612 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Reports
In the Biginelli reaction,10 a ꢀ-keto ester and an aldehyde
react with an urea to give the corresponding 3,4-dihydro-
pyrimidin-2(1H)-one derivatives. Thus, compounds 21.1 and
21.6 were reacted with ethyl acetoacetate and a series of
aldehydes under acidic conditions, affording the cyclic urea
derivatives 22 (Figure 4C). Of course, all compounds were
obtained as a mixture of the diastereomeric products at the
newly generated stereogenic center.
Alali, Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999,
62, 504.
(2) (a) Sinha, S. C.; Chen, Z.; Huang, Z.-Z.; Nakamaru-Ogiso,
E.; Pietraszkiewicz, H.; Edelstein, M.; Valeriote, F. J. Med.
Chem. 2008, 51, 7045. (b) Chen, Z.; Sinha, S. C. Tetrahedron
2008, 64, 1603.
(3) Sasaki, S.; Maruta, K.; Naito, H.; Sugihara, H.; Hiratani, K.;
Maeda, M. Tetrahedron Lett. 1995, 36, 5571.
(4) Derbre, S.; Roue, G.; Poupon, E.; Susin, S. A.; Hocquemiller,
R. ChemBioChem 2005, 6, 979. (b) Abe, M.; Kenmochi, A.;
Ichimaru, N.; Hamada, T.; Nishioka, T.; Miyoshi, H. Bioorg.
Med. Chem. Lett. 2004, 14, 779.
(5) Szabadkai, G.; Duchen, M. R. Physiology 2008, 23, 84.
(6) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2001, 40, 2004. (b) Hawker, C. J.; Fokin, V. V.; Finn,
M. G.; Sharpless, K. B. Aust. J. Chem. 2007, 60, 381. (c)
Minond, D.; Saldanha, S. A.; Subramaniam, P.; Spaargaren,
M.; Spicer, T.; Fotsing, J. R.; Weide, T.; Fokin, V. V.;
Sharpless, K. B.; Galleni, M.; Bebrone, C.; Lassaux, P.;
Hodder, P. Bioorg. Med. Chem. 2009, 17, 5027. (d) Rodriguez,
P.; Loeber, S.; Huebner, H.; Gmeiner, P. J. Comb. Chem.
2006, 8, 252. (e) Kacprzak, K.; Migas, M.; Plutecka, A.;
Rychlewska, U.; Gawronski, J. Heterocycles 2005, 65, 1931.
(7) (a) Ugi, I. Angew. Chem. 1962, 74, 9; Angew. Chem., Int.
Ed. 1962, 1, 8. (b) Ugi, I.; Werner, B.; Do¨mling, A. Molecules
2003, 8, 53. (c) Do¨mling, A.; Ugi, I. Angew. Chem. 2000,
112, 3300; Angew. Chem., Int. Ed. 2000, 39, 3168. (d)
Do¨mling, A. Chem. ReV. 2006, 106, 17. (e) Marcaccini, S.;
Torroba, T. Nat. Protoc. 2007, 2, 632.
(8) (a) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless,
K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192. (b)
Francis, M. B. Chem. Biol. 2007, 2, 593. (c) Li, M.; De, P.;
Gondi, S. R.; Sumerlin, B. S. Macromol. Rapid Commun.
2008, 29, 1172. (d) Lutz, J.-F.; Zarafshani, Z. AdV. Drug
DeliVery ReV. 2008, 60, 958. (dd) Nwe, K.; Brechbiel, M. W.
Cancer Biother. Radiopharm. 2009, 24, 289.
The azide-alkyne Click reaction and the Ugi and Biginelli
MCRs offer rapid access to libraries of non-natural compounds
that are highly complex and otherwise inaccessible or difficult
to synthesize. While the azide-alkyne Click reaction provides
the triazole derivatives in high yield, Ugi and Biginelli MCRs
provide access to compounds that have higher orders of
complexity. Here, by using mono- and bis-THF rings, as well
as both symmetrical and unsymmetrical intermediates, as the
next set of starting materials, one can increase not only the
number of new chemical libraries, but also their complexities
and overall shape, simply by changing the relative stereochem-
istry of the THF rings. For one set of compounds, there can be
four sets of stereoisomeric products in a mono-THF library,
and as many as sixteen sets for a bis-THF library.11 Because
the mono-THF and bis-THF compounds, as well as some
nitrogen analogs and higher-order THF rings, can be readily
obtained starting with the all-carbon skeletons, and using
numerous oxidative processes, including the Re(VII),12 Co(II),
Os(VIII),13 and Ru(VIII)14 oxide-mediated/catalyzed OC reac-
tions, this approach offers opportunities for the design and
synthesis of an unprecedented set of non-natural compounds
by the combination with Click and MCR reactions. Presumably,
the THF-based chemical space can be further increased by
introducing additional substitution on the THF rings and adding
new synthetic transformations. Such isomeric compound librar-
ies can demonstrate novel biological properties, which can be
determined through high-throughput screening (HTS).
(9) Inoki, S.; Mukaiyama, T. Chem. Lett. 1990, 67.
(10) Biginelli, P. Berichte 1891, 24, 2962. (b) Kappe, C. O. Acc.
Chem. Res. 2000, 33, 879. (c) Kappe, C. O.; Stadler, A. In
Organic Reactions; Paquette, L. A., Ed.; Wiley-Interscience:
New York, 2004; Vol. 63, p 1 and references cited therein. .
(d) Werner, S.; Turner, D. M.; Lyon, M. A.; Huryn, D. M.;
Wipf, P. Synlett 2006, 2334. (e) Studer, A.; Jeger, P.; Wipf,
P.; Curran, D. P. J. Org. Chem. 1997, 62, 2917. (f) Wipf, P.;
Cunningham, A. Tetrahedron Lett. 1995, 36, 7819.
(11) For stereochemical diversity-directed synthesis, see: (a) Shang,
S.; Iwadare, H.; Macks, D. E.; Ambrosini, L. M.; Tan, D. S.
Org. Lett. 2007, 9, 1895. (b) Burke Martin, D.; Schreiber
Stuart, L. Angew. Chem., Int. Ed. 2004, 43, 46. (c) Nielsen,
T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47, 48.
(12) Keinan, E.; Sinha, S. C. Pure Appl. Chem. 2002, 74, 93.
(13) Donohoe, T. J.; Wheelhouse, K. M. P.; Linsay-Scott, P. J.;
Glossop, P. A.; Nash, I. A.; Parker, J. S. Angew. Chem., Int.
Ed. 2008, 47, 2872.
An efficient synthetic approach was developed for the
construction of a new class of tetrahydrofuran-based hybrid
molecules using the Sharpless azide-alkyne Click reaction
and the Ugi and Biginelli MCRs as key transformations.
Numerous mono- and bis-tetrahydrofuran triazoles, peptides,
and acyclic and cyclic urea derivatives with diverse structural
features were prepared in fair to good yields from the readily
available mono- and bis-tetrahydrofuranyl azides and amines.
Selected compounds have been submitted for evaluation
under the MLSCN/MLPCN programs.15
(14) Goehler, S.; Roth, S.; Cheng, H.; Goeksel, H.; Rupp, A.;
Haustedt, L. O.; Stark, C. B. W. Synthesis 2007, 2751.
(15) (a) For other hybrid molecule syntheses, see: (a) Chen, C.;
Li, X.; Neumann, C. S.; Lo, M. M. C.; Schreiber, S. L. Angew.
Chem., Int. Ed. 2005, 44, 2249. (b) Banerjee, A.; Sergienko,
E.; Vasile, S.; Gupta, V.; Vuori, K.; Wipf, P. Org. Lett. 2009,
11, 65. (c) Wright, C. M.; Chovatiya, R. J.; Jameson, N. E.;
Turner, D. M.; Zhu, G.; Werner, S.; Huryn, D. M.; Pipas,
J. M.; Day, B. W.; Wipf, P.; Brodsky, J. L. Bioorg. Med.
Chem. 2008, 16, 3291. (d) Jiang, J.; Belikova, N. A.; Hoye, A. T.;
Zhao, Q.; Epperly, M. W.; Greenberger, J. S.; Wipf, P.; Kagan, V. E.
Int. J. Radiat. Oncol., Biol., Phys. 2008, 70, 816.
Acknowledgment. We are thankful to NIH/NIGMS
(P50GM067082) for financial support.
Supporting Information Available. Details of experi-
mental procedures and spectroscopic data for synthesized
compounds. This material is available free of charge via the
References and Notes
(1) (a) McLaughlin, J. L. J. Nat. Prod. 2008, 71, 1311. (b)
Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.;
Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269. (c)
CC1000709