Diastereoselective intermolecular radical addition to nitrones

Article abstract of DOI:10.1021/jo050603z

The intermolecular radical addition to chiral nitrones 2, 4, 5, and 16 was studied. The isopropyl radical addition to Oppolzer's camphorsultam derivative 2 of glyoxylic nitrone proceeded with excellent diastereoselectivity to give the desired isopropylated product 3a accompanied by the diisopropylated product 3b. A high degree of stereocontrol in the reaction of cyclic nitrone 4 was achieved. The ethyl radical addition to nitrone 4 with triethylborane afforded the desired ethylated product 9a accompanied by the diethylated product 10a and the ethylated nitrone 11a. To evaluate the utility of cyclic nitrone 4, several alkyl radicals were employed in the addition reaction, which afforded the alkylated products 9b-d with excellent diastereoselectivities. In the presence of Mg(ClCO₄)₂, the ethyl radical addition to BIGN 16 afforded selectively syn isomers. In contrast, the alkyl radical addition to 16 took place even in the absence of Lewis acid to give anti isomers.

Full text of DOI:10.1021/jo050603z

Diastereoselective Intermolecular Radical Addition to Nitrones
Masafumi Ueda,† Hideto Miyabe,‡ Masako Teramachi,† Okiko Miyata,† and Takeaki Naito*,†
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan, and Graduate
School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
taknaito@kobepharma-u.ac.jp
Received March 25, 2005
The intermolecular radical addition to chiral nitrones 2, 4, 5, and 16 was studied. The isopropyl
radical addition to Oppolzer’s camphorsultam derivative 2 of glyoxylic nitrone proceeded with
excellent diastereoselectivity to give the desired isopropylated product 3a accompanied by the
diisopropylated product 3b. A high degree of stereocontrol in the reaction of cyclic nitrone 4 was
achieved. The ethyl radical addition to nitrone 4 with triethylborane afforded the desired ethylated
product 9a accompanied by the diethylated product 10a and the ethylated nitrone 11a. To evaluate
the utility of cyclic nitrone 4, several alkyl radicals were employed in the addition reaction, which
afforded the alkylated products 9b-d with excellent diastereoselectivities. In the presence of
Mg(ClO4)2, the ethyl radical addition to BIGN 16 afforded selectively syn isomers. In contrast, the
alkyl radical addition to 16 took place even in the absence of Lewis acid to give anti isomers.
Introduction
carbon bond-forming radical reactions of imines is a
subject of current interest.4
The carbon-nitrogen double bond has attracted sig-
nificant attention as an excellent radical acceptor.1
Compared with the extensive investigations into radical
cyclization of imine derivatives,2,3 the intermolecular
radical addition to imines has not been widely studied.
Therefore, the development of intermolecular carbon-
Hart’s group reported the first study on the inter-
molecular alkyl radical addition to the sterically less
hindered formaldoxime ether.5 Recently, the inter-
molecular radical-mediated acylation using R-sulfonyl
oxime ethers has been reported by the research group of
Kim.6 We have also reported that the intermolecular
radical addition reactions to a wide range of aldoxime
ethers proceeded smoothly in the presence of BF3‚OEt2.7
Additionally, Bertrand’s and our groups have inde-
pendently reported the diastereofacial control in inter-
molecular radical addition to glyoxylic imine derivatives
for the synthesis of R-amino acids.8,9 More recently,
† Kobe Pharmaceutical University.
‡ Kyoto University.
(1) For reviews, see: (a) Miyabe, H.; Miyata, O.; Naito, T. J. Synth.
Org. Chem., Jpn. 2002, 60, 1087. (b) Naito, T. Heterocycles 1999, 50,
505. (c) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543. (d)
Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K.
J.; Trach, F. Org. React. (N.Y.) 1996, 48, 301.
(2) For our examples of the radical cyclization of oxime ethers and
hydrazones, see: (a) Miyabe, H.; Ueda, M.; Fujii, K.; Nishimura, A.;
Naito, T. J. Org. Chem. 2003, 68, 2003. (b) Ueda, M.; Miyabe, H.;
Nishimura, A.; Miyata, O.; Takemoto, Y.; Naito, T. Org. Lett. 2003, 5,
3835. (c) Miyabe, H.; Nishiki, A.; Naito, T. Chem. Pharm. Bull. 2003,
51, 100. (d) Miyabe, H.; Fujii, K.; Tanaka, H.; Naito, T. Chem. Commun.
2001, 831. (e) Miyabe, H.; Fujii, K.; Goto, T.; Naito, T. Org. Lett. 2000,
2, 4071. (f) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.;
Naito, T. J. Org. Chem. 1998, 63, 4397.
(3) For some selected examples, see: (a) Friestad, G. K. Org. Lett.
1999, 1, 1499. (b) Zhang, J.; Clive, D. L. J. J. Org. Chem. 1999, 64,
770. (c) Keck, G. E.; Wager, T. T.; McHardy, S. F. J. Org. Chem. 1998,
63, 9164. (d) Iserloh, U.; Curran, D. P. J. Org. Chem. 1998, 63, 4711.
(e) Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J. Org. Chem. 1998, 63,
5877. (f) Marco-Contelles, J.; Balme, G.; Bouyssi, D.; Destabel, C.;
Henriet-Bernard, C. D.; Grimaldi, J.; Hatem, J. M. J. Org. Chem. 1997,
62, 1202. (g) Noya, B.; Alonso, R. Tetrahedron Lett. 1997, 38, 2745. (h)
Booth, S. E.; Jenkins, P. R.; Swain, C. J. J. Chem. Soc., Chem.
Commun. 1991, 1248.
(4) For reviews, see: (a) Miyabe, H.; Ueda, M.; Naito, T. Synlett.
2004, 1140. (b) Friestad, G. K. Tetrahedron 2001, 57, 5461. (b) Miyabe,
H.; Naito, T. J. Synth. Org. Chem., Jpn. 2001, 59, 35.
(5) Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988, 110, 1633.
(6) (a) Kim, S.; Lee, I. Y.; Yoon, J.-Y.; Oh, D. H. J. Am. Chem. Soc.
1996, 118, 5138. (b) Kim, S.; Yoon, J.-Y. J. Am. Chem. Soc. 1997, 119,
5982. (c) Ryu, I.; Kuriyama, H.; Minakata, S.; Komatsu, M.; Yoon, J.-
Y.; Kim, S. J. Am. Chem. Soc. 1999, 121, 12190.
(7) (a) Miyabe, H.; Shibata, R.; Ushiro, C.; Naito, T. Tetrahedron
Lett. 1998, 39, 631. (b) Miyabe, H.; Shibata, R.; Sangawa, M.; Ushiro,
C.; Naito, T. Tetrahedron 1998, 54, 11431. (c) Miyabe, H.; Fujii, K.;
Naito, T. Org. Lett. 1999, 1, 569. (d) Miyabe, H.; Fujii, K.; Naito, T.
Org. Biomol. Chem. 2003, 1, 381.
(8) Bertrand’s group recently reported their studies on the radical
addition to glyoxylic imines. See: (a) Bertrand, M. P.; Feray, L.;
Nouguier, R.; Stella, L. Synlett 1998, 780. (b) Bertrand, M. P.; Feray,
L.; Nouguier, R.; Perfetti, P. Synlett 1999, 1148. (c) Bertrand, M. P.;
Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem. 1999, 64, 9189.
10.1021/jo050603z CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/27/2005
J. Org. Chem. 2005, 70, 6653-6660
6653

Ueda et al.
SCHEME 1
Friestad’s group reported the diastereo- and enantio-
selective radical additions to acylhydrazone.10,11
Nitrones are well-known to be reactive substrates for
the 1,3-dipolar cycloaddition reaction, nucleophilic addi-
tion of organometallic reagents, and so on.12,13 Although
nitrones have also evolved as a useful trap for short-lived
reactive radicals,14 synthetically useful radical reactions
of nitrones are not available.15 We have investigated the
viability of nitrones as radical acceptors and recently
reported the highly diastereoselective radical addition to
chiral nitrone for the asymmetric synthesis of R-amino
acids.16 As a part of our program directed toward the
screening of reactive imino radical acceptors,17,18 we now
describe full details of a radical reaction of chiral ni-
trones.
TABLE 1. Isopropyl Radical Addition to Nitrone 2
yield (%)a
selectivity
Results and Discussion
entry
conditions
i-PrI (30 equiv) in benzene 28
i-PrI (90 equiv) in benzene 43 12
i-PrI: benzene (3:1) 47 18
3a 3b 3c
of 3ab
Diastereoselective Radical Addition to Nitrone
Bearing Oppolzer’s Camphorsultam. As a prelimi-
nary experiment, we investigated the radical addition to
1c
2c
3d
7
16
9
>95% de
>95% de
>95% de
7
a Isolated yield. b Diastereoselectivities were determined by 1H
NMR analysis. c Reactions of 2 were carried out with i-PrI (30 or
90 equiv) and Et3B (5.0 equiv) in boiling benzene. d Reaction of 1
was carried out with Et3B (5.0 equiv) in boiling i-PrI-benzene (3:
1, v/v).
(9) (a) Miyabe, H.; Ushiro, C.; Naito, T. Chem. Commun. 1997, 1789.
(b) Miyabe, H.; Fujishima, Y.; Naito, T. J. Org. Chem. 1999, 64, 2174.
(c) Miyabe, H.; Yoshioka, N.; Ueda, M.; Naito, T. J. Chem. Soc., Perkin
Trans. 1 1998, 3659. (d) Miyabe, H.; Ueda, M.; Yoshioka, N.; Naito, T.
Synlett 1999, 465. (e) Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa,
K.; Naito, T. J. Org. Chem. 2000, 65, 176. (f) Miyabe, H.; Ueda, M.;
Naito, T. J. Org. Chem. 2000, 65, 5043. (g) Miyabe, H.; Konishi, C.;
Naito, T. Org. Lett. 2000, 2, 1443. (h) Miyabe, H.; Ueda, M.; Nishimura,
A.; Naito, T. Org. Lett. 2002, 4, 131. (i) Miyabe, H.; Nishimura, A.;
Ueda, M.; Naito, T. Chem. Commun. 2002, 1454. (j) Miyabe, H.;
Nishimura, A.; Fujishima, Y.; Naito, T. Tetrahedron 2003, 59, 1901.
(k) Ueda, M.; Miyabe, H.; Nishimura, A.; Sugino, H.; Naito, T.
Tetrahedron: Asymmetry 2003, 14, 2857. (l) Miyabe, H.; Ueda, M.;
Nishimura, A.; Naito, T. Tetrahedron 2004, 60, 4227. (m) Miyabe, H.;
Naito, T. Org. Biomol. Chem. 2004, 2, 1267. (n) Ueda, M.; Miyabe, H.;
Sugino, H.; Naito, T. Org. Biomol. Chem. 2005, 3, 1124.
(10) (a) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122, 8329.
(b) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2001, 123, 9922. (c)
Friestad, G. K.; Shen, Y.; Ruggles, E. L. Angew. Chem., Int. Ed.. 2003,
42, 5061.
(11) For other examples, see: (a) Risberg, E.; Fischer, A.; Somfai,
P. Chem. Commun. 2004, 2088. (b) Singh, N.; Anand, R. D.; Trehan,
S. Tetrahedron Lett. 2004, 45, 2911. (c) Ferna´ndez, M.; Alonso, R. Org.
Lett. 2003, 5, 2461. (d) Yamada, K.; Yamamoto, Y.; Tomioka, K. Org.
Lett. 2003, 5, 1797. (e) Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa,
Y.; Taga, T.; Tomioka, K. Org. Lett. 2002, 4, 3509. (f) Torrente, S.;
Alonso, R. Org. Lett. 2001, 3, 1985. (g) Russell, G. A.; Wang, L.;
Rajaratnam, R. J. Org. Chem. 1996, 61, 8988.
(12) For reviews, see: (a) Lombardo, M.; Trombini, C. Synthesis
2000, 759. (b) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T.
Synthesis 2000, 442. (c) Osborn, H. M. I.; Gemmell, N.; Harwood: L.
M. J. Chem. Soc., Perkin Trans. 1 2002, 2419.
(13) For 1,3-dipolar cycloaddition reactions of chiral nitrones pre-
pared from L-phenylananine and glyoxylic acid, see: (a) Tamura, O.;
Gotanda, K.; Terashima, R.; Kikuchi, M.; Miyawaki, T.; Sakamoto, M.
Chem. Commun. 1996, 1861. (b) Tamura, O.; Kuroki, T.; Sakai, Y.;
Takizawa, J.; Yoshino, J.; Morita, Y.; Mita, N.; Gotanda, K.; Sakamoto
M. Tetrahedron Lett. 1999, 40, 895. (c) Tamura, O.; Shiro, T.; Toyao,
A.; Ishibashi, H. Chem. Commun. 2003, 2678.
(14) For some examples, see: (a) Becker, D. A. J. Am. Chem. Soc.
1996, 118, 905. (b) Park, Y.-T.; Kim, K.-W. J. Org. Chem. 1998, 63,
4494.
glyoxylic nitrone 2, because its reactivity toward the
nucleophilic carbon radical would be enhanced by the
neighboring electron-withdrawing substituent (Scheme
1). The auxiliary of choice was Oppolzer’s camphor-
sultam, since it had shown good characteristics in our
previous work on radical reactions of oxime ether and
hydrazone.9
Condensation of hemiacetal 119 with N-benzylhydroxyl-
amine proceeded in the presence of CaCl2 to give the
unstable nitrone 2 as an E/Z mixture after being stirred
at 20 °C for 24 h. The nitrone 2 could not be easily
isolated and hence was used in a crude state, after simple
filtration to remove CaCl2. To avoid the use of the
commonly used toxic tin reagents, we have explored tin-
free, iodine atom-transfer reactions.11,13 Et3B was used
as a radical initiator for isopropyl radical addition to 2;
formation of the ethylated byproduct 3c was shown to
be dependent on the reaction temperature. Thus, chang-
ing the temperature from 20 °C to reflux in benzene led
to a decrease in the ratio of ethylated byproduct 3c to
the desired isopropylated products 3a and 3b. A similar
trend has been observed in our recent studies on the
radical reaction of oxime ethers.20 The reaction with
isopropyl iodide (30 equiv) in boiling benzene proceeded
within 30 min to give the isopropylated product 3a in
28% yield, accompanied by a 7% yield of the C- and
O-diisopropylated product 3b and a 16% yield of the
ethylated product 3c (Table 1, entry 1). A high degree of
diastereoselectivity was attained even at the high reac-
tion temperature. The diastereomeric purity of 3a was
found to be not less than 95% de by 1H NMR analysis.21
As the best result, the predominant formation of desir-
(15) For recent reports on the SmI2-induced radical coupling reaction
of nitrones, see: (a) Masson, G.; Py, S.; Valle´e, Y. Angew. Chem., Int.
Ed. 2002, 41, 1772. (b) Masson, G.; Cividino, P.; Py, S.; Valle´e, Y.
Angew. Chem., Int. Ed. 2003, 42, 2265. (c) Riber, D.; Skrydstrup, T.
Org. Lett. 2003, 5, 229. (d) Zhong, Y.-W.; Xu, M.-H.; Lin, G.-Q. Org.
Lett. 2004, 6, 3953. (e) Chavarot, M.; Rivard, M.; Rose-Munch, F.; Rose,
E.; Py, S. Chem. Commun. 2004, 2330.
(16) Ueda, M.; Miyabe, H.; Teramachi, M.; Miyata, O.; Naito, T.
Chem. Commun. 2003, 426.
(17) We reported that N-sulfonylimines have evolved as a useful
radical acceptor toward nucleophilic carbon radicals. See: Miyabe, H.;
Ueda, M.; Naito, T. Chem. Commun. 2000, 2059.
(19) (a) Bauer, T.; Jezewski, A.; Chapuis, C.; Jurczak, J. Tetra-
hedron: Asymmetry 1996, 7, 1385. (b) Oppolzer, W.; Chapuis, C.;
Bernardinelli, G. Helv. Chim. Acta 1984, 67, 1397.
(20) Miyabe, H.; Ueda, M.; Yoshioka, N.; Yamakawa, K.; Naito, T.
Tetrahedron 2000, 56, 2413.
(18) We recently reported the radical reaction of ketimines prepared
from o-hydroxy aniline. See: Miyabe, H.; Yamaoka, Y.; Takemoto, Y.
Synlett 2004, 2597.
6654 J. Org. Chem., Vol. 70, No. 17, 2005

Radical Addition to Nitrones
SCHEME 2
SCHEME 4
TABLE 2. Ethyl Radical Addition to Cyclic Nitrone 4
yield (%)a
selectivity
of 9ab
entry
solvent
T (°C)
9a
10a
11a
1c
2c
3c
4d
5d
CH2Cl2
CH2Cl2
benzene
benzene
CH2Cl2
+20
-78
reflux
+20
-78
50
36
55
50
64
32
trace
14
trace
trace
16
>95% de
>95% de
>95% de
>95% de
>95% de
22
15
trace
trace
a Isolated yield. b Diastereoselectivities were determined by 1H
NMR analysis. c Reactions of 4 were carried out with Et3B (5.0
equiv) in the presence of 20 mL of O2 under N2 atmosphere.
d Reactions of 4 were carried out with Bu3SnH (1.2 equiv) and
Et3B (5.0 equiv) in the presence of 20 mL of O2 under N2
atmosphere.
SCHEME 3
(1S,2R)-diphenylaminoethanol,24 was protected as the
TBDMS derivative 7 in 98% yield. Next, the oxidation of
secondary amine 7 to nitrone 5 was investigated under
several reaction conditions. Methyltrioxorhenium(VII)
(MTO)-catalyzed oxidation of 7 with a urea-hydrogen
peroxide complex (UHP) was effective for preparing the
conjugated nitrone 5 as an E/Z mixture.25 According to
Williams’ method,24 the amino alcohol 6 was protected
as the N-Boc derivative, which was then treated with
p-TsOH in benzene at reflux to give the morpholinone
8a in 61% yield from 6. Deprotection of the N-tert-
butoxycarbonyl group followed by oxidation with MTO
and UHP gave the cyclic nitrone 4.26
The addition of an ethyl radical to cyclic nitrone 4 was
studied by using Et3B (5.0 equiv) as an ethyl radical
source under several reaction conditions (Scheme 4). At
first, the reaction was carried out in the presence of 20
mL of O2 under N2 atmosphere (Table 2). As expected,
the reaction of 4 in CH2Cl2 proceeded smoothly at 20 °C
to give the desired product 9a in 50% yield and the
diethylated product 10a in 32% yield (entry 1). Changing
the reaction temperature from 20 to -78 °C led to an
increase in the formation of undesired nitrone 11a (entry
2). In contrast, treatment of 4 with Et3B in boiling
benzene afforded the desired product 9a in 55% yield,
along with 15% yield of the diethylated product 10a
(entry 3). A high degree of diastereoselectivity was
obtained even at the elevated reaction temperature. The
undesired nitrone 11a would be obtained as a result of a
disproportionation reaction of intermediate radical C
(Scheme 5). To suppress the formation of the undesired
products 10a and 11a, Bu3SnH was employed as a
hydride atom donor (entries 4 and 5). In the presence of
Bu3SnH, the formation of 10a was diminished remark-
ably leading to 64% yield of 9a after being stirred in
ably isopropylated products 3a and 3b was achieved in
the reaction by using i-PrI-benzene (3:1, v/v) as a solvent
(entry 3). Treatment of nitrone 2 with Et3B in boiling
i-PrI-benzene (3:1, v/v) for 30 min gave the product 3a
in 47% yield as a single diastereomer (entry 3).
In this reaction, Et3B worked as not only a radical
initiator but also a chain transfer agent to trap the
intermediate radical A to give an adduct B and a chain-
propagating ethyl radical. Therefore, an excess amount
of Et3B was required for the present reaction (Scheme
2).22,23
Diastereoselective Radical Addition to Cyclic
and Acyclic Nitrones. For the synthesis of various
types of R-amino acids, we next investigated the reaction
of cyclic nitrone 4 (Scheme 3). For comparison, the
reaction of acyclic nitrone 5 was also studied. The acyclic
nitrones 2 and 5 exist as a mixture of E- and Z-isomers
concerning the geometry of the C-N double bond, which
were easily isomerized. In marked contrast to acyclic
nitrones, the cyclic nitrone 4 has the advantage of
increased rigidity and stability.
As shown in Scheme 3, the nitrones 4 and 5 were
prepared. The amino alcohol 6, which was prepared from
(21) The absolute configuration of 3a was determined to be R by
conversion into amino acid derivatives: reductive cleavage of the N-O
bond with Zn in acidic condition followed by hydrogenolysis of the
benzyl group afforded the known amino acid derivative. See ref 9e.
(22) The reaction of nitroxide radical with triethylborane is presum-
ably a slow process and the formation of diisopropylated product 3b
may result from the accumulation of the nitroxide radical in the
reaction mixture due to the persistent radical effect.
(24) (a) Williams, R. M.; Shinclair, P. J.; Zhai, D.; Chen, D. J. Am.
Chem. Soc. 2000, 110, 1547. (b) Williams, R. M.; Zhai, W.; Aldous, D.
J.; Aldous, S. C. J. Org. Chem. 1992, 57, 6527.
(25) Goti, A.; Nannelli, L. Tetrahedron Lett. 1996, 37, 6025.
(26) Baldwin, S. W.; Young, B. G.; McPhail, A. T. Tetrahedron Lett.
1998, 39, 6819.
(23) For an example of the reaction of nitrones with Et3B, see:
Hollis, W. G., Jr.; Smith, P. L.; Hood, D. K.; Cook, S. M. J. Org. Chem.
1994, 59, 3485.
J. Org. Chem, Vol. 70, No. 17, 2005 6655

Ueda et al.
SCHEME 5
FIGURE 1. Stereochemical feature of radical addition to
nitrone 4.
SCHEME 7
TABLE 3. Effect of Oxygen on Ethyl Radical Addition
to Cyclic Nitrone 4
yield (%)a,b
entry
solvent
T (°C)
O2 (equiv)
9a
10a
11a
1c
2c
3c
CH2Cl2
CH2Cl2
CH2Cl2
+20
+20
+20
0.05
5
50
65
40
26
9
18
38
trace
trace
trace
a Isolated yield. b Diastereoselectivities of 9a and 10a were
>95% de. c Reactions of 4 were carried out with Et3B (5.0 equiv)
under Ar atmosphere.
TABLE 4. Alkyl Radical Addition to Cyclic Nitrone 4
yield (%)a
selectivity
SCHEME 6
entry
conditions
product 9b-d 9a
of 9b-db
>95% de
1c
2d
3d
4d
i-PrI (90 equiv) in benzene
i-PrI:benzene (3:1)
c-Hexyl I:benzene (3:1)
c-Pentyl I:benzene (3:1)
9b
9b
9c
9d
60
82
72
72
18
trace >95% de
3
12
>95% de
>95% de
a Isolated yield; a small amount of alkylated nitrones was
formed. b Diastereoselectivities were determined by 1H NMR
analysis. c Reaction of 4 was carried out with i-PrI (90 equiv) and
Et3B (2.5 equiv) in boiling benzene. d Reactions of 4 were carried
out with Et3B (2.5 equiv) in boiling RI-benzene (3:1, v/v).
CH2Cl2 at -78 °C for 2 h, though the ethylated nitrone
11a was still obtained in 16% yield (entry 5).27
We next examined the effect of oxygen on the ratio of
ethylated product 9a to diethylated product 10a. After a
solution of 4 in CH2Cl2 was strictly degassed, Et3B was
added to the reaction mixture under Ar and O2 atmo-
sphere (Table 3). In the presence of a catalytic amount
of O2, the radical reaction gave ethylated product 9a in
65% yield along with only 9% yield of diethylated product
10a (entry 1). On the other hand, the undesired formation
of 10a dramatically increased in the presence of an excess
amount of oxygen probably due to the accumulation of
ethyl radical generated from Et3B and O2 (entries 2 and
3). These results indicated that the radical chain process
proceeded effectively in the presence of a catalytic
amount of O2 as a result of the suppressed formation of
the undesired diethylated product 10a.
The absolute configuration of 9a was assigned to be R
by converting the product 9a into authentic N-Cbz-amino
acid 13.28 The reductive cleavage of the N-O bond of 9a
with Mo(CO)6 gave the amine 12 in 84% yield. Subse-
quent hydrogenolysis of 12 in the presence of Pd(OH)2
followed by treatment with CbzCl afforded the enantio-
merically pure (R)-N-Cbz-amino acid 13 without any loss
of optical purity (Scheme 6).
The stereochemical features of this reaction can be
rationalized in terms of steric control as shown in Figure
1. The alkyl radical addition takes place predominantly
from the less hindered re-face to avoid the steric interac-
tion with the phenyl group.
Next, we explored the alkyl radical addition to nitrone
4 under the iodine atom-transfer reaction conditions
(Scheme 7). The isopropyl radical addition to nitrone 4
proceeded smoothly by using isopropyl iodide (90 equiv)
and Et3B (2.5 equiv) in boiling benzene, to give the
desired isopropylated product 9b in 60% yield, ac-
companied by an 18% yield of the ethylated product 9a
(Table 4, entry 1). The predominant formation of the
isopropylated product 9b was observed in the reaction
with Et3B (2.5 equiv) in boiling RI-benzene (3:1, v/v),
although a trace amount of 9a was formed (entry 2).
Excellent diastereoselectivities were observed in the
reactions with cyclohexyl and cyclopentyl radicals (entries
3 and 4).
The reaction of acyclic nitrone 5 was studied by using
triethylborane as an ethyl radical source (Scheme 8). In
the case of acyclic nitrone 5, the predominant formation
of diethylated product 15 was observed in organic sol-
vents (Table 5, entries 1 and 2). To a solution of 5 in
benzene was added a 1.0 M solution of Et3B in hexane
(5.0 equiv) and then the reaction mixture was stirred at
20 °C. The diethylated product 15 was obtained in 61%
yield with 34% de, accompanied by a 14% yield of the
(27) The stannyl radical, which is generated by the reduction of
nitroxide radical with tin hydride, is known to dimerize to form the
corresponding ditin compound. See: Fossey, J.; Lefort, D.; Sorba, J.
Free Radicals in Organic Chemistry; translated by J. Lomas; John
Wiley & Sons: New York, 1995.
(28) Saksena, A. K.; Lovey, R. G.; Girijavallabhan, V. M.; Ganguly,
A. K.; McPhail, A. T. J. Org. Chem. 1986, 51, 5024.
6656 J. Org. Chem., Vol. 70, No. 17, 2005

Radical Addition to Nitrones
SCHEME 8
SCHEME 9
TABLE 6. Radical Addition to Acyclic Nitrone 16
yield (%)a
T (°C) 17a 18a 18ab anti:syn
Lewis
acid
selectivity of
entry solvent
1c
2c
3d
CH2Cl2 none
benzene none
CH2Cl2 Mg(ClO4)2
20
reflux 18
trace 47
trace 46
85:15
82:18
3:97
54
TABLE 5. Ethyl Radical Addition to Acyclic Nitrone 5a
0
yield (%)b,c
a Isolated yield. b Selectivities of anti and syn isomers were
determined by 1H NMR analysis. c Reactions of 16 were carried
out with Et3B (5.0 equiv). d Reaction of 16 was carried out with
Et3B (5.0 equiv) in the presence of Mg(ClO4)2 (1.0 equiv).
Lewis
entry
solvent
acid
none
none
T (°C)
14
15
1
benzene
CH2Cl2
20 14 (22% de) 61 (34% de)
20 15 (31% de) 53 (31% de)
20 44 (30% de) 27 (21% de)
2
3
H2O-EtOH none
4d
5d
6d
CH2Cl2
CH2Cl2
CH2Cl2
TiCl4
Cu(OTf)2
20 8 (27% de)
0
dipolar cycloaddition reactions30 and nucleophilic addi-
tions of organometallic reagents.31 However, radical
reaction of 16 has not been explored. We finally studied
the diastereoselective radical addition to BIGN 16 (Scheme
9). In the absence of Lewis acid, the ethyl radical addition
to 16 in CH2Cl2 proceeded smoothly to give an 85:15 anti/
syn mixture of diethylated product 18a in 46% yield
(Table 6, entry 1). The reaction of 16 in boiling benzene
proceeded with better chemical efficiency (entry 2). In
marked contrast to the radical reaction giving the anti
isomer, selective formation of the syn isomer was re-
ported in the reaction of 16 with Grignard reagents.31b
Therefore, the effect of Lewis acid on anti/syn selectivity
was investigated. As expected, the selective formation of
syn isomer 18a was observed in the presence of Mg(ClO4)2
(entry 3).
20 13 (23% de) 43 (33% de)
Cu(OTf)2 -78 16 (20% de) 54 (4% de)
a Reactions of 5 were carried out with Et3B (5.0 equiv). b Isolated
yield of diastereomeric mixture. c Diastereoselectivities were de-
termined by 1H NMR analysis. d Lewis acid (1.0 equiv) was
employed.
FIGURE 2. Isomerization of E- and Z-isomers.
ethylated product 14 (entry 1). A similar result was
obtained in the reaction of 5 in CH2Cl2 (entry 2). In
contrast to acyclic nitrone 2, the acyclic nitrone 5 was
stable even in aqueous media. The radical addition to 5
in H2O-MeOH gave 44% yield of ethylated product 14
and 27% yield of diethylated product 15 (entry 3). The
absolute configuration of 14 was assigned to be R by
converting the major diastereoisomer of 14 into cyclic
product 9a. Deprotection of the TBDMS group followed
by lactonization with p-TsOH gave the cyclic (R)-product
9a. The acyclic nitrone 5 existed as an E/Z mixture with
a ratio of 5:7 in CDCl3, which was determined by 1H
NMR. Isomerization of the E-isomer led exclusively to
the Z-isomer in the presence of TiCl4 or Cu(OTf)2 as
In the absence of Lewis acid, dipole-dipole interaction
controls the rotamer population and is responsible for the
observed stereoselection in radical reaction (Figure 3).
Thus, the rotamer B having the N-O bond moiety anti
to the acetal oxygen atom would be favored in order to
minimize the dipole-dipole interaction between these
moieties. The syn selectivity observed in the reaction with
Mg(ClO4)2 can be explained by invoking a favorable
conformer C.
The alkyl radical addition to 16 was carried out in the
absence of Lewis acid (Scheme 10). The isopropyl radical
addition to 16 also proceeded by using i-PrI and Et3B to
give the isopropylated product 17b and the diisopro-
pylated product 18b with high diastereoselectivity, re-
spectively. Excellent anti selectivity was also achieved
in the reactions with a cyclopentyl radical. It is important
to note that anti selectivity in the reaction of 16 with
Grignard reagent has been difficult to achieve.
1
observed by H NMR (Figure 2).29 An improvement in
the diastereoselectivity was expected in the presence of
these Lewis acids; however, only moderate diastereo-
selectivities were obtained (entries 4-6).
Diastereoselective Radical Addition to BIGN.
N-Benzyl-2.3-O-isopropylidene-D-glyceraldehyde nitrone
(BIGN) 16 is known to be a reactive substrate for 1,3-
(30) Merino, P.; Mates, J. A.; Revuelta, J.; Tejero, T.; Chiacchio,
U.; Romeo, G.; Iannazzo, D.; Romeo, R. Tetrahedron: Asymmetry 2002,
13, 173.
(31) (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Tetra-
hedron: Asymmetry 1997, 8, 3489. (b) Merino, P.; Castillo, E.; Franco,
S.; Merchan, F. L.; Tejero, T. Tetrahedron 1998, 54, 12301. (c) Merino,
P.; del Alamo, E. M.; Bona, M.; Franco, S.; Merchan, F. L.; Tejero, T.;
Vieceli, O. Tetrahedron Lett. 2000, 41, 9239. (d) Merino, P.; Franco,
S.; Merchan, F. L.; Revuelta, J.; Tejero, T. Tetrahedron Lett. 2002, 43,
459.
(29) Tamura’s group reported that tandem transesterification, E,Z-
isomerization, and cycloaddition of nitrones proceeded in the presence
of titanium tetraisopropoxide. See: (a) Tamura, O.; Yamaguchi, T.;
Noe, K.; Sakamoto, M. Tetrahedron Lett. 1993, 34, 4009. (b) Tamura,
O.; Okabe, T.; Yamaguchi, T.; Gotanda, K.; Noe, K.; Sakamoto, M.
Tetrahedron 1995, 51, 107.
J. Org. Chem, Vol. 70, No. 17, 2005 6657

Ueda et al.
and then extracted with CHCl3. The organic phase was dried
over MgSO4 and concentrated under reduced pressure. Puri-
fication of the residue by preparative TLC (hexane/AcOEt 3:1)
afforded 3a-c.
(3aR,6S,7aS)-Hexahydro-8,8-dimethyl-1-[3-methyl-1-
oxo-2-[hydroxy(phenylmethyl)amino]butyl]-3H-3a,6-meth-
ano-2,1-benzisothiazole 2,2-Dioxide (3a). A colorless oil.
1
IR (CHCl3) 3568, 2966, 1689 cm-1; H NMR (CDCl3) δ 7.40-
7.21 (5H, m), 5.70 (1H, br s), 4.21 (1H, d, J ) 14 Hz), 4.04
(1H, t, J ) 6.5 Hz), 3.93 (1H, d, J ) 8.5 Hz), 3.81 (1H, d, J )
14 Hz), 3.53, 3.49 (2H, ABq, J ) 14 Hz), 2.51-2.43 (1H, m),
2.16 (2H, br d, J ) 6 Hz), 1.99-1.85 (3H, m), 1.49-1.35 (2H,
m), 1.21, 1.10 (each 3H, d, J ) 7 Hz), 1.16, 0.99 (each 3H, s);
13C NMR (CDCl3) δ 174.5, 138.5, 128.6, 128.1, 126.9, 73.3, 65.2,
61.6, 53.3, 48.0, 47.7, 44.6, 38.5, 33.0, 30.5, 26.4, 20.7, 20.3,
20.0, 19.3; HRMS calcd for C22H32N2O4S (M+) 420.2081, found
420.2087. [R]18 +17.4 (c 1.04, CHCl3).
D
(3aR,6S,7aS)-Hexahydro-8,8-dimethyl-1-[3-methyl-1-
oxo-2-[1-methylethoxy(phenylmethyl)amino]butyl]-3H-
3a,6-methano-2,1-benzisothiazole 2,2-Dioxide (3b). A col-
orless oil. IR (CHCl3) 2967, 2928, 1686 cm-1; 1H NMR (CDCl3)
δ 7.40-7.21 (5H, m), 4.23-4.12 (1H, br m), 4.18, 4.04 (each
1H, d, J ) 14 Hz), 4.07-4.01 (1H, br m), 3.47-3.45 (2H, ABq,
J ) 14 Hz), 3.40-3.30 (1H, br m), 2.24-2.06 (3H, m), 1.95-
1.85 (3H, m), 1.48-1.36 (2H, m), 1.26, 1.04 (each 3H, d, J ) 7
Hz), 1.15, 0.96 (each 3H, s), 1.00, 0.64 (each 3H, d, J ) 6 Hz);
13C NMR (CDCl3) δ 172.8, 139.7, 130.2, 127.8, 126.8, 73.8, 72.9,
65.5, 57.4, 53.2, 47.7, 44.4, 38.6, 33.0, 31.3, 29.7, 26.5, 20.60,
20.57, 20.5, 20.3, 20.0, 19.8; HRMS calcd for C25H38N2O4S (M+)
FIGURE 3. Stereochemical feature of radical addition to
nitrone 16.
SCHEME 10
462.2550, found 462.2547. [R]17 +73.3 (c 0.60, CHCl3).
D
(3aR,6S,7aS)-Hexahydro-8,8-dimethyl-1-[1-oxo-2-[hy-
droxy(phenylmethyl)amino]butyl]-3H-3a,6-methano-2,1-
benzisothiazole 2,2-Dioxide (3c). Colorless crystals. Mp
126-129 °C (AcOEt/hexane). IR (CHCl3) 3569, 2966, 1697
Conclusion
1
cm-1; H NMR (CDCl3) δ 7.42-7.21 (5H, m), 5.77 (1H, br s),
We have demonstrated that nitrones are excellent
radical acceptors for intermolecular carbon-carbon bond-
forming radical reactions. In addition to intermolecular
radical reaction of oxime ethers, hydrazones, and N-
sulfonylimines, the diastereoselective reaction of nitrones
disclosed a broader aspect of the utility of imino radical
acceptors for the synthesis of various types of amino
compounds.
4.09 (1H, dd, J ) 7.5, 5.5 Hz), 4.08, 3.95 (each 1H, d, J ) 14
Hz), 3.98 (1H, t, J ) 6.5 Hz), 3.51, 3.46 (2H, ABq, J ) 14 Hz),
2.14-1.82 (7H, m), 1.50-1.30 (2H, m), 1.15, 0.98 (each 3H, s),
1.10 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 174.1, 137.9, 128.9,
128.2, 127.1, 69.3, 64.9, 61.5, 53.0, 48.4, 47.8, 44.5, 38.3, 32.8,
26.4, 23.8, 20.7, 19.9, 10.5; HRMS calcd for C21H30N2O4S (M+)
406.1924, found 406.1921. Anal. Calcd for C21H30N2O4S: C,
62.04; H, 7.44; N, 6.89; S, 7.89. Found: C, 62.17; H, 7.62; N,
6.88; S, 7.95. [R]19 +20.0 (c 0.69, CHCl3).
D
Ethyl Radical Addition to 4 (Table 2, entries 1-3). To
a solution of nitrone 4 (50 mg, 0.19 mmol) in CH2Cl2 or benzene
(5 mL) was added Et3B (1.0 M in hexane, 0.94 mL, 0.94 mmol)
in the presence of 20 mL of O2 under N2 atmosphere at +20
or -78 °C or reflux. After being stirred at the same temper-
ature for 2 h, the reaction mixture was concentrated under
reduced pressure. Purification of the residue by preparative
TLC (hexane/AcOEt 3:1, 2-fold developments) afforded 9a-
11a.
Ethyl Radical Addition to 4, Using Bu3SnH (Table 2,
entries 4 and 5). To a solution of nitrone 4 (50 mg, 0.19 mmol)
in CH2Cl2 (5 mL) were added Bu3SnH (0.060 mL, 0.23 mmol)
and Et3B (1.0 M in hexane, 0.94 mL, 0.94 mmol) in the
presence of 20 mL of O2 under N2 atmosphere at +20 or -78
°C. After being stirred at the same temperature for 2 h, the
reaction mixture was concentrated under reduced pressure.
Purification of the residue by preparative TLC (hexane/AcOEt
3:1, 3-fold developments) afforded 9a-11a.
Ethyl Radical Addition to 4 under Ar and O2 Atmo-
sphere (Table 3). A solution of nitrone 4 (50 mg, 0.19 mmol)
in CH2Cl2 (5 mL) was degassed. To the mixture was added
Et3B (1.0 M in hexane, 0.94 mL, 0.94 mmol) in the presence
of 0.05, 5, or 50 equiv of O2 under Ar atmosphere at +20 °C.
After being stirred at the same temperature for 2 h, the
reaction mixture was concentrated under reduced pressure.
Purification of the residue by preparative TLC (hexane/AcOEt
3:1) afforded 9a-11a.
Experimental Section
(3aR,6S,7aS)-Hexahydro-8,8-dimethyl-1-[[oxide(phen-
ylmethyl)imino]acetyl]-3H-3a,6-methano-2,1-benziso-
thiazole 2,2-Dioxide (2). To a solution of N-benzylhydroxyl-
amine (20 mg, 0.16 mmol) and hemiacetal 1 (50 mg, 0.16
mmol) in CH2Cl2 (5 mL) was added CaCl2 (27 mg, 0.24 mmol)
under N2 atmosphere at room temperature. After being stirred
at room temperature for 24 h, the reaction mixture was filtered
through a pad of Celite. The filtrate was concentrated at
reduced pressure to afford nitrone 2 as a colorless oil (E:Z )
1:2). After characterization by 1H and 13C NMR spectra,
1
unstable 2 was immediately subjected to radical reaction. H
NMR (CDCl3) δ 7.54-7.22 (5H, m), 5.18 (2/3H, s), 5.01 (1/3H,
s), 4.22-3.88 (3H, m), 3.54-3.38 (2H, m), 2.34-1.76 (5H, m),
1.50-1.20 (2H, m), 1.15, 0.97 (each 6/3H, s), 1.08, 0.95 (each
3/3H, s); 13C NMR (CDCl3) δ 158.3, 156.6, 133.1, 131.5, 129.7,
129.5, 129.2, 129.0, 128.8, 128.6, 126.8, 124.7, 73.7, 67.9, 65.0,
64.8, 53.0, 52.9, 48.8, 48.7, 47.9, 47.8, 44.6, 44.5, 38.3, 38.0,
32.8, 32.7, 26.5, 26.4, 20.7, 19.8.
General Procedure for Radical Reaction of 2. To a
solution of 2 (0.16 mmol) in benzene (5 mL) or i-PrI-benzene
(4 mL, 3:1, v/v) were added i-PrI (0.48 mL, 4.8 mmol or 1.4
mL, 14 mmol) and Et3B (1.0 M in hexane, 0.80 mL, 0.80 mmol)
in the presence of 20 mL of O2 under N2 atmosphere at reflux.
After being stirred at the same temperature for 30 min, the
reaction mixture was diluted with saturated aqueous NaHCO3
6658 J. Org. Chem., Vol. 70, No. 17, 2005

Radical Addition to Nitrones
(3R,5R,6S)-3-Ethyl-4-hydroxy-5,6-diphenyl-2-morpholi-
none (9a). Colorless crystals. Mp 174-176 °C (AcOEt/hexane).
General Procedure for Ethyl Radical Addition to 5.
To a solution of nitrone 5 (50 mg, 0.12 mmol) in benzene,
CH2Cl2, or H2O-EtOH (3:2, v/v) (5 mL) was added Et3B (1.0
M in hexane, 0.59 mL, 0.59 mmol) in the presence of 20 mL of
O2 under N2 atmosphere at 20 °C. After being stirred at the
same temperature for 90 min, the reaction mixture was diluted
with saturated aqueous NaHCO3 and then extracted with
CH2Cl2. The organic phase was dried over MgSO4 and con-
centrated under reduced pressure. Purification of the residue
by preparative TLC (hexane/AcOEt 5:1) afforded 14-15.
IR (CHCl3) 3572, 1740 cm-1 1H NMR (CDCl3) δ 7.32-7.14
;
(10H, m), 6.17 (1H, d, J ) 3.5 Hz), 4.95 (1H, br s), 4.85 (1H, d,
J ) 3.5 Hz), 3.60 (1H, t, J ) 4.5 Hz), 2.15-2.00 (2H, m), 1.05
(3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 170.5, 135.8, 131.4,
130.7, 128.4, 128.3, 127.7, 125.4, 78.6, 68.7, 64.3, 22.0, 9.6;
HRMS calcd for C18H19NO3 (M+) 297.1364, found 297.1364.
Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found:
C, 72.45; H, 6.41; N, 4.72. [R]26 -7.0 (c 1.00, CHCl3).
D
(3R,5R,6S)-4-Ethoxy-3-ethyl-5,6-diphenyl-2-morpholi-
[(1R,2S)-N-(2-tert-Butyldimethylsilyloxy-1,2-diphenyl-
ethyl)-N-hydroxy]-2-ethylglycine Ethyl Ester (14). Major
isomer: A colorless oil. IR (CHCl3) 3556, 1730 cm-1; 1H NMR
(CDCl3) δ 7.40-7.18 (10H, m), 5.48 (1H, s), 5.32 (1H, d, J )
6.9 Hz), 4.05-3.91 (2H, m), 3.87 (1H, d, J ) 6.9 Hz), 3.24 (1H,
t, J ) 6 Hz), 1.73-1.62 (2H, m), 1.18 (3H, t, J ) 7.2 Hz), 0.68
(9H, s), 0.64 (3H, t, J ) 7.5 Hz), -0.18, -0.30 (each 3H, s);
13C NMR (CDCl3) δ 173.2, 143.7, 136.4, 130.5, 127.5, 127.4,
127.0, 75.6, 74.9, 67.3, 60.3, 25.5, 21.4, 17.9, 14.0, 9.6, -4.7,
-5.5; HRMS calcd for C26H40NO4Si (M + H+) 458.2724, found
1
none (10a). A colorless oil. IR (CHCl3) 1743 cm-1; H NMR
(CDCl3) δ 7.35-7.14 (6H, m), 6.16 (1H, br d, J ) 3.5 Hz), 4.86
(1H, d, J ) 3.5 Hz), 4.04-3.90 (2H, m), 3.56 (1H, t, J ) 4.5
Hz), 2.10-1.96 (2H, m), 1.26 (3H, t, J ) 7.5 Hz), 1.06 (3H, t,
J ) 7 Hz); 13C NMR (CDCl3) δ 170.8, 136.0, 132.1, 130.7, 128.3,
128.1, 127.6, 125.4, 78.8, 68.4, 65.6, 63.4, 21.9, 14.1, 9.8; HRMS
calcd for C20H23NO3 (M+) 325.1676, found 325.1688. [R]29
-59.1 (c 1.10, CHCl3).
D
(5R,6S)-3-Ethyl-5,6-dihydro-5,6-diphenyl-2H-1,4-oxadin-
2-one 4-Oxide (11a). Colorless crystals. Mp 158-160 °C
458.2721. [R]23 +56.2 (c 1.26, CHCl3). Minor isomer:
A
D
1
(AcOEt/hexane). IR (CHCl3) 3033, 1721, 1549 cm-1; H NMR
colorless oil. IR (CHCl3) 3581, 2958, 2931, 2857, 1703, 1472,
1
1454 cm-1; H NMR (CDCl3) δ 7.30-6.84 (10H, m), 5.78 (1H,
(CDCl3) δ 7.32-7.15 (6H, m), 7.03 (2H, m), 6.82 (2H, m), 6.05
(1H, d, J ) 3.3 Hz), 5.15 (1H, d, J ) 3.3 Hz), 3.02-2.80 (2H,
m), 1.26 (3H, t, J ) 7.5 Hz); 13C NMR (CDCl3) δ 159.6, 140.6,
132.5, 129.4, 129.2, 128.9, 128.5, 128.3, 127.6, 126.0, 78.1, 77.2,
19.1, 9.1; HRMS calcd for C18H17NO3 (M+) 295.1207, found
295.1222. Anal. Calcd for C18H17NO3‚1/4H2O: C, 72.10; H, 5.88;
s), 5.61 (1H, d, J ) 2.7 Hz), 4.15-4.00 (2H, m), 3.95 (1H, d, J
) 2.7 Hz), 3.17 (1H, dd, J ) 9.5, 5.5 Hz), 2.06-1.62 (2H, m),
1.16 (3H, t, J ) 7.2 Hz), 1.00 (3H, t, J ) 7.2 Hz), 0.90 (9H, s),
-0.14, -0.16 (each 3H, s); 13C NMR (CDCl3) δ 174.0, 142.9,
135.5, 130.7, 127.5, 127.2, 127.0, 126.7, 126.6, 77.8, 73.8, 65.4,
60.2, 25.8, 23.6, 18.2, 14.1, 10.9, -4.9; HRMS calcd for C26H40-
NO4Si (M + H+) 458.2724, found 458.2744. [R]22D +38.9 (c 1.47,
CHCl3).
N, 4.67. Found: C, 72.18; H, 5.85; N, 4.71. [R]27 +573.0 (c
D
1.01, CHCl3).
General Procedure for Alkyl Radical Addition to 4.
To a solution of nitrone 4 (50 mg, 0.19 mmol) in RI-benzene
(5 mL, 3:1, v/v) was added Et3B (1.0 M in hexane, 0.47 mL,
0.47 mmol) in the presence of 20 mL of O2 under N2 atmo-
sphere at reflux. After being stirred at the same temperature
for 30 min, the reaction mixture was concentrated under
reduced pressure. Purification of the residue by preparative
TLC (hexane/AcOEt 2:1) afforded the alkylated products 9b-d
and the ethylated product 9a.
[(1R,2S)-N-(2-tert-Butyldimethylsilyloxy-1,2-diphenyl-
ethyl)-N-ethoxy]-2-ethylglycine Ethyl Ester (15). A color-
less oil (a 2:1 mixture of diastereoisomers). IR (CHCl3) 2958,
1
1732 cm-1; H NMR (CDCl3) δ 7.30-6.84 (10H, m), 5.29 (1H,
d, J ) 4.8 Hz), 4.31-4.00 (2 + 1/3 + 1H, m), 3.90-3.62 (4/3H,
m), 3.52 (2/3H, dd, J ) 9.6, 4.5 Hz), 3.27 (1/3H, t, J ) 7.5 Hz),
2.04-1.72 (2H, m), 1.37 (6/3H, t, J ) 6.9 Hz), 1.30 (6/3H, t, J
) 6.9 Hz), 1.03 (3H, t, J ) 6.9 Hz), 0.95 (9/3H, s), 0.89 (18/3H,
s), 0.88 (6/3H, t, J ) 7.5 Hz), 0.11, -0.34 (each 3/3H, s), 0.06,
-0.30 (each 6/3H, s); 13C NMR (CDCl3) δ 171.6, 170.8, 142.9,
136.8, 136.0, 131.7, 131.3, 128.3, 127.7, 127.5, 127.3, 127.2,
127.1, 127.0, 126.82, 126.77, 126.6, 77.2, 76.7, 75.6, 74.9, 74.8,
71.2, 70.5, 67.6, 60.1, 59.8, 53.4, 25.8, 25.7, 23.4, 18.1, 18.0,
14.24, 14.20, 13.7, 10.8, 10.6, -3.8, -4.2, -5.1, -5.3; HRMS
(3R,5R,6S)-4-Hydroxy-3-isopropyl-5,6-diphenyl-2-mor-
pholinone (9b). Colorless crystals. Mp 104-106 °C (AcOEt/
hexane). IR (CHCl3) 3569, 1740 cm-1; 1H NMR (CDCl3) δ 7.27-
7.14 (10H, m), 5.98 (1H, d, J ) 3 Hz), 4.98 (1H, br s), 4.76
(1H, d, J ) 3 Hz), 3.63 (1H, d, J ) 3 Hz), 2.46 (1H, m), 1.21,
1.15 (each 3H, d, J ) 7 Hz); 13C NMR (CDCl3) δ 170.0, 135.4,
131.2, 130.7, 128.4, 128.3, 127.9, 125.7, 79.2, 70.6, 69.7, 31.0,
19.5, 18.7; HRMS calcd for C19H21NO3 (M+) 311.1521, found
311.1530. Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N,
calcd for C28H43NO4Si (M+) 485.2959, found 485.2940. [R]21
+68.5 (c 1.09, CHCl3).
D
General Procedure for Ethyl Radical Addition to 16.
To a solution of nitrone 16 (50 mg, 0.21 mmol) and Mg(ClO4)2
(47 mg, 0.21 mmol or none) in CH2Cl2 or benzene (5 mL) was
added Et3B (1.0 M in hexane, 1.1 mL, 1.1 mmol) in the
presence of 20 mL of O2 under N2 atmosphere at 20 or -78 °C
or reflux. After being stirred at the same temperature for 2-4
h, the reaction mixture was diluted with saturated aqueous
NaHCO3 and then extracted with CH2Cl2. The organic phase
was dried over MgSO4 and concentrated under reduced pres-
sure. Purification of the residue by preparative TLC (hexane/
AcOEt 10:1, 2-fold developments) afforded 17a and 18a.
4.50. Found: C, 73.38; H, 6.81; N, 4.56. [R]28 +51.6 (c 0.61,
D
CHCl3).
(3R,5R,6S)-3-Cyclohexyl-4-hydroxy-5,6-diphenyl-2-mor-
pholinone (9c). Colorless crystals. Mp 152-155 °C (AcOEt/
hexane). IR (CHCl3) 3569, 1730 cm-1; 1H NMR (CDCl3) δ 7.28-
7.11 (10H, m), 5.94 (1H, d, J ) 3.5 Hz), 4.94 (1H, br s), 4.73
(1H, d, J ) 3.5 Hz), 3.66 (1H, d, J ) 2.5 Hz), 2.15-1.16 (11H,
m); 13C NMR (CDCl3) δ 170.3, 135.4, 131.4, 130.6, 128.4, 128.2,
127.9, 125.8, 79.2, 70.8, 69.8, 41.6, 29.7, 29.5, 26.7, 26.2; HRMS
calcd for C22H25NO3 (M+) 351.1833, found 351.1833. Anal.
Calcd for C22H25NO3: C, 75.19; H, 7.17; N, 3.99. Found: C,
(3S,4S)-1,2,3-Trideoxy-3-[hydroxy(phenylmethyl)ami-
no]-4,5-O-(1-methylethylidene)pentitol (anti-17a) and
(3R,4S)-1,2,3-Trideoxy-3-[hydroxy(phenylmethyl)amino]-
4,5-O-(1-methylethylidene)pentitol (syn-17a). A colorless
oil (a 6:1 mixture of anti-17a and syn-17a). IR (CHCl3) 3576,
74.89; H, 7.09; N, 3.95. [R]28 +19.7 (c 0.60, CHCl3).
D
(3R,5R,6S)-3-Cyclopentyl-4-hydroxy-5,6-diphenyl-2-mor-
pholinone (9d). Colorless crystals. Mp 161-164 °C (AcOEt/
hexane). IR (CHCl3) 3569, 1741 cm-1; 1H NMR (CDCl3) δ 7.27-
7.16 (10H, m), 6.18 (1H, d, J ) 3.5 Hz), 5.10 (1H, br s), 4.80
(1H, d, J ) 3.5 Hz), 3.68 (1H, d, J ) 5.5 Hz), 2.60-2.51 (1H,
m), 2.08-1.40 (8H, m); 13C NMR (CDCl3) δ 170.6, 136.0, 132.3,
130.4, 128.4, 128.3, 127.7, 125.6, 78.3, 69.1, 66.9, 41.5, 30.4,
29.4, 25.4, 24.9; HRMS calcd for C21H23NO3 (M+) 337.1677,
found 337.1701. Anal. Calcd for C21H23NO3: C, 74.75; H, 6.87;
N, 4.15. Found: C, 74.48; H, 6.82; N, 4.14. [R]28D +17.5 (c 1.00,
CHCl3).
1
1455 cm-1; H NMR (CDCl3) δ 7.37-7.22 (5H, m), 5.20-4.94
(1H, br s), 4.50-4.40 (1/7H, m), 4.32 (6/7H, q, J ) 7 Hz), 4.14-
4.32 (4H, m), 2.83-2.74 (1/7H, m), 2.70-2.60 (6/7H, m), 1.92-
1.56 (2H, m), 1.43, 1.39 (each 3/7H, s), 1.41, 1.36 (each 18/7H,
s), 1.08 (18/7H, t, J ) 7.5 Hz), 1.02 (3/7H, t, J ) 7 Hz); 13C
NMR (CDCl3) δ 138.3, 129.4, 128.3, 127.2, 108.7, 76.0, 69.7,
68.6, 60.1, 26.6, 25.5, 19.6, 12.1; HRMS calcd for C15H23NO3
(M+) 265.1677, found 265.1668. [R]18 -4.7 (c 0.96, CHCl3).
D
J. Org. Chem, Vol. 70, No. 17, 2005 6659

Ueda et al.
(3S,4S)-1,2,3-Trideoxy-3-[ethoxy(phenylmethyl)amino]-
4,5-O-(1-methylethylidene)pentitol (anti-18a). A colorless
oil. IR (CHCl3) 2984, 1455 cm-1; 1H NMR (CDCl3) δ 7.36-7.22
(5H, m), 4.28 (1H, q, J ) 7 Hz), 4.16 (1H, dd, J ) 6.5, 8.5 Hz),
3.84 (2H, s), 3.77 (1H, dd, J ) 7, 8.5 Hz), 3.39-3.28 (2H, m),
2.74 (1H, td, J ) 7, 5 Hz), 1.79-1.68 (2H, m), 1.38, 1.36 (each
3H, s), 1.11 (3H, t, J ) 7.5 Hz), 0.88 (3H, t, J ) 7 Hz); 13C
NMR (CDCl3) δ 138.7, 129.5, 128.0, 127.0, 108.6, 76.1, 69.1,
68.4, 58.0, 26.6, 25.5, 20.3, 13.9, 12.3; HRMS calcd for
C17H27NO3 (M+) 293.1989, found 293.1985. [R]23D -13.6 (c 1.88,
CHCl3).
amino]-1,2-O-(1-methylethylidene)-1,2-propanediol
(syn-17c). A white solid (a 9:1 mixture of anti-17c and
syn-17c). IR (CHCl3) 3574, 1454 cm-1 1H NMR (CDCl3) δ
;
7.42-7.22 (5H, m), 5.41 (1/10H, br s), 5.19 (9/10H, br s), 4.54-
4.49 (1/10H, m), 4.47 (9/10H, q, J ) 6.5 Hz), 4.10 (9/10H, dd,
J ) 8, 6.5 Hz), 3.94, 3.86 (18/10H, ABq, J ) 13.5 Hz), 3.86-
3.60 (2/10H+1H, m), 2.83 (1/10H, dd, J ) 8.5, 5 Hz), 2.74 (9/
10H, dd, J ) 7, 6 Hz), 2.26-2.20 (1H, m), 1.94-1.85 (2H, m),
1.72-1.30 (6H, m), 1.43, 1.37 (each 3H, s); 13C NMR (CDCl3)
δ 138.7, 129.3, 128.3, 127.2, 108.7, 74.9, 71.1, 68.5, 60.4, 39.5,
31.5, 30.5, 26.7, 25.4, 25.3, 24.2; HRMS calcd for C18H28NO3
(M + H+) 306.2068, found 306.2069.
(3R,4S)-1,2,3-Trideoxy-3-[ethoxy(phenylmethyl)amino]-
4,5-O-(1-methylethylidene)pentitol (syn-18a). A colorless
oil. IR (CHCl3) 2983, 1455 cm-1; 1H NMR (CDCl3) δ 7.40-7.22
(5H, m), 4.54 (1H, ddd, J ) 8, 6.5, 4.5 Hz), 4.05, 3.98 (2H, ABq,
J ) 13 Hz), 4.01, 3.80 (each 1H, d, J ) 8 Hz), 3.53-3.41 (2H,
m), 2.78 (1H, dt, J ) 9, 4.5 Hz), 1.62-1.44 (2H, m), 1.41, 1.38
(3S,4S)-1,2,3-Trideoxy-2-methyl-3-[1-methylethoxy-
(phenylmethyl)amino]-4,5-O-(1-methylethylidene)pentitol
(anti-18b). A colorless oil. IR (CHCl3) 2974, 1455 cm-1 1H
;
NMR (CDCl3) δ 7.34-7.22 (5H, m), 4.43-4.35 (1H, br m),
4.18-4.14 (1H, m), 3.86, 3.83 (2H, ABq, J ) 13.5 Hz), 3.75-
3.66 (1H, br m), 3.56-3.48 (1H, m), 2.61 (1H, br m), 2.33-
2.25 (1H, m), 1.35, 1.33 (each 3H, s), 1.16, 1.08 (each 3H, d, J
) 7 Hz), 0.95 (3H, br s), 0.90 (3H, d, J ) 6 Hz); 13C NMR
(CDCl3) δ 138.4, 129.9, 128.0, 127.2, 121.3, 108.5, 74.4, 73.5,
69.5, 59.3, 26.6, 26.4, 25.5, 22.6, 21.5, 21.4, 19.8; HRMS calcd
(each 3H, s), 1.00 (3H, t, J ) 7 Hz), 0.95 (3H, t, J ) 7 Hz); 13
C
NMR (CDCl3) δ 138.6, 129.5, 128.0, 127.0, 107.7, 74.3, 69.1,
66.6, 66.4, 59.8, 26.4, 25.2, 19.4, 13.9, 11.9; HRMS calcd for
C17H27NO3 (M+) 293.1989, found 293.1985. [R]21D +42.0 (c 1.41,
CHCl3).
General Procedure for Alkyl Radical Addition to 16.
To a solution of nitrone 16 (50 mg, 0.21 mmol) in benzene (5
mL) were added RI (19 mmol) and Et3B (1.0 M in hexane, 0.52
mL, 0.52 mmol) in the presence of 20 mL of O2 under N2
atmosphere at reflux. After being stirred at the same temper-
ature for 2 h, the reaction mixture was diluted with saturated
aqueous NaHCO3 and then extracted with CHCl3. The organic
phase was dried over MgSO4 and concentrated under reduced
pressure. Purification of the residue by preparative TLC
(hexane/AcOEt 5:1) afforded 17b,c and 18b,c.
for C19H31NO3 (M+) 321.2303, found 321.2305. [R]18 -4.1 (c
D
1.58, CHCl3).
(2S,3S)-3-Cyclopentyl-3-[cyclopentyloxy(phenylmethyl)-
amino]-1,2-O-(1- methylethylidene)-1,2-propanediol (anti-
18c). A colorless oil. IR (CHCl3) 3032, 1455 cm-1 1H NMR
;
(CDCl3) δ 7.38-7.24 (5H, m), 4.46-4.38 (1H, br m), 4.16 (1H,
dd, J ) 8.5, 6.5 Hz), 3.87, 3.72 (each 1H, d, J ) 13.5 Hz), 3.84-
3.78 (1H, br m), 3.76-3.70 (1H, br m), 2.88 (1H, t, J ) 6.5
Hz), 2.25-2.15 (1H, br m), 2.00-1.20 (16H, m), 1.38, 1.37 (each
3H, s); 13C NMR (CDCl3) δ 138.9, 129.9, 129.8, 127.94, 127.92,
127.0, 121.3, 108.5, 82.9, 69.5, 69.3, 57.7, 39.8, 31.9, 31.6, 31.5,
30.6, 26.6, 25.6, 25.4, 24.1, 23.3, 23.1; HRMS calcd for
C23H35NO3 (M+) 373.2615, found 373.2629. [R]16D -7.6 (c 1.24,
CHCl3).
(3S,4S)-1,2,3-Trideoxy-3-[hydroxy(phenylmethyl)ami-
no]-2-methyl-4,5-O-(1-methylethylidene)pentitol (anti-
17b) and (3R,4S)-1,2,3-Trideoxy-3-[hydroxy(phenylmeth-
yl)amino]-2-methyl-4,5-O-(1- methylethylidene)pentitol
(syn-17b). A white solid oil (a 9:1 mixture of anti-17b and syn-
Acknowledgment. This work was supported in part
by Grant-in-Aid for Scientific Research (B) (T.N.) and
for Young Scientists (B) (M.U. and H.M.) from the
Ministry of Education, Culture, Sports, Science and the
Science Research Promotion Fund of the Japan Private
School Promotion Foundation for research grants.
1
17b). IR (CHCl3) 3577, 1455 cm-1; H NMR (CDCl3) δ 7.35-
7.25 (5H, m), 4.64 (1H, br s), 4.47 (1/10H, q, J ) 7 Hz), 4.46
(9/10H, q, J ) 7 Hz), 4.16-4.11 (1H, m), 3.93-3.89 (3H, m),
2.67 (9/10H, dd, J ) 7, 3.5 Hz), 2.63(1/10H, dd, J ) 7, 4 Hz),
2.33-2.26 (1H, m), 1.42, 1.37 (each 3H, s), 1.11, 1.09 (each
27/10H, d, J ) 7 Hz), 1.10, 1.08 (each 3/10H, d, J ) 7 Hz); 13
C
NMR (CDCl3) δ 138.5, 129.2, 129.1, 128.6, 128.5, 128.3, 127.3,
108.4, 74.5, 74.4, 72.3, 68.7, 62.0, 61.9, 27.1, 26.7, 25.3,
21.4, 19.8; HRMS calcd for C16H25NO3 (M+) 279.1833, found
279.1834.
(2S,3S)-3-Cyclopentyl-3-[hydroxy(phenylmethyl)ami-
no]-1,2-O-(1-methylethylidene)-1,2-propanediol (anti-
17c) and (2S,3R)-3-Cyclopentyl-3-[hydroxy(phenylmethyl)-
Supporting Information Available: Experimental pro-
cedure and characterization data for compounds 1, 4, 5, 7, 12,
13, and 16, and 1H and 13C NMR spectra of all obtained
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO050603Z
6660 J. Org. Chem., Vol. 70, No. 17, 2005