pubs.acs.org/joc
reaction sites may serve as a powerful synthetic strategy that
Three-Component Assembly of Amines, Boronic
Acids, and a Polyfunctionalized Furanose: A Concise
Entry to Furanose-Based Carbohydrate Templates
should provide enormous opportunity for diversity-oriented
synthesis as well as target-oriented synthesis.2 In this sense,
the design of novel molecular platforms that allow a stereo-
determined, three-dimensional orientation of pharmaco-
phores remains an important goal in drug discovery.3 In
this context, the successful use of carbohydrates as scaffolds
in the area of peptidomimetics4 has triggered a considerable
research effort on the use of sugar derivatives as templates in
bioactive compound discovery.5 Thus, carbohydrate tem-
plates have been generated from pyranoses, furanoses, dis-
accharides, and bicyclic derivatives, and most of these
strategies have relied on the stepwise derivatization of ortho-
gonally protected carbohydrate derivatives.6-8
ꢀ
Ana M. Gomez,* Aitor Barrio, Ana Pedregosa,
ꢀ
Serafın Valverde, and J. Cristobal Lopez*
ꢀ
´
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Instituto de Quımica Organica General, CSIC, Juan de la
Cierva 3, 28006 Madrid, Spain
anagomez@iqog.csic.es; clopez@iqog.csic.es
Received June 15, 2009
Recently, we inititated a research project aimed at building
small libraries of functionalized carbohydrates.9 In
this context, we have became interested in developing syn-
thetic strategies in which the incorporation of some of
the appendages on the carbohydrate templates could be
effected by means of palladium-catalyzed reactions on ortho-
gonally functionalized carbohydrate derivatives. We reported
the preparation of epoxy exo-glycal 1 (four steps from
D-mannose) and its transformation into allylic amines,
e.g., 2, via an intermediate π-allyl palladium complex
(Scheme 1a).10 We also reported the Suzuki cross-coupling
reaction11 of halo-exo-glycals, e.g., 3,12 leading to substi-
tuted exo-glycals, e.g., 4 (Scheme 1b).13 We envisioned that
A highly functionalyzed furanose derivative, accessible in
five steps from D-mannose, comprising a halo-alkenyl
allylic-oxirane system, undergoes a palladium catalyzed
one-pot, three component, assembly with boronic acids
(or alkyl boranes) and amines to give, in a complete regio-
and stereocontrolled manner, a sugar based derivative
with two sites of molecular diversity.
(5) Recent reviews on the preparation of carbohydrate derived templates:
(a) Murphy, P. V. Eur. J. Org. Chem. 2007, 4177–4180. (b) Velter, I.; LaFerla,
B.; Nicotra, F. J. Carbohydr. Chem. 2006, 25, 97–138. (c) Becker, B.; Condie,
G. C.; Le, G. T.; Meutermans, W. Mini-Rev. Med. Chem. 2006, 1, 1164–1194.
(d) Meutermans, W.; Le, G. T.; Becker, B. Chem. Med. Chem. 2006, 1, 1164–
1194. (e) Murphy, P. V.; Dunne, J. L. Curr. Org. Synth. 2006, 3, 403–437.
(f) Cipolla, L.; Peri, F.; LaFerla, B.; Redaelli, C.; Nicotra, F. Curr. Org.
Synth. 2005, 2, 153–173. (g) Le, G. T.; Abbenante, G.; Becker, B.; Grathwohl,
M.; Halliday, J.; Tometzki, G.; Zuegg, J.; Meutermans, W. Drug Discovery
Today 2003, 8, 701–709. (h) Kanemitsu, T.; Kanie, O. Trends Glycosci.
Glycotechnol. 1999, 11, 267–276. (i) Sofia, J. J.; Silva, D. J. Curr. Opin. Drug
Discovery Dev. 1999, 2, 365–376.
The muticomponent assembly reaction has emerged as a
powerful means for rapid generation of molecular complex-
ity and diversity.1 In particular, the orthogonal and sequen-
tial functionalization of a simple molecule bearing multiple
€
(6) (a) Hunger, H.; Ohnsmann, J.; Kunz, H. Angew. Chem., Int. Ed. 2004,
43, 1104–1107. (b) Opatz, T.; Kallus, C.; Wunberg, T.; Schmidt, W.; Henke,
S.; Kunz, H. Eur. J. Org. Chem. 2003, 1527–1536. (c) Wunberg, T.; Kallus,
C.; Opatz, T.; Henke, S.; Schmidt, W.; Kunz, H. Angew. Chem., Int. Ed. 1998,
37, 2503–2505.
(7) (a) Jain, R.; Kamau, M.; Wang, C.; Ippolito, R.; Wang, H.; Dulina,
R.; Anderson, J.; Gange, D.; Sofia, M. J. B. Bioorg. Med. Chem. Lett. 2003,
13, 2185–2189. (b) Sofia, M. J.; Hunter, R.; Chan, T. Y.; Vaughan, A.;
Dulina, R.; Wang, H.; Gange, D. J. Org. Chem. 1998, 63, 2802–2803.
(8) (a) Elmouelhi, N.; Aich, U.; Paruchuri, V. D. P.; Meledeo, M. A.;
Campbell, C. T.; Wang, J. J.; Srinivas, R.; Khanna, H. S.; Yarema, K. J.
J. Med. Chem. 2009, 52, 2515–2530. (b) Castoldi, S.; Cravini, M.; Micheli, F.;
Piga, E.; Russo, G.; Seneci, P.; Lay, L. Eur. J. Org. Chem. 2004, 2853–2862.
(1) (a) Dmling, A. Chem. Rev. 2006, 106, 17–89. (b) Multicomponent reac-
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tions; Zhu, J., Bienayme, H., Eds.; Wiley: Weinheim, 2005. (c) Ramon, D. J.; Yus,
M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634.
(2) (a) Schreiber, S. L. Science 2000, 287, 1964–1969. (b) Burke, M. D.;
Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–58. (c) Newman, D. J.;
Gragg, G. M. J. Nat. Prod. 2007, 70, 461–477. (d) Koehn, F. E.; Carter, G. T.
Nature Rev. Drug Discovery 2005, 4, 206–220.
ꢀ ꢀ
(9) (a) Gomez, A. M.; Barrio, A.; Pedregosa, A.; Valverde, S.; Lopez, J. C.
(3) Ariens, E. J.; Beld, A. J.; Rodrigues de Miranda, J. F.; Simonis, A. M.
In The Receptors: A Comprehensive Treatise; O’Brien, R. D., Ed.; Plenum:
New York, 1979; pp 33-91.
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Tetrahedron Lett. 2003, 44, 8433–8435. (b) Gomez, A. M.; Pedregosa, A.;
Barrio, A.; Valverde, S.; Lopez, J. C. Tetrahedron Lett. 2004, 45, 6307–6310.
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(c) Gomez, A. M.; Barrio, A.; Amurrio, I.; Jarosz, S.; Valverde, S.; Lopez, J.
C. Tetrahedron Lett. 2006, 47, 6243–6246.
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(4) (a) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino, J.;
Leahy, E. M.; Sprengeler, P. A.; Furst, G.; Smith, A. B. III; Strader, C. D.;
Cascieri, M. A.; Candelore, M. R.; Donaldson, C.; Vale, W.; Maechler, L.
J. Am. Chem. Soc. 1992, 114, 9217–9218. (b) Hirschmann, R.; Nicolaou, K.
C.; Pietranico, S.; Leahy, E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors,
P. G.; Shakespeare, W. C.; Sprengeler, P. A.; Hamley, P.; Smith, A. B. III;
Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale, W.; Freidinger,
R. M.; Cascieri, M. R.; Strader, C. D. J. Am. Chem. Soc. 1993, 115, 12550–
12568.(c) Nicolaou, K. C.; Salvino, J. M.; Raynor, K.; Pietranico, S.; Reisine, T.;
Freidinger, R. M.; Hirschmann, R. In Peptides: Chemical Structure and Biology;
Proceedings of the 11th American Peptide Symposium; Marshall, G. R., Ed.;
Escom: Leiden, 1990; pp 881-884.
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(10) Gomez, A. M.; Pedregosa, A.; Valverde, S.; Lopez, J. C. Chem.
Commun. 2002, 2022–2023.
(11) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(b) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; VCH: Weinheim, 1998; pp 49-97. (c) Suzuki, A. J. Organo-
met. Chem. 1999, 576, 147–168.
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(12) Gomez, A. M.; Danelon, G. O.; Pedregosa, A.; Valverde, S.; Lopez,
J. C. Chem. Commun. 2002, 2024–2026.
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Lett. 2003, 44, 6111–6116.
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(13) Gomez, A. M.; Pedregosa, A.; Valverde, S.; Lopez, J. C. Tetrahedron
DOI: 10.1021/jo9012817
r
Published on Web 07/14/2009
J. Org. Chem. 2009, 74, 6323–6326 6323
2009 American Chemical Society