Enantioselective PhSe-group-transfer tandem radical cyclization reactions catalyzed by a chiral Lewis acid

Article abstract of DOI:10.1002/anie.200503056

(Chemical Equation Presented) A radical change: α-Phenylselenyl- β-ketoesters (e.g., 1) undergo radical cyclization in the presence of a chiral Lewis acid complex Mg(ClO₄)₂-3 with Et ₃B/O₂ as the radical initiat

Full text of DOI:10.1002/anie.200503056

Angewandte
Chemie
Radical Cyclization
DOI: 10.1002/anie.200503056
Enantioselective PhSe-Group-Transfer Tandem
Radical Cyclization Reactions Catalyzed by a
Chiral Lewis Acid**
Dan Yang,* Bao-Fu Zheng, Qiang Gao, Shen Gu, and
Nian-Yong Zhu
Tandem radical cyclization, which is a powerful method for
the synthesis of polycyclic compounds, is used widely in the
syntheses of natural products.[1] Only a few asymmetric
tandem radical cyclization reactions are known,[2,3a] however,
and no enantioselective group-transfer radical reactions have
been reported.[4] Herein we report a catalytic enantioselective
group-transfer radical cyclization reaction and its applications
in tandem reactions.
[*] Prof. D. Yang, B.-F. Zheng, Q. Gao, S. Gu, N.-Y. Zhu
Department of Chemistry
The University of Hong Kong
Pokfulam Road, Hong Kong (P. R. China)
Fax: (+852)2859-2159
E-mail: yangdan@hku.hk
Prof. D. Yang
Department of Chemistry
Fudan University
Shanghai, 200433 (P. R. China)
[**] This study was supported by the University of Hong Kong, the Hong
Kong Research Grants Council (Project No. HKU7121/02P), and the
National Natural Science Foundation of China (Project No.
20229201). D.Y. thanks the Bristol-Myers Squibb Foundation for an
Unrestricted Grant in Synthetic Organic Chemistry and the
Croucher Foundation for a Senior Research Fellowship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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To investigate the enantioselective PhSe-group-transfer
As Table 1 indicates, cyclization of 1a, after purification
by column chromatography, gave the 6-exo product 2a as a
single diastereoisomer in 82% yield with 89% ee (Table 1,
entry 1). Although the addition of activated 4-Š molecular
sieves did not improve the ee value, it accelerated the reaction
dramatically and made it possible to use a catalytic amount of
the chiral catalyst (Table 1, entries 2–4).[7] Substrate 1b, the
trans olefin analogue of 1a, gave the same product (+)-2a in
comparable yield and enantioselectivity (Table 1, entries 5
and 6). When we used a catalytic amount (0.3 equiv) of the
chiral Lewis acid, the yield decreased slightly but the
enantioselectivity increased to 87% ee (Table 1, entry 6).
The absolute configuration of (+)-2a was determined to be
(2R,3S,11R).[8] The excellent control of the configuration at
the contiguous stereogenic centers is in contrast to the results
obtained from the corresponding bromine-atom-transfer
radical cyclization reactions, in which two diastereomeric
products were obtained in a poor ratio.[3b] Substrate 1c gave
exclusively the 6-endo product 2c in 63% yield with 69% ee
(Table 1, entry 7). For the cyclization of 1d, the a-radical
center attacked the less-substituted side of the alkene to form
the seven-membered ring product 2d exclusively in moderate
yield and enantioselectivity (Table 1, entry 8). The cyclization
of substrate 1e proceeded smoothly to produce the bicyclic
product 2e with 87% ee. A lower catalyst loading (0.3 equiv)
led to a large decrease in the ee value (Table 1, entries 9 and
10). These results represent the first known enantioselective
group-transfer radical cyclization reactions catalyzed by
chiral Lewis acids.
radical cyclization reactions of unsaturated a-phenylseleno-b-
ketoesters, we prepared compounds 1a–e and subjected them
to cyclization conditions, with Et3B/O2 as the radical initiator
(Table 1). In the absence of a Lewis acid, no cyclization
reaction occurred, and only reductive dephenylselenate
products were obtained (data not shown). Clearly Lewis
acids promoted this phenylseleno-transfer radical cyclization
reaction. We found that the complex formed between Mg-
(ClO4)2 and the bisoxazoline ligand[5] 3 was the most suitable
catalyst for the cyclization reaction.[6]
Table 1: Chiral Lewis acid catalyzed group-transfer radical monocycliza-
tion reactions.[a]
Entry Substrate
LA[b]
[equiv]
t [h] Product
Yield ee
[%][c] [%][d]
1
1.0
6
82
89
2[e]
3
1.0
0.3
0.3
8
10
12
80
81
<5
89
84
4[e]
Because PhSe-transfer radical cyclization reactions have
been demonstrated previously to have great potential for use
in tandem cyclization reactions,[9] we expected to obtain
bicyclic PhSe-transfer products when applying our new
method to a series of diene substrates (Table 2). In contrast
to the low yields and enantioselectivities (< 33%) in the
corresponding Br-transfer radical cyclization,[3a] substrate 1 f
gave the cis-6,5-fused ring product 2 f in 70% yield with
73% ee (Table 2, entry 1). The use of 0.3 equivalents of chiral
Lewis acid did not decrease the yield or the ee value
significantly (Table 2, entry 2). Substrate 1g underwent 6-
endo/6-exo cyclization (Table 2, entry 3) to give the 6,6-trans-
fused ring product 2g with excellent enantioselectivity
(97% ee) albeit in low yield (31%); high selectivity
(87% ee) was attained even when using 0.3 equivalents of
the chiral Lewis acid catalyst (Table 2, entry 4). In this case we
also isolated approximately of the monocyclization product
because the 1,3-diaxial interactions of two methyl groups
rendered the second cyclization unfavorable. Substrate 1h,
which has an allyl substituent in the a-position, underwent
sequential 6-exo and 5-exo cyclizations in the presence of a
stoichiometric amount of the chiral Lewis acid to give the
bicyclic product 2h in 44% yield with 91% ee (Table 2,
entry 5). Each of these tandem cyclization reactions success-
fully creates four stereogenic centers in a single step with
moderate to high enantioselectivity, which further demon-
strates the power of this chiral Lewis acid promoted PhSe-
group-transfer radical cyclization.
5
6
1.0
0.3
7
71
66
81
87
10
7
8
1.0
1.0
8
9
63
65
69
66
9
1.0
0.3
8
9
75
62
87
58
10
[a] Unless otherwise indicated, all reactions were performed with
0.2 mmol of the substrate at a concentration of 0.025m in toluene in
the presence of activated 4-Š molecular sieves (powder, 500 mgmmolÀ1
substrate) and the indicated amount of Mg(ClO4)2 and (S,S)-3 (ligand/
Lewis acid=1.1:1). [b] LA=Lewis acid. [c] Yield of isolated product.
[d] The enantiomeric excess was determined through HPLC analysis by
using a Chiralcel AD column. [e] In the absence of the 4-Š molecular
sieves (M.S.).
The model proposed to account for the high stereoselec-
tivity is similar to that for the corresponding Br-transfer
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Table 2: Chiral Lewis acid catalyzed group-transfer radical tandem
cyclization reactions.[a]
Entry Substrate
LA[b]
[equiv]
t [h] Product
Yield ee
[%][c] [%][d]
1
2
1.0
0.3
9
70
70
73
67
10
3
4
1.0
0.3
12
12
31
33
97
87
5
1.0
12
44
91
[a] Unless otherwise indicated, all reactions were performed with
0.2 mmol of the substrate at a concentration of 0.025m in toluene in
the presence of activated 4-Š molecular sieves (powder, 500 mgmmolÀ1
substrate) and the indicated amounts of Mg(ClO4)2 and (S,S)-3 (ligand/
Lewis acid=1.1:1). [b] LA=Lewis acid. [c] Yield of isolated product.
[d] The enantiomeric excess was determined through HPLC analysis by
using a Chiralcel OD or AD column.
Figure 1. Transition-state model proposed for the enantioselective group-
transfer radical cyclization.
[1] For recent reviews on tandem radical cyclization reactions, see:
a) M. Malacria, Chem. Rev. 1996, 96, 289 – 306; b) B. B. Snider,
Chem. Rev. 1996, 96, 339 – 363; c) P. J. Parsons, C. S. Penkett,
A. J. Shell, Chem. Rev. 1996, 96, 195 – 206; d) A. J. McCarroll,
J. C. Walton, Angew. Chem. 2001, 113, 2282 – 2307; Angew.
Chem. Int. Ed. 2001, 40, 2224 – 2248; for recent reviews on free
radical reactions used in the synthesis of natural products, see:
e) C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91,
1237 – 1286; f) P. J. Parsons, C. S. Penkett, A. J. Shell, Chem. Rev.
1996, 96, 195 – 206.
[2] For excellent reviews on enantioselective radical reactions and
Lewis acid catalyzed radical reactions, see: a) B. GuØrin, W. W.
Ogilvie, Y. Guindon in Radicals in Organic Synthesis, Vol. 1
(Eds.: P. Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001,
chap. 4.4; b) M. P. Sibi, N. A. Porter, Acc. Chem. Res. 1999, 32,
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radical cyclizations we reported earlier (Figure 1). We assume
that the dicarbonyl moiety of substrate 1a chelates to the
magnesium center, which adopts an octahedral geometry in
which ClO4 ions occupy the two axial positions.[10] To avoid
À
steric interactions with the a-tert-butyl group, the olefin
moiety prefers to approach from the Re face of the a-radical
center (transition states A and B). In TS B, steric interactions
are found between the olefin group and the b-tert-butyl group.
Thus TS A would be favored over TS B, affording the cyclic
radical intermediate C. For the most stable conformer of
radical intermediate C, SePh abstraction takes place prefer-
entially from the less-hindered Re face to yield product 2a as a
single diastereoisomer. Thus, the lower transfer rate of the
SePh group to the alkyl radical—relative to that of Br-atom
transfer—and its bulk cause the SePh abstraction to be more
stereoselective.[11]
In conclusion, we have developed Lewis acid catalyzed,
highly enantioselective PhSe-group-transfer radical cycliza-
tion reactions for the construction of a variety of monocyclic
and bicyclic compounds that include the core structures of
many biologically interesting natural products.
[3] a) D. Yang, S. Gu, Y.-L. Yan, H.-W. Zhao, N.-Y. Zhu, Angew.
Chem. 2002, 114, 3140 – 3143; Angew. Chem. Int. Ed. 2002, 41,
3014 – 3017; b) D. Yang, S. Gu, Y.-L. Yan, N.-Y. Zhu, K.-K.
Cheung, J. Am. Chem. Soc. 2001, 123, 8612 – 8613.
[4] For references on atom-and groupt-ransfer radical reactions,
see: a) D. P. Curran, M.-H. Chen, D. Kim, J. Am. Chem. Soc.
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Chem. 1989, 54, 3140 – 3157; c) D. P. Curran, M.-H. Chen, D.
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Org. Chem. 1991, 56, 2746 – 2750; f) for a recent review, see: J.
Byers in Radicals in Organic Synthesis, Vol. 1 (Eds.: P. Renaud,
M. P. Sibi), Wiley-VCH, Weinheim, 2001, chap. 1.5.
Received: August 27, 2005
Revised: September 30, 2005
Published online: November 28, 2005
[5] For reviews on the use of C2-symmetric chiral bisoxazoline
ligands in asymmetric catalysis, see: a) J. S. Johnson, D. A.
Evans, Acc. Chem. Res. 2000, 33, 325 – 335; b) A. K. Ghosh, P.
Keywords: asymmetric synthesis · enantioselectivity ·
ketoesters · Lewis acids · tandem cyclization
.
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257

Communications
Mathivanan, J. Cappiello, Tetrahedron: Asymmetry 1998, 9, 1 –
45.
[6] We found that the use of other Lewis acids, including Yb(OTf)3,
Cu(OTf)2, and Sc(OTf)3, was ineffective.
[7] The role of activated molecular sieves in the cyclization
reactions is not yet fully understood. One possibility is that
molecular sieves absorb water, as Mg(ClO4)2 is moisture
sensitive. A similar effect was found in our Br-atom-transfer
radical cyclization reactions.[3b]
[8] The relative configuration of 2a was determined by X-ray
crystallographic analysis of a 2,4-DNP (DNP = dinitrophenyl-
hydrazine derivative of (Æ )-2a; the absolute configurations of
the stereogenic centers C2 and C3 were determined by
comparison of optical rotation data of the reductive dephenyl-
seleno product of (+)-2a with those of the reductive debromo
product of a known compound (see Supporting Information for
details).
[9] a) D. Yang, Q. Gao, O.-Y. Lee, Org. Lett. 2002, 4, 1239 – 1241;
b) D. Yang, Q. Gao, B.-F. Zheng, N.-Y. Zhu, J. Org. Chem. 2004,
69, 8821 – 8828.
[10] For a MgII–bisoxazoline complex with octahedral geometry, see:
a) G. Desimoni, G. Faita, P. P. Righetti, Tetrahedron Lett. 1996,
37, 3027 – 3030; b) G. Desimoni, G. Faita, A. G. Invernizzi, P. P.
Righetti, Tetrahedron 1997, 53, 7671 – 7688; c) J. M. Takacs, E. C.
Lawson, M. J. Reno, M. A. Youngman, D. A. Quincy, Tetrahe-
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R. G. Hazell, K. A. Jorgensen, J. Org. Chem. 1998, 63, 118 – 121.
[11] D. P. Curran, A. A. Martin-Esker, S.-B. Ko, M. Newcomb, J. Org.
Chem. 1993, 58, 4691 – 4695.
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