J. Am. Chem. Soc. 1999, 121, 5579-5580
5579
Lanthanide Triflates Catalyze Mn(III)-Based
Oxidative Radical Cyclization Reactions.
Enantioselective Synthesis of (-)-Triptolide,
(-)-Triptonide, and (+)-Triptophenolide
Dan Yang,* Xiang-Yang Ye, Shen Gu, and Ming Xu
Figure 1.
Department of Chemistry
The UniVersity of Hong Kong
Pokfulam Road, Hong Kong
Scheme 1
ReceiVed January 19, 1999
The Mn(OAc)
3
-mediated oxidative free radical cyclization
method has been successfully used for construction of polycyclic
ring structures found in many natural products, especially
1
terpenoids. The excellent stereoselectivities, mild reaction condi-
Scheme 2
Scheme 3
tions, and compatibility with a range of functional groups render
the radical cyclization method an attractive alternative to the
olefin-cation polycyclization method. However, enantioselective
radical cyclization remains a significant challenge. Herein we
report a highly enantioselective radical cyclization approach to
2
3
(
-)-triptolide (Figure 1), a potent antitumor and immunosup-
pressive agent isolated from the Chinese medicinal plant Trip-
terygium wilfordii Hook F (Lei Gong Teng).4
In our synthetic route to (()-triptolide and its various ana-
5
logues, a Mn(OAc)
3
-mediated radical cyclization reaction of
compound 4a or 4b was employed to construct the tricyclic core
Scheme 1), providing trans product 5a or 5b, respectively, as
(
3a
the major isomer. On the basis of Snider’s method, we used
-)-8-phenylmenthol as the chiral auxiliary, and obtained up to
:1 diastereomer ratio of 8 and 9 for the radical cyclization of
Lanthanide triflates, Ln(OTf) , have been used as Lewis acid
3
(
9
catalysts in protic solvents for a variety of reactions, such as Aldol
8
9
condensations and aza Diels-Alder reactions. Thus, several
chiral â-keto ester 7 (Scheme 2). The oxidative radical cyclization
lanthanide triflates were tested in the Mn(OAc) -mediated radical
3
reactions were proposed to proceed in at least three steps (Scheme
cyclization of achiral compounds 4a and 4b (Table 1). Without
6
3
). Mn(OAc)
3
functions as a Lewis acid (LA) to promote enol
Ln(OTf) , cyclization reactions were very slow in HOAc at room
3
formation and then as a single electron oxidant to generate the
electrophilic radical, which subsequently adds to the CdC double
bond. We conjectured that, when a stronger LA is used, the enol
formation would be more favorable and the electrophilicity of
the radical would be enhanced by chelation to the LA, thereby
increasing the rates for radical cyclization reactions. Furthermore,
recent studies reveal that LA may enhance the stereoselectivity
temperature or in CF CH OH at 0 °C (entries 1-3). However, in
3
2
the presence of ytterbium triflate, the reactions proceeded
remarkably faster, providing higher yields as well as better
stereoselectivities (entries 4-6). The reaction in CF CH OH at 0
3
2
°C appeared to be faster than that in HOAc at room temperature
(entry 4 vs 5). Among the lanthanide triflates tested, Yb(OTf)3
and Er(OTf) were found to be better than others (entries 5-13).
3
7
of radical addition reactions. Therefore, the effect of LA on the
oxidative radical cyclization reactions was investigated.
Most importantly, the use of a catalytic amount of Ln(OTf) did
3
not result in a significant decrease in yields (entry 7 vs 8). These
results clearly indicate that lanthanide triflates catalyze the Mn-
(
1) (a) For a recent review on manganese(III)-based oxidative free radical
(OAc)
-mediated radical cyclization reactions.10
3
cyclization reactions, see: Snider, B. B. Chem. ReV. 1996, 96, 339. (b) Snider,
B. B.; Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1998, 63, 7945. (c)
Dombroski, M. A.; Kates, S. A.; Snider, B. B. J. Am. Chem. Soc. 1990, 112,
For radical cyclization of the (-)-8-phenylmenthyl ester 7a,
the syn and anti orientations of the two carbonyl groups may lead
to opposite chiral induction based on the favorable chairlike
transition states (Figure 2). In the syn orientation, the 8-phenyl
group can effectively shield the (si)-face of the radical and restrict
the cyclization to the (re)-face to give 8a. In the anti orientation,
however, only the (si)-face is accessible for the radical cyclization,
providing diastereomer 9a. As the bidentate chelation of â-keto
2
759. (d) Snider, B. B.; Dombroski, M. A. J. Org. Chem. 1987, 52, 5487. (e)
Snider, B. B.; Mohan, R. M.; Kates, S. A. Tetrahedron Lett. 1987, 28, 841.
f) Zoretic, P. A.; Fang, H.; Ribeiro, A. A. J. Org. Chem. 1998, 63, 4779. (g)
Zoretic, P. A.; Zhang, Y.; Fang, H.; Ribeiro, A. A.; Dubay, G. J. Org. Chem.
998, 63, 1162. (h) Zoretic, P. A.; Wang, M.; Zhang, Y.; Shen, Z. J. Org.
Chem. 1996, 61, 1806.
2) (a) For a recent review on olefin-cation cyclization reactions, see:
(
1
(
Sutherland, J. K. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Flemming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, Chapter 1.9. For
examples of asymmetric olefin-cation cyclization reactions, see: (b) Johnson,
W. S.; Harbert, C. A.; Ratcliffe, B. E.; Stipanovic, R. D. J. Am. Chem. Soc.
3
esters to Ln(OTf) would lock the two carbonyl groups in a syn
orientation, we expect to obtain higher diastereoselectivity for
1
1
976, 98, 6188. (c) Corey, E. J.; Luo, G.; Lin, L. S. Angew. Chem., Int. Ed.
998, 37, 1126, and references therein.
(7) (a) Guindon, Y.; Lavallee, J.-F.; Llinas-Brunet, M.; Horner, G.;
Rancourt, J. J. Am. Chem. Soc. 1991, 113, 9701. (b) Guindon, Y.; Guerin,
B.; Chabot, C.; Ogilvie, W. J. Am. Chem. Soc. 1996, 118, 12528. (c) Nishida,
M.; Ueyama, E.; Hayashi, H.; Ohtake, Y.; Yamaura, Y.; Yanaginuma, E.;
Yonemitsu, O.; Nishida, A.; Kawahara, N. J. Am. Chem. Soc. 1994, 116, 6455.
(d) Sibi, M. P.; Jasperse, C. P.; Ji, J. J. Am. Chem. Soc. 1995, 117, 10779. (e)
Sibi, M. P.; Ji, J. J. Am. Chem. Soc. 1996, 118, 3063. (f) Sibi, M. P.; Ji, J.
Angew. Chem., Int. Ed. Engl. 1996, 35, 190. (g) Sibi, M. P.; Ji, J. J. Org.
Chem. 1996, 61, 6090. (h) Sibi, M. P.; Ji, J. Angew. Chem., Int. Ed. Engl.
1997, 36, 274.
(
3) (a) Zhang, Q.; Mohan, R. M.; Cook, L.; Kazanis, S.; Peisach, D.;
Foxman, B. M.; Snider, B. B. J. Org. Chem. 1993, 58, 7640. (b) Snider, B.
B.; Wan, B. Y.-F.; Buckman, B. O.; Foxman, B. M. J. Org. Chem. 1991, 56,
3
28. (c) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: Weinheim, 1996.
(4) (a) Kupchan, S. M.; Court, W. A.; Dailey, R. G.; Gilmore, C. J.; Bryan,
R. F. J. Am. Chem. Soc. 1972, 94, 7194. (b) Kupchan, S. M.; Schubert, R. M.
Science 1974, 185, 791.
(5) Yang, D.; Ye, X.-Y.; Xu, M.; Pang, K.-W.; Zou, N.; Letcher, R. M. J.
Org. Chem. 1998, 63, 6446.
6) (a) Snider, B. B.; Patricia, J. J.; Kates, S. A. J. Org. Chem. 1988, 53,
137. (b) Curran, D. P.; Morgan, T. M.; Schwartz, C. E.; Snider, B. B.;
Dombroski, M. A. J. Am. Chem. Soc. 1991, 113, 6607.
(8) Kobayashi, S.; Hachiya, I. J. Org. Chem. 1994, 59, 3590.
(9) Yu, L.-B.; Li, J.; Ramirez, J.; Chen, D.-P.; Wang, P. G. J. Org. Chem.
1997, 62, 903.
(
2
(10) Further investigation on the role of LA in these reactions is underway.
1
0.1021/ja9901664 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/29/1999