Diastereo- And enantioselective conjugate addition of α-ketoesters to nitroalkenes catalyzed by a chiral Ni(OAc)2 complex under mild conditions

Article abstract of DOI:10.1021/ja909457b

(Figure Presented) A highly efficient, catalytic, dlastereo- and enantloselectlve conjugate addition of a-ketoesters to nltroalkenes has been devised. The reaction was applicable to various substrates. Notably, the combination of endogenous and exogenous bases was effective, allowing a small amount of the catalyst (0.1 -1 mol % NI) to promote the reaction efficiently. The synthetic utility of this reaction was demonstrated In the synthesis of substituted pyrrolidine derivatives, whose stereochemistry Is closely related to biologically Important natural products such as kainic add. Copyright

Full text of DOI:10.1021/ja909457b

Diastereo- and Enantioselective Conjugate Addition of α-Ketoesters to
Nitroalkenes Catalyzed by Chiral Ni(OAc) Complex under Mild Conditions
2
†
,‡,§
†
¶
†
Ayako Nakamura,
Sylvain Lectard, Daisuke Hashizume, Yoshitaka Hamashima, and Mikiko
,†
Sodeoka*
RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan, Graduate
School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama
3
38-8570, Exploratory Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi,
Nogi-Machi, Shimotsuga-Gun, Tochigi 329-0114, Japan, and Advanced Technology Support
Division, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
sodeoka@riken.jp
Supporting Information
(
A) Recent selected papers on catalytic asymmetric conjugate addition of pronucleophiles to
nitroalkenes
(
(
(
(
B) General
C) Preparation of α-ketoesters and nitroalkenes used in this work
D) Synthesis of metal catalysts
E) Optimization studies
(
(
(
E-1) Experimental procedure for optimization of the reaction of 1a with 2a
E-2) Solvent effect
E-3) Ester effect
(
(
(
(
(
F) Investigation on non-linear effect
G) General procedure for the conjugate addition of α-ketoesters to nitroalkenes
H) Application to the synthesis of kainoid analog 12
I) X-ray crystal structure analysis of 3a
J) NMR spectra
S-1

(
A) Recent selected papers on catalytic asymmetric conjugate addition of pronucleophiles to
nitroalkenes
1
,3-Dicarbonyls: (a) Li, X.-J.; Liu, K.; Ma, H.; Nie, J.; Ma, J.-A. Synlett 2008, 3242. (b) Janka, M.;
He, W.; Haedicke, I. E.; Fronczek, F. R.; Frontier, A. J.; Eisenberg, R. J. Am. Chem. Soc. 2006, 128,
5312. (c) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454. (d) Okino, T.; Hoashi,
Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (e) Watanabe, M.; Ikagawa,
A.; Wang, H.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2004, 126, 11148. (f) Evans, D. A.; Mito, S.;
Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583, and references therein.
Oxindoles: (g) Kato, Y.; Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.; Shibasaki, M. J.
Am. Chem. Soc. 2009, 131, 9168. (h) Bui, T.; Syed, S.; Barbas III, C. F. J. Am. Chem. Soc. 2009, 131,
8758. (i) He, R.; Shirakawa, S.; Maruoka, K. J. Am. Chem. Soc. 2009, 131, 16620.
Ketones and aldehydes: (j) Scroggins, S. T.; Chi, Y.; Fréchet, J. M. J. Angew. Chem. Int. Ed. 2009,
early view (anie.200902945). (k) RiRocco, D. A.; Oberg, K. M.; Dalton, D. M.; Rovis, T. J. Am.
Chem. Soc. 2009, 131, 10872. (l) Rasappan, R.; Reiser, O. Eur. J. Org. Chem. 2009, 1305. (m) Tan,
B.; Zeng, X.; Lu, Y.; Chua, P. J.; Zhong, G. Org. Lett. 2009, 11, 1927. (n) Mandal, T.; Zhao, C.-G.
Angew. Chem. Int. Ed. 2008, 47, 7714. (o) Wiesner, M.; Revell, J. D.; Wennemers, H. Angew. Chem.
Int. Ed. 2008, 47, 1871. (p) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441,
861. (q) Palomo, C.; Vera, S.; Mielgo, A.; Gómez-Bengoa, E. Angew. Chem. Int. Ed. 2006, 45, 5984.
(
r) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem. Int. Ed. 2007, 46, 4922. (s)
Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624. (t) Huang, H.; Jacobsen, E. N. J. Am.
Chem. Soc. 2006, 128, 7170. (u) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem. Eur. J.
2006, 12, 4321. (v) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas III, C. F. J. Am.
Chem. Soc. 2006, 128, 4966. (w) Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc.
2004, 126, 9558. (x) Wiesner, M.; Upert, G.; Angelici, G.; Wennemers, H. J. Am. Chem. Soc. 2010,
132, 6. (y) Zeng, Z.; Perkins, B. L.; Ni, B. J. Am. Chem. Soc. 2010, 132, 50.
Nitroalkanes: (z) Yang, X.; Zhou, X.; Lin, L.; Chang, L.; Liu, X.; Feng, X. Angew. Chem. Int. Ed.
008, 47, 7079. (aa) Rabalakos, C.; Wulff, W. D. J. Am. Chem. Soc. 2008, 130, 13524. (bb) Lu, S.-F.;
2
Du, D.-M.; Xu, J.; Zhang, S.-W. J. Am. Chem. Soc. 2006, 128, 7418.
-Furanone: (cc) Trost, B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572.
2
Heteroaromatics: (dd) Trost, B. M.; Müller, C. J. Am. Chem. Soc. 2008, 130, 2438. (ee) Arai, T.;
Yokoyama, N. Angew. Chem. Int. Ed. 2008, 47, 4989.
(
B) General
1
1
13
NMR spectra were recorded at 400 MHz for H-NMR, 100.4 MHz for C-NMR, or at 500 MHz
1
13
for H-NMR, 125.8 MHz for C-NMR. Chemical shifts were reported downfield from TMS (= 0) for
S-2

1
13
3
H-NMR. For C-NMR, chemical shifts were reported in the scale relative to CDCl or acetone as an
internal reference. FAB-LRMS and HRMS were taken using m-nitrobenzyl alcohol (mNBA) or
glycerol as matrix. IR was measured by attenuated total reflectance (ATR). Flash column
chromatography was performed with silica gel N 60 (40-100 µm). In some case, purification was
carried out using medium pressure liquid chromatography (MPLC) or precoated thin layer
chromatography (TLC) plates (silica gel 60 F254, 0.50 mm). Precoated TLC plates (silica gel 60 F254
.25 mm) were used for the TLC analysis. The enantiomeric excesses (ees) were determined by chiral
HPLC analysis. Dehydrated solvents used in this paper were purchased and used directly without
further purification. Triethylamine was distilled from calcium hydride. Pd(OAc) , Ni(OAc) ·4H O,
Cu(OAc) ·2H O, Zn(OAc) ·2H O, NiBr , (R)-BINAP and (S,S)-(-)-tert-Bu-BOX were obtained from
,
0
2
2
2
2
2
2
2
2
commercial source and were used as received. Other reagents were purified by usual methods. Known
ligands and nitroalkenes were prepared according to literature procedures.
(
(
C) Preparation of α-ketoesters and nitroalkenes used in this work
C-1) General procedure for α-ketoesters
1
General procedure A
1
1
) Mg, R CH Br
2
O
Et O
O
2
Ot-Bu
R1
t-BuO
2
) THF, -78 ºC
CO t-Bu
2
O
Magnesium turnings (0.29 g, 11.9 mmol) were placed inside 3-necked flask. Diethyl ether (2 mL)
and a piece of iodine were added, and the resulting mixture was stirred until the yellow color of iodine
had faded out. The alkyl bromide (16.4 mmol) in diethyl ether (3 mL) was added dropwise over 30
min at 0 °C. The reaction mixture was stirred for 1 h. To di-tert-butyl-glyoxylate (2.00 g, 11.9 mmol)
in dichloromethane (20 mL) was added the resulting Grignard solution by dropwise over 30 min at
-
78 °C. The reaction mixture was stirred for 1 h at -78 °C and quenched with saturated aqueous
NH Cl (20 mL). The aqueous layer was extracted with dichloromethane (15 mL x 3). The combined
organic layers were washed with brine, then dried over Na SO , and concentrated under reduced
), followed by recrystallization from
4
2
4
pressure. Further purification by column chromatography (SiO
2
n-hexane/diethyl ether gave the product.
1
Weinstock, L. M.; Currie, R. B.; Lovell, A. V. Synth. Commun. 1981, 11, 943.
S-3

2
General procedure B
step1
step2
O
1
1
) Mg, R CH Br
2
O
1
) t-BuOH
THF, 0 ºC
MeO
Ot-Bu
O
Et O
2
N
Cl
Cl
R1
Me
O
CO t-Bu
2) THF, -78 ºC
2
2
) MeO(Me)NH⋅HCl
O
S1
Step1: tert-Butanol (24 mL, 251 mmol) was added in one batch to a solution of oxalyl chloride
distilled, 22 mL, 257 mmol) in THF (400 mL) at 0 °C under N atmosphere. After 1 h, N,
(
2
O-dimethylhydroxylamine hydrochloride (25.0 g, 256 mmol) and triethylamine (107 mL, 769 mmol)
were added and the solution was stirred for 2 h. Water (200 mL) was added, and THF was evaporated
under reduced pressure. The aqueous layer was extracted with ethyl acetate (100 mL x 3). The
combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na
concentrated under reduced pressure. The residue was purified by column chromatography (SiO
n-hexane/ethyl acetate = 5:1) to give mono-tert-butyloxalic acid-N-methoxy-N-methylamide (S1) in
1% yield as a slightly yellow oil (33.7 g).
2 4
SO and
2
,
7
mono-tert-Butyloxalic acid-N-methoxy-N-methylamide (S1)
IR (neat) ν 2982, 2941, 1736, 1674, 1260, 1151, 1090, 993, 844 cm ; H-NMR (400 MHz, CDCl
-1 1
3
) δ
) δ 162.2, 161.7, 84.3, 62.1, 31.3,
1
3
3
2
.75 (s, 3H), 3.20 (s, 3H), 1.56 (s, 9H); C-NMR (100 MHz, CDCl
3
+
8.0; MS (CI+) m/z 190 [M+H] ; HRMS (CI+) calcd for C H NO 190.1079, found 190.1066.
8
16
4
Step2: Magnesium turnings (972 mg, 40.0 mmol) were placed inside 3-necked flask. Diethyl ether (5
mL) and a piece of iodine were added, and the resulting mixture was stirred until the yellow color of
iodine had faded out. The alkyl bromide (30.0 mmol) in diethyl ether (5 mL) was added dropwise
over 30 min at 0 °C. The reaction mixture was stirred for 1 h. To S1 (3.78 g, 20.0 mmol) in
dichloromethane (75 mL) was added the Grignard solution dropwise over 30 min at -78 °C. The
mixture was stirred at -78 °C for 1.5 h and quenched with saturated aqueous NH
aqueous layer was extracted with dichloromethane (50 mL x 3). The combined organic layers were
washed with brine (100 mL), then dried over Na SO and concentrated under reduced pressure. The
4
Cl (75 mL). The
2
4
residue was purified by column chromatography, and distillation or recrystallization gave the pure
product.
2
(
a) Nimitz, J. S.; Mosher, H. S. J. Org. Chem. 1981, 46, 211. (b) Heras, M. A; Vaquero, J. J.;
Garcia-Navio, J. L.; Alvarez-Builla, J. J. Org. Chem. 1996, 61, 9009. (c) Chiu, C. C.; Jordan, F. J. Org.
Chem. 1994, 59, 5763.
S-4

3
O
tert-Butyl 2-oxo-4-phenylbutanoate (1a)
The title compound was prepared according to the general procedure A
using 2-bromoethylbenzene as the bromide and purified by column
CO t-Bu
2
2
chromatography (SiO , n-hexane/ethyl acetate = 10:1), followed by
recrystallization from n-hexane/diethyl ether to give 1a in 52% yield as colorless crystals.
-1 1
Mp 52-53 °C; IR (neat) ν 2984, 1738, 1367, 1251, 1155, 1082, 833, 753 cm ; H-NMR (400 MHz,
1
3
CDCl
3
) δ 7.34-7.13 (m, 5H), 3.11 (t, J = 7.6 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H), 1.52 (s, 9H); C-NMR
(
100 MHz, CDCl ) δ 194.5, 160.3, 140.2, 128.5, 128.3, 126.2, 84.0, 40.9, 29.2, 27.8; MS (CI+) m/z
3
+
2
19 3
35 [M+H] ; HRMS (CI+) calcd for C14H O 235.1334, found 235.1338.
3
O
tert-Butyl 4-(4’-methoxyphenyl)-2-oxobutanoate (S2)
CO t-Bu The title compound was prepared according to the general procedure
2
A using 4-methoxyphenethyl bromide as the bromide and purified by
MeO
column chromatography (SiO
2
, n-hexane/ethyl acetate = 10:1, and
then SiO
2
, dichloromethane/n-hexane = 1:2 to 2:1) to give the product in 57% yield as a colorless
solid. Before use, the solid was recrystallized from n-hexane/diethyl ether to give S2 as a
microcrystalline colorless powder.
-1 1
Mp 62-63 °C; IR (neat) ν 2985, 1715, 1511, 1260, 1242, 1156, 1078, 1015 cm ; H-NMR (400 MHz,
CDCl ) δ 7.11 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H), 3.07 (t, J = 7.6 Hz, 2H), 2.88
3
1
3
(
t, J = 7.6 Hz, 2H), 1.53 (s, 9H); C-NMR (100 MHz, CDCl
3
) δ 194.6, 160.3, 158.0, 132.2, 129.3,
+
1
13.9, 84.0, 55.3, 41.1, 28.3, 27.8; MS (EI+) m/z 264 [M] ; HRMS (EI+) calcd for C15
H
20
O
4
264.1362, found 264.1398.
3
O
tert-Butyl 4-(4’-chlorophenyl)-2-oxobutanoate (S3)
CO t-Bu
The title compound was prepared according to the general procedure
B using 4-chlorophenethyl bromide as the bromide and purified by
2
Cl
2
column chromatography (SiO , n-hexane/ethyl acetate = 8:1) to give
the product in 75% yield as a pale yellow oil. The product was further purified by recrystallization
from n-hexane/diethyl ether to give S3 in 46% yield as colorless crystals.
-1
1
Mp 50-52 °C; IR (neat) ν 2980, 1742, 1366, 1252, 1154, 1082, 1016 cm ; H-NMR (400 MHz,
CDCl ) δ 7.25 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 3.09 (t, J = 7.6 Hz, 2H), 2.91 (t, J = 7.6
3
3
Rueppel, M. L.; Rapoport, H. J. Am. Chem. Soc. 1972, 94, 3877.
S-5

1
3
Hz, 2H), 1.53 (s, 9H); C-NMR (100 MHz, CDCl
3
) δ 194.2, 160.1, 138.6, 132.0, 129.7, 128.6, 84.1,
+
4
0.6, 28.5, 27.8; MS (CI+) m/z 269 [M+H] ; HRMS (CI+) calcd for C14
H
18ClO
3
269.0944, found
269.0974.
4
O
tert-Butyl 2-oxobutanoate (S4)
CO t-Bu
Di-tert-butyl-glyoxylate (2.02 g, 10.0 mmol) was dissolved in THF (6 mL) and
2
diethyl ether (14 mL) and cooled to -78 °C. The ethyl magnesium bromide (1.0 M
in THF, 10 mL) was added dropwise over 30 min with stirring. The solution was allowed to warm up
to room temperature over 4.5 h and quenched with saturated aqueous NH Cl (20 mL). The resulting
mixture was extracted with diethyl ether (20 mL x 3). The combined organic layers were washed with
brine (20 mL), dried over Na SO and concentrated under reduced pressure. The residue was purified
by column chromatography (SiO , n-hexane/ethyl acetate = 100:0 to 5:1) and distillation (18 mmHg,
0 °C) gave S4 in 30% as a colorless oil (0.47 g).
4
2
4
2
9
-
1 1
IR (neat) ν 2982, 2941, 1721, 1099 cm ; H-NMR (400 MHz, CDCl
3
) δ 2.80 (q, J = 7.2 Hz, 2H), 1.55
) δ 196.0, 160.6, 83.8, 32.6, 27.9, 7.1;
159.1021, found 159.1047.
1
3
(
s, 9H), 1.11 (t, J = 7.2 Hz, 3H); C-NMR (100 MHz, CDCl
3
+
MS (CI+) m/z 159 [M+H] ; HRMS (CI+) calcd for C
8
15
H O
3
O
tert-Butyl 2-oxohex-5-enoate (S5)
The title compound was prepared according to the general procedure A using
-bromo-1-butene as the bromide and purified by column chromatography
, n-hexane/diethyl ether = 15:1, and then SiO , n-hexane/dichloromethane = 2:1) to give S5 in
1% yield as a pale yellow oil.
IR (neat) ν 3081, 2982, 1720, 1642, 1138, 1070 cm ; H-NMR (400 MHz, CDCl
H), 5.06 (dd, J = 17.1, 1.5 Hz, 1H), 5.01 (dd, J = 10.0 Hz, 1H), 2.88 (t, J = 7.3 Hz, 2H), 2.37
CO t-Bu
2
4
(
SiO
2
2
5
-1 1
3
) δ 5.89-5.74 (m,
1
1
3
(
apparent q, J = 7.1 Hz, 2H), 1.55 (s, 9H); C-NMR (100 MHz, CDCl ) δ 194.7, 160.4, 136.2, 115.7,
3
+
8
3.9, 38.3, 27.8, 27.1; MS (CI+) m/z 185 [M+H] ; HRMS (CI+) calcd for C10
17 3
H O 185.1178, found
185.1179.
tert-Butyl 3-cyclohexyl-2-oxopropanoate (S6)
O
The title compound was prepared according to the general procedure A
using (bromomethyl)cyclohexane as the bromide and purified by column
CO t-Bu
2
4
Hari, Y.; Tanaka, S.; Takuma, Y.; Aoyama, T. Synlett 2003, 14, 2151.
S-6

2
chromatography (SiO , n-hexane/ethyl acetate = 20:1) to give S6 in 31% yield as a colorless oil.
-1 1
IR (neat) ν 2924, 2853, 1718, 1162, 1143, 1047 cm ; H-NMR (400 MHz, CDCl ) δ 2.63 (d, J = 6.8
3
Hz, 2H), 1.94-1.79 (m, 1H), 1.77-1.61 (m, 5H), 1.54 (s, 9H), 1.41-1.08 (m, 3H), 1.04-0.91 (m, 2H);
1
3
C-NMR (100 MHz, CDCl
3
) δ 195.3, 160.9, 83.8, 46.6, 33.7, 33.2, 28.0, 26.2, 26.1; MS (CI+) m/z
+
2
27 [M+H] ; HRMS (CI+) calcd for C13
H
23
O
3
227.1647, found 227.1655.
O
tert-Butyl 5-(benzyloxy)-2-oxopentanoate (S7)
BnO
CO t-Bu
The title compound was prepared according to the general procedure A
using benzyl 3-bromopropylether as the bromide and purified by
2
column chromatography (SiO
to give S7 in 52% yield as a colorless oil.
IR (neat) ν 2980, 2861, 1718, 1369, 1162, 1099, 1029, 736, 698 cm ; H-NMR (400 MHz, CDCl ) δ
2
, n-hexane/ethyl acetate = 10:1, and then n-hexane/ethyl acetate = 5:1)
-1 1
3
7
.42-7.36 (m, 5H), 4.46 (s, 2H), 3.49 (t, J = 6.1 Hz, 2H), 2.89 (t, J = 7.1 Hz, 2H), 1.95 (tt, J = 7.1, 6.1
1
3
Hz, 2H), 1.52 (s, 9H); C-NMR (100 MHz, CDCl
3
) δ 195.0, 160.3, 138.1, 128.2, 127.5, 127.4, 83.6,
+
7
2.8, 68.8, 36.1, 27.8, 23.7; MS (CI+) m/z 279 [M+H] ; HRMS (CI+) calcd for C16
H
23
O
4
279.1569,
found 279.1586.
tert-Butyl tetrahydro-2-hydroxyfuran-2-carboxylate (S8)
OH
CO t-Bu
O
2
A solution of S7 (200 mg, 0.719 mmol) in methanol (2.5 mL) with 10% Pd/C (10
wt%) was submitted to a hydrogen atmosphere for 18 h. The mixture was filtered
through a pad of celite to remove Pd/C. After evaporation, the residue was purified by column
chromatography (SiO , n-hexane/ethyl acetate = 5:1 to 0:100) to give S8 in 66% as a colorless oil.
2
-1 1
IR (neat) ν 3455 (br), 2980, 2884, 1729, 1143, 1053 cm ; H-NMR (400 MHz, CDCl
3
) δ 4.15-4.06
(
m, 1H), 4.00 (s, 1H), 4.00-3.93 (m, 1H), 2.41-2.29 (m, 1H), 2.18-2.07 (m, 1H), 2.07-1.96 (m, 2H),
1
3
1
2
.51 (s, 9H); C-NMR (100 MHz, CDCl ) δ 170.1, 102.3, 83.0, 69.4, 35.0, 27.9, 25.5; MS (FAB) m/z
3
+
11 [M+Na] ; HRMS (FAB) calcd for C
9
H
16NaO
4
211.0946, found 211.0943.
(
C-2) General procedure for nitro-alkenes
5
b
5b
1
-Methoxy-4-[(E)-2-nitrovinyl]benzene , 1-bromo-4-[(E)-2-nitrovinyl]benzene ,
5
c
5d
2
-[(E)-2-nitrovinyl]furan , and [(E)-2-nitrovinyl]cyclohexane were prepared according to the
S-7

5
a
reported procedure.
ｔe rt-Butyldimethylsilyl [(E)-4-nitro-but-3-enyl]ether (S9)
NO2
TBSO
To a solution of 3-(tert-butyldimethylsilanoxy)propionaldehyde (1.17 g,
6
.21 mmol) and nitromethane (1.7 mL, 31.1 mmol) was added
triethylamine (86 µL, 0.62 mmol) dropwise at room temperature. The reaction mixture was stirred for
h at room temperature then filtered through a pad of SiO (n-hexane/ethyl acetate = 1:1). The filtrate
8
2
was concentrated under reduced pressure to yield the crude nitro-alcohol, which was used in the next
step without further purification.
The crude nitro-alcohol was dissolved in dichloromethane (30 mL) at 0 ºC. Methanesulfonyl
chloride (0.96 mL, 12.4 mmol) and diisopropylethylamine (3.8 mL, 21.7 mmol) were added
successively and the mixture was stirred at 0 ºC for 30 min and at room temperature for 15 min. Brine
(
20 mL) was added and the aqueous phase was separated. The aqueous layer was extracted with
dichloromethane (15 mL x 3). The combined organic layers were dried over MgSO , filtered and
4
concentrated under reduced pressure. The residue was purified by column chromatography (SiO2,
n-hexane/ethyl acetate = 20:1) to give S9 in 43% yield as a yellow oil (619 mg).
-1 1
IR (neat) ν 2954, 2929, 2857, 1650, l529, 1472, 1351, 1254, 1096, 971, 832, 775 cm ; H-NMR (400
MHz, CDCl ) δ 7.29 (dt, J = 13.5, 7.3 Hz, 1H), 7.05 (dt, J = 13.5, 1.5 Hz, 1H), 3.78 (t, J = 6.0 Hz,
3
1
3
2
H), 2.47 (dtd, J = 7.3, 6.0, 1.5 Hz, 2H), 0.89 (s, 9H), 0.06 (s, 6H); C-NMR (100 MHz, CDCl
3
) δ
+
1
40.5, 139.7, 60.6, 31.8, 25.8, 18.2, -5.4; MS (FAB) m/z 254 [M+Na] ; HRMS (FAB) calcd for
C H NNaO Si 254.1183, found 254.1194.
1
0
21
3
N-Methoxy-N-methyl-3-nitroacrylamide (S10)
O
O
1
) KOAc, CH NO
3
2
MeO
MeO
H
N
N
Me
S10
Me
O
2) MsCl, Et
3
N
NO2
CH Cl , -20 ºC
2
2
Step1. Potassium acetate (0.94 g, 9.57 mmol) was added to
a
solution of
6
formyl-N-methoxy-N-methylformamide (1.12 g, 9.57 mmol) in nitromethane (10 mL) under N
2
atmosphere. The mixture was stirred for 1.5 h and quenched with water (10 mL). The aqueous layer
5
(
a) McNulty, J.; Steere, J. A.; Wolf, S. Tetrahedron Lett. 1998, 39, 8013. (b) Batra, S.; Sabnis, Y. A.;
Rosenthal, P. J.; Avery, M. A. Bioorg. Med. Chem. 2003, 11, 2293. (c) Mahmood, S. Y.; Lallemand,
M.-C.; Sader-Bakaouni, L.; Charton, O.; Vérité, P.; Dufat, H.; Tillequin, F. Tetrahedron 2004, 60,
5
105. (d) Trost, B. M.; Müller, C. J. Am. Chem. Soc. 2008, 130, 2438.
Parhi, A. K.; Frank, R. W. Org. Lett. 2004, 6, 3063.
6
S-8

was extracted with diethyl ether (20 mL x 3). The combined organic layers were washed with brine
20 mL), dried over Na SO and concentrated under reduced pressure. The residue was purified by
, n-hexane/ethyl acetate = 1:2) to give nitro-alcohol in 55% yield as a
(
2
4
column chromatography (SiO
2
colorless oil (0.94 g).
1
H-NMR (400 MHz, CDCl
3
) δ 5.00 (ddd, J = 7.6, 7.1, 3.2 Hz, 1H), 4.75 (dd, J = 12.7, 3.2 Hz, 1H),
1
3
4
.51 (dd, J = 12.7, 7.6 Hz, 1H), 3.81 (d, J = 7.1 Hz, 1H), 3.80 (s, 3H), 3.31 (s, 3H); C-NMR (100
MHz, CDCl ) δ 169.2, 77.8, 66.6, 61.8, 32.7.
3
Step2. Triethylamine (2.04 mL, 14.7 mmol) was added to a solution of nitro-alcohol (0.87 g, 4.91
mmol) and methanesulfonyl chloride (1.14 mL, 14.7 mmol) in dichloromethane (12 mL) at -20 °C
under N
2
atmosphere. The reaction mixture was stirred for 15 min at -20 °C and then quenched with
water (10 mL). The aqueous layer was extracted with dichloromethane (10 mL x 3). The combined
organic layers were washed with brine (10 mL), dried over Na
pressure. The residue was purified by column chromatography (SiO
:1) to give S10 in 84% yield as a pale yellow solid (0.66 g).
Mp 36-38 °C; IR (neat) ν 3115, 2991, 1660, 1626, 1512, 1354, 947 cm ; H-NMR (400 MHz, CDCl
2
SO
4
and concentrated under reduced
2
, n-hexane/ethyl acetate = 2:1 to
1
-1 1
3
)
1
3
δ 7.73 (d, J = 13.2 Hz, 1H), 7.68 (d, J = 13.2 Hz, 1H), 3.79 (s, 3H), 3.32 (s, 3H); C-NMR (100 MHz,
+
CDCl
3
) δ 161.7, 148.5, 126.0, 62.6, 32.5; MS (EI+) m/z 160 [M] ; HRMS (EI+) calcd for C
5
H
8
N
2
O
4
160.0484, found for 160.0465.
(
(
D) Synthesis of metal catalysts
D-1) Preparation of palladium complex 5
7
The palladium µ-hydroxo complex 5 was prepared according to the reported procedures.
(D-2) Preparation of diamine ligands
8
a
(
R,R)-N,N’-Dibenzylcyclohexane-1,2-diamine 7 and (R,R)-N,N’-dibenzyl-1,2-diphenyl-1,2-ethane-
7
(
a) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450. (b) Hamashima, Y.;
Yagi, K.; Takano, H.; Tamás, L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530. (c) Dubs, C.;
Hamashima, Y.; Sasamoto, N.; Seidel, T. M.; Suzuki, S.; Hashizume, D.; Sodeoka, M. J. Org. Chem.
2008, 73, 5859.
8
(
a) Denmark, S. E.; Stadler, H.; Dorow, R. L.; Kim, J. H. J. Org. Chem. 1991, 56, 5063. (b) Hamada,
T.; Manabe, K.; Kobayashi, S. Angew. Chem. Int. Ed. 2003, 42, 3927. (c) Hamada, T.; Manabe, K.;
S-9

8
a-c
8a,d
diamine 8 were prepared according to the reported procedure.
1
7
2
1
8
: H-NMR (400 MHz, CDCl
3
) δ 7.36-7.18 (m, 10H), 3.89 (d, J = 13.2 Hz, 2H), 3.65 (d, J = 13.2 Hz,
H), 2.32-2.21 (m, 2H), 2.20-2.08 (m, 2H), 1.84 (br s, 2H), 1.78-1.63 (m, 2H), 1.31-1.15 (m, 2H),
13
.12-0.94 (m, 2H); C-NMR (100 MHz, CDCl
3
) δ 141.0, 128.2, 128.0, 126.6, 60.9, 50.9, 31.6, 25.1.
1
: H-NMR (400 MHz, CDCl ) δ 7.31-7.03 (m, 20H), 3.71 (s, 2H), 3.66 (d, J = 13.5 Hz, 2H), 3.49 (d,
3
1
3
J = 13.5 Hz, 2H); C-NMR (100 MHz, CDCl
3
) δ 141.0, 140.5, 128.2, 128.0, 127.9, 127.9, 126.8,
126.7, 68.3, 51.4.
(D-3) Preparation of isolated nickel-diamine complex
A mixture of diamine 7 (123 mg, 0.418 mmol) and nickel acetate tetrahydrate (104 mg, 0.418
mmol) in ethanol (17 mL) was stirred for 1.5 h at room temperature. The resulting solution was
filtered through a membrane filter. The filtrate was concentrated under reduced pressure. The residue
was dissolved in dichloromethane and concentrated under reduced pressure to give the complex as a
blue powder (197 mg).
(
(
E) Optimization studies
E-1) Experimental procedure for optimization of the reaction of 1a with 2a.
Metal acetate n hydrate (5 mol%) and corresponding ligand (5 mol%) were combined under N2
atmosphere in 2-propanol (100 µL) and the mixture was stirred for 30 min at room temperature.
tert-Butyl 2-oxo-4-phenylbutanoate (1a, 23.4 mg, 0.100 mmol) and trans-β-nitrostyrene (2a, 15.0 mg,
0
.101 mmol) were added to the resulting solution and the mixture was stirred for the time given in the
main text (Table 1). During the reaction, the product started to precipitate out, and the resulting
suspension was dissolved in ethyl acetate (1 mL). The solution was passed through a pad of SiO and
2
1
concentrated under reduced pressure. H-NMR of the residue was measured to determine the
diastereomeric ratio. Purification by MPLC gave pure products.
Ph
O
(3R,4R)-tert-Butyl 3-benzyl-5-nitro-2-oxo-4-phenylpentanoate (3a)
The title compound was prepared according to the experimental procedure
and purified by MPLC (n-hexane/ethyl acetate = 9:1) to give 3a as a
colorless solid. Single recrystallization from IPA gave optically pure
O N
2
CO t-Bu
2
Bn
Kobayashi, S. Chem. Eur. J. 2006, 12, 1205. (d) Corey, E. J.; Jardine, P. D.; Virgil, S.; Yuen, P.;
Connell, R. D. J. Am. Chem. Soc. 1989, 111, 9243.
S-10

compound in 79% (>99% ee).
Mp 135-136 °C; IR (neat) ν 2983, 2937, 1733, 1540, 1284, 1157, 700 cm ; H-NMR (400 MHz,
CDCl ) δ 7.16-7.34 (m, 8H), 7.11 (d, J = 7.3 Hz, 2H), 4.81 (dd, J = 12.7, 5.4 Hz, 1H), 4.75 (dd, J =
2.7, 9.3 Hz, 1H), 4.22 (apparent q, J = 8.0 Hz, 1H), 3.93 (apparent td, J = 9.3, 5.4 Hz, 1H), 2.99 (d, J
-1
1
3
1
1
3
=
8.0 Hz, 2H), 1.28 (s, 9H); C-NMR (100 MHz, CDCl
3
) δ 196.2, 159.1, 137.0, 136.6, 129.0, 128.9,
+
1
28.7, 128.1, 128.1, 126.9, 84.1, 77.7, 50.8, 45.6, 35.9, 27.5; MS (CI+) m/z 384 [M+H] ; HRMS
3
0
(
CI+) calcd for C H NO 384.1811, found 384.1809; [α]
3
+34.2 (c 1.01, CHCl ) (>99% ee);
2
2
26
5
D
HPLC (DAICEL CHIRALCEL OD-H, n-hexane/IPA = 9:1, 1.0 mL/min, 254 nm, τminor 22.8 min,
τmajor 59.6 min).
Before recrystallization (93% ee)
After recrystallization (>99% ee)
HO CO t-Bu
2
Bn
Ph
NO2
(
1R,2R,3R,4S,5R,6S)-tert-Butyl-2-benzyl-1-hydroxy-4,6-dinitro-3,5-diphenyl-
Ph
cyclohexanecarboxylate (4a)
NO2
The title compound was prepared according to the experimental procedure and
purified by MPLC (n-hexane/ethyl acetate = 9:1) to give 4a as a colorless solid.
-1
1
Mp 159-161 °C (n-hexane/ethyl acetate); IR (neat) ν 3445, 2984, 1721, 1550, 700 cm ; H-NMR
400 MHz, CDCl ) δ 7.41-7.18 (m, 13H), 6.90-6.80 (m, 2H), 5.26 (d, J = 12.2 Hz, 1H), 5.17 (dd, J =
2.4, 6.4 Hz, 1H), 4.56 (t, J = 12.4 Hz, 1H), 4.25 (s, 1H), 3.63 (t, J = 6.4 Hz, 1H), 3.07-2.97 (m, 1H),
(
3
1
2
1
1
3
.59-2.46 (m, 2H), 1.66 (s, 9H); C-NMR (100 MHz, CDCl
3
) δ 171.2, 137.2, 134.7, 131.9, 128.8,
28.7, 128.5, 128.4, 128.3, 128.1, 126.8, 92.6, 90.3, 86.5, 77.6, 47.2, 45.7, 40.4, 33.7, 28.0; MS (ESI-)
-
29
m/z 531 [M-H] ; HRMS (ESI-) calcd for C30
.19, CHCl ) (93% ee); HPLC (DAICEL CHIRALPAK IA, n-hexane/IPA = 9:1, 1.0 mL/min, 254 nm,
τminor 10.5 min, τmajor 18.2 min).
H
31
N
2
O
7
531.21313, found 531.21322; [α]
D
+41.7 (c
0
3
S-11

(
E-2) Solvent effect
The reactions in usual organic solvents basically took longer time to reach >70% yield.
O
HO CO t-Bu
2
Bn
Ph
NO2
Ph
CO t-Bu Ni(OAc) •(H O) + 7 (1:1)
Ph
O
2
2
2
4
O N
2
(5 mol %)
1a
CO t-Bu
+
2
+
Ph
solvent, rt
Bn
3a
NO2
NO2
4a
Ph
2a
Entry
Solvent
Time
h)
3a
yield (%)
%ee]b
epi-3a
yield (%)a
4a
yield (%)a
(
a
[
1
2
3
4
5
6
ethanol
12
48
53
24
29
6
58 [83]
78 [46]
75 [85]
81 [79]
79 [94]
trace
-
11
2,2,2-trifluoroethanol
dichloromethane
toluene
7
13
9
13
not detected
4
not detected
trace
THF
dimethoxyethane
91 [92] not detected
a
b
Isolated yield based on 1a. The ee was determined by chiral HPLC analysis.
c
The catalyst was prepared in situ.
(
E-3) Ester effect
The corresponding ethyl ester gave a lower enantioselectivity.
Ni(OAc) •(H O) + 7 (1:1)
2
2
4
Ph
O
O
(1 mol %)
NO2
O N
2
+
Ph
CO Et
2
Ph
CO Et
2
Et N (5 mol %)
3
Bn
5% (75% ee)
2-propanol, rt, 4 h
6
(F) Investigation on non-linear effect
S-12

In order to obtain insight into the mechanism of the reaction, the relationship between the
2
enantiomeric excess values of 3a and ligand 7 was investigated. The linear relationship (R = 0.9957)
was observed and it suggests that the active catalyst is a monomeric species.
100
2
R = 0.9957
90
80
70
60
50
40
30
20
10
0
0
10
20
30
40
50
60
70
80
90
100
%
ee of ligand 7
(
G) General procedure of the conjugate addition of α-ketoesters to nitroalkenes for generality of
the reaction
Ni(OAc)
2
·(H
2
O)
4
+ 7 complex (isolated, 0.5 mg, 1 mol % or 2.5 mg, 5 mol %) and triethylamine
atmosphere in 2-propanol (100 µL) at room temperature.
(
0.7 µL, 5 mol %) were combined under N
2
α-Ketoester (0.100 or 0.150 mmol) and nitroalkene (0.101 mmol) were added to the resulting mixture
and the mixture was stirred for the time given in the main text (Chart 1). During the reaction, the
product started to precipitate out, and the resulting suspension was dissolved in ethyl acetate (1 mL).
2
The solution was passed through a pad of SiO . After evaporation of solvent, the residue was purified
by MPLC or preparative thin layer chromatography to give the corresponding product.
tert-Butyl 3-(4’-methoxybenzyl)-5-nitro-2-oxo-4-phenylpentanoate
Ph
O
O N
2
(3b)
CO t-Bu
2
The title compound was prepared according to the general procedure
and purified by MPLC (n-hexane/ethyl acetate = 9:1) to give 3b in 82%
yield as a colorless solid.
p-MeO-C H
6
4
S-13

-1
Mp 142-143 °C (n-hexane/ethyl acetate); IR (neat) ν 2982, 1722, 1538, 1287, 1255, 1158, 1026 cm ;
1
H-NMR (400 MHz, CDCl
3
) δ 7.35-7.15 (5H, m), 7.03 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H),
4
.80 (dd, J = 12.9, 5.4 Hz, 1H), 4.73 (dd, J = 12.9, 9.3 Hz, 1H), 4.18 (td, J = 8.8, 6.6 Hz, 1H), 3.91 (td,
1
3
J = 9.3, 5.4 Hz, 1H), 2.99-2.90 (m, 2H), 1.29 (s, 9H); C-NMR (100 MHz, CDCl
3
) δ 196.4, 159.1,
158.4, 136.7, 129.9, 128.9, 128.8, 128.1, 114.1, 84.1, 77.8, 55.2, 51.0, 45.6, 35.1, 27.5; MS (CI+) m/z
+
29
4
14 [M+H] ; HRMS (CI+) calcd for C23
H
28NO
6
414.1917, found for 414.1907; [α]
D
+28.7 (c 1.01,
CHCl ) (91% ee); HPLC (DAICEL CHIRALCEL OD-H, n-hexane/IPA = 9:1, 1.0 mL/min, 254 nm,
3
τminor 29.9 min, τmajor 35.5 min).
tert-Butyl 3-(4’-chlorobenzyl)-5-nitro-2-oxo-4-phenylpentanoate
(3c)
Ph
O
O N
2
CO t-Bu
2
The title compound was prepared according to the general procedure
and purified by MPLC (n-hexane/ethyl acetate = 9:1) to give 3c in 75%
yield (93% ee) as a colorless solid. Single recrystallization from IPA
p-Cl-C H4
6
gave optically pure compound in 63% (>99% ee).
Mp 113-114 °C; IR (neat) ν 3448, 2981, 1722, 1558, 1493, 1362, 1281, 1135, 759, 699 cm ; H-NMR
400 MHz, CDCl ) δ 7.35-7.16 (m, 7H), 7.04 (d, J = 8.3 Hz, 2H), 4.81 (dd, J = 12.9, 6.1 Hz, 1H),
.77 (dd, J = 12.9, 8.4 Hz, 1H), 4.19 (dt, J = 8.1, 7.6 Hz, 1H), 3.92 (ddd, J = 8.4, 8.1, 6.1 Hz, 1H),
-1 1
(
3
4
2
1
1
3
.95 (d, J = 7.6 Hz, 2H), 1.30 (s, 9H); C-NMR (100 MHz, CDCl ) δ 195.8, 159.1, 136.3, 135.4,
3
32.7, 130.2, 129.0, 128.7, 128.2, 128.0, 84.4, 77.4, 50.8, 45.6, 35.0, 27.6; MS (CI+) m/z 418
+
30
D
[
M+H] ; HRMS (CI+) calcd for C22
H
25ClNO
5
418.1421, found 418.1425; [α]
+25.1 (c 1.01,
CHCl
3
) (>99% ee, after recrystallization); HPLC (93% ee, DAICEL CHIRALCEL OD-H,
n-hexane/IPA = 9:1, 1.0 mL/min, 254 nm, τminor 26.0 min, τmajor 29.9 min).
Before recrystallization (93% ee)
After recrystallization (>99% ee)
S-14

Ph
O
tert-Butyl 3-methyl-5-nitro-2-oxo-4-phenylpentanoate (3d)
The title compound was prepared according to the general procedure and
purified by MPLC (n-hexane/ethyl acetate = 9:1) to give 3d in 77% yield
as a colorless solid.
O N
2
CO t-Bu
2
Me
-1
Mp 121-122 °C (n-hexane/ethyl acetate); IR (neat) ν 2987, 1716, 1541, 1306, 1160, 1013, 701 cm ;
1
H-NMR (400 MHz, CDCl
3
) δ 7.34-7.18 (m, 5H), 4.76 (dd, J = 12.9, 5.9 Hz, 1H), 4.72 (dd, J = 12.9,
9
.0 Hz, 1H), 3.90 (td, J = 9.0, 5.9 Hz, 1H), 3.79-3.70 (m, 1H), 1.45 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H);
1
3
C-NMR (100 MHz, CDCl
3
) δ 195.9, 159.9, 137.1, 128.9, 127.9, 127.8, 84.5, 77.3, 45.2, 44.7, 27.8,
+
1
3.5; MS (CI+) m/z 308 [M+H] ; HRMS (CI+) calcd for C16
H
22NO
5
308.1498, found 308.1469;
2
8
[
α]D +9.2 (c 1.09, acetone) (94% ee); HPLC (DAICEL CHIRALPAK IC, n-hexane/ethanol = 98:2,
1
.0 mL/min, 280 nm, τminor 12.8 min, τmajor 22.3 min).
Ph
O
tert-Butyl 3-(2’-nitro-1’-phenylethyl)-2-oxohex-5-enoate (3e)
The title compound was prepared according to the general procedure and
purified by MPLC (n-hexane/ethyl acetate = 9:1) to give 3e in 77% yield
as a colorless solid.
O N
2
CO t-Bu
2
-1 1
Mp 85-87 °C (n-hexane/ethyl acetate) IR (neat) ν 2982, 1709, 1550, 704 cm ; H-NMR (400 MHz,
CDCl ) δ 7.34-7.16 (m, 5H), 5.76-5.62 (m, 1H), 5.14-5.03 (m, 2H), 4.79 (dd, J = 12.7, 5.0 Hz, 1H),
.71 (dd, J = 12.7, 9.0 Hz, 1H), 3.95-3.82 (m, 2H), 2.56-2.38 (m, 2H), 1.42 (s, 9H); C-NMR (100
MHz, CDCl ) δ 195.5, 159.8, 136.7, 133.1, 128.9, 128.1, 118.6, 84.3, 77.6, 48.9, 44.7, 33.4, 27.7; MS
3
1
3
4
3
+
30
D
(
CI+) m/z 334 [M+H] ; HRMS (CI+) calcd for C18
H
24NO
5
334.1654, found 334.1627; [α]
+4.0 (c
1
.01, CHCl ) (91% ee); HPLC (DAICEL CHIRALPAK IC, n-hexane/IPA = 98:2, 1.0 mL/min, 254
3
nm, τminor 13.1 min, τmajor 23.6 min).
S-15

Ph
O
tert-Butyl 3-cyclohexyl-5-nitro-2-oxo-4-phenylpentanoate (3f)
The title compound was prepared according to the general procedure and
purified by MPLC (n-hexane/ethyl acetate = 9:1) to give 3f in 60% yield
as a colorless solid.
O N
2
CO t-Bu
2
c-Hex
-1
Mp 139-140 °C (n-hexane/ethyl acetate); IR (neat) ν 2929, 2854, 1736, 1540, 1154, 701 cm ;
1
H-NMR (400 MHz, CDCl
3
) δ 7.29-7.15 (m, 5H), 4.73 (dd, J = 12.2, 4.4 Hz, 1H), 4.62 (dd, J = 12.2,
1
1
1
0.0 Hz, 1H), 4.02 (dd, J = 11.2, 4.4 Hz, 1H), 3.99-3.90 (m, 1H), 1.92-1.63 (m, 6H), 1.38 (s, 9H),
1
3
.31-1.04 (m, 4H), 0.96 (dq, J = 12.2, 3.2 Hz, 1H); C-NMR (100 MHz, CDCl
3
) δ 196.3, 160.1,
37.1, 128.8, 128.2, 127.9, 83.9, 78.6, 52.6, 42.9, 39.1, 32.2, 27.6, 27.0, 26.9, 26.3, 26.1; MS (CI+)
+
27
D
m/z 376 [M+H] ; HRMS (CI+) calcd for C21
CHCl ) (93% ee); HPLC (DAICEL CHIRALPAK IC, n-hexane/IPA = 98:2, 1.0 mL/min, 254 nm,
τminor 9.8 min, τmajor 11.3 min).
H
30NO
5
376.2124, found 376.2102; [α]
+59.1 (c 1.00,
3
Ph
O
tert-Butyl 3-[2’-(benzyloxy)ethyl]-5-nitro-2-oxo-4-phenylpentanoate
O N
2
(
3g)
CO t-Bu
2
BnO
The title compound was prepared according to the general procedure and
purified by MPLC (n-hexane/ethyl acetate = 9:1) to give 3g in 93% yield
as a colorless solid.
Mp 83-84 °C (n-hexane/ethyl acetate); IR (neat) ν 2931, 2873, 1719, 1539, 1290, 1103, 1016, 698
-1 1
cm ; H-NMR (400 MHz, CDCl
3
) δ 7.34-7.14 (m, 10H), 4.79 (dd, J = 12.9, 4.9 Hz, 1H), 4.70 (dd, J
=
12.9, 9.3 Hz, 1H), 4.35 (d, J = 13.2 Hz, 1H), 4.32 (d, J = 13.2 Hz, 1H), 3.94-3.80 (m, 2H), 3.50-3.39
1
3
(
m, 2H), 2.24-2.12 (m, 1H), 1.93-1.83 (m, 1H), 1.30 (s, 9H); C-NMR (100 MHz, CDCl
3
) δ 194.8,
1
2
59.3, 137.5, 136.9, 128.8, 128.2, 128.1, 127.9, 127.5, 127.4, 83.6, 77.8, 72.7, 67.8, 47.4, 45.4, 30.4,
+
6
7.5; MS (CI+) m/z 428 [M+H] ; HRMS (CI+) calcd for C24H30NO 428.2073, found 428.2070;
2
D
7
[α]
-13.8 (c 1.03, CHCl
3
) (93% ee); HPLC (DAICEL CHIRALPAK AD-H, n-hexane/IPA = 90:10,
S-16

1
.0 mL/min, 254 nm, τminor 14.0 min, τmajor 15.1 min).
Ph
tert-Butyl tetrahydro-2-hydroxy-3-(2’-nitro-1’-phenylethyl)furan-
2-carboxylate (3h)
HO
CO t-Bu
2
O N
2
O
The title compound was prepared according to the general procedure and
purified by MPLC (n-hexane/ethyl acetate = 9:1) to give 3h in 84% yield
as a colorless solid.
-1
Mp 90-91 °C (n-hexane/ethyl acetate); IR (neat) ν 3551, 2976, 2898, 1733, 1552, 1251, 1056 cm ;
1
H-NMR (400 MHz, CDCl
3
) δ 7.33-7.15 (m, 5H), 4.75-4.63 (m, 2H), 4.24 (s, 1H), 4.19 (td, J = 8.5,
1
.6 Hz, 1H), 3.96-3.85 (m, 1H), 3.82-3.72 (m, 1H), 2.98 (td, J = 11.5, 7.6 Hz, 1H), 2.28-2.16 (m, 1H),
1
3
2
.14-2.00 (m, 1H), 1.20 (s, 9H); C-NMR (100 MHz, CDCl
3
) δ 168.8, 137.6, 128.6, 128.3, 127.7,
+
1
00.8, 83.5, 79.7, 67.7, 48.3, 44.1, 29.3, 27.5; MS (ESI+) m/z 355 [M+NH
4
] ; HRMS (ESI+) calcd
2
8
for C H N O 355.18691, found 355.18785; [α]
3
+42.6 (c 1.02, CHCl ) (92% ee); HPLC
17
27
2
6
D
(
DAICEL CHIRALPAK IC, n-hexane/IPA = 9:1, 1.0 mL/min, 254 nm, τminor 13.1 min, τmajor 20.9
min).
OMe
tert-Butyl 3-benzyl-4-(4’-methoxyphenyl)-5-nitro-2-oxopentanoate (3i)
The title compound was prepared according to the general procedure and
purified by MPLC (n-hexane/ethyl acetate = 4:1) to give 3i in 81% yield
as a colorless solid.
O
O N
2
CO t-Bu
2
Mp 113-115 ºC; IR (neat) ν 3087, 3062, 3032, 3010, 2981, 2920, 1738,
Bn
-
1
1
722, 1537, 1514, 1278, 1254, 1180, 1156, 1033, 837, 806, 748, 699 cm ;
) δ 7.28-7.15 (m, 3H), 7.15-7.09 (m, 4H), 6.81 (m, 2H), 4.78 (dd, J = 12.6,
.2 Hz, 1H), 4.70 (dd, J = 12.6, 9.5 Hz, 1H), 4.18 (dt, J = 9.0, 7.8 Hz, 1H), 3.86 (apparent td, J = 9.5,
1
H-NMR (400 MHz, CDCl
3
5
5
1
3
.2 Hz, 1H), 3.76 (s, 3H), 2.98 (d, J = 7.8 Hz, 2H), 1.29 (s, 9H); C-NMR (100 MHz, CDCl ) δ 196.3,
3
S-17

159.2, 159.1, 137.0, 129.2, 128.9, 128.7, 128.3, 126.9, 114.3, 84.1, 78.0, 55.2, 50.9, 45.1, 36.0, 27.5;
+
MS (FAB) m/z 436 [M+Na] ; HRMS (FAB) calcd for C23
H
27NNaO
6
436.1731, found 436.1732;
2
D
7
[α]
3
+27.8 (c 0.67, CHCl ) (90% ee); HPLC (DAICEL CHIRALCEL OD-H, n-hexane/IPA/ethyl
acetate = 90:7:3, 1.0 mL/min, 254 nm, τminor 26.3 min, τmajor 65.7 min).
Br
tert-Butyl 3-benzyl-4-(4’-bromophenyl)-5-nitro-2-oxopentanoate (3j)
The title compound was prepared according to the general procedure and
purified by MPLC (n-hexane/ethyl acetate = 85:15) to give 3j in 81%
yield as a colorless solid.
O
O N
2
CO t-Bu
2
Mp 124-125 ºC; IR (neat) ν 3028, 2980, 2927, 2854, 1738, 1723, 1713,
Bn
-
1 1
1
552, 1491, 1371, 1259, 1157, 1075, 1011, 832, 752, 701 cm ; H-NMR
) δ 7.42 (d, J = 8.0 Hz, 2H), 7.30-7.16 (m, 3H), 7.14-7.08 (m, 4H), 4.79 (dd, J =
2.7, 5.1 Hz, 1H), 4.70 (dd, J = 12.7, 9.5 Hz, 1H), 4.19 (dt, J = 8.3, 7.6 Hz, 1H), 3.89 (apparent td, J =
(
400 MHz, CDCl
3
1
9
1
1
3
.5, 5.1 Hz, 1H), 2.97 (d, J = 7.6 Hz, 2H), 1.29 (s, 9H); C-NMR (100 MHz, CDCl
3
) δ 196.0, 159.2,
36.6, 135.7, 132.1, 129.8, 128.8, 128.8, 127.0, 122.2, 84.4, 77.5, 50.4, 45.1, 36.0, 27.5; MS (FAB)
+
26
D
m/z 484 [M+Na] ; HRMS (FAB) calcd for C H BrNNaO 484.0730, found 484.0736; [α] +24.5
2
2
24
5
(
c 1.20, CHCl
3
) (92% ee); HPLC (DAICEL CHIRALCEL OD-H, n-hexane/IPA/ethyl acetate = 90:7:3,
1
.0 mL/min, 280 nm, τminor 22.1 min, τmajor 72.7 min).
tert-Butyl 3-benzyl-4-(furan-2’-yl)-5-nitro-2-oxopentanoate (3k)
The title compound was prepared according to the general procedure and
purified by MPLC (n-hexane/ethyl acetate = 9:1) to give 3k in 72% yield
as a colorless solid.
O
O
O N
2
CO t-Bu
2
Bn
Mp 59-60 ºC; IR (neat) ν 3318, 3087, 3064, 3030, 2981, 2935, 1741, 1722,
-1 1
1
713, 1552, 1507, 1371, 1256, 1156, 1066, 1015, 915, 848, 834, 740, 700 cm ; H-NMR (400 MHz,
CDCl
3
) δ 7.37-7.32 (m, 1H), 7.31-7.16 (m, 3H), 7.15-7.09 (m, 2H), 6.29 (dd, J = 3.3, 1.8 Hz, 1H),
S-18

6
4
.22-6.08 (m, 1H), 4.78 (dd, J = 13.2, 8.0 Hz, 1H), 4.74 (dd, J = 13.2, 5.8 Hz, 1H), 4.18-4.10 (m, 1H),
.10-4.02 (m, 1H), 2.97 (dd, J = 13.6, 9.2 Hz, 1H), 2.92 (dd, J = 13.6, 5.8 Hz, 1H), 1.39 (s, 9H);
1
3
C-NMR (100 MHz, CDCl
3
) δ 195.6, 159.3, 149.8, 137.0, 128.9, 128.7, 126.9, 110.6, 108.7, 84.5,
+
7
5.4, 49.3, 38.9, 35.0, 27.6; MS (FAB) m/z 396 [M+Na] ; HRMS (FAB) calcd for C20
H
23NNaO
6
2
D
5
396.1418, found 396.1435; [α]
-4.7 (c 0.60, THF) (90% ee); HPLC (DAICEL CHIRALCEL OD-H,
n-hexane/IPA/ethyl acetate = 90:7:3, 1.0 mL/min, 254 nm, τminor 14.2 min, τmajor 30.1 min).
OTBS
tert-Butyl 6-(tert-butyldimethylsilyloxy)-3-methyl-4-(nitromethyl)-
-oxohexanoate (3l)
2
O
O N
2
The title compound was prepared according to the general procedure and
purified by MPLC (n-hexane/ethyl acetate = 9:1) to give 3l in 83% yield
as a colorless oil.
CO t-Bu
2
Me
-1 1
IR (neat) ν 2931, 2858, 1721, 1553, 1255, 1097, 835, 777 cm ; H-NMR (400 MHz, CDCl ) δ 4.46
3
(
dd, J = 13.1, 6.1 Hz, 1H), 4.42 (dd, J = 13.1, 6.6 Hz, 1H), 3.70 (t, J = 5.9 Hz, 2H), 3.48 (qd, J = 7.3,
4
3
3
C
.9 Hz, 1H), 2.89-2.77 (m, 1H), 1.66 (apparent q, J = 5.9 Hz, 2H), 1.56 (s, 9H), 1.15 (d, J = 7.3 Hz,
1
3
H), 0.88 (s, 9H), 0.05 (s, 6H); C-NMR (100 MHz, CDCl ) δ 196.9, 160.7, 84.6, 76.4, 60.8, 42.9,
3
+
6.1, 32.5, 27.9, 26.0, 18.3, 11.7, -5.3, -5.3; MS (CI+) m/z 390 [M+H] ; HRMS (CI+) calcd for
2
D
8
18
H
36NO
6
Si 390.2312, found 390.2311, [α]
3
-9.3 (c 0.88, CHCl ) (94% ee).
Determination of the ee of 3l
Since 3l was not separable on chiral HPLC, the ee of 3l was determined after reduction below. The
major isomer of alcohol S11 was separable on chiral HPLC.
OTBS
OTBS
OH
O
L-Selectride
O N
2
O N
2
CO t-Bu
2
CO t-Bu THF, -78 °C
2
Me
Me
S11
tert-Butyl 6-(tert-butyldimethylsilyloxy)-2-hydroxy-3-methyl-4-(nitromethyl)hexanoate (S11)
To a solution of 3l (10.0 mg, 0.0257 mmol) in THF (0.6 mL) was added L-Selectride (1.0 M in THF,
S-19

7
7 µL) at -78 °C. The reaction mixture was stirred for 1 h and then quenched with saturated aqueous
NH Cl (2 mL). The aqueous layer was separated and extracted with ethyl acetate (3 mL x 3). The
combined organic layers were washed with brine (2 mL), dried over Na SO , and concentrated under
4
2
4
reduced pressure. The residue was purified by preparative thin layer chromatography (n-hexane/ethyl
acetate = 10:1) to give S11 in 83% yield as a colorless oil.
-1 1
IR (neat) ν 3505, 2930, 2858, 1722, 1551, 1253, 1150, 1091, 834, 776 cm ; H-NMR (400 MHz,
CDCl ) δ 4.82 (dd, J = 12.7, 4.9 Hz, 1H), 4.31 (dd, J = 12.7, 8.7 Hz, 1H), 4.00 (t, J = 4.9 Hz, 1H),
3
3
1
8
.71-3.59 (m, 2H), 2.91 (d, J = 4.6 Hz, 1H), 2.58-2.45 (m, 1H), 2.17-2.04 (m, 1H), 1.73-1.58 (m, 2H),
1
3
.52 (s, 9H), 1.01 (d, J = 7.3 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H); C-NMR (100 MHz, CDCl ) δ 173.0,
3
+
3.3, 78.1, 74.4, 61.0, 37.8, 36.2, 33.5, 28.2, 26.0, 18.4, 12.7; MS (CI+) m/z 392 [M+H] ; HRMS
2
8
(
(
CI+) calcd for C18
H38NO
6
Si 392.2468, found 392.2471; [α]
D
3
+3.0 (c 0.53, CHCl ) (94% ee); HPLC
DAICEL CHIRALPAK IC, n-hexane/IPA = 99:1, 1.0 mL/min, 280 nm, τmajor 16.8 min, τminor 19.4
min).
OTBS
tert-Butyl 3-benzyl-6-(tert-butyldimethylsilyloxy)-4-(nitromethyl)-
-oxohexanoate (3m)
2
O
O N
2
The title compound was prepared according to the general procedure
and purified by preparative thin layer chromatography (toluene) to give
CO t-Bu
2
Bn
3
m in 77% yield as a light yellow oil.
IR (neat) ν 3030, 2954, 2930, 2858, 1738, 1722, 1552, 1370, 1254, 1159, 1098, 1048, 1031, 981, 888,
-
1 1
8
6
2
1
1
3
34, 776, 751, 732, 699 cm ; H-NMR (400 MHz, CDCl ) δ 7.31-7.07 (m, 5H), 4.54 (dd, J = 13.3,
.0 Hz, 1H), 4.48 (dd, J = 13.3, 6.5 Hz, 1H), 3.82 (apparent dt, J = 9.3, 5.6 Hz, 1H), 3.76-3.60 (m,
H), 2.92 (dd, J = 13.5, 9.3 Hz, 1H), 2.82 (dd, J = 13.5, 5.6 Hz, 1H), 2.79-2.70 (m, 1H), 1.82-1.71 (m,
1
3
H), 1.69-1.58 (m, 1H), 1.39 (s, 9H), 0.84 (s, 9H), 0.01 (s, 6H); C-NMR (100 MHz, CDCl ) δ 197.0,
3
60.3, 137.6, 128.9, 128.6, 126.7, 84.4, 76.5, 60.8, 49.6, 36.1, 34.2, 31.9, 27.7, 25.9, 18.3, -5.4, -5.4;
+
MS (FAB) m/z 488 [M+Na] ; HRMS (FAB) calcd for C24
H
39NNaO
6
Si 488.2439, found 488.2447;
2
6
[
α]D +2.1 (c 0.48, CHCl ) (92% ee).
3
Determination of the ee of 3m
Since 3m was not separable on chiral HPLC, the ee of 3m was determined after conversion to 3n
S-20

according to the following procedure.
NO2
OTBS
OH
O
AcCl, MeOH
O
Ph
HO
O N
2
O N
2
CO t-Bu
CO t-Bu
2
2
O
t-BuO C
2
Ph
Ph
3n
tert-Butyl 3-benzyl-tetrahydro-2-hydroxy-4-(nitromethyl)-2H-pyran-2-carboxylate (3n)
To a solution of 3m (72.1 mg, 0.154 mmol) in methanol (1 mL) was added acetyl chloride (2 µL,
0
.028 mmol). The resulting solution was stirred at room temperature for 5 min, then the desired
compound was directly purified by preparative thin layer chromatography (n-hexane/ethyl acetate =
5:15) to give 3n in 94% yield as a colorless oil (50.1 mg).
IR (neat) ν 3478 (br), 3062, 3028, 2979, 2935, 1738, 1727, 1548, 1370, 1291, 1141, 1080, 1024, 841,
8
-
1
1
7
4
2
1
4
3
3
35, 699 cm ; H-NMR (400 MHz, CDCl ) δ 7.37-7.14 (m, 5H), 4.28 (dd, J = 12.0, 3.9 Hz, 1H),
.13-3.99 (m, 2H), 3.76 (dt, J = 11.5, 2.9 Hz, 1H), 3.71 (dd, J = 11.5, 11.2 Hz, 1H), 2.80-2.70 (m, 1H),
.66 (dd, J = 15.9, 3.2 Hz, 1H), 2.57 (dd, J = 15.9, 8.4 Hz, 1H), 2.48-2.39 (m, 1H), 1.68-1.50 (m, 2H),
1
3
.49 (s, 9H); C-NMR (100 MHz, CDCl
3
) δ 169.2, 139.8, 128.9, 128.2, 126.7, 96.1, 84.2, 79.7, 60.0,
+
3.0, 36.8, 36.5, 29.2, 27.8; MS (FAB) m/z 374 [M+Na] ; HRMS (FAB) calcd for C H NNaO
1
8
25
6
2
8
74.1574, found 374.1573; [α]
D
3
+40.8 (c 1.06, CHCl ) (92% ee); HPLC (DAICEL CHIRALPAK
AS-H, n-hexane/IPA = 95:5, 1.0 mL/min, 254 nm, τminor 10.2 min, τmajor 11.9 min).
OMe
tert-Butyl 4-(N-methoxy-N-methylcarbamoyl)-3-[2’-(benzyloxy)ethyl]-
5-nitro-2-oxopentanoate (3o)
N
O
Me
O
O N
2
The title compound was prepared according to the general procedure and
purified by MPLC (n-hexane/ethyl acetate = 3:1) to give 3o in 89% yield
as a colorless oil.
CO t-Bu
2
BnO
-
1
1
IR (neat) ν 2980, 2868, 1720, 1659, 1554, 1370, 1161, 1100, 1028, 750, 698 cm ; H-NMR (400
MHz, CDCl ) δ 7.33-7.22 (m, 5H), 4.87 (dd, J = 14.4, 9.3 Hz, 1H), 4.63 (dd, J = 14.4, 3.4 Hz, 1H),
.37 (s, 2H), 4.00-3.87 (m, 1H), 3.87-3.85 (m, 1H), 3.78 (s, 3H), 3.44 (t, J = 6.1 Hz, 2H), 3.19 (s, 3H),
3
4
2
1
3
.04-1.96 (m, 2H), 1.46 (s, 9H); C-NMR (100 MHz, CDCl
3
) δ 194.4, 170.2, 159.7, 137.6, 128.2,
S-21

+
1
27.5, 127.4, 83.9, 77.2, 72.6, 67.6, 61.5, 43.1, 40.6, 32.3, 28.1, 27.7; MS (CI+) m/z 439 [M+H] ;
2
3
HRMS (CI+) calcd for C21
H
31
N
2
O
8
439.2080, found 439.2041; [α]
D
3
-18.9 (c 1.00, CHCl ) (92% ee);
HPLC (DAICEL CHIRALPAK IC, n-hexane/IPA = 9:1, 1.0 mL/min, 220 nm, τminor 33.2 min, τmajor
6.7 min).
5
9
(
H) Application to the synthesis of kainoid analog 12
Ni(OAc) -(S,S)-7
2
(
3
1 mol %)
O
Ar
O
NO2
Et N (5 mol %)
O N
2
+
CO t-Bu
CO t-Bu
2
2
2
-propanol
OMe
BnO
BnO
Ar = o-MeOC H4
2
7 °C, 4 h
6
93% (91% ee)
10
OBn
OR2
OMe
N
OMe
N
Raney Ni
NaH, DBU
H (90 atm)
2-methyl-2-propanol
2
CO t-Bu
CO t-Bu
EtOH
5 °C, 4 h
2
benzene
86%
2
7
2
R1 R = H (S12)
1
R = Bn (11)
Pd/C, H
THF
76%
Boc
2
(
Boc) O
2
2
1
R = Boc (S13)
DCM
R = H (S14)
94%
99%
OMe
OMe
1
) Dess-Martin
CO H
2
CO H
2
periodinane, DCM
TFA, DCM
90%
CO t-Bu
2
CO H
2
2
) NaH PO ·2H O
2
4
2
N
Boc
S15
NaClO , 2-methyl-2-butene
N
2
H
2
-methyl-2-propanol, H O
2
12
82% (2 steps)
(
Ni(OAc)
and triethylamine (7 µL, 5 mol %) were combined under N
3S,4S)-tert-Butyl 3-[2’-(benzyloxy)ethyl]-5-nitro-2-oxo-4-(2’-methoxy)-phenylpentanoate (10)
·(H O) —(S,S)-N,N’-dibenzylcyclohexane-1,2-diamine complex (isolated, 5 mg, 1 mol %)
atmosphere in 2-propanol (1 mL) at
7 °C. α-Ketoester (278 mg, 1.00 mmol) and 1-methoxy-2-[(E)-2-nitrovinyl]benzene (179 mg, 1.00
2
2
4
2
2
9
(
a) Hashimoto, K.; Horikawa, M.; Shirahama, H. Tetrahedron Lett. 1990, 31, 7047. (b) Hashimoto,
K.; Shirahama, H. Tetrahedron Lett. 1991, 32, 2625. (c) Baldwin, J. E.; Fryer, A. M.; Spyvee, M. R.;
Whitehead, R. C.; Wood, M. E. Tetrahedron Lett. 1996, 37, 6923. (d) Baldwin, J. E.; Bamford, S. J.;
Fryer, A. M.; Rudolph, M. P. W.; Wood, M. E. Tetrahedron 1997, 53, 5255. (e) Maeda, H.; Kraus, G.
A. J. Org. Chem. 1997, 62, 2314. (f) Maeda, H.; Selvakumar, N.; Kraus, G. A. Tetrahedron 1999, 55,
943. (g) Peixoto da Silva, K.; Godoi, M. N.; Correia, C. R. D. Org. Lett. 2007, 9, 2815.
S-22

mmol) were added to the resulting mixture and the mixture was stirred for 4 h. During the reaction,
the product started to precipitate out, and the resulting suspension was dissolved in ethyl acetate (4
2
mL). The solution was passed through a pad of SiO . After evaporation of solvent, the residue was
purified by MPLC (SiO , n-hexane/ethyl acetate = 9:1) to give 10 in 93 % yield as a colorless oil (425
2
mg).
-
1 1
IR (neat) ν 2975, 1866, 1721, 1551, 1247, 1026 cm ; H-NMR (400 MHz, CDCl
3
) δ 7.34-7.16 (m,
H), 7.05 (dd, J = 7.6, 1.7 Hz, 1H), 6.87-6.79 (m, 2H), 4.90 (dd, J = 12.9, 8.3 Hz, 1H), 4.79 (dd, J =
2.9, 5.1 Hz, 1H), 4.35 (s, 2H), 4.11-4.05 (m, 1H), 4.05-3.97 (m, 1H), 3.81 (s, 3H), 3.47 (dd, J = 6.8,
6
1
4
1
3
.6 Hz, 2H), 2.25-2.13 (m, 1H), 1.89 (ddd, J = 13.9, 8.3, 4.6 Hz, 1H), 1.31 (s, 9H); C-NMR (100
MHz, CDCl
3
) δ 194.7, 159.5, 157.0, 137.7, 130.5, 129.2, 128.2, 127.4, 127.4, 124.5, 120.7, 111.1,
+
83.2, 76.8, 72.6, 68.1, 55.3, 45.7, 42.7, 30.9, 27.5; MS (FAB) m/z 458 [M+H] ; HRMS (FAB) calcd
2
5
for C H NO 458.2179, found 458.2180; [α]
3
+8.3 (c 1.01, CHCl ) (91% ee); HPLC (DAICEL
2
5
32
7
D
CHIRALPAK IC, n-hexane/IPA = 95:5 1.0 mL/min, 254 nm, τmajor 25.2 min, τminor 30.3 min).
(
2R,3S,4S)-tert-Butyl 3-[(2’-benzyloxy)ethyl]-4-phenylpyrrolidine-2-carboxylate (S12)
Compound 10 (410 mg, 0.897 mmol) was hydrogenated using Raney nickel (966 mg) in ethanol (10
1
0
mL) under hydrogen atmosphere (90 atm) at 75 °C for 4 h. The mixture was cooled to room
temperature and filtered through a pad of celite. The catalyst and the celite were washed with ethyl
acetate. The combined organic solvent was concentrated under reduced pressure. The residue was
purified by column chromatography (SiO
yield as a colorless oil (281 mg).
2
, dichloromethane/methanol = 20:1) to give S12 in 76%
-1 1
IR (neat) ν 2971, 2932, 2870, 1722, 1240, 1154 cm ; H-NMR (400 MHz, CDCl ) δ 7.36-7.10 (m,
3
7
H), 6.89 (td, J = 7.4, 0.7 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 4.21 (d, J = 12.0 Hz, 1H), 4.16 (d, J =
2.0 Hz, 1H), 4.02 (d, J = 6.3 Hz, 1H), 3.82 (dt, J = 10.3, 7.3 Hz, 1H), 3.76 (s, 3H), 3.48 (apparent t, J
1
=
10.3 Hz, 1H), 3.19 (dd, J = 9.8, 7.3 Hz, 1H), 3.07-2.98 (m, 1H), 2.97-2.89 (m, 1H), 2.86-2.79 (m,
1
3
1
1
2
3
H), 1.79 (br s, 1H), 1.52-1.32 (m, 11H); C-NMR (100 MHz, CDCl ) δ 172.5, 157.5, 138.4, 128.1,
27.9, 127.5, 127.4, 127.3, 127.2, 120.1, 109.9, 81.5, 72.4, 69.3, 65.8, 55.2, 48.3, 42.7, 40.8, 28.3,
+
6.1; MS (FAB) m/z 412 [M+H] ; HRMS (FAB) calcd for C25
H
34NO
4
412.2488, found 412.2490;
2
D
6
[α]
3
-62.2 (c 1.03, CHCl ).
1
0
Barluenga, J.; Aznar, F.; Ribas, C.; Valdés C. J. Org. Chem. 1998, 63, 10052.
S-23

(
2R,3S,4S)-Di-tert-butyl
-[2-(benzyloxy)ethyl]-4-(2-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (S13)
To a solution of S12 (358 mg, 0.869 mmol) of dichloromethane (2.7 mL) and triethylamine (242 µl,
.74 mmol), di-tert-butyl dicarbonate (195 mg, 0.895 mmol) was added and stirred at room
3
1
temperature for 30 min. After quenching with water, the aqueous layer was extracted with
dichloromethane (8 mL x 3). The combined organic layers were washed with brine (5 mL), dried over
Na
chromatography (SiO
440mg).
This compound exists as a mixture of rotamers in CDCl at 23 °C, and contains the epimer 11.
2
SO
4
and concentrated under reduced pressure. The residue was purified by column
2
, n-hexane/ethyl acetate = 5:1) to give S13 in 99% yield as a colorless oil
(
3
-1 1
IR (neat) ν 2975, 2931, 1692, 1391, 1365, 1242, 1151 cm ; H-NMR (400 MHz, CDCl
3
) δ 7.35-7.15
(
m, 7H), 6.89 (t, J = 7.4 Hz, 1H), 6.82-6.75 (m, 1H), 4.43 (d, J = 7.8 Hz, 0.4H [minor]), 4.37 (d, J =
8
.3 Hz, 0.6H [major]), 4.27 (s, 2H), 3.99-3.65 (m, 6H), 3.25-2.98 (m, 3H), 1.60-1.36 (m, 20H);
1
3
C-NMR (100 MHz, CDCl ) δ 167.0, 169.9, 157.2, 157.2, 154.1, 138.4, 128.6, 128.3, 128.1, 127.7,
3
127.7, 127.5, 127.4, 127.3, 127.3, 127.0, 126.9, 120.3, 120.2, 109.9, 109.7, 81.3, 79.9, 72.5, 69.1, 68.9,
63.9, 63.8, 55.2, 55.2, 49.9, 49.7, 41.0, 40.3, 39.7, 39.2, 28.6, 28.5, 28.2, 28.1, 26.8, 26.5; MS (FAB)
+
26
D
m/z 512 [M+H] ; HRMS (FAB) calcd for C30
CHCl3).
H42NO
6
512.3012, found 512.2999; [α]
-42.9 (c 1.06,
(
2S,3S,4S)-Di-tert-butyl
3
-[2-(benzyloxy)ethyl]-4-(2-methoxyphenyl)pyrrolidine-1,2-dicarboxylate (11)
To a solution of S13 (307 mg, 0.600 mmol) and DBU (412 µL, 3.00 mmol) in benzene (6 mL) and
-methyl-2-propanol (307 µl, 3.23 mmol) was added sodium hydride (55%, 65.5 mg, 1.50 mmol) at
2
1
1
room temperature and stirred for 18 h. After quenching with water (3 mL), the aqueous layer was
extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10
mL), dried over Na
n-hexane/ethyl acetate = 80:20) to give 11 in 86% yield as a colorless oil (246 mg).
This compound exists as a mixture of rotamers in CDCl at 22 °C.
2 4
SO and concentrated under reduced pressure. The residue was purified by MPLC
(
3
-1
1
IR (neat) ν 2976, 2927, 1693, 1392, 1365, 1244, 1154, 1121 cm ; H-NMR (400 MHz, CDCl ) δ
3
7
4
.33-7.19 (m, 6H), 7.09-7.02 (m, 1H), 6.89 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.41 (s, 2H),
.10 (d, J = 2.9 Hz, 0.4H [minor]), 4.08 (d, J = 4.2 Hz, 0.6H [major]), 4.01-3.89 (m, 1H), 3.87-3.64
13
(
m, 5H), 3.49-3.34 (m, 2H), 2.83-2.72 (m, 1H), 1.55-1.24 (m, 20H); C-NMR (100 MHz, CDCl ) δ
3
1
1
Modified condition of Ogasawara’s method (Takano, S.; Iwabuchi, Y.; Ogasawara, K. J. Am. Chem.
Soc. 1987, 109, 1204).
S-24

1
1
4
71.7, 171.6, 157.1, 157.1, 154.2, 153.9, 138.3, 128.1, 127.7, 127.5, 127.4, 127.3, 127.3, 127.2, 127.1,
26.8, 120.4, 120.4, 110.2, 110.1, 80.9, 80.9, 79.8, 79.6, 72.8, 68.8, 68.5, 64.7, 64.5, 55.3, 55.2, 49.3,
+
8.4, 44.0, 42.8, 38.8, 38.3, 28.7, 28.6, 28.5, 28.2, 28.1, 28.1; MS (FAB) m/z 512 [M+H] ; HRMS
2
D
6
(
FAB) calcd for C30
H
42NO
6
512.3012, found 512.2997; [α]
3
-40.7 (c 1.07, CHCl ).
(
(
2S,3S,4S)-Di-tert-butyl 3-[2-(hydroxy)ethyl]-4-(2-methoxyphenyl)pyrrolidine-1,2-dicarboxylate
S14)
Compound 11 (150.2 mg, 0.294 mmol) was hydrogenated in THF (2 mL) for 3 h in presence of 10%
Pd/C (10 wt%). The mixture was filtered through a pad of celite. The catalyst and the celite were
washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was
purified by MPLC (SiO
colorless oil (117 mg).
2
, hexane/ethyl acetate = 83:37 to 50:50) to give S14 in 94% yield as a
This compound exists as a mixture of rotamers in CDCl at 23 °C.
3
-1 1
IR (neat) ν 3435 (br), 2976, 1692, 1402, 1367, 1365, 1245, 1157, 1133 cm ; H-NMR (400 MHz,
CDCl ) δ 7.22 (apparent td, J = 8.1, 1.5 Hz, 1H), 7.05 (ddd, J = 8.1, 7.3, 1.5 Hz, 1H), 6.91 (td, J = 7.3,
.7 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 4.07 (d, J = 4.6 Hz, 0.4H [minor]), 4.00 (d, J = 3.9 Hz, 0.6H
major]), 3.99-3.90 (m, 1H), 3.87-3.66 (m, 5H), 3.65-3.50 (m, 2H), 2.79-2.67 (m, 1H), 1.65-1.55 (m,
3
0
[
1
3
1
1
5
3
H), 1.56-1.43 (m, 18H), 1.43-1.24 (m, 2H); C-NMR (100 MHz, CDCl ) δ 171.9, 171.8, 157.0,
56.9, 153.8, 127.8, 127.4, 127.0, 120.6, 120.6, 110.3, 110.2, 81.2, 80.0, 79.7, 64.6, 64.3, 61.3, 61.2,
+
5.4, 49.8, 48.9, 44.1, 43.1, 39.0, 38.4, 31.7, 28.6, 28.5, 28.1, 28.1; MS (FAB) m/z 422 [M+H] ;
2
D
7
HRMS (FAB) calcd for C H NO 422.2543, found 422.2549; [α] -67.9 (c 1.03, CHCl3).
2
3
36
6
2
-[(2S,3S,4S)-1,2-Di-(tert-butoxycarbonyl)-4-(2-methoxyphenyl)pyrrolidin-3-yl]acetic acid (S15)
To a solution of S14 (74.1 mg, 0.176 mmol) in dichloromethane (1.5 mL) was added Dess-Martin
periodinane (89.5 mg, 0.211 mmol). The mixture was stirred at room temperature for 2 h. The reaction
mixture was filtered and concentrated under reduced pressure. The residue was purified by column
chromatography (SiO
To a solution of the aldehyde (43.5 mg, 0.104 mmol) in 2-methyl-2-butene (281µL, 2.65 mmol) and
-methyl-2-propanol (3.4 mL) at 0 ºC was added a solution of NaClO (178 mg, 1.97 mmol) and
NaH PO ·2H O (146 mg, 0.93 mmol) in H O (0.8 mL). The reaction mixture was stirred at room
S-25
2
, n-hexane/ethyl acetate = 2:1) to give the aldehyde as a colorless oil.
2
2
2
4
2
2

temperature for 0.5 h. The reaction was quenched by saturated aqueous NH
ethyl acetate (8 mL x 3). The combined organic layers were washed with brine (10 mL), dried over
Na SO and concentrated under reduced pressure. The residue was purified by MPLC (n-hexane/ethyl
4
Cl and extracted with
2
4
acetate = 95:5 and then chloroform/methanol = 95:5) to give S15 in 82% yield (2 steps) as a colorless
oil (44 mg).
This compound exists as a mixture of rotamers in CDCl
IR (neat) ν 3216 (br), 2977, 2927, 1738, 1704, 1397, 1368, 1247, 1161 cm ; H-NMR (400 MHz,
CDCl ) δ 7.22 (apparent td, J = 8.3, 1.5 Hz, 1H), 7.01 (t, J = 7.1 Hz, 1H), 6.90 (t, J = 7.1 Hz, 1H),
.83 (d, J = 8.3 Hz, 1H), 4.06-3.69 (m, 7H), 3.18-3.06 (m, 1H), 2.30-2.22 (m, 1H), 2.02 (dd, J = 17.0,
3
at 25 °C.
-1 1
3
6
7
1
6
1
3
.2 Hz, 1H), 1.50 (s, 9H), 1.48 (s, 9H); C-NMR (100 MHz, CDCl ) δ 177.5, 177.5, 171.1, 170.9,
3
57.1, 157.1, 154.0, 153.9, 128.2, 127.2, 126.4, 126.0, 120.7, 120.7, 110.0, 81.3, 81.2, 80.3, 79.9, 64.1,
3.9, 55.0, 49.8, 49.0, 43.2, 42.2, 38.3, 37.7, 33.3, 33.2, 28.5, 28.4, 28.0, 28.0; MS (FAB) m/z 436
+
25
D
[
M+H] ; HRMS (FAB) calcd for C23
H
34NO
7
436.2335, found 436.2345; [α]
3
-63.4 (c 1.07, CHCl ).
(
2S,3S,4S)-3-(Carboxymethyl)-4-(2-methoxyphenyl)pyrrolidine-2-carboxylic acid (12)
To a solution of S15 (34.8 mg, 0.080 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic
acid (0.3 mL) at room temperature, and the resulting mixture was stirred for 2 h. After concentration
under reduced pressure, the residue was added to a column containing Dowex-50 WX8 hydrogen
3
form (50-100 mesh). After elution with 3% aqueous NH , and the collected fractions were
freeze-dried to give 12 in 90% as a white solid (20 mg).
-1 1
Mp 167-169 ºC; IR (neat) ν 2944 (br), 2835, 1710, 1601, 1495, 1384, 1245 cm ; H-NMR (400 MHz,
O) δ 7.39 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.00 (t, J = 7.3 Hz,
D
2
1
H), 4.08 (d, J = 7.4 Hz, 1H), 3.98 (dd, J = 15.9, 7.8 Hz, 1H), 3.86 (s, 3H), 3.86-3.79 (m, 1H),
3
.79-3.70 (m, 1H), 3.23-3.13 (m, 1H), 2.48 (dd, J = 16.4, 4.9 Hz, 1H), 2.02 (dd, J = 16.4, 10.3 Hz,
1
3
1
H); C-NMR (100 MHz, CDCl
3
) δ 177.6, 173.9, 157.6, 130.2, 129.8, 124.6, 121.1, 111.7, 66.1, 55.8,
-
4
8.4, 43.2, 41.9, 35.9; MS (FAB, negative mode) m/z 278 [M-H] ; HRMS (FAB, negative mode)
2
D
5
calcd for C14
H
16NO
5
278.1028, found 278.1039; [α]
2
+7.7 (c 0.58, H O).
(
I) X-ray crystal structure analysis of 3a
CCDC-752633 (3a) contains the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
S-26

Crystal data: C22
H
25
O
5
N, FW = 383.43, orthorhombic P2
2
1 1
2
1
, a = 6.14599(11), b = 17.8565(3), c
3
-3
-1
=
19.4532(4) Å, V = 2134.91(7) Å ; D = 1.193 Mg m ; Z = 4; µ(Cu Kα) = 0.691 mm , T = 300 K.
X
The crystals of 3a showed solid-to-solid phase transition below room temperature. Since the single
crystal of 3a was decomposed on the phase transition, the measurements were performed at 300 K.
Block shaped colorless crystals were grown from a n-hexane/chloroform solution of 3a. A single
crystal with the dimensions of 0.20 x 0.13 x 0.08 mm was mounted on a glass capillary and set on a
Rigaku RAXIS-RAPID diffractomter.
The diffraction data were collected using
graphite-monochromated Cu Kα radiation. The unit cell dimensions were determined using 28379
reflections with 6.8 ≤ 2θ ≤ 136.6°. The diffraction data of 38239 within 6.7 ≤ 2θ ≤ 136.5° were
collected and merged to give 3827 unique reflections with Rint of 0.0240. The structure was solved by
2
a direct method and refined on F by a least-squares method by the programs SIR2004 and
SHELXL97, respectively. The final R values against 2620 unique reflections with I > 2σ(I) are 0.0458
2
and 0.1177 for R(F) and wR(F ), respectively. The phenyl and benzyl groups were disordered.
The absolute structure of the crystal was determined by comparing four Bijvoet pairs, which
differed in intensities each other, significantly. The reflections were 2 1 1, 3 4 3, 3 1 2 and 1 7 6, and
their Bivoet pairs. The result was confirmed by Flack parameter, which was refined using reflections
of 2θ <120°. 1846 Friedel pairs, χ = 0.0(3).
Programs used: SIR2004: Burla, M. C., Caliandro, R., Camalli, M., Carrozzini, B., Cascarano, G. L.,
De Caro, L., Giacovazzo, C., Polidori, G., Spagna, R. J. Appl. Cryst. 2005, 38, 381-388; SHELXL97:
Sheldrick, G. M. Acta Crystallogr. Sect. A, 2008, 64, 112-122.
S-27

(R)
Ph
O
O N
2
CO t-Bu
2
Ph
(R)
(R,R)-3a
Figure 1. Molecular structure of 3a. Only the major parts of the phenyl and benzyl groups were
drawn. Displacement ellipsoids are drawn at the 30 % probability level.
(
J) NMR spectra
S-28

0
. 0 0 0 0
1
1
1
1
. 5 0 0 5
. 5 2 7 3
. 5 5 4 8
. 5 6 9 4
9
. 0 8
0
. 6 5
2
2
2
3
3
3
. 9 1 6 7
. 9 3 5 0
. 9 5 4 0
. 0 9 0 0
. 1 0 9 6
. 1 2 7 9
1
. 9 8
2 . 0 0
7
7
7
7
7
7
. 1 8 8 7
. 2 0 7 6
. 2 5 2 2
. 2 6 5 6
. 2 8 3 3
. 3 0 2 8
5 . 2 7

2
2
7 . 8 4 1 4
9 . 1 5 3 1
4
0 . 8 5 0 8
7
7
7
6 . 6 8 6 5
7 . 0 0 0 0
7 . 3 2 1 7
8
4 . 0 2 0 3
1
1
1
2 6 . 2 2 4 6
2 8 . 3 1 1 7
2 8 . 4 6 8 5
1
4 0 . 1 8 2 7
1
6 0 . 2 6 1 9
1
9 4 . 4 9 7 3