Supplementary Material
Advanced asymmetric synthesis of
(1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by
alkylation/cyclization of newly designed axially chiral Ni(II) complex of
glycine Schiff base
Aki Kawashima,a Shuangjie Shu,b Ryosuke Takeda,a Akie Kawamura,a Tatsunori Sato,a Hiroki
Moriwaki,*a Jiang Wang,b Kunisuke Izawa,a José Luis Aceña,c Vadim A. Soloshonok,*c,d Hong
Liu*b
a
b
Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 533-0024, Japan
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu
Chong Zhi Road, Shanghai 201203, China.
c
Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo
Manuel Lardizábal 3, 20018 San Sebastián, Spain.
d
IKERBASQUE, Basque Foundation for Science, Maria Diaz de Haro 3, 48013 Bilbao, Spain.
CONTENTS
Experimental procedures and characterization data (synthesis of 9 and 10)
Determination of the diastereomeric ratio of (S)(2R)-7 and (S)(2S)-7
Determination of the diastereomeric purity of (S)(2R,3S)-8
Determination of the optical purity of (1R,2S)-11 (for method A)
Determination of the optical purity of (1R,2S)-12
Determination of the optical purity of (1R,2S)-13
Copies of 1H- and 13C-NMR spectra
S1
S2
S5
S7
S9
S11
S12
S13
Experimental procedures and characterization data
Synthesis of butenylene-bridged dimeric Ni(II) complex, 9
Cl
S
Br
S
6
Br
N
LiOt-Bu
N
O
O
Ni
O
N
O
O
Ph
Ni
O
THF
N
N
N
Ph
N
N
O
Ni
O
Ph
O
N
S
Cl
9
Cl
(S)-4
To a solution of (S)-4 (200 mg, 0.29 mmol) in THF (4 mL) were added
trans-1,4-dibromo-2-butene (6) (32 mg, 0.15 mmol) and lithium tert-butoxide (71 mg,
0.88 mmol) at 0 ºC and the mixture was stirred at the same temperature for 2 h under
argon atmosphere. The mixture was diluted with water (5 mL) and ethyl acetate (5 mL)
and the whole was stirred for 30 min, then separated the organic phase. The aqueous
phase was extracted with ethyl acetate (2 x 5 mL) and the combined organic phase was
washed with brine (5 mL), dried (Na2SO4), concentrated and dried in vacuo at 50 ºC for
16 h to give the crude product (210 mg), which was purified by column chromatography
on silica gel (CH2Cl2/acetone = 40/1) affording 9 (108 mg, 52%) as a red solid. mp
313.8 ºC (dec.) (CH2Cl2/acetone). [α]D25 = –2477 (c = 0.052, CHCl3). 1H-NMR (200
MHz, CDCl3): δ 2.19 (2H, br dd, J = 13.7, 7.1 Hz, one of bridging butenylene CH2),
2.36 [2H, d, J = 12.1 Hz, one of azepine C(α)H2N], 2.61 (2H, d, J = 16.2 Hz, one of
acetanilide NCOCH2), 2.63-2.85 (2H, m, one of bridging butenylene CH2), 2.74 [2H, d,
J = 13.7 Hz, one of azepine C(α')H2N], 3.97 [2H, d, J = 13.7 Hz, one of azepine
C(α')H2N], 4.15-4.21 (2H, m, α-H of AA part), 4.48 [2H, d, J = 12.1 Hz, one of azepine
C(α)H2N], 4.95 (2H, d, J = 16.2 Hz, one of acetanilide NCOCH2), 6.05 (2H, ddd, J =
8.3, 7.1, 0.9 Hz, CH=CH), 6.59 (2H, d, J = 8.6 Hz, ArH), 6.63 (2H, d, J = 2.6 Hz, ArH),
6.86-7.62 (26H, m, ArH), 7.69 (2H, d, J = 8.1 Hz, ArH), 7.93 (2H, d, J = 7.9 Hz, ArH),
8.12 (2H, d, J = 8.2 Hz, ArH), 8.42 (2H, d, J = 9.2 Hz, ArH), 8.76 (1H, d, J = 8.4 Hz,
ArH). 13C-NMR (50.3 MHz, CDCl3): δ 36.3 (CH2), 55.5 (CH2), 61.5 (CH2), 64.6 (CH2),
70.3 (α-CH), 124.7 (CH), 125.2 (CH), 125.5 (quaternary ArC), 125.6 (ArCH), 125.8
(ArCH), 126.1 (ArCH), 126.7 (CH), 127.1 (ArCH), 127.4 (ArCH), 127.5 (ArCH), 127.6
(ArCH), 127.9 (ArCH), 128.3 (quaternary ArC), 128.4 (ArCH), 128.5 (ArCH), 128.8
(ArCH), 129.3 (ArCH), 130.3 (ArCH), 130.6 (quaternary ArC), 130.9 (quaternary ArC),
S2
132.4 (ArCH), 132.7 (ArCH), 133.2 (quaternary ArC), 133.3 (quaternary ArC), 133.9
(quaternary ArC), 136.0 (quaternary ArC), 141.9 (quaternary ArC), 170.6, 175.7, 178.7
(CN and 2 x CO). HRMS calcd for C82H61Cl2N6Ni2O6 [M + H]+ 1411.2737, found
1411.2710.
Synthesis of ridge-tile-like binuclear Ni(II) complex, 10
S
Cl
50% aq. KOH
TBAI
N
O
O
Ph
O
toluene
Ni
O
N
N
N
N
N Ni
N
N
O
Ph
Ph
Cl
Ni
N
(S)-4
10
Cl
To a solution of (S)-4 (200 mg, 0.29 mmol) in toluene (4 mL) were added
tetrabutylammonium iodide (54 mg, 0.15 mmol) and 50% aqueous potassium hydroxide
solution (4.0 mL, 35.6 mmol) and the reaction mixture was stirred at rt for 3 h. After
separation of the organic phase, the aqueous phase was extracted with ethyl acetate (2 x
5 mL) and the combined organic phase was washed with brine (5 mL), dried (Na2SO4),
concentrated and dried in vacuo at 50 ºC for 16 h to give the crude product, which was
purified by column chromatography on silica gel (hexane/ethyl acetate = 1/1) affording
10 (160 mg, 88%) as a dark brown solid. mp 371.7 ºC (dec.) (ethyl acetate/hexane).
[α]D25 = –1111 (c = 0.027, CHCl3). 1H-NMR (200 MHz, CDCl3): δ 1.11 [2H, br d, J =
13.7 Hz, one of azepine C(α')H2N], 2.59 [2H, d, J = 13.7 Hz, one of azepine C(α')H2N],
3.48 (2H, d, J = 15.9 Hz, one of acetanilide NCOCH2), 3.49 (2H, d, J = 5.5 Hz), 3.57
[2H, d, J = 12.1 Hz, one of azepine C(α)H2N], 4.49 (2H, d, J = 15.9 Hz, one of
acetanilide NCOCH2), 4.67 (2H, br d, J = 7.9 Hz), 5.63 (2H, br t, J = 7.5 Hz), 6.73 (2H,
d, J = 2.4 Hz, ArH), 6.86 (2H, br t, J = 7.5 Hz), 6.98 [2H, d, J = 12.1 Hz, one of azepine
C(α)H2N], 7.06-7.53 (18H, m, ArH), 7.62-7.72 (4H, m, ArH), 7.92 (4H, d, J = 8.2 Hz,
ArH), 8.91 (2H, d, J = 9.0 Hz, ArH), 9.11 (2H, br d, J = 7.9 Hz, ArH). 13C-NMR (50.3
MHz, CDCl3): δ 56.1 (CH2), 64.3 (CH2), 64.8 (CH2), 124.5 (CH), 125.5 (quaternary
ArC), 125.8 (ArCH), 126.2 (ArCH), 126.3 (ArCH), 126.5 (ArCH), 127.0 (ArCH), 127.5
(ArCH), 127.6 (ArCH), 128.1 (ArCH), 128.4 (ArCH), 128.5 (ArCH), 128.8 (ArCH),
128.9 (ArCH), 129.0 (ArCH), 129.4 (ArCH), 130.3 (ArCH), 130.6 (quaternary ArC),
131.0 (quaternary ArC), 131.2 (quaternary ArC), 131.6 (quaternary ArC), 133.5
S3
(quaternary ArC), 133.7 (quaternary ArC), 134.6 (quaternary ArC), 135.4 (quaternary
ArC), 138.6 (quaternary ArC), 140.3 (quaternary ArC), 167.3 and 174.0 (CN and CO).
HRMS calcd for C74H52Cl2N6Ni2O2 M+ 1242.2236, found 1242.2233.
S4
Determination of the diastereomeric ratio of the intermediate alkylation product
(S)(2R)-7 and (S)(2S)-7 derived from (S)-4 and trans-1,4-dibromo-2-butene (6)
Br
6
S
Br
S
S
30% aq. NaOH
TBAI
N
O
O
Ni
O
N
N
CH2Cl2/H2O
N
O
Ni
O
N
Ph
Cl
(S)-4
O
+
N
N
Br
O
N
Ph
Cl
A. Starting from 50 mg of (S)-4
S5
(S)(2R)-7
O
Ni
R
O
S
N
Br
Ph
Cl
(S)(2S)-7
HPLC retention time (min)
Ratio
(S)(2R)-7
(S)(2S)-7
[(S)(2R)-7 : (S)(2S)-7]
27.8
29.1
41. 6% de (70.8 : 29.2)
B. Starting from 33.0 g of (S)-4
HPLC retention time (min)
Ratio
(S)(2R)-7
(S)(2S)-7
[(S)(2R)-7 : (S)(2S)-7]
27.8
29.0
40.4% de (70.2 : 29.8)
S6
Determination of the diastereomeric purity of (S)(2R,3S)-8
S
S
N
O
Ni
O
N
O
tert-BuONa
+
N
Br
O
N
Ph
Cl
(S)(2R)-7
O
Ni
R
N
S
O
N
THF
N
Br
O
N
Ph
Cl
O
Ni
S
O
R
N
S
H
Ph
(S)(2S)-7
A. Starting from 1.00 g of a mixture of (S)(2R)-7 and (S)(2S)-7
S7
Cl
(S)(2R,3S)-8
HPLC retention time (min)
Ratio
(S)(2R,3S)-8
another isomer
[(S)(2R,3S)-8 : another isomer]
27.8
29.5
99.6% de (99.8 : 0.2)
B. Starting from 53.0 g of a mixture of (S)(2R)-7 and (S)(2S)-7
HPLC retention time (min)
Ratio
(S)(2R,3S)-8
another isomer
[(S)(2R,3S)-8 : another isomer]
27.9
29.6
99.5% de (99.75 : 0.25)
S8
Determination of the optical purity of (1R,2S)-11 (for method A) by HPLC analysis
on a chiral stationary phase
S
1. aq. HCl, MeOH
N
O
Ni
O
N
BocHN
CO2H
R
N
DCHA
BocHN
CO2H
・DCHA
O
2. EDTA-2Na
S
H
3. Boc2O
crude (1R,2S)-12
(1R,2S)-11
Ph
Cl
(S)(2R,3S)-8
A. Determination of the optical purity of the crude (1R,2S)-12 as an intermediate
S9
HPLC retention time (min)
Ratio
(1S,2R)-isomer
(1R,2S)-11
[(1S,2R)-isomer : (1R,2S)-11]
6.2
11.9
99.6% ee (0.2 : 99.8)
B. Determination of the optical purity of the purified (1R,2S)-11
HPLC retention time (min)
Ratio
(1S,2R)-isomer
(1R,2S)-12
[(1S,2R)-isomer : (1R,2S)-12]
6.2
11.6
99.8% ee (0.1 : 99.9)
S10
Determination of the optical purity of (1R,2S)-12 by HPLC analysis on a chiral
stationary phase
BocHN
CO2H
aq. AcOH
・DCHA
(1R,2S)-11
BocHN
CO2H
(1R,2S)-12
HPLC retention time (min)
Ratio
(1S,2R)-isomer
(1R,2S)-12
[(1S,2R)-isomer : (1R,2S)-12]
6.1
11.5
99.6% ee (0.2 : 99.8)
S11
Determination of the optical purity of (1R,2S)-13 by HPLC analysis on a chiral
stationary phase
BocHN
TMSCHN2
CO2H
BocHN
CO2Me
MeOH/toluene
(1R,2S)-13
(1R,2S)-12
HPLC retention time (min)
Ratio
(1R,2S)-13
(1S,2R)-isomer
[(1R,2S)-13 : (1S,2R)-isomer]
16.4
18.3
99.2% ee (99.6 : 0.4)
S12
Copies of 1H and 13C-NMR spectra
1H-NMR of (S)-4
S13
13C-NMR
of (S)-4
S14
1H-NMR
of diastereomeric mixture of (S)(2R)-7 and (S)(2S)-7
S15
13C
-NMR of diastereomeric mixture of (S)(2R)-7 and (S)(2S)-7
S16
1H-NMR
of (S)(2R)-7
S17
13C-NMR
of (S)(2R)-7
S18
1H-NMR
of (S)(2S)-7
S19
13C-NMR
of (S)(2S)-7
S20
1H-NMR
of (S)(2R,3S)-8
S21
13C-NMR
of (S)(2R,3S)-8
S22
1H-NMR
of (1R,2S)-vinyl-ACCA (obtained by disassembly of the Ni(II) complex), measured in CD3OD-CDCl3 (20:1)
S23
1H-NMR
of (1R,2S)-11
S24
13C-NMR
of (1R,2S)-11
S25
1H-NMR
of (1R,2S)-12
S26
13C-NMR
of (1R,2S)-12
S27
1H-NMR
of (1R,2S)-13
S28
13C-NMR
of (1R,2S)-13
S29
1H-NMR
of 9
S30
13C-NMR
of 9
S31
1H-NMR
of 10
S32
13C-NMR
of 10
S33