69451 Weinheim, Germany - Wiley-VCHS tereos elective S im m on s-S m ith C yc lop rop an ation s of...

Supporting Information

© Wiley-VCH 2007

69451 Weinheim, Germany

Stereoselective Simmons-Smith Cyclopropanations of Chiral Enamides.

authored by

Zhenlei Song, Ting Lu, Richard P. Hsung*, Ziyad F. Al-Rashid, Changhong Ko, and Yu Tang

Division of Pharmaceutical Sciences and Department of Chemistry

7111 Rennebohm Hall, 777 Highland Avenue

University of Wisconsin, Madison, WI 53705

S2

EXPERIMENTAL SECTION

Cyclopropanation reactions performed in flame-dried glassware under nitrogen atmosphere. Solvents

were distilled prior to use. Reagents were used as purchased (Aldrich, Acros, Alfa Aesar, TCI), except

where noted. Chromatographic separations were performed using Bodman 60 Å SiO2. 1H and 13C NMR

spectra were obtained on Varian VI-400 and VI-500 spectrometers using CDCl3 (except where noted)

with TMS or residual solvent as standard. Melting points were determined using a Laboratory Devices

MEL-TEMP and are uncorrected/calibrated. Infrared spectra were obtained using NaCl plates on a

Midac M2000 FTIR. TLC analysis was performed using Aldrich 254 nm polyester-backed plates (60 Å,

250 µm) and visualized using UV and KMnO4 stains. Low-resolution mass spectra were obtained using

an Agilent 1100 series LS/MSD and are APCI. High-resolution mass spectral analyses performed at

University of Wisconsin School of Pharmacy Mass Spectrometry Laboratory. X-Ray analysis performed

at University of Minnesota Department of Chemistry X-Ray facility. All spectral data obtained for new

compounds are reported here.

Preparations of Enamides. Enamides 5, 8, 9, 10, 11, 12, 14, 15, 26 were prepared using the following

general procedure: A mixture of an oxazolidinone or imidazolidinone (1.00 mmol) and an aldehyde

(1.10 mmol) of choice and PTS or PPTS (10 mol %) in toluene was refluxed with a Dean-Stark set up

for remove water. The reaction was monitored via TLC analysis and when it was complete, evaporation

of the solvent under reduced pressure afforded the crude product. Silica gel flash column

chromatography of the crude afforded chiral enamides as an oil or solid. Enamides 24 and 25 were

prepared by following the reported procedure of our group.1 Enamide 13 was prepared by following the

reported procedure of Buchwald’s group.2

___________________________

Reference 1. Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.;

Tracey, M. R. J. Org. Chem. 2006, 71, 4170. 2. Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667.

Characterizations.

NO

O

Ph

5

Rf = 0.67 [50% EtOAc in hexane]; [!]20D = - 85.6 o [c 0.79 in CH2Cl2];

1H NMR (500 MHz, CDCl3) " 0.84 (t, 3 H, J = 7.0 Hz), 1.03-1.09 (m, 2 H), 1.15-1.21 (m, 4 H), 1.88

(ddt, 2 H, J = 1.5, 7.0, 7.0 Hz), 4.15 (dd, 1 H, J = 5.5, 8.5 Hz), 4.60 (dt, 1 H, J = 7.0, 14.5 Hz), 4.70 (t, 1

H, J = 8.5 Hz), 5.00 (dd, 1 H, J = 5.5, 8.5 Hz), 6.56 (dd, 1H, J = 1.5, 14.5 Hz), 7.24-7.41 (m, 5 H); 13C

(500 MHz, CDCl3) " 14.0, 22.4, 29.4, 29.9, 30.9, 58.7, 70.5, 114.0, 122.4, 125.9, 128.6, 129.2, 138.4,

155.9; IR (thin film) cm-1 3032m, 2926m, 1748s, 1436m, 1041w; mass spectrum (LCMS): m/e (%

S3

relative intensity) 260 (70) (M+H+), 216 (100), 176 (15); HRMS (APCI) m/e calcd for C16H22NO2

[M+H]+ 260.1651, found 260.1648.

NO

O

Ph

2

OTBS

8 Rf = 0.34 [20% EtOAc/hexanes]; [!]

D23 = - 68.7 o [c 0.49, CHCl3];

1H NMR (400MHz, CDCl3) " -0.01 (s, 6H), 0.87 (s, 9H), 1.42 (tt, 2H, J = 6.8, 7.2 Hz), 1.98 (q, 2H, J =

7.2 Hz), 3.43 (t, 2H, J = 6.8 Hz), 4.11 (dd, 1H, J = 5.2, 9.2 Hz), 4.62 (dt, 1H, J = 7.2, 14.4 Hz), 4.71 (dd,

1H, J = 9.2, 9.2 Hz), 5.00 (dd, 1H, J = 5.2, 9.2 Hz), 6.60 (d, 1H, J = 14.4 Hz), 7.23-7.27 (m, 2H), 7.33-

7.42 (m, 3H); 13C NMR (100 MHz, CDCl3) " -5.4, 18.2, 25.9, 26.2, 32.7, 58.5, 61.9, 70.5, 112.9, 122.8,

125.8, 128.6, 129.2, 138.3, 155.8 (missing 4 carbons due to overlap); IR (thin film) cm-1 2928m, 2856m,

1764s, 1672m, 1483m; HRMS (MALDI) m/e calcd for C20H31NNaO3Si [M+Na]+ 384.1971, found

384.202.

NO

O

Bn

2

OTBS

9 Rf = 0.32 [20% EtOAc/hexanes]; [!]

D23 = - 26.6 o [c 0.61, CHCl3];

1H NMR (400MHz, CDCl3) " 0.00 (s, 6H), 0.84 (s, 9H), 1.60 (tt, 2H, J = 6.8, 7.2 Hz), 2.13 (dddt, 2H, J

= 1.2, 2.0, 7.2, 8.0 Hz), 2.71 (dd, 1H, J = 8.8, 14.4 Hz), 3.15 (dd, 1H, J = 3.2, 14.4Hz), 3.59 (t, 2H, J =

6.8 Hz), 4.10 (dd, 1H, J = 2.8, 8.0 Hz), 4.15 (dd, 1H, J = 8.0, 8.0 Hz), 4.19 (dddd, 1H, J = 2.8, 3.2, 8.0,

8.8 Hz), 5.04 (dt, 1H, J = 7.2, 14.8 Hz), 6.53 (dt, 1H, J = 1.2, 14.8 Hz), 7.09-7.1 (m, 2H), 7.12-7.24 (m,

1H), 7.25-7.30 (m, 2H); 13C NMR (100 MHz, CDCl3) " 0.0, 23.6, 31.2, 31.8, 38.4, 41.4, 60.3, 67.6,

71.7, 116.9, 128.2, 132.6, 134.2, 134.5, 140.6, 160.4; IR (thin film) cm-1 3056m, 2986m, 1755s, 1419s,

1265s; mass spectrum (APCI): m/e (% relative intensity) 376 (M+H)+ (100), 376 (30).

NO

O

Ph

n-Bu

Ph

10

Rf = 0.55 [33% EtOAc/hexanes]; mp 144-146 oC; [!] D

23 = - 7.0 o [c 0.43, CH2Cl2];

1H NMR (400 MHz, CDCl3) " 0.76 (t, 1H, J = 7.2 Hz), 1.07-1.20 (m, 4H), 1.85-1.90 (m, 2H), 4.61 (ddd,

1H, J = 7.2, 7.2, 14.4 Hz), 5.23 (d, 1H, J = 8.4 Hz), 5.89 (d, 1H, J = 8.4 Hz), 6.67 (d, 1H, J = 14.4 Hz)

6.88-6.90 (m, 2H), 6.93-7.13 (m, 8H); 13C NMR (100 MHz, CDCl3) " 14.0, 22.0, 29.7, 32.1, 64.0, 80.6,

114.5, 122.6, 126.5, 127.3, 128.1, 128.3, 128.38, 128.40, 133.8, 134.1, 155.7; IR (neat) cm-1 3037w,

2940m, 2869w, 2306w, 1728s, 1673m, 1455m, 1411s, 1344w; mass spectrum (APCI): m/e (% relative

S4

intensity) 322 (45) (M+H)+, 278 (100) (M+H-CO2)+.

NN

O

Ph

11

OMe

Rf = 0.5 [33% EtOAc/hexanes]; mp 163-166 oC; [!]

D25

= - 53.3 o [c 3.40, CH2Cl2]; 1H NMR (500 MHz, CDCl3) "!0.79 (d, 3H, J = 6.5 Hz), 2.83 (s, 3H), 3.73 (s, 3H), 3.90 (dq, 1H, J = 6.5,

7.5 Hz), 4.94 (d, 1H, J = 9.0 Hz), 5.26 (d, 1H, J = 15.0 Hz), 6.73(dd, 2H, J = 2.0, 7.0 Hz), 7.07 (dd, 2H,

J = 1.5, 7.5 Hz), 7.15-7.16 (m, 2H), 7.29-7.30 (m, 1H), 7.32-7.35 (m, 2H), 7.42 (d, 1H, J = 15.0Hz); 13C

NMR (125 MHz, CDCl3) " 15.5, 29.1, 55.6, 56.0, 60.8, 108.5, 114.3, 122.8, 126.3, 128.5, 128.9, 130.2,

135.7, 158.0, 158.1 (missing 1 carbon due to overlap); IR (neat) cm-1 2975bm, 1702s, 1650s, 1606m,

1511m, 1426s, 1397s; mass spectrum (APCI): m/e (% relative intensity) 323 (100) (M+H)+, 191 (6).

NN

O

Ph

Ph

12 Rf = 0.4 [33% EtOAc/hexanes]; mp 186-188 oC; [!]

D23

= - 60.0 o [c 1.25, CH2Cl2]; 1H NMR (400 MHz, CDCl3) " 0.87 (d, 3H, J = 6.0 Hz),!2.90 (s, 3H), 3.99 (dq, 1H, J = 6.5, 7.5 Hz),

5.03 (d, 1H, J = 8.5 Hz), 5.35 (d, 1H, J = 15.0 Hz), 7.09-7.12 (m, 1H), 7.19-7.23 (m, 5H), 7.32-7.42 (m,

4H), 7.61 (d, 1H, J = 15.0 Hz); 13C NMR (100 MHz, CDCl3) " 15.5, 29.1, 55.9, 60.8, 108.8, 124.2,

125.3, 125.8, 128.5, 128.9, 135.6, 137.5, 158.0 (missing 2 carbons due to overlap); IR (film) cm-1 1679s,

1645m, 1430s, 1396s; mass spectrum (APCI): m/e (% relative intensity) 293 (100) (M+H)+, 259 (10),

234 (27), 191 (40).

NO

O

Ph

13


23 = - 21.8 o [c 1.3, CH2Cl2];

1H NMR (400 MHz, CDCl3) " 2.11 (s, 1H),!4.07 (dd, 1H, J = 5.6, 8.8 Hz), 4.23 (m, 2H), 4.65 (dd, 1H, J

= 8.8, 8.8 Hz), 5.10 (dd, 1H, J = 5.6, 8.8 Hz), 7.25-7.28 (m, 2H), 7.32-7.42 (m, 3H); 13C NMR (100

MHz, CDCl3) " 20.7, 60.8, 69.8, 102.1, 126.1, 128.9, 129.5, 139.08, 139.14, 155.7; IR (neat) cm-1

3031w, 2920w, 1742s, 1631m, 1476w, 1454m, 1400s, 1349s; mass spectrum (APCI): m/e (% relative


S5

NO

O

Ph

Et

14

Rf = 0.28 [33 % EtOAc/hexanes]; mp 102-103 ºC; [!] D

23 = + 25.6 o [c 1.71, CH2Cl2]; 1H NMR (400 MHz, CDCl3) " 0.96 (t, 3H, J = 7.6 Hz), 1.64 (ddd, 3H, J = 1.2, 1.6, 6.8 Hz), 1.87 – 2.04

(m, 2H), 4.21 (dd, 1H, J = 8.8, 8.8 Hz), 4.70 (dd, 1H, J = 8.8, 8.8 Hz), 5.01 (dd, 1H, J = 8.8, 8.8 Hz),

5.36 (qt, 1H, J = 1.0, 6.8 Hz), 7.31 – 7.33 (m, 2H), 7.36 - 7.41 (m, 3H); 13C NMR (125 MHz, CDCl3) "

11.7, 13.4, 26.2, 60.3, 70.2, 121.6, 127.3, 129.2, 134.7, 137.6, 155.9 (missing 1 carbon due to overlap);

IR (thin film) cm-1 3039w, 2970w, 1744s, 1678m, 1396s; mass spectrum (APCI): m/e (% relative

intensity) 232 (100) (M+1)+, 188 (60), 112 (5); HRMS (MALDI) m/e calcd for C14H17NO2Na (M+Na+)

254.1152, found 254.1146.

NO

O

Ph

15


23 = - 54.0 o [c 1.00, CH2Cl2];

1H NMR (400 MHz, CDCl3) " 1.42-1.48 (m, 2H), 1.55-1.61 (m, 2H), 1.93-2.01 (m, 2H), 2.10 (m, 1H),

2.37 (m, 1H),!4.08 (dd, 1H, J = 6.4, 8.8 Hz), 4.63 (dd, 1H, J = 8.8, 8.8 Hz), 5.04 (dd, 1H, J = 6.4, 8.8

Hz), 5.45 (m, 1H), 7.26-7.28 (m, 2H), 7.32-7.42 (m, 3H); 13C NMR (100 MHz, CDCl3) " 21.8, 22.7,

24.5, 26.5, 60.9, 70.0, 119.8, 126.7, 128.9, 129.3, 133.3, 139.1, 156.3; IR (neat) cm-1 3032w, 2932m,

2839w, 1743s, 1669m, 1486m, 1456s, 1397m, 1343m; mass spectrum (APCI): m/e (% relative intensity)

244 (100) (M+H)+, 200 (36) (M+H-CO2)+.

NO

O

Ph

Ph

26 Rf = 0.41 [40 % EtOAc/hexanes]; mp 124-126 oC; [!]

D23

= - 98.8 o (c 0.65, CH2Cl2); 1H NMR (500 MHz, CDCl3) "!4.19 (dd, 1H, J = 5.0, 9.0 Hz), 4.78 (dd, 3H, J = 9.0, 9.0), 5.16 (dd, 1H, J

= 5.0, 9.0 Hz), 5.58 (d, 1H, J = 15.0 Hz), 7.11-7.16 (m, 3H), 7.20-7.23 (m, 2H), 7.31-7.38 (m, 4H), 7.41-

7.44 (m, 2H); 13C NMR (100 MHz, CDCl3) " 58.8, 71.0, 113.2, 123.2, 125.7, 126.1, 126.9, 128.8, 129.2,

129.8, 136.1, 138.2, 156.0; IR (neat) cm-1 3047w, 2942w, 1751s, 1652s, 1476m, 1401s, 1366s; mass

spectrum (APCI): m/e (% relative intensity) 266 (100) (M+H)+, 222 (37).

S6

General Procedure for Simmons-Smith Cyclopropanations of Chiral Enamides.

To a solution of chiral enamide 25 (50.0 mg, 0.189 mmol) in anhyd ClCH2CH2Cl (1.9 mL) were added

MS 4Å (50.0 mg), ICH2Cl (140.0 µL, 1.89 mmol, 10.0 equiv). After stirring at rt for 30 min, a solution

of ZnEt2 (0.94 mL, 1.0 M in hexane, 0.94 mmol, 4.9 equiv) was added carefully dropwise. After

additional stirring at rt for 48 h, all the starting material 25 was consumed as evident by TLC analysis.

The reaction mixture was first quenched with sat aq NaHCO3 (5 mL), and then extracted with CH2Cl2 (2

x 10 mL). The combined organic phases were washed with sat aq NaCl (2 x 5 mL), dried over Na2SO4,

and concentrated under reduced pressure to afford the crude product as a 72 : 28 mixture as determined

by crude 1H NMR. Purification of the crude residue via silica gel flash column chromatography

(gradient eluent: 15-33% of EtOAc/hexanes) afforded the pure major isomer 28 (30.0 mg, 64%) as white

solid.

28

NO

O

Ph

Ph

H

H

Rf = 0.14 [20% EtOAc/hexanes]; mp 113-113.5 oC; [!]

D23 = - 87.5 o [c 0.80, CHCl3];

1H NMR (500 MHz, CDCl3) " 1.43 (ddd, 1H, J = 7.5, 7.5, 9.0 Hz), 1.92 (ddd, 1H, J = 4.5, 7.5, 7.5 Hz),

2.11 (ddd, 1H, J = 7.5, 7.5, 9.0 Hz), 2.44 (ddd, 1H, J = 4.5, 7.5, 7.5 Hz), 3.61 (dd, 1H, J = 4.5, 9.0 Hz ),

3.95 (dd, 1H, J = 4.5, 9.0 Hz), 4.05 (dd, 1H, J = 9.0, 9.0 Hz), 7.10-7.40 (m, 10H); 13C NMR (125 MHz,

CDCl3) " 11.7, 22.7, 31.5, 60.0, 69.6, 126.9, 127.2, 127.8, 128.6, 129.2, 129.5, 136.9, 138.5, 158.8; IR

(film) cm-1 1740s, 1407m, 1126s, 1051m, 1031m, 1011m; mass spectrum (ESI): m/e (% relative

intensity) 302 (100) (M+Na)+, 280 (40) (M+H)+; HRMS (ESI) m/e calcd for C18H17NO2Na 302.1157,

found 302.1163.

NO

O

Ph

n-pent

H

H

7

Rf = 0.47 [40% EtOAc/hexanes]; [!] D

23 = - 18.8 o [c 7.46, CH2Cl2];

1H NMR (400 MHz, CDCl3) "!0.62 (ddd, 1H, J = 1.2, 6.4, 11.6 Hz), 0.82 (t, 3H, J = 6.8 Hz), 0.86-0.91

(m, 2H), 0.99-1.04 (m, 2H), 1.06-1.20 (m, 6H), 2.10 (ddd, 1H, J = 3.2, 3.2, 6.4 Hz), 4.12 (dd, 1H, J =

5.2, 8.4 Hz), 4.54 (dd, 1H, J = 8.8, 8.8 Hz), 4.64 (dd, 1H, J = 5.2, 8.8 Hz), 7.29-7.32 (m, 2H), 7.35-7.43

(m, 3H); 13C NMR (100 MHz, CDCl3) " 13.9, 14.2, 19.0, 22.5, 28.3, 30.8, 31.5, 32.3, 61.3, 69.6, 126.8,

128.8, 129.2, 138.9, 158.0; IR (neat) cm-1 2940m, 2855w, 1752s, 1457m, 1408s, 1362w; mass spectrum

(APCI): m/e (% relative intensity) 274 (100) (M+H)+, 230. (10), 176 (27), 132 (7); HRMS (MALDI)

m/e calcd for C17H24NO2 (M+H)+ 274.1807, found: 274.1808.

S7

NO

O

Ph

H

H

2

OTBS

16


23 = - 11.5 o [c 0.37, CHCl3]; 1H NMR (400MHz, CDCl3) " 0.00 (s, 6H), 0.63 (ddd, 1H, J = 5.6, 5.6, 7.2 Hz), 0.87 (s, 9H), 0.87-0.96

(m, 1H), 1.00-1.06 (m, 2H), 1.10-1.19 (m, 1H), 1.21-1.42 (m, 2H), 2.01 (ddd, 2H, J = 3.2, 3.6, 7.2 Hz),

3.47 (t, 2H, J = 6.4 Hz), 4.13 (dd, 1H, J = 5.6, 8.8Hz), 4.54 (dd, 1H, J = 8.8, 8.8Hz), 4.64 (dd, 1H, J =

5.6, 8.8Hz), 7.30-7.32 (m, 2H), 7.35-7.43 (m, 3H); 13C NMR (100 MHz, CDCl3) " -5.1, 14.4, 18.5, 19.0,

26.1, 28.8, 31.1, 32.0, 61.5, 62.8, 127.1, 129.1, 129.4, 139.0, 158.3 (missing 1 carbon due to overlap); IR

(thin film) cm-1 2952m, 2928m, 1753s, 1472s, 1327s, 1090s; mass spectrum (APCI): m/e (% relative

intensity) 378 (10), 377 (30), 376 .2 (M+H)+ (100), 244 (10).

NO

O

Bn

H

H

2

OTBS

17


23 = + 35.4 o [c 0.43, CHCl3], 1H NMR (400MHz, CDCl3) " 0.05 (s, 6H), 0.82 (ddd, 1H, J = 4.8, 5.2, 6.8 Hz), 0.89 (s, 9H), 1.01-1.11

(m, 2H), 1.31 (ddt, 1H, J = 6.8, 7.2, 14.0 Hz), 1.38 (ddt, 1H, J = 6.8, 7.2, 14.0 Hz), 1.70 (tt, 2H, J = 6.4,

7.2 Hz), 2.26 (ddd, 1H, J = 3.2, 3.6, 6.8 Hz), 2.71 (dd, 1H, J = 9.6, 13.2 Hz), 3.30 (dd, 1H, J = 4.0,

13.2Hz), 3.66 (t, 2H, J =6.4 Hz), 3.85 (dddd, 1H, J = 4.0, 4.4, 8.0, 9.6 Hz), 4.01 (dd, 1H, J = 4.0, 8.8

Hz), 4.05 (dd, 1H, J = 8.0, 8.8 Hz), 7.16-7.20 (m, 2H), 7.25-7.29 (m, 1H), 7.31-7.36 (m, 2H); 13C NMR

(100 MHz, CDCl3) " -5.1, 15.4, 18.5, 19.1, 26.2, 28.9, 30.6, 32.6, 58.6, 62.9, 66.4, 127.4, 129.2, 129.4,

136.1, 157.9 (missing 1 carbon due to overlap); IR (thin film) cm-1 2954m, 2930m, 1760s, 1389s, 1253s,

1096s; mass spectrum (APCI): m/e (% relative intensity) 390 (M+H)+ (100), 258 (10).

NO

O

Ph

n-Bu

Ph

H

H

18


23 = - 68.0 o [c 1.74 CH2Cl2];

1H NMR (400 MHz, CDCl3) " 0.73 (t, 3H, J = 7.2 Hz), 0.74-1.28 (m, 9H), 2.15 (ddd, 2H, J = 3.2, 3.2,

6.8 Hz), 4.87 (d, 1H, J = 8.0 Hz), 5.91 (d, 1H, J = 8.0 Hz), 6.90-6.93 (m, 2H), 6.99-7.01 (m, 2H), 7.07-

7.13 (m, 6H); 13C NMR (125 MHz, CDCl3) " 14.2, 15.1, 19.5, 22.5, 31.2, 31.6, 32.2, 67.0, 79.9, 87.6,

126.3, 128.0, 128.08, 128.11, 128.46, 128.54, 134.8, 134.9, 158.5; IR (neat) cm-1 2952w, 2924m,

2580w, 2360w, 1736s, 1498m, 1454m, 1411m, 1342m; mass spectrum (APCI): m/e (% relative


S8

NN

O

Ph

H

H

19

OMe


23 = + 81.4 o [c 1.00s, CH2Cl2];

1H NMR (400 MHz, CDCl3) "!0.80 (d, 3H, J = 6.5 Hz), 1.20 (ddd, 1H, J = 7.0, 7.0, 7.0 Hz), 1.39 (ddd,

1H, J = 4.0, 5.6, 9.6 Hz), 2.00 (ddd, 1H, J = 3.2, 6., 9.6 Hz), 2.41 (ddd, 1H, J = 4.0, 7.2, 10.0 Hz), 2.75

(s, 3H), 3.70 (s, 3H), 3.73 (m, 1H), 4.58 (d, 1H, J = 8.0 Hz), 6.64 (ddd, 2H, J = 2.4, 2.4, 9.2 Hz), 6.70

(ddd, 2H, J = 2.8, 2.8, 9.2 Hz), 7.19-7.22 (m, 2H), 7.26-7.35 (m, 3H); 13C NMR (100 MHz, CDCl3) "

15.1, 16.2, 22.3, 29.0, 34.0, 55.4, 56.0, 64.0, 113.8, 128.4, 128.4, 128.5, 128.7, 132.6, 136.7, 158.1,

162.1; IR (neat) cm-1 2975bm, 1689s, 1517m, 1429s, 1400s; mass spectrum (APCI): m/e (% relative

intensity) 337 (100) (M+H)+, 203 (7); HRMS (MALDI) m/e calcd for C21H25 N2O2 (M+H)+ 337.1916,

found 337.1910.

NN

O

Ph

Ph

H

H

20

Rf = 0.30 [33 % EtOAc/hexanes]; mp 117-119 oC; [!] D

23 = + 82.6 o (c 0.70, CH2Cl2);

1H NMR (500 MHz, CDCl3) "!0.80 (d, 3H, J = 6.5 Hz), 1.25 (ddd, J = 6.5, 6.5, 6.5 Hz, 3H,), 1.45 (ddd,

J = 4.5, 6.0, 10.0 Hz, 1H), 2.05 (ddd, J = 3.5, 6.5, 9.5 Hz, 1H), 2.48 (ddd, J = 4.0, 4.0, 7.5 Hz, 1H), 2.75

(s, 3H), 3.73 (dq, J = 6.5, 7.5 Hz, 1H), 4.57 (d, J = 8.5 Hz, 1H), 6.79 (m, 2H), 7.04-7.12 (m, 3H), 7.19-

7.20 (m, 2H), 7.26-7.33 (m, 3H); 13C NMR (100 MHz, CDCl3) " 15.1, 16.6, 23.1, 29.1, 34.4, 56.1, 64.1,

126.2, 127.2, 128.38, 128.44, 128.8, 136.6, 140.6, 162.1 (missing 1 carbon due to overlap); IR (neat)

cm-1 3727w, 3028w, 1687s, 1455s, 1430m; mass spectrum (APCI): m/e (% relative intensity) 307 (100)

(M+H)+, 203 (7); HRMS (MALDI) m/e calcd for C20H23ON2 (M+H)+ 306.1732, found: 307.1805.

NO

O

Ph

H

H

21


23 = - 60.5 o (c 1.2, CH2Cl2);

1H NMR (400 MHz, CDCl3) " 0.45 (ddd, J = 4.8, 8.0, 11.2 Hz), 0.55 (ddd, J = 4.8, 8.0, 11.2 Hz), 0.63!

(ddd, J = 4.8, 6.0, 10.4 Hz), 0.90!(ddd, J = 5.2, 6.4, 10.8 Hz), 1.07 (s, 3H), 4.19 (dd, 1H, J = 6.0, 8.8

Hz), 4.54 (dd, 1H, J = 8.8, 8.8 Hz), 4.70 (dd, 1H, J = 6.4, 8.8 Hz), 7.35-7.43 (m, 5H); 13C NMR (100

MHz, CDCl3) " 12.9, 14.6, 21.5, 31.9, 60.6, 69.9, 127.7, 129.2, 129.3, 139.7, 157.9; IR (neat) cm-1

2973w, 2878w, 1731s, 1731w, 1413w, 1381m; mass spectrum (APCI): m/e (% relative intensity) 218

(100) (M+H)+, 174 (65).

S9

NO

O

Ph

Et

H

22 Rf = 0.31 [33 % EtOAc/hexanes]; 1H NMR (400 MHz, CDCl3) " 0.97–1.07 (brs, 1H), 0.57 (dd, 1H, J = 8.0, 8.0 Hz), 0.88–0.94 (m, 4H),

1.05–1.10 (m, 1H), 1.15 (d, 3H, J = 6.0 Hz), 1.65–1.84 (m, 1H), 4.22 (dd, 1H, J = 5.5, 9.0 Hz), 4.61 (dd,

1H, J = 9.0, 9.0 Hz), 4.85 (dd, 1H, J = 6.0, 9.0 Hz), 7.37 – 7.44 (m, 5H); minor 0.10 (brs, 1H), 0.61–0.65

(m, 1H), 1.26-1.40 (m, 1H), and 4.32 (dd, 1H, J = 6.5, 9.5 Hz); 13C NMR (125 MHz, CDCl3) " 10.7,

14.5, 19.0, 29.5, 29.7, 41.7, 61.7, 70.3, 127.7, 129.1, 129.2, 140.6, 158.8; IR (neat) cm-1 3032w, 2965w,

1747s, 1401s; mass spectrum (APCI): m/e (% relative intensity) 246 (100) (M+1)+, 202 (30), 164 (7);

HRMS (MALDI) m/e calcd for C15H20NO2 (M + H+) 246.1489, found 246.1484.

NO

O

Ph

23


23 = - 25.8 o [c 0.80, CH2Cl2];

1H NMR (400 MHz, CDCl3) " 0.42 (dd, 1H, J = 6.0, 6.0 Hz), 0.76 (dd, 1H, J = 5.2, 10.0 Hz), 0.82-1.03

(m, 4H), 1.25 (m, 1H), 1.39-1.54 (m, 2H), 1.81 (ddd, 1H, J = 6.8, 6.8, 9.6 Hz), 2.00 (1H, ddd, J = 4.8,

7.2, 8.8 Hz),!4.22 (dd, 1H, J = 6.8, 8.8 Hz), 4.54 (dd, 1H, J = 8.8, 8.8 Hz), 4.71 (dd, 1H, J = 6.4, 8.8

Hz), 7.36-7.43 (m, 5H); 13C NMR (100 MHz, CDCl3) " 18.3, 18.6, 20.4, 21.2, 23.5, 29.6, 34.2, 60.5,

69.7, 128.2, 129.3, 139.4, 157.9 (missing 1 carbon due to overlap); IR (neat) cm-1 2933m, 2869w, 1715s,

1457m, 1404s; mass spectrum (APCI): m/e (% relative intensity) 258 (100) (M+1)+, 214 (30), 164 (25);

HRMS (MALDI) m/e calcd for C16H19NO2 (M+H)+ 258.1494, found 258.1499.

NO

O

Ph

n-hex

H

H

27 Rf = 0.16 [20% EtOAc/hexanes]; [!]

D23 = + 32.0 o [c 0.59, CHCl3];

1H NMR (500 MHz, CDCl3) " 0.54-0.58 (m, 1H), 0.67-0.73 (m, 1H), 0.76-0.84 (m, 4H), 0.97-1.05 (m,

1H), 1.15-1.30 (m, 6H), 1.32-1.40 (m, 2H), 1.68 (td, 1H, J = 7.5, 12.5 Hz), 2.11 (ddd, 1H, J = 4.0, 7.0,

7.0 Hz), 4.11 (dd, 1H, J = 5.0, 8.0, Hz), 4.49, (dd, 1H, J = 8.5, 8.5 Hz), 4.64 (dd, 1H, J = 5.0, 8.5 Hz),

7.20-7.40 (m, 5H); 13C NMR (125 MHz, CDCl3) " 11.0, 14.4, 17.7, 22.9, 28.2, 29.5, 29.6 30.1, 32.1,

62.1, 69.7, 127.3, 129.2, 129.5, 139.0, 159.2; IR (film) cm-1 2854m, 2340s, 2271s, 1684s, 1370m; mass

spectrum (ESI): m/e (% relative intensity) 310 (100) (M+Na)+, 288 (30), 235 (12); HRMS (ESI) m/e

calcd for C18H25NO2Na 310.1783, found 310.1790.

S10

NO

O

Ph

Ph

H

H

29 Rf = 0.32 [40 % EtOAc/hexanes]; [!]

D23

= -25.5 o [c 0.40, CH2Cl2]; 1H NMR (500 MHz, CDCl3) " 1.23 (ddd, 1H, J = 6.5, 6.5, 13.5 Hz), 1.45 (ddd, 1H, J = 4.5, 6.5, 10.0

Hz), 2.17 (ddd, 1H, J = 3.5, 6.5, 10.0 Hz), 2.45 (ddd, 1H, J = 3.5, 3.5, 7.5 Hz), 4.21 (dd, 1H, J = 5.5, 9.0

Hz), 4.61 (dd, 3H, J = 8.5, 8.5 Hz), 4.78 (dd, 1H, J = 6.0, 9.0 Hz), 6.87 (d, 2H, J = 7.0 Hz), 7.10-7.19

(m, 3H), 7.32-7.42 (m, 5H); 13C NMR (100 MHz, CDCl3) " 15.7, 23.4, 34.0, 61.7, 69.9, 126.5, 127.0,

127.2, 128.5, 129.3, 129.5, 138.6, 139.8, 158.1; IR (neat) cm-1 3030w, 2919w, 1750s, 1604w, 1480w,

1409s, 1360w; mass spectrum (APCI): m/e (% relative intensity) 280 (100) (M+H)+, 236 (50), 176 (20),

164 (12); HRMS (MALDI) m/e calcd for C18H18NO2 (M+H)+ 280.1338, found 280.1344.

Synthesis of Chiral Amino Cyclopropane 34.

BrOBn

NHO

O

PhPh

2.0 equiv K2CO3, toluene, 80 oC, 3 d2) Lindlar hydrogenation

32: Only Z

5.0 equiv ZnEt210.0 equiv ICH2I [or ICH2Cl]

MS 4Å, ClCH2CH2Clrt, 30 min

33: [dr = 86 : 14]

10% Pd-C, 60 psi H2

93% overall yield

NO

O

PhPh

OBn

NO

O

PhPh

OBn

HH

1) 10 mol % CuSO4-5H2O

NH2

OH

HCl

AcOH, 48 h, rt, and then HCl [1.25 M in MeOH]

3430

31

95% overall yield

20 mol % 1,10-Phenanthroline

To a mixture of oxazolidinone 30 (900.0 mg, 3.77 mmol), K2CO3 (1.06 g, 7.60 mmol), CuSO4·5H2O

(92.0 mg, 0.38 mmol) and 1,10-phenanthroline (142.0 mg, 0.76 mmol) in a reaction vial was added a

solution of 1-bromoalkyne 31 (900.0 mg, 4.00 mmol) in toluene (15.0 mL) under nitrogen. The reaction

mixture was sealed and heated in an oil bath at 80°C for 3 d while being monitored with TLC analysis.

Upon completion, the reaction mixture was cooled to room temperature and diluted with EtOAc and

filtered through CeliteTM, and the filtrate was concentrated in vacuo. The crude product was purified by

silica gel flash column chromatography (Gradient eluent: 15% to 25% of EtOAc/hexane) to afford the

desired ynamide S1 (1.40 g, 96%) as a white solid.

N

OBn

O

O

PhPh

S1 Rf = 0.5 [33% EtOAc/hexanes]; mp 80-82 oC; [!]

D25

= + 117.5 o [c 1.50, CH2Cl2]; 1H NMR (400 MHz, CDCl3) " 4.20 (ABq, 2H, JAB = 16.0 Hz), 4.40 (ABq, 2H, JAB = 12.2 Hz), 5.35 (d,

1H, J = 8.4 Hz), 5.94 (d, 1H, J = 8.4 Hz), 6.90-6.95 (m, 4H), 7.09-7.15 (m, 7H), 7.170-7.190 (m, 1H),

7.26-7.30 (m, 3H); 13C NMR (100 MHz, CDCl3) " 57.4, 67.2, 69.1, 71.2, 76.3, 81.2, 126.3, 127.7, 128.0,

S11

128.3, 128.4, 128.5, 128.6, 128.8, 129.0, 132.9, 133.5, 127.5, 156.3; IR (neat) cm-1 3033w, 1773s,

1496w, 1455m, 1402s; mass spectrum (APCI): m/e (% relative intensity) 358 (18) (M+3H-CO)+, 310

(39), 264 (75), 211 (70), 196 (100).

32

NO

O

PhPh

OBn

A mixture of S1 (800.0 mg, 2.10 mmol) and 1% Lindlar catalyst (80.0 mg, 5% w/w Pd on CaCO3

support poisoned with Pb) in CH2Cl2 (30 ml) was stirred for 30 min at rt under 1 atm hydrogen

atmosphere. After filtration through CeliteTM, the filtrate was concentrated in vacuo. The crude product

was purified by silica gel flash column chromatography (Gradient eluent: 15% to 33% of

EtOAc/hexane) to afford the desired Z-enamide 32 (780.0 mg, 97%) as a white solid.


25 = + 66.3 o [c 1.50, CH2Cl2];

1H NMR (400 MHz, CDCl3) " 3.78 (ddd, 1H, J = 0.4, 6.8, 12.4 Hz), 3.95 (ddd, 1H, J = 2.0, 6.8, 12.8

Hz), 4.33 (d, 1H, J = 12.0 Hz), 4.48 (d, 1H, J = 12.0 Hz), 5.08 (ddd, 1H, J = 6.8, 6.8, 10.0 Hz), 5.29 (d,

1H, J = 8.0 Hz), 5.77 (d, 1H, J = 8.0 Hz), 6.47 (d, 1H, J = 9.6 Hz), 6.66-6.68 (m, 2H), 6.88-6.90 (m,

2H), 7.04-7.15 (m, 7H), 7.31-7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) " 64.9, 65.4, 72.2, 80.6, 112.4,

124.4, 126.5, 126.7, 127.2, 128.0, 128.1, 128.3, 128.5, 128.6, 128.7, 133.8, 134.4, 128.3, 156.6; IR

(neat) cm-1 3034w, 1744s, 1670m, 1497w, 1454m, 1423m; mass spectrum (APCI): m/e (% relative

intensity) 234 (100) (M-CO2-BnO), 117 (5).

33

NO

O

PhPh

OBn

H

H

To a solution of chiral enamide 32 (640.0 mg, 1.66 mmol) in anhyd ClCH2CH2Cl (40 mL) were added

MS 4Å (640.0 mg), ICH2I (1.44 mL, 16.6 mmol, 10.0 equiv). After stirring at rt for 30 min, a solution of

ZnEt2 (8.5 mL, 1.0 M in hexane, 5.0 equiv) was added carefully dropwise. After 30 min, the reaction

was complete and the mixture was first quenched with sat aq NaHCO3 (20 mL), and then extracted with

CH2Cl2 (2 x 50 mL). The combined organic phases were washed with sat aq NaCl (2 x 20 mL), dried

over Na2SO4, and concentrated under reduced pressure to afford the crude product as an 86 : 14 mixture.

The crude product was purified by silica gel flash column chromatography (Gradient eluent: 15% to

33% of EtOAc/hexane) to afford the desired major isomer (511.0 mg, 80%) as a white solid.

Rf = 0.2 [33% EtOAc in hexanes]; mp 127-129 oC; [!] D

25= - 31.8 o [c 1.60, CH2Cl2]; 1H NMR (400 MHz, CDCl3) " 1.10 (dd, 1H, J = 5.6, 10.8 Hz), 1.15-1.25(m, 2H), 2.37 (ddd, 1H, J = 4.8,

6.8, 6.8 Hz), 3.36 (dd, 1H, J = 10.0, 10.0 Hz), 3.92 (dd, 1H, J = 6.8, 10.8 Hz), 4.52 (d, 1H, J = 12.0 Hz),

S12

4.74 (d, 1H, J = 12.0 Hz), 5.14 (d, 1H, J = 7.6 Hz), 5.49 (d, 1H, J = 7.6 Hz), 6.85-6.86 (m, 2H), 6.89-

6.912 (m, 2H), 7.04-7.09 (m, 6H), 7.35-7.46 (m, 5H); 13C NMR (100 MHz, CDCl3) " 10.0, 17.2, 29.4,

66.8, 69.6, 73.5, 79.8, 126.1, 127.9, 128.04, 128.09, 128.31, 128.36, 128.4, 128.5, 128.9, 134.58, 134.61,

138.3, 159.1; IR (neat) cm-1 3034w, 2868w, 1754s, 1499w, 1456m, 1408m, 1381m; mass spectrum

(APCI): m/e (% relative intensity) 400 (40) (M+1)+, 292 (60), 248 (75); HRMS (MALDI) m/e calcd for

C26H25O3NNa (M+Na)+ 422.1732, found: 422.1727.

NH2

OH

HCl

34

A mixture of amido cyclopropane 33 (200.0 mg, 0.50 mmol) and 10% Pd/C (60.0 mg) in AcOH (5 mL)

was stirred for 2 d at rt under a hydrogen atmosphere (60 psi). After filtration through filter paper, the

filtrate was diluted with a methanolic solution of hydrogen chloride (1.25 M, 6 mL) and concentrated in

vacuo. After which hexane (2 mL) was added to afford two phases. The hexane phase containing the

organic impurities was at the top level and was removed, and this process was repeated 5 times to get rid

of all of impurities. Ethyl ether (5 mL) was then added to the remaining phase and the mixture was

concentrated in vacuo to afford the pure amino cyclopropane as HCl-salt 34 (58.0 mg, 95%) as a yellow

solid, which could be recrystallized from EtOH-ether to give a colorless crystal (20.0 mg).

mp 115-117 oC; [!] D

25 = - 10.0 o [c 1.50, CH2Cl2];

1H NMR (400 MHz, D2O) " 0.77 (ddd, 1H, J = 4.8, 6.8, 6.8 Hz), 1.07 (dd, 1H, J = 8.0, 16.0 Hz), 1.33-

1.42 (m, 1H), 2.73 (dd, 1H, J = 7.2, 12.0 Hz), 3.69 (dd, 1H, J = 7.2, 12.0 Hz), 3.90 (dd, 1H, J = 7.2, 12.0

Hz); 13C NMR (100 MHz, CDCl3) " 7.16, 16.0, 26.9, 59.1; IR (neat) cm-1 3238s, 2919s, 1626m, 1578m,

1518m, 1438m; mass spectrum (APCI): m/e (% relative intensity) 88 (40) (M-Cl)+, 70 (100).

69451 Weinheim, Germany - Wiley-VCHS tereos elective S im m on s-S m ith C yc lop rop an ation s of...

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Transcript of 69451 Weinheim, Germany - Wiley-VCHS tereos elective S im m on s-S m ith C yc lop rop an ation s of...