sequence providing access to such building blocks from
unprotected reducing sugars would be useful.
Str ea m lin ed Syn th esis of P er -O-a cetyla ted
Su ga r s, Glycosyl Iod id es, or Th ioglycosid es
fr om Un p r otected Red u cin g Su ga r s1
We have previously demonstrated that iodine can serve
as a promoter for sugar per-O-acetylation,10 that sugar
per-O-acetates can be converted to the corresponding
glycosyl iodides by treatment with TMS-I,11 and that
sugar per-O-acetates can also be converted directly into
thioglycosides by treatment with TMS-I in the presence
of thiols.12 In both of these latter reactions, TMS-I was
generated in situ from iodine and hexamethyldisilane
(HMDS).13 Noting recent reports of iodine-promoted
acetylation of simple alcohols with stoichiometric acetic
anhydride14 and Cu(OTf)2-catalyzed solvent-free synthe-
sis of acetylated sugars together with subsequent conver-
sion to thioglycosides upon addition of boron trifluoride
etherate and thiol,7f we were encouraged to extend
studies on iodine-mediated sugar modification reactions.
We now report a facile, one-pot reaction sequence from
unprotected reducing sugars, employing stoichiometric
reagents, minimal workup, and purification, that pro-
vides access to per-O-acetylated sugars, the correspond-
ing glycosyl iodides, or thioglycosides in excellent yield
and with essentially complete anomeric stereoselectivity.
Per-O-acetylation of D-glucose with 5.1 molar equiv of
acetic anhydride (i.e., 1.02 molar equiv per hydroxyl
group) and iodine (0.7 mol % with respect to the sugar)
gave complete reaction within 2 h, giving only D-glucopy-
ranosyl esters (Table 1); no trace of furanosyl products
was detectable by 1H NMR spectroscopy of the crude
Balaram Mukhopadhyay,†
K. P. Ravindranathan Kartha,‡ David A. Russell,† and
Robert A. Field*,†
Centre for Carbohydrate Chemistry, School of Chemical
Sciences and Pharmacy, University of East Anglia,
Norwich NR4 7TJ , U.K., and Department of Medicinal
Chemistry, National Institute of Pharmaceutical Education
and Research, Sector 67, S.A.S Nagar,
Punjab 160062, India
r.a.field@uea.ac.uk
Received J uly 1, 2004
Abstr a ct: Solvent-free per-O-acetylation of sugars with
stoichiometric acetic anhydride and catalytic iodine proceeds
in high yield (90-99%) to give exclusively pyranose products
as anomeric mixtures. Without workup, subsequent ano-
meric substitution employing iodine in the presence of
hexamethyldisilane (i.e., TMS-I generated in situ) gives the
corresponding glycosyl iodides in 75-95% isolated yield.
Alternatively, and without workup, further treatment with
dimethyl disulfide or thiol (ethanethiol or thiocresol) gives
anomerically pure thioglycosides in more than 75% overall
yield.
(7) For recent examples of the use of per-O-acetylated sugars as
donors in O-glycoside synthesis, see: (a) J unot, N.; Meslin, J . C.;
Rabiller, C. Tetrahedron: Asymmetry 1995, 6, 1387. (b) Binch, H.;
Stangier, K.; Thiem, J . Carbohydr. Res. 1998, 306, 409. (c) Bhaskar,
P. M.; Loganathan, D. Synlett 1999, 129. (d) Kumareswaran, R.;
Pachamuthu, K.; Vankar, Y. D. Synlett 2000, 11, 1652. (e) Lee, J .-C.;
Tai, C.-A.; Hung, S.-C. Tetrahedron Lett. 2002, 43, 851. (f) Tai, C.-A.;
Kulkarni, S. S.; Hung, S.-C. J . Org. Chem. 2003, 68, 8719. (g) Davis,
B. J .; Chambers, D.; Cumpstey, I.; France, R.; Gamblin, D. In Best
Synthetic Methods: Carbohydrates; Osborn, H. M. I., Ed.; Academic
Press: 2003; pp 69-120.
(8) For recent examples of the use of glycosyl iodides in O-, C-, N-,
and S-glycoside synthesis, see: (a) Gervay, J .; Hadd, M. J . J . Org.
Chem. 1997, 62, 6961. (b) Gervay, J . Organic Synthesis: Theory and
Applications; J AI Press, Inc.: New York, 1998: Vol. 4, p 121. (c) Hadd,
M. J .; Gervay, J . Carbohydr. Res. 1999, 320, 61. (d) Bhat, A. S.; Gervay-
Hague, J . Org. Lett. 2001, 3, 2081. (e) Lam, S. N.; Gervay-Hague, J .
Carbohydr. Res. 2002, 337, 1953. (f) Lam, S. N.; Gervay-Hague, J . Org.
Lett. 2002, 4, 2039. (g) Dabideen, D. R.; Gervay-Hague, J . Org. Lett.
2004, 6, 973. (h) Miquel, N.; Vignando, S.; Russo, G.; Lay, L. Synlett
2004, 2, 341.
(9) For recent examples of the use of thioglycosides in O-glycoside
syntheses, see: (a) Garegg, P. J . Adv. Carbohydr. Chem. Biochem.
1997, 52, 1179. (b) Das, S. K.; Roy, J .; Reddy, K. A.; Abbineni, C.
Carbohydr. Res. 2003, 338, 2237. (c) Yu, H.; Ensley, H. E. Tetrahedron
Lett. 2003, 44, 9363. (d) Mukhopadhyay, B.; Roy, N. Carbohydr. Res.
2003, 338, 589. (e) Alpe, M.; Oscarson, S.; Svahnberg, P. J . Carbohydr.
Chem. 2003, 22, 565. (f) Kartha, K. P. R.; Field, R. A. In Best Synthetic
Methods: Carbohydrates; Osborn, H. M. I., Ed.; Academic Press:
Oxford, UK, 2003; pp 121-145. (g) Mukhopadhyay, B.; Field, R. A.
Carbohydr. Res. 2004, 339, 1285. (h) Code´e, J . D. C.; van den Bos, L.
J .; Litjens, R. E. J . N.; Overkleeft, H. S.; van Boeckel, C. A. A.; van
Boom, J . H.; van der Marel, G. A. Tetrahedron 2004, 60, 1057.
(10) Kartha, K. P. R.; Field, R. A. Tetrahedron 1997, 53, 11753.
(11) Kartha, K. P. R.; Field, R. A. Carbohydr. Lett. 1998, 3, 179.
(12) Kartha, K. P. R.; Field, R. A. J . Carbohydr. Chem. 1998, 17,
693.
The growing realization that carbohydrates are central
to a wide array of biological processes2 has led to the
search for more practical methods for their synthesis.
While major advances have been made in the application
of reactivity tuning,3 based on the concept of armed and
disarmed glycosylation reagents,4 further extension to so-
called “programmable” syntheses,5 and ultimately auto-
mated oligosaccharide synthesis,6 the need remains for
efficient syntheses of appropriately protected and/or
activated sugar building blocks. Per-O-acetylated reduc-
ing sugars,7 the corresponding glycosyl iodides,8 and
thioglycosides9 are frequently used as the building blocks
in oligosaccharide synthesis. A practical one-pot reaction
* Author to whom correspondence should be addressed. Fax: 0044-
1603-592003.
† University of East Anglia.
‡ National Institute of Pharmaceutical Education and Research.
(1) Iodine: a versatile reagent in carbohydrate chemistry XVI. For
part XV, see: Marsh, S. J .; Kartha, K. P. R.; Field, R. A. Synlett 2003,
1376.
(2) (a) Varki, A. Glycobiology 1993, 3, 97. (b) Essentials of Glyco-
biology; Varki, A., Cummings, R., Esko, J ., Freeze, H., Hart, G., Marth,
J ., Eds.; Cold Spring Harbor Laboratory Press: Cold Spring Harbor,
NY, 1999. (c) Sears, P.; Wong, C.-H. Science 2001, 291, 2344.
(3) Baeschlin, D. K.; Green, L. G.; Hahn, M. G.; Hinzen, B.; Ince, S.
J .; Ley, S. V. Tetrahedron: Asymmetry 2000, 11, 173.
(4) (a) Fraser-Reid, B.; Udodong, U. E.; Wu, Z. F.; Ottosson, H.;
Merritt, J . R.; Rao, C. S.; Roberts, C.; Madsen, R. Synlett 1992, 927.
(b) Veeneman, G. H.; van Boom, J . H. Tetrahedron Lett. 1990, 31, 275.
(5) (a) Ye, X. S.; Wong, C.-H. J . Org. Chem. 2000, 65, 2410. (b)
Reviewed in: Sears, P.; Wong, C.-H. Science 2001, 291, 2344.
(6) (a) Plante, O. J .; Palmacci, E. R.; Seeberger, P. H. Science 2001,
291, 1523. (b) Seeberger, P. H., Ed. Solid Support Oligosaccharide
Synthesis and Combinatorial Carbohydrate Libraries; Wiley-Inter-
science: New York, 2001.
(13) (a) Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R.
Angew. Chem., Int. Ed. Engl. 1979, 18, 612. (b) Olah, G. A.; Narang,
S. C. Tetrahedron 1982, 38, 2225.
(14) Phukan, P. Tetrahedron Lett. 2004, 45, 4785.
10.1021/jo048890e CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/25/2004
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