Preparation of a new chiral building block containing a benzylic quaternary stereogenic center and a formal total synthesis of (-)-physostigmine

Article abstract of DOI:10.1016/j.tetasy.2008.09.021

This paper describes the preparation of a new chiral building block containing a benzylic quaternary stereogenic center via the highly enantioselective PLE-mediated hydrolysis of dimethyl 2-(2-chloro-5-methoxyphenyl)-2-methylmalonate, as well as the absolute configuration of the new chiral building block, which has been elucidated through the formal total synthesis of (-)-physostigmine.

Full text of DOI:10.1016/j.tetasy.2008.09.021

Tetrahedron: Asymmetry 19 (2008) 2304–2309
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Tetrahedron: Asymmetry
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Preparation of a new chiral building block containing a benzylic quaternary
stereogenic center and a formal total synthesis of (ꢀ)-physostigmine
*
Kaori Asakawa, Naoyoshi Noguchi, Shingo Takashima, Masahisa Nakada
Department of Chemistry and Biochemistry, Advanced School of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper describes the preparation of a new chiral building block containing a benzylic quaternary ste-
reogenic center via the highly enantioselective PLE-mediated hydrolysis of dimethyl 2-(2-chloro-5-
methoxyphenyl)-2-methylmalonate, as well as the absolute configuration of the new chiral building
block, which has been elucidated through the formal total synthesis of (ꢀ)-physostigmine.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 23 August 2008
Accepted 19 September 2008
Available online 22 October 2008
1. Introduction
using acetylcholinesterase obtained from human tissues,9 that is,
(ꢀ)-physostigmine is some 1000 times more potent than its (+)-
(ꢀ)-Physostigmine (Scheme 1),1 initially isolated from the seeds
of Physostigma venenosum in 1864,2,3 has been clinically used for
the treatment of glaucoma, myasthenia gravis, atropine, and organo-
phosphate intoxication, and for the relief of intoxication induced
by overdoses of antidepressants, antihistamines, antipsychotics,
and benzodiazepines.1,4–6 (ꢀ)-Physostigmine is a potent inhibitor
of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE),
thereby showing wide biological activities. (ꢀ)-Physostigmine
has been evaluated in clinical trials for the symptomatic treatment
of Alzheimer’s disease,1,4–6 and various derivatives of (ꢀ)-physo-
stigmine with improved pharmacological profile against Alzhei-
mer’s disease have been prepared.1,7,8 Interestingly, the inhibition
of AChE has been found to be enantioselective from the studies
enantiomer,9 thus implying the importance of the enantioselective
total synthesis of (ꢀ)-physostigmine and its derivatives.
Recently, we reported the highly enantioselective preparation
of a new chiral building block 2 by the PLE (pig liver esterase)-
mediated hydrolysis of dimethyl 2-(2-chlorophenyl)-2-methyl-
malonate 1.10a The mono-ester 2 (99% ee) prepared in 92% yield
was successfully converted into the synthetic intermediate 3,
which was reported by Kita et al. in the synthesis of (ꢀ)-physostig-
mine7g (Scheme 1).
However, the conversion of alcohol 3 into (ꢀ)-physostigmine
requires the introduction of an oxygen atom at the benzene ring,
and the overall yield of the two requisite steps is moderate.8 These
facts prompted us to investigate the preparation and enantioselec-
tive PLE-mediated hydrolysis of a new substrate incorporating a
hydroxyl or equivalent group on the benzene ring of dialkyl 2-(2-
chlorophenyl)-2-methylmalonate, since such
a suitable chiral
CO2Me
CO2Me
CO2H
PLE
building block corresponding to mono-ester 2 not only would be
useful for the enantioselective total synthesis of (ꢀ)-physostig-
mine, but also could be applied to the syntheses of (ꢀ)-aphanor-
phine, (ꢀ)-eptazocine, and their congeners (Fig. 1). Herein, we
report the preparation of a new chiral building block by the highly
enantioselective PLE-mediated hydrolysis of dimethyl 2-(2-chloro-
5-methoxyphenyl)-2-methylmalonate 9 and the formal total syn-
thesis of (ꢀ)-physostigmine.
CO2Me
potassium phosphate
bufer (pH=8), 30 oC
2 d, 92%, 99% ee
Cl
Cl
1
2
OH
R
N
H
O
N
N
R=MeHNCO2
3
(_)-physostigmine
HO
HO
NMe
NMe
Scheme 1. Enantioselective PLE-mediated hydrolysis of dimethyl 2-(2-chloro-
phenyl)-2-methylmalonate 1 and a formal total synthesis of (ꢀ)-physostigmine.10a
H
H
(_)-aphanorphine
(_)-eptazocine
* Corresponding author. Tel./fax: +813 5286 3240.
E-mail address: mnakada@waseda.jp (M. Nakada).
Figure 1. Respective structures of (ꢀ)-aphanorphine and (ꢀ)-eptazocine.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.09.021

K. Asakawa et al. / Tetrahedron: Asymmetry 19 (2008) 2304–2309
2305
which was treated with sodium nitrite in aqueous hypophospho-
rous acid solution to afford the dimethyl ester 9 (80% yield).
The PLE-mediated hydrolysis of dimethyl ester 9 was performed
under conventional conditions10a (Scheme 4). The PLE-mediated
hydrolysis required two days to afford the corresponding mono-
ester 10 in 86% yield. The mono-ester 10 was converted into the
anilide 11 (95% yield, two steps), which was subsequently sub-
jected to HPLC analysis using a chiral column to determine that
the ee of the anilide 11 was 99%. This result also indicates that
the ee of the mono-ester 10 prepared by the PLE-mediated hydro-
lysis of the dimethyl ester 9 is 99%.
2. Results and discussion
We successfully induced the regioselective reaction of 1,2-di-
chloro-4-nitrobenzene with the anion of dimethyl 2-methylmalo-
nate (Scheme 2) to afford compound 4 in 63% yield.10a Therefore,
compound 7 (Scheme 3) was expected to be prepared by the same
method. For this purpose, compound 5 was first prepared from a
known compound, 4,5-dichloro-2-nitrophenol,11 by methylation
with iodomethane and potassium carbonate (99%). However,
although we attempted to induce the reaction of compound 5 with
the anion of dimethyl 2-methylmalonate, no products were
formed. Comparing with 1,2-dichloro-4-nitrobenzene, compound
5 would be deactivated by the electron-donating methoxy group.
CO2H
PLE
MeO
CO2Me
9
CO2Me
potassium phosphate
bufer (pH=8), 30 oC
2 d, 86%, 99% ee
CH3CH(CO2Me)2
Cl
Cl
Cl
CO2Me
10
NaH, THF, 70 oC
12 h, 63%
O2N
O2N
Cl
1) (COCl)2 (3.0 equiv),
DMF (cat.)
4
CONHPh
CO2Me
Scheme 2. Preparation of dimethyl 2-(2-chloro-4-nitrophenyl)-2-methylmalonate
4.10a
CH2Cl2, rt, 4 h
MeO
2) aniline (3.0 equiv)
CH2Cl2, rt, 12 h
95% (2 steps)
Cl
11
Next, the conversion of compound 5 into the dimethyl ester 7
was carried out in a stepwise manner (Scheme 3). The reaction of
methyl ether 5 with the anion of dimethyl malonate in DMF at
100 °C proceeded successfully in a regioselective manner to afford
the desired compound 6, which was subsequently methylated with
sodium hydride and iodomethane to provide dimethyl ester 7 (79%
yield, two steps). Although the catalytic hydrogenation of the di-
methyl ester 7 in methanol resulted in over-reduction, thus afford-
ing a product with no chlorine atom, the reaction in ethyl acetate
successfully provided arylamine 8 chemoselectively (98% yield),
99% ee
Scheme 4. Enantioselective PLE-mediated hydrolysis of prochiral diester 9 and the
preparation of the anilide 11.
In order to determine the absolute configuration of the mono-
ester 10, we converted it into the known compound 20 (Scheme
6), which is a synthetic intermediate in Brossi’s synthesis of (ꢀ)-
physostigmine.7v Although we did not determine the absolute con-
figuration of the mono-ester 10 at this point, we assumed its abso-
lute structure as shown in Scheme 4 on the basis of analogy with
the PLE-mediated hydrolysis of the similar dimethyl ester 1
(Scheme 1).
Mono-ester 10 was converted into the corresponding acid chlo-
ride (Scheme 5), which was reduced with sodium borohydride to
provide alcohol 12 in 93% yield (two steps).12 Alcohol 12 was sub-
sequently converted into the MOM ether 13 (93% yield), which
resisted conversion to amide 15 under any conditions. This can
be attributed to the steric hindrance due to the quaternary carbon
adjacent to the ester group. Therefore, the MOM ether 13 was sub-
jected to hydrolysis, and the resulting carboxylic acid 14 was con-
verted into the reactive acid chloride, followed by reaction with
ammonia to provide amide 15. Amide 15 was successfully con-
verted into the lactam 16 under optimized conditions in excellent
yield (96%).10a,13
Lactam 16 was treated with sodium hydride and iodomethane
to afford the N-methylated lactam 17 (Scheme 6), followed by
the deprotection of the MOM group to provide the alcohol 18
(73% yield, two steps). The iodination of the alcohol 18 under con-
ventional conditions afforded the iodide 19 (66% yield), which was
subjected to a reaction with sodium cyanide, providing compound
20 (86% yield). The compound 20 synthesized was spectroscopi-
cally identical to the known compound in all respects, indicating
that the absolute structure of the mono-ester 10 was determined
as shown in Scheme 4, and thus marking the completion of the for-
mal total synthesis of (ꢀ)-physostigmine.
K2CO3 (2.0 equiv),
MeI (3.0 equiv)
MeO
O2N
Cl
Cl
HO
Cl
Cl
O2N
acetone, rt, 12 h
99%
5
CO2Me
NaH (2.0 equiv),
CH2(CO2Me)2 (2.5 equiv)
MeO
O2N
CO2Me
DMF, 100 oC, 8 h
Cl
6
NaH (1.4 equiv),
MeI (1.5 equiv)
CO2Me
CO2Me
MeO
O2N
THF, 40 oC, 12 h
79% (2 steps)
Cl
7
Pd/C (cat.),
H2 (1 atm)
CO2Me
CO2Me
MeO
H2N
AcOEt, rt, 4 h
98%
Cl
8
CO2Me
CO2Me
MeO
NaNO2 (2.5 equiv)
3. Conclusion
50% aq. H3PO2, 0 oC, 2 h
80%
Cl
9
In conclusion, we have prepared a new chiral building block
with a benzylic quaternary stereogenic center, a chlorine atom at
C2, and an oxygen atom at C5 of the benzene ring by the highly
Scheme 3. Preparation of dimethyl 2-(2-chloro-5-methoxyphenyl)-2-methylmal-
onate 9.

2306
K. Asakawa et al. / Tetrahedron: Asymmetry 19 (2008) 2304–2309
OMOM
O
1) (COCl)2 (3.0 equiv)
DMF (cat.)
CH2Cl2, rt, 4 h
NaH (1.3 equiv),
MeI (1.5 equiv)
OH
MeO
MeO
16
CO2Me
10
THF, 0 oC, 3 h
N
2) NaBH4 (3.0 equiv)
MeOH, THF
Me
Cl
17
-30 oC, 3 h
12
OH
93% (2 steps)
conc. HCl (cat.)
MeO
MOMCl (3.0 equiv)
DIPEA (6.0 equiv)
NaI (0.1 equiv)
MeOH, 50 oC, 12 h
73% (2 steps)
O
OMOM
CO2Me
N
Me
MeO
18
CH2Cl2, reflux, 4 h
93%
PPh3 (3.0 equiv),
imidazole (3.0 equiv),
I2 (2.5 equiv)
Cl
I
13
14
MeO
OMOM
CO2H
O
1M NaOH
toluene, reflux, 12 h
66%
MeO
N
Me
MeOH, reflux, 12 h
97%
19
Cl
CN
NaCN (4.0 equiv)
1) (COCl)2 (3.0 equiv)
DMF (cat.)
CH2Cl2, rt, 4 h
MeO
OMOM
CONH2
O
DMSO, 80 oC, 12 h
86%
MeO
N
Me
2) NH3, THF
0 oC, 30 min
20
Cl
[α]D25 +58.9 (c 1.42, CHCl3)
[α]D +57.5 (c 0.50, CHCl3)7v
15
K2CO3 (2.0 equiv)
CuI (0.5 equiv)
N,N'-dimethylethylenediamine
Scheme 6. Conversion of the lactam 16 into compound 20, a known intermediate
in Brossi’s synthesis7v of (ꢀ)-physostigmine.
OMOM
O
(1.0 equiv)
MeO
tions were carried out under an argon atmosphere with dry, freshly
distilled solvents under anhydrous conditions, unless otherwise
noted. All reactions were monitored by thin-layer chromatography
carried out on 0.25 mm E. Merck silica gel plates (60F-254) using
UV light as visualizing agent and phosphomolybdic acid and heat
as developing agents. E. Merck silica gel (60, particle size 0.040–
0.063 mm) was used for flash column chromatography. Preparative
thin-layer chromatography (PTLC) separations were carried out on
self-made 0.3 mm E. Merck silica gel plates (60F-254). THF was dis-
tilled from sodium/benzophenone ketyl and methylene chloride
(CH2Cl2), and benzene from calcium hydride. Toluene was distilled
from sodium. DMF and DMSO were distilled from CaH2 under
reduced pressure. All reagents were purchased from Aldrich, TCI,
Merck, or Kanto Chemical Co. Ltd.
DMF, reflux, 12 h
96% (3 steps)
N
H
16
Scheme 5. Conversion of the mono-ester 10 into compound 16.
enantioselective PLE-mediated hydrolysis of dimethyl 2-(2-chloro-
5-methoxyphenyl)-2-methylmalonate. The newly synthesized chi-
ral building block might be useful for the total synthesis of natural
products incorporating a benzylic quaternary stereogenic center in
a fused ring system, such as (ꢀ)-aphanorphine, (ꢀ)-eptazocine, and
their congeners.
4. Experimental
4.2. 1,2-Dichloro-4-methoxy-5-nitrobenzene 5
4.1. General procedures
To a stirred solution of 4,5-dichloro-2-nitrophenol (3.17 g,
15.2 mmol) in acetone (80 mL) were added K2CO3 (4.21 g,
30.4 mmol) and MeI (2.85 mL, 45.6 mmol) successively at room
temperature. After 12 h, saturated aqueous NH4Cl solution
(80 mL) was added to the reaction mixture. The resultant solution
was concentrated under reduced pressure, and the residue was
extracted with Et2O (80 mL ꢁ 2). The combined organic layer was
dried over Na2SO4, filtered, and evaporated. The residue was puri-
fied by flash chromatography (hexane/ethyl acetate = 30:1) to
afford 5 (3.32 g, 99%) as a yellow solid: Rf = 0.44 (hexane/ethyl
acetate = 4:1); mp 66–71 °C; 1H NMR (400 MHz, CDCl3) d 7.99
(1H, s), 7.20 (1H, s), 3.98 (3H, s); 13C NMR (100 MHz, CDCl3) d
151.9, 138.6, 137.9, 127.0, 123.9, 115.6, 57.1; IR (KBr) mmax 1515,
1H and 13C NMR spectra were recorded on a JEOL AL-400 spec-
trometer. 1H and 13C chemical shifts are reported in ppm downfield
from tetramethylsilane (TMS, d scale) with the solvent resonances
as internal standards. The following abbreviations were used to
explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quar-
tet; m, multiplet; br, broad. IR spectra were recorded on a JASCO
FT/IR-8300. Melting points (mp) are uncorrected, recorded on a
Yanaco melting point apparatus equipped with a digital thermom-
eter. Optical rotations were measured using a 2 mL cell with a
1 dm path length on a JASCO DIP-1000. Chiral HPLC analysis was
performed on a JASCO PU-980 and UV-970. Mass spectrometric
analyses and elemental analyses were provided at the Materials
Characterization Central Laboratory, Waseda University. All reac-
1343, 1269, 933 cmꢀ1
.

K. Asakawa et al. / Tetrahedron: Asymmetry 19 (2008) 2304–2309
2307
4.3. Dimethyl 2-(2-chloro-5-methoxy-4-nitrophenyl)-
malonate 6
was dried over Na2SO4, filtered, and evaporated. The residue was
purified by flash chromatography (hexane/ethyl acetate = 8:1) to
afford 9 (2.27 g, 80%) as a white solid: Rf = 0.21 (hexane/ethyl ace-
tate = 4:1); mp 71–72 °C; 1H NMR (400 MHz, CDCl3) d 7.29 (1H, d,
J = 8.8 Hz), 6.77 (1H, dd, J = 8.8, 2.9 Hz), 6.71 (1H, d, J = 2.9 Hz), 3.80
(6H, s), 3.78 (3H, s), 1.91 (3H, s); 13C NMR (100 MHz, CDCl3) d
170.6, 158.0, 138.1, 131.4, 124.6, 115.1, 112.8, 59.6, 55.1, 52.8,
21.6; IR (KBr) mmax 2958, 1751, 1723, 1602, 1576, 1295, 1253,
1113, 1045 cmꢀ1; HRMS (FAB) [M+H]+ Calcd for C13H16ClO5:
287.0686, found: 287.0699.
To a suspension of NaH (1.03 g, 25.8 mmol) in DMF (100 mL)
was added dimethyl malonate (3.69 mL, 32.3 mmol) dropwise at
0 °C, and the reaction mixture was stirred at room temperature
for 30 min. Then, to the reaction mixture was added a solution of
5 (2.84 g, 12.9 mmol) in DMF (10 mL) via a cannula at 0 °C, and
the reaction mixture was warmed to 100 °C. After 8 h, the reaction
mixture was quenched with saturated aqueous NH4Cl solution
(100 mL), and the aqueous layer was extracted with Et2O
(100 mL ꢁ 2). The combined organic layer was dried over Na2SO4,
filtered, and evaporated. The crude di-ester 6 was used for the next
step without further purification: Rf = 0.32 (hexane/ethyl ace-
tate = 2:1); mp 93–96 °C; 1H NMR (400 MHz, CDCl3) d 7.92 (1H,
s), 7.37 (1H, s), 5.28 (1H, s), 3.98 (3H, s), 3.82 (6H, s); 13C NMR
(100 MHz, CDCl3) d 167.1, 151.5, 139.1, 136.6, 126.1, 125.2,
115.8, 56.9, 53.5, 53.4; IR (KBr) mmax 1770, 1739, 1573, 1526,
4.7. (R)-2-Methoxycarbonyl-2-(2-chloro-5-
methoxyphenyl)propanoic acid 10
To a suspension of 9 (2.27 g, 7.92 mmol) in pH 8 phosphate buf-
fer (190 mL) was added PLE (1900 units, esterase solution, from
porcine liver suspension in 3.2 M (NH4)2SO4 solution, pH 8,
purchased from Sigma–Aldrich), and the reaction mixture was stir-
red at 30 °C for 2 days. After the reaction was completed, to the
reaction mixture was added 2 M HCl to make the pH of the solution
to pH 3. The aqueous layer was extracted with EtOAc (50 mL ꢁ 2),
dried over Na2SO4, filtered, and evaporated. The residue was puri-
fied by flash chromatography (hexane/ethyl acetate = 4:1) to afford
10 (1.86 g, 86%) as a colorless oil: Rf = 0.18 (CH2Cl2/MeOH = 10:1);
1H NMR (400 MHz, CDCl3) d 11.35 (1H, br), 7.29 (1H, d, J = 8.8 Hz),
7.02 (1H, d, J = 2.9 Hz), 6.84 (1H, dd, J = 8.8, 2.9 Hz), 3.83 (3H, s),
3.79 (3H, s), 1.98 (3H, s); 13C NMR (100 MHz, CDCl3) d 176.8,
171.8, 158.4, 137.2, 130.5, 124.9, 115.6, 113.5, 56.5, 55.5, 54.2,
23.2; IR (neat) mmax 2956, 1744, 1604, 1578, 1414, 1296, 1250,
1114, 1044 cmꢀ1; HRMS (FAB) [M+H]+ Calcd for C12H14ClO5:
1271, 1221, 1144 cmꢀ1
;
HRMS (FAB) [M+H]+ Calcd for
C12H13ClNO7: 318.0381, found: 318.0374.
4.4. Dimethyl 2-(2-chloro-5-methoxy-4-nitrophenyl)-2-
methylmalonate 7
To a suspension of NaH (723 mg, 18.1 mmol) in THF (100 mL)
was added a solution of 6 in THF (10 mL) dropwise at 0 °C, and
the reaction mixture was stirred for 30 min. Then, to the reaction
mixture was added MeI (1.21 mL, 19.4 mmol) at 0 °C, and stirring
was continued at 40 °C for 12 h. The reaction mixture was
quenched with saturated aqueous NH4Cl solution (100 mL). The
aqueous layer was extracted with Et2O (100 mL ꢁ 2), and the com-
bined organic layer was dried over Na2SO4, filtered, and evapo-
rated. The residue was purified by flash chromatography
(hexane/ethyl acetate = 8:1) to afford 7 (3.38 g, 79% (2 steps)) as
a yellow solid: Rf = 0.28 (hexane/ethyl acetate = 2:1); mp 101–
104 °C; 1H NMR (400 MHz, CDCl3) d 7.93 (1H, s), 7.01 (1H, s),
3.95 (3H, s), 3.82 (6H, s), 1.95 (3H, s); 13C NMR (100 MHz, CDCl3)
d 170.0, 151.4, 143.7, 138.1, 127.8, 124.8, 114.0, 59.7, 56.6, 53.4,
21.9; IR (KBr) mmax 1752, 1728, 1570, 1509, 1266, 1222,
273.0530, found: 273.0540; ½a D21
¼ þ27:1 (c 1.44, CHCl3).
ꢂ
4.8. (R)-Methyl 2-phenylcarbamoyl-2-(2-chloro-5-
methoxyphenyl)propanoate 11
To a stirred solution of 10 (72.2 mg, 0.265 mmol) in CH2Cl2
(2 mL) were added (COCl)2 (0.070 mL, 0.802 mmol) and one drop
of DMF with a Pasteur pipet at 0 °C, and the reaction mixture
was stirred at room temperature for 4 h. All volatile materials were
removed under reduced pressure to afford the crude carboxylic
acid chloride, which was used for the next step without further
purification. To a solution of the carboxylic acid chloride in CH2Cl2
(2 mL) was added aniline (0.075 mL, 0.814 mmol) at 0 °C, and the
reaction mixture was stirred at room temperature for 12 h. After
the reaction was completed, to the reaction mixture was added
H2O (1 mL), and the aqueous layer was extracted with ether
(1 mL ꢁ 3). The combined organic layer was washed with 2 M
HCl, saturated aqueous NaHCO3, and brine. The organic layer was
dried over Na2SO4, filtered, and evaporated. The residue was puri-
fied by PTLC (hexane/ethyl acetate = 2:1) to afford 11 (87.3 mg,
95% (2 steps)) as a pale yellow solid: Rf = 0.43 (hexane/ethyl ace-
tate = 2:1); mp 105–106 °C; 1H NMR (400 MHz, CDCl3) d 10.29
(1H, s), 7.60 (2H, dd, J = 8.3, 1.2 Hz), 7.32 (2H, dd, J = 8.3, 7.3 Hz),
7.26 (1H, d, J = 8.5 Hz), 7.10 (1H, tt, J = 7.3, 1.2 Hz), 7.02 (1H, d,
J = 2.9 Hz), 6.80 (1H, dd, J = 8.5, 2.9 Hz), 3.80 (3H, s), 3.74 (3H, s),
1.99 (3H, s); 13C NMR (100 MHz, CDCl3) d 175.9, 168.1, 158.4,
139.1, 137.9, 130.4, 128.9, 125.2, 124.3, 120.0, 115.8, 113.1, 57.8,
55.4, 53.5, 24.0; IR (KBr) mmax 2951, 1720, 1678, 1599, 1549,
1298, 1270, 1126, 1038 cmꢀ1; HRMS (FAB) [M+H]+ Calcd for
1113 cmꢀ1
;
HRMS (FAB) [M+H]+ Calcd for C13H15ClNO7:
332.0537, found: 332.0551.
4.5. Dimethyl 2-(4-amino-2-chloro-5-methoxyphenyl)-2-
methylmalonate 8
A mixture of 7 (3.35 g, 10.1 mmol), 10% Pd/C, and AcOEt
(100 mL) was stirred under H2 atmosphere (1 atm) at room tem-
perature for 4 h. After the reaction was completed, the mixture
was filtered through a plug of Celite, and the filtrate was concen-
trated under reduced pressure. The residue was purified by flash
chromatography (hexane/ethyl acetate = 8:1) to afford 8 (2.99 g,
98%) as a white solid: Rf = 0.21 (hexane/ethyl acetate = 2:1); mp
106–108 °C; 1H NMR (400 MHz, CDCl3) d 6.70 (1H, s), 6.55 (1H,
s), 3.80 (3H, s), 3.79 (6H, s), 1.89 (3H, s); 13C NMR (100 MHz, CDCl3)
d 171.6, 145.4, 136.6, 126.1, 125.3, 116.5, 110.1, 59.2, 55.5, 53.0,
22.4; IR (KBr) mmax 3441, 3358, 2958, 1730, 1578, 1514, 1259,
1229, 1114, 1035 cmꢀ1; HRMS (FAB) [M]+ Calcd for C13H16ClNO5:
301.0717, found: 301.0720.
4.6. Dimethyl 2-(2-chloro-5-methoxyphenyl)-2-
methylmalonate 9
C18H19NClO4: 348.1003, found: 348.1001; ½a D21
¼ ꢀ16:5 (c 1.49,
ꢂ
CHCl3); 99% ee; ee was determined by HPLC using racemic 11 as
the standard; DICEL CHIRALCEL OD-H 0.46 cm a ꢁ 25 cm; hex-
ane/2-propanol = 9:1; flow rate = 0.5 mL/min; retention time:
16.6 min for (S)-methyl 2-phenylcarbamoyl-2-(2-chloro-5-
methoxyphenyl)propanoate, 19.3 min for (R)-methyl 2-phenylcar-
bamoyl-2-(2-chloro-5-methoxyphenyl)propanoate.
To a stirred solution of 8 (2.99 g, 9.91 mmol) in aqueous 50%
H3PO2 (80 mL) was added NaNO2 (1.71 g, 25.7 mmol) at 0 °C. After
2 h, K2CO3 was added to the reaction mixture. The aqueous layer
was extracted with Et2O (60 mL ꢁ 2). The combined organic layer

2308
K. Asakawa et al. / Tetrahedron: Asymmetry 19 (2008) 2304–2309
4.9. (R)-Methyl 2-(2-chloro-5-methoxyphenyl)-3-hydroxy-2-
methylpropanoate 12
J = 2.9 Hz), 6.76 (1H, dd, J = 8.8, 2.9 Hz), 4.60 (1H, d, J = 6.6 Hz),
4.54 (1H, d, J = 6.6 Hz), 4.12 (1H, d, J = 9.5 Hz), 4.03 (1H, d,
J = 9.5 Hz), 3.80 (3H, s), 3.24 (3H, s), 1.72 (3H, s); 13C NMR
(100 MHz, CDCl3) d 179.0, 158.2, 139.4, 131.2, 125.0, 115.6,
112.8, 96.5, 70.9, 55.5, 55.3, 50.9, 21.6; IR (neat) mmax 3084, 2944,
1710, 1602, 1576, 1472, 1294, 1244, 1152, 1046 cmꢀ1; HRMS
(FAB) [M]+ Calcd for C13H17ClO5: 288.0765, found: 288.0755;
To a stirred solution of 10 (1.20 g, 4.40 mmol) in CH2Cl2 (40 mL)
were added (COCl)2 (1.15 mL, 13.2 mmol) and one drop of DMF
with a Pasteur pipet, and the reaction mixture was stirred at room
temperature for 4 h. All volatile materials were removed under
reduced pressure to afford the crude carboxylic acid chloride,
which was used for the next step without further purification. To
a solution of the carboxylic acid chloride in THF (40 mL) was added
NaBH4 (499 mg, 13.2 mmol) portionwise at ꢀ30 °C, and then
MeOH was added (4.4 mL) at the same temperature. After 3 h,
2 N HCl was slowly added to the reaction mixture to adjust pH of
the solution to pH 2, and the aqueous layer was extracted with
Et2O (30 mL ꢁ 2). The combined organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The residue
was purified by flash chromatography (hexane/ethyl acetate = 4:1)
to afford 12 (1.06 g, 93% (2 steps)) as a colorless oil: Rf = 0.22 (hex-
ane/ethyl acetate = 2:1); 1H NMR (400 MHz, CDCl3) d 7.26 (1H, d,
J = 8.8 Hz), 6.98 (1H, d, J = 2.9 Hz), 6.77 (1H, dd, J = 8.8, 2.9 Hz),
4.32 (1H, d, J = 11.5 Hz), 3.81 (3H, s), 3.72 (3H, s), 3.55 (1H, d,
J = 11.5 Hz), 2.76 (1H, br), 1.71 (3H, s); 13C NMR (100 MHz, CDCl3)
d 177.0, 158.5, 139.1, 131.3, 125.0, 115.2, 113.0, 67.2, 55.5, 52.5,
51.6, 21.2; IR (neat) mmax 3444, 2952, 1732, 1602, 1576, 1414,
1296, 1246, 1114, 1048 cmꢀ1; HRMS (FAB) [M+H]+ Calcd for
½
a 2D4
ꢂ
¼ þ10:9 (c 1.92, CHCl3).
4.12. (R)-2-(2-Chloro-5-methoxyphenyl)-3-methoxymethoxy-
2-methylpropanamide 15
To a stirred solution of 14 (0.745 g, 2.58 mmol) in CH2Cl2
(25 mL) were added (COCl)2 (0.675 mL, 7.74 mmol) and one drop
of DMF with Pasteur pipet, and the reaction mixture was stirred
at room temperature for 4 h. All volatile materials were removed
under reduced pressure affording the crude carboxylic acid chlo-
ride, which was used for the next step without further purification.
Into a stirred solution of the carboxylic acid chloride in THF
(25 mL) was bubbled NH3 gas at 0 °C for 30 min. After the reaction
was completed, the mixture was concentrated under reduced pres-
sure. The crude amide 15 was used for the next step without fur-
ther purification.
4.13. (R)-5-Methoxy-3-methoxymethoxymethyl-3-
methylindolin-2-one 16
C12H16ClO4: 259.0737, found: 259.0734; ½a D22
ꢂ
¼ þ52:3 (c 1.61,
CHCl3).
To a stirred solution of 15 in DMF (60 mL) were added K2CO3
(0.713 g, 5.16 mmol), CuI (0.246 g, 1.29 mmol), and N,N0-dimethyl-
ethylenediamine (0.283 mL, 2.58 mmol) successively at room tem-
perature, and the mixture was refluxed for 12 h. After the reaction
was completed, the mixture was concentrated under reduced pres-
sure. The residue was purified by flash chromatography (hexane/
ethyl acetate = 4:1) to afford 16 (0.622 g, 96% (3 steps)) as a white
solid: Rf = 0.20 (hexane/ethyl acetate = 1:1); mp 77–80 °C; 1H NMR
(400 MHz, CDCl3) d 9.23 (1H, s), 6.87 (1H, d, J = 2.4 Hz), 6.86 (1H, d,
J = 8.3 Hz), 6.74 (1H, dd, J = 8.3, 2.4 Hz), 4.52 (1H, d, J = 6.6 Hz), 4.48
(1H, d, J = 6.6 Hz), 3.83 (1H, d, J = 9.3 Hz), 3.79 (3H, s), 3.78 (1H, d,
J = 9.3 Hz), 3.24 (3H, s), 1.37 (3H, s); 13C NMR (100 MHz, CDCl3) d
181.7, 155.7, 134.5, 134.3, 112.3, 110.4, 110.2, 96.2, 71.6, 55.7,
55.1, 50.0, 19.7; IR (KBr) mmax 3283, 1721, 1682, 1493, 1200,
1116, 1049, 1030 cmꢀ1; HRMS (FAB) [M]+ Calcd for C13H17NO4:
4.10. (R)-Methyl 2-(2-chloro-5-methoxyphenyl)-3-
methoxymethoxy-2-methylpropanoate 13
To a stirred solution of 12 (1.00 g, 3.87 mmol) in CH2Cl2 (40 mL)
were added NaI (57.9 mg, 0.387 mmol), DIPEA (4.04 mL,
23.2 mmol), and MOMCl (0.881 mL, 11.6 mmol) successively at
room temperature, and the mixture was refluxed for 4 h. After
the reaction was completed, saturated aqueous NaHCO3 solution
(40 mL) was slowly added to the reaction mixture, and the aqueous
layer was extracted with CH2Cl2 (20 mL ꢁ 2). The combined organ-
ic layer was dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography (hex-
ane/ethyl acetate = 10:1) to afford 13 (1.09 g, 93%) as a colorless
oil: Rf = 0.44 (hexane/ethyl acetate = 2:1); 1H NMR (400 MHz,
CDCl3) d 7.26 (1H, d, J = 8.5 Hz), 6.94 (1H, d, J = 2.9 Hz), 6.75 (1H,
dd, J = 8.5, 2.9 Hz), 4.58 (1H, d, J = 6.6 Hz), 4.52 (1H, d, J = 6.6 Hz),
4.12 (1H, d, J = 9.5 Hz), 4.01 (1H, d, J = 9.5 Hz), 3.80 (3H, s), 3.70
(3H, s), 3.23 (3H, s), 1.67 (3H, s); 13C NMR (100 MHz, CDCl3) d
175.0, 158.2, 140.2, 131.1, 124.9, 115.6, 112.5, 96.5, 71.2, 55.4,
55.2, 52.4, 50.9, 21.7; IR (neat) mmax 2948, 1736, 1602, 1576,
1470, 1296, 1250, 1110, 1046 cmꢀ1; HRMS (FAB) [M]+ Calcd for
251.1158, found: 251.1161; ½a D21
¼ ꢀ36:6 (c 1.34, CHCl3).
ꢂ
4.14. (R)-5-Methoxy-3-methoxymethoxymethyl-1,3-
dimethylindolin-2-one 17
To a suspension of NaH (0.123 g, 3.07 mmol) in THF (20 mL) was
added a solution of 16 (0.594 g, 2.36 mmol) in THF (2 mL) dropwise
at 0 °C, and the reaction mixture was stirred for 30 min. Then, to the
reaction mixture was added MeI (0.221 mL, 3.55 mmol) at 0 °C, and
stirring was continued at 0 °C for 3 h. After the starting material dis-
appeared, the reaction mixture was quenched with saturated aque-
ous NH4Cl solution (20 mL). The aqueous layer was extracted with
Et2O (10 mL ꢁ 2). The combined organic layer was dried over
Na2SO4, filtered, and evaporated. The crude 17 was sufficiently
pure, and was used for the next step without further purification:
Rf = 0.30 (hexane/ethyl acetate = 1:1); 1H NMR (400 MHz, CDCl3) d
6.91 (1H, d, J = 2.4 Hz), 6.80 (1H, dd, J = 8.3, 2.4 Hz), 6.76 (1H, d,
J = 2.4 Hz), 4.50 (1H, d, J = 6.6 Hz), 4.45 (1H, d, J = 6.6 Hz), 3.80
(3H, s), 3.78 (1H, d, J = 9.3 Hz), 3.77 (1H, d, J = 9.3 Hz), 3.21 (3H, s),
3.17 (3H, s), 1.34 (3H, s); 13C NMR (100 MHz, CDCl3) d 178.5,
155.9, 137.1, 134.1, 111.9, 110.6, 108.1, 96.3, 71.7, 55.8, 55.1,
49.3, 26.3, 19.8; IR (neat) mmax 2944, 1712, 1500, 1148, 1112,
1042 cmꢀ1; HRMS (FAB) [M]+ Calcd for C14H19NO4: 265.1314,
C14H19ClO5: 302.0921, found: 302.0912; ½a D22
¼ þ10:5 (c 0.84,
ꢂ
CHCl3).
4.11. (R)-2-(2-Chloro-5-methoxyphenyl)-3-methoxymethoxy-
2-methylpropanoic acid 14
To a stirred solution of 13 (1.08 g, 3.57 mmol) in MeOH (15 mL)
was added 1 M NaOH (15 mL) at room temperature, and the mix-
ture was refluxed for 12 h. After the reaction was completed, the
mixture was concentrated under reduced pressure. 2 M HCl was
slowly added to the aqueous layer to adjust pH of the solution to
pH 3, and the aqueous layer was extracted with Et2O
(30 mL ꢁ 2). The combined organic layer was dried over Na2SO4
and concentrated under reduced pressure. The residue was puri-
fied by flash chromatography (hexane/ethyl acetate = 4:1) to afford
14 (1.00 g, 97%) as a colorless oil: Rf = 0.50 (CH2Cl2/MeOH = 2:1);
1H NMR (400 MHz, CDCl3) d 7.27 (1H, d, J = 8.8 Hz), 6.94 (1H, d,
found: 265.1311; ½a D26
¼ ꢀ47:3 (c 1.32, CHCl3).
ꢂ

K. Asakawa et al. / Tetrahedron: Asymmetry 19 (2008) 2304–2309
2309
4.15. (R)-3-Hydroxymethyl-5-methoxy-1,3-dimethylindolin-2-
one 18
Acknowledgments
This work was financially supported in part by a Waseda Uni-
versity Grant for Special Research Projects, a Grant-in-Aid for Sci-
entific Research (B), and Young Scientists (No. 19890231), and
the Global COE Program ‘Center for Practical Chemical Wisdom’
by MEXT.
To a stirred solution of crude 17 in MeOH (20 mL) was added a
few drops of concd HCl with Pasteur pipet, and the reaction mix-
ture was stirred at 50 °C for 12 h. After the starting material disap-
peared, the reaction mixture was quenched with saturated
aqueous NaHCO3 solution (20 mL). The aqueous layer was
extracted with AcOEt (20 mL ꢁ 2). The combined organic layer
was dried over Na2SO4, filtered, and evaporated. The residue was
purified by flash chromatography (hexane/ethyl acetate = 4:1) to
afford 18 (0.382 g, 73% (2 steps)) as a white solid: Rf = 0.11 (hex-
ane/ethyl acetate = 1:1); mp 134–140 °C; 1H NMR (400 MHz,
CDCl3) d 6.84 (1H, d, J = 2.4 Hz), 6.82 (1H, dd, J = 8.3, 2.4 Hz), 6.78
(1H, d, J = 8.3 Hz), 3.83 (1H, d, J = 10.7 Hz), 3.80 (3H, s), 3.73 (1H,
d, J = 10.7 Hz), 3.20 (3H, s), 1.40 (3H, s); 13C NMR (100 MHz, CDCl3)
d 179.5, 156.2, 137.0, 133.1, 112.2, 110.5, 108.5, 67.6, 55.8, 50.3,
26.3, 19.0; IR (KBr) mmax 3385, 2927, 1686, 1493, 1294,
1042 cmꢀ1; HRMS (FAB) [M]+ Calcd for C12H15NO3: 221.1052,
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19
To a stirred solution of 18 (0.127 g, 0.574 mmol) in toluene
(5 mL) were added imidazole (0.117 g, 1.72 mmol), PPh3 (0.452 g,
1.72 mmol), and I2 (0.364 g, 1.44 mmol) successively at room tem-
perature, and the mixture was refluxed for 12 h. After the reaction
was completed, a mixture of saturated aqueous NaHCO3 solution
(3 mL) and saturated aqueous Na2S2O3 solution (3 mL) was added
to the reaction mixture, and the aqueous layer was extracted with
Et2O (5 mL ꢁ 2). The combined organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The residue
was purified by flash chromatography (hexane/ethyl acetate = 4:1)
to afford 19 (0.125 g, 66%) as a colorless solid: Rf = 0.52 (hexane/
ethyl acetate = 1:1); mp 114–116 °C; 1H NMR (400 MHz, CDCl3) d
6.90 (1H, d, J = 2.4 Hz), 6.86 (1H, dd, J = 8.5, 2.4 Hz), 6.79 (1H, d,
J = 8.5 Hz), 3.82 (3H, s), 3.51 (1H, d, J = 9.8 Hz), 3.41 (1H, d,
J = 9.8 Hz), 3.23 (3H, s), 1.51 (3H, s); 13C NMR (100 MHz, CDCl3) d
177.5, 156.0, 136.6, 133.9, 112.5, 110.3, 108.5, 55.8, 48.9, 26.4,
23.0, 10.8; IR (KBr) mmax 1705, 1693, 1498, 1224 cmꢀ1; HRMS
(FAB) [M]+ Calcd for C12H14INO2: 331.0069, found: 331.0070;
½
a 2D8
ꢂ
¼ ꢀ17:3 (c 1.35, CHCl3).
4.17. (S)-(5-Methoxy-1,3-dimethyl-2-oxoindolin-3-
yl)acetonitrile 20
To a stirred solution of 19 (75.3 mg, 0.227 mmol) in DMSO
(3 mL) was added a NaCN (44.6 mg, 0.910 mmol), and the reaction
mixture was stirred at 80 °C. After the starting material disap-
peared, the reaction mixture was quenched with saturated aque-
ous NaHCO3 solution (3 mL). The aqueous layer was extracted
with Et2O (5 mL ꢁ 2). The combined organic layer was dried over
Na2SO4, filtered, and evaporated. The residue was purified by flash
chromatography (hexane/ethyl acetate = 2:1) to afford 20
(45.0 mg, 86%) as a colorless oil: Rf = 0.35 (hexane/ethyl ace-
tate = 1:1); 1H NMR (400 MHz, CDCl3) d 7.10 (1H, d, J = 2.4 Hz),
6.87 (1H, dd, J = 8.5, 2.4 Hz), 6.82 (1H, d, J = 8.5 Hz), 3.82 (3H, s),
3.23 (3H, s), 2.85 (1H, d, J = 16.6 Hz), 2.57 (1H, d, J = 16.6 Hz),
1.52 (3H, s); 13C NMR (100 MHz, CDCl3) d 177.1, 156.4, 136.0,
132.2, 116.5, 113.4, 110.4, 109.1, 55.8, 45.2, 26.5, 26.3, 22.1; IR
(neat) mmax 1712, 1602, 1506, 1454, 1292, 1042 cmꢀ1; HRMS
(FAB) [M]+ Calcd for C13H14N2O2: 230.1055, found: 230.1055;
12. Soai, K.; Yokoyama, S.; Mochida, K. Synthesis 1987, 647–648.
13. (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421–
7428; (b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7727–7728.
½
a 2D5
ꢂ
¼ þ58:9 (c 1.42, CHCl3), lit. ½a D
ꢂ
¼ þ57:5 (c 0.50, CHCl3).7v