) 12, Pd(PPh3)2Cl2, CuI, Et3N, DMF,
60 1C, 76%; (d) I2, NaHCO3, CH3CN, 25 1C, 76%; (e) I2, NaHCO3,
CH3CN, 25 1C 94%.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9212–9214 9213

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(Scheme 5).23,24
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The Ru-catalyzed 1,3-dipolar cycloaddition of azides to
terminal alkynes (RuAAC)25 represents a straightforward
possibility to produce heteroaromatics with a vicinal diglyco-
sylation pattern. For example, fucosylacetylene 17 reacts with
the pivaloylated and acetylated galactosylazides26 26 and 27 to
the corresponding 1,5-diglycosylated 1,2,3-triazoles 28 and 29.
The regioisomeric 1,4-disubstituted products like 30 can be
obtained from the same reactants using Cu(I) as the catalyst
(CuAAC, Scheme 6).27
In summary, several general methods for the preparation of
diglycosylated aromatic and heteroaromatic templates have been
developed. Particular attention has been paid to the synthesis of
products with two neighboring hexose residues as this pattern is
frequently found in natural oligosaccharides. The presented
compounds may serve as starting materials for the synthesis of
functional glycomimetics with improved metabolic stability.
This work was supported by the German Federal Ministry
for Education and Research (TO, grant no. 0315139).
Notes and references
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c
9214 Chem. Commun., 2011, 47, 9212–9214
This journal is The Royal Society of Chemistry 2011