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