Beilstein J. Org. Chem. 2012, 8, 2085–2090.
6. Burkhard, R. Angew. Chem., Int. Ed. Engl. 1967, 6, 885.
Conclusion
These results highlight the usefulness of the Ugi-4CR for the
diversity-oriented synthesis of natural N-methyl peptides, such
as viridic acid and its derivatives. Considering the attractive-
ness of the anthranilic acid moiety as a promising building
block for drug-like molecules and the diverse properties exhib-
ited by natural products containing it [8,50], further biological
trials involving such components are currently being pursued.
The advantages of the MCR protocol are speed, variability,
insensitivity to steric crowding, safe peptoid-moiety formation,
and access to equally distributed stereoisomers (which can be a
disadvantage though, once the most active isomer is identified).
7. Larsen, T. O.; Gareis, M.; Frisvad, J. C. J. Agric. Food Chem. 2002, 50,
8. Komatsu, K.; Shigemori, H.; Kobayashi, J. J. Org. Chem. 2001, 66,
9. Lan, H.-Q.; Ye, J.-L.; Wang, A.-E.; Ruan, Y.-P.; Huang, P.-Q.
10.Nakao, K.; Hamada, Y.; Shioiri, T. Chem. Pharm. Bull. 1989, 37,
11.Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447–2467.
12.De Moliner, F.; Banfi, L.; Riva, R.; Basso, A.
Comb. Chem. High Throughput Screening 2011, 14, 782–810.
13.Miller, S. M.; Simon, R. J.; Ng, S.; Zuckermann, R. N.; Kerr, J. M.;
Moos, W. H. Drug Dev. Res. 1995, 35, 20–32.
The improved classical approach gave the natural product in
much lower overall yield and more steps but, after careful
choice of conditions, in optically pure form. A set of
N-alkylated derivatives were screened against Aliivibrio
fischeri, but only the (N-methylated) natural product displayed
noteworthy activity of ca. 40 μM IC50, independent of stereo-
chemistry.
14.Pando, O.; Stark, S.; Denkert, A.; Porzel, A.; Preusentanz, R.;
Wessjohann, L. A. J. Am. Chem. Soc. 2011, 133, 7692–7695.
15.Boger, D. L.; Lee, J. K. J. Org. Chem. 2000, 65, 5996–6000.
16.Belleau, B.; Malek, G. J. Am. Chem. Soc. 1968, 90, 1651–1652.
17.Akazome, M.; Enzu, M.; Takagi, K.; Matsumoto, S. Chirality 2011, 23,
Supporting Information
18.Ślebioda, M. Tetrahedron 1995, 51, 7829–7834.
Supporting Information File 1
Complete experimental procedures and characterization.
19.Neves Filho, R. A. W.; de Oliveira, R. N.; Srivastava, R. M.
J. Braz. Chem. Soc. 2007, 18, 1410–1414.
20.Joullie, M. M.; Lassen, K. M. ARKIVOC 2010, No. viii, 189–250.
21.Kobayashi, K.; Nakashima, T.; Mano, M.; Morikawa, O.; Konishi, H.
22.Abbas, M.; Wessjohann, L. Org. Biomol. Chem. 2012, 10, 9330–9333.
Supporting Information File 2
Figures of 1H and 13C NMR spectra.
23.de Greef, M.; Abeln, S.; Belkasmi, K.; Dömling, A.; Orru, R. V. A.;
Wessjohann, L. A. Synthesis 2006, 3997–4004.
24.Pick, R.; Bauer, M.; Kazmaier, U.; Hebach, C. Synlett 2005, 757–760.
Acknowledgements
The authors acknowledge support from the state of Saxony-
Anhalt (MK-LSA, WZW project “Lipopeptide”). We thank
Dr. Jürgen Schmidt and Ms. Annett Werner for HRMS and
HPLC support, respectively. R.A.W.N.F. is grateful to Brazilian
funds from CNPq for a Ph.D. fellowship.
25.Nenajdenko, V. G., Ed. Isocyanide Chemistry: Applications in
Synthesis and Material Science; Wiley-VCH: Weinheim, Germany,
26.Kreye, O.; Westermann, B.; Wessjohann, L. A. Synlett 2007,
27.Neves Filho, R. A. W.; Stark, S.; Morejon, M. C.; Westermann, B.;
Wessjohann, L. A. Tetrahedron Lett. 2012, 53, 5360–5363.
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