of artemisinin via transition-metal-catalyzed intramolecular
C-H bond insertion reactions with carbenoids and nitrenoids.
In this work, four transition metal catalysts including Rh2-
(OAc)4, Rh2(pfb)4, [Rh(TTP)Cl], and [Ru(TTP)CO] were
used (Scheme 2). Three types of novel artemisinin derivatives
Scheme 1
Scheme 2
C-H functionalization via carbenoid and nitrenoid insertions
would be an appealing approach to achieve selective
modification of natural products such as artemisinin because
these reactions could be conducted under mild reaction
conditions. Artemisinin (Qinghaosu, 1)8 is a sesquiterpene
lactone endoperoxide which has been currently used for
clinical treatment of malaria.9 In addition, artemisinin and
its derivatives exhibit potent in vitro cytotoxicities against
cancer cells.10 Artemisinin derivatives were mainly synthe-
sized via chemical modifications of artemisinin at its C10 or
C16 position.11,12 Here, we report selective modification
have been synthesized through transition-metal-catalyzed
intramolecular C-H bond functionalization at the 1° (C16)
and 2° (C8 and C10) C-H bonds of artemisinin. Notably,
the delicate endoperoxide bridge remains intact over the
course of the C-H bond functionalization reactions.
At the outset, diazoester 3 and carbamate 4 were prepared
from readily available 10-dihydroartemisinin (DHA, 2) in
74% and 70% yields, respectively (Scheme 3, see Supporting
(5) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; Wiley: New York, 1998. (b) Doyle, M. P.; Forbes, D. C. Chem.
ReV. 1998, 98, 911-935. (c) Davies, H. M. L.; Beckwith, R. E. J. Chem.
ReV. 2003, 103, 2861-2903. (d) Davies, H. M. L.; Long, M. S. Angew.
Chem., Int. Ed. 2005, 44, 3518-3520. (e) Davies, H. M. L. Angew. Chem.,
Int. Ed. 2006, 45, 6422-6425. (f) Fiori, K. W.; Du Bois, J. J. Am. Chem.
Soc. 2007, 129, 562-568.
Scheme 3
(6) (a) Bode, J. W.; Doyle, M. P.; Protopopova, M. N.; Zhou, Q. L. J.
Org. Chem. 1996, 61, 9146-9155. (b) Davies, H. M. L.; Jin, Q.
Tetrahedron: Asymmetry 2003, 14, 941-949. (c) Wehn, P. M.; Du Bois,
J. J. Am. Chem. Soc. 2002, 124, 12950-12951. (d) Hinman, A.; Du Bois,
J. J. Am. Chem. Soc. 2003, 125, 11510-11511.
(7) (a) Li, Y.; Huang, J. S.; Zhou, Z. Y.; Che, C. M.; You, X. Z. J. Am.
Chem. Soc. 2002, 124, 13185-13193. (b) Li, Y.; Huang, J. S.; Zhou, Z.
Y.; Che, C. M. Chem. Commun. 2003, 1362-1363. (c) Cheung, W. H.;
Zheng, S. L.; Yu, W. Y.; Zhou, G. C.; Che, C. M. Org. Lett. 2003, 5,
2535-2538. (d) Choi, M. K. W.; Yu, W. Y.; Che, C. M. Org. Lett. 2005,
7, 1081-1084. (e) Au, S. M.; Huang, J. S.; Yu, W. Y.; Fung, W. H.; Che,
C. M. J. Am. Chem. Soc. 1999, 121, 9120-9132. (f) Liang, J. L.; Yuan, S.
X.; Huang, J. S.; Yu, W. Y.; Che, C. M. Angew. Chem., Int. Ed. 2002, 41,
3465-3468. (g) Liang, J. L.; Yuan, S. X.; Huang, J. S.; Che, C. M. J. Org.
Chem. 2004, 69, 3610-3619. (h) Leung, S. K. Y.; Tsui, W. M.; Huang, J.
S.; Che, C. M.; Liang, J. L.; Zhu, N. J. Am. Chem. Soc. 2005, 127, 16629-
16640. (i) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am. Chem. Soc. 2006,
128, 9048-9049.
(8) (a) Klayman, D. L. Science 1985, 228, 1049-1055. (b) Eckstein-
Ludwig, U.; Webb, R. J.; van Goethem, I. D. A.; East, J. M.; Lee, A. G.;
Kimura, M.; O’Neill, P. M.; Bray, P. G.; Ward, S. A.; Krishna, S. Nature
2003, 424, 957-961. (c) Renslo, A. R.; McKerrow, J. H. Nat. Chem. Biol.
2006, 2, 701-710.
Information). Several attempts to synthesize the sulfamate
ester derivative of 2 failed, and only the dehydrated product
5 was obtained.
Treatment of diazoester 3 with 5 mol % of Rh2(OAc)4,
Rh2(pfb)4, or [Rh(TTP)Cl] at room temperature in 3 h gave
(9) (a) Robert, A.; Dechy-Cabaret, O.; Cazelles, J.; Meunier, B. Acc.
Chem. Res. 2002, 35, 167-174. (b) Li, Y.; Wu, Y. L. Curr. Med. Chem.
2003, 10, 2197-2230. (c) O’Neill, P. M.; Posner, G. H. J. Med. Chem.
2004, 47, 2945-2964. (d) Posner, G. H.; O’Neill, P. M. Acc. Chem. Res.
2004, 37, 397-404. (e) Haynes, R. K.; Ho, W. Y.; Chan, H. W.; Fugmann,
B.; Stetter, J.; Croft, S. L.; Vivas, L.; Peters, W.; Robinson, B. L. Angew.
Chem., Int. Ed. 2004, 43, 1381-1385. (f) Haynes, R. K. Angew. Chem.,
Int. Ed. 2005, 44, 2064-2065. (g) Haynes, R. K.; Fugmann, B.; Stetter, J.;
Rieckmann, K.; Heilmann, H. D.; Chan, H. W.; Cheung, M. K.; Lam, W.
L.; Wong, H. N.; Croft, S. L.; Vivas, L.; Rattray, L.; Stewart, L.; Peters,
W.; Robinson, B. L.; Edstein, M. D.; Kotecka, B.; Kyle, D. E.; Beckermann,
B.; Gerisch, M.; Radtke, M.; Schmuck, G.; Steinke, W.; Wollborn, U.;
Schmeer, K.; Romer, A. Angew. Chem., Int. Ed. 2006, 45, 2082-2088. (h)
Haynes, R. K. Curr. Top. Med. Chem. 2006, 6, 509-537.
(10) (a) Lai, H.; Sasaki, T.; Singh, N. P. Expert Opin. Ther. Tar. 2005,
9, 995-1007. (b) Disbrow, G. L.; Baege, A. C.; Kierpiec, K. A.; Yuan, H.;
Centeno, J. A.; Thibodeaux, C. A.; Hartmann, D.; Schlegel, R. Cancer Res.
2005, 65, 10854-10861. (c) Posner, G. H.; D’Angelo, J.; O’Neill, P. M.;
Mercer, A. Expert Opin. Ther. Pat. 2006, 16, 1665-1672. (d) Lee, S. Mini-
ReV. Med. Chem. 2007, 7, 411-422.
(11) (a) Ref 9. (b) Ref 10. (c) Chorki, F.; Grellepois, F.; Crousse, B.;
Hoang, V. D.; Hung, N. V.; Bonnet-Delpon, D.; Begue, J. P. Org. Lett.
2002, 4, 757-759. (d) Grellepois, F.; Crousse, B.; Bonnet-Delpon, D.;
Begue, J. P. Org. Lett. 2005, 7, 5219-5222.
4108
Org. Lett., Vol. 9, No. 21, 2007