Gold-catalyzed reactions of 2-c-branched carbohydrates: Mild glycosidations and selective anomerizations

Article abstract of DOI:10.1002/ejoc.201100134

2-C-branched methyl glycosides react with various alcohols under gold catalysis to transglycosylated products. The method is applicable for the convenient synthesis of disaccharides. Without nucleophile a selective anomerization occurs, giving first acces

Full text of DOI:10.1002/ejoc.201100134

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100134
Gold-Catalyzed Reactions of 2-C-Branched Carbohydrates: Mild
Glycosidations and Selective Anomerizations
Srinivasa Rao Vidadala,[a] Tukaram M. Pimpalpalle,[b] Torsten Linker,*[b] and
Srinivas Hotha*[c]
Keywords: Anomerization / Carbohydrates / Glycosidation / Gold / Synthetic methods
2-C-branched methyl glycosides react with various alcohols
under gold catalysis to transglycosylated products. The
method is applicable for the convenient synthesis of disac-
charides. Without nucleophile a selective anomerization oc-
curs, giving first access to α-configured 2-C-nitromethyl gly-
cosides. The results are interesting for the mechanism of
gold-catalyzed glycosidations.
Introduction
Glycosamine-containing glycopeptides and glycolipids
play pivotal roles in a variety of cellular processes such as
cell–cell adhesion, cell growth, fertilization and infection.[1]
Glycosamine-lacking glycopeptides are found to be ineffec-
tive as anti-freeze agents or other biological applications
thereby emphasizing the overall significance of glycos-
amines.[2] Artificial and unnatural N-functionalized glucos-
amines were studied as substrates for the inhibition of N-
acetylglucosaminyl transferases.[3] Additionally, glycosam-
ine homologs (e.g. 3) are interesting, because they modulate
the cellular molecular recognition events.[4] During our
studies on transition-metal-mediated radical reactions in
carbohydrate chemistry,[5] we developed a convenient entry
to glycosamine homologs 3 (Scheme 1).[6]
Radical addition of nitromethane to protected glycals 1
proceeds smoothly in the presence of cerium ammonium
nitrate (CAN) via glycosyl carbenium ions A. Cyclization
with the adjacent nitro group to the intermediate B stabi-
lizes reversibly the whole system. This explains the highly
stereoselective attack of methanol from the opposite face to
afford exclusively 1,2-trans-configured 2-C-branched chain
carbohydrates 2. Finally, glycosamine homologs 3 are ob-
Scheme 1. Syntheses of 2-C-branched chain carbohydrates 2 and 3.
tained by catalytic hydrogenation and acetylation in good
yields in analytically pure form (Scheme 1). Although our
method is applicable to unsaturated hexoses, pentoses and
disaccharides, the predetermined configuration at the an-
omeric center is disadvantageous. Thus, due to the selective
opening of intermediate B, methyl α-glucosides are not
available, which would represent interesting structures com-
mon in nature. Furthermore, the formation of more com-
plex glycosidic bonds, especially attractive disaccharides,
during the radical addition of nitromethane is not possible,
since methanol is the superior solvent for such reactions.
Thus, activation of the anomeric position of the methyl gly-
cosides was the only way to afford either lactol or transgly-
cosylated products. However, conventional procedures like
heating in acidic medium failed, due to the lability of the
branched chain carbohydrates. Herein, we describe a mild
and convenient method for the transglycosidation, which
gives access to disaccharides and to α-configured glycosides
by a simple anomerization.
[a] Division of Organic Chemistry, Combi Chem. – Bio Resource
Center National Chemical Laboratory,
Pune 411008, India
Fax: +92-20-2590-2624
E-mail: sr.vidadala@ncl.res.in
[b] Department of Chemistry, University of Potsdam,
Karl-Liebknecht-Strasse 24–25, 14476 Potsdam, Germany
Fax: +49-331-977-5076
E-mail: linker@uni-potsdam.de
[c] Department of Chemistry, Indian Institute of Science
Education & Research,
Results and Discussion
Pune 411021, India
Fax: +92-20-2589-9790
During the course of our studies on gold-catalyzed gly-
cosidations, we employed propargyl glycosides as stable gly-
cosyl donors.[7] More recently, a serendipitous observation
E-mail: s.hotha@iiserpune.ac.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100134.
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Gold-Catalyzed Reactions of 2-C-Branched Carbohydrates
from our laboratory indicated that methyl glycosides react to follow an interesting mechanism, giving evidence in fav-
under similar conditions as well.[8] This is very attractive our of an endocyclic C–O bond cleavage, which was ob-
for the nitromethyl carbohydrates 2, which might directly served to be completely diminished with 3 equiv. of the ag-
serve as precursors for transglycosidations. We started our lycon, and the overall yield increased to 80% (Table 1, En-
initial studies with the gluco isomer 2a, which is easily avail- try 1). Thus, gold(III) bromide is an ideal catalyst for the
able and has the most common configuration in nature. In- transglycosidation of 2-C-nitromethyl carbohydrates.
deed, reaction with 1 equiv. of 4-penten-1-ol (4a) proceeded
To further extend this method and to prove its generality
smoothly in the presence of 10 mol-% of AuBr3 in acetoni- we investigated other nucleophiles 4 (Table 1). Thus, benzyl
trile at 70 °C, and an α/β (4:1) mixture of transglycosylated glucoside 5b was synthesized from another primary alcohol
n-pentenyl glucoside 5a was isolated in 65% yield after 2 h. (BnOH, 4b) in good yield as an anomeric mixture (Entry 2).
Surprisingly, methyl 3,4,6-tri-O-benzyl-2-deoxy-2-C-ni- Surprisingly, sterically demanding secondary alcohols such
tromethyl α-d-glucopyranoside (6a) was obtained as by- as menthol (4c) and cholesterol (4d) afforded the corre-
product in 20% yield. This anomerization was hypothesized sponding glycosides 5c and 5d as sole α-anomers after pro-
Table 1. Gold-catalyzed reaction of nitromethyl carbohydrate 2a with various alcohols ROH (4).
[a] Reaction of nitromethyl carbohydrate 2a (0.2 mmol) and alcohol ROH (3 equiv.) in the presence of 10 mol-% AuBr3 in CH3CN. [b]
Determined by NMR spectroscopy of the crude products. [c] Yield of analytically pure product, isolated by column chromatography.
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S. R. Vidadala, T. M. Pimpalpalle, T. Linker, S. Hotha
SHORT COMMUNICATION
longed reaction times (Entries 3 and 4). The moderate yield general applicability of 2-C-branched methyl glycosides as
of cholesteryl α-glucopyranoside 5d is due to the bad solu- glycosyl donors in the presence of AuBr3.
bility of cholesterol (4d) in acetonitrile. Finally, syntheti-
The selective formation of α-anomers is interesting from
cally interesting disaccharides 5e–g are available according the mechanistic point of view. During our studies on radical
to the same procedure from sugar aglycones (4e–g). Again, additions of nitromethane to glycals,[6] we established a sta-
only α-anomers were isolated in moderate yields (Entries 5– bilization of anomeric cations by the adjacent nitro group
7). Thus, we developed a general strategy for the introduc- (Scheme 1). Thus, nucleophiles can only attack from the op-
tion of the nitromethyl group in the non-reducing sugar posite face, resulting in β-glucosides with high selectivity.
moiety of disaccharides, whereas in our previous studies The difference in our herein described gold-catalyzed reac-
only the terminal or reducing sugar could be C-function- tions might be a complexation of the nitro group by the
alized.[6]
transition-metal atom, inhibiting its propensity for neigh-
Our successful method of gold-catalyzed transglycosida- boring-group participation. On the other hand, we see a
tions under mild conditions could be applied for other 2- remarkable time dependence on the α/β ratio when the
deoxy-C-nitromethyl pyranosides 2 (Table 2). Thus, the ga- transglycosylation was conducted between 2a and 4a to give
lacto isomer 2b afforded various 2-C-branched carbo- 5a (Tables 1 and 2),[9] which speaks for a gold-catalyzed an-
hydrates 5h–k in moderate to good yields. Again, longer omerization with formation of the thermodynamically more
reaction times were necessary, resulting in the selective for- stable α-glycoside after longer reaction times.[10] In the first
mation of α-anomers. Even pentose derivative 2c reacted step, the Lewis-acidic AuBr3 might activate the anomeric
smoothly to the disaccharides 5l and 5m, demonstrating the center by coordination to the adjacent exocyclic oxygen
Table 2. Synthesis of various 2-C-nitromethyl branched glycosides 5h–m.
[a] Reaction of glycosyl donor (0.2 mmol) with 3 equiv. of ROH. [b] Yield of analytically pure product, isolated by column chromatog-
raphy.
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Gold-Catalyzed Reactions of 2-C-Branched Carbohydrates
Scheme 2. Proposed mechanism of glycoside activation with AuBr3.
atom (intermediate C), as postulated very recently for AuI- Murphy for other Lewis acids and ester groups very re-
catalyzed glycosidations.[7h] However, our studies reveal cently.[12] Finally, α-configured products are isolated with
that the ring oxygen atom (intermediate D) might be at- high selectivities after longer reaction times.
tacked as well. The issue of exo- or endocyclic oxygen acti-
To demonstrate the generality of this anomerization, we
vation during anomerization has been discussed for many investigated various carbohydrates under gold catalysis
years[11] and was kinetically examined very recently.[12] Both without addition of a nucleophile (Table 3). Thus, 2-deoxy-
pathways afford different oxocarbenium ions E and F, lead- C-nitromethyl pyranosides β-2a–c reacted smoothly with
ing to transglycosylated products 5 or α/β-anomerization 10 mol-% of AuBr3 in acetonitrile at 70 °C. Complete con-
(Scheme 2).
version was achieved within 1–2 h, and the α-methyl glycos-
This mechanistic rationale is in accordance to our ob- ides α-6a–c were isolated in good to high yields (Entries 1–
served α/β selectivities (Tables 1 and 2). Thus, intermediate 3). Interestingly, this anomerization proceeds faster than the
C is only formed if R is small (e.g. Me), which explains why transglycosidations, which explains why compound α-6a
only methyl glycosides serve as donors in gold-catalyzed re- was formed as by-product in our initial experiments
actions. For other simple primary alcohols 4a and 4b the (Table 1).
transglycosidation is still possible to some extent, and α/β
Furthermore, simple methyl per-O-benzyl-β-glycosides
mixtures result (Table 1, Entries 1 and 2). On the other 7a and 7b reacted selectively to the corresponding α-ano-
hand, secondary alcohols and disaccharides are sterically mers 8a and 8b (Table 3, Entries 3 and 4). This important
too demanding, and only intermediate D can be formed. finding demonstrates that the complexation of AuIII by the
Therefore, the exocyclic C–O bond cannot be cleaved any- nitro group is not a prerequisite for the anomerizations. Fi-
more, but the anomerization takes place. Additionally, a co- nally, propargyl glucoside β-7c and even disaccharide β-9
ordination of Au to the nitro group has to be taken into can be converted into their α-anomers 8c and 10 in slightly
account, resulting in a faster anomerization as discussed by lower yields (Entries 5 and 6). Although anomerizations in
Table 3. Gold-catalyzed anomerizations of various β-glycosides.
[a] Yield of analytically pure product, isolated by column chromatography.
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S. R. Vidadala, T. M. Pimpalpalle, T. Linker, S. Hotha
SHORT COMMUNICATION
supports by the Deutsche Forschungsgemeinschaft (Li 556/7-3) and
the University of Potsdam. S. R. V. acknowledges a fellowship from
the Council of Scientific & Industrial Research, New Delhi.
the presence of SnCl4 or other Lewis acids are known for
many years,[11] our gold-catalyzed reactions proceed under
mild conditions and give very high α-selectivities.
Conclusions
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Gold-catalyzed transglycosidations can be applied for 2-
C-branched carbohydrates. Methyl glycosides are suitable
donors, which react with various alcohols at the anomeric
center. Thus, 2-C-nitromethyl-containing glycosides are
available for the first time. The reactions proceed with mod-
erate to good yields and with high selectivity for the α-ano-
mers. Our method is applicable for simple benzyl glycosides,
the introduction of menthyl or steroidal substituents, and
even the synthesis of disaccharides. All products contain
nitro groups, which might be reduced and offer an easy en-
try to analogs of glycosamines. During the gold catalysis
we observed an interesting anomerization, which was hy-
pothesized to undergo the cleavage of the endocyclic C–O
bond, and the reaction was applied to various other carbo-
hydrates. Thus, gold(III) bromide is an efficient catalyst for
transglycosidations of 2-C-branched carbohydrates and can
be employed for β- to α-anomerizations as well. Studies for
further chemical transformations, especially into analogs of
glycosamines are currently in progress.
[2]
[3]
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Experimental Section
General Procedure for AuBr3-Mediated Transglycosylations: To a
solution of glycosyl donor (0.2 mmol) and aglycon (0.6 mmol) in
anhydrous acetonitrile (5 mL) was added AuBr3 (10 mol-%) under
argon at room temperature. The resulting mixture was heated to
70 °C and stirred until TLC showed complete conversion. The reac-
tion mixture was concentrated in vacuo to obtain a crude residue,
which was purified by silica gel column chromatography using ethyl
acetate/petroleum ether as mobile phase.
Supporting Information (see footnote on the first page of this arti-
cle): Spectral charts of all compounds.
[11] a) B. Lindberg, Acta Chem. Scand. 1949, 3, 1153–1169; b)
R. U. Lemieux, W. P. Shyluk, Can. J. Chem. 1955, 33, 120–127.
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Received: January 28, 2011
Acknowledgments
S. H. thanks the Department of Science & Technology, New Delhi
for a SwarnaJayanti Fellowship. T. L. acknowledges the generous
Published Online: March 4, 2011
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