These were synthesized as described in the Supporting
(JH1,H2 ) 0-1.7 Hz), characteristic of R-arabinofuranosides,
and two as doublets (JH1,H2 ) 4.6 Hz), indicative of the
â-arabinofuranosyl linkages.15,16 An HMQC experiment
Information (4, 5) or as reported previously (7).5a,11
As illustrated in Scheme 1, access to these building blocks
enabled the synthesis of tetrasaccharide 8 in 74% yield by
the reaction of 7 with an excess of thioglycoside 4 using
N-iodosuccinimide/silver triflate activation at 0 °C. In the
subsequent step, the chloroacetate protecting groups were
removed (91% yield) by the treatment of 8 with hydrazine
acetate. With 9 in hand, the stage was set for the introduction
of the â-D-arabinofuranosyl residues.
1
correlated the H resonances with JH1,H2 ) 4.6 Hz with the
13C resonances at 101.16 and 101.05 ppm.
We are currently exploring the scope of this reaction to
determine if other alcohols are glycosylated by 5 with a
similarly high degree of stereocontrol. If so, this should
become an extremely attractive method for the synthesis of
other oligosaccharide fragments of mycobacterial arabinan.
Particularly advantageous is that, rather than resorting to
more elaborate methods for the assembly of these linkages
(e.g., intermolecular aglycon delivery),6a-c,8b,9b excellent
stereocontrol appears to be achieved using a readily acces-
sible donor simply by carrying out the glycosylation at low
temperature.
In summary, we report here the first chemical synthesis
of the hexasaccharide (as its methyl glycoside, 3) found at
the nonreducing termini of mycobacterial LAM and AG. The
key step in the synthesis is the stereoselective formation of
the two â-D-arabinofuranosyl linkages simultaneously. To
the best of our knowledge, there are no previous reports of
the stereoselective formation of two 1,2-cis-â-glycosyl
linkages in a single glycosylation reaction. At this time, we
are unsure of the origin of the remarkable stereoselectivity
observed in the reaction of 9 with 5, but it may result via
the same ion-pair SN1 pathway proposed7b for glycosylation
of methanol with 6. Routine access to compounds of this
type will enable a more detailed investigation of the role
that this motif plays in the immunological response arising
from mycobacterial infections.
In previous work, we8a and others7 have demonstrated that
the unstable tri-O-benzylated arabinofuranosyl chloride 6 can
be used for the stereoselective synthesis of â-D-arabinofura-
nosides of simple alcohols in modest (40-60%) yields. In
the case of methanol, this reaction has been shown7b to
proceed through an SN1 ion pair mechanism, resulting in net
inversion of the anomeric stereochemistry. Unfortunately,
in our hands, all attempts to glycosylate either primary or
secondary carbohydrate alcohols with 6 failed to give any
glycosylation product. We haVe now found that reaction of
diol 9 with thioglycoside 512 at -78 °C, in the presence of
N-iodosuccinimide and silVer triflate, affords hexasaccharide
10 in excellent (81%) yield and with extremely high stereo-
control. Under these conditions, no R-glycoside products
were isolated.13 The temperature at which the glycosylation
was conducted was critical. When the reaction was carried
out at either -40 or 0 °C, significant amounts of side
products were formed, which were chromatographically
indistinguishable from the desired product.14 Deprotection
of 10 was achieved by treatment with catalytic sodium
methoxide followed by hydrogenolysis affording hexasac-
charide 3 in 86% yield over the two steps.
Acknowledgment. We thank Christopher S. Callam and
Joseph D. Ayers for technical assistance. This work was
supported by the National Institutes of Health (AI44045-
01), the National Science Foundation (CHE-9875163), and
the Petroleum Research Fund (32026-G1), administered by
the American Chemical Society.
The anomeric stereochemistry of the glycosyl residues in
1
3 was determined unequivocally by both H and 13C NMR
spectroscopy. The 13C NMR spectrum showed six anomeric
carbons at 108.83, 107.86, 106.07, 105.90, 101.16, and
1
101.05 ppm.15 Similarly, in the H NMR spectrum, four of
the six anomeric hydrogens appeared as singlets or doublets
Supporting Information Available: Experimental pro-
cedures and analytical data for compounds 3-5, 8-10, and
the precursors leading to 4 and 5. This material is available
(10) The synthesis of a related, partially protected pentasaccharide has
recently been reported: Mereyala, H. B.; Hotha, S.; Gurjar, M. K. J. Chem.
Soc., Chem. Commun. 1997, 685.
(11) D’Souza, F. W.; Ayers, J. D.; McCarren, P. R.; Lowary, T. L. J.
Am. Chem. Soc. 2000, 122, 1251.
OL005907G
(12) Ratio R: â ) 8:2.
(13) All other products detected by TLC were isolated and screened by
1H NMR for the presence of the hexasaccharide containing only R-ara-
binofuranosyl linkages. It was not detected.
(15) Anomeric carbons in R-arabinofuranosides resonate between 105
and 110 ppm, and those of â-arabinofuranosides resonate between 100 and
104 ppm: Mizutani, K.; Kasai, R.; Nakamura, M.; Tanaka, O.; Matsuura,
H. Carbohydr. Res. 1989, 185, 27.
(16) Unlike pyranosides, JC1,H1 values cannot be used reliably in
determinations of anomeric stereochemistry in furanosides; see ref 15.
(14) These impurities may be R-glycoside products; however, given the
identical chromatographic properties of 10 and these byproducts, we were
unable to determine their structures.
1
Org. Lett., Vol. 2, No. 10, 2000
1495