Defining oxyanion reactivities in base-promoted glycosylations

Article abstract of DOI:10.1039/c1cc11690h

Saccharide oxyanions obtained by base treatment could be employed in glycosylation to give oligosaccharides with high stereo- and regioselectivities.

Full text of DOI:10.1039/c1cc11690h

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COMMUNICATION
Defining oxyanion reactivities in base-promoted glycosylationswz
Martin Matwiejuk and Joachim Thiem*
Received 24th March 2011, Accepted 8th June 2011
DOI: 10.1039/c1cc11690h
Saccharide oxyanions obtained by base treatment could be
employed in glycosylation to give oligosaccharides with high
stereo- and regioselectivities.
It was noted that the base promoted glycosylation
methodology with a donor possessing a C-2 methyl ether
resulted uniformly in the clean formation of the b-galacto-
pyranosides, unambiguously demonstrated by the coupling
constant J1,2 = 7.6 Hz. This outcome allowed a simple
determination of the relative yields by integration of the
anomeric or other well separated proton signals.
Due to the structural diversity of carbohydrates the synthesis
of complex oligosaccharides does not present a routine process
and requires to be solved on a case by case basis. Enormous
efforts have been made for regio- and stereoselective glycosidic
bond formations in the last decades.1–3 However, in order to
improve the efficiency of oligosaccharide synthesis alternative
methods are of particular interest.4,5
This work describes studies on base-promoted glycosylation6,7
by formation of oxyanions using partially protected acceptors.
Deprotonation of acceptor OH groups giving oxyanions
should lead to direct and selective glycosylation on partially
protected or unprotected sugars, respectively, and result in
shorter routes to oligosaccharides essentially decreasing the step
economy of the overall process.
Considering the lack of a neighbouring participating group
at C-2 of donor 9 and the decisive choice of DMF as an
aprotic solvent the b-stereoselectivity should be attributed to a
‘‘SN2-like’’ reaction by inversion of the configuration at the
anomeric center. Bimolecular nucleophilic substitution at C-1
with a-glycopyranosyl halides and aliphatic or aromatic
aglycons was previously reported.10 However, the use of sugar
alcoholates and their direct reaction with a-glycopyranosyl
halides in the absence of a promoter resulting in successful
formation of stereospecific glycosidic linkages was not studied
hitherto and represents an unprecedented approach.
Tables 1 and 2 summarise the absolute and relative yields of
disaccharides obtained after NaH promoted glycosylation of
partially methylated methyl a-D-glucopyranosides 1–8 with
2,3,4,6-tetra-O-methyl-a-D-galactopyranosyl chloride (Gal–Cl, 9).
Intriguing trends were observed considering the distribution
of regioisomers. Analysing the results for acceptors 1–4
(trimethylated derivatives, Table 1, entry 1) activated
(deprotonated) 2-OH groups were found to be most reactive
for glycosylation with permethylated donor 9. The next pre-
ferentially glycosylated position is 4-OH followed by 6-OH
which in turn is slightly more reactive than 3-OH. Thus, the
reactivity arrangement of isolated and activated OH groups is:
2-OH 4 4-OH 4 6-OH 4 3-OH.
A preferred formation of the b-1–2 linkage could be caused
by the singular cis-vicinal position of OH-2 to the anomeric
group which might facilitate the formation of an oxyanion.
Steric effects can be excluded as apparent from the results with
the activated primary 6-OH group. Throughout the b-1–6
linkage is not favoured most likely due to the less reactive
alkoholate. Moreover, the competition between nucleophilicity
and basicity of the alkoholates formed may have influence on
the reactivity scale.
The studies were started with a systematic survey using
initially partially methylated methyl a-D-glucopyranosides
1–8 (Tables 1 and 2)8 as acceptors and 2,3,4,6-tetra-O-
methyl-a-D-galactopyranosyl chloride (Gal–Cl, 9)9 as a donor
model compound with the purpose to study underlying
mechanistic principles of base-promoted glycosylation.
The applied glycosylation method was a base promoted
attachment of acceptor alkoxide(s) to a glycopyranosyl halide.
Therefore the acceptor hydroxyl groups of the selectively
methylated derivatives 5–8 were treated with NaH as base in
DMF at room temperature followed by addition of permethyl-
ated galactopyranosyl chloride 9 (Table 2). Subsequent
acetylation of the remaining free hydroxyl groups and
purification by column chromatography afforded the corres-
ponding disaccharide (mixtures) 14–21 (Table 2).
Trimethylated methyl a-D-glucopyranosides 1–4 were
applied as an equimolar mixture and after reaction with 9
disaccharides 10–13 were obtained in different ratios, hence a
reactivity order could be established (Table 1).
Department of Chemistry, University of Hamburg,
Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
E-mail: thiem@chemie.uni-hamburg.de; Fax: +49 (0) 42838 4325;
Tel: +49 (0) 42838 4241
w This article is part of the ‘‘Glycochemistry and glycobiology’’
web-theme issue for ChemComm.
z Electronic supplementary information (ESI) available: Experimental
details, characterization data and 1H and 13C NMR spectra. See DOI:
10.1039/c1cc11690h
Glycosylations of dimethylated methyl a-D-glucopyrano-
sides 5 and 6 and monomethylated compounds 7 and 8
exhibited other product distributions than of derivatives 1–4
with isolated hydroxyl groups.
Base-promoted glycosylation is assumed to proceed by
partial deprotonation on acceptor diols 5 and 6 and acceptor
c
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Chem. Commun., 2011, 47, 8379–8381 8379

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Table
1
Absolute and relative yields of disaccharides 10–13 obtained after NaH promoted glycosylation of trimethylated methyl
a-D-glucopyranosides 1–4 as equimolar mixture with 2,3,4,6-tetra-O-methyl-a-D-galactopyranosyl chloride (Gal–Cl, 9)a
Relative yieldb [%]
Entry
Acceptors
Products
Yield [%]
20
b-1–2
b-1–3
b-1–4
b-1–6
10 (b-1–2)
11 (b-1–3)
12 (b-1–4)
13 (b-1–6)
1
1, 2, 3, 4
40
11
26
23
a
b
Reaction conditions: NaH (2 eq.), DMF, r.t., 1 h, then donor 15 (2 eq.), r.t., 4 h, then Py, Ac2O, r.t., 18 h. The ratio determined by 1H-NMR.
Table 2 Base-promoted glycosylation of partially methylated methyl a-D-glucopyranosides 4–8 with 2,3,4,6-tetra-O-methyl-a-D-galactopyranosyl
chloride (Gal–Cl 9)a
Relative yieldb [%]
Entry
1
Acceptor
Products
Yield [%]
17
b-1–2
b-1–3
b-1–4
b-1–6
c
14 (b-1–2)
100
—
ꢀ
ꢀ
15 (b-1–4)
16 (b-1–6)
2
3
62
ꢀ
ꢀ
20
80
17 (b-1–4)
18 (b-1–6)
30
40
ꢀ
—
39
10
61
58
19 (b-1–2)
20 (b-1–4)
4
32
ꢀ
21 (b-1–6)
a
b
General reaction conditions: NaH (3–4 eq.), DMF, r.t., 1 h, then donor 9 (3–4 eq.), r.t., 4 h, then Py, Ac2O, r.t., 18 h. The ratio determined by
1H-NMR. Methylated position, no linkage possible.
c
triols 7 and 8 in which the negative charge is delocalised
between hydroxyl groups and oxyanions stabilized by hydrogen
bonding (Table 2).11
oxyanions at 4- and 6-position, Table 1), however, contrary
to expectation, the b-1–6-linked disaccharide 16 was favoured.
The disaccharide distribution obtained after glycosylation of
3,4,6-triol 7 (Table 2, entry 3) showed a high regioselectivity
towards position 6.
Reaction of the 2,3-diol acceptor 5 with Gal–Cl 9 led to a
regiospecific formation of only b-1–2-linked disaccharide 14 in the
presence of two hydroxyl groups. Glycosylation of the 4,6-diol
acceptor 6 with 9 provided disaccharides 15 and 16 in high yields.
Interestingly, analysing the disaccharide distribution of 15
and 16 the b-1–4-linked product 15 was not formed preferentially
as observed for 4-OH free derivative 3 and 6-OH free
derivative 4 (reactivity order of compounds with isolated
Base-promoted glycosylation of 2,4,6-triol 8 with Gal–Cl 9
provided disaccharides 19–21 the distribution of which clearly
showed that activated diol structures were more reactive than
isolated hydroxyl groups (Table 2, entry 4).
In the presence of a 4,6-diol structure glycosylation occurred
preferentially at position 6 as observed before for 4,6-diol 6.
c
8380 Chem. Commun., 2011, 47, 8379–8381
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Table 3 Base-promoted glycosylation of acceptor 22 with donor 23a
Relative yieldb [%]
Entry
Acceptor
Donor
Product
Yield [%]
48
b-1–2
b-1–3
b-1–4
b-1–6
24 (b-1–2)
c
1
13
ꢀ
—
87
25 (b-1–6)
a
b
Reaction conditions: NaH (3 eq.), DMF, r.t., 1 h, then donor 23 (3 eq.), r.t., 20 h. 24 and 25 were separated by column chromatography.
c
Benzylated position, no linkage possible.
The observed high selectivity towards O-2 and O-6 in diol
assembly incorporating a partially protected acceptor into a
preferred disaccharide. Elaboration of the synthetic scope of
the base-promoted glycosylation methodology is the subject of
ongoing investigations employing other methyl a-D-glyco-
pyranosides. Further, other glycopyranosyl halides as donor
substrates with gluco and manno configurations will be used
and the influence of the stereochemistry as well as the base
promoter studied.
and triol acceptors could be interpreted by an interplay of
intramolecular proton shifts and hydrogen bond stabilizations
following partial deprotonation. Accordingly, the negative
charge is most likely located at O-2 and O-6, respectively,
arising from the most acidic hydroxyl groups OH-2 and OH-6,
which finally result in an enhanced reactivity of these positions.
Moreover, the high reactivity of vicinal hydroxyl groups
provided strong support that hydrogen bonding decreases
the basicity of the oxyanions initially formed and elimination
of 9 as the suggested side reaction.
Notes and references
1 (a) X. Zhu and R. R. Schmidt, Angew. Chem., Int. Ed., 2009, 48,
1900–1934; (b) K. Toshima and K. Tatsuta, Chem. Rev., 1993, 93,
1503–1531; (c) R. R. Schmidt, Angew. Chem., Int. Ed. Engl., 1986,
25, 212–235; (d) The Organic Chemistry of Sugars, ed. D. E. Levy
After successful elaboration of the model system the final
focus was on the application of the base-promoted glycosylation
methodology for partially protected acceptor units as an
alternative access to expeditious oligosaccharide synthesis.
Therefore, the methyl protecting groups were systematically
replaced by benzyl groups, which may be removed under mild
conditions by hydrogenolysis. The utility was highlighted by
formation of disaccharides 24 and 25 using 2,3,4-tri-O-benzyl-
a-D-fucopyranosyl chloride 2312 as donor and glucose acceptor
2213 with three unblocked hydroxyl groups (Table 3). Initial
treatment of 22 with NaH followed by addition of 23 afforded
compounds 24 and 25 of which 25 was formed with high
regioselectivity. It should be noted that in this case the
formation of five other glycosylation products was expected.
However, detectable amounts of further regioisomers or
higher glycosylated branched products were not found. Thus,
fucosylation of compound 22 clearly demonstrated the feasibility
of a regio- and stereoselective glycosylation using the base-
promoted glycosylation methodology.
and P. Fugedi, Taylor
&
Francis, Boca Raton, 2006;
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(e) Preparative Carbohydrate Chemistry, ed. S. Hanessian, Marcel
Dekker Inc., New York, 1997.
2 R. R. Schmidt and J. Michel, Angew. Chem., 1980, 92, 763–764
(Angew. Chem., Int. Ed. Engl., 1980, 19, 731).
3 H. Paulsen, Angew. Chem., 2006, 94, 184–201 (Angew. Chem., Int.
Ed. Engl., 1982, 21, 155).
4 O. J. Plante, E. R. Palmacci and P. H. Seeberger, Science, 2001,
291, 1523–1527; P. Stallforth, B. Lepenies, A. Adibekian and
P. H. Seeberger, J. Med. Chem., 2009, 52, 5561–5577.
5 (a) P. J. Garegg, J.-L. Malosiel and S. Oscarson, Synthesis, 1995,
409–414; (b) E. Kaji and N. Harita, Tetrahedron Lett., 2000, 41,
53–56; (c) N. Moitessier and Y. Chapleur, Tetrahedron Lett., 2003,
44, 1731–1735.
6 (a) A. Steinmann, J. Thimm, N. Wollik and J. Thiem, Curr. Org.
Chem., 2008, 12, 1010–1020; (b) A. Steinmann, J. Thimm and
J. Thiem, Eur. J. Org. Chem., 2007, 5506–5513.
7 A. Steinmann, J. Thimm, M. Matwiejuk and J. Thiem, Macro-
molecules, 2010, 43, 3606–3612.
8 Partially methylated methyl a-D-glucopyranosides 1–8 were
synthesized applying standard orthogonal protecting group
chemistry––see ESIz and (a) L. E. Franzen and S. Svensson,
Carbohydr. Res., 1979, 73, 309–312; (b) E. J. Bourne and S. Peat,
Adv. Carbohydr. Chem., 1950, 5, 145–186; (c) T. W. Greene and
P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edn,
Wiley, New York, 1999.
9 T. Iversen and D. R. Bundle, Carbohydr. Res., 1982, 103, 29–40.
10 (a) A. J. Rhind-Tutt and C. A. Vernon, J. Chem. Soc., 1960,
4637–4644; (b) K. Krohn and J. Thiem, J. Chem. Soc., Perkin
Trans. 1, 1977, 1186–1190; (c) R. M. Hann, J. Am. Chem. Soc.,
1934, 56, 1631.
In this contribution studies on base-promoted glycosylation
by formation of oxyanions were performed in detail using
model donor and acceptor systems. Initial experiments showed
that deprotonation led to more distinct reactivity differences of
the competing hydroxyl groups/oxyanions and achievements
of high regioselectivities. Hydrogen-bond networks based
on partial deprotonation of vicinal hydroxyl groups affect
the relative oxyanion reactivities. Remarkably, the applied
glycosylation methodology gave exclusively b-glycosides in
the absence of participating groups at C-2.
11 For mechanistic consideration of base-promoted glycosylation,
see ESIz.
12 J. R. Pougny, J. C. Jacquinet, M. Nassr, D. Duchet, M. L. Milat
and P. Sinay, J. Am. Chem. Soc., 1977, 99, 6762–6763.
This approach may improve glycosylation chemistry and
omit protecting group schemes as demonstrated by a rapid
13 J. M. Kuster and I. Dyong, Liebigs Ann. Chem., 1975, 2179–2189.
¨
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8379–8381 8381