Tandem carbon-carbon bond-forming radical addition-cyclization reaction of oxime ether and hydrazone

Article abstract of DOI:10.1021/jo0341057

The novel tandem radical addition-cyclization of oxime ethers and hydrazones intramolecularly connected with the α,β-unsaturated carbonyl group is described. The radical reaction of oxime ethers 1, 2, and 4 connected with acryloyl and methacryloyl moieties proceeded smoothly to give the heterocycles via a tandem C - C bond-forming process. The tandem reaction of hydrazone 5 took place in the presence of Zn(OTf)₂ as a Lewis acid to give the trans-cyclic product 17 without the formation of the cis-isomer. The diastereoselective radical addition-cyclization reaction of chiral oxime ether 19 was also studied. The tandem reaction of 19 proceeded smoothly even in aqueous media, providing the novel method for asymmetric synthesis of γ-butyrolactones and β-amino acid derivatives.

Full text of DOI:10.1021/jo0341057

Ta n d em Ca r bon -Ca r bon Bon d -F or m in g Ra d ica l
Ad d ition -Cycliza tion Rea ction of Oxim e Eth er a n d Hyd r a zon e
Hideto Miyabe,‡ Masafumi Ueda,† Kayoko Fujii,† Azusa Nishimura,† and Takeaki Naito*,†
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, J apan, and Graduate
School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, J apan
taknaito@kobepharma-u.ac.jp
Received J anuary 27, 2003
The novel tandem radical addition-cyclization of oxime ethers and hydrazones intramolecularly
connected with the R,â-unsaturated carbonyl group is described. The radical reaction of oxime ethers
1, 2, and 4 connected with acryloyl and methacryloyl moieties proceeded smoothly to give the
heterocycles via a tandem C-C bond-forming process. The tandem reaction of hydrazone 5 took
place in the presence of Zn(OTf)2 as a Lewis acid to give the trans-cyclic product 17 without the
formation of the cis-isomer. The diastereoselective radical addition-cyclization reaction of chiral
oxime ether 19 was also studied. The tandem reaction of 19 proceeded smoothly even in aqueous
media, providing the novel method for asymmetric synthesis of γ-butyrolactones and â-amino acid
derivatives.
SCHEME 1
In tr od u ction
Strategies involving radical reactions have become
preeminent tools in organic synthesis.1 Free-radical-
mediated cyclization has developed as a powerful method
for preparing various types of cyclic compounds via
carbon-carbon bond-forming processes. Although a num-
ber of extensive investigations into radical reactions were
reported in recent years, the majority of them employ
methods utilizing conventional radical acceptors such as
alkenes or typical radical precursors such as halides,
selenides, and xanthates. One drawback in traditional
procedures using such radical acceptors and precursors
is loss of the inherent functional groups. Our laboratory
is interested in developing effective and convenient
methods for the synthesis of highly functionalized cyclic
compounds. For this purpose, we have focused our efforts
on radical reactions using the oxime ether group as a
radical acceptor.2-4 In this paper, we describe full details
of the radical addition-cyclization reaction of substrates
having two different radical acceptors such as acrylate
and aldimine moieties (Scheme 1).5 A remarkable feature
of this reaction is the construction of two carbon-carbon
bonds via a tandem process.6
Resu lts a n d Discu ssion
Ta n d em Ra d ica l Ad d ition -Cycliza tion of Oxim e
Eth er s. Free-radical-mediated cyclization of imine de-
rivatives has been an important method for the construc-
tion of various types of cyclic amino compounds. Although
there has been extensive investigations into radical
cyclization of oxime ethers and hydrazones,7 the difficulty
in achieving tandem construction of multiple carbon-
carbon bonds has remained unresolved. Thus, the con-
struction of two carbon-carbon bonds based on tandem
radical reaction and its stereocontrol are subjects of
† Kobe Pharmaceutical University.
(3) (a) Naito, T.; Nakagawa, K.; Nakamura, T.; Kasei, A.; Ninomiya,
I.; Kiguchi, T. J . Org. Chem. 1999, 64, 2003. (b) Naito, T.; Tajiri, K.;
Harimoto, T.; Ninomiya, I.; Kiguchi, T. Tetrahedron Lett. 1994, 35,
2205. (c) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.;
Naito, T. J . Org. Chem. 1998, 63, 4397. (d) Miyabe, H.; Torieda, M.;
Kiguchi, T.; Naito, T. Synlett 1997, 580. (e) Naito, T.; Torieda, M.;
Tajiri, K.; Ninomiya, I.; Kiguchi, T. Chem. Pharm. Bull. 1996, 44, 624.
(f) Miyabe, H.; Kanehira, S.; Kume, K.; Kandori, H.; Naito, T.
Tetrahedron 1998, 54, 5883. (g) Naito, T.; Fukumoto, D.; Takebayashi,
K.; Kiguchi, T. Heterocycles 1999, 51, 489. (h) Kiguchi, T.; Yuumoto,
Y.; Ninomiya, I.; Naito, T. Chem. Pharm. Bull. 1997, 45, 1212. (i)
Kiguchi, T.; Okazaki, M.; Naito, T. Heterocycles 1999, 51, 2711. (j)
Kiguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T. Tetrahedron 2000, 56,
5833. (k) Naito, T.; Nair, J . S.; Nishiki, A.; Yamashita, K.; Kiguchi, T.
Heterocycles 2000, 53, 2611. (l) Miyata, O.; Muroya, K.; Koide, J .; Naito,
T. Synlett 1998, 271. (m) Miyabe, H.; Tanaka, H.; Naito, T. Tetrahedron
Lett. 1999, 40, 8387. (n) Miyabe, H.; Fujii, K.; Tanaka, H.; Naito, T.
Chem. Commun. 2001, 831.
‡ Kyoto University.
(1) (a) Fossey, J .; Lefort, D.; Sorba, J . In Free Radicals in Organic
Chemistry; Translated by Lomas, J .; J ohn Wiley & Sons Inc.: New
York, 1995. (b) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996,
96, 177. (c) Snider, B. B. Chem. Rev. 1996, 96, 339. (d) Giese, B.;
Kopping, B.; Go¨bel, T.; Dickhaut, J .; Thoma, G.; Kulicke, K. J .; Trach,
F. Org. React. (NY) 1996, 48, 301. (e) Curran, D. P.; Porter, N. A.; Giese,
B. In Stereochemistry of Radical Reactions: Concepts, Guidelines, and
Synthetic Applications; VCH: Weinheim, 1996. (f) Renaud, P.; Gerster,
M. Angew. Chem., Int. Ed. 1998, 37, 2562. (g) Sibi, M. P.; Porter, N.
A. Acc. Chem. Res. 1999, 32, 163. (h) Bowman, W. R.; Bridge, C. F.;
Brookes, P. J . Chem. Soc., Perkin Trans. 1 2000, 1. (i) In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: New
York, 2001.
(2) For reviews on the radical cyclization of imines, see: (a) Fallis,
A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543. (b) Naito, T.
Heterocycles 1999, 50, 505.
10.1021/jo0341057 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/18/2003
5618
J . Org. Chem. 2003, 68, 5618-5626

Addition-Cyclization of Oxime Ether and Hydrazone
SCHEME 3
F IGURE 1. Oxime ethers 1-4 and hydrazone 5.
SCHEME 2
of the oxime ether moiety.8 R-Chloroacetaldoxime ether
8 was prepared from chloroacetaldehyde and O-benzyl-
hydroxyamine hydrochloride.9 The reaction of 8 with
commercially available 2-aminoethanol gave the second-
ary amine 9 in 88% yield. Oxime ethers 2-4 were readily
prepared by the reaction of 9 with the corresponding acid
chlorides in 87%, 70%, and 83% yields, respectively, as
an E/Z mixture. In our recent studies on the radical
reaction of oxime ethers, we have observed no remarkable
effect of the geometry of the starting oxime ether group
on either the chemical yield or stereoselectivity by
employing geometrically pure E- and Z-isomers.3c Thus,
oxime ethers 1-4 were subjected to the following radical
reactions without the separation of E/Z-isomers.
At first, we examined the alkyl radical addition-
cyclization reaction of oxime ether 1 (Scheme 3). Treat-
ment of an E/Z mixture of 1 with 1 M Et3B in hexane in
boiling toluene gave a 3:1 mixture of two cyclized
products 10a and 10b in favor of trans-product 10a . We
were able to separate and purify each isomer by either
PTLC or medium-pressure column chromatography to
give 41% yield of 10a and 14% yield of 10b. The relative
stereochemistry of 10a and 10b was determined by
NOESY experiments. Treatment of oxime ether 1 with
isopropyl iodide and 1 M Et3B in hexane in boiling
toluene gave a 4:1 mixture of two isopropylated products
trans-11a and cis-11b in 54% combined yield. A favorable
experimental feature of this reaction is that the reaction
proceeds smoothly even in the absence of toxic tin hydride
or heavy metals via a route involving an iodine atom
transfer process. However, it is also important to note
the limitation that a primary radical and unstablized
alkyl radical other than ethyl radical will not work under
the iodine atom transfer reaction conditions.
The rationale of the reaction pathway of tandem
reaction is that the alkyl radical initially reacted with
acrylate moiety to form carbonyl-stabilized radical B,
which attacked intramolecularly the oxime ether group
as in 5-exo-trig radical cyclization (Figure 2). The inter-
mediate benzyloxyaminyl radical C would be trapped by
Et3B to give the product D and ethyl radical; therefore,
more than a stoichiometric amount of Et3B was required.
The following crucial points would make these reactions
a success of this tandem reaction: (i) the overall differ-
ence in the intermolecular reactivity of a nucleophilic
carbon radical between two electrophilic radical acceptors
considerable interest. This investigation is the first
example of the reaction between oxime ethers and
carbonyl-stabilized radicals.
We investigated the reaction of several imine deriva-
tives 1-5 (Figure 1). Oxime ethers 1, 2, 3, and 4 were
prepared as shown in Scheme 2. Oxime ether 7 was
readily prepared from glycolaldehyde dimer 6 and O-
benzylhydroxyamine hydrochloride. The reaction of 7
with acryloyl chloride gave the oxime ether 1 in 92% yield
as an E/Z mixture in a 3:2 ratio. The E/Z ratios were
determined by 1H NMR spectroscopy. In general, the
signals due to the imino hydrogen of the E-oxime ethers
are shifted downfield by the influence of the alkoxy group
(4) For intermolecular radical reactions of imines by using trieth-
ylborane, see: (a) Miyabe, H.; Ueda, M.; Naito, T. Chem. Commun.
2000, 2059. (b) Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito,
T. J . Org. Chem. 2000, 65, 176. (c) Miyabe, H.; Ueda, M.; Naito, T. J .
Org. Chem. 2000, 65, 5043. (d) Miyabe, H.; Konishi C.; Naito, T. Org.
Lett. 2000, 2, 1443. (e) Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999,
1, 569. (f) Miyabe, H.; Ueda, M.; Yoshioka, N.; Naito, T. Synlett 1999,
465.
(5) Miyabe, H.; Fujii, K.; Goto, T.; Naito, T. Org. Lett. 2000, 2, 4071.
(6) Radical cascade reaction of oxime ethers was reported. See: Ryu,
I.; Kuriyama, H.; Minakata, S.; Komatsu, M.; Yoon, J .-Y.; Kim, S. J .
Am. Chem. Soc. 1999, 121, 12190.
(7) For some selected examples of the radical reaction of oxime
ethers, 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) Miyabe, H.;
Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito, T. J . Org. Chem.
1998, 63, 4397. (e) Iserloh, U.; Curran, D. P. J . Org. Chem. 1998, 63,
4711. (f) Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J . Org. Chem. 1998,
63, 5877. (g) Marco-Contelles, J .; Balme, G.; Bouyssi, D.; Destabel, C.;
Henriet-Bernard, C. D.; Grimaldi, J .; Hatem, J . M. J . Org. Chem. 1997,
62, 1202. (h) Marco-Contelles, J .; Gallego, P.; Rodr´ıguez-Ferna´ndez,
M.; Khiar, N.; Destabel, C.; Bernabe´, M.; Mart´ınez-Grau, A.; Chiara,
J . L. J . Org. Chem. 1997, 62, 7397. (i) Noya, B.; Alonso, R. Tetrahedron
Lett. 1997, 38, 2745. (j) Booth, S. E.; J enkins, P. R.; Swain, C. J . J .
Chem. Soc., Chem. Commun. 1991, 1248. (k) Hanamoto, T.; Inanaga,
J . Tetrahedron Lett. 1991, 32, 3555.
(8) McCarty, C. G. In The Chemistry of Functional Groups; The
chemistry of the carbon-nitrogen double bond; Patai, S., Ed.; J ohn
Wiley & Sons Inc.: New York, 1970; pp 383-392.
(9) Stach, L. J . U.S. Patent 3,920,772, 1975; Chem. Abstr. 1976, 84,
89603d.
J . Org. Chem, Vol. 68, No. 14, 2003 5619

Miyabe et al.
TABLE 1. Ta n d em Ra d ica l Ad d ition -Cycliza tion of
Oxim e Eth er 2
entry
RI
none
i-PrI
c-hexyl I toluene 80
c-pentyl I toluene 80
solvent T (°C)
producta
yield (%)b
1
2
3
4
5
6
toluene reflux 12a A:12bA ) 4:1
toluene 80
69
67
58
55
71
63
12a B:12bB ) 3:1
12a C:12bC ) 3:1
12a D:12bD ) 3:1
12a E:12bE ) 4:1
12a B:12bB ) 3:1
s-BuI
i-PrI
toluene 80
H2O 80
a
b
Selectivities were determined by 1H NMR analysis. Isolated
yield.
SCHEME 5
product D but a tandem radical route involving the
conversion of water-resistant radical intermediate B into
cyclic product D (Figure 2).10 In our recent studies on the
radical addition to highly reactive acceptors such as
glyoxylic oxime ethers and BF3-activated aldoxime ethers,
the competitive addition of an ethyl radical, generated
from triethylborane, was observed as a significant side
reaction.4 In the present reactions, it is noteworthy that
no competitive addition of ethyl radical was observed
because of the slightly low reactivity of the acrylate
moiety on 2 as a radical acceptor.
F IGURE 2. Reaction pathway and stereochemical feature.
SCHEME 4
We next examined ethyl radical addition-cyclization
reaction of oxime ethers 3 and 4 (Scheme 5). Oxime ether
3 having a crotonyl group did not work under similar
reaction conditions. In the case of oxime ether 4 having
a methacryloyl group, the tandem radical reaction pro-
ceeded slowly, compared with oxime ether 2 having a
acryloyl group, to give cyclic product 13 having a qua-
ternary carbon.
Ta n d em Ra d ica l Ad d ition -Cycliza tion of Hyd r a -
zon e. We next investigated the reaction of hydrazone 5,
which was prepared as shown in Scheme 6. The acylation
of amino alcohol 14 with acryloyl chloride followed by
treatment with saturated Na2CO3 in methanol gave the
alcohol 15 in 95% yield. Selective oxidation of an alcohol
in 15 with PDC gave the hemiacetal 16 in 36% yield.
Hydrazone 5 was prepared as an E-isomer by the reaction
of 16 and N,N-diphenylhydrazine hydrochloride in 91%
yield.
in the first step, and (ii) the high reactivity of triethylbo-
rane as a trapping reagent toward a key intermediate
aminyl radical C. The preferential formation of the trans-
isomers could be explained by steric repulsions between
the radical moiety and the oxime ether group as shown
in Figure 2.
Oxime ether 2 having a 2-hydroxyethylated amide
moiety, which would exist in the preferable conformer
for intramolecular cyclization, has shown good reactivity
(Scheme 4). Treatment of 2 with 1 M Et3B in hexane in
boiling toluene gave a 4:1 mixture of two cyclized
products 12a A and 12bA in 69% combined yield in favor
of trans-product 12a A (Table 1, entry 1). Good chemical
yields were also observed in the radical reaction using
different radical precursors such as isopropyl, cyclohexyl,
and cyclopentyl iodides under the iodine atom transfer
reaction conditions (entries 2-5). From the viewpoint of
elucidating the reaction mechanism, it is important to
note that the tandem reaction of 2 proceeded even in
aqueous media (entry 6). The observation suggests that
the major reaction pathway is not a route involving the
conversion of water-unstable boryl enolate E into cyclic
The tandem addition-cyclization reaction of hydrazone
5 with an ethyl radical gave the desired cyclic product
17 and the N-ethylated cyclic product 18, the latter of
which was formed as a result of the additional N-
(10) The reaction between Et3B and R-carbon radical of an ester is
less effective than the corresponding reaction of the R-carbon radical
derived from ketones and aldehydes. For the discussions, see: (a)
Ollivier, C.; Renaud, P. Angew. Chem., Int. Ed. 2000, 39, 925. (b)
Brown, H. C.; Negishi, E. J . Am. Chem. Soc. 1971, 93, 3777. (c) Beraud,
V.; Gnanou, Y.; Walton, J . C.; Maillard, B. Tetrahedron Lett. 2000,
41, 1195.
5620 J . Org. Chem., Vol. 68, No. 14, 2003

Addition-Cyclization of Oxime Ether and Hydrazone
SCHEME 6
F IGURE 3. Chiral oxime ethers 19 and 20.
SCHEME 7
F IGURE 4. Conformation of intermediate radicals.
TABLE 2. Ta n d em Ra d ica l Ad d ition -Cycliza tion of
Hyd r a zon e 5
studied. As described above, the cyclization of conforma-
tionally flexible oxime ether 1 took place slowly because
R-carbonyl radical exists in an s-trans conformer F , while
the cyclization requires an s-cis conformer G (Figure 4).
The oxime ether 2 having N-alkyl amide moiety would
exist in preferable conformer I for cyclization; thus the
reaction of 2 proceeded smoothly. Therefore, we expected
that the presence of bulky substituent of chiral oxime
ether 19 would be important not only for stereoselectivity
but also for efficiency in cyclization. Studies concerning
the conformer of ester moiety have been reported in the
radical cyclization.12 We have also reported the effective
radical-mediated construction of γ-lactones using hy-
droximates as a tether.13
As shown in Scheme 8, the chiral substrates 19 and
20 having acrylate and aldoxime ether moieties were
prepared from D-mannitol. Oxime ether 22 was prepared
from chiral aldehyde 21 and O-benzylhydroxyamine
hydrochloride.14 The reaction of 22 with pyridinium
p-toluenesulfonate in methanol gave the alcohol 23 in
89% yield. The alcohol 23 was protected as the TBDPS
derivative 24 in good yield by treatment with tert-
butyldiphenylsilyl chloride in the presence of imidazole.
The reaction of 24 with acryloyl chloride gave the oxime
ether 19 in 64% yield, as an E/Z mixture in a 3:1 ratio.
For the preparation of oxime ether 20, the benzyl
derivative 25 was prepared from the alcohol 24 in 75%
yield (%)a
17 18
entry
Lewis acid
T (°C)
time (h)
1
2
3
4
5
none
none
MgBr2‚OEt2
MAD
20
24
3
3
3
3
0
18
28
22
50
19
58
21
0
reflux
reflux
reflux
reflux
Zn(OTf)2
0
a
Isolated yield.
ethylation (Scheme 7). A remarkable feature of the
reaction of hydrazone is the selective formation of trans-
products 17 and 18 with no detection of cis-isomers. The
results of the reaction of hydrazone 5 are summarized
in Table 2. In the absence of Lewis acid, the reaction
proceeded slowly at 20 °C to give the N-ethylated cyclic
product 18 in 19% yield after 24 h (entry 1). The reaction
in refluxing benzene proceeded smoothly to give the
desired cyclic product 17 and the N-ethylated cyclic
product 18 in 18% and 58% yields, respectively. To
suppress the formation of the N-ethylated cyclic product
18, several Lewis acids were employed (entries 3-5). In
the presence of either MAD or Zn(OTf)2, the formation
of 18 was not observed giving 50% yield of the desired
product 17 in the latter case (entries 4 and 5).
Dia ster eoselective Ta n d em Ra d ica l Ad d ition -Cy-
cliza tion of Oxim e Eth er . For the asymmetric synthe-
sis of various types of γ-butyrolactones,11 we next inves-
tigated the reaction of chiral oxime ether 19 having a
bulky substituent (Figure 3). The six-membered ring
formation employing chiral oxime ether 20 was also
(12) (a) Wang, C.; Russell, G. A. J . Org. Chem. 1999, 64, 2066. (b)
Curran, D. P.; Tamine, J . J . Org. Chem. 1991, 56, 2746. (c) J ung, M.
E.; Gervay, J . J . Am. Chem. Soc. 1991, 113, 224. (d) Stork, G.; Mook,
R., J r.; Biller, S. A.; Rychnovsky, S. D. J . Am. Chem. Soc. 1983, 105,
3741. (e) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M.
J . Am. Chem. Soc. 1982, 104, 5564.
(11) For reviews on asymmetric synthesis of γ-butyrolactones and
â-amino acids, see: (a) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996,
25, 117. (b) Cole, D. C. Tetrahedron 1994, 50, 9517. (c) Ogliaruso, M.
A.; Wolfe, J . F. In Synthesis of Lactones and Lactams; J ohn Wiley &
Sons: New York, 1993.
(13) Miyata, O.; Nishiguchi, A.; Ninomiya, I.; Aoe, K.; Okamura, K.;
Naito, T. J . Org. Chem. 2000, 65, 6922.
(14) Schmid, C. R.; Bryant, J . D.; Dowlatzedah, M.; Phillips, J . L.;
Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J . Org. Chem.
1991, 56, 4056.
J . Org. Chem, Vol. 68, No. 14, 2003 5621

Miyabe et al.
SCHEME 8
SCHEME 10
SCHEME 11
SCHEME 9
trace amount of other diastereomers 27cA and 27d A
were also formed. The relative stereochemistry of 27a A-
27d A was determined by NOESY experiments. The
reaction in refluxing benzene also gave 27a A in 64% with
moderate diastereoselectivity (entry 2). The degree of
stereoselectivity was shown to be dependent on the
reaction temperature; thus, changing the temperature to
20 °C in toluene led to an increase in diastereoselectivity
to 18:1 (entry 3). The reaction in CH2Cl2 at 20 °C gave
27a A in 53% isolated yields with moderate diastereose-
lectivity (entry 4). Interestingly, the tandem reaction of
19 proceeded even in aqueous media to afford 27a A in
55% yield (entry 5).
As shown in Scheme 10, the γ-butyrolactone 27a A was
converted to a â-amino acid derivative 29. Hydrogenolysis
of the benzyloxyamino group of 27a A in the presence of
Pd(OH)2-C gave the amine, which was protected as the
N-Cbz derivative 28 by treatment with CbzCl. The
treatment of 28 with benzylamine in the presence of
2-pyridinol16 gave â-amino acid derivative 29 in 56%
yield.
For the asymmetric synthesis of various types of chiral
γ-butyrolactones, we next investigated the reaction using
different radical precursors under the iodine atom trans-
fer reaction conditions (Scheme 11). The tandem reaction
of 19 with an isopropyl radical was carried out in boiling
benzene for 15 min by using isopropyl iodide (6 equiv)
and triethylborane (3 equiv). As expected, the reaction
proceeded smoothly to give the isopropylated product
27a B in 68% yield along with a small amount of another
diastereomer 27bB. Other secondary alkyl radicals worked
well under similar reaction conditions, allowing facile
incorporation of structural variety. Under the iodine atom
transfer reaction conditions, the tandem reaction of 19
also proceeded in aqueous media to afford 27a B-27a D
(Scheme 12).
TABLE 3. Ta n d em Eth yl Ra d ica l Ad d ition -Cycliza tion
of Oxim e Eth er 19
yield
(%)a
selectivityb
27a A:27bA
entry
solvent
toluene
benzene
toluene
CH2Cl2
H2O/MeOH (1:4, v/v)
T (°C)
1
2
3
4
5
reflux
reflux
20
20
reflux
70
64
53
53
55
8:1
12:1
18:1
10:1
9:1
a
b
Isolated yield of major diastereomer. Selectivities were de-
termined by 1H NMR analysis which indicates the ratio of a major
diastereomer and a second diastereomer.
yield under the mild reaction conditions.15 After the
deprotection of the TBDPS group, acylation with acryloyl
chloride gave the oxime ether 20 in 50% yield, as an E/Z
mixture in a 3:1 ratio. Oxime ethers 19 and 20 were
subjected to the following radical reactions, without the
separation of E/Z-isomers.
We initially studied the reaction of oxime ether 19 with
an ethyl radical by using triethylborane (Scheme 9). The
reaction in refluxing toluene proceeded smoothly to give
a major diastereomer 27a A in 70% yield along with a
small amount of another diastereomer 27bA (Table 3,
entry 1). Extensive studies of this reaction showed that
(16) (a) Tan, D. S.; Foley, M. A.; Shair, M. D.; Schreiber, S. L. J .
Am. Chem. Soc. 1999, 121, 9073. (b) Openshaw, H. T.; Whittaker, N.
J . Chem. Soc. C 1969, 89.
(15) (a) Iversen, T.; Bundle, D. R. Chem. Commun. 1981, 1240. (b)
White, J . D.; Kawasaki, M. J . Org. Chem. 1992, 57, 5292.
5622 J . Org. Chem., Vol. 68, No. 14, 2003

Addition-Cyclization of Oxime Ether and Hydrazone
ethers as a radical acceptor for the synthesis of various
types of amino compounds. Additionally, the reactions
of oxime ethers with carbonyl-stabilized radicals is a new
alternative to the intramolecular Mannich reaction.17
Exp er im en ta l Section
Ta n d em Ra d ica l Rea ction of 1 w ith Et3B. To a boiling
solution of 1 (200 mg, 0.91 mmol) in toluene (40 mL) was added
Et3B (1.0 M in hexane, 4.6 mL, 4.6 mmol) at reflux. After being
stirred at reflux for 15 min, the reaction mixture was diluted
with aqueous NaHCO3 and then extracted with CH2Cl2. The
organic phase was dried over MgSO4 and concentrated at
reduced pressure. Purification of the residue (a trans/cis
mixture in 3:1) by preparative TLC (hexane/AcOEt 4:1, 2-fold
development) afforded trans-10a (94 mg, 41%) and cis-10b (31
mg, 14%).
tr a n s-Dih yd r o-4-[(p h en ylm et h oxy)a m in o]-3-p r op yl-
2(3H)-fu r a n on e (10a ). A colorless oil: IR (CHCl3) 2965, 1773,
1
1455 cm-1; H NMR (CDCl3) δ 7.42-7.28 (5H, m), 5.62-5.38
(1H, br m), 4.70 (2H, s), 4.32 (1H, dd, J ) 9.6, 6.3 Hz), 4.13
(1H, dd, J ) 9.6, 4.5 Hz), 3.63 (1H, br m), 2.45 (1H, m), 1.75
(1H, m), 1.55 (1H, m), 1.45 (2H, m), 0.94 (3H, t, J ) 7.2 Hz);
13C NMR (CDCl3) δ 178.0, 137.0, 128.7, 128.5, 128.2, 77.1, 69.6,
61.9, 42.7, 31.2, 20.2, 13.8; HRMS calcd for C14H19NO3 (M+)
249.1364, found 249.1377.
F IGURE 5. Stereochemical feature.
cis-Dih ydr o-4-[(ph en ylm eth oxy)am in o]-3-pr opyl-2(3H)-
fu r a n on e (10b). A colorless oil: IR (CHCl3) 2965, 1774, 1455
SCHEME 12
1
cm-1; H NMR (CDCl3) δ 7.4-7.3 (5H, m), 5.62-5.45 (1H, br
m), 4.71, 4.68 (each 1H, d, J ) 11.5 Hz), 4.37 (1H, d, J ) 10.0
Hz), 4.20 (1H, dd, J ) 10.0, 4.5 Hz), 3.78 (1H, br dd, J ) 6.5,
4.5 Hz), 2.52 (1H, m), 1.80 (1H, m), 1.55-1.4 (3H, m), 0.96
(3H, t, J ) 7.0 Hz); 13C NMR (CDCl3) δ 177.7, 137.0, 128.6,
128.5, 128.2, 76.9, 70.1, 58.5, 42.2, 25.8, 21.1, 14.0; HRMS calcd
for C14H19NO3 (M+) 249.1364, found 249.1391.
Ta n d em Ra d ica l Rea ction of 1 w ith i-P r I a n d Et3B.
To a solution of 1 (200 mg, 0.91 mmol) and i-PrI (0.45 mL, 4.6
mmol) in toluene (40 mL) was added Et3B (1.0 M in hexane,
4.6 mL, 4.6 mmol) at reflux. After being stirred at reflux for
15 min, the reaction mixture was diluted with aqueous
NaHCO3 and then extracted with CH2Cl2. The organic phase
was dried over MgSO4 and concentrated at reduced pressure.
Purification of the residue by preparative TLC (hexane/AcOEt
4:1, 2-fold development) afforded 11a and 11b (a trans/cis
mixture in 4:1, 129 mg, 54%). Purification of the mixture of
trans/cis isomers by preparative TLC (hexane/AcOEt 4:1, 4-fold
development) afforded trans-11a as a sole isolable isomer.
tr a n s-Dih yd r o-3-[(2-m et h yl)p r op yl]-4-[(p h en ylm et h -
oxy)am in o]-2(3H)-fu r an on e (11a). A colorless oil: IR (CHCl3)
2962, 1771, 1455 cm-1; 1H NMR (CDCl3) δ 7.41-7.29 (5H, m),
5.62-5.41 (1H, br m), 4.70 (2H, s), 4.32 (1H, dd, J ) 9.6, 6.3
Hz), 4.15 (1H, dd, J ) 9.9, 3.9 Hz), 3.59 (1H, br m), 2.51 (1H,
m), 1.80 (1H, m), 1.62 (1H, m), 1.40 (1H, m), 0.95, 0.92 (each
3H, d, J ) 6.9 Hz); 13C NMR (CDCl3) δ 178.3, 136.9, 128.5,
128.3, 128.0, 76.8, 69.3, 62.2, 41.0, 38.1, 25.6, 22.5, 21.7; HRMS
calcd for C15H21NO3 (M+) 263.1520, found 263.1508.
Ta n d em Ra d ica l Rea ction of 2 w ith Et3B. To a solution
of 2 (200 mg, 0.76 mmol) in toluene (6 mL) was added Et3B
(1.0 M in hexane, 2.3 mL, 2.3 mmol) at reflux. After the
reaction mixture was stirred at the same temperature for 25
min, the reaction mixture was diluted with aqueous NaHCO3
and then extracted with CH2Cl2. The organic phase was dried
over MgSO4 and concentrated at reduced pressure. Purification
of the residue containing a 4:1 mixture of trans/cis isomers by
preparative TLC (AcOEt) afforded 12a A (154 mg, 69%).
SCHEME 13
The preferential formation of the trans-isomers
27a A-27a D could be explained by invoking a favorable
conformer minimizing A1,3-strain effects between the
Et3B bonding-oxime ether group and substituents at the
chiral carbon (Figure 5). There are less steric repulsions
in the radical N leading to the trans-isomer 27a A-27a D
than those in the radicals L and M leading to the cis-
isomers 27d A-27d D and 27bA-27bD.
We finally studied the reaction of oxime ether 20 with
an isopropyl radical under the iodine atom transfer
reaction conditions (Scheme 13). Although the tandem
radical reaction of 20 proceeded slowly, the desired six-
membered product 30 was obtained in 18% yield as a
major diastereomer.
Con clu sion s
We have shown new free-radical-mediated tandem
reactions of oxime ethers for the synthesis of heterocycles
via two C-C bond-forming processes. In addition to
radical cyclization of oxime ethers, the tandem radical
reactions disclosed a broader aspect of the utility of oxime
(17) For a review on the Mannich reaction, see: (a) Arend, M.;
Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (b)
Overman, L. E.; Ricca, D. J . In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford,
1991; Vol. 2, p 1007. (c) Tramontiti, M.; Angiolini, L. Tetrahedron 1990,
46, 1791.
J . Org. Chem, Vol. 68, No. 14, 2003 5623

Miyabe et al.
tr a n s-1-(2-Hyd r oxyeth yl)-4-[(p h en ylm eth oxy)a m in o]-
3-p r op yl-2-p yr r olid in on e (12a A). A colorless oil: IR (CHCl3)
59.2, 51.2, 45.9, 45.2, 37.6, 36.0, 32.9, 32.1, 25.1, 24.8; HRMS
calcd for C19H28N2O3 (M+) 332.2098, found 332.2112.
3401, 1670 cm-1 1H NMR (CDCl3) δ 7.38-7.30 (5H, m),
;
cis-3-(Cyclopen tylm eth yl)-1-(2-h ydr oxyeth yl)-4-[(ph en -
ylm eth oxy)a m in o]-2-p yr r olid in on e (12bD). A colorless
5.66-5.40 (1H, br m), 4.70 (2H, s), 3.72 (2H, t, J ) 5.0 Hz),
3.57-3.50 (2H, m), 3.43 (1H, m), 3.36-3.30 (2H, m), 2.30 (1H,
dt, J ) 8.5, 4.5 Hz), 2.08-1.90 (1H, br m), 1.71 (1H, m), 1.51-
1.36 (3H, m), 0.92 (3H, t, J ) 7.0 Hz); 13C NMR (CDCl3) δ
176.6, 137.3, 128.6, 128.5, 128.1, 76.7, 60.6, 59.2, 51.5, 46.1,
1
oil: IR (CHCl3) 3401, 2951, 2464, 1678, 1485 cm-1; H NMR
(CDCl3) δ 7.40-7.25 (5H, m), 5.72-5.28 (1H, br m), 4.71 (1H,
d, J ) 11.6 Hz), 4.65 (1H, d, J ) 11.6 Hz), 3.76-3.67 (3H, m),
3.52-3.24 (4H, m), 3.18-2.81 (1H, br m), 2.51 (1H, m), 2.00-
1.00 (11H, m); 13C NMR (CDCl3) δ 176.2, 137.1, 128.6, 128.3,
128.0, 76.4, 60.5, 56.3, 51.2, 46.1, 44.1, 38.0, 33.0, 32.0, 29.7,
25.0, 24.9; HRMS calcd for C19H28N2O3 (M+) 332.2099, found
332.2127.
45.8, 32.0, 20.2, 14.0; HRMS calcd for
292.1785, found 292.1803.
C
16H24N2O3 (M+)
cis-1-(2-H yd r oxyet h yl)-4-[(p h en ylm et h oxy)a m in o]-3-
p r op yl-2-p yr r olid in on e (12bA). A colorless oil: IR (CHCl3)
3371, 1673, 1454 cm-1; 1H NMR (CDCl3) δ 7.37-7.30 (5H, m),
5.69-5.43 (1H, br m), 4.69 (1H, d, J ) 11.5 Hz), 4.66 (1H, d,
J ) 11.5 Hz), 3.71 (2H, t, J ) 5.0 Hz), 3.49-3.29 (4H, m),
2.51-2.47 (1H, m), 1.75-1.71 (1H, m), 1.47-1.33 (3H, m), 0.94
(3H, t, J ) 7.0 Hz); 13C NMR (CDCl3) δ 176.2, 137.2, 128.7,
128.5, 128.1, 76.5, 60.5, 56.1, 51.3, 46.1, 44.8, 26.1, 21.1, 14.1;
HRMS calcd for C16H24N2O3 (M+) 292.1785, found 292.1781.
Gen er a l P r oced u r e for Ta n d em Ra d ica l Rea ction of
2 w ith RI a n d Et3B. To a solution of 2 (100 mg, 0.38 mmol)
and RI (11.5 mmol) in toluene (3 mL) was added Et3B (1.0 M
in hexane, 1.15 mL, 1.15 mmol) three times in every 5 min at
reflux. After being stirred at reflux for 25 min, the reaction
mixture was diluted with aqueous NaHCO3 and then extracted
with CH2Cl2. The organic phase was dried over MgSO4 and
concentrated at reduced pressure. Purification of the resi-
due by preparative TLC (AcOEt) afforded pyrrolidinones
12a B-12bE.
tr a n s-1-(2-Hyd r oxyeth yl)-3-(2-m eth ylbu tyl)-4-[(p h en -
ylm eth oxy)a m in o]-2-p yr r olid in on e (12a E) (1:1 mixture of
diastereomers concerning sec-butyl group). A colorless oil: IR
(CHCl3) 3396, 2963, 1664, 1488, 1455 cm-1; 1H NMR (CDCl3)
δ 7.40-7.25 (5H, m), 4.70 (2H, s), 3.71 (2H, t, J ) 5.4 Hz),
3.61-3.24 (5H, m), 2.42-2.30 (1H, m), 1.78-0.80 (11H, m);
13C NMR (CDCl3) δ 176.4, 137.2, 128.5, 128.4, 128.3, 127.9,
76.5, 60.3, 59.7, 59.4, 51.2, 51.0, 45.8, 43.8, 43.7, 37.1, 36.7,
31.94, 31.85, 29.9, 28.4, 19.2, 18.3, 11.1, 10.9; HRMS calcd for
C
18H28N2O3 (M+) 320.2098, found 320.2088.
cis-1-(2-H yd r oxyet h yl)-3-(2-m et h ylb u t yl)-4-[(p h en yl-
m eth oxy)a m in o]-2-p yr r olid in on e (12bE) (1:1 mixture of
diastereomers concerning sec-butyl group). A colorless oil: IR
(CHCl3) 3401, 2962, 1674, 1455 cm-1 1H NMR (CDCl3) δ
;
7.40-7.25 (5H, m), 4.71 (1H, d, J ) 11.6 Hz), 4.65 (1H, d, J )
11.6 Hz), 3.75-3.65 (3H, m), 3.52-3.24 (4H, m), 2.64-2.50
(1H, m), 1.80-0.80 (11H, m); 13C NMR (CDCl3) δ 176.3, 137.0,
128.6, 128.4, 128.0, 76.4, 60.5, 56.6, 56.0, 51.22, 51.18, 46.1,
42.7, 42.6, 32.3, 32.2, 30.6, 30.14, 30.08, 28.5, 19.4, 18.5, 11.3,
tr a n s-1-(2-Hyd r oxyeth yl)-3-(2-m eth ylp r op yl)-4-[(p h en -
ylm eth oxy)a m in o]-2-p yr r olid in on e (12a B). A colorless
oil: IR (CHCl3) 2959, 1670, 1488, 1455 cm-1; 1H NMR (CDCl3)
δ 7.40-7.25 (5H, m), 5.69-5.43 (1H, br m), 4.70 (2H, s), 3.78-
3.63 (2H, m), 3.60-3.23 (6H, m), 2.34 (1H, m), 1.82-1.50 (2H,
m), 1.40-1.21 (1H, m), 0.928 (3H, d, J ) 6.2 Hz), 0.908 (3H,
d, J ) 6.2 Hz); 13C NMR (CDCl3) δ 176.7, 137.3, 128.6, 128.4,
128.1, 76.7, 60.4, 59.6, 51.2, 45.9, 44.1, 39.1, 25.8, 23.1, 21.8;
HRMS calcd for C17H26N2O3 (M+) 306.1941, found 306.1955.
cis-1-(2-Hyd r oxyeth yl)-3-(2-m eth ylp r op yl)-4-[(p h en yl-
m eth oxy)a m in o]-2-p yr r olid in on e (12bB). A colorless oil:
11.0; HRMS calcd for
320.2088.
C
18H28N2O3 (M+) 320.2098, found
1-(2-Hyd r oxyeth yl)-3-m eth yl-4-[(p h en ylm eth oxy)a m i-
n o]-3-p r op yl-2-p yr r olid in on e (13). To a solution of oxime
ether 4 (100 mg, 0.36 mmol) in boiling toluene was added Et3B
(1.0 M in hexane, 0.72 mL, 0.72 mmol) four times in every 15
min. After being heated at reflux for 1 h, the reaction mixture
was diluted with saturated aqueous NaHCO3 and then ex-
tracted with CH2Cl2. The organic phase was dried over MgSO4
and concentrated at reduced pressure. Purification of the
residue by preparative TLC (hexane/AcOEt 1:3) afforded 13
(52 mg, 47%) as a colorless oil. The presence of trans/cis
isomers precluded a comprehensive assignment of all protons
and carbons: IR (CHCl3) 3401, 3022, 2963, 1673 cm-1; 1H NMR
(CDCl3) δ 7.35 (5H, m), 5.70-5.38 (1H, br m), 4.68 (2H, s),
3.70 (2H, t, J ) 5.1 Hz), 3.56-3.23 (5H, m), 1.51-1.05 (7H,
m), 0.88 (3H, t, J ) 7.1 Hz); 13C NMR (CDCl3) δ 178.8, 137.1,
128.5 (2C), 128.3, 128.2, 127.9, 76.2, 63.1, 60.2, 59.9, 50.2, 49.9,
46.8, 46.4, 45.7, 39.4, 34.0, 21.8, 17.5, 17.3, 16.2, 14.5, 14.3;
HRMS calcd for C17H26N2O3 (M+) 306.1942, found 306.1935.
Ta n d em Ra d ica l Rea ction of 5 w ith Et3B. To a solution
of 5 (52 mg, 0.16 mmol) in benzene (5 mL) was added Et3B
(1.0 M in hexane, 0.39 mL, 0.39 mmol) three times in every 1
h at reflux. After being stirred at reflux for 8 h, the reaction
mixture was diluted with aqueous NaHCO3 and then extracted
with CH2Cl2. The organic phase was dried over MgSO4 and
concentrated at reduced pressure. Purification of the residue
by preparative TLC (CHCl3/MeOH 30:1) afforded monoethy-
lated product 17 (10 mg, 18%) and diethylated product 18 (34
mg, 58%).
1
IR (CHCl3) 2959, 1674, 1486, 1467 cm-1; H NMR (CDCl3) δ
7.40-7.25 (5H, m), 5.62-5.39 (1H, br m), 4.69 (1H, d, J ) 11.8
Hz), 4.66 (1H, d, J ) 11.8 Hz), 3.79-3.62 (3H, m), 3.58-3.23
(4H, m), 3.18-2.97 (1H, br m), 2.57 (1H, m), 1.80-1.21 (3H,
m), 0.926 (3/3H, d, J ) 6.2 Hz), 0.911 (3/3H, d, J ) 6.2 Hz);
13C NMR (CDCl3) δ 176.3, 137.0, 128.6, 128.3, 128.0, 76.4, 60.5,
56.2, 51.2, 46.0, 42.8, 32.5, 26.0, 23.1, 21.7; HRMS calcd for
C
17H26N2O3 (M+) 306.1941, found 306.1941.
tr a n s-3-(Cycloh exylm eth yl)-1-(2-h ydr oxyeth yl)-4-[(ph en -
ylm eth oxy)a m in o]-2-p yr r olid in on e (12a C). A colorless
oil: IR (CHCl3) 2926, 1671, 1488, 1450 cm-1; 1H NMR (CDCl3)
δ 7.40-7.25 (5H, m), 4.70 (2H, s), 3.70 (2H, t, J ) 5.2 Hz),
3.61-3.26 (6H, m), 2.37 (1H, m), 1.77-0.83 (14H, m); 13C NMR
(CDCl3) δ 177.1, 137.3, 128.6, 128.5, 128.1, 76.7, 60.4, 59.7,
51.2, 45.9, 43.4, 37.6, 35.2, 33.9, 32.5, 26.5, 26.2, 26.1; HRMS
calcd for C20H30N2O3 (M+) 346.2254, found 346.2249.
cis-3-(Cycloh exylm eth yl)-1-(2-h yd r oxyeth yl)-4-[(p h en -
ylm eth oxy)a m in o]-2-p yr r olid in on e (12bC). A colorless
oil: IR (CHCl3) 2926, 1674, 1486, 1449 cm-1; 1H NMR (CDCl3)
δ 7.40-7.25 (5H, m), 5.61-5.33 (1H, br m), 4.71 (1H, d, J )
11.6 Hz), 4.65 (1H, d, J ) 11.6 Hz), 3.72 (2H, t, J ) 5.0 Hz),
3.66 (1H, m), 3.52-3.24 (4H, m), 3.15-2.92 (1H, br m), 2.59
(1H, m), 1.80-0.45 (13H, m); 13C NMR (CDCl3) δ 176.5, 137.2,
128.8, 128.5, 128.2, 76.5, 60.7, 56.5, 51.3, 46.2, 42.3, 35.6, 33.9,
32.7, 31.2, 26.5, 26.3, 26.2; HRMS calcd for C20H30N2O3 (M+)
346.2254, found 346.2239.
tr a n s-1-(2-Hyd r oxyeth yl)-4-(2,2-d ip h en ylh yd r a zin o)-3-
p r op yl-2-p yr r olid in on e (17). A colorless oil: IR (CHCl3)
3386, 1671 cm-1 1H NMR (CDCl3) δ 7.33-7.02 (10H, m),
;
4.18-3.82 (1H, br m), 3.80-3.72 (2H, m), 3.53-3.35 (5H, m),
3.10-2.83 (1H, br m), 2.31 (1H, m), 1.65 (1H, m), 1.41 (1H,
m), 1.34-1.26 (2H, m), 0.88 (3H, t, J ) 7.0 Hz); 13C NMR
(CDCl3) δ 177.1, 147.7, 129.3, 122.9, 120.3, 61.1, 56.1, 51.8,
47.7, 46.4, 31.7, 20.5, 14.0; HRMS calcd for C21H27N3O2 (M+)
353.2102, found 353.2109.
tra ns-3-(Cyclopentylmethyl)-1-(2-hydroxyethyl)-4-[(phen-
ylm eth oxy)a m in o]-2-p yr r olid in on e (12a D). A colorless
1
oil: IR (CHCl3) 2952, 2468, 1670, 1489, 1454 cm-1; H NMR
(CDCl3) δ 7.40-7.25 (5H, m), 4.70 (2H, s), 3.71 (2H, t, J ) 5.6
Hz), 3.62-3.26 (6H, m), 2.30 (1H, m), 2.02-0.90 (11H, m); 13
C
tr a n s-4-(1-Eth yl-2,2-d ip h en ylh yd r a zin o)-1-(2-h yd r oxy-
eth yl)-3-p r op yl-2-p yr r olid in on e (18). A colorless oil: IR
NMR (CDCl3) δ 176.7, 137.2, 128.5, 128.3, 127.9, 76.5, 60.3,
5624 J . Org. Chem., Vol. 68, No. 14, 2003

Addition-Cyclization of Oxime Ether and Hydrazone
(CHCl3) 3609, 1670, 1492 cm-1; 1H NMR (CDCl3) δ 7.36-6.90
(10H, m), 3.62-3.15 (6H, m), 2.88-2.52 (4H, m), 1.68-1.22
m eth oxy)a m in o]-2(3H)-fu r a n on e (27a B). A colorless oil:
[R]23D +115.0 (c 1.1, CHCl3); IR (CHCl3) 2932, 1771, 1428 cm-1
;
(4H, m), 1.11 (3H, t, J ) 7.0 Hz), 0.93 (3H, t, J ) 7.0 Hz); 13
C
1H NMR (CDCl3) δ 7.67-7.61 (4H, m), 7.46-7.27 (11H, m),
4.67 (2H, s), 4.37 (1H, m), 3.88, 3.75 (each 1H, dd, J ) 12.0,
3.0 Hz), 3.64 (1H, br dd, J ) 7.5, 7.0 Hz), 2.73 (1H, m),
1.88-1.79 (1H, m), 1.74-1.68 (1H, m), 1.52-1.45 (1H, m),
1.034 (9H, s), 1.030, 0.92 (each 3H, d, J ) 7.0 Hz); 13C NMR
(CDCl3) δ 177.5, 137.1, 135.6, 135.5, 132.9, 132.5, 129.89,
129.86, 128.6, 128.5, 128.2, 127.9, 127.81, 127.80, 80.6, 76.8,
63.63, 63.56, 40.7, 39.2, 26.8, 25.5, 22.8, 21.9, 19.2; HRMS calcd
for C32H41NO4Si (M+) 531.2803, found 531.2784.
NMR (CDCl3) δ 176.9, 146.6, 129.1, 128.9, 122.8, 121.8, 120.2,
118.5, 117.8, 63.6, 61.2, 50.4, 48.9, 46.0, 43.9, 32.3, 20.1, 14.0,
12.9; HRMS calcd for
381.2418.
C
23H31N3O2 (M+) 381.2415, found
Gen er a l P r oced u r e for Ta n d em Ra d ica l Rea ction of
19. To a solution of 19 (100 mg, 0.205 mmol) and R2I (2.46 or
1.23 mmol) in solvent (20 mL) was added Et3B (1.0 M in
hexane, 0.615 or 1.23 mmol) at reflux or 20 °C. After being
stirred at the same temperature for 15 min, the reaction
mixture was diluted with aqueous NaHCO3 and then extracted
with CH2Cl2. The organic phase was dried over MgSO4 and
concentrated at reduced pressure. Purification of the residue
by medium-pressure column chromatography (hexane/AcOEt
6:1) or preparative TLC (hexane/AcOEt 6:1, 2-fold develop-
ment) afforded 27a A-bD.
[3S-(3r,4â,5r)]-3-[(Cycloh exyl)m eth yl]d ih yd r o-5-[[(1,1-
d im e t h yle t h yl)d ip h e n ylsilyloxy]m e t h yl]-4-[(p h e n yl-
m eth oxy)a m in o]-2(3H)-fu r a n on e (27a C). A colorless oil:
[R]23D +89.7 (c 1.5, CHCl3); IR (CHCl3) 2930, 1771, 1430 cm-1
;
1H NMR (CDCl3) δ 7.67-7.61 (4H, m), 7.45-7.26 (11H, m),
4.68 (2H, s), 4.39 (1H, m), 3.89, 3.76 (each 1H, dd, J ) 12.0,
3.0 Hz), 3.64 (1H, m), 2.78 (1H, m), 1.78-0.84 (13H, m), 1.03
(9H, s); 13C NMR (CDCl3) δ 177.5, 136.9, 135.5, 135.4, 132.8,
132.4, 129.7, 128.4, 128.3, 127.9, 127.6, 80.6, 76.3, 63.43, 63.39,
39.9, 37.5, 34.6, 33.3, 32.3, 26.6, 26.3, 26.0, 25.8, 19.0; HRMS
calcd for C35H45NO4Si (M+) 571.3115, found 571.3102.
[3S -(3r,4â,5r)]-D ih y d r o -5-[[(1,1-d im e t h y le t h y l)d i-
ph en ylsilyloxy]m eth yl]-4-[(ph en ylm eth oxy)am in o]-3-pr o-
p yl-2(3H)-fu r a n on e (27a A). A colorless oil: [R]25 -38.4 (c
D
0.5, CHCl3); IR (CHCl3) 2932, 1770, 1428 cm-1
;
1H NMR
(CDCl3) δ 7.68-7.61 (4H, m), 7.46-7.26 (11H, m), 5.62-5.54
(1H, br m), 4.64 (2H, s), 4.34 (1H, m), 3.88, 3.76 (each 1H, dd,
J ) 11.5, 3.5 Hz), 3.67 (1H, br dd, J ) 8.0, 6.0 Hz), 2.66 (1H,
m), 1.81-1.73 (1H, m), 1.64-1.55 (1H, m), 1.51-1.39 (2H, m),
1.04 (9H, s), 0.92 (3H, t, J ) 7.0 Hz); 13C NMR (CDCl3) δ 177.3,
137.1, 135.7, 135.6, 132.9, 132.6, 129.92, 129.89, 128.6, 128.5,
128.2, 127.8, 80.6, 76.8, 63.5, 62.8, 42.7, 31.4, 26.8, 20.1, 19.2,
13.9; HRMS calcd for C31H39NO4Si (M+) 517.2647, found
517.2661.
[3S-(3r,4â,5r)]-3-[(Cyclopen tyl)m eth yl]dih ydr o-5-[[(1,1-
d im e t h yle t h yl)d ip h e n ylsilyloxy]m e t h yl]-4-[(p h e n yl-
m eth oxy)a m in o]-2(3H)-fu r a n on e (27a D). A colorless oil:
[R]23D +143.5 (c 0.9, CHCl3); IR (CHCl3) 2933, 1770, 1428 cm-1
;
1H NMR (CDCl3) δ 7.67-7.64 (4H, m), 7.45-7.27 (11H, m),
5.62-5.45 (1H, br m), 4.65 (2H, s), 4.35 (1H, m), 3.88, 3.75
(each 1H, dd, J ) 12.0, 3.5 Hz), 3.67 (1H, br dd, J ) 7.5, 6.0
Hz), 2.66 (1H, m), 2.04-1.96 (1H, m), 1.86-1.01 (10H, m), 1.03
(9H, s); 13C NMR (CDCl3) δ 177.5, 137.1, 135.7, 135.6, 132.9,
132.6, 129.88, 129.86, 128.6, 128.5, 128.1, 127.8, 80.9, 76.7,
63.6, 63.4, 42.1, 37.4, 36.1, 32.9, 32.3, 26.8, 25.1, 25.0, 19.2;
HRMS calcd for C34H43NO4Si (M+) 557.2959, found 557.2952.
[3R -(3r,4r,5â)]-Dih y d r o -5-[[(1,1-d im e t h yle t h y l)d i-
ph en ylsilyloxy]m eth yl]-4-[(ph en ylm eth oxy)am in o]-3-pr o-
p yl-2(3H)-fu r a n on e (27bA). A colorless oil: [R]25 +8.92 (c
D
0.8, CHCl3); IR (CHCl3) 2932, 1772, 1472, 1428 cm-1; 1H NMR
(CDCl3) δ 7.66-7.60 (4H, m), 7.46-7.27 (11H, m), 5.58 (1H,
br m), 4.67 (2H, s), 4.47 (1H, m), 3.89 (1H, dd, J ) 11.5, 3.5
Hz), 3.75 (1H, dd, J ) 11.5, 3.0 Hz), 3.78-3.74 (1H, m), 2.92
(1H, m), 1.84-1.75 (1H, m), 1.55-1.42 (3H, m), 1.03 (9H, s),
0.95 (3H, t, J ) 7 Hz); 13C NMR (CDCl3) δ 178.2, 137.0, 135.6,
135.5, 132.7, 132.2, 130.0, 128.52, 128.48, 128.1, 127.9, 81.8,
76.7, 64.7, 60.4, 42.2, 26.8, 26.1, 21.4, 19.2, 14.0; HRMS calcd
for C31H39NO4Si (M+) 517.2647, found 517.2636.
[3S -(3r,4â,5r)]-D ih y d r o -5-[[(1,1-d im e t h y le t h y l)d i-
p h en ylsilyloxy]m et h yl]-4-[[(p h en ylm et h oxy)ca r b on yl]-
a m in o]-3-p r op yl-2(3H)-fu r a n on e (28). A suspension of 10%
Pd(OH)2-C (629 mg) in MeOH (5 mL) was stirred under a
hydrogen atmosphere at room temperature for 30 min. To this
suspension was added a solution of 27a A (500 mg, 0.97 mmol)
in MeOH (2 mL). After being stirred under a hydrogen
atmosphere at room temperature for 10 h, the reaction mixture
was filtered, and the filtrate was concentrated at reduced
pressure to afford the crude amine. To a solution of the
resulting crude amine in acetone (5 mL) was added a solution
of Na2CO3 (200 mg, 1.9 mmol) in H2O (3 mL) under a nitrogen
atmosphere at room temperature. After a solution of CbzCl
(330 mg, 1.9 mmol) in acetone (2 mL) was added dropwise at
room temperature, the reaction mixture was stirred at room
temperature for 14 h. After the reaction mixture was concen-
trated at reduced pressure, the resulting residue was diluted
with water and then extracted with CH2Cl2. The organic phase
was dried over MgSO4 and concentrated at reduced pressure.
Purification of the residue by preparative TLC (hexane/AcOEt
4:1) afforded 28 (377 mg, 72%) as a colorless oil: [R]28D +158.1
[3R -(3r,4â,5â)]-D ih y d r o -5-[[(1,1-d im e t h y le t h y l)d i-
ph en ylsilyloxy]m eth yl]-4-[(ph en ylm eth oxy)am in o]-3-pr o-
p yl-2(3H)-fu r a n on e (27cA). A colorless oil: [R]25 -41.4 (c
D
0.59, CHCl3); IR (CHCl3) 2932, 1772, 1590, 1428 cm-1; 1H NMR
(CDCl3) δ 7.67-7.61 (4H, m), 7.48-7.27 (11H, m), 6.18 (1H,
br m), 4.64 (2H, s), 4.50 (1H, m), 4.09 (1H, dd, J ) 11.5, 2.5
Hz), 3.95 (1H, dd, J ) 11.5, 3.5 Hz), 3.77 (1H, br dd, J ) 17,
9.5 Hz), 2.59 (1H, m), 1.80-1.72 (1H, m), 1.60-1.52 (2H, m),
1.50-142 (1H, m), 1.01 (9H, s), 0.95 (3H, t, J ) 7 Hz); 13C
NMR (CDCl3) δ 177.3, 137.5, 135.6, 135.5, 132.5, 131.8, 130.0,
128.5, 128.4, 128.0, 127.94, 127.92, 127.8, 79.0, 76.5, 63.6, 63.0,
43.5, 32.1, 26.8, 19.9, 19.0, 13.8; HRMS calcd for C31H39NO4Si
(M+) 517.2646, found 517.2640.
(c 1.1, CHCl3); IR (CHCl3) 2962, 1774, 1723, 1456 cm-1 1H
;
NMR (CDCl3) δ 7.72-7.63 (4H, m), 7.45-7.22 (11H, m), 5.32
(1H, br m), 4.62 (2H, s), 4.4-4.28 (1H, br m), 4.18-4.09
(1H, br m), 3.86, 3.77 (each 1H, br m), 2.64-2.53 (1H, br m),
1.8-1.3 (4H, m), 1.04 (9H, br s), 0.90 (3H, br t, J ) 6.9 Hz);
13C NMR (CDCl3) δ 176.4, 155.6, 140.6, 135.4, 132.6, 132.4,
129.6, 128.3, 128.2, 127.8, 127.6, 127.2, 126.7, 82.3, 66.7, 64.6,
61.9, 45.6, 30.6, 26.4, 19.4, 18.9, 13.7; HRMS calcd for
[3S -(3r,4r,5r)]-D ih y d r o -5-[[(1,1-d im e t h y le t h y l)d i-
ph en ylsilyloxy]m eth yl]-4-[(ph en ylm eth oxy)am in o]-3-pr o-
p yl-2(3H)-fu r a n on e (27d A). A colorless oil: [R]25 +26.8 (c
D
1.16, CHCl3). IR (CHCl3) 2961, 1773, 1464, 1428 cm-1; 1H NMR
(CDCl3) δ 7.66-7.60 (4H, m), 7.46-7.16 (11H, m), 5.82 (1H,
br m), 4.52, 4.43 (each 1H, d, J ) 12 Hz), 4.47-4.20 (1H, m),
4.09 (2H, d, J ) 6.5 Hz), 3.71 (1H, dd, J ) 7, 5 Hz), 2.56 (1H,
dt, J ) 7, 2 Hz), 1.90-1.80, 1.66-1.58 (each 1H, m), 1.53-
145 (2H, m), 1.03 (9H, s), 0.96 (3H, t, J ) 7.5 Hz); 13C NMR
(CDCl3) δ 177.4, 136.9, 135.8, 135.62, 135.55, 135.5, 133.0,
132.8, 129.9, 132.8, 129.9, 128.5, 128.4, 128.3, 128.2, 128.0,
127.92, 127.89, 127.85, 127.8, 80.5, 75.7, 62.2, 60.0, 43.4, 26.9,
26.8, 26.1, 21.2, 19.2, 14.1; HRMS calcd for C31H39NO4Si (M+)
517.2646, found 517.2627.
C
32H39N10O5Si (M+) 545.2596, found 545.2588.
(2S,3S,4S)-4-H yd r oxy-5-[(1,1-d im et h ylet h yl)d ip h en -
y lsilylo xy ]-3-[[(p h e n y lm e t h o xy)c a r b on y l]a m in o ]-N -
p h en ylm eth yl-2-p r op ylp en ta n a m id e (29). To a solution of
28 (100 mg, 0.18 mmol) in THF (8 mL) were added benzyl-
amine (0.5 mL, 4.6 mmol) and 2-pyridinol (87 mg, 0.92 mmol)
under a nitrogen atmosphere at room temperature. After being
stirred at the same temperature for 20 h, the reaction mixture
was concentrated at reduced pressure and then diluted with
[3S -(3r,4â,5r)]-D ih y d r o -5-[[(1,1-d im e t h y le t h y l)d i-
p h en ylsilyloxy]m eth yl]-3-[(2-m eth yl)p r op yl]-4-[(p h en yl-
J . Org. Chem, Vol. 68, No. 14, 2003 5625

Miyabe et al.
Et2O. The organic phase was washed with 5% HCl, water, and
brine, dried over MgSO4, and concentrated at reduced pres-
sure. Purification of the residue by preparative TLC (hexane/
AcOEt 2:1) afforded 29 (67.4 mg, 56%) as colorless crystals:
reduced pressure. Purification of the residue by preparative
TLC (hexane/AcOEt 6:1) afforded 30 (26.4 mg, 18%) a color-
less oil: [R]22 +36.28 (c 0.69, CHCl3); IR (CHCl3) 3014, 1742,
D
1
1454 cm-1; H NMR (CDCl3) δ 7.38-7.22 (10H, m), 5.55 (1H,
mp 145-148 °C (AcOEt/hexane); [R]28 -8.65 (c 0.19, CHCl3);
br s), 5.08 (1H, br m), 4.61 (2H, s), 4.58 (2H, d, J ) 11.5 Hz),
4.38 (1H, dd, J ) 12, 5.5 Hz), 4.12 (1H, dd, J ) 12, 6.5 Hz),
3.92-3.88 (1H, m), 3.45 (1H, br m), 2.89 (1H, br dd, J ) 13, 7
Hz), 1.85-1.79 (1H, m), 1.73-1.64 (1H, m), 1.36-1.29 (1H,
m), 0.92, 0.91 (each 3H, d, J ) 4 Hz); 13C NMR (CDCl3) δ 173.2,
137.6, 137.0, 128.7, 128.6, 128.5, 128.1, 128.0, 127.7, 76.6, 72.7,
71.6, 67.5, 61.1, 36.8, 34.4, 25.2, 22.9, 22.0; HRMS calcd for
D
1
IR (CHCl3) 2962, 1721, 1666, 1428 cm-1; H NMR (CDCl3) δ
7.65-7.55 (4H, m), 7.45-7.10 (16H, m), 5.98 (1H, br m), 5.43
(1H, br m), 4.66 (2H, s), 4.36, 4.31 (each 1H, d, J ) 5.0 Hz),
4.23 (1H, m), 3.97 (1H, m), 3.80-3.60 (2H, br m), 2.41 (1H, br
m), 1.75-1.10 (4H, br m), 1.06 (9H, s), 0.86 (3H, t, J ) 7.0
Hz); 13C NMR (CDCl3) δ 173.4, 156.5, 140.8, 137.9, 135.5,
132.7, 132.4, 129.8, 128.5, 128.4, 128.3, 127.9, 127.73, 127.65,
127.4, 127.3, 126.8, 71.8, 66.7, 65.5, 65.1, 55.5, 43.4, 31.3, 26.8,
20.7, 19.0, 13.9; HRMS calcd for C39H48N2O5Si (M+) 652.3330,
found 652.3354.
C
23H29NO4 (M+) 383.2095, found 383.2094.
Ack n ow led gm en t. We thank a Grant-in-Aid for
Scientific Research (B) from J apan Society for the
Promotion of Science and the Science Research Promo-
tion Fund of the J apan Private School Promotion
Foundation for research grants.
[3R -(3r,4â,5r)]-Te t r a h yd r o-3-[(2-m e t h yl)p r op yl]-5-
p h en ylm eth oxy-4-[(p h en ylm eth oxy)a m in o]-2H-p yr a n -2-
on e (30). To a solution of 20 (130 mg, 0.38 mmol) and i-PrI
(0.46 mL, 4.6 mmol) in toluene (20 mL) was added Et3B (1.0
M in hexane, 1.15 mL, 1.15 mmol) at reflux. After the mixture
was stirred at the same temperature for 10 min, i-PrI (0.46
mL, 4.6 mmol) and Et3B (1.0 M in hexane, 1.15 mL, 1.15 mmol)
were added to the reaction mixture. After being stirred at the
same temperature for 10 min, the reaction mixture was diluted
with aqueous NaHCO3 and then extracted with CH2Cl2. The
organic phase was dried over MgSO4 and concentrated at
Su p p or tin g In for m a tion Ava ila ble: Preparation proce-
dure and characterization data for compounds 1-5, 7, 9, 15,
1
16, 19, 20, and 23-26, NOESY data for 27a A-27d A, and H
NMR spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O0341057
5626 J . Org. Chem., Vol. 68, No. 14, 2003