Mechanistic aspects of Vinca-type dimers superacidic ... · 1 equiv) and (R)-Koga’s amine (686...

S1

Supporting Information

Enantioselective Synthesis of Levomilnacipran

Julien Alliot, Edmond Gravel, Florence Pillon, David-Alexandre Buisson, Marc Nicolas, and

Eric Doris.

General ................................................................................................................................... 2

N1-N3-bis((R)-1-phenyl-2-(piperidin-1-yl)ethyl)propane-1,3-diamine (Koga’s amine) ........ 3

(2S)-phenylpent-4-enoic acid (3) ........................................................................................... 5

(3S,5R)-5-(iodomethyl)-3-phenyldihydrofuran-2(3H)-one (4) .............................................. 7

Methyl 3-((S)-oxiran-2-yl)-2-phenylpropanoate (5) .............................................................. 9

(1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one (2) ........................................................ 11

(1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide (7) .............. 13

(1S,2R)- 2-(chloromethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide (8) ................. 15

(1S,2R)-2-((1,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-1-

phenylcyclopropanecarboxamide (9) ................................................................................... 17

(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide (1) .................. 19

(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide ....................... 21

hydrochloride (1·HCl) ......................................................................................................... 21

Model for the selective deprotonation of epoxy-ester 5 ....................................................... 23

Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2012

S2

General

Unless otherwise specified, chemicals were purchased from Aldrich and used without further

purification. Reactions were carried out under nitrogen using dry solvents, unless otherwise

stated. THF was distilled from sodium/benzophenone before use. 1,4-Dioxane and toluene

were distilled from sodium and stored under argon over 4Å molecular sieve. Flash

chromatography was carried out on Kieselgel 60 (230–240 mesh, Merck) and analytical TLC

was performed on Merck precoated silica gel plates (60 F254); visualization was carried out

with UV and/or heating with a solution of KMnO4 in water. HRMS were recorded at the

“Service de Spectrométrie de Masse de l’Institut de Chimie des Substances Naturelles” in

Gif-sur-Yvette (France). 1H and 13C NMR spectra were recorded on a Bruker Avance DPX

400 spectrometer at 400 and 100 MHz respectively. Chemical shifts (δ) are given in ppm and

coupling constants (J) in hertz. IR spectra were recorded on a Perkin-Elmer System 2000 FT-

IR. Optical rotations were determined using the sodium D line (589 nm) on a Perkin Elmer

341 polarimeter.


S3

N1-N3-bis((R)-1-phenyl-2-(piper idin-1-yl)ethyl)propane-1,3-diamine (Koga’s amine)1

Under N2, (R)-styrene oxide (2 g, 16.6 mmol, 1 equiv) was

diluted in EtOH (10 mL) before piperidine (2 mL, 1.2

equiv) was added. The solution was heated to reflux for 5 h. Volatiles were removed under

vacuum by azeotropic distillation with toluene (2 × 6 mL). The mixture was then diluted in

MTBE (18 mL) before NEt3 (8.7 mL, 3.8 equiv) was added. After 10 min at rt, the reaction

mixture was cooled down to –15 °C and stirred for additional 10 min. Methane sulfonyl

chloride (1.54 mL, 1.2 equiv) was then added dropwise over 25 min and under vigorous

stirring. After 40 min at –15 °C, 1,3-diaminopropane (0.7 mL, 0.5 equiv) was added, followed

by H2O (8.2 mL). The reaction mixture was warmed to rt over 1 h during which time the

precipitate dissolved. The organic phase was collected and the aqueous layer was extracted

with MTBE (2 × 10 mL). The combined organic layers were washed with brine, dried over

Na2SO4, filtered, and concentrated under reduced pressure. The crude residue (3.1 g) was first

purified by flash chromatography (CH2Cl2/MeOH/NH4OH 99:0.5:0.5 → 85:14.5:0.5). The

product was then recrystallized from i-PrOH/H2O at 0 °C, collected and dried under vacuum

for 72 h. The title compound was recovered as a white solid (2.3 g, 62%).

1H NMR (CDCl3): δ 1.33–1.68 (14H, m), 2.21–2.53 (18H, m), 3.71 (2H, dd, J = 10.8 Hz, J =

3.5 Hz), 7.21–7.36 (10H, m).

13C NMR (CDCl3): δ 24.5, 26.1, 31.5, 46.2, 54.6, 60.1, 66.6, 126.8, 127.3, 128.2, 143.3.

IR (neat): 3301, 2934, 2801, 1452 cm-1.

[α]20 D –111.6 (c 0.56, CHCl3); (lit.,1 [α]20

D –112 (c 5.45, CHCl3), 99.9% ee).

MS (ES+): 449 [M+H]+.

1 Org. Process Res. Dev. 2007, 11, 215.


S4

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm

1.484

1.499

1.509

1.524

1.539

1.547

1.563

1.578

1.646

1.662

1.679

2.213

2.222

2.244

2.253

2.390

2.418

2.446

2.461

2.495

2.512

3.700

3.708

3.727

3.736

7.218

7.236

7.263

7.279

7.298

7.316

7.333

7.351

14.6

2

18.0

2

2.00

10.8

9

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

24.448

26.077

30.477

46.227

54.572

60.129

66.558

76.620

76.937

77.254

126.846

127.304

128.177

143.273


S5

(2S)-phenylpent-4-enoic acid (3)2

Under N2 and at 0 °C, to a solution of phenylacetic acid (200 mg, 1.47 mmol,

1 equiv) and (R)-Koga’s amine (686 mg, 1.04 equiv) in dry THF (10 mL), n-

BuLi (2.35 mL of a 2.5 M soln in hexane, 4 equiv) was added over 5 min. The

reaction mixture was stirred at 0 °C for 15 min, cooled down to –78 °C, and allyl bromide

(509 µL, 4 equiv) was added over 10 min. After the addition, the reaction was immediately

quenched with MeOH/THF 1:3 (1.9 mL) and stirred for 5 min. 1 M HCl (10 mL) and EtOAc

(10 mL) were added. The organic phase was collected and the aqueous layer was extracted

with EtOAc (2 × 10 mL). The combined organic layers were washed with 1 M HCl (5 mL),

brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give

compound 3 (214 mg, 83%) as a yellowish oil. No further purification was needed for this

product.

Rf 0.40 (MeOH/CH2Cl2 4:96).

1H NMR (CDCl3): δ 2.49–2.57 (1H, m), 2.79–2.87 (1H, m), 3.65 (1H, dd, J = 8.0 Hz, J = 7.6

Hz), 5.02 (1H, dd, , J = 10.0 Hz, J = 1.6 Hz), 5.09 (1H, dd, J = 17.2 Hz, J = 1.6 Hz), 5.67–

5.78 (1H, m), 7.25–7.37 (5H, m).

13C NMR (CDCl3): δ 36.9, 51.2, 117.1, 127.5, 127.9 (2C), 128.6, (2C), 134.8, 137.7, 179.0.

IR (neat): 3067, 1706, 1415, 918, 697 cm-1.

Chiral HPLC: Chiralcel OJ 250 × 4.6 mm, n-hexane/i-PrOH 9:1, flow rate: 1 mL min-1,

detection at 220 nm, tmajor = 9.6 min, tminor = 11.5 min, 88% ee.

[α]20 D +77.6 (c 0.85, CHCl3); (lit.,2 [α]20

D +77.2 (c 1.00, CHCl3), 93% ee).

MS (ES+): 177 [M+H]+.

2 J. Am. Chem. Soc. 2011, 133, 11936.


S6

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

2.499

2.516

2.534

2.552

2.569

2.794

2.812

2.831

2.848

2.868

3.633

3.652

3.672

5.007

5.032

5.067

5.071

5.110

5.113

5.676

5.693

5.701

5.710

5.718

5.736

5.744

5.753

5.761

5.778

7.263

7.277

7.287

7.291

7.298

7.311

7.324

7.332

7.356

1.01

1.00

0.99

0.98

0.98

0.96

4.82

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

36.997

51.192

76.627

76.944

77.261

117.222

127.532

127.983

128.643

134.797

137.736

179.036


S7

(3S,5R)-5-(iodomethyl)-3-phenyldihydrofuran-2(3H)-one (4)

Under N2 and at 0 °C, to a solution of acid 3 (330 mg, 1.87 mmol, 1 equiv) in

Et2O (12 mL), K2CO3 (310 mg, 1.2 equiv) was added, followed by I2 (522 mg,

1.1 equiv) portionwise over 20 min. The dark mixture was stirred at 0 °C for 1

h and 5 h at rt. Iodide in excess was neutralized with sat Na2S2O3 (5 mL). The organic phase

was collected and the aqueous layer was extracted with Et2O (2 × 5 mL). The combined

organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated

under reduced pressure. The crude mixture was purified by flash chromatography (EtOAc/n-

hexane 2:8) to give cis-isomer 4 as a white solid (365 mg, 65%).

Spectral data obtained for 4 are in agreement with those previously reported in the literature

for the racemic iodolactone.3

Rf 0.40 (EtOAc/c-hexane 3:7).

1H NMR (CDCl3): δ 2.10–2.19 (1H, m), 2.92–2.99 (1H, m), 3.37 (1H, dd, J = 10.6 Hz, J =

7.2 Hz), 3.53 (1H, dd, J = 10.6 Hz, J = 4.4 Hz), 3.95 (1H, dd, J = 12.4 Hz, J = 8.8 Hz), 4.48–

4.55 (1H, m), 7.25–7.40 (5H, m).

13C NMR (CDCl3): δ 6.4, 38.3, 47.3, 76.1, 127.8, 128.0 (2C), 128.8 (2C), 135.9, 175.7.

IR (KBr): 1771, 1154, 1005, 698 cm-1.

Chiral HPLC: Daicel OJ-R 150 × 4.6 mm, H2O/MeOH 1:9, flow rate: 1 mL min-1, detection

at 254 nm, tminor = 4.1 min, tmajor = 5.0 min, 88% ee.

[α]20 D +30.9 (c 0.50, CHCl3).

MS (ES+): 303 [M+H]+.

3 J. Med. Chem. 1992, 35, 885.


S8

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.547

2.108

2.133

2.140

2.165

2.172

2.197

2.928

2.942

2.950

2.960

2.964

2.974

2.982

2.996

3.353

3.371

3.379

3.397

3.505

3.515

3.531

3.542

3.930

3.952

3.961

3.983

4.485

4.499

4.504

4.510

4.515

4.518

4.521

4.524

4.529

4.535

4.540

4.554

7.263

7.301

7.317

7.322

7.337

7.339

7.369

7.386

7.404

1.07

1.07

1.05

1.07

1.01

1.00

4.76

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

6.431

38.382

47.365

76.171

76.625

76.942

77.147

77.260

127.799

128.040

128.895

135.925

175.793


S9

Methyl 3-((S)-oxiran-2-yl)-2-phenylpropanoate (5)

To a solution of lactone 4 (264 mg, 0.87 mmol, 1 equiv) in MeOH (8.7 mL)

K2CO3 (241 mg, 2 equiv) was added. The mixture was stirred for 2 h at rt, and

the solvent was removed in vacuo. The solid was suspended in Et2O, filtered,

and washed twice with Et2O (2 × 4 mL). Volatiles were evaporated under vacuum to give

compound 5 as a colorless oil (175 mg, 98%).


1H NMR (CDCl3): δ 1.80–1.87 (1H, m), 2.11–2.17 (2H, m), 2.40–2.47 (2H, m), 2.51–2.53

(1H, m), 2.67–2.70 (1H, m), 2.75–2.80 (2H, m), 2.95–2.98 (1H, m), 3.67 (3H, s), 3.68 (3H, s),

3.78–3.84 (2H, m), 7.27–7.37 (10H, m).

13C NMR (CDCl3): δ 36.1, 36.4, 47.2, 47.3, 48.3, 48.4, 49.9, 50.3, 52.0, 52.1, 127.4, 127.5

(2C), 127.6, 127.7 (2C), 127.9 (2C), 128.7 (2C), 137.9, 138.5, 173.6, 173.7.

IR (neat): 1734, 1260, 1167 cm-1.

MS (ES+): 207 [M+H]+.

HRMS: calcd for C12H15O3 [M+H]+ 207.1017, found 207.1023.


S10

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.860

2.140

2.155

2.159

2.174

2.410

2.420

2.426

2.433

2.445

2.507

2.514

2.519

2.526

2.674

2.684

2.696

2.752

2.763

2.775

2.784

2.792

2.955

2.961

2.966

2.972

2.978

3.674

3.684

3.783

3.802

3.812

3.823

3.837

7.262

7.271

7.290

7.299

7.307

7.316

7.333

7.346

1.02

2.04

2.00

1.03

1.00

2.02

1.00

5.95

2.06

9.27

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

36.163

36.453

47.242

47.322

48.365

48.466

49.963

50.376

52.098

52.130

76.669

76.987

77.305

127.441

127.492

127.591

127.744

127.949

128.747

128.848

137.991

138.503

173.626

173.745


S11

(1S,5R)-1-phenyl-3-oxabicyclo[3.1.0]hexan-2-one (2)

LDA (2 mL of a 0.6 M soln in THF, 1.2 equiv) was added to a refluxing solution

of epoxy ester 5 (202 mg, 0.98 mmol, 1 equiv) in anhydrous 1,4-dioxane (9 mL)

and HMPA (1.2 mL). After 2 min, the reaction was cooled down to rt and HCl

was bubbled until pH < 1. Et2O (10 mL) and H2O (10 mL) were added. The organic phase

was collected and the aqueous layer was extracted with Et2O (2 × 10 mL). The combined

organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated

under reduced pressure. The cyclopropyl lactone was separated from the trans-cyclopropane

by column chromatography (EtOAc/c-hexane 2:8) to afford compound 2 as a colorless liquid

(94 mg, 55%).

Spectral data obtained for 2 are in agreement with those previously reported in the literature.4


1H NMR (CDCl3): δ 1.37 (1H, t, J = 4.8 Hz), 1.65 (1H, dd, J = 7.6 Hz, J = 4.8 Hz), 2.54–2.58

(1H, m), 4.29 (1H, d, J = 9.4 Hz), 4.47 (1H, dd, J = 9.4 Hz, J = 4.8 Hz), 7.28–7.45 ppm (5H,

m).

13C NMR (CDCl3): δ 20.0, 25.0, 31.6, 67.9, 127.6, 128.2 (2C), 128.5 (2C), 134.0, 175.9 ppm.

IR (neat): 1760, 1249 cm-1.

Chiral HPLC: Daicel OJ-R 150 × 4.6 mm, H2O/MeOH 4:6, flow rate: 1 mL min-1, detection

at 254 nm, tmajor = 15.4 min, tminor = 17.7 min, 88% ee.

[α]20D –62.4 (c 0.48, MeOH); (lit.,5

MS (ES+): 175 [M+H]+.

[α]20D –78.5 (c 1.42, MeOH), 96% ee).

4 Bioorg. Med. Chem. Lett. 2007, 17, 2834. 5 J. Org. Chem. 1996, 61, 915.


S12

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm

1.366

1.378

1.390

1.546

1.642

1.654

1.661

1.673

2.554

2.565

2.573

4.292

4.315

4.460

4.471

4.482

4.494

7.263

7.300

7.318

7.341

7.360

7.378

7.423

7.441

7.445

1.03

1.00

0.94

0.99

1.00

4.84

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

20.072

25.018

31.635

67.994

76.622

76.940

77.143

77.257

127.630

128.233

128.552

134.005

175.923


S13

(1S,2R)-N,N-diethyl-2-(hydroxymethyl)-1-phenylcyclopropanecarboxamide (7)

Under N2, diethylamine (210 µL, 2.6 equiv) was added to a suspension

of AlCl3 (137 mg, 1.3 equiv) in anhydrous toluene (1.5 mL). After 10

min, lactone 2 (138 mg, 0.79 mmol, 1 equiv) diluted in toluene (2 mL)

was added dropwise. The suspension was stirred for 2 h and quenched with 0.1 N HCl (3 mL).

The organic phase was collected and the aqueous layer extracted with toluene (2 × 3 mL). The

combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, and

concentrated under reduced pressure. The crude mixture was purified by filtration over silica

(CH2Cl2/EtOAc 99:1 → 80:20) to give compound 7 as a colorless oil (176 mg, 90%).



1H NMR (CDCl3): δ 0.91 (3H, t, J = 7.0 Hz), 1.09 (1H, t, J = 5.6 Hz), 1.13 (3H, t, J = 8.4

Hz), 1.54–1.60 (1H, m), 1.66 (1H, dd, J = 8.4 Hz, J = 5.6 Hz), 2.35 (1H, brs), 3.18 (1H, dd, J

= 12.0 Hz, J = 10.4 Hz), 3.35–3.43 (3H, m), 3.47-3.55 (1H, m), 4.05 (1H, dd, J = 12.4 Hz, J =

4.8 Hz), 7.19–7.32 (5H, m).

13C NMR (CDCl3): δ 12.3, 13.0, 16.6, 31.9, 34.3, 39.4, 41.9, 64.8, 125.6, 126.5, 128.6, 140.2,

171.1.

IR (neat): 3418, 1616, 1431, 699 cm-1.

[α]20 D +50.8 (c 0.51, CHCl3).

MS (ES+): 248 [M+H]+.

6 Adv. Synth. Catal. 2001, 343, 299.


S14

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm

1.126

1.144

1.162

1.549

1.560

1.571

1.583

1.641

1.655

1.663

1.676

2.357

3.151

3.177

3.181

3.207

3.353

3.371

3.389

3.394

3.406

3.412

3.423

3.429

3.487

3.505

3.523

3.541

4.030

4.041

4.060

4.072

7.194

7.212

7.221

7.232

7.240

7.263

7.281

7.300

7.319

2.91

1.11

2.91

0.98

0.99

1.10

2.87

1.10

0.97

3.14

2.13

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

12.305

13.079

16.645

31.939

34.315

39.475

41.921

64.847

76.617

76.934

77.139

77.252

125.671

126.568

128.631

140.218

171.184


S15

(1S,2R)- 2-(chloromethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide (8)

Under N2, SOCl2 (77 µL, 1.6 equiv) was added dropwise to a solution of

alcohol 7 (164 mg, 0.66 mmol, 1 equiv) in anhydrous toluene (4 mL).

After 2 h, volatiles were removed in vacuo. The crude residue was

purified by filtration over silica gel (CH2Cl2/EtOAc 99:1 → 80:20) to give compound 8 as a

white solid (168 mg, 96%).


1H NMR (CDCl3): δ 0.55 (3H, t, J = 7.1 Hz), 1.12 (3H, t, J = 7.4 Hz), 1.18 (1H, dd, J = 9.2

Hz, J = 5.2 Hz), 1.61–1.66 (1H, m), 2.16–2.21 (1H, m), 3.04–3.10 (1H, m), 3.12–3.19 (1H,

m), 3.50–3.70 (4H, m), 7.20–7.33 (5H, m).

13C NMR (CDCl3): δ 12.2, 12.3, 21.2, 26.9, 37.3, 39.6, 42.3, 45.6, 126.5 (2C), 126.8, 128.7

(2C), 140.2, 168.9.

IR (KBr): 1630, 1427, 1141, 699 cm-1.

[α]20 D +146 (c 0.62, CHCl3).

MS (ES+): 266 [M+H]+.


S16

1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5 ppm

1.136

1.161

1.173

1.183

1.196

1.550

1.627

1.641

1.655

2.167

2.184

2.205

3.040

3.058

3.076

3.094

3.136

3.153

3.169

3.187

3.515

3.532

3.549

3.568

3.586

3.598

3.616

3.643

3.662

3.672

3.691

7.205

7.222

7.232

7.251

7.263

7.291

7.310

7.329

2.53

2.54

0.96

0.95

0.97

1.01

1.00

3.73

2.90

1.77

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

12.184

12.246

21.243

26.924

37.302

39.648

42.355

45.580

76.684

77.001

77.319

126.466

126.752

128.743

140.252

168.888


S17

(1S,2R)-2-((1,3-dioxoisoindolin-2-yl)methyl)-N,N-diethyl-1-

phenylcyclopropanecarboxamide (9)

Under N2, cyclopropane 8 (120 mg, 0.45 mmol, 1 equiv) was

diluted in anhydrous toluene (2 mL) and potassium phtalimide

(167 mg, 2 equiv) was added. The reaction mixture was heated to

reflux for 3 h, cooled down to rt, and quenched with H2O (3 mL). The organic phase was

collected and the aqueous layer was extracted with toluene (2 × 3 mL). The combined organic

layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under

reduced pressure to give 9 as a white solid (148 mg, 88%).


Rf 0.30 (EtOAc/cyclohexane 3:7).

1H NMR (CDCl3): δ 0.65 (3H, t, J = 7.0 Hz), 1.08–2.19 (4H, m), 1.65 (1H, t, J = 5.8 Hz),

1.99–2.05 (1H, m), 3.10–3.17 (1H, m), 3.29–3.35 (1H, m), 3.41–3.49 (2H, m), 3.53–3.59 (1H,

m), 4.16 (1H, dd, J = 14.0 Hz, J = 4.0 Hz), 7.10–7.35 (5H, m), 7.68–7.73 (2H, m), 7.81–7.85

(2H, m).

13C NMR (CDCl3): δ 12.5, 12.7, 20.6, 24.5, 34.8, 39.3, 39.5, 41.8, 128.1 (2C), 126.0 (2C),

126.5, 128.6 (2C), 132.1 (2C), 133.9 (2C), 140.3, 168.2 (2C), 169.1.

IR (KBr): 1771, 1714, 1632, 1426, 1386, 722 cm-1.

[α]20 D –64.6 (c 0.46, CHCl3).

MS (ES+): 377 [M+H]+.

7 J. Med. Chem. 1987, 30, 318.


S18

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.166

1.180

1.193

1.643

1.658

1.672

1.996

2.007

2.018

2.028

2.038

2.052

3.111

3.128

3.146

3.164

3.291

3.308

3.325

3.342

3.410

3.436

3.446

3.453

3.471

3.487

3.531

3.549

3.567

3.584

4.141

4.151

4.176

4.186

7.156

7.173

7.191

7.209

7.244

7.262

7.282

7.691

7.699

7.705

7.713

7.722

7.817

7.827

7.835

7.841

7.848

3.04

4.11

1.01

1.09

1.03

1.03

2.03

1.04

1.00

5.11

2.03

1.96

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

12.472

12.711

20.563

24.529

34.751

39.336

39.504

41.776

76.704

77.023

77.340

123.140

125.957

126.506

128.594

132.092

133.864

140.318

168.173

169.093


S19

(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide (1)

Under N2, phtalimide 9 (61 mg, 0.16 mmol, 1 equiv) was diluted in

anhydrous toluene (2 mL) and ethanolamine (98 µL, 10 equiv) was

added. The reaction mixture was heated to 100 °C for 3 h, cooled down

to rt, and quenched with 20% NaCl (3 mL). The aqueous layer was extracted with toluene (2

× 3 mL). The combined organic layers were washed with 20% NaCl (2 × 3 mL) and extracted

with 1 M HCl (2 × 3 mL). The organic phase was discarded. The combined aqueous layers

were basified with 20% NaOH and extracted with toluene (3 × 3 mL). The combined organic

layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under

reduced pressure to give compound 1 as an oil (36 mg, 89%).


Rf 0.10 (CH2Cl2/MeOH 9:1).

1H NMR (CDCl3): δ 0.66 (3H, t, J = 7.3 Hz), 1.09 (3H, t, J = 7.6 Hz), 1.15 (1H, dd, J = 8.3

Hz, J = 5.2 Hz), 1.30–1.34 (1H, m), 1.56 (2H, brs), 1.72–1.77 (1H, m), 2.65 (1H, dd, J = 13.0

Hz, J = 7.2 Hz), 2.78 (1H, dd, J = 13.0 Hz, J = 7.2 Hz), 3.11–3.25 (2H, m), 3.44–3.55 (2H,

m), 7.10–7.30 (5H, m).

13C NMR (CDCl3): δ 12.3, 12.7, 19.4, 29.5, 34.7, 39.2, 41.6, 43.6, 125.9 (2C), 126.3, 128.6

(2C), 141.1, 170.1.

IR (neat): 3421, 3364, 1626, 1429 cm-1.

Chiral HPLC:

Enantiomeric excess was measured on N-acetyl-levomilnacipran which was obtained by

acetylation of levomilnacipran 1. Daicel OJ-R 150 × 4.6 mm, H2O/MeOH 5:5, flow rate: 1

mL min-1, detection at 200 nm, tmajor = 7.0 min, tminor = 8.9 min, 88% ee.

[α]20 D –88.3 (c 1.0, CHCl3).

MS (ES+): 247 [M+H]+.

8 Adv. Synth. Catal. 2001, 343, 299.


S20

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

1.155

1.168

1.305

1.321

1.334

1.560

1.722

1.739

1.743

1.760

2.624

2.642

2.656

2.674

2.759

2.776

2.791

2.809

3.118

3.135

3.153

3.171

3.190

3.208

3.224

3.242

3.440

3.458

3.475

3.492

3.511

3.529

3.547

7.169

7.191

7.211

7.247

7.265

7.285

3.00

2.95

1.09

1.03

2.19

1.03

1.01

1.00

2.04

2.04

5.09

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

12.332

12.741

19.393

29.532

34.758

39.181

41.578

43.597

76.680

76.999

77.316

125.924

126.299

128.571

141.063

170.019


S21

(1S,2R)-2-(aminomethyl)-N,N-diethyl-1-phenylcyclopropanecarboxamide

hydrochloride (1·HCl)

To a solution of 1 (18 mg, 0.073 mmol) in Et2O (2 mL), was added a

saturated solution of HCl in Et2O (0.5 mL). The hydrochloride of 1

precipitated out spontaneously. The reaction mixture was further

stirred for 15 min, decanted, and the supernatant was discarded. The solid was suspended in

Et2O (2 mL), stirred for 15 min, decanted, and the supernatant was discarded. The washing

step was repeated twice. Finally, the solid was collected and dried under vaccum overnight to

give compound 1·HCl as a white solid (20 mg, 97 %).

Analytical data obtained for 1·HCl are in agreement with those previously reported in the

literature.9

1H NMR (CDCl3): δ 0.90 (3H, t, J = 7.0 Hz), 1.09–1.31 (4H, m), 1.62–1.80 (1H, m), 1.82–

1.87 (1H, m), 2.35–2.53 (1H, m), 3.27–3.47 (4H, m), 3.72–3.84 (1H, m), 7.15–7.30 (5H, m),

8.83 (3H, brs).

13C NMR (CDCl3): δ 12.2, 13.0, 17.9, 25.5, 34.6, 39.6, 42.0, 43.1, 125.6 (2C), 127.3, 128.9

(2C), 138.1, 170.7.

IR (KBr): 3409, 1615, 1467 cm-1.

[α]20 D +72.5 (c 0.70, CHCl3); (lit.,10

[α]20 D +72.8 (c 0.95, CHCl3), 96% ee).

9 J. Med. Chem. 1995, 38, 2967. 10 Tetrahedron Lett. 1996, 37, 641.


S22

9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm

0.884

0.901

0.919

1.092

1.109

1.127

1.708

1.751

1.834

1.847

1.869

2.449

3.274

3.291

3.307

3.325

3.337

3.354

3.371

3.385

3.401

3.416

3.433

3.451

3.469

3.744

7.157

7.176

7.196

7.215

7.232

7.263

7.269

7.289

7.306

8.829

3.10

3.97

1.35

0.95

0.97

1.02

4.06

1.00

1.93

1.08

1.78

2.78

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 ppm

12.192

12.977

17.931

25.491

34.634

39.590

41.960

43.127

76.622

76.940

77.146

77.257

125.643

127.253

128.941

138.131

170.696


S23

Model for the selective deprotonation of epoxy-ester 511

Figure S1

11 J. Org. Chem. 1980, 45, 1066.


Mechanistic aspects of Vinca-type dimers superacidic ... · 1 equiv) and (R)-Koga’s amine (686...

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Transcript of Mechanistic aspects of Vinca-type dimers superacidic ... · 1 equiv) and (R)-Koga’s amine (686...