Beilstein J. Org. Chem. 2011, 7, 1504–1507.
ponent reaction was completed by the addition of (S)-2-
methylbutanoic acid, Boc-Gly, Boc-Ala, Boc-Val, Boc-Leu,
Boc-Phe and Boc-Ile and tert-butyl isocyanide. Following this
procedure, the desired optically active compounds 6a–g were
obtained in 55–63% yields. Their structures were confirmed by
1H, 13C NMR and HRMS spectra.
Supporting Information
Supporting Information File 1
Experimental procedures and analytical data.
Finally, the Ugi-4CR was utilized for the synthesis of a molec-
ular probe prototype of 1, which can be used for intercalation
studies (Scheme 3). For this propose, the natural product scaf-
fold should be attached through a spacer to a reporter tag, which
is normally a luminescent group or a dye. The advanced inter-
mediate 5 was converted to the respective imine as depicted in
Scheme 2 and then reacted with (S)-2-methylbutanoic acid and
isonitrile 7 to afford the intermediate 8 in 61% yield. This com-
pound was then hydrogenated to afford 9 and then directly
coupled with 1-pyrenemethylamine, by using EDCl as coupling
reagent, to yield the designed probe prototype 10 in 80% yield
(from 8).
Acknowledgements
The authors thank Dr. Jürgen Schmidt and Mr. Torsten Geißler
for the HRMS and emission spectra and Ms. Leah M. Harris for
a kind revision of this manuscript. R.A.W.N.F. is grateful to
CNPq for a Ph.D. fellowship.
References
1. Hulme, C.; Dietrich, J. Mol. Diversity 2009, 13, 195–207.
2. Anastasi, C. A. Asoc. Quim. Argent. 1925, 13, 348–356.
3. Aboagye, F. A.; Sam, G. H.; Massiot, G.; Lavaud, C. Fitoterapia 2000,
4. Suárez, A. I.; Blanco, Z.; Delle Monache, F.; Compagnone, R. S.;
Arvelo, F. Nat. Prod. Res. 2004, 18, 421–426.
Pyrene derivative 10 exhibited strong blue luminescence in both
solution and solid phase. This probe may be used for tracking
the (−)-julocrotine in biological systems, in particular in
promastigote and amastigote forms of protozoan Leishmania
amazonensis (L.). It could be helpful to elucidate the to-date
unknown mode of action of this natural product in the parasite.
5. Nakano, T.; Djerassi, C.; Corral, R. A.; Orazi, O. O. Tetrahedron Lett.
6. Nakano, T.; Djerassi, C.; Corral, R. A.; Orazi, O. O. J. Org. Chem.
7. Moreira, R. Y. O.; Brasil, D. S. B.; Alves, C. N.; Guilhon, G. M. S. P.;
Santos, L. S.; Arruda, M. S. P.; Müller, A. H.; Barbosa, P. S.;
Abreu, A. S.; Silva, E. O.; Rumjanek, V. M.; Souza, J., Jr.;
da Silva, A. B. F.; de A. Santos, R. H. Int. J. Quantum Chem. 2008,
Conclusion
In summary, a highly efficient method to synthesize (−)-
julocrotine (1) in three steps from Cbz-glutamine 2 was devel-
oped. The approach affords the natural product in 51% overall
yield. The versatility of the developed protocol was
demonstrated in the synthesis of seven julocrotine analogues
and a molecular probe utilizing Ugi-4CRs. The desired com-
pounds 6a–g and 10 were obtained in good yields.
8. Guimarães, L. R. C.; Rodrigues, A. P. D.; Marinho, P. S. B.;
Müller, A. H.; Guilhon, G. M. S.; Santos, L. S.; do Nascimento, J. L. M.;
Silva, E. O. Parasitol. Res. 2010, 107, 1075–1081.
Scheme 3: Reactions and conditions: (a) (CH2O)n, MeOH, r.t., 2 h then, (S)-2-methylbutanoic acid and 7, r.t. 18 h, 61%. (b) H2, 10% w/w Pd/C,
MeOH, r.t., 10 h. (c) 1-pyrenemethylamine hydrochloride, Et3N, EDCl, DMAP, CH2Cl2, r.t., 24 h, 80% over two steps.
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