First enantioselective syntheses of (+)- and (-)-wilforonide by using chiral auxiliaries derived from the same chiral source.

Article abstract of DOI:10.1021/ol015722p

[see structure]. The first enantioselective syntheses of both (+)-wilforonide (>98% ee) and (-)-wilforonide (>98% ee) have been accomplished by employing chiral auxiliaries derived from the same chiral source, (R)-pulegone. The bicyclic skeleton of wilforonide was constructed by using Mn(III)-based oxidative radical cyclization reactions of chiral beta-keto esters. The absolute configuration of natural wilforonide has been established to be (5aR,9aR).

Full text of DOI:10.1021/ol015722p

ORGANIC
LETTERS
2001
Vol. 3, No. 12
1785-1788
First Enantioselective Syntheses of
(+)- and (−)-Wilforonide by Using Chiral
Auxiliaries Derived from the Same
Chiral Source
Dan Yang* and Ming Xu
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong
yangdan@hku.hk
Received February 17, 2001
ABSTRACT
The first enantioselective syntheses of both (+)-wilforonide (>98% ee) and (−)-wilforonide (>98% ee) have been accomplished by employing
chiral auxiliaries derived from the same chiral source, (R)-pulegone. The bicyclic skeleton of wilforonide was constructed by using Mn(III)-
based oxidative radical cyclization reactions of chiral â-keto esters. The absolute configuration of natural wilforonide has been established to
be (5aR,9aR).
Wilforonide, a terpenoid isolated from the Chinese medicinal
herb Triperygium wilfordii Hook F (Lei Gong Teng),1 was
found to have significant antiinflammatory activity.2 It was
also effective in inhibiting T-cell proliferation and cytokine
release.2 As a potential probe molecule for investigating
inflammation and immunosuppression processes, wilforonide
became an important target for organic synthesis. The first
synthesis of (()-wilforonide, taking 10 steps starting from
commercially available compounds, was synthesized by
Coghlan and co-workers in 1998.3 However, the absolute
configuration of wilforonide was still unknown due to the
minute quantities available from natural sources.4 It is more
challenging to complete the chiral syntheses of both enan-
tiomers of wilforonide and examine the difference of their
biological activities, which is essential for the development
of more selective chiral wilforonide analogues. Recently, on
the basis of the pioneering work by Snider and co-workers,5
we developed an asymmetric Mn(III)-mediated oxidative
radical cyclization method for the construction of polycyclic
natural products by using chiral auxiliaries derived from the
same chiral source, (R)-pulegone.6 Here, we report the
application of this method in the first enantioselective
syntheses of both enantiomers of wilforonide and the
establishment of the absolute configuration of natural wil-
foronide.
Our retrosynthetic scheme for racemic wilforonide is
shown in Figure 1. The key steps involve (1) lactone
(1) Chen, K.; Yang, R.; Wang, C. Zhongcaoyao 1986, 17, 242.
(2) (a) Lipsky, P. E.; Tao, X. L.; Cai, J.; Kovacs, W. J.; Olsen, N. J.
U.S. Patent 5616458, 1997; Chem. Abstr. 1997, 126, 246818h. (b) Lipsky,
P. E.; Tao, X. L.; Cai, J. U.S. Patent 5580562, 1996; Chem. Abstr. 1996,
126, 70141r.
(3) Schkeryantz, J. M.; Luly, J. R.; Coghlan, M. J. Synlett 1998, 723.
(4) The absolute configuration of natural wilforonide was proposed to
be (5aR,9aR) on the basis of similar CD absorption patterns of wilforonide
and tripdiolide. See: Zhou, B. N.; Zhu, D. Y.; Deng, F. X.; Huang, C. G.;
Kutney, J. P.; Roberts, M. Planta Med. 1988, 330.
Figure 1.
10.1021/ol015722p CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/12/2001

an R-chloro substituent afforded only the trans-ring junction
products 5b and 6b, which were subsequently dechlorinated
with Zn/HOAc11 to give 5c and 6c (ratio 3.1:1) in 63% yield
in two steps. Following the method developed by Crisp,12
vinyl triflates 7a/b and 8a/b were obtained by treating the
cyclization products 5a/c and 6a/c with KHMDS followed
by PhNTf2. DIBAL-H reduction of 7a/b and 8a/b in
dichloromethane produced allylic alcohols 9 and 10, which
could be separated by using flash column chromatography.
Subsequent Pd-catalyzed carbonylation of allylic alcohol 9
provided lactone 11 in 94% yield. Oxidative cleavage of 11
Scheme 1a
13
with OsO4/NaIO4 afforded (()-wilforonide in 85% yield.
Thus far, a concise total synthesis of (()-wilforonide was
accomplished in eight steps in 14.0% total yield or in nine
steps in 16.4% total yield, which was about 10 times higher
than the one reported in recent literature (1.5% total yield
for 10 steps).3
For the asymmetric syntheses of both enantiomers of
wilforonide, chiral auxiliaries 16 and 20,6 derived from the
same chiral source, (R)-pulegone,14 were incorporated into
chiral â-keto esters 12 (Scheme 2) and 17 (Scheme 3),
respectively, by ester exchange with achiral precursor 4a.15
Cyclization of 12 with Mn(OAc)3 and Cu(OAc)2 in CF3CH2-
OH at 0 °C16 provided products 13 and 14 (ratio 1:1.2) in
50% yield. Because the R-protons of â-keto esters 13 and
Scheme 2a
a Reagents and conditions: (a) Mg, THF, 0 to 25 °C, 15 h; CuI,
2-methyl-2-vinyloxirane, -20 °C, 1 h, 97% (E/Z ratio 13:1); (b)
MsCl, Et3N, CH2Cl2, -40 to -20 °C, 2 h; LiBr, THF, -20 to 25
°C, 3 h, 90%; (c) (i) CH3COCH2COOCH3, NaH, n-BuLi, THF, 0
°C, 2 h, 82% of 4a; (ii) CH3COCHClCOOCH2CH3, LDA, THF,
-10 °C, 2 h, 70% of 4b; (d) (i) Mn(OAc)3‚2H2O, Cu(OAc)2, HOAc,
25 °C, 24 h, 50% of 5a and 6a (ratio 2.5:1); (ii) Mn(OAc)3‚2H2O,
Cu(OAc)2, HOAc, 25 °C, 5 h, 70% of 5b and 6b (ratio 3.1:1); (e)
Zn, HOAc, 25 °C, 5 h, 90% of 5c and 6c (ratio 3.1:1); (f) KHMDS,
PhNTf2, THF, -78 to 0 °C, 5 h; (g) DIBAL-H, CH2Cl2, -78 to
-20 °C, 6 h, 56% in two steps (9: 74% based on the amount of
5a or 5c in the mixtures of 5a and 6a or 5c and 6c; (h) LiCl, Et3N,
Pd(PPh3)4, CO (1 atm), CH3CN, 60 °C, 14 h, 94%; (i) NaIO4, OsO4,
t-BuOH, H2O, 85%.
formation, (2) radical cyclization, and (3) acyclic precursor
construction.
As shown in Scheme 1, allylic alcohol 2 was prepared in
97% yield (E/Z ) 13:1) by treating the Grignard reagent of
3-chloro-2-methyl-1-propene with 2-methyl-2-vinyloxriane
in the presence of CuI.7 Allylic alcohol 2 was converted to
bromide 3,8 which upon treatment with the dianion of methyl
acetoacetate or ethyl 2-chloroacetoacetate furnished acyclic
precursor 4a or 4b, respectively.9 Oxidative radical cycliza-
tion10 of 4a using Mn(OAc)3 and Cu(OAc)2 provided trans-
ring junction compounds 5a and 6a (ratio 2.5:1) as major
products (50% yield), along with a cis-ring junction product
(18% yield). Meanwhile, cyclization of precursor 4b with
a Reagents and conditions: (a) DMAP, toluene, reflux, 30 h,
95%; (b) Mn(OAc)3‚2H2O, Cu(OAc)2, CF3CH2OH, 0 °C, 12 h, 51%
of 13 and 14 (ratio 1:1.2); (c) (i) KHMDS, PhNTf2, THF; (ii)
DIBAL-H, CH2Cl2, 12% of (-)-9, 20% of 10, 10% of 15, and
recovered 83% of 16 in two steps; (d) LiCl, Et3N, Pd(PPh3)4, CO
(1 atm), CH3CN, 60 °C, 14 h, 94%; (e) NaIO4, OsO4, t-BuOH,
H2O, 85%; (f) 2,4-DNP, EtOH/H+, 60%.
1786
Org. Lett., Vol. 3, No. 12, 2001

Scheme 3a
Figure 2.
(OTf)3 (1.0 equiv)6 in CF3CH2OH at -10 to 0 °C afforded
a mixture of 18 and 19 (ratio 1.2:1). Because of less shielding
of the R-protons of â-keto esters 18 and 19 by the aromatic
group,19 the deprotonation occurred smoothly with KHMDS,
and the desired vinyl triflate (+)-9 was obtained in 33% yield
over two steps (61% yield based on the amount of 18 in the
mixture of 18 and 19). After the Pd-catalyzed carbonylation
and the oxidative cleavage reaction, compound (+)-9 was
converted to (-)-wilforonide ([R]D -26.6° (c 0.14, CH2Cl2)),
which showed the same sign of the specific optical rotation
as natural (-)-wilforonide ([R]D -26.8° (c 0.045, CH2Cl2)).20
HPLC analysis of the 2,4-DNP derivative 22 of synthetic
(-)-wilforonide revealed that its ee value was also greater
than 98%.
The assignments of stereochemistry for the cyclization
products 13/14 and 18/19 were made by comparison to
closely related systems in which the absolute stereochemistry
was proved by conversion to compounds of known absolute
configuration.6c As shown in Figure 3, in the cyclization of
a Reagents and conditions: (a) DMAP, toluene, reflux, 30 h,
97%; (b) Mn(OAc)3‚2H2O, Cu(OAc)2, Yb(OTf)3, CF3CH2OH, -10
to 0 °C, 10 h, 50% of 18 and 19 (ratio 1.2:1); (c) (i) KHMDS,
PhNTf2, THF; (ii) DIBAL-H, CH2Cl2, 33% of (+)-9, 20% of 10,
and recovered 82% of 20 in two steps; (d) LiCl, Et3N, Pd(PPh3)4,
CO (1 atm), CH3CN, 60 °C, 14 h, 94%; (e) NaIO4, OsO4, t-BuOH,
H2O, 85%; (f) 2,4-DNP, EtOH/H+, 60%.
14 were shielded by the phenyl group of the auxiliary17 and
the angular methyl group of the cyclic skeleton (Figure 2),
the deprotonation, followed by reduction with DIBAL,
resulted in a low chemical yield of the desired product (-)-9
(12% yield, 27% based on the amount of 13 in the mixture
of 13 and 14) along with a side product, 15. With the chiral
intermediate (-)-9 in hand, we accomplished the first
enantioselective synthesis of (+)-wilforonide ([R]D +25.1°
(c 0.18, CH2Cl2)) by following the same procedure shown
in Scheme 1. While the direct determination of the enan-
tiomeric purity of synthetic (+)-wilforonide failed, the HPLC
analysis of its 2,4-DNP derivative 2118 showed more than
98% ee.
Figure 3.
12, the 8-phenyl group of the chiral auxiliary can effectively
shield the (si)-face of the Mn(III)-enolate21 and restrict the
As shown in Scheme 3, cyclization of 17 with Mn(OAc)3
(2.1 equiv) and Cu(OAc)2 (0.5 equiv) in the presence of Yb-
(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.
(5) (a) Zhang, Q.-W.; 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, 328. (c) Zoretic, P. A.; Weng, X.; Biggers, C. K.; Biggers, M. S.; Caspar,
M. L.; Davis, D. G. Tetrahedron Lett. 1992, 33, 2637. (d) Garcia-Ruano,
J. L.; Rumbero, A. Tetrahedron: Asymmetry 1999, 10, 4427.
(6) (a) Yang, D.; Ye, X.-Y.; Gu, S.; Xu, M. J. Am. Chem. Soc. 1999,
121, 5579. (b) Yang, D.; Ye, X.-Y.; Xu, M. J. Org. Chem. 2000, 65, 2208.
(c) Yang, D.; Xu, M.; Bian, M.-Y. Org. Lett. 2001, 3, 111.
(10) For recent examples of Mn(III)-based oxidative free-radical cy-
clization reactions, see: (a) Pettus, T. R. R.; Inoue, M.; Chen, X.-T.;
Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6160. (b) Snider, B. B.;
Kiselgof, J. Y.; Foxman, B. M. J. Org. Chem. 1998, 63, 7945. (c) Zoretic,
P. A.; Fang, H.; Ribeiro, A. A. J. Org. Chem. 1998, 63, 4779. (d) Zoretic,
P. A.; Zhang, Y.; Fang, H.; Ribeiro, A. A.; Dubay, G. J. Org. Chem. 1998,
63, 1162. (e) Jones, P.; Pattenden, G. Synlett 1997, 398. For a review, see:
(f) Snider, B. B. Chem. ReV. 1996, 96, 339.
(11) Corey, E. J.; Gross, A. W. Tetrahedron Lett. 1985, 26, 4291.
(12) Crisp, G. T.; Meyer, A. G. J. Org. Chem. 1992, 57, 6972.
(13) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
(7) (a) Baker, K. V.; Brown, J. M.; Hughes, N.; Skarnulis, A. J.; Sexton,
A. J. Org. Chem. 1991, 56, 698. (b) Cahiez, C.; Alexakis, A.; Normant, J.
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(8) Corey, E. J.; Tius, M. A.; Das, J. J. Am. Chem. Soc. 1980, 102, 1742.
Org. Lett., Vol. 3, No. 12, 2001
1787

cyclization to the (re)-face to give 13 and 14 as major
products. However, in the case of 17, the (re)-face of the
R-radical is shielded and the (si)-face is more accessible,
yielding 18 and 19 as the major products. Therefore, the
absolute configuration of (-)-wilforonide was determined
to be (5aR,9aR).
Acknowledgment. This work was supported by The
University of Hong Kong and Hong Kong Research Grants
Council. We thank Professor Yuan-Chao Li of the Shanghai
Institute of Materia Medica for providing the authentic
sample of natural wilforonide.
In summary, by using chiral auxiliaries derived from the
same chiral source, (R)-pulegone, we have completed the
first enantioselective syntheses of natural (-)-wilforonide
in greater than 98% ee in 8.5% total yield (nine steps) and
its enantiomer (+)-wilforonide in more than 98% ee. Our
efficient synthetic schemes should allow rapid access to chiral
wilforonide analogues for the development of novel antiin-
flammatory and immunosuppressive drugs.
Supporting Information Available: The experimental
details; HPLC analysis of the 2,4-DNP derivatives of
synthetic (+)-wilforonide and (-)-wilforonide; the CD
spectra of (+)-wilforonide and (-)-wilforonide; and NMR
spectra of compounds 4a, 4b, 5a/6a, 5c/6c, 9-14, 17-19,
21, and wilforonide. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL015722P
(14) (a) Buschmann, H.; Scharf, H.-D. Synthesis 1988, 827. (b) Corey,
E. J.; Ensley, H. E.; Suggs, J. W. J. Org. Chem. 1976, 41, 380. (c) Corey,
E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908.
(15) Taber, D. F.; Amedio. J. C., Jr.; Patel, Y. K. J. Org. Chem. 1985,
50, 3619.
(16) For the oxidative cyclization of substrate 12, the addition of Lewis
acid Yb(OTf)3 resulted in a low chemical yield of the desired product.
(17) The chemical shifts of the R-protons of â-keto esters 13 and 14
were more upfield than 2.5 ppm whereas those of 5a and 6a were about
3.2 ppm.
(18) Behforouz, M.; Bolan, J. L.; Flynt, M. S. J. Org. Chem. 1985, 50,
1186.
(19) The chemical shifts of the R-protons of â-keto esters 18 and 19
were about 3.1 ppm.
(20) The authentic sample of natural (-)-wilforonide was obtained from
the Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
P. R. China.
(21) Snider, B. B.; Patricia, J. J.; Kates, S. A. J. Org. Chem. 1988, 53,
2137.
1788
Org. Lett., Vol. 3, No. 12, 2001