Oligomeric thioglycosides with α-D-manno-(1′→2) linkages from a glycal-1,2-episulfide

Article abstract of DOI:10.1021/ol990702x

(Matrix presented) Under basic conditions, phenyl 1,2-dithio-α-D-mannopyranoside forms a glycal-1,2-episulfide, which undergoes controlled oligomerization to afford a family of thio-oligo-α-D-mannopyranosides in a single reaction. The episulfide can also be intercepted by added thiolates, which leads to other sorts of thioglycosides. These α-(1→2)-linked thio-mannopyranosides might have application as mimics of natural structures such as viral high-mannose glycoproteins or ManLAM.

Full text of DOI:10.1021/ol990702x

ORGANIC
LETTERS
1999
Vol. 1, No. 4
611-613
Oligomeric Thioglycosides with
r-D-manno-(1′f2) Linkages from a
Glycal-1,2-episulfide
Spencer Knapp* and Krishnan Malolanarasimhan
Department of Chemistry, Rutgers-The State UniVersity of New Jersey,
New Brunswick, New Jersey 08854-8087
knapp@rutchem.rutgers.edu
Received June 2, 1999
ABSTRACT
Under basic conditions, phenyl 1,2-dithio-r-D-mannopyranoside forms a glycal-1,2-episulfide, which undergoes controlled oligomerization to
afford a family of thio-oligo-r-D-mannopyranosides in a single reaction. The episulfide can also be intercepted by added thiolates, which leads
to other sorts of thioglycosides. These r-(1f2)-linked thio-mannopyranosides might have application as mimics of natural structures such
as viral high-mannose glycoproteins or ManLAM.
1-Thioglycosides, carbohydrate derivatives that bear a sulfur
atom instead of oxygen at the anomeric linkage, are more
resistant to cleavage by glycosidases than the naturally
occurring O-glycosides.1 Because of their structural similarity
to the natural substrates, 1-thioglycosides can serve as modest
competitive inhibitors of glycosidases2 and as enzyme-
resistant scaffolds to support ligands whose enzyme binding
or other interactions may be of interest.3 1-Thioglycosides
are usually assembled by S-glycosylation of simple thiols
or by SN2 displacement reactions that take advantage of the
nucleophilicity of the thiolate anion. The multistep nature
of these approaches has limited the synthesis of S,S-
trisaccharides and S,S,S-tetrasaccharides to just a few ex-
amples.4 With a contrasting strategy, we have found that a
glycal-1,2-episulfide 5 (Scheme 1) can be slowly generated
in solution. Remarkably, 5 undergoes controlled oligomer-
ization to afford a family of thio-oligo-R-D-mannopyrano-
sides (7-9) in a single reaction. These R-(1f2)-linked thio-
mannopyranosides might have application as mimics of
natural structures with similar linkages, such as the outer
surface of high-mannose glycoproteins such as gp120 in the
viral coat of HIV5 or the mannosylated lipoglycan, ManLAM,
that mediates human macrophage phagocytosis of virulent
strains of Mycobacterium tuberculosis.6 They might also
serve as inhibitors of R-mannosidases with 1,2-linkage
specificity.7
The precursor to 5 was made (Scheme 1) from methyl
2,3-di-S,O-acetyl-4,6-O-(phenylmethylene)-2-thio-R-D-man-
nopyranoside 1, which itself had been prepared from
commercial methyl 4,6-O-(phenylmethylene)-R-D-glucopy-
(4) Contour-Galcera, M.-O.; Guillot, J.-M.; Ortiz-Mellet, C.; Pflieger-
Carrara, F.; Defaye, J.; Gelas, J. Carbohydr. Res. 1996, 281, 99-118.
Contour-Galcera, M.-O.; Ding, Y.; Ortiz-Mellet, C.; Defaye, J. J. Carbohydr.
Res. 1996, 281, 119-128.
(5) Matsuo, I.; Miyazaki, T.; Isomura, M.; Sakakibara, T.; Ajisaka, K.
J. Carbohydr. Chem. 1998, 17, 1249-1258, and references therein.
(6) Schlessinger, L. S.; Hull, S. R.; Kaufman, T. M. J. Immunol. 1994,
152, 4070-4079.
(7) Maruyama, Y.; Nakajima, T.; Ichishima, E. Carbohydr. Res. 1994,
251, 89-98, and references therein.
(1) Reviews: Defaye, J.; Gelas, J. In Studies in Natural Products
Chemistry; Rahman, A., Ed.; Elsevier: New York, 1991; Vol. 8, pp 315-
357. Carbohydr. Chem. (UK) 1998, 30, 159-166.
(2) Witczak, Z. J.; Boryczewski, D. Bioorg. Med. Chem. Lett. 1998, 8,
3265-3268, and references therein.
(3) For some recent examples, see: Zanini, D.; Roy, R. J. Org. Chem.
1998, 63, 3486-3491, and references therein.
10.1021/ol990702x CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/22/1999

disaccharide 7, R-linked according to the anomeric JC-H’s,
was further characterized as its heptaacetate, which exhibited
the expected H resonances and IR absorbances for its
Scheme 1. Synthesis of 2-Thio-(1f2)-mannopyranoside
1
Oligomers
S-acetyl and six O-acetyl residues.
Thiirane 5 can be intercepted by thiolates unrelated to 4,
which leads to other sorts of thioglycosides. As an example,
phenyl 1,6-dithio-R-D-mannopyranoside 11 was prepared
from mannose pentaacetate 10 by standard transformations
(Scheme 2). Deacetylation of 11 in methanol presumably
Scheme 2. Glycal-1,2-episulfide Trapping Experiments
ranoside in two steps.8 Acid hydrolysis of the benzylidene
protecting group and subsequent acetylation gave the tet-
raacetate 2, and then acetal exchange with thiophenol9 led
to the phenyl thioglycoside 3. The (C-1)-R stereochemistry
of 3 is indicated by its 13C-1H coupling constant of 173
Hz.10 Deacetylation of 3 under Zemplen conditions gave rise
not only to the expected mercaptotriol 6 but also to a mixture
of oligomeric thioglycosides (7-9) still bearing the 2-mer-
capto substituent.
led to the formation of the 6-thiolate, which was trapped by
adding thiirane precursor 3 to the same solution. To facilitate
isolation of the products, air oxidation (which could not be
altogether prevented anyway) was allowed to proceed during
workup. The pseudo-trisaccharide 12 was obtained in 31%
yield (based on 3), along with two disulfides, 13 and 14,
that formed from 11 as byproducts. Thiirane 5 is implicated
as the likely intermediate leading to 12, and the thiolate
derived from 11 evidently competed successfully for 5 with
other thiolates present in solution. Another primary thiolate
precursor, protected cysteine 15, was converted to the
glycopeptide11 mimic 16 by sequential treatment with sodium
methoxide and 3 (Scheme 2).
The thioglycoside products 6-9 were characterized by
1
their IR, FAB-MS, and H and 13C NMR spectra. Each
showed the expected number of anomeric thioglycoside C’s
at 88-92 ppm and anomeric H’s at 5.5-5.8 ppm. The
(8) Knapp, S.; Naughton, A. B. J.; Jaramillo, C.; Pipik, B. J. Org. Chem.
1992, 57, 7328-7334.
(9) Ferrier, R. J.; Furneaux, R. H. Methods Carbohydr. Chem. 1980, 8,
251.
(10) Uhrinova, S.; Uhrin, D.; Liptaj, T.; Bella, J.; Hirsh, J. Magn. Reson.
Chem. 1991, 29, 912-922, and references therein.
Phenyl 1,2-dithio-R-D-mannopyranoside 3 and the derived
1,2-episulfide 5 exhibit reactivity that is unusual in several
(11) Review: Taylor, C. M. Tetrahedron 1998, 54, 11317-11362.
Org. Lett., Vol. 1, No. 4, 1999
612

respects. Phenylthiolate (PhS-), a reactive nucleophile, is not
normally considered a leaving group at the anomeric position
of sugars. For example, phenyl 1-thio-R-D-mannopyrano-
side,12 prepared from 10 in two steps, is stable to methanolic
sodium methoxide. We have found that certain other 2-thio-
R-D-mannopyranosides, such as p-nitrophenyl, do decompose
during S-deacetylation at C-2 but methyl 2-thio-R-D-man-
nopyranoside can be made from its peracetate 2 by treatment
with methanolic sodium methoxide without loss of methoxide
at C-1. Treatment of 11 with sodium methoxide likewise
does not lead to thiolate ring closure at C-1, and the 2-thio-
glycoside products 7-9 are isolable from methoxide solution
with the 1-thio linkage intact. One can thus attribute the ring
closure reaction of 4 to a favorable SN2 trajectory13 and
softness match14 between the participating thiolate at C-2
and the trans-anti anomeric leaving group (PhS-), as well
as the stability of phenylthiolate as a leaving group relative
to alkylthiolate or methoxide.15
related to 5, but only amorphous sulfide polymer was isolated
from the reaction mixture. The limited oligomerization of 4
observed here may reflect the behavior of the rather reluctant
leaving group that leads to the formation of 5 in low
concentration only. Once formed, 5 is trapped by the most
reactive thiolates present, namely 4 and its lower oligomers.
The less-hindered thiolates derived from 11 and 15 can also
intercept 5 to some extent before it polymerizes. Interestingly,
methanol and methoxide, which react quickly with glycal
epoxides,17 and are present here in excess, do not intercept
glycal episulfide 5 to any detectable extent (NMR, TLC).
This may be another manifestation of the importance of a
softness match for effective ring opening and closing of
thiiranes.
Acknowledgment. We thank Hoechst Celanese for an
Innovative Research Award and David Myers for help with
the preparation of 1.
An earlier study16 on ring closure of â-D-gluco 1-thiolates
provides evidence for the transient formation of thiiranes
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Maity, S. K.; Dutta, S. K.; Banerjee, A. K.; Achari, B.; Singh, M.
Tetrahedron 1994, 50, 6965-6974.
(13) For a recent discussion, see: Collins, P.; Ferrier, R. Monosaccha-
rides; John Wiley & Sons: New York, 1995; pp 89-91, 203-206, 242,
266-269.
(14) Pearson, R. G.; Songstad, J. J. Org. Chem. 1967, 32, 2899-2900.
(15) Analogous ring closure of phenyl glycosides to the glycal epoxide
(with O-2 participation) has been inferred: Ballou, C. E. AdV. Carbohydr.
Chem. 1954, 9, 59-95.
OL990702X
(16) Nakamura, H.; Tejima, S.; Akagi, M. Chem. Pharm. Bull. 1966,
14, 648-657.
(17) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661-6666.
Org. Lett., Vol. 1, No. 4, 1999
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