Asymmetric dieckmann condensation via memory of chirality: synthesis of the key intermediate for as-3201, an aldose reductase inhibitor

Article abstract of DOI:10.3987/COM-08-S(N)126

Asymmetric Dieckmann condensation via memory of chirality has been developed. A key intermediate for the synthesis of AS-3201, an aldose reductase inhibitor, has been prepared in 94% ee by asymmetric Dieckmann condensation of 8 derived from L-aspartic acid.

Full text of DOI:10.3987/COM-08-S(N)126

HETEROCYCLES, Vol. 76, No. 2, 2008
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HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1593 - 1606. © The Japan Institute of Heterocyclic Chemistry
Received, 14th June, 2008, Accepted, 4th August, 2008, Published online, 7th August, 2008. COM-08-S(N)126
ASYMMETRIC DIECKMANN CONDENSATION VIA MEMORY OF
CHIRALITY: SYNTHESIS OF THE KEY INTERMEDIATE FOR AS-3201,
AN ALDOSE REDUCTASE INHIBITOR
Toshihide Watanabe and Takeo Kawabata*
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
E-mail:kawabata@scl.kyoto-u.ac.jp
Abstract – Asymmetric Dieckmann condensation via memory of chirality has
been developed. A key intermediate for the synthesis of AS-3201, an aldose
reductase inhibitor, has been prepared in 94% ee by asymmetric Dieckmann
condensation of 8 derived from L-aspartic acid.
INTRODUCTION
AS-3201 is a structurally novel aldose reductase inhibitor developed by Dainippon Sumitomo Pharma Co.,
Ltd., and is an orally available candidate for the treatment of diabetic disorders.1 The key intermediate
for the synthesis of AS-3201 is succinimide 1 with a tetrasubstituted carbon center (Scheme 1).
Optically pure 1 has been prepared through optical resolution of the racemate with a stoichiometric
amount of cinchonidine (Scheme 1, a).1 Recently, Shibasaki and co-workers has developed an excellent
method for the preparation of 1 via catalytic asymmetric amination (Scheme 1, b).2 Both of the synthetic
routes employ racemic precursors of 1. We report here preparation of 1 by asymmetric Dieckmann
condensation of optically active amino acid derivatives derived from L-aspartic acid in the absence of
external chiral sources, where L-aspartic acid is employed as a functionalized carbon resource as well as a
chiral source for asymmetric induction; i.e., memory of chirality (Scheme 2).
RESULTS AND DISCUSSION
The most straightforward synthesis of 1 might involve Dieckmann condensation of optically active
precursors derived from cheap and readily available L-aspartic acid (Scheme 2). However, this has
never been achieved due to the expected racemization during enolate formation. We have developed
asymmetric intramolecular alkylation of amino acid derivatives via memory of chirality, which proceeds

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HETEROCYCLES, Vol. 76, No. 2, 2008
O
O
NH
NH
(a)
O
N
O
O
NH
N
resolution
O
ZHN
O
CO2Et
NH
ZHN
CO2Et
Br
O
O
O
O
NH
(b)
NH
O
H2N
CO2Et
O
catalytic
asymmetric
amination
F
O
Boc N
AS-3201
CO2Et
CO2Et
1
NHBoc
Scheme 1
R3
asymmetric
Dieckmann condensation
via memory of chirality
R3
O
O
O
N
R4O
N
HO
OH
OEt
O
1
O
O
O
NH2
N
R1 N
R2
CO2Et
R1 R2
L-aspartic acid
Scheme 2
via axially chiral enolate intermediates to give cyclic amino acids with a tetrasubstituted carbon center
(Scheme 3).3 We had expected that asymmetric Dieckmann condensation could proceed also via axially
chiral enolate intermediates to give optically active succinimides with a tetrasubstituted carbon center
(Scheme 4).
We chose N-tert-butoxycarbonyl(Boc)-N-methoxymethyl(MOM)-aspartic acid derivative 2 as a precursor
of asymmetric Dieckmann condensation (Scheme 5), since Boc- and MOM-substituents on the nitrogen
are critical for the generation of axially chiral enolate intermediates.4 Commercially available L-aspartic
MX
OM
CO2Et
R
CO2Et
(CH2)n
EtO
base
(CH2)nX
t
R
N
(CH2)n
CO2 Bu
N
N
R
Boc
Boc
X
X = Br, I
up to 99% ee
Scheme 3

HETEROCYCLES, Vol. 76, No. 2, 2008
1595
R3
OM
MOR4
O
R3
N
R1
EtO
O
N
O
base
N
O
R4O
Boc
OEt
R3 N
CO2Et
Boc N
O
O
N
CO2R4
R1
R1
Boc
Scheme 4
acid β-benzyl ester (3) was transformed to N-Boc α-ethyl ester 4 in 94% yield. Treatment of 4 with 0.95
equiv. of potassium hexamethyldisilazide (KHMDS) followed by addition of chloromethyl methyl ether
at -78 °C gave N-Boc-N-MOM derivative 5 in 78% yield with partial racemization (94% ee).
Carboxylic acid 6 obtained by catalytic hydrogenolysis of 5 was transformed in situ to a mixed anhydride
with pivaloyl chloride at -78 °C and it was treated with lithium N-ethoxycarbonyl-N-p-
methoxybenzylamide to give 2 in 82% yield.
O
O
i) KHMDS (0.95 eq)
i) Boc2O, DIPEA, DMF
BnO
BnO
OEt
OH
ii) MOMCl, -78 °C
78%
ii) K2CO3, EtI
94%
O
NHBoc
O
NH2
3
4
PMB
O
O
O
i) t-BuCOCl, TEA
THF, -78 °C
H2, Pd/C
HOOC
EtO
N
OEt
BnOOC
OEt
OEt
MOM
PMB
CO2Et
EtOH
N
ii)
O
Boc
O
N
N
N
Li
Boc
MOM
Boc
MOM
quant.
5 (94% ee)
82%
6
2
Scheme 5
Asymmetric Dieckmann condensation of 2 was investigated (Table 1). Since KHMDS was a base of
choice for asymmetric cyclization via memory of chirality in retention of configuration,3 Dieckmann
condensation of 2 was examined with KHMDS in various solvents. Treatment of 2 with 1.1 equiv. of
KHMDS in THF gave 10 in 81% ee but in only 10% yield with 74% recovery of 2 (entry 1). Increasing
the amount of KHMDS to 2.2 equiv did not improve the yield (entry 2). Use of DMF as a solvent,
which was the best solvent for asymmetric cyclization via memory of chirality,3 did not give the desired
cyclization product (entry 3). Further screening of the solvents (toluene, ether, diisopropyl ether,
cyclopropyl methyl ether, tert-butyl methyl ether)5 showed that tert-butyl methyl ether gave the best result
(78% ee and 24% yield, entry 4). While addition of TMEDA slightly improved the ee of asymmetric
Dieckmann condensation (81% ee, entry 5), the reaction did not take place in the presence of 18-crown-6

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HETEROCYCLES, Vol. 76, No. 2, 2008
Table 1. Asymmmeric Dieckmann Condensation via Memory of Chirality
PMB
O
PMB
O
N
base (1.1 equiv)
R2O
N
O
OEt
solvent, -78 °C, 2 h
O
O
N
Boc N
R1
CO2Et
R1
Boc
entry substratea
R2
solvent
product
ee (%)c
R1
base
yield (%)b
1
2
2 (94)
2 (94)
2 (94)
2 (94)
2 (92)
2 (94)
2 (94)
2 (94)
7 (90)
8 (96)
9 (92)
Et
Et
Et
Et
Et
Et
Et
Et
Bn
Et
Bn
THF
10
10
10
10
10
10
10
10
10
11
11
81
79
-
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MOM
MEM
MEM
KHMDS
10 (74)
10
KHMDSd
KHMDS
KHMDS
KHMDS
KHMDS
LDA
THF
3e
4
DMF
~0
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
78
81
-
24
5f
6g
7
23
~0
-
~0
8
-
LiTMP
~0
9
82
94
90
KHMDS
KHMDS
KHMDS
25
10
11
37
25h
a) Numbers in the parentheses indicate % ee of the substrate. b) Isolated yield. A number in the
parenthesis indicates % recovery of the starting material. c) (R)-isomer was obtained in each run.
d) 2.2 Equiv. of the base was used. e) The reaction was run at -60 °C. f) TMEDA (5 equiv) was
added. g) 18-crown-6 (1.1 equiv) was added. h) The substrate of 50% ee was recovered in 54%
yield.
(entry 6). Addition of other additives such as tetrabutylammonium halides, LiOTf, ZnBr2, MgBr2, or
DMPU did not improve the yield of the Dieckmann condensation (data not shown). LDA and LiTMP
did not promote Dieckmann condensation (entries 7 and 8). Asymmetric Dieckmann condensation of
other precursors 7-9 was examined (entries 9-11). Benzyl carbamate 7 gave the desired product 10 in
82% ee in 25% yield (entry 9). Use of an N-methoxyethoxymethyl (MEM) group instead of a MOM
group improved both yield (37%) and ee (94%) (entry 10). The corresponding benzyl carbamate 9 gave
the product 11 in 90% ee and 25% yield (entry 11). The low yield seems not due to incomplete enolate
formation because the ee of the recovered substrate was 50%. Thus, asymmetric Dieckmann
condensation via memory of chirality has been developed for the first time. The reactions took place
highly enantioselectively probably via axially chiral enolates, albeit in low yields.
Succinimide 11 (94% ee) obtained by asymmetric Dieckmann condensation was treated with CAN to
give 12 in 75% yield, which was then treated with 4 M HCl to give 1 in 87% yield. Succinimide 10 with
a MOM group (81% ee) was also transformed to 1 by the same treatment in 73% yield. Since the absolute

HETEROCYCLES, Vol. 76, No. 2, 2008
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PMB
O
O
N
NH
CAN
4 M HCl
EtOAc
O
O
1
MeCN-H2O
rt
CO2Et
Boc N
Boc N
MEM
CO2Et
MEM
11
87%
75%
12
Scheme 6
configuration of 1 is known to be R,1 these transformations indicate that the present asymmetric
Dieckmann condensation proceeded in retention of configuration.
In conclusion, we have developed asymmetric Dieckmann condensation via memory of chirality. The
product was transformed to the key intermediate for the synthesis of AS-3201.
EXPERIMENTAL
NMR spectra were obtained with a JEOL JMN 400 spectrometer, chemical shifts being given in ppm
units (tetramethylsilane or chloroform as internal standards, indicating 0 or 7.24, respectively). IR
spectra were recorded with a JACSO FT/IR–300 spectrometer. Specific rotation was measured with a
Horiba SEPA–200 automatic digital polarimeter. MS spectra were recorded with a JEOL JMS–DX300
mass spectrometer. TLC analysis and preparative TLC were performed on commercial glass plates
bearing a 0.25 mm layer and 0.5 mm layer of Merck Kiesel–gel 60 F254, respectively. Silica gel
chromatography was carried out Wakogel C–200, Fuji Silysia BW–1277H, or Nacalai Tesque Silica gel
60 (150–325 mesh). Dry solvents (THF, ether, hexane, dichloromethane, and toluene; <50 ppm water
contents) were purchased from Kanto Chemical CO., Inc. and used without further treatment.
(S)-4-Benzyl 1-ethyl 2-(tert-butoxycarbonylamino)succinate (4)
A
suspension of (S)-2-amino-4-(benzyloxy)-4-oxobutanoic acid
3
(10.0 g, 45 mmol),
diisopropylethylamine (9.40 mL, 54 mmol) and di-tert-butyl dicarbonate (11.7 g, 54 mmol) in DMF (300
mL) was stirred for 5 h at rt. Ethyl iodide (7.20 mL, 90 mmol) and K2CO3 (12.4 g, 90 mmol) were
added to the solution, and the resulting mixture was stirred for 12 h at rt. The reaction mixture was
diluted with EtOAc and washed with water twice, brine, dried over Na2SO4, filtered and evaporated in
vacuo. The residue was purified by column chromatography (SiO2, hexane: EtOAc= 7:1) to give 4 (14.8 g,
94% yield).
Colorless oil. [α]D20 (>99% ee) 22 (c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.38-7.30 (m, 5H), 5.53
(d, J=8.2 Hz, 1H), 5.12 (s, 2H), 4.56 (dt, J=8.2, 5.0 Hz, 1 H), 4.15 (q, J=7.3 Hz, 2H), 3.04 (dd, J=16.9,
13
5.0 Hz, 1 H), 2.87 (dd, J=16.9, 5.0 Hz, 1 H), 1.44 (s, 9H), 1.21 (t, J=7.3 Hz, 3H). C NMR (100 MHz,
CDCl3) δ 171.3, 171.1, 155.8, 135.8, 128.9, 128.74, 128.65, 80.4, 67.1, 62.1, 50.4, 37.2, 28.6, 14.4. IR

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HETEROCYCLES, Vol. 76, No. 2, 2008
(neat, cm-1) 2979, 2933, 1737, 1718, 1499, 1367, 1165, 1028, 698. MS (EI) m/z (rel intensity) 351 (M+, 1),
295 (40), 278 (50), 222 (60), 178 (100). Anal. Calcd for C18H25NO6: C, 61.52; H, 7.17; N, 3.99%. Found:
C, 61.40; H, 7.07; N, 4.07%.
(S)-4-Benzyl 1-ethyl 2-(tert-butoxycarbonyl(methoxymethyl)amino)succinate (5)
Lithium hexamethyldisilazide (0.28 mmol) in THF (1.0 mL) was added slowly to a solution of 4 (105 mg,
0.30 mmol) in THF (3.0 mL) and DMPU (0.36 mL, 3.0 mmol) at -78 °C under Ar. After stirring for 30
min at -78 °C, MOMCl (68 µL, 0.90 mmol) was added and the resulting mixture was stirred for
additional 15 h. The reaction mixture was poured into saturated aq. NH4Cl solution and extracted with
EtOAc twice. The combined organic phase was washed with saturated aq. NaHCO3 solution and brine,
dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by preparative TLC
(hexane: 1, 4-dioxane= 4: 1) to give 5 (85 mg, 80% yield). The enantiomeric purity was determined to
be 94% ee: Daicel Chiralpak AD-H, hexane: EtOH= 98:2, flow 1.0 mL/min., 254 nm, minor peak 18.9
min, major peak 23.7 min.
Colorless oil. [α]D20 (94% ee ) -38 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 5H), 5.14 (ABq,
ΔνAB=12.6 Hz, J=12.8 Hz, 2H), 4.85, 4.77 (two d, J=11.0 Hz, 11.0 Hz, ratio=4:3, 1H), 4.67 (d, J=11.0 Hz,
1H), 4.55 (two t, J= 6.9 Hz, 6.9 Hz, ratio=3:4, 1H), 4.25-4.09 (m, 2H), 3.34, 3.31 (two s, ratio=4:3, 3H),
3.26 (dd, J=16.9, 6.9 Hz, 1H), 2.90, 2.81 (two dd, J=16.9, 6.9 Hz, 16.9, 6.9 Hz, ratio=3:4, 1H), 1.47, 1.43
(two s, ratio=3:4, 9H), 1.27, 1.22 (two t, J=7.3Hz, 7.3Hz, ratio=4:3, 3H). 13C NMR (100 MHz, CDCl3) δ
171.5 and 171.3 (rotamer), 170.8 and 170.7 (rotamer), 155.0 and 154.7 (rotamer), 136.2 and 136.0
(rotamer), 129.0, 128.9, 128.8 and 128.6 (rotamer), 82.0 and 81.7 (rotamer), 80.05 and 79.97 (rotamer),
67.1 and 66.9 (rotamer), 62.0 and 61.9 (rotamer), 56.5, 56.1, 36.8 and 35.8 (rotamer), 28.5, 14.5. IR (neat,
cm-1) 2979, 2934, 1739, 1712, 1368, 1301, 1159, 1093, 861, 698. MS (EI) m/z (rel intensity) 395 (M+, 1),
294 (50), 264 (20), 222 (70), 160 (30), 91 (100), 57 (30). Anal. Calcd for C20H29NO7: C, 60.74; H, 7.39;
N, 3.54%. Found: C, 60.46; H, 7.37; N, 3.57%.
(S)-3-(tert-Butoxycarbonyl(methoxymethyl)amino)-4-ethoxy-4-oxobutanoic acid (6)
A suspension of 5 (2.40 g, 6.1 mmol) and 10% Pd/C (300 mg) in EtOH (40 mL) was stirred under H2 at
room temperature for 12 h. The mixture was filtered and the filtrate was concentrated in vacuo to give 6
(1.85 g, quant).
20
1
Colorless oil. [α]D (94% ee) -47 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ 4.89, 4.82 (two d,
J=11.0 Hz, 11.0 Hz, ratio=4:3, 1H), 4.73 (d, J=11.0 Hz, 1H), 4.50 (two t, J= 6.9 Hz, 6.9 Hz, ratio=3:4,
1H), 4.29-4.12 (m, 2H), 3.37, 3.35 (two s, ratio=4:3, 3H), 3.26 (dd, J=17.0, 6.9 Hz, 1H), 2.88, 2.79 (two
dd, J=17.0, 6.9 Hz, 17.0, 6.9 Hz, ratio=3:4, 1H), 1.48, 1.45 (two s, ratio=3:4, 9H), 1.30, 1.26 (two t,
13
J=6.8Hz, 6.8Hz, ratio=4:3, 3H). C NMR (100 MHz, CDCl3) δ 176.8 and 176.5 (rotamer), 170.9 and
170.8 (rotamer), 155.0 and 154.78 (rotamer), 82.3 and 82.0 (rotamer), 80.1 and 80.0 (rotamer), 62.2 and

HETEROCYCLES, Vol. 76, No. 2, 2008
1599
62.1 (rotamer), 56.5, 56.3 and 56.2 (rotamer), 36.6 and 35.7 (rotamer), 28.6, 14.5. IR (neat, cm-1) 2978,
2924, 1739, 1712, 1369, 1301, 1161, 1094. MS (EI) m/z (rel intensity) 305 (M+, 1), 274 (10), 232 (30),
204 (80), 174 (60), 160 (20), 132 (100), 57 (30). HRMS (EI) calcd for C13H23NO7: 395.1475, found:
395.1485.
(S)-Ethyl 9-(4-methoxybenzyl)-5-(methoxymethyl)-2,2-dimethyl-4,8,10-trioxo-3,11-dioxa-5,9-
diazatridecane-6-carboxylate (2)
Triethylamine (0.53 mL, 3.8 mmol) and pivaloyl chloride (0.26 mL, 2.1 mmol) were added to a solution
of 6 (567 mg, 1.9 mmol) in THF (20 mL) at -78 °C under Ar, and the mixture was stirred at -78 °C for 2 h.
A solution of lithium N-ethoxycarbonyl-N-p-methoxybenzylamide, prepared by LDA (2.1 mmol
in 5.6 mL of THF) and ethyl 4-methoxybenzylcarbamate (439 mg, 2.1 mmol) in THF (4 mL) at 0 °C, was
added to the above reaction mixture and the resulting mixture was stirred at -78 °C for 2 h and then at rt
for 1 h. The reaction mixture was poured into saturated aq. NH4Cl solution and extracted with EtOAc
twice. The combined organic phase was washed with saturated aq. NaHCO3 solution and brine, dried
over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography
(hexane: 1,4-dioxane= 11: 1) to give 2 (775 mg, 82% yield). The enantiomeric purity was determined to
be 94%: Daicel Chiralpak AD-H, hexane: i-PrOH= 90:10, flow 0.7 mL/min., 254 nm, minor peak 20.7
min., major peak 26.1 min.
Colorless oil. [α]D20 (94% ee ) -35 (c 1.2, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J=8.2 Hz, 2H),
6.81 (d, J=8.2 Hz, 2H), 4.86 (s, 2H), 4.83-4.75 (m, 2H), 4.71 (d, J=10.6 Hz, 1H), 4.26-4.10 (m, 4H),
3.92-3.84 (m, 1H), 3.75 (s, 3H), 3.34-3.27 (m, 1H), 3.32, 3.30 (two s, ratio=9:5, 3H), 1.47, 1.45 (two s,
13
ratio=5:9, 9H), 1.30-1.21 (m, 6H). C NMR (100 MHz, CDCl3) δ 173.43 and 173.35 (rotamer), 171.0
and 170.9 (rotamer), 159.0, 155.0 and 154.6 (rotamer), 154.4, 130.0 and 129.9 (rotamer), 129.6, 113.8,
81.4 and 81.1 (rotamer), 79.5 and 79.4 (rotamer), 63.2, 61.5 and 61.3 (rotamer), 56.1, 55.9 and 55.7
(rotamer), 55.3, 46.9, 40.2 and 39.4 (rotamer), 28.3, 14.2. IR (neat, cm-1) 2979, 2935, 1739, 1707, 1514,
1369, 1301, 1248, 1183, 1035. MS (EI) m/z (rel intensity) 496 (M+, 1), 464 (20), 408 (80), 291 (20), 222
(40), 221 (100), 209 (30), 208 (90), 121 (90), 57 (40). Anal. Calcd for C24H36N2O9: C, 58.05; H, 7.31; N,
5.64%. Found: C, 57.92; H, 7.36; N, 5.61%.
(S)-Ethyl 4-(4-methoxybenzyl)-8-(methoxymethyl)-11,11-dimethyl-3,5,9-trioxo-1-phenyl-2,10-dioxa-
4,8-diazadodecane-7-carboxylate (7)
Prepared from 6 (305 mg, 1.00 mmol) and benzyl 4-methoxybenzylcarbamate (298 mg, 1.1 mmol)
according to the procedure for 2. Purification was performed by column chromatography (hexane:
dioxane= 4: 1) to give 7 (217 mg, 39% yield). The enantiomeric purity was determined to be 90%:
Daicel Chiralpak AD-H, hexane: i-PrOH= 90:10, flow 0.8 mL/min., 254 nm, minor peak 19.7 min, major
peak 21.8 min.

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HETEROCYCLES, Vol. 76, No. 2, 2008
Colorless oil. [α]D20 (90% ee) -31 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.36-7.32 (m, 3H), 7.26
(s, 2H), 7.14 (d, J=8.2 Hz, 2H), 6.77 (d, J=8.2 Hz, 2H), 5.19 (s, 2H), 4.87 (s, 2H), 4.84-4.69 (m, 3H),
4.24-4.11 (m, 2H), 3.91-3.84 (m, 1H), 3.78 (s, 3H), 3.32-3.26 (m, 1H), 3.31, 3.28 (two s, ratio=3:2, 3H),
1.47, 1.43 (two s, ratio=2:3, 9H), 1.26, 1.22 (two t, J=7.3 Hz, 7.3 Hz, ratio=3:2, 3H). 13C NMR (100 MHz,
CDCl3) δ 173.8 and 173.7 (rotamer), 171.4 and 171.3 (rotamer), 159.3, 155.3 and 154.9 (rotamer), 154.6,
135.3, 130.2 and 130.1 (rotamer), 129.9, 129.1, 128.9, 114.1, 81.9 and 81.6 (rotamer), 79.8 and 79.6
(rotamer), 69.2, 61.9 and 61.7 (rotamer), 56.5 and 56.4 (rotamer), 56.2 and 56.1 (rotamer), 55.7, 47.3,
40.5 and 39.7 (rotamer), 28.7 and 28.6 (rotamer), 14.6. IR (neat, cm-1) 2977, 1739, 1706, 1514, 1366,
1300, 1248, 1178, 1092, 1035. MS (EI) m/z (rel intensity) 558 (M+, 1), 391 (20), 335 (100), 291 (20), 270
(20), 136 (40), 121 (80), 91 (50). Anal. Calcd for C29H38N2O9: C, 62.35; H, 6.86; N, 5.01%. Found: C,
62.22; H, 6.90; N, 4.90%.
(S)-Ethyl 7-(tert-butoxycarbonyl)-11-(4-methoxybenzyl)-10,12-dioxo-2,5,13-trioxa-7,11-diaza-
pentadecane-8-carboxylate (8)
Sodium hexamethyldisilazide (1.68 M in THF, 0.16 mL, 0.27 mmol) was added slowly to a solution of 4
(105 mg, 0.30 mmol) in THF (3.0 mL) and DMPU (0.36 mL, 3.0 mmol) at -78 °C under Ar. After
stirring the solution for 30 min at -78 °C, MEMCl (103 µL, 0.90 mmol) was added and the resulting
mixture was stirred for 19 h at -78 °C. The reaction mixture was poured into saturated aq. NH4Cl
solution and extracted with EtOAc twice. The combined organic phase was washed with saturated aq.
NaHCO3 solution and brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was
purified by preparative TLC (hexane:Et2O=1:1) to give (S)-4-benzyl 1-ethyl 2-(tert-butoxycarbonyl-
((2-methoxyethoxy)methyl)amino)succinate (112 mg, 85% yield). The enantiomeric purity was
determined to be 96% ee: Daicel Chiralcel OD-H, hexane: i-PrOH= 95:5, flow 1.0 mL/min., 254 nm,
minor peak 12.3 min, major peak 17.8 min.
Colorless oil. [α]D20 (96% ee) -33 (c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 5H), 5.14 (ABq,
ΔνAB=14.7 Hz, J=12.4 Hz, 2H), 4.97, 4.90, (two d, J=11.0 Hz, 11.0 Hz, ratio=5:3, 1H), 4.75 (d, J=11.0
Hz, 1H), 4.59, 4.55 (two t, J=6.9 Hz, 6.9 Hz, ratio=3:5, 1H), 4.25-4.08 (m, 2H), 3.81-3.74 (m, 1H),
3.66-3.54 (m, 1H), 3.51, (t, J=4.6 H, 2H), 3.36 (s, 3H), 3.33-3.22 (m, 1H), 2.92, 2.83 (two dd, J=16.5, 6.8
Hz, 16.5, 6.8 Hz, ratio=3:5, 1H), 1.46, 1.42 (two s, ratio=3:5, 9H), 1.25, 1.21 (two t, J=7.3 Hz, 7.3 Hz,
ratio=5:3, 3H). 13C NMR (100 MHz, CDCl3) δ 171.3 and 171.0 (rotamer), 170.6 and 170.5 (rotamer),
154.8 and 154.4 (rotamer), 136.0 and 135.9 (rotamer), 128.8, 128.7, 128.5 and 128.4 (rotamer), 81.8 and
81.5 (rotamer), 78.7 and 78.6 (rotamer), 71.9, 67.7 and 67.4 (rotamer), 66.8 and 66.6 (rotamer), 61.8 and
61.6 (rotamer), 59.3 and 59.2 (rotamer), 56.2, 36.5 and 35.6 (rotamer), 28.41 and 28.36 (rotamer), 14.3.
IR (neat, cm-1) 2979, 1738, 1709, 1429, 1367, 1159, 1091, 860, 699. MS (EI) m/z (rel intensity) 439 (M+,
1), 369 (5), 338 (60), 269 (70), 190 (40), 91(100). Anal. Calcd for C22H33NO8: C, 60.12; H, 7.57; N,

HETEROCYCLES, Vol. 76, No. 2, 2008
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3.19%. Found: C, 59.83; H, 7.57; N, 3.25%.
A suspension of (S)-4-benzyl 1-ethyl 2-(tert-butoxycarbonyl(methoxymethyl)amino)succinate (1.60 g,
3.6 mmol) and 10% Pd/C (150 mg) in EtOH (30 mL) was stirred under H2 at rt for 8 h. The mixture was
filtered
and
the
filtrate
was
concentrated
in
vacuo
to
give
(S)-3-(tert-butoxycarbonyl((2-methoxyethoxy)methyl)-amino)-4-ethoxy-4-oxobutanoic acid (1.27 g,
quant.).
1
Colorless oil. [α]D20 (96% ee) -52 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3) δ 10.2 (br s, 1H), 4.99,
4.94 (two d, J=11.0 Hz, 11.0 Hz, ratio= 5:3, 1H), 4.82 (d, J=11.0 Hz, 1H), 4.53, (two t, J=6.9 Hz, 6.9 Hz,
ratio=3:5, 1H), 4.26-4.12 (m, 2H), 3.82-3.76 (m, 1H), 3.69-3.58 (m, 1H), 3.55 (t, J=4.6 Hz, 2H), 3.39 (s,
3H), 3.29, 3.24 (two dd, J=16.9, 7.4 Hz, 16.9, 7.4 Hz, ratio=3:5, 1H), 2.91, 2.83 (two dd, J=16.9, 7.4 Hz,
16.9, 7.4Hz, ratio=3:5, 1H), 1.47, 1.44 (two s, ratio=3:5, 9H), 1.28, 1.24 (two t, J=7.4 Hz, 7.4 Hz, ratio
13
=5:3, 3H). C NMR (100 MHz, CDCl3) δ 176.8 and 176.4 (rotamer), 170.8 and 170.7 (rotamer), 155.0
and 154.6 (rotamer), 82.2 and 81.9 (rotamer), 78.9 and 78.8 (rotamer), 72.1, 67.8 and 67.5 (rotamer), 62.1
and 61.9 (rotamer), 59.4 and 59.3 (rotamer), 56.3, 36.5 and 35.6 (rotamer), 28.6 and 28.5 (rotamer), 14.4.
IR (neat, cm-1) 2979, 1739, 1711, 1432, 1369, 1300, 1160, 1091, 859. MS (EI) m/z (rel intensity) 349 (M+,
1), 248 (50), 174 (100), 100 (90), 57 (80). Anal. Calcd for C15H27NO8: C, 51.57; H, 7.79; N, 4.01%.
Found: C, 51.28; H, 7.88; N, 3.91%.
Triethylamine (0.28 mL, 2.0 mmol) and pivaloyl chloride (135 µL, 1.1 mmol) were added to a solution of
(S)-3-(tert-butoxycarbonyl((2-methoxyethoxy)methyl)-amino)-4-ethoxy- 4-oxobutanoic acid (350 mg, 1.0
mmol) in THF (10 mL) and DMPU (0.61 mL, 5.0 mmol) at -78 °C under Ar. After stirring for 2 h at
-78 °C, a solution of lithium N-ethoxycarbonyl-N-p-methoxybenzylamide, prepared by n-BuLi (1.53M in
hexane, 0.72 mL, 1.1 mmol) and ethyl 4-methoxybenzylcarbamate (230 mg, 1.1 mmol) in THF (5 mL) at
0 °C, was added to the reaction mixture and the resulting mixture was stirred at -78 °C and then gradually
warmed to room temperature. The reaction mixture was poured into saturated aq. NH4Cl solution and
extracted with EtOAc twice. The combined organic phase was washed with saturated aq. NaHCO3
solution and brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by
column chromatography (hexane: EtOAc= 7: 3) to give 8 (379 mg, 70% yield). The enantiomeric purity
was determined to be 96% ee: Daicel Chiralpak AD-H, hexane: i-PrOH= 90:10, flow 0.8 mL/min., 254
nm, minor peak 20.2 min, major peak 23.9 min.
Colorless oil. [α]D20 (96% ee) -31 (c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.2 Hz, 2H),
6.81 (d, J=8.2 Hz, 2H), 4.97, 4.90 (two d, J=11.0 Hz, 11.0 Hz, ratio=5:3, 1H), 4.86 (s, 2H), 4.79, 4.77
(two d, J=11.0 Hz, 11.0 Hz, ratio=5:3, 1H), 4.23 (q, J=6.9 Hz, 2H), 4.32-4.09 (m, 2H), 3.90, 3.86 (two dd,
J=17.9, 6.0 Hz, 17.9, 6.0 Hz, ratio=3:5, 1H), 3.79-3.71 (m, 1H), 3.78 (s, 3H), 3.66-3.55 (m, 1H), 3.50 (br
t, J=4.1 Hz, 2H), 3.36 (s, 3H), 3.28 (dd, J=17.9, 6.0 Hz, 1H), 1.46, 1.44 (two s, ratio=3:5, 9H), 1.30 (t,

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HETEROCYCLES, Vol. 76, No. 2, 2008
J=6.9 Hz, 3H), 1.25, 1.21 (two t, J=7.9 Hz, 7.9 Hz, ratio=5:3, 3H). 13C NMR (100 MHz, CDCl3) δ 173.8
and 173.6 (rotamer), 171.4 and 171.2 (rotamer), 155.3 and 154.8 (rotamer), 154.7, 130.4 and 130.3
(rotamer), 130.0, 114.1, 81.9 and 81.6 (rotamer), 78.5, 72.1, 67.8 and 67.4 (rotamer), 63.5, 61.8 and 61.7
(rotamer), 59.5 and 59.4 (rotamer), 56.3, 55.7, 47.2, 40.4 and 39.6 (rotamer), 28.7 and 28.6 (rotamer),
14.6, 14.5. IR (neat, cm-1) 2979, 2934, 1739, 1706, 1515, 1369, 1300, 1249, 1182, 1033. MS (EI) m/z (rel
intensity) 540 (M+, 1), 464 (10), 408 (50), 291 (20), 221 (60), 208 (90), 121 (100), 57 (20). HRMS (EI)
calcd for C26H40N2O10: 540.2683, found: 540.2689.
(S)-Ethy l8-(tert-butoxycarbonyl)-4-(4-methoxybenzyl)-3,5-dioxo-1-phenyl-2,10,13-trioxa-4,8-
diazatetradecane-7-carboxylate (9)
Prepared from (S)-3-(tert-butoxycarbonyl((2-methoxyethoxy)methyl)-amino)-4-ethoxy-4-oxobutanoic
acid (105 mg, 0.30 mmol) and benzyl 4-methoxybenzylcarbamate (90 mg, 0.33 mmol) according to the
procedure for 8. Purification was performed by column chromatography (hexane: Et2O= 2: 3) to give 9
(110 mg, 61% yield). The enantiomeric purity was determined to be 92% ee: Daicel Chiralpak AD-H,
hexane: i-PrOH= 90:10, flow 0.7 mL/min., 254 nm, minor peak 33.5 min, major peak 40.3 min.
Colorless oil. [α]D20 (92% ee) -31 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.36-7.32 (m, 3H), 7.26
(br s, 2H), 7.14 (d, J=8.2 Hz, 2H), 6.77 (d, J=8.2 Hz, 2H), 5.19 (s, 2H), 4.97, 4.90 (two d, J=11.4 Hz,
11.4 Hz, ratio=8:5, 1H), 4.87 (s, 2H), 4.82-4.75 (m, 1H), 4.79 (d, J=11.4 Hz, 1H), 4.25-4.06 (m, 2H), 3.90
(dd, J=17.9, 6.9 Hz, 1H), 3.79-3.70 (m, 1H), 3.77 (s, 3H), 3.66-3.55 (m, 1H), 3.50 (br t, J=4.6 Hz, 2H),
3.34 (s, 3H), 3.30 (dd, J=17.9, 6.9 Hz, 1H), 1.47, 1.42 (two s, ratio=5:8, 9H), 1.25, 1.21 (two t, J=7.3 Hz,
7.3 Hz, ratio=8:5, 3H). 13C NMR (100 MHz, CDCl3) δ 173.8 and 173.6 (rotamer), 171.3 and 171.1
(rotamer), 159.2, 155.3 and 154.7 (rotamer), 154.5, 135.2, 130.1 and 130.0 (rotamer), 129.9, 129.0, 128.9,
114.1, 81.8 and 81.6 (rotamer), 78.5, 72.1, 69.1, 67.7 and 67.4 (rotamer), 61.8 and 61.7 (rotamer), 59.5
and 59.4 (rotamer), 56.2 and 56.1 (rotamer), 55.6, 47.2, 40.4 and 39.6 (rotamer), 28.7 and 28.6 (rotamer),
14.5. IR (neat, cm-1) 2977, 1739, 1705, 1514, 1366, 1300, 1248, 1177, 1033, 860. MS (EI) m/z (rel
intensity) 602 (M+, 1), 526 (5), 427 (5), 335 (90), 291 (20), 270 (20), 136 (40), 121 (100), 91 (50). Anal.
Calcd for C31H42N2O10: C, 61.78; H, 7.02; N, 4.65%. Found: C, 61.54; H, 6.94; N, 4.79%.
(R)-Ethyl 3-(tert-butoxycarbonyl(methoxymethyl)amino)-1-(4-methoxybenzyl)-2,5-
dioxopyrrolidine-3-carboxylate (10): General procedure for asymmetric Dieckmann condensation
via memory of chirality
A base (1.1-2.2 eq) was added slowly to a solution of 2 (0.25 mmol) in solvent (2.5 mL) at -78 °C under
Ar. The reaction mixture was stirred at the temperature indicated in the Table 1 for 2 h. The reaction
mixture was poured into saturated aq. NH4Cl solution and extracted with EtOAc twice. The combined
organic phase was washed with saturated aq. NaHCO3 solution and brine, dried over Na2SO4, filtered and
evaporated in vacuo. The residue was purified by preparative TLC (toluene: Et2O: acetone=7:1:1) to

HETEROCYCLES, Vol. 76, No. 2, 2008
1603
give 10.
10 : HPLC conditions: Daicel Chiralpak AD-H, hexane: i-PrOH= 90:10, flow 0.8 mL/min., 254 nm,
minor peak 17.6 min., major peak 22.5 min. Colorless oil. [α]D20 (>99% ee) -153 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3) δ7.29 (d, J=8.2 Hz, 2H), 6.82 (d, J=8.2 Hz, 2H), 5.17, 4.99 (two br d, J=9.2 Hz, 9.2
Hz, ratio=5:4, 1H), 4.80, 4.75 (two br d, J=9.2 Hz, 9.2 Hz, ratio=5:4, 1H), 4.63 (ABq, ΔνAB=0.031 Hz,
J=14.6 Hz, 2H), 4.29-4.10 (m, 2H), 3.85, 3.74 (two d, J=18.3 Hz, 18.3 Hz, ratio=4:5, 1H), 3.77 (s, 3H),
2.93, 2.88 (two s, ratio=4:5, 3H), 2.79 (d, J=18.3 Hz, 1H), 1.46, 1.43 (two s, ratio=4:5, 9H), 1.27-1.15 (m,
13
3H). C NMR (100 MHz, CDCl3) δ 174.6 and 174.2 (rotamer), 171.0 and 170.4 (rotamer), 168.0 and
167.3 (rotamer), 159.7, 154.7 and 153.8 (rotamer), 130.5, 127.6, 114.3, 83.3 and 82.9 (rotamer), 76.2,
67.8 and 67.5 (rotamer), 63.7 and 63.6 (rotamer), 55.7, 55.4, 44.0 and 43.0 (rotamer), 28.5, 14.3. IR (neat,
cm-1) 2979, 1759, 1714, 1514, 1370, 1298, 1250, 1177. MS (EI) m/z (rel intensity) 450 (M+, 40), 361 (40),
317 (80), 289 (80), 245 (50), 162 (40), 121 (100), 57 (50). HRMS (EI) calcd for C22H30N2O8: 450.2002,
found: 450.1996.
(R)-Ethyl 3-(tert-butoxycarbonyl((2-methoxyethoxy)methyl)amino)-1-(4-methoxybenzyl)-2,5-
dioxopyrrolidine-3-carboxylate (11)
Purified by preparative TLC (hexane: EtOAc=2:1). HPLC conditions: Daicel Chiralpak AD-H, hexane:
i-PrOH= 95:5, flow 1.0 mL/min., 254 nm, minor peak 12.8 min, major peak 15.0 min. Colorless oil.
[α]D20 (94% ee) -108 (c 0.9, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7
Hz, 2H), 5.32,5.14 (two br d, J=10.1 Hz, 10.1 Hz, ratio=5:4, 1H), 5.00, (d, J=10.1 Hz, 1H), 4.62 (ABq,
ΔνAB=0.049 Hz, J=14.2 Hz, 2H), 4.30-4.10 (m, 2H), 3.82, 3.68 (two d, J=18.8 Hz, 18.8 Hz, ratio=4:5,
1H), 3.77 (s, 3H), 3.41-3.27 (m, 2H), 3.24-3.10 (m, 2H), 3.20, 3.14 (two s, ratio=4:5, 3H), 2.92, 2.87 (two
d, J=12.4 Hz, 12.4 Hz, ratio=4:5, 1H), 1.46, 1.43 (two s, ratio=4:5, 9H), 1.20, 1.18 (two t, J=6.8 Hz, 6.8
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 174.6 and 174.3 (rotamer), 171.0 and 170.6 (rotamer), 168.2 and
167.4 (rotamer), 159.7, 154.7 and 154.0 (rotamer), 130.5, 127.7, 114.2, 83.2 and 82.9 (rotamer), 75.9 and
74.7 (rotamer), 71.6, 67.6 and 67.4 (rotamer), 63.6, 59.2, 55.6, 43.9 and 42.8 (rotamer), 42.9, 28.5, 14.3.
IR (neat, cm-1) 2979, 1758, 1713, 1515, 1395, 1299, 1250, 1088. MS (EI) m/z (rel intensity) 494 (M+, 10),
361 (10), 317 (80), 289 (60), 245 (40), 162 (40), 148 (30), 121 (100), 57 (40). HRMS (EI) calcd for
C24H34N2O9: 494.2264, found: 494.2266.
(R)-Ethyl-3-(tert-butoxycarbonyl((2-methoxyethoxy)methyl)amino)-2,5-dioxopyrrolidine-3-
carboxylate (12)
CAN (461 mg, 0.84 mmol) was added to a solution of 11 (210 mg, 0.42 mmol) in MeCN (6 mL) and H2O
(2 mL) at 0 °C, and the mixture was stirred at 0 °C for 4 h. Additional CAN (230 mg, 0.42 mmol) was
added and stirring was continued for additional 4 h. The reaction mixture was diluted with H2O and
extracted with EtOAc three times. Combined organic phase was washed with saturated aq. NaHCO3

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HETEROCYCLES, Vol. 76, No. 2, 2008
solution and brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by
preparative TLC (hexane: EtOAc= 1: 1) to give 12 (118 mg, 70% yield).
Colorless oil. [α]D20 (>99% ee) -129 (c 1.1, CHCl3,). 1H NMR (400 MHz, CDCl3) δ 9.27 (br s, 1H), 5.36,
5.18 (two d, J=10.1 Hz, 10.1 Hz, ratio=5:4, 1H), 5.02, 4.99 (two d, J=10.1 Hz, 10.1 Hz, ratio=4:5, 1H),
4.38-4.14 (m, 2H), 3.86, 3.74 (two d, J= 18.3 Hz, 18.3 Hz, ratio=4:5, 1H), 3.59-3.39 (m, 4H), 3.30 (s, 3H),
2.91 (d, J=18.3 Hz, 1H), 1.47, 1.44 (two s, ratio=4:5, 9H), 1.34-1.24 (m, 3H). 13C NMR (100 MHz,
CDCl3) δ 175.3 and 174.9 (rotamer), 171.5 and 171.0 (rotamer), 168.1 and 167.2 (rotamer), 154.6 and
153.9 (rotamer), 83.4 and 83.0 (rotamer), 76.1 and 74.9 (rotamer), 71.7, 68.8 and 68.4 (rotamer), 67.6,
63.7 and 63.6 (rotamer), 59.1, 44.7 and 43.5 (rotamer), 28.5, 14.3. IR (neat, cm-1) 3227, 2980, 1731, 1369,
1299, 1257, 1154, 1086, 857. MS (EI) m/z (rel intensity) 374 (M+, 1), 273 (20), 204 (40), 199 (100), 148
(80), 125 (50), 89 (40), 57 (60). HRMS (EI) calcd for C16H26N2O8: 374.1689, found: 374.1689.
(R)-Ethyl 3-amino-2,5-dioxopyrrolidine-3-carboxylate (1)
A solution of 12 (80 mg, 0.21 mmol) in EtOAc (1.0 mL) was added to a 4 M HCl solution in EtOAc (5.0
mL) at 0 °C, and the mixture was stirred at room temperature for 1 h. After concentration of the reaction
mixture in vacuo, the residue was dissolved in distillated water and purified by DOWEX 50W to give 11
(34 mg, 87% yield).
Determination of the absolute configuration of 10 and 11
Determination of the absolute configuration of 10 and 11 was performed by the transformation of (R)-11
into (R)-10 and (R)-11.
DIPEA (3.0 mL, 18 mmol) and Boc2O (2.50 g, 12 mmol) were added to a solution of (R)-1 (1.10 g, 5.9
mmol) in DCM (35 mL) at 0 °C, and the mixture was stirred at rt for 14 h. The reaction mixture was
evaporated and the residue was diluted with EtOAc and washed with a 10 % aq. citric acid solution,
saturated aq. NaHCO3 solution and brine, dried over Na2SO4, filtered and evaporated in vacuo. The
crude crystals were purified by recrystallization (hexane/Et2O/acetone) to give (R)-ethyl
3-(tert-butoxycarbonylamino)-2,5-dioxopyrrolidine-3-carboxylate (1.47 g, 87% yield).
1
Colorless crystals. [α]D20 (>99% ee) -45 (c 0.9, CHCl3). H NMR (400 MHz, CDCl3) δ 8.40 (br s, 1H),
6.00 (s, 1H), 4.32 (q, J=6.9 Hz, 2H), 3.17 (ABq, ΔνAB=34.2 Hz, J=18.3 Hz, 2H), 1.45 (s, 9H), 1.30 (t,
13
J=6.9 Hz, 3H). C NMR (100 MHz, CDCl3) δ 174.3, 173.1, 167.3, 154.8, 82.0, 64.9, 64.4, 41.4, 28.6,
14.3. IR (neat, cm-1) 3240, 2980, 2925, 1730, 1490, 1369, 1293, 1259, 1163, 1028. MS (EI) m/z (rel
intensity) 286 (M+, 1), 271 (5), 243 (50), 213 (40), 187 (100), 159 (60), 113 (30). Anal. Calcd for
C12H18N2O6: C, 50.35; H, 6.34; N, 9.79%. Found: C, 50.44; H, 6.25; N, 9.65%.
(R)-Ethyl 3-(tert-butoxycarbonylamino)-1-(4-methoxybenzyl)-2,5-dioxopyrrolidine-3-carboxylate
To a solution of (R)-ethyl 3-(tert-butoxycarbonylamino)-2,5-dioxopyrrolidine-3-carboxylate (1.47 g, 5.1
mmol) in DMF (50 mL) were added K2CO3 (2.1 g, 15.3 mmol), PMBCl (1.4mL, 10.2 mmol), and NaI

HETEROCYCLES, Vol. 76, No. 2, 2008
1605
(1.5 g, 10.2 mmol) at 0 °C and the mixture was stirred at room temperature for 4 h. The reaction
mixture was diluted with EtOAc and washed with H2O twice, dried over Na2SO4, filtered and evaporated
in vacuo. The residue was purified by column chromatography (hexane: EtOAc= 6: 1) to give (R)-Ethyl
3-(tert-butoxycarbonylamino)-1-(4-methoxybenzyl)-2,5-dioxopyrrolidine-3-carboxylate (2.00 g, 97%
yield).
Colorless oil. [α]D20 (>99% ee) -68 (c 1.0, CHCl3,). 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J=8.7 Hz, 2H),
6.82 (d, J=8.7 Hz, 2H), 5.98 (s, 1H), 4.70 (ABq, ΔνAB=47.1 Hz, J=14.2 Hz, 2H), 4.20-4.05 (m, 2H), 3.77
13
(s, 3H), 3.12 (ABq, ΔνAB=34.6 Hz, J=17.9 Hz, 2H) 1.44 (s, 9H), 1.03 (t, J=6.8 Hz, 3H). C NMR (100
MHz, CDCl3) δ 173.8, 172.7, 167.4, 159.6, 154.6, 130.3, 127.8, 114.2, 81.6, 64.0, 63.7, 55.6, 42.9, 40.3,
28.5, 13.9. IR (neat, cm-1) 3427, 2979, 1749, 1715, 1514, 1399, 1250, 1173, 1028. MS (EI) m/z (rel
intensity) 406 (M+, 25), 351 (20), 350 (90), 349 (20), 289 (10), 162 (20), 121 (100). Anal. Calcd for
C20H26N2O7: C, 59.10; H, 6.45; N, 6.89%. Found: C, 58.82; H, 6.59; N, 6.70%.
Sodium hexamethyldisilazide (1.68M in THF, 0.21 mL, 0.36 mmol) was added slowly to a solution of
(R)-ethyl-3-(tert-butoxycarbonylamino)-1-(4-methoxybenzyl)-2,5-dioxopyrrolidine-3-carboxylate (122
mg, 0.30 mmol) in THF (3.0 mL) and DMPU (0.18 mL, 1.50 mmol) at -78 °C under Ar. After stirring
for 30 min, MOMCl (68 µL, 0.90 mmol) was added and the resulting mixture was stirred for 15 h. The
reaction mixture was poured into saturated aq. NH4Cl solution and extracted with EtOAc twice. The
combined organic phase was washed with saturated aq. NaHCO3 solution and brine, dried over Na2SO4,
filtered and evaporated in vacuo. The residue was purified by preparative TLC (hexane: dioxane= 3: 1)
to give (R)-10 (37 mg, 27% yield).
(R)-11 was prepared from (R)-ethyl 3-(tert-butoxycarbonylamino)-1-(4-methoxybenzyl)-2,5-
dioxopyrrolidine-3-carboxylate (610 mg, 1.50 mmol) and MEMCl (0.51 mL, 4.50 mmol) according to the
procedure for (R)-10.
Purification was performed by preparative TLC (hexane: dioxane= 3: 1) to give
(R)-11 (336 mg, 45% yield).
ACKNOWLEDGEMENTS
This work was supported by Dainippon Sumitomo Pharma Co., Ltd. We are grateful to Watanabe
Chemical IND., Ltd. for generous supply of amino acids and the derivatives.
REFERENCES AND NOTES
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Matsumoto, J. Med. Chem., 1998, 41, 4118; M. Kurono, I. Fujiwara, and K. Yoshida, Biochemistry,
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Murata, B. Fujitani, and T. Negoro, Biochem. Pharmacol., 2006, 71, 338; N. Giannoukakis, Curr.

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Opin. Invest. Drugs, 2006, 7, 916.
2. T. Mashiko, K. Hara, D. Tanaka, Y. Fujiwara, N. Kumagai, and M. Shibasaki, J. Am. Chem. Soc.,
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Kawabata, K. Moriyama, S. Kawakami, and K. Tsubaki, J. Am. Chem. Soc., 2008, 130, 4153.
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J. Chen, H. Suzuki, Y. Nagae, T. Kinoshita, S. Chancharunee, and K. Fuji, Org. Lett., 2000, 2, 3883;
T. Kawabata, S. Kawakami, S. Shimada, and K. Fuji, Tetrahedron, 2003, 59, 965; T. Kawabata, J.
Chen, H. Suzuki, and K. Fuji, Synthesis, 2005, 1368.
5. The yield and ee of the Dieckmann condensation of 2 in various solvents are as follows: toluene;
12% yield, 61% ee: ether; 22% yield, 75% ee: diisopropyl ether; 18% yield, 72% ee: cyclopropyl
methyl ether; 17% yield, 67% ee: tert-butyl methyl ether; 24% yield, 78% ee.