Investigation of Mn(III)-based oxidative free radical cyclization reactions toward the synthesis of triptolide: The effects of lanthanide triflates and substituents on stereoselectivity

Article abstract of DOI:10.1021/ja993598n

Mn(III)-mediated oxidative free radical cyclization reactions are useful for construction of polycyclic compounds. In the total synthesis of triptolide (3) and its related compounds, construction of tricyclic skeletons 4 and 5 was achieved by the Mn(OAc)<

Full text of DOI:10.1021/ja993598n

1658
J. Am. Chem. Soc. 2000, 122, 1658-1663
Investigation of Mn(III)-Based Oxidative Free Radical Cyclization
Reactions toward the Synthesis of Triptolide: The Effects of
Lanthanide Triflates and Substituents on Stereoselectivity
Dan Yang,* Xiang-Yang Ye, Ming Xu, Kwan-Wah Pang, and Kung-Kai Cheung
Contribution from the Department of Chemistry, The UniVersity of Hong Kong,
Pokfulam Road, Hong Kong
ReceiVed October 6, 1999
Abstract: Mn(III)-mediated oxidative free radical cyclization reactions are useful for construction of polycyclic
compounds. In the total synthesis of triptolide (3) and its related compounds, construction of tricyclic skeletons
4 and 5 was achieved by the Mn(OAc)3-mediated oxidative radical cyclization of a series of acyclic precursors
6-9. The addition of a catalytic amount of lanthanide triflates was found to significantly improve the rate and
stereoselectivity of those radical cyclization reactions. The effects of the benzylic oxygen substituents and
R-substituents (chloro and methyl) on the radical cyclization reactions were also investigated. Transition-state
models were proposed to explain the observed stereoselectivity.
Introduction
Scheme 1
Mn(III)-mediated oxidative free radical cyclization reactions
are an important class of reactions for organic synthesis.1,2 The
oxidative free radical cylization reactions of unsaturated â-keto
esters were proposed to proceed in at least three steps (Scheme
1).2,3 Mn(OAc)3 promotes enol formation and then functions
as a single-electron oxidant to generate the electrophilic radical,
which subsequently adds to the CdC double bond. These
reactions allow formation of multiple C-C bonds with excellent
stereoselectivities, mild reaction conditions, and compatibility
with a range of functional groups. As an attractive alternative
to the olefin-cation polycyclization method,4 the oxidative
radical cyclization method has been successfully applied to the
construction of monocyclic, bicyclic, tricyclic, and tetracyclic
compounds.5 For examples, Snider et al. used cyclization of
â-keto ester 1 to obtain tricyclic compound 2, the key inter-
mediate for the synthesis of podocarpic acid (Scheme 2).6
Scheme 2
In our total synthesis of triptolide (3)7 and its related com-
pounds, construction of tricyclic skeletons 4 and 5 was achieved
by the Mn(OAc)3-mediated oxidative radical cyclization of a
series of acyclic precursors 6-9 (Chart 1). We found that
lanthanide triflates have significant effects on the rate and
stereoselectivity of those radical cyclization reactions. We also
investigated the effects of the benzylic oxygen substituents and
R-substituents (chloro and methyl) on the radical cyclization
reactions. The results are disclosed herein. A portion of the work
was published earlier.8
(1) (a) Bush, J. B., Jr.; Finkbeiner, H. J. Am. Chem. Soc. 1968, 90, 5903.
(b) Heiba, E. I.; Dessau, R. M.; Koehl, W. J., Jr. J. Am. Chem. Soc. 1968,
90, 5905. (c) Heiba, E. I.; Dessau, R. M.; Rodewald, P. G. J. Am. Chem.
Soc. 1974, 96, 7977 (d) Corey, E. J.; Kang, M-C. J. Am. Chem. Soc. 1984,
106, 5384.
(2) For an excellent recent review on manganese(III)-based oxidative
free radical cyclizations, see: Snider, B. B. Chem. ReV. 1996, 96, 339.
(3) (a) Snider, B. B.; Patricia, J. J.; Kates, S. A. J. Org. Chem. 1988, 53,
2137 and references therein. (b) Curran, D. P.; Morgan, T. M.; Schwartz,
C. E.; Snider, B. B.; Dombroski, M. A. J. Am. Chem. Soc. 1991, 113, 6607.
(c) Dombroski, M. A.; Kates, S. A.; Snider, B. B. J. Am. Chem. Soc. 1990,
112, 2759.
(4) For reviews on olefin cation cyclization reactions, see: (a) Bartlett,
P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New
York, 1984; Vol. 3, part B, p 341. (b) Sutherland, J. K. In ComprehensiVe
Organic Synthesis; Trost, B. M., Flemming, I., Eds.; Pergamon: Oxford,
1991; Vol. 3, Chapter 1.9, p 341.
(5) For examples, see: (a) Snider, B. B.; Kiselgof, J. Y.; Foxman, B.
M. J. Org. Chem. 1998, 63, 7945. (b) Snider, B. B.; Dombroski, M. A. J.
Org. Chem. 1987, 52, 5487. (c) Dombroski, M. A.; Kates, S. A.; Snider,
B. B. J. Am. Chem. Soc. 1990, 112, 2759. (d) Zoretic, P. A.; Fang, H.;
Ribeiro, A. A. J. Org. Chem. 1998, 63, 4779. (e) Zoretic, P. A.; Zhang, Y.;
Fang, H.; Ribeiro, A. A.; Dubay, G. J. Org. Chem. 1998, 63, 1162. (f)
Zoretic, P. A.; Wang, M.; Zhang, Y.; Shen, Z. J. Org. Chem. 1996, 61,
1806. (g) Zoretic, P. A.; Chen, Z.; Zhang, Y.; Ribeiro, A. A. Tetrahedron
Lett. 1996, 37, 7909. (h) Jones, P.; Pattenden, G. Synlett 1997, 398.
Results and Discussion
Oxidative Radical Cyclization Reactions in the Absence
of Lewis Acids. Acyclic precursors 6-9 were designed for the
Mn(III)-based radical cyclization reactions (Chart 1). Com-
pounds 6 and 7 possess oxygen substituents at the benzylic posi-
tion, whereas 8 and 9 have none. Compounds 6b and 9 con-
tain an R-substituent (chloro or methyl) in the â-keto ester
portion. The above precursors were synthesized by dianion dis-
placement6b,9 with various allylic bromides A-D (Scheme 3).
(6) (a) Snider, B. B.; Mohan, R.; Kates, S. A. J. Org. Chem. 1985, 50,
3659. (b) Zhang, Q.-W.; Mohan, R. M.; Cook, L.; Kazanis, S.; Peisach,
D.; Foxman, B. M.; Snider, B. B. J. Org. Chem. 1993, 58, 7640.
(7) Yang, D.; Ye, X.-Y.; Xu, M.; Pang, K.-W.; Zou, N.; Letcher, R. M.
J. Org. Chem. 1998, 63, 6446.
(8) Yang, D.; Ye, X.-Y.; Gu, S.; Xu, M. J. Am. Chem. Soc. 1999, 121,
5579.
10.1021/ja993598n CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/15/2000

Free Radical Cyclization Reactions
J. Am. Chem. Soc., Vol. 122, No. 8, 2000 1659
Chart 1
(TS2). Molecular mechanics calculations using the Macromodel
v4.5 program11 were carried out to account for the observed
stereoselectivity. The minimum global energies for the trans-
ring junction products with different configurations at the
benzylic position were calculated. The acetonide protected
compound 4a was found to be more stable than its benzylic
R-epimer by 1.32 kcal mol-1, and the MOM-protected com-
pound 11 was found to be more stable than its benzylic â-epimer
by 1.36 kcal mol-1, consistent with our experimental result. The
formation of compounds 4a and 11 demonstrated the high
stereoselectivity of the radical cyclization reactions as four stereo
centers were set up in one step.
In Snider’s case (Scheme 2), the cyclization reactions took
place at room temperature, and only the trans products were
found.6a Surprisingly, we obtained both trans- and cis-ring
junction products at 50 °C for radical cyclization of 6-8 (Table
1, entries 1, 3, and 5-7). For substrates 8a-c, the cis products
were isolated in up to 20% yield, and the trans/cis ratio was
only 5.5:2 as compared to the ratio of 5:1 for entries 1 and 3.
The isolation of cis products suggests that the cyclization of
those R-unsubstituted â-keto esters (6a and 7-8) might not go
through the concerted process which leads to the formation of
the trans products (Figure 2). Instead, a two-step process may
proceed. The intermediate radical (or cation) E adopts a chairlike
conformation.12 Further cyclization of this radical (or cation)
may occur in both the axial and the equatorial directions, which
gives the cis and the trans products, respectively.
Scheme 3
The radical cyclization reactions of compounds 6-9 were
carried out in acetic acid with 2.1 equiv of Mn(OAc)3‚2H2O
either at 50 °C or at room temperature. The results are
summarized in Table 1.
Effect of Oxygen Substituent at the Benzylic Position.
Radical cyclization of substrates 6a and 7, both bearing oxygen
substituents at the benzylic position, gave 40% yield for the
trans-ring junction products and 8% yield for the cis-ring
junction products at 50 °C (entries 1 and 3), but no reaction
took place at room temperature (entries 2 and 4). In comparison,
for the radical cyclization of 8a-c that have no benzylic
substituent, both the reaction rate and the yield were increased
(entries 5-7). It seems that substitution at the benzylic position
has a deleterious effect on the rate and yield of the radical
cyclization reactions, probably due to the increased tendency
for hydrogen abstraction at the benzylic position. This is
corroborated by the fact that the benzylic oxidation products
21 and 22 were isolated respectively from the radical cyclization
of 6a in MeOH and 6b under condition B (Scheme 4).
Compound 22 was further converted to its 2,4-DNP derivative
23.10 The structures of 21 and 23 were determined by X-ray
analysis.
The stereochemistries of cyclization products 4a, 10, 11, and
12 were determined by using 2D-COSY and NOESY, and the
structures of 4a and 10 were further confirmed by X-ray
structural analysis. Interestingly, the oxygen substituents at the
benzylic position of trans-ring junction products 4a and 11 have
completely different orientations, that is, the acetonide group
cis to the angular methyl group whereas the OMOM group trans
to it. The observed high stereoselectivities could be explained
using chairlike transition-state models shown in Figure 1. For
the cyclization of 6a, the acetonide group prefers the pseu-
doequatorial position due to ring constraint, affording the
cyclization product 4a with the benzylic oxygen in the â-ori-
entation (TS1). However, the OMOM group at the benzylic
position of 7 prefers the pseudoaxial orientation in order to avoid
the steric interaction with the methoxy group on the phenyl ring
Effect of r-Substituent. r-Chloro Substituent. According
to the literature,13 the presence of an R-chloro group can prevent
the overoxidation of the â-keto esters and increase the yield.
We found that, in the presence of R-chloro group, the substrates
6b and 9a were more reactive and the cyclization reactions could
be carried out at room temperature (entries 8 and 9). The
cyclization products 16-19 all have the trans configuration for
the ring junction, with the ester group of the major diastereomers
16 and 18 in the axial position (cis to the angular methyl group),
whereas that of the minor isomers 17 and 19 in the equatorial
position (trans to the angular methyl group). The structures of
16, 18, and 19 were determined by X-ray analysis. The fact
that no cis-ring junction product was found suggests that in the
presence of R-chloro group the radical cyclization reaction is
fast enough and proceeds through a concerted pathway.
Subsequent dechlorination of compounds 16/17 and 18/19 with
zinc in acetic acid14 afforded the tricyclic products 5a (99%
yield) and 4b (88% yield), respectively. Although one more
step is required, the overall yield of 5a is higher compared with
the direct cyclization of 8a (entry 5).
The stronger preference for the ester group in the axial
position than for the chloro group is surprising given that the
ester group in the axial position of a cyclohexane is less fav-
orable than the chloro group due to larger 1,3-diaxial repulsion.15
However, ab initio calculation using Gaussian 94 program16
(11) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 11, 440.
(12) Jensen, F. R.; Gale, L. H.; Rodgers, J. E. J. Am. Chem. Soc. 1968,
90, 5793.
(13) (a) Snider, B. B.; McCarthy, B. A. Tetrahedron 1993, 49, 9447.
(b) Lee, E.; Lim, J. W.; Yoon, C. H.; Sung, Y.-S.; Kim, Y. K.; Yun, M.;
Kim, S. J. Am. Chem. Soc. 1997, 119, 8391.
(14) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1985, 26, 4291.
(15) In the cyclohexane system, the conformational energies -∆G° (or
A values) for Cl group and COOCH3 group are 0.53-0.64 kcal mol-1 and
1.2-1.3 kcal mol-1, respectively. See: Eliel, E. L.; Wilen, S. H.; Mander,
L. N. In Stereochemistry of Organic Compounds; John Wiley & Sons: New
York, 1994; Chapter 11, pp 695-697.
(9) (a) Axelrod, E. H.; Milne, G. M.; van Tamelen, E. E. J. Am. Chem.
Soc. 1970, 92, 2139. (b) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974,
96, 1082.
(10) Behforouz, M.; Bolan, J. L.; Flynt, M. S. J. Org. Chem. 1985, 50,
1186.

1660 J. Am. Chem. Soc., Vol. 122, No. 8, 2000
Yang et al.
Table 1. Mn(III)-Based Oxidative Free Radical Cyclization of 6-9a
a All reactions were carried out in degassed acetic acid with 2.2 equiv of Mn(OAc)3‚2H2O at 0.1 M of the substrate concentration. b Condition
A: 50 °C, 1 h; condition B: room temperature, 4-6 h. c Isolated yield. d The reaction time was 8-9 h with 80% conversion. e The reaction time
was 8 h.
indeed suggested a slightly stronger preference for the axial
CO2CH3 group than for the axial Cl group (Figure 3).
The H NMR spectra revealed higher percentages of enol
presence of R-methyl substituent also accelerates the radical
cyclization reactions.6 X-ray structural analysis of compound
20 revealed the axial orientation of the ester group. This can be
explained using transition-state models shown in Figure 4. There
are two transition states for the cyclization reaction, one having
the ester group in the axial position and the other having the
ester group in the equatorial position. It is more favorable to
1
forms present in 6b (30%) and 9a (21%) than those in 6a (5%)
and 8a (5%), respectively, due to the electron negativity of the
R-chloro group. The relative reactivity of 6a vs 6b and 8a vs
9a might correlate with the percentage of the enol forms present
at equilibrium.3a Furthermore, the electron-withdrawing chloro
group makes the R-radical more electrophilic, and thus the
addition of this radical to the CdC bond is also accelerated.
r-Methyl Substituent. The cyclization reaction of compound
9b was carried out at room temperature in HOAc, affording
trans-ring junction product 20 as a single isomer in 64% yield
(Table 1, entry 10). No cis-ring junction product was isolated.
Comparing entry 10 with entries 5 and 6, we find that the
(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, T. A.; Peterson, G.
A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski,
V. G.; Oriz, J. V.; Foresman, J. B.; Cioslowski, J.; Stefanov, B. B.;
Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.;
Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.;
Fox, D. J. Binkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-
Gordon, M.; Gonzalez, C.; Pople, J. A. Gaussian 94, revision A.1; Gaussian,
Inc.: Pittsburgh, PA, 1995.

Free Radical Cyclization Reactions
J. Am. Chem. Soc., Vol. 122, No. 8, 2000 1661
entry 1). In the presence of 1.0 equiv of Yb(OTf)3‚H2O, the
radical cyclization reaction of 8a was complete in 9 h with the
trans and cis products isolated in 69 and 6% yields, respectively
(entry 2). Apparently, the reaction was faster and the trans/cis
ratio was improved from 2.2:1 to 11:1.
We then examined the solvent effect. The reaction in DMSO
was slow at room temperature even with 1.0 equiv of Yb(OTf)3
(Table 2, entry 3). In methanol, the reaction was very slow in
the absence of Ln(OTf)3 (entry 4). With the addition of Yb-
(OTf)3 (1 equiv), the reaction in methanol proceeded much faster
(entry 5), but the yield was not satisfactory. In MeOH or HOAc/
MeOH mixed solvents at 0 °C, the radical cyclization resulted
in low yields even in the presence of Yb(OTf)3 (entries 6-8).
Using CF3CH2OH as the solvent, the reaction at 0 °C was very
slow in the absence of Yb(OTf)3 (entry 9). However, with 1.0
equiv of Yb(OTf)3, the reaction was complete in 3 h, and the
trans product was isolated in 69% yield together with 10% of
the cis product (entry 10). Therefore, CF3CH2OH was found to
be a suitable solvent for the radical cyclization of compound
8a, with satisfactory rate and yield.
Figure 1.
Scheme 4
Besides Yb(OTf)3, more than 10 lanthanide triflates were
evaluated in the Mn(III)-based radical cyclization of 8a (Table
2, entries 10-22). Among them, Yb(OTf)3 and Er(OTf)3 are
more effective Lewis acids than others in promoting the radical
cyclization (entries 10 and 13). In addition, the use of a catalytic
amount of lanthanide triflates did not decrease the yields
significantly (entries 10 vs 11, 13 vs 14, and entry 18). These
results clearly indicate that lanthanide triflates catalyze the
Mn(III)-based radical cyclization reactions.
To elucidate the effect of lanthanide triflates, 1H NMR studies
on the enol formation of ethyl acetoacetate in the presence and
in the absence of Yb(OTf)3 were carried out (Table 3). The
results revealed that, in the presence of Yb(OTf)3, the percentage
of the enol form was significantly increased. It seems possible
that the Yb(OTf)3 accelerates the radical cyclization through
the increase of enol population. Furthermore, with the chelation
by Yb(OTf)3, the R-radical may become more electrophilic
(Figure 5), and the addition of this radical to CdC bond may
also be accelerated, hence increasing the reaction rate and the
trans/cis ratio.
We also examined the effect of lanthanide triflates on the
radical cyclization of compounds 6a, 6b, 9a, and 9b. We found
that, in the presence of Yb(OTf)3, substrates 6a, 6b, and 9a
bearing the benzylic acetonide-protecting group or the R-chloro
group decomposed quickly (Table 4, entries 1-3). For the
R-methyl-substituted substrate 9b (entry 4), the radical cycliza-
tion reaction carried out at 0 °C in the absence of Yb(OTf)3
was not complete in 8 h (74% conversion), and two diastere-
omers 20 and 24 were isolated in 26% and 5% yields,
respectively. The predominant formation of 20 is a result of
the steric effect in the transition states as shown in Figure 4. In
contrast, the cyclization of 9b in the presence of 1 equiv of
Yb(OTf)3 proceeded faster as the starting material disappeared
in 8 h (entry 5). The trans-ring junction products 20 and 24
were isolated in 7 and 18% yields, respectively, along with a
side product 25 (31% yield).
have the ester group in the axial position than it is for the methyl
group because the ester group has less 1,3-diaxial repulsion with
the angular methyl group.17 As a result, compound 20 was
obtained as the major cyclization product. This is in agreement
with the selectivity observed by Snider and co-workers for the
cyclization of 1b (Scheme 2).6
Oxidative Radical Cyclization Reactions in the Presence
of Lewis Acids. According to the proposed mechanism for the
Mn(III)-mediated oxidative radical cyclization reactions (Scheme
1),3 one of the functions of Mn(OAc)3 is to act as a Lewis acid
to promote the enol formation. We conjectured that, when a
stronger Lewis acid is used, the enol formation would be more
favorable and the electrophilicity of the radical would be
enhanced by chelation to the Lewis acid, thereby increasing the
rates for radical cyclization reactions. In fact, recent studies
reveal that Lewis acids can accelerate some radical reactions,
including radical addition and atom-transfer reactions, and can
enhance the stereoselectivity of those reactions.18 Therefore, the
effect of Lewis acids on the oxidative radical cyclization
reactions was investigated.
Lanthanide triflates, Ln(OTf)3, have been used as Lewis acid
catalysts in protic solvents for a variety of reactions, such as
Aldol condensation reactions, Michael reactions, Friedel-Crafts
acylations, and Diels-Alder reactions.19 Thus, a series of
lanthanide triflates were tested in the Mn(OAc)3-mediated
radical cyclization of compound 8a (Table 2).
(18) For a recent review of Lewis acids in free radical reactions, see:
Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. 1998, 37, 2562.
(19) (a) For the review of Ln(OTf)3 as Lewis acid catalysts in organic
synthesis, see: Kobayashi, S. Synlett 1994, 689. (b) Kobayashi, S.; Hachiya,
I. J. Org. Chem. 1994, 59, 3590. (c) Kobayashi, S.; Hachiya, I.; Takahori,
T.; Araki, M.; Ishitani, H. Tetrahedron Lett. 1992, 6815. (d) Kawada, A.;
Mitamura, S.; Kobayashi, S. J. Chem. Soc., Chem. Commun. 1993, 1157.
(e) Kawada, A.; Mitamura, S.; Kobayashi, S. Synlett. 1994, 545. (f) Yu,
L.-B.; Li, J.; Ramirez, J.; Chen, D.-P.; Wang, P. G. J. Org. Chem. 1997,
62, 903.
In the absence of lanthanide triflates, the radical cyclization
reaction of 8a was very slow at room temperature in HOAc,
and some starting material remained even after 20 h (Table 2,
(17) In the cyclohexane system, the 1,3-diaxial interaction (expressed
as free energy difference -∆G°) for CH3/CH3 groups and CH3/COOEt
groups are 3.7, and 2.8-3.2 kcal mol-1, respectively. See: Eliel, E. L.;
Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; John
Wiley & Sons: New York, 1994; Chapter 11, pp 706-707.

1662 J. Am. Chem. Soc., Vol. 122, No. 8, 2000
Yang et al.
Table 2. Ln(OTf)3-Promoted Oxidative Free-Radical Cyclization
of 8a Mediated by Mn(OAc)3‚2H2Oa
reaction
yield
Ln(OTf)3
(equiv)
temp reaction
(%)b
entry
solvent
HOAc
(°C)
time (h) 5a/13a
1
2
3
4
5
6
7
none
rt
rt
rt
rt
rt
0
9
9
45/15
69/6
Yb(OTf)3‚H2O (1.0) HOAc
Yb(OTf)3‚H2O (1.0) DMSO
24
24
10
17
24
NAc
none
MeOH
NAc
Yb(OTf)3‚H2O (1.0) MeOH
Yb(OTf)3‚H2O (1.0) MeOH
Yb(OTf)3‚H2O (1.0) HOAc/MeOH
(9:1)
30/trace
26/trace
NAc
0
8
9
Yb(OTf)3‚H2O (1.0) HOAc/MeOH
0
24
NAc
(8:2)
none
CF3CH2OH
0
0
0
0
0
0
0
0
0
0
0
0
0
0
24
3
3.5
36/7
69/10
59/8
52/14
73/2
67/7
63/8
53/9
57/7
63/7
39/13
29/6
33/14
21/3
10d Yb(OTf)3‚H2O (1.0) CF3CH2OH
11 Yb(OTf)3‚H2O (0.3) CF3CH2OH
Figure 2.
12 Eu(OTf)3 (1.0)
13 Er(OTf)3 (1.0)
14 Er(OTf)3 (0.2)
15 Sm(OTf)3 (1.0)
16 Tb(OTf)3 (1.0)
17 Y(OTf)3 (1.0)
18 Pr(OTf)3 (0.2)
19 La(OTf)3 (1.0)
20 Tm(OTf)3 (1.0)
21 Dy(OTf)3 (1.0)
22 Gd(OTf)3 (1.0)
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
CF3CH2OH
2
2.5
6.5
3
2.5
3.5
5
2
2.5
2.5
2
Figure 3.
a
All reactions were carried out at 0.1 M concentration in the
degassed solvent with 2.2 equiv of Mn(OAc)3‚2H2O. b Isolated yield.
c The reaction was very slow. No attempt was made to isolate the
products. d Use of anhydrous Yb(OTf)3 gave similar result.
Table 3. NMR Studies on the Enol Population of Ethyl
Acetoacetatea
Figure 4.
a The 1H NMR spectra (300 MHz) were recorded in CD3OD. b The
percentage of enol form was calculated by the integration of the C-4
methyl signals.
Note that, in the presence of Yb(OTf)3, the ratio of 20/24
was reversed (5.2:1 for entry 4, and 1:2.6 for entry 5). We
explain this result using the Yb(OTf)3 chelation model (Scheme
5). Yb(OTf)3 can bind to the â-keto ester 9b and lock the two
carbonyl groups in a syn orientation, thereby accelerating the
radical cyclization process and affording 24 (the thermodynami-
cally less stable isomer) as the major product. The side product
25 was also formed as a result of the chelation of Yb(OTf)3 to
the two carbonyl groups (Scheme 5). In this case, the first C-C
bond was formed significantly faster than the second one, and
the radical intermediate F was further oxidized by Mn3+ to
cation G, which was then trapped intramolecularly by the ester
group to form 25.
agents.7 In addition, our study opens up the possibility of using
chiral Lewis acids to catalyze the enantioselective Mn(III)-based
free radical cyclization reactions.20 Work in that direction is in
progress.
Experimental Section
Typical Procedure for the Radical Cyclization in the Absence
of Lanthanide Triflates. To a solution of 8c (376 mg, 1.0 mmol) in
degassed acetic acid (10 mL) was added Mn(OAc)3‚2H2O (590 mg,
2.2 mmol). The mixture was stirred at 50 °C for 1 h. A solution of
NaHSO3 (10%) was added to quench the reaction. The mixture was
extracted with CH2Cl2. The extracts were dried with anhydrous sodium
sulfate, filtered, and concentrated. The residue was purified by flash
column chromatography to afford compound 14 (205.7 mg, 55% yield)
and 15 (74.8 mg, 20% yield).
Typical Procedure for the Radical cyclization in the Presence
of Lanthanide Triflates. To a solution of acyclic precursor 8a (346
mg, 1.0 mmol) in degassed CF3CH2OH (10 mL) was added Yb(OTf)3‚
H2O (620 mg, 1.0 mmol) under argon atmosphere. The mixture was
stirred at room temperature for 10 min, then cooled to 0 °C. Mn(OAc)3‚
2H2O (590 mg, 2.2 mmol) was added in one portion. The reaction was
monitored by TLC. Saturated NaHSO3 solution was added to the
In summary, lanthanide triflates can catalyze the Mn(III)-
based oxidative radical cyclization reactions of â-keto esters
with or without R-substituents. For the latter class of substrates,
excellent stereoselectivities and yields have been obtained.
Conclusions
An efficient and stereoselective Mn(OAc)3-mediated oxidative
free radical cyclization method has been developed, which
utilizes lanthanide triflates as Lewis acid catalysts. This method
should have many applications in synthesis of polycyclic natu-
ral products. In fact, compounds 4, 5, 14, and 16 have re-
cently been demonstrated as key intermediates in synthesis of
triptolide (3) and its various analogues in our efforts on
developing new antiinflammatory and immunosuppressive
(20) (a) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1990, 23, 163. (b)
Wu, J. H.; Radinov, R.; Porter, N. A. J. Am. Chem. Soc. 1995, 117, 11029.
(c) Sibi, M. P.; Ji, J. Wu, J. H.; Gurtler, S.; Porter, N. J. Am. Chem. Soc.
1996, 118, 9200. (d) Porter, N. A.; Wu, J. H.; Zhang, G.; Reed, A. D. J.
Org. Chem. 1997, 62, 6702.

Free Radical Cyclization Reactions
J. Am. Chem. Soc., Vol. 122, No. 8, 2000 1663
Table 4. Effect of Lanthanide Triflates on the Mn(III)-Based Radical Cyclization of R-Substituted Acyclic Precursorsa
a All of the reactions were carried out in degassed CF3CH2OH (0.1 M concentration) at 0 °C with 2.1 equiv of Mn(OAc)3‚2H2O. b Isolated
yields. c 74% conversion. d Starting material decomposed.
Scheme 5
Figure 5.
mixture which was then extracted with dichloromethane. The extracts
were dried with anhydrous sodium sulfate, filtered, and concentrated.
The residue was purified by flash column chromatography (8 to 16%
EtOAc in n-hexane) to afford 5a (237 mg, 69% yield) and 13a (34
mg, 10% yield).
Acknowledgment. This work was supported by the Uni-
data for compounds 5b, 11, 12, 13b, and 14-25; 2D-COSY
versity of Hong Kong and the Hong Kong Research Grants
Council. We thank Mr. Man-Fai Ng for performing the ab initio
calculation.
and 2D-NOESY spectra for compounds 16 and 17; X-ray
structural analysis for compounds 16, 18-21, 23, and 24 (print/
PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
Supporting Information Available: Experimental details
for the preparation of acyclic precursors 6-9; characterization
JA993598N