LETTER
Synthesis of New 4-Aza-2,3-didehydropodophyllotoxins
1477
(6) (a) Cortese, F.; Bhattacharyya, B.; Wolff, J. J. Biol. Chem.
1977, 252, 1134. (b) Andreu, J. M.; Timasheff, S. N.
Biochemistry 1982, 21, 6465. (c) Sackett, D. L. Pharm.
Ther. 1993, 59, 163.
(7) Kelly, M. G.; Hartwell, J. L. J. Nat. Cancer Inst. 1954, 14,
967.
(8) Stähelin, H. Eur. J. Cancer 1973, 9, 215.
(9) Stähelin, H. Eur. J. Cancer 1970, 6, 303.
(10) Gordaliza, M.; Castro, M. A.; Miguel del Corral, J. M.; San
With the desired intermediates 8a–c in hand, we next
studied the intramolecular C–N bond-forming reaction.
Buchwald–Hartwig palladium-catalyzed N-arylation25
was first tested using precursor 8a as the model substrate.
Unfortunately, the use of Pd2dba3 or Pd(OAc)2 as palladi-
um sources, 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl
(BINAP), P(o-Tol)3 or P(t-Bu)3 as ligands, and t-BuONa
as base at reflux of toluene did not afford the desired pen-
tacyclic product, the starting material being totally recov-
ered. A copper-mediated Ullmann-type N-arylation was
thus envisioned as an alternative.26 Much to our satisfac-
tion, treatment of the benzhydrylated N-benzyl tetrona-
mide 8a with CuI (1.2 equiv) and Cs2CO3 (2.5 equiv) in
DMF gave, after 16 hours at 90 °C, according to Fukuya-
ma’s protocol,27 the expected 4-aza-2,3-didehydropodo-
phyllotoxin 9a in quantitative yield (Scheme 5).
Analogously, starting from the N-substituted tetronamide
precursors 8b and 8c, the corresponding aza-analogues 9b
and 9c were obtained in 82% and 84% yields, respective-
ly.28,29
Feliciano, A. Curr. Pharm. Des. 2000, 6, 1811.
(11) MacDonald, T. L.; Lehnert, E. K.; Loper, J. T.; Chow, K. C.;
Ross, W. E. On the Mechanism of Interaction of DNA
Topoisomerase II with Chemotherapeutic Agents, In DNA
Topoisomerase in Cancer; Potmesil, M.; Kohn, K. W., Eds.;
Oxford University Press: New York, 1991, 119.
(12) Axelson, M.; Larsson, O. PCT Int. Appl., WO 093781, 2004.
(13) (a) Baserga, R. Cancer Res. 1995, 55, 249. (b) Baserga, R.
Oncogene 2000, 19, 5574. (c) Girnita, L.; Girnita, A.;
Larsson, O. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 8247.
(d) Girnita, L.; Girnita, A.; Brodin, B.; Xie, Y.; Nilsson, G.;
Dricu, A.; Lundeberg, J.; Wejde, J.; Bartolazzi, A.; Wiman,
K. G.; Larsson, O. Cancer Res. 2000, 60, 5278.
(14) For recent examples of aza-analogues of podophyllotoxin,
see: (a) Magedov, I. G.; Manpadi, M.; Rozhkova, E.;
Przheval’skii, N. M.; Rogelj, S.; Shors, S. T.; Steelant, W. F.
A.; Van slambrouck, S.; Kornienko, A. Bioorg. Med. Chem.
Lett. 2007, 17, 1381. (b) Magedov, I. G.; Manpadi, M.;
Van Slambrouck, S.; Steelant, W. F. A.; Rozhkova, E.;
Przheval’skii, N. M.; Rogelj, S.; Kornienko, A. J. Med.
Chem. 2007, 50, 5183. (c) Dorbec, M.; Florent, J.-C.;
Monneret, C.; Rager, M. N.; Bertounesque, E. Synlett 2006,
591. (d) Labruère, R.; Helissey, P.; Desbène-Finck, S.;
Giorgi-Renault, S. J. Org. Chem 2008, 73, 3642.
(15) Hitotsuyanagi, Y.; Kobayashi, M.; Fukuyo, M.; Takeya, K.;
Itokawa, H. Tetrahedron Lett. 1997, 38, 8295.
In summary, three aza-analogues of podophyllotoxin have
been synthesized in two steps using N-alkyl tetronamides
as suitable ambident D-ring generating building blocks.
The cyclization precursors were formed through the
Lewis acid mediated benzhydrylation of N-alkyl tetrona-
mides with a suitably functionalized benzhydrol. The de-
sired pentacyclic structure of the 4-aza-2,3-
didehydropodophyllotoxins was next obtained via an in-
tramolecular copper-mediated Ullmann-type N-arylation.
The elaboration of the cyclization precursors by a multi-
component reaction and the development of a copper-cat-
alyzed N-arylation of these enamines are currently under
investigation.
(16) Hitotsuyanagi, Y.; Fukuyo, M.; Tsuda, K.; Kobayashi, M.;
Ozeki, A.; Itokawa, H.; Takeya, K. Bioorg. Med. Chem. Lett.
2000, 10, 315.
(17) (a) Tratrat, C.; Giorgi-Renault, S.; Husson, H.-P. Org. Lett.
2002, 4, 3187. (b) Giorgi-Renault, S. Ann. Pharm. Fr. 2005,
63, 63. (c) Husson, H.-P.; Giorgi-Renault, S.; Tratrat, C.;
Atassi, G.; Pierre, A.; Renard, P.; Pfeiffer, B. Eur. Patent,
EP1103554, 2000.
Acknowledgment
CNRS, CNR and UPMC are acknowledged for financial support.
The sponsorship of COST Action D40 ‘Innovative Catalysis: New
Processes and Selectivities’ is kindly acknowledged.
(18) Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002,
1823.
(19) Mingoia, F.; Vitale, M.; Madec, D.; Prestat, G.; Poli, G.
Tetrahedron Lett. 2008, 49, 760.
(20) Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456.
(21) For previous use of N-benzyl tetronamides as building block,
see: (a) Sydorenko, N.; Hsung, R. P.; Darwish, O. S.; Hahn,
J. M.; Liu, J. J. Org. Chem. 2004, 69, 6732.
References and Notes
(1) Present address: Istituto per lo Studio dei Materiali
Nanostrutturati, CNR, Via Ugo La Malfa 153, 90146
Palermo, Italy
(b) McLaughlin, M. J.; Hsung, R. P.; Cole, K. C.; Hahn, J.
M.; Wang, J. Org. Lett. 2002, 4, 2017. (c) See also Pévet, I.;
Meyer, C.; Cossy, J. Synlett 2003, 663.
(2) (a) Sellars, J. D.; Steel, P. G. Eur. J. Org. Chem. 2007, 3815.
(b) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75. (c) Ward, R.
S. Nat. Prod. Rep. 1997, 14, 43. (d) Ward, R. S. Nat. Prod.
Rep. 1995, 12, 183. (e) Ward, R. S. Nat. Prod. Rep. 1993,
10, 1.
(22) Momose, T.; Toyooka, N.; Nishi, T.; Takeuchi, Y.
Heterocycles 1988, 27, 1907.
(23) Jung, M. E.; Lam, P. Y. S.; Mansuri, M. M.; Speltz, L. M.
J. Org. Chem. 1985, 50, 1087.
(3) Podwyssotzki, V. Arch. Exp. Pathol. Pharmakol. 1880, 13,
29.
(24) Representative Experimental Procedure for
Benzhydrylation Reaction: To a stirred solution of
benzhydrol 6 (437 mg, 1.1 mmol, 1.1 equiv) and enamine 4a
(189 mg, 1 mmol) in anhyd CH2Cl2 (10 mL) under a N2
atmosphere at r.t. was added BF3⋅OEt2 (0.380 mL, 3 equiv).
The mixture was stirred for 2 h before a sat. aq NaHCO3
solution (10 mL) was added. The aqueous layer was
extracted with Et2O (3 × 10 mL). The organic layers were
washed with brine (5 mL), dried over MgSO4 and
(4) King, L.; Sullivan, M. Science 1946, 104, 244.
(5) For reviews, see: (a) Damayanthi, Y.; Lown, J. W. Curr.
Med. Chem. 1998, 5, 205. (b) Zhang, Y.; Lee, K.-H. Chin.
Pharm. J. 1994, 46, 319. (c) Ramos, A. C.; Pelaéz-
Lamamié de Clairac, R.; Medarde, M. Heterocycles 1999,
51, 1443. (d) Ward, R. S. Chem. Soc. Rev. 1982, 75.
(e) Ward, R. S. Synthesis 1992, 719. (f) Castro, M. A.;
Gómez-Zurita, M. A. Toxicon 2004, 44, 441.
Synlett 2008, No. 10, 1475–1478 © Thieme Stuttgart · New York