Chiral auxiliaries for asymmetric radical cyclization reactions: application to the enantioselective synthesis of (+)-triptocallol.

Article abstract of DOI:10.1021/ol0068243

[figure: see text] A series of epimeric 8-aryl menthyl derivatives 5a-d and 6a-l, prepared from the same chiral source (R)-pulegone, were employed as chiral auxiliaries in the asymmetric radical cyclization reactions of beta-keto esters mediated by Mn(OAc)3. Chiral precursors 8c and 8d provided the cyclization products 10c and 10d, respectively, as single isomers (dr > 99:1), whereas the cyclization of precursor 9k gave 13k with good stereoselectivity (dr = 24:1). Diastereomer 13e was employed as the key intermediate in the enantioselective synthesis of (+)-triptocallol in 90% ee.

Full text of DOI:10.1021/ol0068243

ORGANIC
LETTERS
2001
Vol. 3, No. 1
111-114
Chiral Auxiliaries for Asymmetric
Radical Cyclization Reactions:
Application to the Enantioselective
Synthesis of (+)-Triptocallol
Dan Yang,* Ming Xu, and Mai-Ying Bian
Department of Chemistry, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong
yangdan@hku.hk
Received November 3, 2000
ABSTRACT
A series of epimeric 8-aryl menthyl derivatives 5a−d and 6a−l, prepared from the same chiral source (R)-pulegone, were employed as chiral
auxiliaries in the asymmetric radical cyclization reactions of â-keto esters mediated by Mn(OAc)3. Chiral precursors 8c and 8d provided the
cyclization products 10c and 10d, respectively, as single isomers (dr > 99:1), whereas the cyclization of precursor 9k gave 13k with good
stereoselectivity (dr ) 24:1). Diastereomer 13e was employed as the key intermediate in the enantioselective synthesis of (+)-triptocallol in
90% ee.
The Mn(OAc)3-mediated oxidative free-radical cyclization
method has been widely used in the construction of poly-
cyclic ring structures found in many natural products,
especially terpenoids.1,2 However, few asymmetric radical
cyclizations have been reported.3 Recently, we discovered a
highly diastereoselective oxidative free radical cyclization
reaction of â-keto esters mediated by Mn(OAc)3,4,5 in which
(+)-8-phenylmenthol was employed as a chiral auxiliary and
Yb(OTf)3 as a catalyst to provide major diastereomer 2
(diastereomer ratio 38:1), a key intermediate for the total
synthesis of (-)-triptolide (Scheme 1). However, (+)-8-
Scheme 1
(1) For an excellent recent review on manganese(III)-based oxidative
free-radical cyclizations, see: Snider, B. B. Chem. ReV. 1996, 96, 339.
(2) 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.; Ribeiro, A. A. 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.
(3) (a) Snider, B. B.; Wan, B. Y.-F.; Buckman, B. O.; Foxman, B. M. J.
Org. Chem. 1991, 56, 328. (b) Snider, B. B.; Zhang, Q.-W. Tetrahedron
Lett. 1992, 33, 5921. (c) Zhang, Q.-W.; Mohan, R. M.; Cook, L.; Kazanis,
S.; Peisach, D.; Foxman, B. M.; Snider, B. B. J. Org. Chem. 1993, 58,
7640. (d) Zoretic, P. A.; Weng, X.; Biggers, C. K.; Biggers, M. S.; Caspar,
M. L.; Davis, D. G. Tetrahedron Lett. 1992, 33, 2637.
phenylmenthol, derived from (S)-(-)-citronellol in several
tedious steps,6 is much more expensive than its enantiomer
(-)-8-phenylmenthol. To improve the diastereoselectivities
of radical cyclization reactions and to use inexpensive chiral
source to construct the tricyclic skeleton of (-)-triptolide,
(5) Yang, D.; Ye, X.-Y.; Xu, M. J. Org. Chem. 2000, 65, 2208.
(6) (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.
(4) Yang, D.; Ye, X.-Y.; Gu, S.; Xu, M. J. Am. Chem. Soc. 1999, 121,
5579.
10.1021/ol0068243 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/13/2000

we would like to find suitable chiral menthyl derivatives to
replace (+)-8-phenylmenthol. Furthermore, to synthesize
both enantiomers of natural products in high optical purity
from the same chiral source is very attractive for the
development of more selective chiral drugs.7 Here we report
our efforts in developing new chiral auxiliaries for asym-
metric radical cyclization reactions.
Table 1. Mn(OAc)3-Mediated Asymmetric Radical Cyclization
of Chiral Precursors 8a-da
The chiral auxiliaries 5 and 6 were prepared following
literature procedures (Scheme 2).6,8 Ketone 4 was obtained
dr
(10:11)b
yield
(%)c
entry
substrates
R
1
2
3
4
8a
8b
8c
8d
8d
Ph
38:1
86:1
>99:1
>99:1
24.5:1
77
75
53
67
44
3,5-(MeO)2C6H3
3,5-(i-PrO)2C6H3
2-naphthyl
Scheme 2
5d
2-naphthyl
a Unless otherwise indicated, all reactions were carried out with 1.0 equiv
of Yb(OTf)3 and 2.2 equiv of Mn(OAc)3‚2H2O at 0.067 M substrate
concentration, -5 to 0 °C in CF3CH2OH, 6-10 h. b The diastereomer ratio
was determined by 1H NMR (500 MHz, CDCl3) analysis of the crude
products. c Isolated yield. d Carried out at 50 °C in HOAc without Yb(OTf)3,
1 h.
leads to higher diastereoselectivity. The important effect of
Lewis acid Yb(OTf)3 on this kind of asymmetric radical
cyclization reaction was also confirmed (entry 4 vs 5).
Interestingly, the cyclization of 9a-l gave 13a-l as the
major diastereomers (Table 2), which have the opposite
by treating commercially available (R)-pulegone 3 with
appropriate Grignard reagents in the presence of CuI.
Reduction with LiAlH4 generated two diastereomeric alco-
hols, 5 and 6,9 which were then incorporated into chiral
â-keto esters 8 and 9 in 88-96% yields by ester exchange10
with achiral precursor 711 (Scheme 2).
Table 2. Mn(OAc)3-Mediated Asymmetric Radical Cyclization
of Chiral Precursors 9a-la
The Mn(OAc)3-mediated oxidative free-radical cyclization
reactions of 8a-d were carried out in degassed solvents in
the presence of Yb(OTf)3,4,5,11 and the results are summarized
in Table 1. When the aromatic group at the 8-position of
chiral menthyl auxiliaries was changed from phenyl group
(entry 1) to 3,5-disubstituted phenyl group (entries 2 and 3)
or naphthyl group (entry 4), the diastereomer ratio was
increased dramatically from 38:1 to more than 99:1. For the
cyclization of 8c or 8d, one single isomer with three chiral
centers was obtained in one step. It seems that increasing
the steric bulkiness and electron density of the 8-aryl group
dr
(12:13)b
yield
(%)c
entry
substrate
R
1
2
3d
4
5
6
7
8
9
10
11
12
13
9a
9b
9b
9c
9d
9e
9f
9g
9h
9i
3,5-(CF3)2C6H3
p-NO2C6H4
p-NO2C6H4
2,4-(MeO)2C6H3
o-MeOC6H4
Ph
1:2.8
1:4.1
1:6.0
1:3.7
1:4.5
1:5.7
1:5.8
1:6.7
1:11.5
1:11.2
1:18.1
1:24.2
1:9.2
64
60
55
64
60
70
71
72
62
64
67
55
60
(7) For examples, see: (a) Meyer, L.; Poirier, J.-M.; Duhamel, P.;
Duhamel, L. J. Org. Chem. 1998, 63, 8094. (b) Kobayashi, S.; Horibe, M.
J. Am. Chem. Soc. 1994, 116, 9805. (c) Kobayashi, S.; Kusakabe, K.;
Komiyama, S.; Ishitani, H. J. Org. Chem. 1999, 64, 4220. (d) Kobayashi,
S.; Horibe, M. Tetrahedron 1996, 52, 7277. (e) Kobayashi, S.; Horibe, M.;
Saito, Y. Tetrahedron 1994, 50, 9629. (f) Kobayashi, S.; Hayashi, T. J.
Org. Chem. 1995, 60, 1098. (g) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse,
C. P. J. Am. Chem. Soc. 1998, 120, 6615. (h) Alvarez-Ibarra, C.; Csaky, A.
G.; Maroto, R.; Quiroga, M. L. J. Org. Chem. 1995, 60, 7934. (i) Solladie,
G.; Greck, C.; Demailly, G.; Solladie-Cavallo, A. Tetrahedron Lett. 1982,
23, 5047. (j) Yang, K.-S.; Chen, K. Org. Lett. 2000, 2, 729.
(8) (a) Aoyagi, S.; Tanaka, R.; Naruse, M.; Kibayashi, C. J. Org. Chem.
1998, 63, 8397. (b) d’Angelo, J.; Maddaluno, J. J. Am. Chem. Soc. 1986,
108, 8112. (c) Sato, M.; Aoyagi, S.; Yago, S.; Kibayashi, C. Tetrahedron
Lett. 1996, 37, 9063.
p-Ph-C6H4
p-MeOC6H4
m-MeOC6H4
3,4-(MeO)2C6H3
3,5-(MeO)2C6H3
3,5-(i-PrO)2C6H3
2-naphthyl
9j
9k
9l
a Unless otherwise indicated, all reactions were carried out in degassed
CF3CH2OH with 1.0 equiv of Yb(OTf)3 and 2.2 equiv of Mn(OAc)3‚2H2O
at 0.067 M substrate concentration, -5 to 0 °C, 6-10 h. b The diastereomer
ratio was determined by 1H NMR (500 MHz, CDCl3) analysis of the crude
products. c Isolated yield (including both 12 and 13). d At room temperature
without Yb(OTf)3, 26 h.
(9) No attempt was made to improve the stereoselectivity of the reduction
of intermediate ketone 4 to alcohols 5 or 6.
(10) Taber, D. F.; Amedio, J. C., Jr.; Patel, Y. K. J. Org. Chem. 1985,
50, 3618.
(11) (a) Yang, D.; Ye, X.-Y.; Xu, M.; Pang, K.-W.; Zou, N.; Letcher,
R. M. J. Org. Chem. 1998, 63, 6446. (b) Yang, D.; Ye, X.-Y.; Xu, M.;
Pang, K.-W.; Cheung, K. K. J. Am. Chem. Soc. 2000, 122, 1658.
configuration for the tricyclic skeleton as compared to
cyclization products 10a-d. Low diastereomer ratios were
112
Org. Lett., Vol. 3, No. 1, 2001

obtained when the chiral auxiliaries bearing electron-
withdrawing groups or ortho-substitutents on the 8-phenyl
group were employed (entries 1 and 2, 4 and 5). The
cyclization of 9g-k with electron-donating substituents,
especially those at the meta positions of the 8-aryl ring,
resulted in higher chiral induction (entries 8-12). Most
significantly, diastereomer ratio of 1:24 was obtained for the
cyclization reaction of 9k (entry 12).
cyclization to the (re)-face to give 10d. However, in the case
of 9l, the (re)-face is shielded and the (si)-face is more
accessible, yielding 13l as the major product. The π-stacking
interaction13 between the R-radical center and the 8-aryl
group was invoked to explain the different stereoselectivities
1
observed in the radical cyclization of 8d and 9l. In the H
NMR spectra, the protons R to the two carbonyl groups of
8d showed more upfield chemical shifts (δ 2.38 and 2.22
ppm) than those of 9l (δ 3.23 ppm), indicating that the
equatorial â-keto ester group had much stronger π-stacking
interactions with the 8-naphthalene ring than the axial one.
Therefore, chiral precusor 8d gave a single isomer 10d,
whereas precusor 9l gave a lower diasteromer ratio (13l:12l
) 9:1).
The absolute configuration of the resulting tricyclic
skeleton was determined by using the following transforma-
tions (Scheme 3). Compounds 10d and 13l were reduced by
Scheme 3
In addition, the π-stacking effect became stronger when
the aromatic ring at the 8-position of the chiral auxiliary was
substitued with more electron-releasing groups owing to the
attraction of the electrophilic radical center and the electron-
rich aromatic ring. As a result, the diastereomer ratio was
enhanced by introducing electron-donating substituents on
the aromatic ring. In contrast, the π-stacking effect was
weakened when the aromatic ring was substitued with
electron-withdrawing groups. In the absence of Yb(OTf)3,
the electronic repulsion between the electrophilic radical
center and the electron-deficient aromatic ring would de-
crease and thus higher diastereomer ratio was obtained for
the cyclization of 9b (entry 2 vs 3).
As a result of the steric interactions, ortho substitution on
the aromatic ring of the chiral auxiliary may cause a twist
of aromatic plane and destroy the π-stacking interaction
between the â-keto ester group and the aromatic ring.
Therefore, the diastereoselectivity decreased significantly for
the cyclization of 9c and 9d bearing ortho subsitutents (Table
2, entries 4 and 5). Among all the chiral auxiliaries examined,
those with electron-releasing groups at meta positions gave
the most effective chiral induction due to the electronic and
steric effects (Table 2, entries 11 and 12).
LiAlH4 to diols (-)-14 ([R]D -78°, c 0.50, EtOAc) and (+)-
14 ([R]D +77 °, c 0.20, EtOAc), respectively (Scheme 3).
Diols (-)-14 and (+)-14 gave the specific optical rotations
and CD spectra of opposite signs, suggesting that they are
mirror images. The absolute configuration of cyclization
product 13e was further confirmed by converting 13e to
natural product (+)-triptocallol (vide infra).12a
The opposite chiral induction obtained in the cyclization
of 8 and 9 can be explained using the chelation models shown
in Figure 1. In the presence of Yb(OTf)3, the chelation of
The diastereomer 13e was applied to the enantioselective
synthesis of (+)-triptocallol, a terpenoid isolated from tissue
cultures of Tripterygium wilfordii.12a Alkylation of 13e (dr
5.7:1) with MeI,14 followed by reduction with LiAlH4,
provided (+)-triptocallol ([R] ) +54.8 °, c 0.18, CH2Cl2)
in 25% yield and 90% ee (Scheme 4). The 1H NMR spectrum
Scheme 4
Figure 1. The transition state models of the radical cyclization in
the presence of Yb(OTf)3.
of our synthetic (+)-triptocallol was identical to that of an
authentic sample ([R] ) +42.5° (c 0.4, CHCl3))12 supplied
by Professor Takaishi.15
In summary, we have demonstrated that epimeric chiral
auxiliaries derived from the same chiral source can be used
â-keto ester 8 to Yb(OTf)3 would lock the two carbonyl
groups in a syn orientation.4 In the cyclization of 8d, the
8-naphthyl group can effectively shield the (si)-face of the
radical generated by Mn(III) oxidation and restrict the
Org. Lett., Vol. 3, No. 1, 2001
113

to control of the product configurations in the Mn(OAc)3-
mediated oxidative radical cyclization reactions. In addition,
an enantioselective synthesis of (+)-triptocallol was ac-
complished in high selectivity. The manipulation of chiral
auxiliaries utilized in the radical cyclization reactions may
have tremendous potential in the asymmetric synthesis of
either enantiomer of many polycyclic natural products. Work
in that direction is in progress.
Acknowledgment. This work was supported by The
University of Hong Kong and Hong Kong Research Grants
Council.
(12) (a) Nakano, K.; Oose, Y.; Masuda, Y.; Kamada, H.; Takaishi, Y.
Phytochemistry 1997, 45, 293. (b) Yamamura, I.; Fujiwara, Y.; Yamato,
T.; Irie, O.; Shishido, K. Tetrahedron. Lett. 1997, 38, 4121.
(13) For a review of π-stacking effects in asymmetric synthesis, see:
Jones, G. B.; Chapman, B. J. Synthesis 1988, 827.
(14) (a) Spencer, T. A.; Weaver, T. D.; Villarica, R. M.; Friary, R. J.;
Posler, J.; Schwartz, M. A. J. Org. Chem. 1968, 33, 712. (b) Spencer, T.
A.; Friary, R. J.; Schmiegel, W. W.; Simeone, J. F.; Watt, D. S. J. Org.
Chem. 1968, 33, 719. (c) Kuehne, M. E.; Nelson, J. A. J. Org. Chem. 1970,
35, 161. (d) Kuehne, M. E. J. Org. Chem. 1970, 35, 171.
Supporting Information Available: The preparation of
chiral auxiliaries 5 and 6, experimental details of the radical
cyclization reactions of 8 and 9, determination of diastere-
omer ratios of 10/11 and 12/13, HPLC analysis of synthetic
(+)-triptocallol, and the CD spectra of compounds (+)-14
and (-)-14. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) We thank Professor Yoshihisa Takaishi (University of Tokushima)
1
for a copy of the H NMR spectrum of natural (+)-triptocallol.
OL0068243
114
Org. Lett., Vol. 3, No. 1, 2001