Diastereoselective solid-phase radical addition to oxime ether anchored to polymer support

Article abstract of DOI:10.1248/cpb.51.540

Stereocontrol in radical reactions of oxime ether anchored to polymer support was studied. Highly diastereoselective solid-phase radical reaction was achieved by using triethylborane and diethylzinc as a radical initiator at low reaction temperature, providing a novel method for the synthesis of the α-amino acid derivatives with excellent diastereoselectivities.

Full text of DOI:10.1248/cpb.51.540

540
Chem. Pharm. Bull. 51(5) 540—544 (2003)
Vol. 51, No. 5
Diastereoselective Solid-Phase Radical Addition to Oxime Ether Anchored
to Polymer Support
Hideto MIYABE,1) Chihiro KONISHI, and Takeaki NAITO*
Kobe Pharmaceutical University; Motoyamakita, Higashinada-ku, Kobe 658–8558, Japan.
Received December 27, 2002; accepted February 8, 2003; published online February 10, 2003
Stereocontrol in radical reactions of oxime ether anchored to polymer support was studied. Highly
diastereoselective solid-phase radical reaction was achieved by using triethylborane and diethylzinc as a radical
initiator at low reaction temperature, providing a novel method for the synthesis of the a-amino acid derivatives
with excellent diastereoselectivities.
Key words solid-phase; radical reaction; oxime ether; diastereoselective
Combinatorial chemistry has became a core technology
for the rapid development of novel lead compounds in the
pharmaceutical industry and for the optimization of thera-
peutic efficacy.2—9) Therefore, the development of solid-
phase radical reactions is a new subject of considerable inter-
est as a carbon–carbon bond-forming method on solid sup-
port.10—19) Some recent reports have shown that radical reac-
tions could be performed on solid supports by using AIBN or
SmI2 as a radical initiator. We have also demonstrated that
triethylborane or diethylzinc have the potential to induce in-
termolecular radical reactions on solid support.20—22)
Stereocontrol in free radical-mediated reactions has been
of great importance in organic synthesis. In recent years, a
high degree of stereocontrol in solution-phase radical reac-
tions has been achieved at low reaction temperature mainly
by using triethylborane as a radical initiator. We have re-
cently demonstrated that the employment of triethylborane or
diethylzinc, particularly at low reaction temperature, facili-
tated the control of stereochemistry in solid-phase radical re-
action.20—23) We report here in detail the triethylborane- or di-
Chart 1
ethylzinc-induced diastereoselective radical reaction of Op-
polzer’s camphorsultam derivatives of oxime ether anchored
to polymer support.23)
with 2-hydroxy-2-methoxyacetic acid methyl ester.27) Treat-
ment of oxime ether 7 with (1R)-(ϩ)-2,10-camphorsultam in
the presence of trimethyl aluminum in boiling dichloroethane
Results and Discussion
Our recent studies showed that triethylborane has the po- gave oxime ether 8 having sultam in quantitative yield as a
tential to induce solid-phase radical reaction of oxime ether single E isomer. Treatment of 8 with pyridinium p-toluene-
(TYPE 1) on solid support even at Ϫ78 °C and acts multiply sulfonate in EtOH at 60 °C gave deprotected alcohol 9 in
as a radical initiator, a Lewis acid, and a radical terminator 89% yield. Treatment of alcohol 9 with glutaric anhydride
(Chart 1).20) Based on these results, we next investigated the gave carboxylic acid 10 in 99% yield. The carboxylic acid 10
control of stereochemistry in solid-phase reactions of oxime could be attached to Wang resin by the treatment with DCC
ether (TYPE 2) by using triethylborane and diethylzinc at in the presence of DMAP in CH2Cl2 at 20 °C for 12 h to give
low reaction temperature.23) The auxiliary of choice was Op- the resin-bound oxime ether 1.28) The loading level of the
polzer’s camphorsultam since it had shown good characteris- resin-bound glyoxylic oxime ether 1 was determined to be
tics in our previous work on solution-phase radical reac- 0.83 mmol/g by quantification of nitrogen by elemental
tions.24,25)
Preparation of chiral oxime ether 1 anchored to a polymer
analysis.
Expecting that the direct comparison of the solid-phase
support is shown in Chart 2. Treatment of p-xylylene glycol radical reactions with the solution-phase radical reactions
2 with TBSCl and imidazole gave the t-butyldimethylsily- would lead to informative and instructive suggestions regard-
lated p-xylylene glycol derivative 3 in 62% yield. Mesylation ing reactivity and stereoselection in solid-phase reaction, we
of 3 in the presence of triethylamine in CH2Cl2 followed by also investigated the solution-phase radical addition to oxime
treatment with N-hydroxyphthalimide in one-pot afforded the ether 10 (Chart 3). We first investigated the simple addition
desired imide 5 in 79% yield.26) One-pot preparation of of an ethyl radical, generated from triethylborane and O2, to
oxime ether 7 was achieved by treatment of imide 5 with hy- the oxime ether 10 in CH2Cl2 at Ϫ78 °C (Table 1, entry 1).
drazine monohydrate in MeOH and subsequent condensation As expected, the reaction proceeded smoothly to give the eth-
* To whom correspondence should be addressed. e-mail: taknaito@kobepharma-u.ac.jp
© 2003 Pharmaceutical Society of Japan

May 2003
541
Chart 2
10 was carried out with isopropyl iodide (30 equiv) and tri-
ethylborane (5 eq) in the absence of tributyltin hydride in
CH2Cl2 at 0 °C for 30 min. After purification, the desired iso-
propylated amino acid 11b was obtained in 86% combined
yield and in 90% de. The addition of a cyclohexyl radical
also proceeded smoothly under the same reaction conditions
to give the cyclohexylated product 11c in 79% yield with
good diastereoselectivity (entry 4).
We next investigated the ethyl radical addition to the Wang
resin-bound oxime ether 1 (Chart 4). To a flask containing
oxime ether 9 and undegassed CH2Cl2 was added a commer-
cially available 1.0 M solution of triethylborane in hexane,
and then the reaction mixture was stirred at Ϫ78 °C for 30
min (Table 2, entry 1). The resin 12a was then filtered and
washed successively with CH2Cl2 and AcOEt, and the subse-
quent cleavage of the resin with trifluoroacetic acid
(TFA)/CH2Cl2 (1 : 5, v/v) gave the crude ethylated a-amino
acid derivative which was purified by the preparative TLC
(hexane/AcOEt 2 : 3, v/v) to afford the amino acid derivative
11a in 74% isolated yield. The absolute configuration of
major product was R and the diastereomeric purity was not
less than 95% de. The solid-phase reaction of 1 in toluene
also proceeded smoothly under similar reaction conditions
(entry 2). Recently, Ryu and Komatsu reported that diethyl-
zinc-air system can serve as an initiator of tin hydride-medi-
ated radical reaction as well as triethylborane.31) In order to
test the viability of diethylzinc, we next investigated the ethyl
radical addition to oxime ether 1 using a commercially avail-
able 1.0 M solution of diethylzinc at Ϫ78 °C (entries 3, 4).
Diethylzinc could also be utilized to achieve a high degree of
stereocontrol in solid-phase radical reaction of 1 to afford the
ethylated product 11a in good isolated yields with excellent
diastereoselectivities. It is noteworthy that diethylzinc works
well as an effective radical initiator for the solid-phase radi-
cal reaction without interference of polystyrene skeleton of
the resin, and good chemical yield was observed even at low
reaction temperature.
Chart 3
Table 1. Solution-Phase Radical Addition to 10
Entry
RI
Solvent T (°C) Product Yield (%)c) Selectivityd)
1a)
2a)
3b)
4b)
None
None
i-PrI
CH2Cl2 Ϫ78
Toluene Ϫ78
11a
11a
11b
11c
91
82
86
79
Ͼ95% de
Ͼ95% de
90% de
CH2Cl2
0
0
c-Hexyl I CH2Cl2
91% de
a) Reactions were carried out with Et3B (5 eq) in CH2Cl2 or toluene at Ϫ78 °C.
b) Reactions were carried out with RI (30 eq) and Et3B (5 eq) in CH2Cl2 at 0 °C.
c) Isolated yields. d) Diastereoselectivities were determined by 1H-NMR analysis.
ylated product 11a in 91% yield. The diastereomeric purity
was found to be not less than 95% de. The absolute configu-
ration of major product was assigned to be R since their H-
1
NMR data showed similarity with that of major product in
solution-phase radical reaction showed in our recent re-
port.24,25) The replacement of CH2Cl2 with toluene as a sol-
vent were also effective for the reaction (entry 2). The devel-
opment of tin-free radical reactions has generated consider-
able interest from both economical and environmental points
of view. We recently reported the solution-phase radical addi-
tion to oxime ethers in the absence of Bu3SnH and by using
Et3B or Et2Zn,29,30) which acts multiply as a Lewis acid, a
radical initiator, and a terminator. Thus, we next investigated
the isopropyl radical addition to oxime ether 10 in the ab-
sence of tributyltin hydride under the iodine atom-transfer re-
action conditions (entry 3). The isopropyl radical addition to
To test the generality of the solid-phase radical reaction of
1, we next investigated the reaction using different radical

542
Vol. 51, No. 5
Chart 4
Table 2. Solid-Phase Ethyl Radical Addition to 1a)
Entry
Initiator
Solvent
Yield (%)b)
Selectivityc)
Chart 6
1
2
3
4
Et3B
Et3B
Et2Zn
Et2Zn
CH2Cl2
Toluene
CH2Cl2
Toluene
74
67
67
59
Ͼ95% de
Ͼ95% de
Ͼ95% de
Ͼ95% de
Table 4. Solid-Phase Alkyl Radical Addition to 1 in RI-Toluenea)
Product Yield (%)b) Selectivityc)
Entry Initiator
RI
a) Reactions were carried out with Et3B or Et2Zn (5.0 eq) in CH2Cl2 at Ϫ78 °C.
b) Isolated yields. c) Diastereoselectivities were determined by 1H-NMR analysis.
1
2
3
4
Et3B
Et3B
Et2Zn
Et2Zn
i-PrI
c-Hexyl I
i-PrI
11b
11c
11b
11c
69
58
53
41
92% de
92% de
90% de
90% de
c-Hexyl I
a) Reactions were carried out with Et3B or Et2Zn (10 eq) in i-PrI/toluene (4 : 1, v/v)
at 0 °C. b) Isolated yields of major diastereomers 11b and 11c. c) Diastereoselec-
tivities were determined by 1H-NMR analysis.
Chart 5
Table 3. Solid-Phase Alkyl Radical Addition to 1
was achieved in the reaction using triethylborane in
RI/toluene (4 : 1, v/v) at 0 °C (Chart 6). The isopropyl radical
addition to 1 in i-PrI/toluene (4 : 1, v/v) proceeded smoothly
to give the isopropylated product 11b in 69% isolated yield
with good diastereoselectivity after purification by the
preparative TLC (Table 4, entry 1). The addition of a bulky
cyclohexyl radical proceeded in slightly low chemical effi-
ciency under the same reaction conditions to give the cyclo-
hexylated product 11c in 58% isolated yield (entry 2). Di-
ethylzinc worked well under similar reaction conditions to
give the alkylated products with good selectivity (entries 3,
4). In the solid-phase reactions, the often tedious workup to
remove excess reagents from reaction mixture was elimi-
nated by washing of the resin with solvents. Additionally, the
carbon–carbon bond-forming solid-phase radical reactions
are run without any special precautions such as dry, de-
gassing and purification of solvents and reagents. Thus, em-
ployment of a neutral species such as an uncharged free
radical would overcome the tedious operations with organo-
metallic reagents on solid-phase reactions.
Entry
RI
Additive T (°C) Yield (%)c
Product
1a)
2a)
3a)
4b)
i-PrI
i-PrI
Bu3SnH
Bu3SnH
Ϫ78
43
41
45
78
11b : 11aϭ1 : 4
11b : 11aϭ1 : 1
11c : 11aϭ1 : 5
11b : 11aϭ1 : 4
0
0
0
c-Hexyl I Bu3SnH
i-PrI none
a) Reactions were carried out with RI (30 eq), Bu3SnH (10 eq), and Et3B (5 eq) in
CH2Cl2. b) Reactions were carried out with RI (30 eq) and Et3B (5 eq) in CH2Cl2.
c) Combined yields.
precursors under the stannyl radical-mediated reaction condi-
tions (Chart 5). However, the reactivity of oxime ether 1 an-
chored to polymer support was quite different from that of
oxime ether 10 in solution-phase reactions. In the case of the
isopropyl radical addition to 1 in the presence of Bu3SnH (10
eq) at Ϫ78 °C, the addition of ethyl radical, generated from
triethylborane, competed with the stannyl radical-mediated
isopropyl radical addition to give a small amount of the iso-
propylated product 11b and a large amount of the undesired
ethylated product 11a in 43% combined yield (Table 3, entry
1). The formation of 11b was found to be dependent on the
reaction temperature, thus changing the temperature from
Ϫ78 °C to 0 °C led to an effective increase in the ratio
11b/11a to 1 : 1 (entry 2). The addition of a bulky cyclohexyl
radical proceeded in low chemical efficiency under the same
reaction conditions to give a large amount of the undesired
ethylated product 11a (entry 3). As comparison with the
stannyl radical-mediated reaction, we also investigated the
isopropyl radical addition to 1 in the absence of Bu3SnH (10
eq) at Ϫ78 °C (entry 4). However, the addition of ethyl radi-
cal, generated from triethylborane, competed with iodine
atom-transfer process to give a large amount of the ethylated
product 11a. Although the precise reason for the preferential
ethylation is unclear, triethylborane presumably concentrated
on solid-support as Lewis acid and gave a large amount of
ethyl radical around the surface of resin.
In conclusion, we have demonstrated the utility of tri-
ethylborane and diethylzinc in stereoselective solid-phase
radical reactions. The radical addition to the chiral oxime
ethers anchored to a polymer support proceeded smoothly
even at low reaction temperature to give a-amino acid deriv-
atives with excellent diastereoselectivities.
Experimental
General Melting points are uncorrected. 1H- and 13C-NMR spectra
were recorded at 200 or 300 MHz and at 50 or 125 MHz, respectively. IR
spectra were recorded using FTIR apparatus. Mass spectra were obtained by
electron ionization (EI), chemical ionization (CI), or secondary ion (SI)-MS
methods. Preparative TLC separations were carried out on precoated silica
gel plates (E. Merck 60F254). Flash column chromatography was performed
using E. Merck Kieselgel 60 (230—400 mesh).
4-(t-Butyldimethylsiloxymethyl)phenylmethanol (3) To a solution of
p-xylyene glycol (1.0 g, 7.2 mmol) and imidazole (1.2 g, 18 mmol) in N,N-
dimethylformamide (DMF) (3 ml) was added dropwise a solution of t-butyl-
Selective formation of the desired alkylated products 11 dimethylsilyl chloride (1.1 g, 7.3 mmol) in DMF (5 ml) under a nitrogen at-

May 2003
543
mosphere at 20 °C. After the reaction mixture was stirred at the same tem-
perature for 3 h, the reaction mixture was diluted with Et2O. The organic
phase was washed with water and brine, dried over MgSO4, and concen-
trated at reduced pressure. Purification of the residue by flash chromatogra-
phy (hexane/AcOEt 5 : 1) afforded 3 (1.1 g, 62%) as a colorless oil and 1,4-
di(t-butyldimethylsiloxymethyl)benzene (0.26 g, 10%) as a white solid. 3: IR
(CHCl3) cmϪ1: 3608, 3447, 2930, 1514, 1471. 1H-NMR (CDCl3) d: 7.29
(4H, m), 4.73 (2H, s), 4.62 (2H, br s), 0.94 (9H, s), 0.09 (6H, s). 13C-NMR
(CDCl3) d: 140.7, 139.4, 126.8, 126.1, 65.0, 64.6, 25.8, 18.2, Ϫ5.4. high
resolution (HR)-MS m/z: 252.1554 (Calcd for C14H24O2Si: 252.1544).
1,4-Di(t-butyldimethylsiloxymethyl)benzene: IR (CHCl3) cmϪ1: 2956,
m), 5.30, 4.69 (each 2H, s), 3.98 (1H, dd, Jϭ7.2, 5.8 Hz), 3.51, 3.46 (each
1H, d, Jϭ13.8 Hz), 2.12—2.05 (2H, m), 1.96—1.87 (3H, m), 1.47—1.26
(2H, m), 1.15, 0.97 (each 3H, s). 13C-NMR (CDCl3) d: 158.9, 141.1, 140.8,
135.0, 128.7, 126.9, 77.9, 65.0, 64.7, 52.9, 48.7, 47.7, 44.5, 38.1, 32.7, 26.2,
20.7, 19.7. HR-MS m/z: 406.1560 (Calcd for C20H26N2O5S: 406.1561).
Anal. Calcd for C20H26N2O5S: C, 59.09; H, 6.45; N, 6.89; S, 7.89. Found: C,
59.04; H, 6.69; N, 6.90; S, 7.96.
Glutaric Acid Monoester of N-[(E)-2-(4-(Hydroxymethyl)benzyloxy-
imino)ethanonyl]bornane-10,2-sultam (10) To a solution of 9 (7.2 g, 18
mmol) in pyridine (15 ml) was added glutaric anhydride (2.0 g, 18 mmol)
under a nitrogen atmosphere at 20 °C and the reaction mixture was then
heated at 80 °C for 1 h. After glutaric anhydride (2.0 g, 18 mmol) was added
to the reaction mixture and then the reaction mixture was heated at 80 °C for
1 h, glutaric anhydride (2.0 g, 18 mmol) was added to the reaction mixture.
After being heated at 80 °C for 2 h, the reaction mixture was diluted with
AcOEt and then was washed with 5% HCl, water, brine, dried over MgSO4,
and concentrated at reduced pressure. Purification of the residue by flash
chromatography (hexane/AcOEt 3 : 2) afforded 10 (9.1 g, 99%) as a colorless
oil: [a]D21 ϩ67.1 (cϭ0.92, CHCl3). IR (CHCl3) cmϪ1: 3684, 2969, 1732,
1
1472. H-NMR (CDCl3) d: 7.28 (4H, m), 4.73 (4H, s), 0.94 (18H, s), 0.09
(12H, s). 13C-NMR (CDCl3) d: 140.0, 125.9, 64.8, 25.8, 18.3, Ϫ5.4. HR-MS
m/z: 366.2419 (Calcd for C20H38O2Si2: 366.2408).
N-[4-(t-Butyldimethylsiloxymethyl)benzyloxy]phthalimide (5) To
a
solution of 3 (7.3 g, 29 mmol) and Et3N (4.4 ml, 32 mmol) in CH2Cl2 (40 ml)
was added dropwise mesyl chloride (2.5 ml, 32 mmol) under a nitrogen at-
mosphere at 0 °C. After the reaction mixture was stirred at the same temper-
ature for 1 h, Et3N (4.4 ml, 32 mmol) and N-hydroxyphthalimide (5.9 g, 58
mmol) were added at 20 °C. After being heated at reflux for 8 h, the solvent
was evaporated at reduced pressure. After the resulting residue was dis-
solved in AcOEt, the organic phase was washed with 1 N NaOH, saturated
aqueous NaHCO3, and water, dried over MgSO4, and concentrated at re-
duced pressure. Purification of the residue by recrystallization (hexane/
AcOEt) afforded 5 (9.0 g, 79%) as colorless crystals: mp 82—84 °C
(hexane/AcOEt); IR (CHCl3) cmϪ1: 2956, 1733, 1469. 1H-NMR (CDCl3) d:
7.68—7.81 (4H, m), 7.50, 7.33 (each 2H, d, Jϭ8.0 Hz), 5.20, 4.74 (each 2H,
s), 0.93 (9H, s), 0.08 (6H, s). 13C-NMR (CDCl3) d: 163.3, 142.6, 134.2,
132.1, 129.7, 128.7, 125.9, 123.3, 79.5, 64.5, 25.7, 18.2, Ϫ5.5. HR-MS m/z:
397.1711 (Calcd for C22H27NO4Si: 397.1708). Anal. Calcd for C22H27NO4Si:
C, 66.47; H, 6.85; N, 3.52. Found: C, 66.30; H, 6.82; N, 3.38.
1
1586, 1519. H-NMR (CDCl3) d: 8.20 (1H, s), 7.40—7.31 (4H, m), 5.31,
5.11 (each 2H, s), 3.98 (1H, dd, Jϭ6.8, 5.6 Hz), 3.52, 3.46 (each 1H, d,
Jϭ14.0 Hz), 2.45—2.36 (4H, m), 2.13—1.90 (7H, m), 1.48—1.36 (2H, m),
1.16, 0.98 (each 3H, s). 13C-NMR (CDCl3) d: 178.1, 172.5, 159.0, 140.9,
135.9, 128.7, 128.3, 77.7, 65.8, 65.1, 52.9, 48.8, 47.7, 44.6, 38.1, 33.0, 32.8,
26.2, 20.7, 19.73, 19.67. HR-MS m/z: 520.1903 (Calcd for C25H32N2O8S:
520.1877).
Attachment of the Sultam Derivative to Wang Resin To a suspension
of Wang resin (0.83 mmol/g, 6.0 g, 5.0 mmol) in CH2Cl2 (100 ml) were
added 10 (5.2 g, 10 mmol), DCC (5.1 g, 25 mmol) and DMAP (0.3 g, 2.5
mmol) under a nitrogen atmosphere at 20 °C. After the reaction mixture was
stirred at the same temperature for 1 h and then staid for 11 h, the resin 1
was filtered, washed well with CH2Cl2, AcOEt followed by MeOH and then
dried in vacuo.
Ethyl Radical Addition to Oxime Ether 10 (Table 1, entries 1, 2). To a
solution of oxime ether 10 (234 mg, 0.45 mmol) in CH2Cl2 or toluene (10
ml) was added Et3B (1.0 M in hexane, 2.25 ml, 2.25 mmol) under a nitrogen
atmosphere at ᎐78 °C. After being stirred at the same temperature for 30
min, the reaction mixture was diluted with aqueous NaHCO3 and then ex-
tracted with CH2Cl2. The organic phase was dried over MgSO4, and concen-
trated at reduced pressure. Purification of the residue by preparative TLC
(hexane/AcOEt 2 : 3, 2-fold development) afforded 11a. [a]D19 ϩ70.0
(cϭ0.97, CHCl3). IR (CHCl3) cmϪ1: 2965, 1731, 1457. 1H-NMR (CDCl3) d:
7.36, 7.30 (each 2H, br d, Jϭ7.5 Hz), 5.10 (2H, s), 4.72, 4.66 (each 1H, d,
Jϭ11.7 Hz), 4.28 (1H, dd, Jϭ7.8, 4.8 Hz), 3.96 (1H, br t, Jϭ6.3 Hz), 3.51,
3.48 (each 1H, d, Jϭ14.1 Hz), 2.48—2.36 (4H, m), 2.13—1.80 (7H, m),
1.75—1.23 (4H, m), 1.12, 0.97 (each 3H, s), 0.95 (3H, t, Jϭ7.5 Hz). 13C-
NMR (CDCl3) d: 178.2, 173.7, 172.5, 137.8, 135.0, 128.6, 127.9, 75.1, 66.0,
64.8, 64.1, 52.8, 48.4, 47.6, 44.4, 38.1, 33.0, 32.7, 32.5, 26.2, 23.7, 20.5,
19.7, 19.6, 10.3. SI-MS m/z: 549.3320 (Calcd for C27H38N2O8S–H (negative,
Mϩ–H): 549.3332).
Methyl (E)-2-[4-(t-Butyldimethylsiloxymethyl)benzyloxyimino]ethanate
(7) To a solution of 5 (12 g, 30 mmol) in MeOH (200 ml) was added a so-
lution of hydrazine monohydrate (1.7 g, 33 mmol) in MeOH (10 ml) under a
nitrogen atmosphere at 20 °C. After the reaction mixture was stirred at the
same temperature for 1 h, a solution of 2-hydroxy-2-methoxyacetic acid
methyl ester (7.2 g, 60 mmol) in MeOH (10 ml) was added to the reaction
mixture at 20 °C. After being stirred at the same temperature for 8 h, the re-
action mixture was filtered through a pad of Celite and the filtrate was con-
centrated at reduced pressure. Purification of the residue by flash chromatog-
raphy (hexane/AcOEt 10 : 1) afforded 7 (9.4 g, 93%) as a colorless oil: IR
1
(CHCl3) cmϪ1: 2956, 1737, 1600, 1467. H-NMR (CDCl3) d: 7.54 (1H, s),
7.33 (4H, m), 5.28, 4.74 (each 2H, s), 3.85 (3H, s), 0.94 (9H, s), 0.10 (6H,
s). 13C-NMR (CDCl3) d: 162.3, 141.8, 140.7, 134.3, 128.4, 126.1, 77.9,
64.5, 52.3, 25.8, 18.2, Ϫ5.4. HR-MS m/z: 337.1698 (Calcd for C17H27NO4Si:
337.1708).
N-[(E)-2-[4-(t-Butyldimethylsiloxymethyl)benzyloxyimino]ethanonyl]-
bornane-10,2-sultam (8) To a solution of (1R)-(ϩ)-2,10-camphorsultam
(2.0 g, 9.3 mmol) and glyoxylic oxime ether (3.8 g, 11 mmol) in
7
CH2ClCH2Cl (40 ml) was added Me3Al (1.0 M in hexane, 11 ml, 11 mmol)
under a nitrogen atmosphere at 20 °C. After being heated at reflux for 24 h,
the reaction mixture was diluted with 1 N HCl and then extracted with
CH2Cl2. The organic phase was washed with water, dried over MgSO4, and
concentrated at reduced pressure. Purification of the residue by flash chro-
matography (hexane/AcOEt 4 : 1) afforded 8 (4.8 g, quantitative) as a color-
less oil: [a]D22 ϩ61.9 (cϭ2.3, CHCl3). IR (CHCl3) cmϪ1: 2959, 1693, 1585,
1463. 1H-NMR (CDCl3) d: 8.19 (1H, s), 7.33 (4H, m), 5.29, 4.74 (each 2H,
s), 3.98 (1H, dd, Jϭ7.1, 5.3 Hz), 3.51, 3.45 (each 1H, d, Jϭ13.7 Hz), 2.20—
2.00 (2H, m), 1.95—1.82 (3H, m), 1.48—1.28 (2H, m), 1.15, 0.97 (each 3H,
s), 0.94 (9H, s), 0.10 (6H, s). 13C-NMR (CDCl3) d: 158.9, 141.6, 140.7,
134.2, 128.5, 126.0, 78.0, 65.0, 64.5, 52.8, 48.7, 47.6, 44.5, 38.1, 32.7, 26.1,
25.7, 20.7, 19.6, 18.2, Ϫ5.5. HR-MS m/z: 520.2421 (Calcd for
C26H40N2O5SSi: 520.2425).
Alkyl Radical Addition to Oxime Ether 10 (Table 1, entries 3, 4). To a
solution of oxime ether 10 (292 mg, 0.562 mmol) and RI (16.8 mmol) in
CH2Cl2 (15 ml) was added Et3B (1.0 M in hexane, 2.81 ml, 2.81 mmol) under
a nitrogen atmosphere at 0 °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 con-
centrated at reduced pressure. Purification of the residue by preparative TLC
(hexane/AcOEt 2 : 3, 2-fold development) afforded 11b and 11c. 11b, [a]D19
ϩ59.1 (cϭ1.0, CHCl3). IR (CHCl3) cmϪ1: 2966, 1732, 1456. 1H-NMR
(CDCl3) d: 7.36, 7.30 (each 2H, br d, Jϭ7.8 Hz), 5.10 (2H, s), 4.69, 4.62
(each 1H, d, Jϭ12.0 Hz), 4.14 (1H, br d, Jϭ5.1 Hz), 3.97 (1H, br t, Jϭ6.3
Hz), 3.51, 3.47 (each 1H, d, Jϭ13.5 Hz), 2.48—2.37 (4H, m), 2.14—1.82
(8H, m), 1.48—1.28 (2H, m), 1.12, 0.97 (each 3H, s), 1.00, 0.86 (each 3H,
d, Jϭ6.9 Hz). 13C-NMR (CDCl3) d: 178.4, 174.0, 172.5, 137.9, 134.9,
128.7, 127.9, 75.0, 67.9, 66.0, 64.9, 52.9, 48.2, 47.5, 44.4, 38.3, 33.0, 32.7,
32.6, 30.0, 26.2, 20.5, 19.7, 19.6, 17.6. HR-MS m/z: 565.2572 (Calcd for
C28H40N2O8SϩH (MϩϩH): 565.2582). 11c, [a]D19 ϩ50.0 (cϭ0.98, CHCl3).
N-[(E)-2-(4-(Hydroxymethyl)benzyloxyimino)ethanonyl]bornane-
10,2-sultam (9) To a solution of the silylated sultam derivative 8 (4.8 g,
9.2 mmol) in EtOH (60 ml) was added pyridinium p-toluenesulfonate (4.6 g,
18 mmol) under a nitrogen atmosphere at 20 °C. After being heated at 60 °C
for 2 h, the solvent was evaporated at reduced pressure. After the resulting
residue was dissolved in CH2Cl2, the organic phase was washed with satu-
rated aqueous NaHCO3, and water, dried over MgSO4, and concentrated at
reduced pressure. Purification of the residue by flash chromatography
(hexane/AcOEt 1 : 1) afforded 9 (3.3 g, 89%) as colorless crystals: mp 139—
1
IR (CHCl3) cmϪ1: 2933, 1731, 1451. H-NMR (CDCl3) d: 7.35, 7.29 (each
2H, br d, Jϭ8.1 Hz), 5.10 (2H, s), 4.68, 4.61 (each 1H, d, Jϭ12.0 Hz), 4.14
(1H, m), 3.97 (1H, br t, Jϭ6.3 Hz), 3.51, 3.46 (each 1H, d, Jϭ14.4 Hz),
2.48—2.37 (4H, m), 2.17—1.79 (7H, m), 1.78—0.95 (13H, m), 1.13, 0.97
(each 3H, s). 13C-NMR (CDCl3) d: 178.2, 173.9, 172.5, 138.0, 134.9, 128.7,
127.9, 74.9, 67.7, 66.0, 64.9, 52.9, 48.2, 47.5, 44.4, 39.7, 38.3, 33.0, 32.7,
32.6, 29.6, 28.6, 26.2, 26.1, 26.0, 25.8, 20.4, 19.8, 19.6. HR-MS m/z:
142 °C (hexane/AcOEt); [a]D21 ϩ80.0 (cϭ1.09, CHCl3). IR (CHCl3) cmϪ1
3606, 2964, 1693, 1586, 1458. 1H-NMR (CDCl3) d: 8.20 (1H, s), 7.37 (4H,
:

544
Vol. 51, No. 5
605.2900 (Calcd for C31H44N2O8SϩH (MϩϩH): 605.2894).
References and Notes
1) Present address: Graduate School of Pharmaceutical Sciences, Kyoto
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Ethyl Radical Addition to Oxime Ether 1 (Table 2). To a suspension
of oxime ether 1 (0.83 mmol/g, 200 mg, 0.166 mmol) in CH2Cl2 (10 ml) was
added Et3B or Et2Zn (1.0 M in hexane, 0.83 ml, 0.83 mmol) under a nitrogen
atmosphere at Ϫ78 °C. After the reaction mixture was stirred at the same
temperature for 30 min, the resin was filtered, washed well with CH2Cl2 and
AcOEt, and then dried in vacuo. To a flask with the resulting resin was
added TFA/CH2Cl2 (1 : 5, v/v, 5.0 ml) under a nitrogen atmosphere at 20 °C.
After being stirred at the same temperature for 30 min, the reaction mixture
was filtered and washed with CH2Cl2 (50 ml), and the filtrate was concen-
trated at reduced pressure. After the resulting residue was dissolved in
CH2Cl2, the organic phase was washed with diluted aqueous NaHCO3 and
water, dried over MgSO4, and concentrated at reduced pressure. Purification
of the residue by preparative TLC (hexane/AcOEt 2 : 3, 2-fold development)
afforded the a-amino acid derivative 11a (68 mg, 74%) in the case of Et3B
or (61 mg, 67%) in the case of Et2Zn.
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Alkyl Radical Addition to Oxime Ether 10 (Table 3). To a suspension
of oxime ether 1 (0.83 mmol/g, 200 mg, 0.166 mmol), Bu3SnH (0.45 ml,
1.66 mmol) and RI (4.98 mmol) in CH2Cl2 (10 ml) was added Et3B (1.0 M in
hexane, 0.83 ml, 0.83 mmol) under a nitrogen atmosphere at Ϫ78 or 0 °C.
After the reaction mixture was stirred at the same temperature for 30 min,
the resin was filtered, washed well with CH2Cl2 and AcOEt, and then dried
in vacuo. To a flask with the resulting resin was added TFA/CH2Cl2 (1 : 5,
v/v, 5.0 ml) under a nitrogen atmosphere at 20 °C. After being stirred at the
same temperature for 30 min, the reaction mixture was filtered and washed
with CH2Cl2 (50 ml), and the filtrate was concentrated at reduced pressure.
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washed with diluted aqueous NaHCO3, and water, dried over MgSO4, and
concentrated at reduced pressure. Purification of the residue by preparative
TLC (hexane/AcOEt 3 : 2, 3-fold development) afforded the a-amino acid
derivatives 11b and 11c.
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ments.
Alkyl Radical Addition to Oxime Ether 1 (Table 4) To a suspension
of oxime ether 1 (0.83 mmol/g, 200 mg, 0.166 mmol) in RI/toluene (4 : 1,
v/v, 5 ml) was added Et3B or Et2Zn (1.0 M in hexane, 0.83 ml, 0.83 mmol)
under a nitrogen atmosphere at 0 °C. After the reaction mixture was stirred
at the same temperature for 15 min, Et3B or Et2Zn (1.0 M in hexane, 0.83 ml,
0.83 mmol) was added to the reaction mixture. After the reaction mixture
was stirred at the same temperature for 15 min, the resin was filtered, washed
well with CH2Cl2 and AcOEt, and then dried in vacuo. To a flask with the
resulting resin was added TFA/CH2Cl2 (1 : 5, v/v, 5.0 ml) under a nitrogen at-
mosphere at 20 °C. After being stirred at the same temperature for 30 min,
the reaction mixture was filtered and washed with CH2Cl2 (50 ml), and the
filtrate was concentrated at reduced pressure. After the resulting residue was
dissolved in CH2Cl2, the organic phase was washed with diluted aqueous
NaHCO3, and water, dried over MgSO4, and concentrated at reduced pres-
sure. Purification of the residue by preparative TLC (hexane/AcOEt 3 : 2, 3-
fold development) afforded the a-amino acid derivatives 11b and 11c.
Acknowledgements We thank a Grant-in-Aid for Scientific Research
(B) from the Japan Society for the Promotion of Science (JSPS) and the Sci-
ence Research Promotion Fund of the Japan Private School Promotion Foun-
dation for research grants.
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6335—6336 (1998).