diminished remarkably leading to a 64% yield of the desired
product 2a as a single diastereomer after being stirred in CH Cl
Table 2 Alkyl radical addition of 1 via iodine atom-transfer process using
Et
3
B
2
2
at 278 °C for 2 h, though the ethylated nitrone product 4a was
a
Yield (%)
still obtained in 16% yield (entry 5).
Selectivity
of 2b–d
The absolute configuration of 2a was assigned to be R by
converting the product 2a into authentic N-Cbz-amino acid 5.14
Entry Conditions
Product 2b–d 2a
The reductive cleavage of the N–O bond of 2a with Mo(CO)
6
,
b
c
c
c
i
1
2
3
4
a
Pr I in benzene
Pr
2b
2b
60
82
72
72
18
> 98% de
Trace > 98% de
subsequent hydrogenolysis in the presence of Pd(OH) , and
2
i
I+benzene (3+1)
treatment with CbzCl afforded the enantiomerically pure (R)-N-
Cbz-amino acid 5 without any loss of stereochemical purity
c-C
c-C
6
H
11I+benzene (3+1) 2c
3
12
> 98% de
> 98% de
H
5 9
I+benzene (3+1) 2d
(Scheme 3).
Isolated yields.
B (2.5 equiv.) in benzene (5 mL). Reactions of 1 (50 mg)
were carried out with Et B (2.5 equiv.) in RI–benzene (3+1, v/v, 5 mL).
b
Reaction of 1 (50 mg) was carried out with Pr
i
I (90
c
equiv.) and Et
3
3
In conclusion, we have succeeded in the alkyl radical addition
to chiral glyoxylic nitrone with excellent diastereoselectivities
for the first time, providing a synthetic approach to enantiomer-
ically pure a-amino acids.
Scheme 3 Reagents and conditions: i, Mo(CO)
ii, H , Pd(OH) /C, MeOH, 20 °C; iii, CbzCl, Na
38%, 2 steps).
6
, H
2
O–MeCN, 20 °C (84%);
, acetone–H O, 20 °C
2
2
2
CO
3
2
We thank a Grant-in-Aid for Scientific Research on Priority
Areas (A) from the Ministry of Education, Culture, Sports,
Science and Technology of Japan and the Science Research
Promotion Fund of the Japan Private School Promotion
Foundation.
(
Since most radical reactions are carried out using toxic tin
reagents, an area of continuing and important research is to
develop new methods for radical generation that avoid the use
of tin reagents. Therefore, we have explored the tin-free
reactions of nitrone 1 with alkyl radicals under iodine atom-
transfer reaction conditions using Et
(
3
B as a radical initiator
Scheme 4).15 Good chemical yields of the desired alkylated
Notes and references
products 2b–d were observed in the reaction of 1 with more
nucleophilic secondary alkyl radicals. The formation of the
ethylated byproduct 2a was shown to be dependent on the
reaction temperature; thus changing the temperature from 20 °C
to reflux in benzene led to a decrease in the ratio of ethylated
byproduct 2a to the desired alkylated products 2b–d. A similar
trend has been observed in our recent studies in the radical
reactions of oxime ethers.15
1 For reviews, see: (a) T. Naito, Heterocycles, 1999, 50, 505; (b) A. G.
Fallis and I. M. Brinza, Tetrahedron, 1997, 53, 17543; For some
examples of the radical reaction of oxime ethers, see (c) H. Miyabe, K.
Fujii, T. Goto and T. Naito, Org. Lett., 2000, 2, 4071; (d) G. K. Friestad,
Org. Lett., 1999, 1, 1499; (e) J. Zhang and D. L. J. Clive, J. Org. Chem.,
1
999, 64, 770.
2
For reviews, see: (a) G. K. Friestad, Tetrahedron, 2001, 57, 5461; (b) H.
Miyabe and T. Naito, J. Synth. Org. Chem., Jpn., 2001, 59, 35; (c)
Radicals in Organic Synthesis, Vol. 1 and 2, ed. P. Renaud and M. P.
Sibi, Wiley-VCH, Weinheim, 2001.
Isopropyl radical addition to nitrone 1 proceeded smoothly by
using isopropyl iodide (90 equiv.) and Et
3
B (5 equiv.) in boiling
3 D. J. Hart and F. L. Seely, J. Am. Chem. Soc., 1988, 110, 1633.
4 (a) S. Kim and J.-Y. Yoon, J. Am. Chem. Soc., 1997, 119, 5982; (b) I.
Ryu, H. Kuriyama, S. Minakata, M. Komatsu, J.-Y. Yoon and S. Kim,
J. Am. Chem. Soc., 1999, 121, 12190.
benzene, to give the desired isopropylated product 2b in 60%
yield, accompanied with an 18% yield of the ethylated product
2
a (Table 2, entry 1). A high degree of diastereoselectivity was
5
(a) M. P. Bertrand, L. Feray, R. Nouguier and P. Perfetti, Synlett, 1999,
148; (b) M. P. Bertrand, L. Feray, R. Nouguier and P. Perfetti, J. Org.
observed even at the high reaction temperature. As the best
result, the predominant formation of the desirably alkylated
products 2b–d and excellent diastereoselectivity were achieved
1
Chem., 1999, 64, 9189.
6
7
(a) G. K. Friestad and J. Qin, J. Am. Chem. Soc., 2000, 122, 8329; (b)
G. K. Friestad and J. Qin, J. Am. Chem. Soc., 2001, 123, 9922.
(a) H. Miyabe, C. Konishi and T. Naito, Org. Lett., 2000, 2, 1443; (b)
H. Miyabe, M. Ueda and T. Naito, Chem. Commun., 2000, 2059; (c) H.
Miyabe, M. Ueda, A. Nishimura and T. Naito, Org. Lett., 2002, 4,
131.
in the reaction using Et B (5 equiv.) in RI–benzene (3+1, v/v) at
3
reflux, although a small amount of undesirably alkylated
nitrones 4b–d were formed (entries 2–4). However, bulky
tertiary alkyl radicals were less effective in reaction with nitrone
1.
8
9
For reviews, see: (a) M. Lombardo and C. Trombini, Synthesis, 2000,
The stereochemical features of this reaction can be explained
7
59; (b) P. Merino, S. Franco, F. L. Merchan and T. Tejero, Synthesis,
as follows. The alkyl radical addition takes place predominantly
from the less hindered re-face of 1 to avoid steric interaction
with the phenyl group.
2
000, 442.
(a) D. A. Becker, J. Am. Chem. Soc., 1996, 118, 905; (b) Y.-T. Park and
K.-W. Kim, J. Org. Chem., 1998, 63, 4494.
1
0 Silylnitronates and nitroalkyl anions have been used as radical
acceptors: (a) B. P. Branchaud and G.-X. Yu, Tetrahedron Lett., 1991,
3
2, 3639; (b) S. Kim, J.-Y. Yoon and C. J. Lim, Synlett, 2000, 1151.
1 Nirone 1 was easily prepared by oxidation of 5,6-diphenylmorpholin-
-one with methyltrioxorhenium: (a) R. M. Williams, W. Zhai, D. J.
1
2
Aldous and S. C. Aldous, J. Org. Chem., 1992, 57, 6527; (b) A. Goti and
L. Nannelli, Tetrahedron Lett., 1996, 37, 6025.
1
1
2 For an example of the reaction of nitrones with Et
P. L. Smith, D. K. Hood and S. M. Cook, J. Org. Chem., 1994, 59,
485.
3 Renaud et al. reported that TEMPO reacts with B-alkylcatecholboranes
to generate alkyl radicals: C. Ollivier, R. Chuard and P. Renaud, Synlett,
3
B, see: W. G. Hollis,
3
1
999, 807.
1
1
4 A. K. Saksena, R. G. Lovey, V. M. Girijavallabhan, A. K. Ganguly and
A. T. McPhail, J. Org. Chem., 1986, 51, 5024.
5 H. Miyabe, M. Ueda, N. Yoshioka, K. Yamakawa and T. Naito,
Tetrahedron, 2000, 56, 2413.
Scheme 4
CHEM. COMMUN., 2003, 426–427
427