Carbon-carbon bond construction on solid support: Triethylborane-induced radical reactions of oxime ethers

Article abstract of DOI:10.1016/S0040-4020(03)00154-6

The triethylborane-induced solid-phase radical reaction was studied. The solid-phase radical reaction of oxime ether anchored to Wang resin proceeded smoothly to give the α-amino acid derivatives. The carbon-carbon bond-forming radical reaction of TentaGe

Full text of DOI:10.1016/S0040-4020(03)00154-6

Tetrahedron 59 (2003) 1901–1907
Carbon–carbon bond construction on solid support:
triethylborane-induced radical reactions of oxime ethers
†
Hideto Miyabe, Azusa Nishimura, Yumi Fujishima and Takeaki Naito
*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Received 19 December 2002; accepted 24 January 2003
Abstract—The triethylborane-induced solid-phase radical reaction was studied. The solid-phase radical reaction of oxime ether anchored to
Wang resin proceeded smoothly to give the a-amino acid derivatives. The carbon–carbon bond-forming radical reaction of TentaGel OH
resin-bound glyoxylic oxime ether proceeded even in aqueous media. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
the novel carbon–carbon bond formation based on solid-
phase radical reactions in aqueous media.
Combinatorial chemistry has became a core technology
for the rapid development of novel lead compounds in the
pharmaceutical industry and for the optimization of
therapeutic efficacy.1 In recent years, a variety of reactions
has been performed on solid-phase. However, the carbon–
carbon bond-forming solid-phase reactions are less common
than the carbon–heteroatom bond-forming solid-phase
reactions.1 Therefore, the extension of carbon–carbon
bond-forming radical reactions to solid-phase reactions
would allow further progress in combinatorial organic
synthesis.2–10
2. Results and discussion
2.1. Intermolecular carbon radical addition to glyoxylic
oxime ethers in organic solvent
The preparation of glyoxylic oxime ether 3 anchored to a
polymer support was shown in Scheme 1. The glyoxylic
oxime ether 2 was prepared from glyoxylic acid 1. We
investigated several reaction conditions for attachment of
the glyoxylic oxime ether 2 to Wang resin (Table 1).12
Among them, the glyoxylic oxime ether 2 was attached to
Wang resin by the treatment with DCC in the presence of
DMAP in CH2Cl2 at 208C for 12 h to give the resin-bound
glyoxylic oxime ether 3 in 72% loading level (entry 1). The
loading level of the Wang resin-bound glyoxylic oxime
ether 3 was determined to be 0.83 mmol/g by quantification
of nitrogen by elemental analysis.
Some recent reports have shown that radical cyclizations
could be performed on solid supports by using AIBN or
SmI2 as a radical initiator.2–5 Sibi’s group has reported the
first studies on the solid-phase intermolecular radical
reaction using allyl stannanes and AIBN.9 We have also
demonstrated that triethylborane has the potential to induce
intermolecular radical reactions on solid support, and
employment of triethylborane, particularly at low reaction
temperature, facilitated the control of stereochemistry in
solid-phase radical reaction.11 We report here in detail the
triethylborane-induced solid-phase radical reactions of
oxime ethers.11a Among the different types of radical
acceptors containing a carbon–nitrogen double bond, the
oxime ethers are well known to be excellent radical
acceptors because of the extra stabilization of the inter-
mediate alkoxyaminyl radical provided by the lone pair on
the adjacent oxygen atom. As shown below, we also report
In order to test the viability of triethylborane as a radical
initiator on solid support, we first investigated the addition
Keywords: radical reactions; solid-phase reactions; amino acids; oxime
ethers.
*
Corresponding author. Tel.: þ81-78-441-7554; fax: þ81-78-441-7556;
e-mail: taknaito@kobepharma-u.ac.jp
Present address: Graduate School of Pharmaceutical Sciences, Kyoto
University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
†
Scheme 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00154-6

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H. Miyabe et al. / Tetrahedron 59 (2003) 1901–1907
Table 3. Solid-phase synthesis of a-amino acids 5b–g
Table 1. Attachment of glyoxylic oxime ether 2 to Wang resin
Entry
Reagents
Solvent
Loading level
(%)a
Entry
RI
Solvent
Producta
Yield (%)b
1
2
3
4
5
6
7
i-Pr I
i-Pr I
c-Hexyl I
t-Bu I
s-Bu I
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5b
5b
5c
5d
5e
5f
66
42
61
78
71
24
28
1
2
3
DCC, DMAP
2,6-Dichlorobenzoyl chloride, py DMF
MSNT, Melmb
THF–CH2Cl2
CH2Cl2
72
32
54
Reactions were carried out at 208C for 12 h.
The loading levels were determined by quantification of nitrogen by
elemental analysis.
i-Bu I
Adamantyl I
a
5g
b
MSNT—1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole. Melm—1-
methylimidazole.
All reactions were carried out with RI (7.1 equiv.), Bu3SnH (2.1 equiv.),
and Et3B in hexane (1.1 equiv.).
a
The ethylated product 5a was obtained in 5–30% yields.
Yields of isolated products 5b–g from 3.
b
of an ethyl radical, generated from triethylborane and O2, to
the oxime ether 3 (Scheme 2). The reaction of 3 was run
with a commercially available triethylborane (1.0 M
solution in hexane) in CH2Cl2 at 208C for 1 h (Table 2,
entry 1). The resin 4a was then filtered and washed
successively with CH2Cl2, AcOEt followed by MeOH,
and the subsequent cleavage of the resin with TFA/CHCl3
gave the crude ethylated a-amino acid 5a as a TFA salt.
Purification of the resulting a-amino acid 5a was accom-
plished by a combination of Amberlite IR-120B and the
preparative TLC to afford the amino acid 5a. The
replacement of CH2Cl2 with a nonpolar aromatic solvent
such as toluene was also effective for triethylborane-
induced solid-phase radical reactions to give the ethylated
products 5a in 83% yield from 3 (entry 2). Triethylborane
worked well as an effective radical initiator for the solid-
phase radical reaction even at low reaction temperature
(entries 3 and 4). Ryu and Komatsu reported that
diethylzinc–air system can serve as an initiator as well as
triethylborane.13 As expected, the radical reaction using a
commercially available 1.0 M solution of diethylzinc in
hexane was effective to give good yields of the ethylated
products 5a even at low reaction temperature (entries 5–7).
These results indicate that both triethylborane and diethyl-
zinc work well as an effective radical initiator for the solid-
phase radical reactions without interference of polystyrene
skeleton of the resin.
We next investigated the reaction using different radical
precursors in the presence of tributyltin hydride (Scheme 3).
The isopropyl radical addition to 3 was carried out with
isopropyl iodide, tributyltin hydride and triethylborane in
CH2Cl2 at 208C for 1 h (Table 3, entry 1). The isopropylated
a-amino acid derivative 5b was obtained in 66% yield from
3 after cleavage of the resin followed by purification,
accompanied with a small amount of the ethylated product
5a, which was formed by the competitive reaction with the
ethyl radical generated from triethylborane. Not only
secondary alkyl radicals such as isopropyl, cyclohexyl and
sec-butyl radicals but also a bulky tert-butyl radical worked
well under similar reaction conditions, allowing facile
incorporation of structural variability (entries 1–5). The
unstable primary alkyl radicals such as isobutyl radical and
a more bulky adamantyl radical were less effective for the
Scheme 2.
Table 2. Ethyl radical addition to oxime ether 3
Entry
Initiator
Solvent
T (8C)
Yield (%)a
1b
2b
3b
4b
5c
6c
7c
Et3B
Et3B
Et3B
Et3B
Et2Zn
Et2Zn
Et2Zn
CH2Cl2
Toluene
CH2Cl2
Toluene
CH2Cl2
Toluene
CH2Cl2
20
20
278
278
20
71
83
61
69
72
81
89
20
278
a
Yields of isolated product 5a from 3.
Reactions were carried out with Et3B in hexane (3.6 equiv.).
Reactions were carried out with Et2Zn in hexane (5 equiv.).
b
c
Scheme 3.

H. Miyabe et al. / Tetrahedron 59 (2003) 1901–1907
1903
Scheme 4.
amino acid 5a was obtained in 73% combined yield. We
recently reported that the solution-phase radical reaction of
glyoxylic oxime ethers gave the desired alkylated amino
acids selectively under the similar iodine atom-transfer
reaction conditions. In contrast, in the case of the solid-
phase radical reaction, the addition of ethyl radical,
generated from triethylborane, competed with iodine
atom-transfer process to give a significant amount of the
ethylated product 5a. Although the precise reason for the
preferential ethylation was unclear, triethylborane pre-
sumably concentrated on solid-support as Lewis acid and
gave a large amount of ethyl radical around the surface of
resin (Fig. 1). In the studies on solution-phase radical
reaction, we recently found that the selectivity was largely
dependent on the reaction temperature and solvent, and the
high selectivities were obtained by using toluene as solvent
and at high reaction temperature.14c The replacement of
CH2Cl2 with toluene did not lead to good selectivities
comparable to that obtained in solution-phase radical
reaction (entries 2 and 3). The reaction using isopropyl
iodide (60 equiv.) and triethylborane (5 equiv.) in toluene at
808C gave a 5.7:1 mixture of 5b and 5a in 71% combined
yield (entry 4). In these reactions, triethylborane acts as not
only a radical initiator but also a terminator to trap the
intermediate benzyloxyaminyl radical. Thus, the radical
reaction cycle involving the regeneration of the ethyl radical
proceeds by this quite simple procedure which does not
require the use of moisture-sensitive irritant tin hydride.14b
Additionally, the newly-found solid-phase radical reactions
are run without any special precautions such as drying,
degassing and purification of solvents and reagents and are
thus readily adaptable to parallel synthesis.
Table 4. Isopropyl radical addition to 3 via iodine atom-transfer process
Entry i-Pr I (equiv.) Solvent T (8C) Yield (%)a Ratio (5b/5a)
1
2
3
4
30
30
30
60
CH2Cl2
Toluene
Toluene
Toluene
20
20
80
80
73
69
79
71
2.0:1
2.4:1
3.1:1
5.7:1
All reactions were carried out with Et3B in hexane (5.0 equiv.).
a
Combined yields of products 5b and 5a.
present solid-phase intermolecular radical reaction (entries
6 and 7). The solid-phase radical reaction will be
particularly useful because the often tedious work-up to
remove excess tin residues from the reaction mixture is
eliminated in the solid-phase methodology by washing of
the resin with solvents.
2.2. Tin-free radical addition to glyoxylic oxime ethers
The development of tin-free radical reactions has generated
considerable interest from both economical and environ-
mental points of view. Thus, we next investigated the
isopropyl radical addition to oxime ether 3 in the absence of
tributyltin hydride under the iodine atom-transfer reaction
conditions (Scheme 4).14,15
The isopropyl radical addition to 3 was carried out with
isopropyl iodide (30 equiv.) and triethylborane (5 equiv.) in
the absence of tributyltin hydride in CH2Cl2 at 208C for
30 min (Table 4, entry 1). After cleavage of the resin
followed by purification, a 2.0:1 mixture of the desired
isopropylated amino acid 5b and the undesired ethylated
2.3. Solid-phase radical reaction in aqueous media
The development of new efficient methods for carbon–
carbon bond formation in aqueous media is a challenging
problem. We recently reported that oxime ether, oxime,
hydrazone and nitrone could participate in the aqueous
medium radical reactions involving the construction of the
carbon–carbon bond.16 We next investigated the radical
addition to Wang resin-bound oxime ether 3 in water
(Scheme 5). However, the reaction of oxime ether 3 did not
take place and the glyoxylic oxime ether 2 was recovered in
93% yield after cleavage of the resin, because the Wang
resin-bound substrate 3 did not swell in water.
Thus, we next investigated the reaction of oxime ether 6
anchored to TentaGel OH resin, which has polyethylene-
glycol (PEG) chains and can swell in a wide range of
Figure 1. Radical reaction of oxime ether anchored to resin.

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H. Miyabe et al. / Tetrahedron 59 (2003) 1901–1907
To test the reactivity of TentaGel OH resin-bound
oxime ether 6 in aqueous media, we investigated the
addition of an ethyl radical to 6 in H2O–MeOH (2:1, v/v)
(Scheme 7). The biphasic reaction using a hexane
solution of triethylborane in aqueous media did not take
place to give the recovered glyoxylic oxime ether 2 in
81% after cleavage of the resin (Table 6, entry 1). In the
case of monophasic reactions using a solution of
triethylborane in THF or MeOH, the formation of
ethylated product 5a was observed after being stirred
for only 15 min (entries 2 and 3). The radical reaction of
Scheme 5.
Scheme 6.
Table 5. Attachment of glyoxylic oxime ether 2 to TentaGel OH resin
6 also proceeded in CH2Cl2 by using a solution of
triethylborane in hexane (entry 4).
Entry
Reagents
Solvent
Loading level
(%)a
We finally investigated the alkyl radical addition to
oxime ether 6 in H2O–MeOH (2:1, v/v) under the iodine
atom-transfer reaction conditions (Scheme 8). The
isopropyl radical addition to 6 was carried out with
isopropyl iodide (60 equiv.) and triethylborane in MeOH
(10 equiv.) at 208C (Table 7, entry 1). However, the
reaction proceeded but less effectively to give a 2.9:1
mixture of the desired isopropylated amino acid 5b and
the undesired ethylated amino acid 5a in 23% combined
yield, after cleavage of the resin followed by purification.
The formation of isopropylated product 5b was shown to
be dependent on the reaction temperature; thus, changing
the temperature from 20 to 708C led to a increase in the
chemical yield and the ratio of the isopropylated product
5b and the ethylated product 5a (entry 2). Although
the ratios for the sec-butylated product 5e and cyclo-
pentylated product 5h were moderate, the radical
1
2
3
DCC, DMAP
2,6-Dichlorobenzoyl chloride, Py DMF
MSNT, Melmb
THF–CH2Cl2
CH2Cl2
45
90
59
Reactions were carried out at 208C for 12 h.
The loading levels were determined by quantification of nitrogen by
elemental analysis.
a
b
MSNT—1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole. Melm—1-
methylimidazole.
solvents from toluene to water (Scheme 6). Several reaction
conditions for attachment of the glyoxylic oxime ether 2 to
TentaGel OH resin were investigated (Table 5).12 TentaGel
OH resin-bound glyoxylic oxime ether 6 was prepared in
90% loading level by the treatment with 2,6-dichloro-
benzoyl chloride in the presence of pyridine in DMF at 208C
for 12 h (entry 2).
Scheme 7.
reactions of 6 were found to proceed even in aqueous
media (entries 3–6).
Table 6. Ethyl radical addition to 6 in aqueous media
Entry
Solvent
Et3B
Yield (%)a
1b
2b
3b
4c
H2O–MeOH (2:1, v/v)
H2O–MeOH (2:1, v/v)
H2O–MeOH (2:1, v/v)
CH2Cl2
in hexane
in THF
in MeOH
in hexane
No reaction (81)
3. Conclusion
66
79
57
We have demonstrated that triethylborane can be applied to
the solid-phase radical reaction. The reaction of TentaGel
OH resin-bound glyoxylic oxime ether is the first example
of solid-phase radical reaction in aqueous media.
Furthermore, the radical addition to glyoxylic oxime ethers
a
Isolated yields; yields in parentheses are for the recovered glyoxylic
oxime ether 2.
b
c
Reactions were carried out with Et3B (10 equiv.) at 208C for 15 min.
Reaction was carried out with Et3B (3.6 equiv.) at 208C for 1 h.

H. Miyabe et al. / Tetrahedron 59 (2003) 1901–1907
1905
Scheme 8.
of Wang resin12 (0.83 mmol/g, 25 g) in CH2Cl2 (200 mL)
were added oxime ether 2 (14.9 g, 83 mmol), DCC (21.4 g,
104 mmol) and DMAP (1.27 g, 10 mmol) under a nitrogen
atmosphere at 208C. After the reaction mixture was stirred
at the same temperature for 1 h and then stood for 11 h,
the resin was filtered, washed well with CH2Cl2, AcOEt
followed by MeOH and then dried at reduced pressure.
Table 7. Alkyl radical addition to 6 in aqueous media
Entry
RI (equiv.)
T (8C) Product Yield (%)a Ratio (5b,e,h/5a)
1
2
3
4
5
6
i-Pr I (60)
i-Pr I (60)
s-Bu I (60)
s-Bu I (120)
c-Pentyl (60)
c-Pentyl (120)
20
70
70
70
70
70
5b
5b
5e
5e
5h
5h
23 (54)
69
52
73
43
2.9:1
5.7:1
3.2:1
3.3:1
3.2:1
3.4:1
68
4.1.3. General procedure for ethyl radical addition to
oxime ether 3. To a suspension of oxime ether 3
(0.83 mmol/g, 274 mg, 0.28 mmol) in CH2Cl2 or toluene
(3.0 mL) was added Et3B (1.0 M in hexane, 1.0 mL,
1.0 mmol) or Et2Zn (1.0 M in hexane, 1.4 mL, 1.4 mmol)
under a nitrogen atmosphere at 20 or 2788C. After the
reaction mixture was stirred at the same temperature for
15 min–1 h, the resin was filtered, washed well with
CH2Cl2, AcOEt followed by MeOH and then dried at
reduced pressure. To a flask with the resulting resin 4a was
added TFA/CHCl3 (1:3–1:5, v/v, 4.0 mL) under a nitrogen
atmosphere at 208C. After the reaction mixture was stirred at
the same temperature for 30 min, the reaction mixture was
filtered and washed with MeOH/CHCl3 (1:11, v/v, 60 mL),
and the filtrate was concentrated at reduced pressure.
Purification of the residue by Amberlite IR-120B (eluting
with MeOH) followed by preparative TLC (MeOH/CHCl3
1:10, v/v) afforded the a-amino acid derivative 5a as a white
powder. IR (Nujol) 1603, 1573 cm21. 1H NMR (CD3OD) d
7.34–7.26 (5H, m), 4.68 (2H, s), 3.50 (1H, br t, J¼10.2 Hz),
1.58 (2H, m), 0.95 (3H, t, J¼11.1 Hz). 13C NMR (CD3OD)
d 177.2, 138.9, 129.4, 129.1, 128.7, 76.9, 66.1, 23.6, 10.7.
HRMS: calcd for C11H15NO3 (Mþ): 209.1051, Found:
209.1064.
All reactions were carried out with RI and Et3B (10 equiv.) for 1 h.
a
Combined yields of products 5b,e,h and 5a.; yields in parentheses are for
the recovered glyoxylic oxime ether 2.
anchored to a polymer support provides direct access to
unnatural a-amino acids as useful building blocks exem-
plified by the recent progress in the fields of combinatorial
chemistry and drug discovery.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded at 200 or 300 MHz
and at 50 or 125 MHz, respectively. Mass spectra were
obtained by EI or CI methods. Preparative TLC separations
were carried out on precoated silica gel plates (E. Merck
60F254).
4.1.1. 2-(Benzyloxyimino)ethanoic acid (2).17 To a
solution of glyoxylic acid monohydrate (5.0 g, 54 mmol)
in MeOH (250 mL) were added O-benzyloxyamine hydro-
chloride (13.0 g, 82 mmol) and AcONa (8.9 g, 109 mmol)
under a nitrogen atmosphere at 208C. After the reaction
mixture was stirred at the same temperature for 12 h, the
solvent was evaporated at reduced pressure, and the
resulting residue was added to water and CH2Cl2. The
layers were separated, and the aqueous phase was extracted
with CH2Cl2. The combined organic phase was dried over
MgSO4 and concentrated at reduced pressure. Purification
of the residue by recrystallization (AcOEt/hexane) afforded
oxime ether (6.88 g, 71%) as colorless crystals (2:1 mixture
4.1.4. General procedure for the alkyl radical addition
to oxime ether 3
To a suspension of oxime ether 3 (0.83 mmol/g, 274 mg,
0.28 mmol) in CH2Cl2 or toluene (3.0 mL) were added RI
(2.0 mmol), Bu3SnH (0.16 mL, 0.6 mmol) and Et3B (1.0 M
in hexane, 0.30 mL, 0.30 mmol) under a nitrogen atmos-
phere at 208C. After the reaction mixture was stirred at the
same temperature for 1 h, the resin was filtered, washed well
with CH2Cl2, AcOEt followed by MeOH and then dried at
reduced pressure. To a flask with the resulting resin 4b–g
was added TFA/CHCl3 (1:3, v/v, 4.0 mL) under a nitrogen
atmosphere at 208C. After the reaction mixture was stirred
at the same temperature for 30 min, the reaction mixture
was filtered and washed with MeOH/CHCl3 (1:11, v/v,
60 mL), and the filtrate was concentrated at reduced
pressure. Purification of the residue by Amberlite IR-120B
(eluting with MeOH) followed by preparative TLC
of E/Z-oxime). IR (CHCl3) 1716, 1597, 1497 cm21 1H
.
NMR (CDCl3) d. 7.50 (2/3H, s), 7.29 (5H, s), 7.27 (1/3H, s),
5.18 (4/3, s), 4.89 (2/3, s). 13C NMR (CDCl3) d 165.6, 142.5,
136.0, 135.5, 128.6, 128.43, 128.41, 128.29, 128.25, 77.6,
77.5. HRMS: calcd for C9H9NO3 (Mþ): 179.0582, Found:
179.0569.
4.1.2. Wang resin-bound oxime ether (3). To a suspension

1906
H. Miyabe et al. / Tetrahedron 59 (2003) 1901–1907
(MeOH/CHCl3 1:10, v/v) afforded the a-amino acid
derivatives 5b–g.
the same temperature for 30 min, the reaction mixture was
filtered and washed with MeOH/CHCl3 (1:11, v/v, 60 mL),
and the filtrate was concentrated at reduced pressure.
Purification of the residue by Amberlite IR-120B (eluting
with MeOH) followed by preparative TLC (MeOH/CHCl3
1:10, v/v) afforded the a-amino acid derivatives 5b and 5a.
4.1.5. 2-(Benzyloxyamino)-3-methylbutanoic acid (5b). A
white powder. IR (Nujol) 1603, 1574 cm21 1H NMR
.
(CD3OD) d 7.38–7.26 (5H, m), 4.67 (2H, s), 3.30 (1H, br
m), 1.90–1.70 (1H, m), 0.94 (6H, d, J¼10.1 Hz). 13C NMR
(CD3OD) d 177.2, 139.0, 129.5, 129.1, 128.6, 76.7, 70.6,
29.9, 19.7. HRMS: calcd for C12H17NO3 (Mþ): 223.1207,
Found: 223.1221.
4.1.12. TentaGel OH resin-bound oxime ether (6). To a
suspension of TentaGel OH resin12 (0.26 mmol/g, 0.50 g)
in DMF (2.5 mL) were added oxime ether 2 (107 mg,
0.60 mmol), 2,6-dichlorobenzoyl chloride (0.086 mL,
0.60 mmol) and pyridine (0.08 mL, 0.99 mmol) under a
nitrogen atmosphere at 208C. After the reaction mixture was
stirred at the same temperature for 1 h and then stood for
11 h, the resin was filtered, washed well with CH2Cl2,
AcOEt followed by MeOH and then dried at reduced
pressure.
4.1.6. 2-(Benzyloxyamino)-2-cyclohexylethanoic acid
1
(5c). A white powder. IR (Nujol) 1603, 1574 cm21. H
NMR (CD3OD) d 7.34–7.26 (5H, m), 4.65 (2H, s), 3.31
(1H, m), 1.35–0.78 (11H, m). 13C NMR (CD3OD) d 177.2,
139.0, 129.5, 129.1, 128.6, 76.7, 70.1, 39.5, 30.72, 30.66,
27.1, 27.0. HRMS: calcd for C15H21NO3 (Mþ): 263.1520,
Found: 263.1505.
4.1.13. General procedure for ethyl radical addition to
oxime ether 6 in H2O–MeOH. To a suspension of oxime
ether 6 (0.23 mmol/g, 300 mg, 0.07 mmol) in H2O–MeOH
(2:1, v/v, 3.0 mL) was added Et3B (1.0 M in THF or 1.0 M
in MeOH, 0.70 mL, 0.07 mmol) under a nitrogen atmos-
phere at 208C. After the reaction mixture was stirred at the
same temperature for 15 min, the resin was filtered, washed
well with CH2Cl2, AcOEt followed by MeOH and then
dried at reduced pressure. To a flask with the resulting resin
7a was added TFA/CHCl3 (1:5, v/v, 4.0 mL) under a
nitrogen atmosphere at 208C. After the reaction mixture was
stirred at the same temperature for 30 min, the reaction
mixture was filtered and washed with MeOH/CHCl3 (1:11,
v/v, 60 mL), and the filtrate was concentrated at reduced
pressure. Purification of the residue by Amberlite IR-120B
(eluting with MeOH) followed by preparative TLC
(MeOH/CHCl3 1:10, v/v) afforded the a-amino acid
derivative 5a.
4.1.7. 2-(Benzyloxyamino)-3,3-dimethylbutanoic acid
1
(5d). A white powder. IR (Nujol) 1604, 1574 cm21. H
NMR (CD3OD) d 7.36–7.28 (5H, m), 4.65 (2H, s), 3.31
(1H, br m), 0.94 (9H, s). 13C NMR (CD3OD) d 177.2, 139.1,
129.7, 129.1, 128.6, 76.5, 73.2, 33.3, 27.5. HRMS: calcd for
C13H19NO3 (Mþ): 237.1364, Found: 237.1344.
4.1.8. 2-(Benzyloxyamino)-3-methylpentanoic acid (5e).
1:1 Diastereomeric mixture. A white powder. IR (Nujol)
1603, 1573 cm21. 1H NMR (CD3OD) d 7.38–7.26 (5H, m),
4.65 (2H, s), 3.42 (1H, br m), 1.68–1.38 (2H, m), 1.26–1.11
(1H, m), 0.87 (6H, m). 13C NMR (CD3OD) d 177.4, 177.1,
139.0, 129.5, 129.1, 128.6, 76.1, 69.1, 68.6, 36.8, 36.2, 27.3,
26.9, 16.0, 15.7, 11.8, 11.5. HRMS: calcd for C13H19NO3
(Mþ): 237.1364, Found: 237.1354.
4.1.9. 2-(Benzyloxyamino)-4-methylpentanoic acid (5f).
1
A white powder. IR (Nujol) 1602, 1573 cm21. H NMR
(CD3OD) d 7.36–7.29 (5H, m), 4.68 (2H, s), 3.59 (1H, t, J¼
10.7 Hz), 1.69 (1H, m), 1.34 (2H, m), 0.90 (3H, d, J¼
11.0 Hz), 0.81 (3H, d, J¼11.0 Hz). 13C NMR (CD3OD) d
177.8, 138.9, 129.4, 129.1, 128.6, 76.8, 63.2, 39.5, 26.0,
23.0, 22.7. HRMS: calcd for C13H19NO3 (Mþ): 237.1364,
Found: 237.1348.
4.1.14. General procedure for alkyl radical addition to
oxime ether 6 in H2O–MeOH. To a suspension of oxime
ether 6 (0.23 mmol/g, 300 mg, 0.07 mmol) in H2O–MeOH
(2:1, v/v, 6.0 mL) were added RI (60 or 120 mmol) and Et3B
(1.0 M in MeOH, 0.70 mL, 0.07 mmol) under a nitrogen
atmosphere at 20 or 808C. After the reaction mixture was
stirred at the same temperature for 1 h, the resin was filtered,
washed well with CH2Cl2, AcOEt followed by MeOH and
then dried at reduced pressure. To a flask with the resulting
resin 7 was added TFA/CHCl3 (1:5, v/v, 4.0 mL) under a
nitrogen atmosphere at 208C. After the reaction mixture was
stirred at the same temperature for 30 min, the reaction
mixture was filtered and washed with MeOH/CHCl3 (1:11,
v/v, 60 mL), and the filtrate was concentrated at reduced
pressure. Purification of the residue by Amberlite IR-120B
(eluting with MeOH) followed by preparative TLC
(MeOH/CHCl3 1:10, v/v) afforded the a-amino acid
derivatives 5b, 5e, 5h, and 5a.
4.1.10. 2-(Benzyloxyamino)-2-adamantylethanoic acid
1
(4g). A white powder. IR (Nujol) 1605, 1575 cm21. H
NMR (CD3OD) d 7.38–7.24 (5H, m), 4.62 (2H, s), 3.13
(1H, br s), 2.00–1.26 (15H, m). 13C NMR (CD3OD) d
176.6, 139.1, 129.6, 129.1, 128.6, 76.5, 74.2, 40.3, 37.8,
35.6, 29.6. HRMS: calcd for C19H25NO3 (Mþ): 315.1833,
Found: 315.1825.
4.1.11. General procedure for isopropyl radical addition
to oxime ether 3. To a suspension of oxime ether 3
(0.83 mmol/g, 274 mg, 0.28 mmol) in CH2Cl2 or toluene
(3.0 mL) were added i-PrI (30 or 60 equiv.) and Et3B (1.0 M
in hexane, 1.4 mL, 1.4 mmol) under a nitrogen atmosphere
at 20 or 808C. After the reaction mixture was stirred at the
same temperature for 30 min, the resin was filtered, washed
well with CH2Cl2, AcOEt followed by MeOH and then
dried at reduced pressure. To a flask with the resulting resin
4 was added TFA/CHCl3 (1:5, v/v, 4.0 mL) under a nitrogen
atmosphere at 208C. After the reaction mixture was stirred at
Acknowledgements
We wish to thank Grant-in Aid for Scientific Research (B)
from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan and the Science Research

H. Miyabe et al. / Tetrahedron 59 (2003) 1901–1907
1907
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