Coordination chemistry approach to the long-standing challenge of stereocontrolled chemical glycosylation

Article abstract of DOI:10.1039/b903942b

This study clearly demonstrates that a multi-dentate metal coordination to the leaving group, along with O-5 and/or a protecting group at O-6, has a strong effect on the stereoselectivity of chemical glycosylation.

Full text of DOI:10.1039/b903942b

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COMMUNICATION
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Coordination chemistry approach to the long-standing challenge
of stereocontrolled chemical glycosylationw
Papapida Pornsuriyasak,a Cornelia Vetter,b Sophon Kaeothip,a Michael Kovermann,cd
Jochen Balbach,cd Dirk Steinborn*b and Alexei V. Demchenko*a
Received (in College Park, MD, USA) 25th February 2009, Accepted 8th September 2009
First published as an Advance Article on the web 24th September 2009
DOI: 10.1039/b903942b
This study clearly demonstrates that a multi-dentate metal
coordination to the leaving group, along with O-5 and/or a
protecting group at O-6, has a strong effect on the stereo-
selectivity of chemical glycosylation.
Although complete information about the functions of natural
complex carbohydrates is yet to emerge, some aspects of their
involvement in many biological phenomena are already
known.1,2 Further improvement in this field would be significantly
facilitated if we could rely on detailed knowledge of the
Scheme 1 Direct vs. coordination-mediated glycosylations.
structure, conformation and properties of the carbohydrate
molecules involved. Therefore, the development of effective
(for sugars of the D-series). As a result, the nucleophilic attack
methods for assembling simple carbohydrates into more
of the glycosyl acceptor would be primarily directed from the
elaborate networks (oligosaccharides and conjugates thereof)
opposite side, resulting in an a-D-linked (1,2-cis for D-gluco)
has become critical for the field of glycosciences.3–5
product F. We began investigating this concept by using
Since the O-glycosylation reaction leads to the formation of
conventional thioglycoside 1a9 and trimethylplatinum(IV)
a new chirality (anomeric) center, particular care has to be
complexes thereof.10,11 Typical MeOTf-promoted glycosidation12
taken with regards to stereocontrol, which is particularly
of 1a with glycosyl acceptor 3 provided no stereoselectivity for
important when the synthesis of challenging 1,2-cis-glycosides
the formation of disaccharide 4 (entry 1.1, Table 1). Although
is undertaken.6,7 A generic reaction pathway for glycosyl
donors with a non-participating 2-O-benzyl substituent (A)
Table 1 Investigation of per-benzylated S-ethyl and S-thiazolinyl
is depicted in Scheme 1. Promoter (P) mediated departure of
glycosides as glycosyl donors and ligands
the anomeric leaving group (LG) results in formation of the
oxocarbenium ion B. In uncontrolled glycosylation, nucleo-
philic attack of the glycosyl acceptor (Nu) can then take place
from either the top or the bottom face of the flattened ring,
often leading to anomeric mixtures C (Scheme 1).8
The central hypothesis at the base of this study is whether
metal coordination (MLn), in particular multi-dentate coordi-
nation to the leaving group along with the O-5 and/or remote
position(s) (intermediate D), has an effect on the stereo-
selectivity of glycosylation. We assumed that even upon
promoter-assisted LG ‘‘departure’’, such a complex would
sterically hinder the top face of the key intermediate E
a Department of Chemistry and Biochemistry, University of
Missouri—St. Louis, One University Boulevard, St. Louis,
Missouri 63121, USA. E-mail: demchenkoa@umsl.edu
b Institut fur Chemie-Anorganische Chemie, Martin-Luther-Universitat
¨
¨
Halle-Wittenberg, D-06120 Halle, Kurt-Mothes Straße 2, Germany.
E-mail: dirk.steinborn@chemie.uni-halle.de
Yield
(%)
c Institut fur Physik, Fachgruppe Biophysik, Martin-Luther-Universitat
Halle-Wittenberg, D-06099 Halle (Saale), Germany
Entry
Donor
Promoter
Time
a/b
¨
¨
1.1
1.2
1a
1b–d
MeOTf
10 min
48 h
92
0
1.0/1
—
d Mitteldeutsches Zentrum fur Struktur und Dynamik der Proteine
(MZP), Martin-Luther-Universitat Halle-Wittenberg, D-06099
¨
¨
MeOTf, NIS/TfOH,
or DMTST
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Halle (Saale), Germany
1.3
1.4
1.5
1.6
2a
2b
2c
2d
1 h
95
62
88
79
1.5/1
2.4/1
2.5/1
2.3/1
w Electronic supplementary information (ESI) available: Extended
experimental data, experimental procedures for the synthesis of
new compounds, and their 1H and 13C NMR spectra. See DOI:
10.1039/b903942b.
20 h
15 h
16 h
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a variety of factors, such as the effect of the reaction solvent,
can dramatically increase the stereoselectivity,13–15 herein, we
chose 1,2-dichloroethane (1,2-DCE), which has a minimal
solvation effect on the reactants and intermediates. The
synthesis of various platinum(IV) complexes 1b–d, all of which
are coordinated to the platinum atom via the anomeric sulfur,
was successfully achieved (see the ESIw). Unfortunately,
all of our attempts to glycosidate such complexes under
conventional conditions for thioglycoside activation16 have
failed (entry 1.2). No glycosylation took place and only partial
hydrolysis of glycosyl donor and methylation of glycosyl
acceptor 3 (with MeOTf) were observed as major side
reactions.
Table
S-thiazolinyl glycosides as glycosyl donors and ligands
2
Investigation of 6-O-picolylated S-pyridylthiazolyl and
It is possible that coordination of platinum to the anomeric
sulfur prevents its subsequent interaction with electrophilic
promoters. In this context, glycosyl donors with multiple
reactive centers on the leaving group, such as glycosyl
thioimidates,17 would help to address this concern. Arguably,
even upon complexation, these compounds would allow for
activation via the non-engaged center. Theoretically, either
direct coordination of a metal to the anomeric sulfur or remote
coordination to the nitrogen should improve the thioimidoyl
leaving group ability.18,19 The discovery of the temporary
deactivation concept, however, implies that some complexes
of non-ionizing nature may have an opposite, deactivating,
effect on the thioimidoyl leaving group ability.20,21 It has been
demonstrated that trimethylplatinum complexes coordinate to
carbohydrates and to N,S-heterocycles like thiazoline-2-thione
without being reduced.10,11,22 Therefore, investigation of
S-thiazolinyl (STaz) derivative 2a23,24 was of particular interest.
Encouragingly, glycosidation of complexes 2b–d in the
presence of Cu(OTf)2 provided a notable improvement in
stereoselectivity (entries 1.4–1.6) in comparison to that
achieved in the glycosidation of the uncomplexed glycosyl
donor 2a (entry 1.3). In compounds 2b–d the carbohydrate
ligands were found to coordinate to the platinum atom via
the nitrogen atom of the STaz group and additionally for
compound 2b through the oxygen atoms of glucopyranose (see
the ESIw).
Weakly coordinating donor sites in neutral carbohydrates
afford complexes that are often unstable in the presence of
stronger donor sites. Therefore, these results could not serve as
a reliable proof of the concept of coordination-assisted
improvement in stereoselectivity. These glycosylations could
partially proceed via the complex destruction that would result
in the complete leaving group departure as occurs in direct
glycosylations. Hence, we assumed that targeted enhanced
coordination of the carbohydrate ligands can be achieved by
introducing stronger N-Lewis-basic substituents. To execute
this approach, we obtained 6-O-picolyl derivatives of
4-(pyridin-2-yl)thiazol-2-yl thioglycosides (SPT)21 and STaz
glycosides, 5a and 6a, respectively. Direct glycosidation of
these glycosyl donors proceeded with poor stereoselectivity
(entries 2.1 and 2.2, Table 2), whereas glycosidation of the
corresponding complexes 5b and 6b under essentially the same
activation conditions gave improved (2–2.5 fold) stereo-
selectivity (entries 2.3 and 2.4). This result is a clear indication
that improved stereoselectivity can be achieved by applying
specifically designed ligands capable of stronger coordination.
Entry
Donor
Promoter
Time/h
Yield (%)
a/b
2.1
2.2
2.3
2.4
5a
6a
5b
6b
AgOTf
22
16
20
24
66
83
58
62
1.1/1
2.0/1
2.1/1
5.2/1
Cu(OTf)2
AgOTf
Cu(OTf)2
Table 3 Investigation of 6-O-bipyridine-substituted S-ethyl and
S-thiazolinyl glycosides as glycosyl donors and ligands
Entry
Donor
Promoter
Time/h
Yield (%)
a/b
3.1
3.2
3.3
3.4
8a
9a
8b
9b
AgOTf
14
48
16
24
82
73
67
65
1.5/1
1.7/1
2.2/1
9.4/1
Cu(OTf)2
AgOTf
Cu(OTf)2
In order to pursue this concept further, we obtained glycosyl
donors 8a and 9a bearing a bipyridine protecting group at C-6.
The results of this study are highlighted in Table 3. While the
improvement in the case of the SPT glycosyl donor was
unremarkable, a 5-fold improvement with the complexed
glycosyl donor 9b is significant. Thus, while glycosidation of
9a showed only a slight preference for the a-anomer (1.7/1,
entry 3.2), the glycosidation of its complexed counterpart 9b
allowed a 9.4/1 a/b-anomeric ratio of disaccharide 10 (entry
3.4). The coordination sites in the complex 9b (three nitrogen
atoms as shown in Table 3) were unambiguously proven
(see the ESIw).
Similarly, a 3–3.5 fold improvement was achieved in the
glycosylation of common secondary glycosyl acceptors 11 and
12 with the complexed STaz glycosyl donor 9b. The results of
this study are highlighted in Table 4, and are available in more
detail as a part of the ESI.w
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Table 4 Investigation of secondary glycosyl acceptors 11 and 12
Notes and references
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7 A. V. Demchenko, Curr. Org. Chem., 2003, 7, 35–79.
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and Therapeutic Relevance, ed. A. V. Demchenko, Wiley-VCH,
Weinheim, 2008.
9 F. Andersson, P. Fugedi, P. J. Garegg and M. Nashed, Tetrahedron
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Entry
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Acceptor
Product
Yield (%)
a/b
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4.1
4.2
4.3
4.4
9a
9a
9b
9b
11
12
11
12
13
14
13
14
53
61
50
48
2.2/1
2.0/1
7.2/1
6.0/1
12 H. Lonn, J. Carbohydr. Chem., 1987, 6, 301–306.
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It should be noted that although significant improvements
of the chemical glycosylation have already emerged,8 examples
of highly stereocontrolled glycosylations are still rare. To date,
very little is known about the effect of metal coordination
on the reactivity and stereoselectivity of carbohydrates in
glycosylations. We expect that the studies presented herein
will ultimately evolve into a well-rounded and versatile metal-
assisted methodology for the synthesis of a broad range of
complex glycostructures.
AVD thanks the National Science Foundation (CHE-0547566)
and American Heart Association (0855743G), and DS thanks the
Deutsche Forschungsgemeinschaft for financial support of this
23 A. V. Demchenko, P. Pornsuriyasak, C. De Meo and
N. N. Malysheva, Angew. Chem., Int. Ed., 2004, 43, 3069–3072.
24 P. Pornsuriyasak and A. V. Demchenko, Chem.–Eur. J., 2006, 12,
6630–6646.
work. We also thank Dr R. Kluge (Martin-Luther-Universitat
¨
Halle-Wittenberg) and Dr J. Schmidt (Leibniz-Institut fur
¨
Pflanzenbiochemie) for ESI-MS determinations.
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6379–6381 | 6381