Lewis acid-catalyzed stereoselective lactonization and subsequent glycosidation of 2-C-malonyl carbohydrates

Article abstract of DOI:10.1039/c1cc13425f

Gold(iii) bromide is a suitable catalyst for the stereoselective cyclization of 2-C-malonyl carbohydrates to the anomeric center under retention of one ester group. Reopening of the lactones with alcohols in the presence of TMSOTf affords allyl, propargyl

Full text of DOI:10.1039/c1cc13425f

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COMMUNICATION
Lewis acid-catalyzed stereoselective lactonization and subsequent
glycosidation of 2-C-malonyl carbohydrateswz
Tukaram M. Pimpalpalle,a Srinivasa Rao Vidadala,b Srinivas Hotha*b and Torsten Linker*a
Received 9th June 2011, Accepted 18th July 2011
DOI: 10.1039/c1cc13425f
Gold(III) bromide is a suitable catalyst for the stereoselective
cyclization of 2-C-malonyl carbohydrates to the anomeric center
under retention of one ester group. Reopening of the lactones
with alcohols in the presence of TMSOTf affords allyl,
propargyl and benzyl glycosides with high a-selectivity.
During our studies on gold-catalyzed glycosidations,7
we investigated 2-C-nitromethyl carbohydrates as substrates
very recently.8 However, reactions of the corresponding
2-C-malonyl derivative gluco-2 with various alcohols in the
presence of gold(III) bromide afforded low yields of trans-
glycosylated products besides some lactone gluco-1c. To
further optimize this reaction and to establish a general entry
to carbohydrate 1,2-lactones, we investigated the gold-catalysis
in the less-nucleophilic solvent acetonitrile (Table 1). Without
any additive we found no conversion of the starting material
gluco-2 (entry 1). However, the simple addition of two
equivalents of water afforded the lactone gluco-1c in 75%
yield in analytically pure form (entry 2) (ESIw).9 The galacto-
Lactones 1z represent interesting analogs of naturally occur-
ring carbohydrates, due to their 2-C-functionalization and
fixed conformation (Scheme 1). We synthesized unsubstituted
derivatives 1a (R = H) from malonates 2, which are easily
available by radical addition of dimethyl malonate to glycals,1
in few steps.2 Very recently, Mukherjee et al. published a direct
entry to lactone 1a by reaction of glycals with acetic acid in the
presence of manganese(III) acetate.3 Substituted lactones 1b
are available in high stereoselectivities by alkylation of lactone
1a,4 cyclopropane opening5 or through a four-component
reaction.6 However, lactones 1c (R = CO2Me) were hitherto
unknown, since all attempts to cyclize malonates 2 in the
presence of stronger Brønsted or Lewis acids failed, due to
decarboxylations. Herein we describe the convenient synthesis
of such carbohydrate 1,2-lactones 1c in one step from
malonates 2 in the presence of gold(III) bromide and their
subsequent reaction with alcohols.
configured 2-C-malonyl carbohydrate
2
reacted under
Table 1 Synthesis of carbohydrate 1,2-lactones 1ca
Entry
1
Config.b
Additive
None
Product
—
Yieldc (%)
0
gluco
2
gluco
H2O
75
58
Scheme 1 Lactones 1 and possible synthesis from malonates 2.
3
4
galacto
H2O
H2O
a Department of Chemistry, University of Potsdam,
Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany.
E-mail: linker@uni-potsdam.de; Fax: +49 331 9775076;
Tel: +49 331 9775212
xylo
67
68
b Department of Chemistry, Indian Institute of Science Education &
Research, Pune 411021, India. E-mail: s.hotha@iiserpune.ac.in;
Fax: +91 20 25899790; Tel: +91 20 25908015
5
arabino
H2O
w Electronic supplementary information (ESI) available: Experimental
procedures and analytical data for all compounds. Determination of
the configuration of the lactones by NOE measurements. See DOI:
10.1039/c1cc13425f
a
b
For procedure see ESI.w Configuration of starting material 2.
Yield of analytically pure products, isolated by column chromatography.
c
z This article is part of the ChemComm ‘Glycochemistry and glyco-
biology’ web themed issue.
c
10434 Chem. Commun., 2011, 47, 10434–10436
This journal is The Royal Society of Chemistry 2011

and corresponds nicely to literature-known cyclopropane
openings.5
To demonstrate the potential of lactones 1c as glycosyl
donors, we investigated the opening of the lactone ring with
nucleophiles next. In our previous studies we had found that
scandium(III) triflate is a suitable Lewis acid to catalyze
reactions of unsubstituted derivatives 1a.4 However, this Lewis
acid was too reactive and gave decomposition products.
Therefore, we employed trimethylsilyl triflate (TMSOTf) as
an activator for the opening of lactone gluco-1c. Now the
reaction proceeded smoothly with various alcohols 5, and the
glycosides 6 were isolated in good yields (Table 2, ESIw).10
Only the hexinol 5e required longer reaction time and gave
somewhat lower yield (entry 5).
Scheme 2 Proposed intermediate 3 in the formation of lactones 1c.
the same conditions in somewhat lower yield (entry 3).
Furthermore, pentoses xylo-2 and arabino-2 are suitable sub-
strates for the lactonization as well (entries 4 and 5). Thus,
gold(III) bromide is a mild catalyst for the convenient synthesis
of the hitherto unknown carbohydrate 1,2-lactones 1c from
easily available malonates 2 in only one step.
Interestingly, the methyl ester group remains intact in the
products 6, whereas the former lactone is converted into a new
ester group. Furthermore, the stereocenter at the 7-position is
conserved during the lactone opening, giving access to unsym-
metric 2-C-malonyl carbohydrates 6 in diastereomerically pure
form. This can be rationalized by a selective attack of trimethyl-
silyl triflate at the lactone carbonyl group and subsequent
esterification with alcohols 5. The carbenium ion at the
1-position is trapped by the alcohols in the same step. The
anomeric mixture for methyl glycoside 6a (entry 1) and the very
high a-selectivity for all other products 6b–e (entries 2–5) are in
accordance to our openings of lactone gluco-1a4b and can be
explained by an anomerization during the Lewis acid catalyzed
reaction.8 Thus, all stereocenters of starting material gluco-1c
are conserved during lactone opening and the products 6 might
be suitable precursors for further transformations.
From the mechanistic point of view, the addition of water is
essential for the lactonizations (Table 1, entries 1 and 2).
Therefore, we propose the formation of hemi acetals 3 as
intermediates by cleavage of the methyl glycoside in the first
step (Scheme 2). Subsequent cyclization affords lactones 1c,
and thus both steps are catalyzed by gold(III) bromide. To
further prove this hypothesis, we synthesized hemi acetals 3
independently by radical addition of dimethyl malonate to glucal
4 in the presence of cerium ammonium nitrate (CAN) and water
(Scheme 2). Indeed, reaction of intermediate 3 with gold(III)
bromide or zinc(II) chloride afforded the same lactone 1c. The
influence of water became obvious in a one-pot synthesis of
glycoside 6b from malonate gluco-2 (see below and ESIw).
Interestingly, products 1c are formed as single stereo-
isomers. Obviously, the annelated ring to the g-lactone is
always 1,2-cis-configured, which is predetermined by the pre-
set stereocenter of the starting materials 2. Thus, the lactone
ring is located above the sugar plane for arabino-1c (entry 5),
but below the plane for all other products (entries 2–4). On the
other hand, the ester group might occupy the exo or endo-
position at the lactone ring, but a sole product is formed. We
determined the configurations of these new stereocenters by
detailed 500 MHz NOE measurements (ESIw). Thus, cross-
peaks between 1-H and 2-H prove the cis-orientation of all
g-lactones 1c. More importantly, an NOE effect between 3-H
and the proton at the lactone ring indicates the exo-orientation
of the ester group (Fig. 1).
In conclusion, we have synthesized bicyclic carbohydrate
1,2-lactones with an ester substituent for the first time.
Table 2 Reaction of lactone gluco-1c with alcohols 5a
Entry Alcohol 5
Product 6 Time/h Yieldb (%)
HO–Me
5a
1
6a
6b
4
2
90c
The preferred formation of the exo-isomer 1c for all lacto-
nizations can be explained by steric interactions of the ester
group with the sugar ring, which is minimized in the exo-
configuration. This stereochemistry is in complete accordance
to our previous studies on the alkylation of lactones 1a4
2
78
3
6c
6d
2
2
81
72
HO–Bn
5d
4
5
6e
12
61
a
b
For procedure see ESI.w Yield of analytically pure products,
c
isolated by column chromatography. 0.8 : 1.0 mixture of a- and
b-anomer.
Fig. 1 NOE effect in lactones 1c.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10434–10436 10435

The cyclization of 2-C-malonyl carbohydrates proceeds under
gold-catalysis under mild conditions and affords only one
stereoisomer. Subsequent glycosidations with alcohols were
realized in the presence of trimethylsilyl triflate with high
stereoselectivities. Thus, the two Lewis acids complement each
other in reactivity and can be employed for selective lactoniza-
tions or glycosidations respectively. Overall, the newly synthe-
sized bicyclic carbohydrate 1,2-lactones might be attractive
chiral building blocks in carbohydrate chemistry. Their open-
ing at the anomeric center with carbon nucleophiles would
give access to carbohydrate 1,2-bis-C-analogs. Additionally,
the two different ester groups in products 6 can be transformed
chemoselectively (e.g. cleavage of the benzyl ester in the
presence of the methyl ester) under conversion of the stereo-
genic center. In addition, hydrolysis followed by Curtius
rearrangement would give access to C-2 amino acid appended
glycosides. The unsaturated glycosides 6b and 6c are interest-
ing precursors for ring closing metathesis. Studies for such
further chemical transformations are currently in progress.
TL and TMP acknowledge generous support by the
University of Potsdam. SRV acknowledges the fellowship
from CSIR, New Delhi. SH thanks DST, New Delhi for a
SwarnaJayanti Fellowship.
Chem.–Eur. J., 2007, 13, 10152. Review: E. Elamparuthi,
B. G. Kim, J. Yin, M. Maurer and T. Linker, Tetrahedron, 2008,
64, 11925.
2 J. Yin and T. Linker, Chem.–Eur. J., 2009, 15, 49.
3 S. K. Yousuf, D. Mukherjee, L. Mallikharjunrao and S. C. Taneja,
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8 S. R. Vidadala, T. K. Pimpalpalle, T. Linker and S. Hotha, Eur. J.
Org. Chem., 2011, 2426 An alternative explanation for the high
a-selectivities might be the intermediary formation of a labile
b-triflate and subsequent SN2 reaction with the alcohols. We thank
a reviewer for this suggestion.
9 General procedure for AuBr3-catalyzed lactonizations: to a solution
of methyl glycoside 2 (112 mg, 0.2 mmol) in acetonitrile (3 mL) was
added water (0.4 mmol) and 8 mol% of AuBr3 at room tempera-
ture. The resulting mixture was heated to 70 1C and stirred until
TLC showed complete conversion. The reaction mixture was
concentrated in vacuo to obtain a crude residue which was purified
by silica gel column chromatography (ethyl acetate–petroleum
ether) to give lactones 1c in analytically pure form.
10 General procedure for lactone openings: to a solution of lactone
gluco-1c (106 mg, 0.2 mmol) in acetonitrile (3 mL) was added
nucleophile 5a (0.6 mmol) and TMSOTf (45 mg, 0.2 mmol) at
room temperature. The mixture was stirred at this temperature
until TLC showed complete conversion. After dilution with water
(5 mL), the mixture was extracted with ethyl acetate (3 ꢀ 10 mL).
The combined organic layers were washed with brine (10 mL)
and dried over anhydrous sodium sulfate. After removal of the
solvent in vacuo, the residue was purified by silica gel column
chromatography (ethyl acetate–petroleum ether) to afford the
products 6.
Notes and references
z The name ‘‘carbohydrate 1,2-lactone’’ is used in this communication
for simplicity, although ‘‘2-oxo-hexahydro-furo[2,3-b]pyran’’ would
be the correct IUPAC nomenclature.
1 (a) T. Linker, T. Sommermann and F. Kahlenberg, J. Am. Chem.
Soc., 1997, 119, 9377; (b) J. Yin, T. Sommermann and T. Linker,
c
10436 Chem. Commun., 2011, 47, 10434–10436
This journal is The Royal Society of Chemistry 2011