Et2AlCl-promoted asymmetric phenylseleno group transfer radical cyclization reactions of unsaturated β-hydroxy esters

Article abstract of DOI:10.1021/jo048322z

We have developed a new method for asymmetric phenylseleno group transfer radical cyclization of unsaturated β-hydroxy esters. Various unsaturated α-phenylseleno β-hydroxy esters underwent radical cyclization in the presence of Et₂AlCl in benze

Full text of DOI:10.1021/jo048322z

Et2AlCl-Promoted Asymmetric Phenylseleno Group Transfer
Radical Cyclization Reactions of Unsaturated â-Hydroxy Esters
Dan Yang,* Qiang Gao, Bao-Fu Zheng, and Nian-Yong Zhu
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. China
yangdan@hku.hk
Received September 22, 2004
We have developed a new method for asymmetric phenylseleno group transfer radical cyclization
of unsaturated â-hydroxy esters. Various unsaturated R-phenylseleno â-hydroxy esters underwent
radical cyclization in the presence of Et2AlCl in benzene with sunlamp irradiation at 25-30 °C to
give mono- and bicyclic group-transferred products in an efficient and highly regioselective and
diastereoselective manner. To rationalize the high diastereoselectivities observed in this reaction,
we propose a model based on chelation control of the aluminum alkoxides that are formed in situ.
We devised a general method to prepare chiral radical precursors from which we obtained highly
optically pure mono- and bicyclic group transfer products. The synthetic advantages of this method
are demonstrated by our formal total synthesis of (-)-wilforonide. This paper presents the first
examples of stereoselective group transfer radical cyclizations that occur via 1,2-asymmetric
induction.
SCHEME 1
Introduction
Since the pioneering work of Curran, atom or group
transfer radical cyclization has become an important
method for the synthesis of cyclic compounds.1,2 Scheme
1 outlines the general mechanism for atom or group
transfer radical cyclization reaction. Once generated,
radical B undergoes radical cyclization to form the cyclic
radical C. Following abstraction of an X group from
another substrate A, the radical is terminated to give the
desired product D. The transferred group can be a
halogen atom (X ) Cl, Br, or I) or a phenyl chalcogen
group (X ) SePh or TePh).2c Because the reactive X
group, suitable for further chemical transformations,
remains in the product after the cyclization reaction, the
whole process provides an attractive alternative to the
traditional reductive radical cyclization methods, in
which the radicals are usually terminated by abstraction
of a hydrogen atom.
developments have been achieved in chiral Lewis acid-
mediated enantioselective radical reactions,4 diastereo-
selective radical reactions with chiral auxiliary ap-
proaches,5 and 1,2-asymmetric inductions6 (radicals
bearing an adjacent chiral center), the use of Lewis acids
in atom or group transfer radical reactions is far from
common, particularly in the preparation of chiral cyclic
compounds.4f,6i,7 Recently, we reported the first enantio-
selective atom transfer radical cyclization reaction that
is catalyzed by chiral Lewis acids.8 The cyclization of
It is well-documented in the literature that Lewis acids
can be applied to radical reactions to obtain higher
reactivities and/or stereoselectivities.3 Although exciting
(1) (a) Curran, D. P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc. 1986,
108, 2489-2490. (b) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989,
54, 3140-3157. (c) Curran, D. P.; Chen, M.-S.; Kim, D. J. Am. Chem.
Soc. 1989, 111, 6265-6276. (d) Curran, D. P.; Chen, M.-H.; Spletzer,
E.; Seong, C. M.; Chang, C.-T. J. Am. Chem. Soc. 1989, 111, 8872-
8878. (e) Curran, D. P.; Tamine, J. J. Org. Chem. 1991, 56, 2746-
2750. (f) Jolly, R. S.; Livinghouse, T. J. Am. Chem. Soc. 1988, 110,
7536-7538.
(2) For reviews, see: (a) Jasperese, C. P.; Curran, D. P.; Fevig, T.
L. Chem. Rev. 1991, 91, 1237-1286. (b) Curran, D. P. Synthesis 1988,
489. (c) Byers, J. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 1, Chapter
1.5. (d) Curran, D. P. In Comprehensive Organic Synthesis; Trost, B.
M., Flemming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4, Chapter
4.2.
(3) For recent review on the use of Lewis acids in free radical
reactions, see: Gue´rin, B.; Ogilvie, W. W.; Guindon, Y. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Wein-
heim, Germany, 2001; Vol. 1, Chapter 4.4.
(4) For recent reviews, see: (a) Sibi, M. P.; Rheault, T. R. In Radicals
in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, Germany, 2001; Vol. 1, p 461. (b) Sibi, M. P.; Porter, N. A.
Acc. Chem. Res. 1999, 32, 163-171. (c) Curran, D. P.; Porter, N. A.;
Giese, B., Eds. Stereochemistry of Radical Reactions: Concepts, Guide-
lines, and Synthetic Applications; VCH: Weinheim, Germany, 1996.
(d) Gawley, R. E.; Aube, J. Principles of Asymmetric Synthesis;
Pergamon: Oxford, UK, 1996; Vol. 14. (e) Renaud, P.; Gerster, M.
Angew. Chem., Int. Ed. 1998, 37, 2563-2579. (f) Sibi, M. P.; Manyem,
S.; Zimmerman J. Chem. Rev. 2003, 103, 3263-3295.
10.1021/jo048322z CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/11/2004
J. Org. Chem. 2004, 69, 8821-8828
8821

Yang et al.
unsaturated R-bromo â-keto esters catalyzed by a chiral
Mg(ClO4)2/bis(oxazoline) complex resulted in ee values
of up to 94% for the cyclization product (eq 1). For those
research groups of Guindon and Renaud with respect to
the following types of radical reactions: allylation,6c,i,j
reduction,6k addition,6l and reductive cyclization.11 For
example, Guindon’s group reported that the stereochem-
ical outcome of the R-allylation reaction of 3-methoxy-2-
iodobutyate was completely reversed when the radical
reaction was conducted in the presence of MgBr2. The
reversal of diastereoselectivity was attributed to the
chelation between MgBr2 and the â-alkoxy ester moiety
of the radical intermediate (eq 3).6c
reactions, the presence of an R-alkyl group in the
substrates is essential: the corresponding R-bromo â-keto
esters lacking the R-methyl group were unstable and
difficult to purify9 and their cyclization reactions occurred
with poor enantioselectivities. We also reported the chiral
auxiliary-controlled, Lewis acid-catalyzed highly asym-
metric atom transfer radical cyclization reactions of
unsaturated R-bromo oxazolidinone imides (eq 2).10 Al-
Recently, Renaud and co-workers reported an alumi-
num oxide-controlled tributyltin hydride reductive radical
cyclization reaction (eq 4).11 Through chelation control
from the aluminum oxide formed in situ, high diastereo-
selectivities were observed in the radical addition to the
TMS-substituted electron-rich triple bonds under reduc-
tive radical conditions. The authors also presented the
first example of a cascade radical reaction controlled by
a Lewis acid under similar conditions.
though excellent diastereoselectivities could be achieved,
this approach requires the introduction and removal of
chiral auxiliaries. We believe that a more general and
efficient method to access chiral atom or group trans-
ferred cyclic compounds still requires exploration.
Guindon’s group was the first to report the Lewis acid-
controlled 1,2-asymmetric induction radical reaction;6c
since then, a number of exciting results have been
achieved from the extensive studies undertaken by the
We envisioned that the application of 1,2-asymmetric
induction in atom or group transfer radical cyclization
reactions would provide an efficient method to synthesize
multifunctionalized chiral cyclic compounds and would
overcome the shortages of our previous methods. In
practical terms, we sought to find Lewis acids and radical
initiation conditions for reactions that would meet the
following criteria: (1) They should allow group transfer
radical cyclization reactions that provide more syntheti-
cally useful and terminally functionalized cyclic products.
At the same time, the procedure must eliminate the need
to use toxic tributyltin hydride. (2) The procedure should
be general in allowing the cyclization of readily available
simple and less-electron-rich alkenes, and to provide
(5) For a recent review, see: (a) Porter, N. A. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
Germany, 2001; Vol. 1, Chapter 4.3. For selected recent examples,
see: (b) Sibi, M. P.; Ji, J. Angew. Chem., Int. Ed. Engl. 1996, 35, 190-
192. (c) Yamamoto, Y.; Onuki, S.; Yumoto, M.; Asao, N. J. Am. Chem.
Soc. 1994, 116, 421-422. (d) Sibi, M. P.; Ji, J. Angew. Chem., Int. Ed.
Engl. 1997, 36, 274-275. (e) Sibi, M. P.; Ji, J. J. Org. Chem. 1996, 61,
6090-6091. (f) Sibi, M. P.; Jasperse, C. P.; Ji, J. J. Am. Chem. Soc.
1995, 117, 10779-10780. (g) Mero, C. L.; Porter, N. A. J. Am. Chem.
Soc. 1999, 121, 5155-5160. (h) Mero, C. L.; Porter, N. A. J. Org. Chem.
2000, 65, 775-781. (i) Sibi, M. P.; Rheault, T. R. J. Am. Chem. Soc.
2000, 122, 8873-8879.
(6) (a) Guindon, Y.; Yoakim, C.; Lemieux, R.; Boisvert, L.; Delorme,
D.; Lavalle´e, J.-F. Tetrahedron Lett. 1990, 31, 2845-2848. (b) Guindon,
Y.; Lavalle´e, J.-F.; Boisvert, L.; Chabot, C.; Delorme, D.; Yoakim, C.;
Hall, D.; Lemieux, R.; Simoneau, B. Tetrahedron Lett. 1991, 32, 27-
30. (c) Durkin, K.; Liotta, D.; Rancourt, J.; Lavalle´e, J.-F.; Boisvert,
L.; Guindon, Y. J. Am. Chem. Soc. 1992, 114, 4912-4914. (d) Guindon,
Y.; Yoakim, C.; Gorys, V.; Ogilvie, W. W.; Delorme, D.; Renaud, J.;
Robinson, G.; Lavalle´e, J.-F.; Slassi, A.; Jung, G.; Rancourt, J.; Durkin,
K.; Liotta, D. J. Org. Chem. 1994, 59, 1166-1178. (e) Guindon, Y.;
Slassi, A.; Rancourt, J.; Bantle, G.; Bencheqroun, M.; Murtagh, L.;
Ghiro, E.; Jung, G. J. Org. Chem. 1995, 60, 288-289. (f) Guindon, Y.;
Lavalle´e, J.-F.; Llinas-Brunet, M.; Horner, G.; Rancourt, J. J. Am.
Chem. Soc. 1991, 113, 9701-9702. (g) Guindon, Y.; Gue´rin, B.; Chabot,
C.; Mackintosh, N.; Ogilvie, W. W. Synlett 1995, 449-451. (h) Guindon,
Y.; Gue´rin, B.; Rancourt, J.; Chabot, C.; Mackintosh, N.; Ogilvie, W.
W. Pure Appl. Chem. 1996, 68, 89. (i) Guindon, Y.; Gue´rin, B.; Chabot,
C.; Ogilvie, W. W. J. Am. Chem. Soc. 1996, 118, 12528-12535. (j)
Gerster, M.; Audergon, L.; Moufid, N.; Renaud, P. Tetrahedron Lett.
1996, 37, 6335-6338. (k) Rancourt, J.; Guindon, Y. J. Org. Chem. 1998,
63, 6554-6565. (l) Urabe, H.; Yamashita, K.; Sunuki, K.; Kobayashi,
K.; Sato, F. J. Org. Chem. 1995, 60, 3576-3577. (m) Nagano, H.; Kuno,
Y.; Omori, Y.; Iguchi, M. J. Chem. Soc., Perkin Trans. 1 1995, 389-
394. (n) Nagano, H.; Kuno, Y. J. Chem. Soc., Chem. Commun. 1994,
987-988.
(7) (a) Mero, C. L.; Porter, N. A. J. Org. Chem. 2000, 65, 775-781.
(b) Clark, A. J.; Campo, F. D.; Deeth, R. J.; Filik, R. P.; Gatard, S.;
Hunt, N. A.; Lastecoueres, D.; Thomas, G. H.; Verlhac, J.-B.; Wongtap,
H. J. Chem. Soc., Perkin Trans. 1 2000, 671-680. (c) Kitagawa, O.;
Yamada, Y.; Fujiwara, H.; Taguchi, T. J. Org. Chem. 2002, 67, 922-
927. (d) Fang, X.; Xia, H.; Yu, H.; Dong, X.; Chen, M.; Wang, Q.; Tao,
F.; Li, C. J. Org. Chem. 2002, 67, 8481-8488. (e) Feng, H.; Kavrakova,
I. K.; Pratt, D. A.; Tellinghuisen, J.; Porter, N. A. J. Org. Chem., 2002,
67 6050-6054.
(8) (a) Yang. D.; Gu, S.; Yan, Y.-L.; Zhu, N.-Y.; Cheung, K.-K. J.
Am. Chem. Soc. 2001, 123, 8612-8613. (b) Yang, D.; Gu, G.; Yan, Y.-
L.; Zhao, H.-W.; Zhu, N.-Y. Angew. Chem., Int. Ed. 2002, 41, 3014-
3017.
(9) Yan, Y.-L. Ph.D. Thesis, The University of Hong Kong, 2003.
(10) Yang, D.; Zheng, B.-F.; Gu, S.; Chan, W. H. P.; Zhu, N.-Y.
Tetrahedron: Asymmetry 2003, 14, 2927-2937.
(11) Renaud, P.; Andrau, L.; Schenk, K. Synlett 1999, 1462-1464.
8822 J. Org. Chem., Vol. 69, No. 25, 2004

Asymmetric Phenylseleno Group Transfer Radical Cyclization
SCHEME 2a
a Reagents and conditions: (a) NaBH4, MeOH, 0 °C, 5 min, 85-90%; (b) LDA (2 equiv), THF, -35 °C, then PhSeBr, -78 °C, 70-80%
(1:2 ) 10:1).
SCHEME 3
carbocyclic compounds having various ring sizes and
substituents. (3) A simple, but practical, method to gain
access to chiral radical precursors should be developed
so that optically pure cyclic products can be obtained.
In this paper, we report a new method that addresses
all of the considerations above. We have discovered an
Et2AlCl-promoted asymmetric PhSe group transfer radi-
cal cyclization reaction of unsaturated â-hydroxy esters
and have applied it successfully to tandem cyclization
compounds.15 The signals of the C1 (174.54 ppm), C2
reactions for the construction of various optically pure
(74.68 ppm), and C3 (18.12 ppm) nuclei in 1f are all
bicyclic skeletons.
relatively downfield of those of the C1 (173.65 ppm), C2
(72.67 ppm), and C3 (17.21 ppm) nuclei in 2f.16
Results and Discussion
Optimization of Reaction Conditions. We opti-
mized the reaction conditions for the radical cyclization
of unactivated olefinic â-hydroxy ester 1a by investigat-
ing different Lewis acids, solvents, temperatures, and
initiating methods; Table 1 summarizes the results.
Almost no reaction took place in the absence of Lewis
acids, due to the low electrophilicity of the R-centered
radical intermediate (entry 1). Lewis acids such as
Mg(ClO4)2, Zn(OTf)2, and Ti(Oi-Pr)2Cl2 were inefficient
at promoting the cyclization reactions at 0 °C when using
either Et3B/O2 or UV light to initiate the radical forma-
tion; only 5-10% of the substrates were consumed
(entries 2-4). A similar result was obtained in the
presence of Me3Al (entry 5).11 When Et2AlCl was used in
the Et3B/O2-initiated radical reaction, we obtained a good
yield (65%) of the cyclization products (entry 6), but 3a,
4a, and 5a were obtained as a mixture in a ratio of 1:4.2:
4.8. The formation of the side product 5a might be the
result of disproportionation of the tertiary radical inter-
mediate after the cyclization. To suppress the formation
of 5a, we considered other radical initiation methods. A
remarkable amount of 5a (25%) was obtained even when
AIBN/hv was used to initiate the radical reaction,
although the total yield was improved to 78% (entry 7).
We found that a simple photolysis using a 300-W
sunlamp at 25-30 °C overcame this problem (entry 8):
a highly stereoselective cyclization took place to give 3a
and 4a in a 10:1 ratio in 77% yield; the formation of 5a
was suppressed completely. When the solvent was changed
to toluene, cyclization products 3a, 4a, and 5a were
Preparation of Precursors for Radical Cycliza-
tion Reactions. The preparation of R-phenylseleno-â-
hydroxy esters 1 and 2 is presented in Scheme 2. â-Keto
esters having various olefinic side chains were reduced
with NaBH4 to afford the corresponding â-hydroxy esters
6 in good yield. These â-hydroxy esters were treated with
2 equiv of LDA to generate the corresponding dianions,
and the latter were phenylselenated with PhSeBr in a
highly diastereoselective manner to afford 1 (anti) and 2
(syn) in a 10:1 ratio.12 The relative configurations of 1
and 2 were determined by comparing the 1H NMR
spectroscopic coupling constants between the R and â
protons with those of a literature report.13b Isomers anti-1
usually have larger J values (>7 Hz) than those of syn-2
(5.2 Hz). When compared with the literature procedure
for preparing similar R-phenylseleno compounds, which
involves Lewis acid-promoted aldol condensation,13 the
dianion approach is more efficient and results in higher
anti-selectivity.
Compounds 1f and 2f, which each bear an R-methyl
substituent, were synthesized by the aldol condensation
between methyl-R-(phenylseleno)propionate14 and 5-
methylhex-4-enal (Scheme 3). The relative configurations
of these two compounds were determined by comparing
their 13C NMR spectroscopic data with those of known
(12) For a study on the stereoselective R-alkylation of â-hydroxy
esters, see: Frater, G.; Muller, U.; Gunther, W. Tetrahedron 1984, 40,
1269-1277.
(13) (a) Toru, T.; Hayakawa, T.; Nishi, T.; Watanabe, Y.; Ueon, Y.
Phosphorus Sulphur Silicon 1998, 653-658. (b) Nakamura, S.; Hay-
akawa, T.; Nishi, T.; Watanabe, Y.; Toru, T. Tetrahedron 2001, 57,
6703-6711.
(15) Bouvier, B.; Jung, G.; Liu, Z.; Guerin, B.; Guindon, Y. Org. Lett.
2001, 3, 1391-1394.
(16) Heathcock, C. H.; Pirrung, M. C.; Sohn, J. E. J. Org. Chem.
1979, 44, 4294-4299.
(14) Yamashita, T.; Yasuda, M.; Watanabe, M.; Kojima, R.; Tanabe,
K.; Shima, K. J. Org. Chem. 1996, 61, 6438-6441.
J. Org. Chem, Vol. 69, No. 25, 2004 8823

Yang et al.
TABLE 1. Effects of Lewis Acids and Initiating Conditions on the Diastereoselective Phenylseleno Group Transfer
Radical Cyclization Reaction of 1aa
entry
Lewis acid (equiv)
solvent
temp, °C
initiating condition
time, h
yield, %b (3a:4a:5a)
1
2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
benzene
toluene
benzene
0
0
Et3B/O2
12
6
20
4.5
4.5
4.5
9
7.5
14
2
<5
Mg(ClO4)2 (1.1)
Zn(OTf)2 (1.1)
Ti(Oi-Pr)2Cl2 (1.1)
Me3Al (2)
Et3B/O2 or hv
Et3B/O2 or hv
Et3B/O2
<5
3
0
<5
4
0
<5
5
0
Et3B/O2
Et3B/O2
AIBN/hv
sunlampc
sunlampc
<5
6
Et2AlCl (2)
0
65 (1:4.2:4.8)
78 (3:2.8:2)
77 (10:1:0)
80 (20:1:1)
7
Et2AlCl (2)
rt
rt
rt
rt
8
Et2AlCl (2)
9
Et2AlCl (2)
10
Et2AlCl (2)
a All reactions were conducted with 0.3-0.6 mmol of 1a in the indicated solvent (30 mL/mmol). b Isolated yield. c A 300-W sunlamp
was used.
SCHEME 4
formed in a 20:1:1 ratio in 80% yield (entry 9). No
reaction was observed in the absence of radical initiation
(entry 10), which indicates the radical nature of the
mechanism of this cyclization reaction.
Et2AlCl plays a critical role in enhancing the yield of
this reaction. When treated with Et2AlCl, the radical
precursor forms an aluminum alkoxide quantitatively.6l,17b
For the addition of R-centered radicals toward unacti-
vated olefins under such mild conditions (sunlamp/25-
30 °C), higher cyclization rates should be obtained for
R-centered radicals that are more electron deficient.
Although its Lewis acidity decreased as a result of the
formation of the aluminum alkoxide, EtAlClOR is still
strong enough to cause the R-centered radical to become
more electrophilic and, thus, the cyclization rate is
accelerated. In addition, the PhSe group transfer process
may be faster in the presence of the Lewis acid.7f The
other Lewis acids, such as Me3Al,11 probably also complex
with the â-hydroxy ester moieties, but their Lewis
acidities are not high enough to promote the radical
addition. We did not examine stronger Lewis acids, such
as BF3 or TiCl4, because previous studies have suggested
the possible decomposition of unsaturated R-phenylseleno
ketones in the presence of strong Lewis acids.17a We
added 2 equiv of Et2AlCl to compensate for any Lewis
acid that might be hydrolyzed by traces of moisture.
Because oxygen also destroys this Lewis acid, it is very
important to degas the reaction system with argon before
adding Et2AlCl.
SCHEME 5
complex A1 in which the ester carbonyl group is com-
plexed with the aluminum center. Once the radical is
generated by photolysis, the olefinic group can approach
the radical center only via transition state A2 or A3.
Transition state A2 is less favorable, however, because
of the steric interactions between the pseudoaxial olefinic
Me group and the chelating ring. The 5-exo attack on the
alkene group via transition state A3 results in the five-
membered-ring radical intermediate A4. Subsequent
group transfer would be accomplished when radical A4
abstracts the phenylseleno group from another substrate
molecule to give the cyclization product 3a.
Next, we examined the reactions of various unsatu-
rated R-phenylseleno â-hydroxy ester substrates under
our optimized radical cyclization conditions (Table 2).
These results demonstrate that excellent regio- and
diastereoselectivities can be achieved for the Et2AlCl-
promoted phenylseleno group transfer radical cyclization
We confirmed the structure of 3a by X-ray crystal-
lographic analysis.18 The oxidative elimination of the
phenylseleno group of 3a with H2O2 provided an olefinic
product, which we confirmed spectroscopically to be 4a.
Hydrogenation of 4a gave product 5a (Scheme 4).
In Scheme 5 we propose a chelation control mechanism
to explain the high diastereoselectivity observed in the
radical cyclization reactions.11 Upon reaction with the
Lewis acid (Et2AlCl), 1a forms the alkoxyaluminum
(17) (a) Toru, T.; Kawai, S.; Ueno, Y. Synlett 1996, 539-541. (b)
Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G.; Soncini, P.; Fava, G.
G.; Belicchi, M. F. Tetrahedron Lett 1985, 26, 2021-2024.
(18) See the Supporting Information.
8824 J. Org. Chem., Vol. 69, No. 25, 2004

Asymmetric Phenylseleno Group Transfer Radical Cyclization
TABLE 2. Et2AlCl-Promoted Phenylseleno Group Transfer Monocyclization Reactionsa
a Reaction conditions: 2 equiv of Et2AlCl, 300-W sunlamp, 25-30 °C, 0.3-0.6 mmol of substrate in benzene (30 mL/mmol). b Isolated
yield.
reactions. Cyclization of the syn-isomer 2a gave exclu-
sively the cis, trans products 3a and 4a as a 6:1 mixture
in 71% yield (entry 1). When comparing this reaction with
the cyclization of the anti radical precursor 1a, it is
obvious that the cis, trans cyclic products were formed
preferentially and independent of the stereochemistry of
the radical precursors. We then tested if this substrate
independence could be applied to R-methyl R-phenyl-
seleno â-hydroxy ester substrates 1f and 2f. Indeed, we
obtained similar results. Both the radical precursors,
anti-1f and syn-2f, gave only the cis, trans cyclization
products 3f and 4f in the same ratio (3:1) and in good
yields (79% and 78%, respectively; entries 2 and 3). These
observations indicate that the radical cyclizations of 1f
and 2f proceeded through the same radical intermediate.
For the reaction of the â-hydroxy ester 1b, we isolated
the desired 6-endo product 3b as the only cyclization
product in 77% yield (entry 4). A strong NOE observed
between the R-H and methyl protons provides evidence
to suggest that the methyl group resides in an axial
position. The R-centered radical attacks the disubstituted
olefin predominately from the less-hindered side (Scheme
6). After cyclization, radical B2 abstracts the phenyl-
seleno group of 1b from the â-face to give the product
B3. The approach of 1b from the R-face is apparently
hindered by the two axial hydrogen atoms.
SCHEME 6
(â:R ) 3:4; entry 4). To determine the stereochemistries
of R-3c and â-3c, both isomers were treated indepen-
dently with n-Bu3SnH/Et3B/O2 in benzene at room tem-
perature; reduction products 5c were obtained as a pair
of epimers in the same ratio (R:â ) 4:3; Scheme 7). The
stereochemistries of â-3c and R-5c were established by
the use of 2D NOESY experiments (see the Supporting
Information).
Preparation of Optically Pure Radical Precur-
sors and Their Applications in Tandem Radical
Cyclization Reactions. Multifunctional chiral cyclic
compounds are useful building blocks for the synthesis
of natural products. We expected that an extension of the
group transfer radical reactions described above to chiral
For the cyclization of 1c, the R-centered radical attacks
the less-substituted side of the alkene to form exclusively
the 7-endo cyclization products 3c as a pair of epimers
J. Org. Chem, Vol. 69, No. 25, 2004 8825

Yang et al.
SCHEME 7a
a Reagents and conditions: (a) Bu3SnH, Et3B/O2, benzene, rt.
SCHEME 8a
a Reagents and conditions: (a) H2, 1 atm, RuBr2[(R)-Binap] (3%), 50 °C, 99%, 96% ee; (b) LDA, THF, -35 °C, then PhSeBr, -78 °C,
70%; (c) Et2AlCl, benzene, sunlamp, 25 °C, 77%, 98.2% ee.
precursors would make these cyclization reactions more
attractive and practical for the enantioselective synthesis
of natural products.
suitable for further chemical transformations.2 Tan-
dem radical cyclizations, in which two or more carbon-
carbon bonds are formed in successive steps in one
reaction without the isolation of reaction intermediates,
are regarded as economically favorable synthetic meth-
ods.23 Therefore, atom or group transfer tandem radical
cyclizations that combine the advantages of the two
types of reactions should be simple, highly efficient, and
useful synthetic processes. By applying our monocycliza-
tion method to chiral diene substrates, we expected to
obtain various synthetically useful, bicyclic phenylseleno
group transfer products that contain multiple chiral
centers.
Unfortunately, we found that asymmetric hydrogena-
tion of â-keto esters was inefficient when they bear
terminal olefinic groups (Scheme 9). Under Genet’s
conditions,19d-f the terminal olefin units always reduced
faster than did the keto groups to give products that were
a mixture of 7d and 8d. To prepare chiral unsaturated
â-hydroxy esters, we converted the â-keto ester into its
potassium salt 9d and attempted a bakers’ yeast reduc-
tion of this salt; we abandoned this approach because of
the poor yield and the tedious workup procedure.24
Chiral radical precursors can be obtained readily by
phenylselenation of optically pure â-hydroxy esters ac-
cording to Scheme 2. Chiral â-hydroxy esters are usually
prepared by asymmetric reduction of â-keto esters19,20 as
well as by kinetic enzymatic resolution of â-hydroxy
esters.21 Chiral â-hydroxy ester (R)-6a was prepared
readily from the corresponding â-keto ester in quantita-
tive yield and 96% ee following Genet’s protocol (Scheme
8),19f under which the trisubstituted olefin was not
reduced. Chiral radical precursor (+)-1a was prepared
from (R)-6a following the same procedure as that de-
scribed in Scheme 2. Radical cyclization of (+)-1a under
our optimized reaction condition (entry 8, Table 1)
provided (-)-3a, which contains three adjacent chiral
centers, in up to 98% ee. We determined the absolute
configuration of (-)-3a by X-ray crystallographic struc-
tural analysis.18
Previously, we demonstrated the advantages that
phenylseleno groups have in group transfer tandem
radical cyclization reactions.22 The transferred group is
(19) For examples of the asymmetric hydrogenation of â-keto esters,
see: (a) Burk, M. J. Acc. Chem. Res. 2000, 33, 363-372. (b) Noyori,
R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.;
Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J.
Am. Chem. Soc. 1989, 111, 9134-9135. (c) Burk, M. J.; Harper, G. P.;
Kalberg, C. S. J. Am. Chem. Soc. 1995, 117, 4423-4424. (d) Genet, J.
P.; Pinel, C.; Ratovelomanana-Vidal, V.; Mallart, S.; Pfister, X.; Cano
de Andrade, M. C.; Lafitte, J. A. Tetrahedron: Asymmetry 1994, 5, 665-
674. (e) Genet, J. P.; Ratovelomanana-Vidal, V.; Cano de Andrade, C.;
Pfister, X.; Guerreiro, P.; Lenoir, J. Y. Tetrahedron Lett. 1995, 36,
4801-4804. (f) Greck, C.; Ferreira, F.; Genet, J. P. Tetrahedron Lett.
1996, 37, 2031-2034.
(20) For reviews on the reduction of â-keto esters with bakers’ yeast,
see: (a) Davies, F. H. G.; Green, R. H.; Kelly, D. R.; Roberts, S. M.
Biotransformations in Preparative Organic Chemistry. The Use of
Isolated Enzymes and Whole Cell Systems in Synthesis; Academic
Press: London, UK, 1989; Chapter 3. (b) Servi, S. Synthesis 1990,
1-25. (c) Csuk, R.; Glanzer, B. I. Chem. Rev. 1991, 91, 49-97. (d)
Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A. Chem. Rev.
1992, 92, 1071-1140. (e) D’Arrigo, P.; Pedrocchi Fantoni, G.; Servi,
S.; Strini, A. Tetrahedron: Asymmetry 1997, 8, 2375-2379.
(21) (a) Akita, H.; Matsukura, H.; Oishi, T. Tetrahedron Lett. 1986,
27, 5241-5244. (b) Itoh, T.; Kuroda, K.; Tomosada, M.; Takagi, Y. J.
Org. Chem. 1991, 56, 797-804.
(22) Yang, D.; Gao, Q.; Lee, O.-Y. Org. Lett. 2002, 4, 1239-1241.
(23) For recent reviews on tandem radical cyclization reactions,
see: (a) Malacria, M. Chem. Rev. 1996, 96, 289-306. (b) McCarroll,
A. J.; Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224. (c) Snider,
B. B. Chem. Rev. 1996, 96, 339-363. (d) Parsons, P. J.; Penkett, C. S.;
Shell, A. J. Chem. Rev. 1996, 96, 195-206. For recent examples, see:
(e) Curran, D. P.; Sisko, J.; Balog, A.; Sonoda, N.; Nagahara, K.; Ryu,
I. J. Chem. Soc., Perkin Trans. 1 1998, 10, 1591-1953. (f) Kim, S.;
Cheong, J. H.; Yoo, J. Synlett 1998, 981-982. (g) Yang, D.; Ye, X.-Y.;
Gu, S.; Xu, M. J. Am. Chem. Soc. 1999, 121, 5579-5580. (h) Kizil, M.;
Patro, B.; Callaghan, O.; Murphy, J. A.; Hursthouse, M. B.; Hibbs, D.
J. Org. Chem. 1999, 64, 7856-7862. (i) Sha, C.-K.; Lee, F.-K.; Chang,
C.-J. J. Am. Chem. Soc. 1999, 121, 9875-9876. (j) Patro, B.; Murphy,
J. A. Org. Lett. 2000, 2, 3599-3601. (k) Hiton, S. T.; Jones, K.; Tim,
C. T.; Pljevaljcic, G.; Schulte, M. Chem. Commun. 2001, 209-210. (l)
Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2001, 123, 4717-4727. (m)
Njardarson, J. T.; McDonald, I. M.; Spiegel, D. A.; Inoue, M.; Wood, J.
L. Org. Lett. 2001, 3, 2435-2438. (n) Haruo, Y.; Hasegawa, T.; Tanaka,
H.; Takahashi, T. Synlett 2001, 1935-1937. (o) Zhou, S.; Bommezijn,
S.; Murphy, J. A. Org. Lett. 2002, 4, 443-445.
(24) (a) Hayakawa, K.; Nagatsugi, F.; Kanematsu, K. J. Org. Chem.
1988, 53, 860-863. (b) Hirama, M.; Shimizu, M.; Iwasjita, M. J. Chem,
Soc., Chem. Commun. 1983, 559-600.
8826 J. Org. Chem., Vol. 69, No. 25, 2004

Asymmetric Phenylseleno Group Transfer Radical Cyclization
SCHEME 9
SCHEME 10
SCHEME 11
Finally, we found that the application of lipase Amano
PS, which has been used in the resolution of saturated
â-hydroxy esters,25 was a better choice for effecting the
resolution. We obtained the chiral â-hydroxy ester (R)-
6d readily in 45% yield and 94% ee when using this
enzyme-catalyzed transesterification method (Amano PS/
vinyl acetate/n-hexane; Scheme 10). To the best of our
knowledge, this reaction is the first example of the
application of lipases in the resolution of unsaturated
â-hydroxy esters; this method is a highly efficient one
that provides operationally simple access to both enan-
tiomers of these types of compounds.
SCHEME 12
To examine the tandem radical cyclization reactions,
radical precursors (+)-1d were prepared from (R)-6d
according to the method outlined in Scheme 2. After the
radical cyclization of (+)-1d, the cis-6,5-fused ring product
3d was isolated in high yield (75%) as a mixture of
epimers (R:â ) 1:1.6; Scheme 11). The relative configu-
ration of R-3d was confirmed by the X-ray crystal-
lographic analysis.18 Oxidative elimination of the PhSe
group from 3d provided the exocyclic olefinic compound
(-)-4d, which possesses three new chiral centers, in high
optical purity (97.1% ee).
Scheme 12 provides an explanation of the stereo-
chemical outcome of the cyclization of 1d. The less-
substituted side of the olefin group approaches the radical
center via transition state D1 to give a 6-endo cyclization
intermediate, which undergoes a 5-exo cyclization via
transition states D2 and D3 to produce the two epimers
of the group transfer cyclization products r-3d and â-3d,
respectively.
Formal Total Synthesis of (-)-Wilforonide. Wil-
foronide, a terpenoid isolated from the Chinese medicinal
herb Triperygium wilfordii Hook F (Lei Gong Teng), has
significant antiinflammatory activity and is effective in
inhibiting T-cell proliferation and cytokine release.26 To
demonstrate the synthetic advantages of our Et2AlCl-
promoted phenylseleno group transfer radical cyclization
reaction, we prepared compound (-)-4e, which we have
used previously in our group as a key intermediate in
the total synthesis of (-)-wilforonide.27 By using the
transesterification method described above, we readily
obtained the chiral â-hydroxy esters (R)-6e in 44% yield
and 94.8% ee (Scheme 13). The chiral radical precursor
(26) (a) Chen, K.; Yang, R.; Wang, C. Zhongcaoyao 1986, 17, 242.
(b) Lipsky, P. E.; Tao, X. L.; Cai, J.; Kovacs, W. J.; Olsen, N. J. U.S.
Patent 5616458, 1997; Chem. Abstr. 1997, 126, 246818h. (c) Lipsky,
P. E.; Tao, X. L.; Cai, J. U.S. Patent 5580562, 1996; Chem. Abstr. 1996,
126, 70141r. (d) Schkeryantz, J. M.; Luly, J. R.; Coghlan, M. J. Synlett
1998, 723-724.
(25) Bornscheuer, U.; Herar, A.; Kreye, L.; Wendel, V.; Capewell,
A.; Meyer, H. H.; Scheper, T.; Kolisis, F. N. Tetrahedron: Asymmetry
1993, 4, 1007-1016.
(27) Yang, D.; Xu, M. Org. Lett. 2001, 3, 1785-1788.
J. Org. Chem, Vol. 69, No. 25, 2004 8827

Yang et al.
SCHEME 13a
a Reagents and conditions: (a) LDA (2 equiv), THF, -35 °C, then PhSeBr, -78 °C, 80%; (b) Et2AlCl (2 equiv), 30 °C, benzene, sunlamp,
rt, 13 h; (c) H2O2, THF; (d) Dess-Martin reagent, CH2Cl2, 46% for three steps.
SCHEME 14
Conclusion
We have developed a new method of asymmetric
phenylseleno group transfer radical cyclization of unsat-
urated â-hydroxy esters. Various unsaturated R-phenyl-
seleno â-hydroxy esters underwent radical cyclization to
give mono- and bicyclic group-transferred products in an
efficient and highly regioselective and diastereoselective
manner. To rationalize the high diastereoselectivities
observed in this reaction, we propose a model based on
chelation control of the aluminum alkoxides that are
formed in situ. We devised a general method to prepare
chiral radical precursors from which we obtained highly
optically pure mono- and bicyclic group transfer products.
The synthetic advantages of this method are demon-
strated by our formal total synthesis of (-)-wilforonide.
This paper presents the first examples of stereoselective
group transfer radical cyclizations that occur via 1,2-
asymmetric induction.
(+)-1e was prepared in 80% yield from (R)-6e by following
the procedure outlined in Scheme 2. The cyclization of
(+)-1e gave an inseparable mixture of products, but after
two consecutive oxidationssi.e., the oxidative elimination
of the PhSe group and the oxidation of the hydroxyl unit
to give a ketone groupswe isolated (-)-4e as the only
bicyclic product. Compound (-)-4e is a core structure that
is also found in many other naturally occurring bioactive
terpenoids, such as andrographolide28 and candelalides.29
The successful extension of our asymmetric group trans-
fer radical cyclization method to tandem reactions sug-
gests that this process will be an attractive method for
the asymmetric synthesis of multifunctional bicyclic
compounds.
Scheme 14 provides an explanation for the stereo-
chemical outcome of the cyclization of 1e. The 6-endo-
chairlike cyclization of the radical intermediate E1 yields
a six-membered cyclic radical E2, which undergoes
another 6-endo-chairlike cyclization to form the bicyclic
radical E3 having a trans-6,6-ring junction.
Acknowledgment. This work was supported by The
University of Hong Kong, Hong Kong Research Grants
Council (7124/00P and 7121/02P). D.Y. acknowledges
the Bristol-Myers Squibb Foundation for an Unre-
stricted Grant in Synthetic Organic Chemistry and the
Croucher Foundation for a Croucher Senior Research
Fellowship Award.
Supporting Information Available: Experimental de-
tails; X-ray crystallographic data for compounds (-)-3a and
R-3d. This material is available free of charge via the Internet
at http://pubs.acs.org.
(28) Puri, A.; Saxena, R.; Saxena, R. P.; Saxena, K. C.; Srivastava,
V.; Tandon, J. S. J. Nat. Prod. 1993, 56, 995-999.
(29) Singh, S. B.; Zink, D. L.; Dombrowski, A. W.; Dezeny, G.; Bills,
G. F.; Felix, J. P.; Slaughter, R. S.; Goetz, M. A. Org. Lett. 2001, 3,
247-250.
JO048322Z
8828 J. Org. Chem., Vol. 69, No. 25, 2004