Highly enantioselective atom-transfer radical cyclization reactions catalyzed by Chiral Lewis acids [10]

Full text of DOI:10.1021/ja016383y

8612
J. Am. Chem. Soc. 2001, 123, 8612-8613
Scheme 1
Highly Enantioselective Atom-Transfer Radical
Cyclization Reactions Catalyzed by Chiral Lewis
Acids
Dan Yang,* Shen Gu, Yi-Long Yan, Nian-Yong Zhu, and
Kung-Kai Cheung
Department of Chemistry, The UniVersity of Hong Kong
Table 1. Lewis Acid-Catalyzed Atom-Transfer Radical Cyclization
Reactionsa
Pokfulam Road, Hong Kong
entry substr Lewis acid (equiv) solvent timeb (h) yieldc (%)
ReceiVed June 11, 2001
1
2
3
4
5
6
7
8
9e
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1d
Yb(OTf)3 (0.5)
Yb(OTf)3 (0.05)
Mg(ClO4)2 (0.4)
Yb(OTf)3 (0.3)
Mg(ClO4)2 (0.3)
Mg(ClO4)2 (0.3)
Yb(OTf)3 (0.3)
Mg(ClO4)2 (0.3)
Mg(ClO4)2 (0.3)
Yb(OTf)3 (0.5)
Mg(ClO4)2 (0.3)
Et2O
Et2O
toluene
Et2O
CH2Cl2
toluene
Et2O
CH2Cl2
toluene
Et2O
9.5
9.5
6.5
5
4.5
4.5
5
4.5
4.5
10
70
60
62
Free radical reactions are powerful and versatile tools for the
formation of carbon-carbon bonds.1 In recent years, significant
progress has been made in enantioselective conjugate radical
addition reactions2 catalyzed by chiral Lewis acids.3 However,
no success was reported for the enantioselective atom-transfer
radical reactions.4 Here we report highly enantioselective atom-
transfer radical cyclization reactions catalyzed by chiral Lewis
acids.
A typical atom-transfer radical cyclization reaction involves
the transfer of a halogen atom from one carbon center to another
with concomitant ring formation (Scheme 1).5,6 The advantage
of this reaction over other radical reactions is that the halogen
atom is retained in the product, which allows for further
functionalization. A recent study by Porter and co-workers showed
that Lewis acids could catalyze intermolecular atom-transfer
radical addition reactions.4a We have been focused on atom-
transfer radical cyclization reactions, as they hold promise for
highly selective formation of multiple chiral centers.
78 (2.4/1)d
75 (1.3/1)d
84 (1/1.9)d
74 (2.5/1)d
78 (1/1.1)d
81 (1/2.2)d
71
10
11
toluene
9
55
a Unless otherwise indicated, all reactions were carried out at -78
°C with 0.2-0.3 mmol of substrate, the indicated amount of Lewis
acid, 10 mL of solvent, 2 equiv of Et3B/O2 for substrates 1a and 1d, or
5 equiv of Et3B/ O2 for substrates 1b and 1c. b Time for complete
reaction. c Isolated yield. d Ratio of 2b and 2c. e 1 mmol of substrate.
in Et2O, providing compounds 2a-d as the major products in
high yields (entries 1, 4, 7, and 10).8 For substrate 1a, the catalyst
loading could even be reduced to 5 mol % without significant
decrease in yield (entry 2). In the cyclization of substrate 1b or
1c of trans- or cis-olefinic double bonds, respectively, only two
isomers 2b/c differing in the stereochemistry of the exocyclic
chiral center were isolated (entries 4-9). After reductive debro-
mination of 2b/c with tin hydride, a single product 3 was isolated
in 92% yield (eq 1). When the atom-transfer radical cyclization
reactions were carried out in CH2Cl2 or toluene, Mg(ClO4)2 turned
out to be the best Lewis acid (entries 3, 5, 6, 8, 9, and 11). Thus
the reaction systems of Yb(OTf)3/Et2O, Mg(ClO4)2/toluene, and
Mg(ClO4)2/CH2Cl2 were found to be suitable for almost all the
substrates.
A series of unsaturated â-keto esters 1a-d were used to probe
the conditions for atom-transfer cyclization reactions with Et3B/
O2 as the radical initiator (Table 1).7 Without the addition of any
Lewis acid, no cyclization reaction occurred, and only reductive
debromination products were obtained (data not shown). In the
presence of 0.3-0.5 equiv of Yb(OTf)3, intramolecular atom-
transfer radical cyclization reactions of 1a-d took place efficiently
(1) (a) Curran, D. P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Flemming, I.; Semmelhack, M. F., Eds.; Pergamon: Oxford, 1991; Vol. 4,
Chapter 4.2. (b) Curran, D. P. Synthesis 1988, 417-439. (c) Curran, D. P.
Synthesis 1988, 489-513. (d) Giese, B. Radicals in Organic Synthesis.
Formation of Carbon-Carbon Bonds; Pergamon: Oxford, 1986.
(2) (a) For an excellent review on enantioselective radical reactions, see:
Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163-171. (b) Sibi, M.
P.; Ji, J.; Wu, J. H.; Gu¨rtler, S.; Porter, N. A. J. Am. Chem. Soc. 1996, 118,
9200-9201. (c) Sibi, M. P.; Ji, J. J. Org. Chem. 1997, 62, 3800-3801. (d)
Sibi, M. P.; Shay, J. J.; Ji, J. Tetrahedron Lett. 1997, 38, 5955-5958. (e)
Mikami, K.; Yamaoka, M. Tetrahedron Lett. 1998, 39, 4501-4504. (f)
Nishida, M.; Hayashi, H.; Nishida, A.; Kawahara, N. Chem. Commun. 1996,
579-580.
(3) For an excellent review on the use of Lewis acids in free radical
reactions, see: Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. 1998, 37,
2562-2579.
(4) (a) Mero, C. L.; Porter, N. A. J. Am. Chem. Soc. 1999, 121, 5155-
5160. For examples of enantioselective allyl transfer radical reactions, see:
(b) Murakata, M.; Jono, T.; Mizuno, Y.; Hoshino, O. J. Am. Chem. Soc. 1997,
119, 11713-11714. (c) Wu, J. H.; Zhang, G.; Porter, N. A. Tetrahedron Lett.
1997, 38, 2067-2070. (d) Porter, N. A.; Wu, J. H.; Zhang, G.; Reed, A. D.
J. Org. Chem. 1997, 62, 6702-6703. (e) Wu, J. H.; Radinov, R.; Porter, N.
A. J. Am. Chem. Soc. 1995, 117, 11029-11030. (f) Nagano, H.; Kuno, Y. J.
Chem. Soc., Chem. Commun. 1994, 987-988.
(5) (a) Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54, 3140-3157.
(b) Curran, D. P.; Chen, M.-S.; Kim, D. J. Am. Chem. Soc. 1989, 111, 6265-
6276. (c) Curran, D. P.; Chen, M.-H.; Spletzer, E.; Seong, C. M.; Chang,
C.-T. J. Am. Chem. Soc. 1989, 111, 8872-8878. (d) Curran, D. P.; Tamine,
J. J. Org. Chem. 1991, 56, 2746-2750. (e) Yorimitsu, H.; Nakamura, T.;
Shinokubo, H.; Oshima, K.; Omoto, K.; Fujimoto, H. J. Am. Chem. Soc. 2000,
122, 11041-11047.
Note that those Lewis acid-catalyzed atom-transfer radical
cyclization reactions exhibited excellent stereocontrol: only
products 2a-d with the 2-ester group trans to the 3-alkyl group
were obtained. In contrast, atom transfer radical cyclization of
1b/c using the (Me3Sn)2/hν conditions reported by Curran et al.
gave mainly the cis products.9 This indicates that Lewis acids
cannot only promote the atom-transfer radical cyclization but also
dramatically affect the stereochemical outcome of those reactions.
(6) For recent examples of copper-catalyzed atom-transfer radical cycliza-
tion reactions, see: (a) 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. (b) Clark, A. J.;
Filik, R. P.; Haddleton, D. M.; Radigue, A.; Sanders, C. J.; Thomas, G. H.;
Smith, M. E. J. Org. Chem. 1999, 64, 8954-8957.
(8) Other solvents such as toluene, CF3CH2OH, and CH2Cl2 gave much
lower yields. With Et2O as the solvent, other Lewis acids such as Sc(OTf)3
and Zn(OTf)2 were found to be less efficient than Yb(OTf)3.
(9) Curran, D. P.; Morgan, T. M.; Schwartz. C. E.; Snider, B. B.;
Dombroski, M. A. J. Am. Chem. Soc. 1991, 113, 6607-6617.
(7) No reaction took place in the absence of Et3B/O2.
10.1021/ja016383y CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/09/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 35, 2001 8613
Table 2. Asymmetric Atom-Transfer Radical Cyclization
Reactionsa
We then investigated the chiral Lewis acid-catalyzed atom-
transfer cyclization reactions. In the presence of chiral ligands
such as bisoxazoline 4,10 the reactions catalyzed by Yb(OTf)3 in
Et2O were found to be very slow and only racemic cyclization
products were obtained. But the Mg(ClO4)2/CH2Cl2 and Mg-
(ClO4)2/toluene systems were found to be effective, especially
with chiral ligand 4. As shown in Table 2, the reactions carried
out in toluene generally gave better ee values than those reactions
in CH2Cl2 (entries 1 vs 2; 8 vs 9; 11 vs 12). Most notably, the
addition of activated 4 Å molecular sieves not only led to a
dramatic increase in yield and ee, but also made it possible for
the use of catalytic amounts of the chiral catalyst (entries 4, 5, 9,
10, 13, 14, and 17).11 The loading of Lewis acid can be reduced
to as low as 30% in many cases without significant compromise
in yield and ee. Up to 95% ee was obtained for the cyclization of
1a-d.12 These are the first enantioselective radical cyclization
reactions catalyzed by chiral Lewis acids.13 Here activated
molecular sieves most likely act as a drying agent, supported by
the fact that the addition of 1 equiv of water resulted in a decrease
in the rate and ee for the radical cyclization of 1a (entries 2 vs
6).
To account for the high stereoselectivity, the following model
is proposed (Figure 1). The â-keto ester group of substrates 1a-d
is assumed to chelate to the chiral Mg/4 complex in a planar
geometry. Considering the steric interactions between the sub-
strates and the tert-butyl groups of the chiral ligand (S,S)-4, the
radical cyclization from the re-face (transition states A and B)
should be more favorable than that from the si-face (not shown).
In addition, due to the lack of steric interactions between
substituents on the olefinic CdC bond and the â-dicarbonyl group,
transition state B would be favored over A, resulting in the
cyclization product 2 of (2R,3S) configuration and a trans
relationship between the 2-ester group and the 3-alkyl group.
In summary, we have developed a Lewis acid-catalyzed, highly
enantioselective atom-transfer radical cyclization method for the
formation of cyclic 2,3-disubstituted ketones. Applications of this
method in enantioselective total synthesis of natural products will
be reported in due course.
catalyst
entry substr (equiv) solvent timeb (h) yieldc (%) eed,e (%)
1
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1.1
1.1
0.6
0.5
0.3
1.1
1.0
1.0
1.0
0.3
1.0
1.0
1.0
0.3
1.1
0.6
0.5
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
toluene
toluene
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
7.5
5
68
67
71
94
2
3
7
7
7
9
9.5
7
6.5
12
4
6.5
4
9.5
7.5
63
65
68
53
85
93
92
21
4f
5f,g
6h
7
57 (1/1.2)i
62 (1.3/1)i
68 (1/1.3)i
58 (1/1)i
60 (1/1.1)i
62 (1/1.3)i
82 (1/1.4)i
81 (1/1.4)i
62
68/78j
44/54j
83/91j
74/87j
50/72j
52/78j
70/92j
74/95j
93
8
9f
10f
11
12
13f
14f,g
15
16
10
7.5
22
53
82
94
17f
a Unless otherwise indicated, all reactions were carried out at -78
°C with 0.2 mmol of substrate, the indicated amount of Mg(ClO4)2,
(S,S)-4 (1.1-fold relative to Mg(ClO4)2), 10 mL of solvent, 3 equiv of
Et3B/O2 for substrates 1a and 1d, or 5 equiv of Et3B/O2 for substrates
1b and 1c. b Time for complete reaction. c Isolated yield. d The enan-
tiomeric excess was determined by HPLC analysis using a Chiralcel
OD or AD column. e The absolute configuration of the product was
determined to be (2R,3S). f Activated 4 Å molecular sieves (powder,
500 mg/mmol substrate) was added to the reaction mixture. g 1 mmol
of substrate. h 1.0 equiv of water was added to the reaction mixture.
i Ratio of 2b and 2c. j The ee values for 2b and 2c, respectively.
Figure 1.
(10) For reviews on the use of C2-symmetric chiral bisoxazoline ligands
in asymmetric catalysis, see: (a) Johnson, J. S.; Evans, D. A. Acc. Chem.
Res. 2000, 33, 325-335. (b) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.
Tetrahedron: Asymmetry 1998, 9, 1-45.
Acknowledgment. This work was supported by The University of
Hong Kong and Hong Kong Research Grants Council. Y.-L.Y. acknowl-
edges a Hui Pun Hing Scholarship for Postgraduate Research and D.Y.
is a recipient of a Bristol-Myers Squibb Unrestricted Grant in Synthetic
Organic Chemistry.
(11) For examples on the use of MS 4A in catalytic asymmetric reactions,
see: (a) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922-
1925. (b) Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima,
M.; Sugimoto, J. J. Am. Chem. Soc. 1989, 111, 5340-5345. (c) Mikami, K.;
Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990, 112, 3949-3954. (d) Evans,
D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J. Am.
Chem. Soc. 1993, 115, 5328-5329. (e) Iida, T.; Yamamoto, N.; Sasai, H.;
Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 4783-4784.
Supporting Information Available: Experimental details; determi-
nation of the absolute configurations of products 2a-d; HPLC analysis
of enantiomeric excesses of products 2a-d; X-ray structural analysis of
products 2a, 2c, and the 2,4-DNP derivative of 2b containing tables of
atomic coordinates, thermal parameters, bond lengths, and angles (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
(12) While the absolute configurations of the radical cyclization products
2a and 2b/c were determined by X-ray analysis, the stereochemical assignments
of 2d were made by correlation of CD spectra of the debromination products
of 2b and 2d. See Supporting Information for details.
(13) For a related Lewis acid-catalyzed enantioselective iodocarbocycliza-
tion reaction via an ionic pathway, see: Kitagawa, O.; Taguchi, T. Synlett
1999, 1191-1199.
JA016383Y