R. Jain et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2185–2189
2189
Figure 2.
Fmoc-histidine (Trt), was first coupled to the support
(Scheme 8).Removal of the Fmoc protecting group
was then followed by coupling of scaffold 2 to the free
amino group by amide bond formation to the C-2 car-
boxymethyl group of 2.The resin-bound scaffold was
then treated with a series of isocyanates in the presence
of CuCl in DMF to generate the corresponding C-6
carbamates.Reduction of the C-3 azido group with
trimethylphosphine generated the desired amines which
were then reacted with a series of carboxylic acids to
provide the corresponding amides.
unique ligands for a wide variety of biomolecular drug
targets.To exploit this potential, we have developed a
series of 3-azido glycopyranosides.
References and Notes
1. Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy,
E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors, P. G.;
Shakespear, 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.
2.Hirschmann, R; Yao, W;. Cascieri, M.A;. Strader, C.D;.
Maechler, L.; Cichy-Knight, M. A.; Hynes, J., Jr; van Rijn, R. D.;
Sprengeler, P. A.; Smith, A. B., III J. Med. Chem. 1996, 39, 2441.
3. Wunberg, T.; Kallus, C.; Opatz, T.; Henke, S.; Schmidt,
W.; Kunz, H. Angew. Chemie. Int. Ed. Engl. 1998, 37, 2503.
4. Sofia, M. J.; Hunter, R.; Chan, T. Y.; Vaughan, A.; Dulina,
R.; Wang, H.; Gange, D. J. Org. Chem. 1998, 63, 2802.
5.Sofia, M. J. Med. Chem. Res. 1998, 8, 362.
A library of 48 compounds was prepared using the
directed sorting mix-and-split synthesis method15
(Fig.2 ).
All 48 compounds were analyzed by LC/MS using eva-
porative light-scattering detection (ELSD).The yield of
each product was determined from the ELSD trace
using standard curves and product identity was deter-
mined by electrospray mass spectal analysis.The aver-
age yield for the six-step sequence was 55%.One of the
library products was further purified by preparative
HPLC and its structure was confirmed by NMR spec-
troscopy and LC/MS analysis to be the desired com-
pound 40.16
6. Holla, E. W.; Sinnwell, V.; Klaffke, W. Synlett 1992, 5, 413.
7. Montero, J.-L.; Winum, J.-Y.; Leydet, A.; Kamal, M.;
Pavia, A. A.; Roque, J.-P. Carbohydr. Res. 1997, 297, 175.
8.Johansson, R;.Samuelsson, B. J. Chem. Soc., Chem. Com-
mun. 1984, 201.
9. Oikawa, Y.; Yshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 885.
10. Allanson, N. M.; Liu, D.; Chi, F.; Jain, R. K.; Chen, A.;
Ghosh, M.; Hong, L.; Sofia, M. J. Tetrahedron Lett. 1998, 39,
1889.
11.Johansson, R;. Samuelsson, B.
Trans. 1 1994, 2317.
J. Chem. Soc., Perkin
12. El-Sokkary, R. I.; Silwanis, B. A.; Nashed, M. A. Carbo-
hydr. Res. 1990, 203, 319.
13.Fugedi, P;. Kovac, J.XV International Carbohydrate
Symposium, Aug.12–17, 1990, p 77.
14.Purchased from Novabiochem.
15.Radiofrequency tagging system.Nicolaou, K.C;. Xiao,
X. Y.; Parandoosh, Z.; Senyei, A.; Nova, M. P. Angew. Chem.
Int. Ed. Engl. 1995, 34, 2289.
16.NMR diagnostic signals at d 8.04 (d, 1H), 7.39 (s, 1H),
6.07 (s, 2H), 4.48 (d, 1H, J=7.5 Hz), 3.73 (s, 3H), 3.70 (s, 3H).
In conclusion, we believe that carbohydrate scaffolds
are biologically relevant molecular platforms that can
be used in combinatorial library strategies to identify