ORGANIC
LETTERS
2012
Vol. 14, No. 1
174–177
N-Heterocyclic Carbene Catalyzed
C-Glycosylation: A Concise Approach
from Stetter Reaction
Seenuvasan Vedachalam, Shi Min Tan, Hui Ping Teo, Shuting Cai, and Xue-Wei Liu*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371
Received November 3, 2011
ABSTRACT
Described herein is the first example of an organocatalytic approach for acylanion addition to the anomeric carbon of 2-nitroglucal using an
N-heterocyclic carbene catalyst. Control over the reaction conditions gives β-selective and nitro-eliminated C-glycosides, providing opportunities
to produce new classes of C-glycoside.
Due to the fact that C-glycosides show attractive utility as
potential drug candidates, their importance has grown over
the years.1 Therefore, the search for new methodologies for
the expedient synthesis of C-glycosides has become of great
interest to researchers. The development of new types of
C-glycoside integrated with various heterocycleshas gained
much attention in recent times.2 The potential pharmaceu-
tical significance of this class of compounds has prompted
various groups to develop different methodologies for
C-glycosylation, including Lewis acid,3a metal-mediated,3b
radical,3c and base-mediated glycosylation.3d
Lewisacidmediatedglycosylation,4a Pd-catalyzed decarboxy-
lative glycosylation,4b enol-triflate coupling glycosylation,4c
and glycosidations based upon sulfur ylide cycloaddition
reactions4d and sequential Rh-catalyzed aziridination/In-
mediated Barbier allylation.4e In addition to these meth-
odologies, we substantiated the importance of C-glycosides
by demonstrating the high activities of certain C-glycosides
toward biological systems.5
Some time ago, Schmidt, Vanker, and other groups
devised a base-mediated glycosylation technique that used
2-nitroglucal derivatives.6 Since 2-nitroglucal is a versatile
Michael-type glycosyl donor under basic conditions, we
envisioned that NHC catalyzed acylanion addition to
Recently, our group has actively investigated efficient
and stereoselective C-glycosylation techniques, such as
(1) (a) He, X.-P.; Wang, X.-W.; Jin, X.-P.; Zhou, H.; Shi, X.-X.; Chen,
G.-R.; Long, Y.-T. J. Am. Chem. Soc. 2011, 133, 3649. (b) van Kasteren,
S. I.; Kramer, H. B.; Jensen, H. H; Campbell, S. J.; Kirkpatrick, J.; Oldham,
N. J.; Anthony, D. C.; Davis, B. G. Nature 2007, 446, 1105. (c) Fischbach,
M. A.; Lin, H.; Liu, D. R.; Walsh, C. T. Proc. Natl. Acad. Sci. U.S.A. 2005,
102, 571.
(4) (a) Zeng, J.; Vedachalam, S.; Xiang, S.; Liu, X.-W. Org. Lett.
2011, 13, 42. (b) Xiang, S.; Cai, S.; Zeng, J.; Liu, X.-W. Org. Lett. 2011,
13, 4608. (c) Bai, Y.; Leow, M.; Zeng, J.; Liu, X.-W. Org. Lett. 2011, 13,
5648. (d) Cai, S.; Xiang, S.; Zeng, J.; Gorityala, B. K.; Liu, X.-W. Chem.
Commun. 2011, 47, 8676. (e) Lorpitthaya, R.; Suryawanshi, S. B.; Wang,
S.; Pasunooti, K. K.; Cai, S.; Ma, J.; Liu, X.-W. Angew. Chem., Int. Ed.
2011, 50, 12054.
(5) Vedachalam, S.; Choi, B.-H.; Pasunooti, K. K.; Ching, K. M.;
Lee, K.; Yoon, H. S.; Liu, X.-W. Med. Chem. Commun. 2011, 2, 371.
(6) (a) Kancharla, P. K.; Vankar, Y. D. J. Org. Chem. 2010, 75, 8457.
(b) Xue, W.; Sun, J.; Yu, B. J. Org. Chem. 2009, 74, 5079. (c) Geiger, J.;
Reddy, B. G.; Winterfeld, G. A.; Weber, R.; Przybylski, M.; Schmidt,
R. R. J. Org. Chem. 2007, 72, 4367. (d) Gopal Reddy, B.; Vankar, Y. D.
Angew. Chem., Int. Ed. 2005, 44, 2001. (e) Pachamuthu, K.; Figueroa-
Perez, I.; Ali, I. A. I.; Schmidt, R. R. Eur. J. Org. Chem. 2004, 3959. (f)
Barroca, N.; Schmidt, R. R. Org. Lett. 2004, 6, 1551. (g) Winterfeld,
G. A.; Khodair, A. I.; Schmidt, R. R. Eur. J. Org. Chem. 2003, 1009.
(2) (a) Zhou, H.; Danger, D. P.; Dock, S. T.; Hawley, L.; Roller,
S. G.; Smith, C. D.; Handlon, A. L. ACS Med. Chem. Lett. 2010, 1, 19.
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(b) Stambasky, J.; Hocek, M.; Kocovsky, P. Chem. Rev. 2009, 109, 6729.
(c) Bililign, T.; Griffith, B. R.; Thorson, J. S. Nat. Prod. Rep. 2005, 22,
742. (d) Weizman, H.; Tor, Y. J. Am. Chem. Soc. 2001, 123, 3375.
(3) Methods for C-glycosylation: (a) Larsen, C. H.; Ridgway, B. H.;
Shaw, J. T.; Smith, D. M.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127,
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10879. (b) Gong, H.; Sinisi, R.; Gagne, M. R. J. Am. Chem. Soc. 2007,
129, 1908. (c) Guindon, Y.; Bencheqroun, M.; Bouzide, A. J. Am. Chem.
Soc. 2005, 127, 554. (d) Schmidt, R. R.; Vankar, Y. D. Acc. Chem. Res.
2008, 41, 1059.
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10.1021/ol202959y
Published on Web 12/20/2011
2011 American Chemical Society