Application of asymmetric alkylation of malonic diester with phase-transfer catalysis: Synthesis of LFA-1 antagonist BIRT-377

Article abstract of DOI:10.1016/j.tetasy.2015.01.006

An efficient asymmetric synthesis of LFA-1 antagonist BIRT-377 using enantioselective phase-transfer catalytic alkylation has been developed. The alkylation of α-monosubstituted tert-butyl methyl malonate was catalyzed by a quaternary ammonium salt derived from a cinchona alkaloid to obtain the product with a quaternary stereogenic carbon in high yield and with high enantioselectivity. The chiral α,α-disubstituted product thus obtained was transformed into BIRT-377 through alternating chemoselective deprotection of the two ester groups followed by Curtius rearrangement.

Full text of DOI:10.1016/j.tetasy.2015.01.006

Tetrahedron: Asymmetry 26 (2015) 214–218
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Application of asymmetric alkylation of malonic diester with
phase-transfer catalysis: synthesis of LFA-1 antagonist BIRT-377
⇑
Takuya Kanemitsu, Saeka Furukoshi, Michiko Miyazaki, Kazuhiro Nagata, Takashi Itoh
School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient asymmetric synthesis of LFA-1 antagonist BIRT-377 using enantioselective phase-transfer
catalytic alkylation has been developed. The alkylation of -monosubstituted tert-butyl methyl malonate
was catalyzed by a quaternary ammonium salt derived from a cinchona alkaloid to obtain the product
with a quaternary stereogenic carbon in high yield and with high enantioselectivity. The chiral -disub-
Received 8 December 2014
Accepted 31 December 2014
Available online 28 January 2015
a
a,a
stituted product thus obtained was transformed into BIRT-377 through alternating chemoselective
deprotection of the two ester groups followed by Curtius rearrangement.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
BIRT-377 is an inhibitor of the interaction between LFA-1 and
intercellular adhesion molecule-1 (ICAM-1) under cell-cell interac-
Phase-transfer catalysis is regarded as one of the most efficient
synthesis methods in organic chemistry, since it is both inexpensive
and relatively environmentally benign.1 The development of asym-
metric phase-transfer catalysis has attracted much attention for the
construction of quaternary stereogenic carbon centers because the
resulting products are versatile precursors for the synthesis of vari-
tions of the immune system. ICAM-1 and LFA-1 are involved in the
binding of lymphocytes to the antigen-presenting cells or to the
vascular endothelial cells.6 In this context, the development of
effective synthetic methods for BIRT-377 has attracted much
attention for the treatment of inflammatory and immune disor-
ders.7 Among them, asymmetric syntheses using organocatalysts
have afforded promising results. Barbas et al. developed the first
catalytic asymmetric synthesis of BIRT-377.7d The quaternary ste-
ous compounds.2 The phase-transfer catalytic
a-alkylation of car-
bonyl compounds has been extensively studied, and several
powerful methods have been developed.3 Recently, we have
reported one such development for the asymmetric synthesis of
malonic esters using cinchona alkaloid derivatives as inexpensive
reocenter was constructed through
L-proline–tetrazole-catalyzed
direct enantioselective -amination. Maruoka et al. synthesized
a
BIRT-377 through enantioselective phase-transfer alkylation of an
alanine-derived Schiff base.7e,g Over the course of our studies, we
envisioned that an approach to BIRT-377 could be accomplished
phase-transfer catalysts.4 This method provides access to
a,
a
-disubstituted malonic diesters containing an all-carbon substi-
tuted quaternary stereocenter. The chiral -disubstituted malonic
diesters thus obtained have been used to synthesize -disubsti-
tuted amino acids. It should be noted that in this transformation,
both (S)- and (R)- -disubstituted amino acids have been prepared
from the same stereoisomer using selective de-esterification.
Therefore, the chiral -disubstituted malonates are important
a
,a
by the construction of an
Herein, we report the efficient asymmetric synthesis of BIRT-377
via phase-transfer catalytic alkylation of -monosubstituted tert-
a,a-disubstituted malonate (Scheme 1).
a,a
a
a,a
butyl methyl malonate in the presence of N-(9-anthracenylmeth-
yl)cinchoninium chloride as an inexpensive phase-transfer
catalyst.
a,a
intermediates in the synthesis of biologically active compounds.
Nevertheless, there are few other reports of enantioselective cata-
2. Results and discussion
lytic additions at the
a-position of malonates, and few synthetic
methods have been disclosed.5 Over the course of our research on
phase-transfer catalysis, we predicted that it would be applicable
to the synthesis of BIRT-377 1, a lymphocyte function associated
antigen-1 (LFA-1) antagonist.
We predicted that both (R)- and (S)-a,a-disubstituted malonic
diesters could be converted into the target molecule through the
chemoselective de-esterification of the tert-butyl or methyl ester
(Scheme 1). tert-Butyl and methyl esters are simple protecting
groups that can be readily cleaved chemoselectively under acidic
and alkaline conditions, respectively. Thus, we initially prepared
⇑
Corresponding author. Tel.: +81 3 3784 8184; fax: +81 3 3784 5982.
E-mail address: itoh-t@pharm.showa-u.ac.jp (T. Itoh).
the tert-butyl methyl
a-monoalkylated malonates 3 and 4
http://dx.doi.org/10.1016/j.tetasy.2015.01.006
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

T. Kanemitsu et al. / Tetrahedron: Asymmetry 26 (2015) 214–218
215
O
O
O
Cl
∗
OCH3
chemoselective
transformation
O
H3C
Cl
N
CH3
N
O
Br
H3C
Br
1
: BIRT-377
2
O
O
O
O
asymmetric phase-transfer
catalytic alkylation
O
OCH3
O
OCH3
or
CH3
Br
3
4
Scheme 1. Retrosynthetic analysis of BIRT-377.
O
O
HfCl4•(THF)2
CH3OH
91%
tert-BuOH
reflux
O
O
O
OH
O
O
quant
5
6
O
O
CH3-I or 4-BrC6H4CH2-Br
NaH
O
O
O
OCH3
O
OCH3
DMF
R
7
3: R = CH3 (77%)
4
: R = 4-BrC6H4CH2 (79%)
Scheme 2. Synthesis of a-monoalkyl tert-butyl methyl malonates 3 and 4.
(Scheme 2). tert-Butyl malonate 6 was prepared from Meldrum’s
acid 5 through solvolysis by tert-butanol in quantitative yield.
The subsequent esterification was catalyzed by a hafnium(IV) salt8
to afford tert-butyl methyl malonate 7 in 91% yield. Malonate 7
was then alkylated with methyl iodide or 4-bromobenzyl bromide
under basic conditions to afford
a-monoalkyl tert-butyl methyl
Table 1
Substrate and catalyst screening for preparation of
a,
a
-dialkyl tert-butyl methyl malonate 2
O
O
catalyst (10 mol%)
∗
O
O
O
OCH3
R'-X
H3C
50% KOH aq.
O
OCH3
R
toluene
–20ºC, 72 h
3
: R = CH3
4: R = 4-BrC6H4CH2
Br
2
Cl
Cl
Cl
OH
H
OH
H
H
N
N
N
H
H
OH
H
N
N
N
8
9
10
Entrya
Substrate
Catalyst
R0-X
Yieldb (%)
eec (%)
Configuration
1
2
3
4
3
4
4
4
8
8
9
10
4-BrC6H4CH2-Br
CH3-I
CH3-I
94
91
72
79
76
89
27
37
(S)
(R)
(R)
(S)
CH3-I
a
b
c
The reaction was performed with
Isolated yields.
Determined by chiral HPLC.
a
-monoalkyl tert-butyl methyl malonate (3 or 4), R0-X, catalyst, and 50% KOH aq at ꢀ20 °C for 72 h.

216
T. Kanemitsu et al. / Tetrahedron: Asymmetry 26 (2015) 214–218
malonates 3 or 4 in 77% or 81% yield, respectively. The
a
-monoal-
accomplished by comparison of the specific rotation with the liter-
ature value.7g
kyl malonates 3 and 4 were then used as substrates for the asym-
metric alkylation reaction in order to evaluate the performance of
the catalysts.
3. Conclusion
In order to obtain the enantioenriched
ic diester 2, we screened several substrates and catalysts (Table 1).
The alkylation of -methyl malonate 3 or -4-bromobenzyl malon-
a,a-disubstituted malon-
In conclusion, we have described an efficient asymmetric
synthesis of LFA-1 antagonist BIRT-377 using enantioselective
a
a
ate 4 was carried out under the phase-transfer conditions previ-
ously reported.4 Malonate 3 or 4 was treated with alkyl halide,
50% KOH, and the representative cinchona alkaloid derivatives
phase-transfer catalytic alkylation. Methylation of a-4-bromoben-
zyl tert-butyl methyl malonate in the presence of N-(9-anthrace-
nylmethyl)cinchoninium chloride afforded the product with a
quaternary stereogenic carbon in high yield and with high enanti-
8–10 at ꢀ20 °C in toluene.
a
-Methyl malonate 3 with N-(9-anth-
racenylmethyl)cinchoninium chloride 8 afforded
a,a-disubstituted
oselectivity. The
a,a-disubstituted product thus obtained was
malonic diester 2 with the (S)-enantiomer in excess in high chemi-
cal yield, but the enantioselectivity was unsatisfactory (Table 1,
entry 1). In the case of a-4-bromobenzyl malonate 4 using catalyst
transformed into BIRT-377 through alternating chemoselective
transformation of the two ester groups. Over the course of these
studies, a one-pot Curtius rearrangement/3,5-dichloroaniline intro-
duction/ring closing method for synthesis of hydantoin was
developed.
8, the (R)-isomer was obtained in high chemical yield with high
enantioselectivity (Table 1, entry 2). However, N-benzylcinchonini-
um chloride 9 afforded a moderate chemical yield and low
enantioselectivity (Table 1, entry 3). N-(9-Anthracenylmethyl)
cinchonidinium chloride 10 was also obtained in moderate yield
and low enantioselectivity (Table 1, entries 4). As anticipated, cata-
lyst 10, a pseudo-enantiomer of catalyst 8, led to the formation of
the (S)-enantiomer in excess. According to these experiments, the
4. Experimental
4.1. General
All materials were purchased from commercial suppliers and
used without further purification. Progress of the reactions was
monitored by thin layer chromatography (TLC) performed on Merck
Art. 5715 Kieselgel 60 F254/0.25 mm thickness plates. Visualization
was accomplished with UV light and cerium sulfate-ammonium
molybdate solution followed by heating. Column chromatography
was performed using forced flow of the indicated solvent on Sigma
best result was obtained when using a combination of
enzyl malonate 4 as the substrate and compound 8 as the catalyst.
Although we have attempted to obtain enantiopure -disubsti-
tuted malonic diester 2 by recrystallization, the access was limited
in our hands. Thus, we decided to use the 89% ee of -4-bromophe-
a-4-bromob-
a,a
a
nyl methyl malonate 2 for the asymmetric synthesis of BIRT-377
(Scheme 3).
H-type silica Gel 60 N (100–210 l
m). 1H and 13C NMR spectra were
Next, we investigated the synthetic route to BIRT-377 from
recorded with JEOL JNM AL-400 instrument (400 MHz for 1H and
100 MHz for 13C) or JEOL JMN ECA-500 instrument (500 MHz for
1H and 125 MHz for 13C) in deuterated solvent, using tetramethylsil-
2. The tert-butyl ester of
a,a-disubstituted malonic diester 2 was
chemoselectively cleaved by TFA to afford carboxylic acid 11 in
quantitative yield. Next, a one-pot Curtius rearrangement followed
by 3,5-dichloroaniline introduction, accompanied by a ring closure,
was accomplished for the synthesis of hydantoin 12 in high yield,
i.e., carboxylic acid 11 was converted into the isocyanate through
Curtius rearrangement using diphenylphosphoryl azide (DPPA)9
in the presence of triethylamine, followed by urea formation with
3,5-dichloroaniline and ring closure through an ester-amide
exchange reaction to afford hydantoin 12 in 75% yield. Subsequent
N-methylation of the hydantoin 12 was carried out with lithium
bis(trimethylsilyl)amide and methyl iodide to obtain BIRT-377 1
in 89% yield. The confirmation of the stereochemistry of 1 was
ane (d = 0.0 ppm in 1H NMR spectra) and CDCl3 (d = 77.0 ppm in 13
C
NMR spectra) as internal standards. 1H data are reported as follows:
chemical shift (d in ppm), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet) and coupling constant (J in Hz). Optical rota-
tions were measured on a JASCO P1020 polarimeter operating at the
sodium D line at room temperature. Concentration is given in
g/100 mL. The HPLC analyses were performed with Shimadzu
equipment (210 k absorbance Detector) using Chiralcel OD column
with hexane/ethyl alcohol mixture Daicel Chemical Industries, LTD.
The HPLC method was calibrated with the corresponding racemic
O
O
O
O
O
OCH3
HO
H3C
OCH3
DPPA, Et3N, toluene, reflux, 2 h
TFA
H3C
CH2Cl2
rt, 48 h
then, 3,5-dimethylaniline, Na2CO3,
DMSO, reflux, 14 h
75%
Br
Br
quant
2
11
Cl
Cl
CH3-I
O
O
LHMDS
Cl
N
CH3
Cl
N
N
DMF
NH
0ºC, 2 h
O
Br
O
Br
H3C
: BIRT-377
Scheme 3. Synthesis of BIPN-377 1.
H3C
12
89%
1

T. Kanemitsu et al. / Tetrahedron: Asymmetry 26 (2015) 214–218
217
mixture. High-resolution mass spectra (HRMS) were measured with
JEOL JMS-MS700V using p-nitrobenzyl alcohol as a matrix. The
known compounds have been identified by comparison of spectral
data with those reported. The absolute configurations of the opti-
cally active compounds were determined on the basis of the mea-
sured specific rotation compared with literature values.
3.70 (s, 3H), 3.53 (t, J = 7.8 Hz, 1H), 3.13 (d, J = 7.8 Hz, 2H), 1.40
(s, 9H); 13C NMR (100 MHz, CDCl3) d 169.4, 167.5, 137.0, 131.5,
130.6, 120.5, 83.2, 54.3, 52.4, 34.0, 27.8; HR-FAB MS calcd for
C
15H20BrO4 [M+H]+ 343.0545, found 343.0558.
4.6. Optimized procedure for asymmetric synthesis of methyl 1-
tert-butyl 3-methyl 2-(4-bromobenzyl)-2-malonate 2
4.2. 1-tert-Butyl malonate 6
A 50 mL round-bottom flask equipped with a stirring bar was
A 200 mL round-bottom flask equipped with a stirring bar was
charged with 2,2-dimethyl-1,3-dioxane-4,6-dione 5 (Meldrum’s
acid, 5.0 g, 34.7 mmol) and tert-butyl alcohol (40 mL). The reaction
was allowed to stir for 6 h at reflux conditions. The reaction mix-
ture was concentrated in vacuo to afford the desired product 6
(5.56 g, 100%) as a colorless oil. 1H NMR (400 MHz, CDCl3) d
10.51 (br s, 1H), 3.35 (s, 2H), 1.42 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 171.8, 166.3, 81.9, 42.1, 27.9; HR-FAB MS calcd for
C7H13O4 [M+H]+ 161.0814, found 161.0809.
charged with compound
(65 mg, 0.125 mmol), and toluene (12.5 mL), and the apparatus
was cooled to ꢀ20 °C. To the mixture, methyl iodide (390 L,
4 (430 mg, 1.25 mmol), catalyst 8
l
6.26 mmol) and 50% KOH aq (2.5 mL) were added and the mixture
was stirred vigorously at ꢀ20 °C for 72 h, after which the reaction
mixture was neutralized with 1 M HCl and poured into an extrac-
tion funnel. The mixture was extracted with CH2Cl2 (3ꢁ), dried over
MgSO4, and concentrated in vacuo. The remaining residue was puri-
fied by silica gel column chromatography (hexanes/AcOEt = 90:10)
to afford the desired product 2 (407 mg, 91%) as a white solid. The
ee value of the product was determined by chiral-phase HPLC anal-
4.3. 1-tert-Butyl 3-methyl malonate 7
ysis. mp 48–50 °C; [
a
]
D
20 = ꢀ2.5 (c 1.6, CHCl3); 1H NMR (400 MHz,
A 200 mL round-bottom flask equipped with a stirring bar was
charged with compound 6 (3.0 g, 18.7 mmol) and methyl alcohol
(70 mL). To the solution, hafnium(IV) chloride tetrahydrofuran
complex (1:2) (88 mg, 0.19 mmol) was added. The reaction was
allowed to stir for 2 days at room temperature. To the reaction
mixture, brine was added and extracted with CH2Cl2 (3ꢁ), dried
over MgSO4, and concentrated in vacuo. The remaining residue
was purified by silica gel column chromatography (hexanes/
AcOEt = 50:50) to afford the desired product 7 (3.0 g, 91%) as a col-
orless oil. 1H NMR (400 MHz, CDCl3) d 3.74 (s, 3H), 3.30 (s, 2H), 1.47
(s, 9H); 13C NMR (100 MHz, CDCl3) d 167.5, 165.8, 82.1, 52.3, 42.7,
27.9; HR-FAB MS calcd for C8H15O4 [M+H]+ 175.0883, found
175.0875.
CDCl3) d 7.38 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 3.72 (s,
3H), 3.17 (d, J = 13.7 Hz, 1H), 3.10 (d, J = 13.9 Hz, 1H), 1.44 (s, 9H),
1.29 (s, 3H); 13C NMR (100 MHz, CDCl3) d 170.5, 170.7, 135.4,
131.9, 131.2, 120.9, 81.9, 55.2, 52.3, 40.4, 27.8, 19.7; HR-FAB MS
calcd for C16H22BrO4 [M+H]+ 357.0701, found 357.0721; Enantio-
meric excess: 89%; HPLC (Daicel Chiralcel OD, hexane/EtOH 500:1,
flow rate 0.5 mL/min, k = 210 nm): major isomer: tR = 16.0 min;
minor isomer: tR = 17.5 min.
4.7. Methyl (R)-1-methyl 2-(4-bromobenzyl)-2-malonate 11
A 50 mL round-bottom flask equipped with a stirring bar was
charged with compound
(5 mL). To the mixture, TFA (250
2
(300 mg, 0.84 mmol) and CH2Cl2
L) was added and the mixture
l
4.4. 1-tert-Butyl 3-methyl 2-methylmalonate 3
was stirred at room temperature for 48 h. The reaction mixture
was concentrated in vacuo. The remaining residue was purified by
silica gel column chromatography (CH2Cl2/MeOH/AcOH = 50:50:1)
to afford the desired product 11 (253 mg, 100%) as a white solid.
A 100 mL round-bottom flask equipped with a stirring bar was
charged with compound
7 (1920 mg, 11.0 mmol) and DMF
(25 mL). To the solution, sodium hydride (60% oil suspension,
446 mg, 11.0 mmol) was added. The reaction was allowed to stir
at 0 °C for 30 h. To the mixture, methyl iodide (670 lL, 11.0 mmol)
mp 86–88 °C; [a]
22 = +0.7 (c 3.0, CHCl3); 1H NMR (400 MHz, CDCl3)
D
d 9.09 (br s, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 3.76
(s, 3H), 3.26 (d, J = 13.9 Hz, 1H), 3.15 (d, J = 13.9 Hz, 1H), 1.39 (s, 3H);
13C NMR (100 MHz, CDCl3) d 177.3, 171.9, 134.6, 131.8, 131.4, 121.2,
54.7, 52.8, 40.6, 19.8; HR-FAB MS calcd for C12H14BrO4 [M+H]+
301.0075, found 301.0100.
was added at 0 °C and the mixture was stirred at room tempera-
ture for 18 h. To the reaction mixture, H2O was added, and the mix-
ture was extracted with CH2Cl2 (3ꢁ), dried over MgSO4, and
concentrated in vacuo. The remaining residue was purified by silica
gel column chromatography (hexanes/AcOEt = 90:10) to afford the
desired product 3 (1597 mg, 77%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) d 3.73 (s, 3H), 3.35 (q, J = 7.3 Hz, 1H), 1.46 (s,
9H), 1.38 (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 170.9,
169.2, 81.6, 52.2, 47.0, 27.8, 13.5.
4.8. (R)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-5-methyl-
imidazolidine-2,4-dione 12
A 50 mL round-bottom flask equipped with a stirring bar was
charged with compound 11 (93 mg, 0.31 mmol) and toluene
(6 mL). To the solution, triethylamine (65
lL, 0.47 mmol) and DPPA
4.5. 1-tert-Butyl 3-methyl 2-(4-bromobenzyl)malonate 4
(100 L, 0.46 mmol) were added. The reaction was allowed under
l
reflux conditions. After 2 h, 3,5-dichloroaniline (75 mg, 0.46 mmol)
was added and the mixture was stirred at reflux for 8 h. To the
mixture, Na2CO3 (66 mg, 0.62 mmol) and DMSO (6 mL) were added
and the mixture was stirred at reflux for 6 h. To the reaction mix-
ture, brine was added, and the mixture was extracted with CH2Cl2
(3ꢁ), dried over MgSO4, and concentrated in vacuo. The remaining
residue was purified by silica gel column chromatography (hex-
anes/AcOEt = 60:40) to afford the desired product 12 (99 mg,
A 100 mL round-bottom flask equipped with a stirring bar was
charged with compound 7 (1000 mg, 5.8 mmol) and DMF (20 mL).
To the solution, sodium hydride (60% oil suspension, 233 mg,
5.8 mmol) was added. The reaction was allowed to stir at 0 °C for
1 h. To the mixture, 4-bromobenzyl bromide (1437 mg, 5.8 mmol)
was added at 0 °C and the mixture was stirred at room tempera-
ture for 20 h. To the reaction mixture, H2O was added, and the mix-
ture was extracted with CH2Cl2 (3ꢁ), dried over MgSO4, and
concentrated in vacuo. The remaining residue was purified by silica
gel column chromatography (hexanes/AcOEt = 90:10) to afford the
desired product 4 (1551 mg, 79%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) d 7.39 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H),
75%) as colorless syrup. [a]
21 = +107.3 (c 2.7, CHCl3); 1H NMR
D
(400 MHz, CDCl3) d 7.46 (d, J = 8.3 Hz, 2H), 7.34 (t, J = 1.8 Hz, 1H),
7.06 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 2.0 Hz, 2H), 5.89 (s, 1H), 3.14
(d, J = 13.7 Hz, 1H), 2.91 (d, J = 13.7 Hz, 1H), 1.61 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 174.0, 154.0, 135.2, 132.9, 132.7, 131.9,

218
T. Kanemitsu et al. / Tetrahedron: Asymmetry 26 (2015) 214–218
131.7, 128.5, 124.5, 122.1, 62.5, 43.7, 23.5; HR-FAB MS calcd for
17H14BrCl2N2O2 [M+H]+ 426.9616, found 426.9648; enantiomeric
excess: 89%; HPLC (Daicel Chiralpak AD-H, hexane/EtOH 9:1, flow
rate 1.0 mL/min, k = 210 nm): major isomer: tR = 11.6 min; minor
isomer: tR = 5.8 min.
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4.9. (R)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-1,
5-dimethyl-imidazolidine-2,4-dione 1: BIRT-377
A 50 mL round-bottom flask equipped with a stirring bar was
charged with compound 12 (45 mg, 0.11 mmol) and DMF (2 mL).
To the solution, LHMDS (1.0 M in THF, 160
added and the mixture was stirred at 0 °C for 1 h. To the mixture,
methyl iodide (13 L, 0.21 mmol) was added and the reaction was
lL, 0.16 mmol) was
l
stirred at room temperature. After 2 h, H2O was added, and the mix-
ture was extracted with CH2Cl2 (3ꢁ), dried over MgSO4, and concen-
trated in vacuo. The remaining residue was purified by silica gel
column chromatography (hexanes/CH2Cl2 = 50:50 ? 0:100) to
afford the desired product 1 (41 mg, 89%) as colorless syrup;
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[a] a]
21 = +115.6 (c 1.4, CHCl3) {Ref., [ 22 = +132.4 (c 1.02, CHCl3)7g};
D D
1H NMR (400 MHz, CDCl3) d 7.42 (d, J = 8.5 Hz, 2H), 7.29 (t,
J = 2.0 Hz, 1H), 6.95 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 2.0 Hz, 2H), 3.09
(d, J = 14.1 Hz, 1H), 3.06 (s, 3H), 2.97 (d, J = 14.1 Hz, 1H), 1.62 (s,
3H); 13C NMR (100 MHz, CDCl3) d 173.3, 153.4, 135.0, 133.0,
132.8, 131.8, 131.1, 128.3, 124.5, 122.0, 65.7, 40.7, 25.3, 21.0; HR-
FAB MS calcd for
C
18H16BrCl2N2O2 [M+H]+ 440.9772, found
440.9780; enantiomeric excess: 89%; HPLC (Daicel Chiralpak AD-
H, hexane/2-PrOH 95:5, flow rate 1.0 mL/min, k = 210 nm): major
isomer: tR = 14.4 min; minor isomer: tR = 12.0 min.
Acknowledgments
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9. (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203–6205;
(b) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151–2157.
This work was supported by a ‘High-Tech Research Center’ Pro-
ject for Private Universities: matching fund subsidy from MEXT
(Ministry of Education, Culture, Sports, Science and Technology)
of Japan, and a Grant-in-Aid for Scientific Research (C) from the
Japan Society for the Promotion of Science.