O-Alkylated heavy atom carbohydrate probes for protein X-ray crystallography: Studies towards the synthesis of methyl 2-O-methyl-L-selenofucopyranoside

Article abstract of DOI:10.3762/bjoc.12.282

Selenoglycosides are used as reactive glycosyl donors in the syntheses of oligosaccharides. In addition, such heavy atom analogs of natural glycosides are useful tools for structure determination of their lectin receptors using X-ray crystallography. Some

Full text of DOI:10.3762/bjoc.12.282

O-Alkylated heavy atom carbohydrate probes for protein X-ray
crystallography: Studies towards the synthesis of
methyl 2-O-methyl-L-selenofucopyranoside
Roman Sommer1,2, Dirk Hauck1,2, Annabelle Varrot3, Anne Imberty3, Markus Künzler4
and Alexander Titz*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 2828–2833.
1Chemical Biology of Carbohydrates, Helmholtz Institute for
Pharmaceutical Research Saarland (HIPS), D-66123 Saarbrücken,
Germany, 2Deutsches Zentrum für Infektionsforschung (DZIF),
Standort Hannover-Braunschweig, Germany, 3Centre de Recherche
sur les Macromolécules Végétales (CERMAV-UPR5301), CNRS and
Université Grenoble Alpes, BP53, F-38041 Grenoble cedex 9, France
and 4Institute of Microbiology, Swiss Federal Institute of Technology
(ETH) Zürich, 8093 Zürich, Switzerland
doi:10.3762/bjoc.12.282
Received: 17 October 2016
Accepted: 09 December 2016
Published: 22 December 2016
Associate Editor: S. Flitsch
© 2016 Sommer et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Alexander Titz* - alexander.titz@helmholtz-hzi.de
* Corresponding author
Keywords:
carbohydrate chemistry; fucose; lectin; selenoglycoside
Abstract
Selenoglycosides are used as reactive glycosyl donors in the syntheses of oligosaccharides. In addition, such heavy atom analogs of
natural glycosides are useful tools for structure determination of their lectin receptors using X-ray crystallography. Some lectins,
e.g., members of the tectonin family, only bind to carbohydrate epitopes with O-alkylated ring hydroxy groups. In this context, we
report the first synthesis of an O-methylated selenoglycoside, specifically methyl 2-O-methyl-L-selenofucopyranoside, a ligand of
the lectin tectonin-2 from the mushroom Laccaria bicolor. The synthetic route required a strategic revision and further optimiza-
tion due to the intrinsic lability of alkyl selenoglycosides, in particular for the labile fucose. Here, we describe a successful synthe-
tic access to methyl 2-O-methyl-L-selenofucopyranoside in 9 linear steps and 26% overall yield starting from allyl L-fucopyra-
noside.
Introduction
Since the discovery of seleno mercaptan by Siemens in 1847 tives are nowadays used as powerful tools in organic chemistry
[1], organoselenium compounds have attracted high attention. [6]. Synthetic selenoglycosides are versatile synthons in glyco-
Besides their biological and pharmaceutical relevance, e.g., sylation reactions as glycosyl donors for the synthesis of glyco-
selenocysteine or ebselen [2-5], selenium-containing deriva- sides and oligosaccharides, where their aglycon acts as a
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leaving group [7-9]. They can be selectively activated due to
their enhanced reactivity in the presence of other chalcogen-
containing glycosides such as O- or S-glycosides. By exploiting
these properties, one-pot multi-step glycosylation reactions
have been developed recently [10,11]. Natural selenosugars,
such as methylseleno N-acetyl-β-D-glucosamine, have been de-
scribed in rats as metabolites for detoxifying inorganic selenite
intake [12,13].
Selenium-containing compounds are also widely used as tools
for protein X-ray crystallography in structural biology. The de-
termination of a protein structure depends on the correct phase
recovering because only the amplitude of the scattered waves
can be directly determined from an X-ray diffraction pattern
[14]. Several methods have been developed to solve the
so-called “phase problem” such as molecular and isomorphous
replacement and multi-wavelength anomalous diffraction
(MAD) [14,15]. Molecular replacement is a straight forward
method when atomic coordinates of structurally similar pro-
teins are available. For unknown protein structures, heavy
Figure 1: Alkylseleno glycosides, such as 1, are used as tools for
X-ray crystallography of lectins. Some lectins require O-alkylation for
carbohydrate recognition, e.g., the fungal Lb-Tec2 binds to 2-O-methyl
fucoside 2. The heavy-atom probe 3 bearing the required O-methyla-
tion in position 2 could solve the phase problem for Lb-Tec2 structure
determination.
atoms, e.g., salts of Hg, Fe, or lanthanides, are incorporated into an important role in fungal defense against bacteria and nema-
the protein or the crystal. The changes in intensities of some todes. The determination of the Lb-Tec2 structure by X-ray
classes of reflections will enable the localization of heavy metal crystallography promised to be difficult since no suitable model
positions and hence determination of the phases [14,15]. Cova- was available for molecular replacement and the protein
lently modified detergents, for example selenium-containing contains only one methionine and no cysteine residues, which is
alkyl glycosides, have been used to incorporate heavy atoms insufficient to consider incorporation of selenomethionine in the
into the crystal [16-18]. To overcome problems in locating nu- protein for the structure elucidation. Its carbohydrate-binding
merous rather positionally undefined heavy atoms obtained specificity was determined and a preference for O-methylated
after an unspecific ligand-soaking procedure, new methods carbohydrate ligands was demonstrated (e.g., 2, Figure 1).
were developed. One highly defined method is to directly O-Methylation of carbohydrates is a rare modification, but
substitute methionine by selenomethionine in recombinantly widespread in nature as it has been observed in bacteria,
expressed proteins [19,20]. On the other hand, the co-crystalli- protozoa, animals and plants but not in mammals [29,30].
zation of a protein in complex with selenium-containing ligands Besides fungal and animal tectonins that recognize O-methyl-
can enable the phase determination without the need for recom- ated glycans in pathogens or parasites, numerous other lectins
binant incorporation of amino acid analogues. Buts et al. first recognize such O-alkylated ligands, e.g., the pilus adhesin from
reported the use of a selenoglycoside as ligand for a carbo- Pseudomonas aeruginosa PAK [31] or PapG from Escherichia
hydrate-binding protein, and its use for X-ray crystallographic coli [32]. In contrast, methylation of lectin ligands can also
structure determination [21,22]. This method has now success- prevent binding, as observed with O-methylated fucose and
fully been applied to solve the structure of the bacterial lectins mannose for P. aeruginosa LecB or B. cenocepacia BC2L-A
RSL from Ralstonia solanacearum [23], BC2L-C from Burk- [33]. Thus, O-methylation of glycans can tune biological recog-
holderia cenocepacia [24], and the fungal lectin AFL from nition events.
Aspergillus fumigatus [25] using methyl α-L-selenofucoside (1,
Figure 1) as heavy atom containing ligand as well as PVL lectin In contrast to the literature reports on the synthesis of unmodi-
from Psathyrella velutina [26] using methyl β-D- fied seleno glycosides, the synthesis of selectively O-alkylated
selenoGlcNAc. Recently, the crystal structure of human derivatives to study their interactions with lectins has not been
galectin-9 in complex with a selenium-containing lactose disac- described. Here, we report for the first time the synthesis of a
charide has been described [27].
selectively ring-substituted methylseleno-fucoside and provide
insight into the reactivity and reagent tolerability of seleno-
In 2014, we have characterized the toxin Tectonin-2 from the glycosides. The methods described will be useful for applica-
mushroom Laccaria bicolor (Lb-Tec2) [28], a protein that tion in the synthesis of heavy-atom probes for O-alkyl carbo-
belongs to the tectonin family of β-propeller lectins and plays hydrate binding lectins.
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Results and Discussion
idene acetal could be achieved through in situ evaporation of
The first synthetic approach towards O-methylated selenofuco- the reaction byproduct methanol as previously reported by
side 3 was based on the reported syntheses of unmodified Evans [35] for methyl O-glucosides. Using the same conditions,
methyl α-L-selenofucoside (1) [23] and of the reported tectonin 4,6-benzylidene protection was successfully introduced into a
ligand allyl 2-O-methyl-α-L-fucoside (2) [28]. After the intro- phenylseleno glucoside by Fairbanks et al. [36] without ob-
duction of the seleno aglycon, a subsequent selective methyla- served degradation at ambient pressure. The increased insta-
tion was expected to lead to the desired derivative 3. For this bility in our system was likely resulting both from the more
purpose, L-fucose (4) was fully acetylated and then treated with reactive methyl aglycon and the more reactive fucose carbo-
TMSBr following the protocols from Gilliard et al. [34] to give hydrate part, in analogy to the differences in reactivity of
glycosyl bromide 5 (Scheme 1). The introduction of the related thioglycosides [37]. Next, the free hydroxy group was
methylseleno moiety was performed by nucleophilic substitu- methylated using methyl iodide to give derivative 6 in 67%
tion of the α-bromide in 5 with methylselenol obtained by in yield over two steps (Scheme 1). To prevent degradation of the
situ reduction of dimethyl diselenide with NaBH4 [23]. The ob- labile seleno moiety, the reaction times were kept as short as
tained crude methyl β-selenofucoside was anomerized under possible.
Lewis acid catalysis to give the anomeric mixture in a ratio of
α/β = 2:1. After separation of the anomers, pure methyl α-L- Various conditions were tested for the deprotection of 6 to give
selenofucoside (1) was finally obtained after deprotection of the the desired methyl 2-O-methyl-L-selenofucoside (3) (Table 1).
α-anomer in 25% over 5 steps from L-fucose (4).
Under mild acidic conditions (chloroform, Table 1, entry 1) no
conversion was observed. Therefore, more acidic conditions
A selective methylation of the hydroxy group in position 2 were used but treatment of 6 with acetic acid led to degradation
requires prior protection of the cis-diol in position 3 and 4 in (Table 1, entry 2). The isolated reaction products were devoid
selenofucoside 1. The introduction of a 3,4-O-benzylidene of the characteristic NMR signals of the methyl aglycon of the
protecting group using benzaldehyde dimethyl acetal under selenofucoside at ≈2 ppm (1H NMR) and ≈2 ppm (13C NMR).
standard conditions was ineffective and degradation was ob- To prevent acidic degradation, 6 was treated with palladium on
served by TLC. However, the formation of the 3,4-O-benzyl- charcoal under a hydrogen atmosphere (Table 1, entries 3–5). In
Scheme 1: Synthesis of 3 through initial introduction of the seleno aglycon and subsequent O-methylation. Reagents and conditions: (a) NaOAc,
Ac2O, 140 °C, 3 h; (b) TMSBr, CH2Cl2, 0 °C–rt, 6 h; (c) Me2Se2, NaBH4, MeCN, 90 °C, 1.5 h; (d) BF3·OEt2, CH2Cl2, rt, 3 h; (e) NaOMe, MeOH, rt,
1 h; (f) PhCH(OMe)2, camphorsulfonic acid, DMF, 50 °C, 20 mbar, 30 min; (g) 1. NaH, DMF, 0 °C, 1 h, 2. MeI, DMF, 0 °C, 10 min; (h) various condi-
tions, see Table 1; (i) t-BuOK, MeI, THF, rt, 24 h.
Table 1: Tested reaction conditions for the deprotection of benzylidene derivative 6.
Entry
Reaction conditions
Product formation
1
2
3
4
5
6
CHCl3/H2O 30:1, rt, 12 h
–a
AcOH/H2O 4:1, rt, 20 h
degradationb
transglycosylation
–a
10 wt % Pd/C, H2, MeOH, rt, 13 h
10 wt % Pd/C, H2, 1,4-dioxane, rt, 12 h
20 wt % Pd/C, H2, THF, rt, 12 h
Na, t-BuOH, THF, NH3, −78 °C, 10 min
degradationb
degradationb
aNo conversion observed by TLC. bDegradation was confirmed by NMR spectroscopy of the reaction products where the characteristic peaks for the
methyl aglycon of the selenofucoside (≈2 ppm in 1H NMR and ≈2 ppm in 13C NMR) could not be observed.
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MeOH as the solvent, transglycosylation of the seleno glyco- L-fucose (4) in a Fischer-type glycosylation and pure allyl
side 6 to its methyl O-glycoside was observed (Table 1, entry α-fucoside (7) was obtained after crystallization in 43% yield
3). Changing the solvent to the non-nucleophilic 1,4-dioxane or (Scheme 2). Selective protection of the 3,4-cis-diol as an
THF led to either no conversion (dioxane, Table 1, entry 4) or acetonide followed by methylation of the hydroxy group in po-
complete degradation and formation of various side products sition 2 yielded derivative 8 in 85% yield over two steps. Then,
(THF, Table 1, entry 5). Finally, Birch reduction conditions the acetonide protecting group in 8 was removed by treatment
were employed, however, without success leading to degrada- with acetic acid to give 2 [28] in 99% yield. For activation of
tion of 6 (Table 1, entry 6). Due to the unsuccessful removal of the anomeric center, the allyl aglycon was subsequently cleaved
the benzylidene group in 6, unprotected selenofucoside 1 was by palladium-catalyzed transallylation to methanol and the fully
directly methylated with MeI (Scheme 1). However, only a acetylated donor 9 was generated in refluxing acetic anhydride
slow conversion was observed and various products were and sodium acetate as base.
detected on TLC lacking predominant formation of only one
regioisomer.
From this acetylation reaction, a chromatographically insepa-
rable mixture of isomeric per-O-acetylated pyranosides 9α/9β
To overcome the difficulties of the deprotection reaction in the and a single furanoside 10 in a ratio of 9α/9β/10 = 3:1:3 was ob-
presence of the labile seleno aglycon, the strategy was changed tained in 42% yield over the two steps (Scheme 2). The
and the seleno moiety was introduced after methylation of isomeric mixture of acetates was then activated using TMSBr
fucose in position 2. As in our previous synthesis of 2-O- and different retention times of pyranosyl bromides and unde-
methylated fucoside [28], allyl alcohol was glycosylated with sired furanosyl bromides on TLC were observed. However,
Scheme 2: Synthesis of compound 3 via initial selective 2-O-methylation followed by the introduction of the seleno aglycon. Reagents and conditions:
(a) allyl alcohol, Amberlite IR120 (H+), 70 °C, 18 h; (b) 2,2-dimethoxypropane, p-toluenesulfonic acid, acetone, rt, 1 h; (c) 1. NaH, DMF, 0 °C, 1 h;
2. MeI, DMF, 0 °C, 30 min; (d) AcOH, H2O, 90 °C, 30 min; (e) PdCl2, CH2Cl2, MeOH, rt, 24 h; (f) NaOAc, Ac2O, 90 °C, 1.5 h; (g) TMSBr, CH2Cl2,
0 °C, 2.5 h; (h) (Me2Se2, NaBH4, MeCN, 90 °C, 1 h), CH2Cl2, 90 °C 15 min–1 h; (i) NaOMe, MeOH, rt, 30 min–2 h; (j) Ac2O, pyridine, 0 °C to rt, 3 h;
(k) Ac2O, BF3·OEt2, 0 °C to rt, 17 h; (l) BF3·OEt2, CH2Cl2, rt, 20 h.
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preparative chromatographic separation failed probably due to Conclusion
an enhanced reactivity of the partially ‘armed’ ether protected Unsubstituted seleno glycosides are used for structure determi-
halogen glycosides [38] and degradation was observed. There- nation of complexes with protein receptors. The synthesis of
fore, the glycosylation of methyl selenol using the mixture of O-methylated analogs has been not reported to date, despite
donors 9/10 was performed first. After Zemplén deprotection of their importance for many lectins. The first synthetic route
the acetate protecting groups, separation of the unprotected starting from the known methyl selenofucoside 1 failed due to
pyranose/furanose isomers was achieved and seleno pyrano- the rather high stability of the 3,4-benzylidene protecting group
sides 3 (3α/3β = 1:18, Scheme 2) as well as one seleno fura- required for the selective O-methylation in position 2. Because
noside 11 were obtained over three steps in 70% and 23% yield, the instability of the selenium aglycon was the limiting factor,
respectively.
we then first selectively methylated the protected fucose in po-
sition 2 and introduced the selenium moiety subsequently.
By this route, the desired seleno glycoside 3 could be success- Despite the fact that methyl 2-O-methyl-L-selenofucoside was
fully synthesized with a high β/α ratio of 18:1. Previously, the obtained following this synthetic route, the yield was reduced
tectonins were shown to bind the α-anomer of 2-O-methylated due to extensive furanoside formation as a result of the methyla-
fucoside, and natural fucosides are generally α-linked across all tion in position 2. Optimization of the protecting group strategy
kingdoms of life, in glycoproteins, glycolipids, bacterial finally yielded the desired methyl 2-O-methyl L-selenofucoside
lipopolysaccharides, or low-molecular weight glycoconjugates (3) in 26% yield over nine linear steps from allyl L-fucoside.
such as glycosylated natural products. β-Linked fucosides are We have soaked compound 3 into crystals of tectonin which
rarely observed, for example in the bacterial polysaccharide allowed phasing by MAD and solution of the structure at
colanic acid [39,40] or plant natural products [41]. In order to 1.65 Angstroms and these details will be reported in due course.
optimize the synthesis of 3 by avoiding the formation of the
furanose acetate 10 and increasing the α-selectivity, we revised
Supporting Information
our synthetic approach. The problematic formation of furano-
sides has been reported by Kovac et al. for xylose derivatives
Supporting Information File 1
bearing a benzyl ether protecting group in O-2 position [42]. By
varying the reaction conditions during the acetylation step, the
authors were able to reduce the formation of furanoses but com-
plete suppression was not achieved. Therefore, our strategy was
to block the hydroxy group in position 4 and, thus, to prevent
5-membered ring formation by this group. The cis-dihydroxy
groups in position 3 and 4 of compound 2 were acetylated
(→ 12) prior to the deprotection of the anomeric center.
Following this sequence, allyl 3,4-di-O-acetyl-2-O-methyl-α-L-
fucoside (12) was synthesized in 50% yield over four steps from
the unprotected allyl fucoside 7 without the need of time-
consuming purification of the intermediates. Then, cleavage of
the allyl group and subsequent introduction of the anomeric
acetate was catalyzed with BF3·OEt2 in the presence of acetic
anhydride. Under these conditions [43] a simultaneous cleavage
and in situ acetylation resulted in the pyranose mixture 9αβ with
excellent yield (90%, 9α/9β = 4:1) and prevention of unwanted
furanoside side products. The seleno moiety was then intro-
duced as described before and 13αβ (13α/13β = 1:3) was ob-
tained in 78% yield. Further Lewis acid catalyzed anomeriza-
tion improved the ratio towards the α-anomer (13α/13β = 5:1
after 24 h). This α/β-ratio of 5:1 is likely to be the equilibrium
of this reaction since it was determined after 2 h and remained
constant (see Supporting Information File 1). Finally, the
desired methyl 2-O-methyl selenofucoside (3) could be isolated
after Zemplén deprotection in 99% yield and a ratio of
α/β = 5:1.
Chemical synthesis, 1H NMR and 13C NMR traces of
synthesized compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-282-S1.pdf]
Acknowledgements
The authors thank Dr. Josef Zapp (Saarland University) for
recording NMR spectra and Michael Hoffmann (Helmholtz
Institute for Pharmaceutical Research Saarland, HIPS) for
HRMS measurements. We are grateful to the Helmholtz Asso-
ciation (grant no. VH-NG-934) and the Deutsche Forschungs-
gemeinschaft (grant no. Ti756/2-1) for financial support.
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