ORGANIC
LETTERS
2005
Vol. 7, No. 6
1145-1148
Carbohydrate Sulfonyl Chlorides for
Simple, Convenient Access to
Glycoconjugates
Lisbet Kværnø, Moritz Werder,† Helmut Hauser,† and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Ho¨nggerberg HCI H335,
CH-8093 Zu¨rich, Switzerland
Received February 2, 2005
ABSTRACT
The use of carbohydrate sulfonyl chlorides is introduced as a new, facile glycoconjugation method which could find broad applications. We
demonstrate the approach by synthesizing a number of glycosylated cholesterol absorption inhibitors which display high inhibitory efficacies
in our recently established in vitro assay. Furthermore, we highlight an advantage of the electron-withdrawing nature of the sulfonyl linkage
which allowed the synthesis of otherwise unstable azetidine conjugates.
The chemical and analytical tools for studying the biological
functions of carbohydrates and glycoconjugates have seen
explosive development within recent years.1,2 The structural
and synthetic complexity of densely functionalized carbo-
hydrates renders the introduction of carbohydrate domains
onto molecules of interest a nontrivial exercise. Moreover,
the issues of reactivity and stereoselectivity at the anomeric
center during glycosylation adds to the synthetic challenge.1,3
We have become interested in exploring the effect of
glycosylation of small-molecule inhibitors of intestinal
cholesterol absorption.4 In this context, we initiated a study
into the development of new strategies for the synthesis of
carbohydrate conjugates (Scheme 1).
Examples from the wide range of important applications
involving glycoconjugation methods include the synthesis
of neoglycoconjugates by Staudinger ligation to cell sur-
faces,5 the use of neoglycopeptides as oligosaccharyl trans-
ferase inhibitors,6 and the enhanced biological activities of
drugs.4,7 Thus, for instance, ezetimibe (10, Scheme 2)8
† Present address (M.W., H.H.): Lipideon Biotechnology, Hermann-
Hiltbrunnerweg 25, 8713 Uerikon, Switzerland.
(1) (a) Glycoscience; Fraser-Reid, B., Tatsuta, K., Thiem, J., Eds.;
Springer-Verlag: Berlin, Heidelberg, New York, 2001. (b) Bioorganic
Chemistry: Carbohydrates; Hecht, S. M., Ed.; Oxford University Press:
New York, Oxford, 1999.
(4) Kværnø, L.; Ritter, T.; Werder, M.; Hauser, H.; Carreira, E. M.
Angew. Chem., Int. Ed. 2004, 43, 4653-4656.
(5) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007-2010.
(6) Peluso, S.; Ufret, M. D.; O’Reilly, M. K.; Imperiali, B. Chem. Biol.
2002, 9, 1323-1328.
(2) (a) Carbohydrate-based Drug DiscoVery; Wong, C.-H., Ed.; Wiley-
VCH: Weinheim, 2003. (b) Glycochemistry. Principles, Synthesis and
Applications; Wang, G., Bertozzi, C. R., Eds.; Marcel Dekker Inc.: New
York, Basel, 2001. (c) Palmacci, E. R.; Plante, O. J.; Hewitt, M. C.;
Seeberger, P. H. HelV. Chim. Acta 2003, 86, 3975-3990.
(7) Vaccaro, W. D.; Davis, H. R. Bioorg. Med. Chem. Lett. 1998, 8,
313-318.
(8) (a) Clader, J. W. J. Med. Chem. 2004, 47, 1-9. (b) Rosenblum, S.
B.; Huynh, T.; Afonso, A.; Davis, H. R.; Yumibe, N.; Clader, J. W.; Burnett,
D. A. J. Med. Chem. 1998, 41, 973-980.
(3) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
10.1021/ol0502127 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/22/2005