Supporting Information

© Wiley-VCH 2007

69451 Weinheim, Germany

Total Synthesis of (�)-Episilvestrol and (�)-Silvestrol Supporting Information Page 1

OO

OBn

OPMB

TBSO

OH

13

OOH

OHBnOHO

OPMB

11

Total Synthesis of (�)-Episilvestrol and (�)-Silvestrol

Mariana El Sous, Mui Ling Khoo, Georgina Holloway, David Owen, Peter J. Scammells and Mark A.

Rizzacasa*

Selected Physical Data

Benzyl ether 11: Colourless solid; m.p. 104-106°C; [!]25

D �29.3° (c 1.01, CH2Cl2); IR

(KBr) "max 3403, 2985, 2956, 1643, 1612, 1461 cm-1

; 1H NMR (500 MHz) # 1.90 (t, J

= 6 Hz, 1H), 2.48 (s, 1H), 2.59 (s, 1H), 3.37-3.42 (m, 2H), 3.50 (t, J = 9.0 Hz, 1H), 3.71 (td, J = 9.0, 1.5

Hz, 1H), 3.72-3.77 (m, 1H), 3.81 (s, 3H), 3.89-3.93 (m, 1H), 4.39 (d, J = 7.5 Hz, 1H), 4.70 (ABq, J =

11.5 Hz, 2H), 4.79 (ABq, J = 11.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 7.27-7.38 (m, 7H); 13

C NMR

(75.5 MHz) # 26.4, 55.2, 62.0, 70.6, 71.2, 73.9, 74.6, 75.2, 76.5, 101.4, 113.9, 128.0, 128.1, 128.5,

128.9, 129.8, 138.1, 159.5; HRMS (ESI): Calcd for C21H26NaO7+ [M+Na]

+ : 413.1576, found 413.1572.

TBS ether 13: Pale yellow oil; IR (thin film) "max 3434, 2957, 2934, 1642, 1615,

1515 cm-1; 1H NMR (400 MHz) ! 0.003 (s, 6H, major), 0.01 (s, 6H, minor), 0.84 (s,

18H), 2.27 (d, J = 5.2 Hz, 1H), 3.30-3.81 (m, 6H), 3.74 (s, 6H), 3.96 (t, J = 11.2 Hz,

2H), 3.97 (d, J = 2.4 Hz, 1H, minor), 4.00 (d, J = 2.8 Hz, 1H, major), 4.06-4.10 (m, 1H, minor), 4.21-

4.26 (m, 1H, major), 4.50 (s, 1H, minor), 4.53 (ABq, J = 11.6 Hz, 4H), 4.54 (s, 1H, major), 4.61 (ABq,

J = 11.6 Hz, 4H), 4.74 (s, 1H, minor), 4.76 (s, 1H, major), 6.79-6.82 (m, 4H), 7.18-7.27 (m, 14H); 13

C

NMR (100 MHz) # �5.5, �5.4, �5.4, 18.2, 18.2, 25.9, 25.9, 55.2, 59.8, 60.4, 62.1, 62.3, 65.6, 65.8, 67.2,

68.2, 68.9, 70.5, 72.7, 72.8, 79.3, 79.7, 89.2, 91.2, 93.8, 94.2, 1137.8, 113.8, 127.6, 127.6, 127.7, 127.8,

128.3, 129.8, 138.2, 138.2, 159.3, 159.4;HRMS (ESI): Calcd for C27H40NaO7Si+ [M+Na]

+ : 527.2441,

found 527.2442.

Methyl ketal 14: Colourless oil. [!]24

D �94.7 (c 1.07, CH2Cl2); IR (thin film) "max

2937, 2858, 1739, 1614, 1587, 1515, 1469, 1245 cm-1

; 1H NMR (400 MHz) #

0.003 (s, 3H), 0.011 (s, 3H), 0.84 (s, 9H), 3.31 (s, 3H), 3.39-3.42 (m, 1H), 3.63

(dd, J = 11.2, 2.8 Hz, 1H), 3.70 (dd, J = 11.2, 5.2 Hz, 1H), 3.73 (s, 3H), 3.77 (t, J = 11.2 Hz, 1H), 3.82

(dd, J = 11, 3.2 Hz, 1H), 4.20-4.25 (m, 1H), 4.29 (s, 1H), 4.47 (s, 1H), 4.55 (ABq, J = 11.2 Hz, 2H),

4.57 (ABq, J = 11.6 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 7.19-7.27 (m, 7H); 13

C NMR (100 MHz) # �5.4,

�5.4, 18.3, 25.9, 54.8, 55.2, 60.2, 62.1, 65.5, 68.0, 72.7, 79.8, 93.7, 95.7, 113.8, 127.6, 127.9, 128.3,

129.1, 129.9, 138.3, 159.3; HRMS (ESI): Calcd for C28H42NaO7Si+ [M+Na]

+ : 541.2597, found

541.2602.

OO

OBn

OPMB

TBSO OMe

14

Total Synthesis of (�)-Episilvestrol and (�)-Silvestrol Supporting Information Page 2

Methyl ketal 15: Colourless oil. [!]18

D �27.5° (c 2.00, CH2Cl2); IR (thin film) "max

2930, 2856, 1728, 1612, 1514, 1463, 1250 cm-1

; 1H NMR (400 MHz, CDCl3) #

0.065 (s, 3H), 0.069 (s, 3H), 0.90 (s, 9H), 3.40-3.46 (m, 1H), 3.50 (s, 3H), 3.66 (t, J

= 10 Hz, 1H), 3.67 (dd, J = 11, 5.2 Hz, 1H), 3.78 (dd, J = 11, 4 Hz, 1H), 3.79 (s, 3H), 4.12 (dd, J = 12,

2.8 Hz, 1H), 4.14-4.18(m, 1H), 4.39 (d, J = 1.6 Hz, 1H), 4.60 (s, 1H), 4.65 (ABq, J = 12 Hz, 2H), 4.66

(ABq, J = 11.2 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 7.28-7.34 (m, 7H); 13

C NMR (100 MHz) # �5.4, �5.4,

18.3, 25.9, 55.3, 58.5, 60.2, 62.3, 65.7, 67.1, 68.0, 72.4, 72.8, 80.0, 94.0, 94.6, 113.8, 127.6, 127.9,

128.3, 129.2, 129.9, 138.4, 159.3; HRMS (ESI): Calcd for C28H42NaO7Si+ [M+Na]

+ : 541.2597, found

541.2591.

TBS ether 16 : Colourless oil; [!]18

D �109.7 (c 1.17, CH2Cl2); 1H NMR (400

MHz, CDCl3) # 0.08 (s, 3H), 0.09 (s, 3H), 0.11 (s, 3H), 0.11 (s, 3H), 0.91 (s,

9H), 0.92 (s, 9H), 3.38 (s, 3H), 3.64-3.72 (m, 4H), 3.77 (s, 3H), 3.88 (t, J =

11.2 Hz, 1H), 4.18-4.22 (m, 1H), 4.35 (s, 1H), 4.53 (s, 1H), 4.59 (ABq, J = 12.0 Hz, 2H), 6.87 (d, J

= 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H); 13

C NMR (100 MHz, CDCl3) # -5.5, -5.1, -4.4, 17.9, 18.2,

25.7, 25.7, 25.8, 54.4, 54.9, 59.8, 64.4, 66.2, 67.8, 74.0, 93.5, 95.6, 113.6, 129.0, 129.7, 159.2.

Lactols 6: Colourless oil; IR (thin film) "max 3307, 2954, 1727, 1472, 1464,

1376, 1253 cm-1

; 1H NMR (500 MHz, CDCl3) # 0.05 (s, 12H), 0.07 (s, 6H),

0.07 (s, 6H), 0.88 (s, 18H), 0.89 (s, 18H), 3.42 (s, 3H), 3.47 (s, 3H), 3.56-3.91

(m, 10H), 4.20-4.24 (m, 2H), 4.37 (s, 1H), 4.39 (d, J = 2 Hz, 1H), 4.72 (dd, J = 12.5, 2 Hz, 1H),

4.86 (d, J = 6 Hz, 1H); 13

C NMR (125 MHz, CDCl3) ! -5.5, -5.5, -5.5, -5.0, -4.9, -4.4, -4.4, 18.0,

18.1, 18.2, 18.3, 25.7, 25.7, 25.8, 25.8, 25.9, 54.6, 55.1, 59.4, 59.7, 64.2, 64.5, 66.3, 73.7, 74.1,

74.2, 90.1, 91.6, 95.5, 96.1.

Dioxane 18: Colourless oil; [!]23

D �106.4 (c 1.88, CH2Cl2); 1H NMR

(500 MHz, CDCl3) # -0.00 (s, 3H), 0.05 (s, 3H), 0.14 (s, 3H), 0.15 (s,

3H), 0.87 (s, 9H), 0.94 (s, 9H), 3.48 (dd, J = 10.5, 5.5 Hz, 1H), 3.55 (s,

3H), 3.65 (dd, J = 10.5, 3.5 Hz, 1H), 3.73 (dt, J = 5.5, 3.5 Hz, 1H), 3.79

(dd, J = 11, 3 Hz, 1H), 3.84 (s, 3H), 4.00 (t, J = 11 Hz, 1H), 4.19 (ddd, J = 11, 5.5, 3 Hz, 1H), 4.65

(s, 1H), 5.32 (s, 1H), 6.63 (dd, J = 8, 2.5 Hz, 1H), 6.69-6.73 (m, 2H), 7.23 (t, J = 8 Hz, 1H); 13

C

NMR (125 MHz, CDCl3) # �5.6, �5.6, �5.0, �4.2, 18.1, 18.3, 25.8, 25.9, 54.8, 55.2, 60.0, 64.8,

67.3, 74.2, 93.6, 95.5, 102.5, 107.5, 108.3, 129.8, 157.4, 160.7; HRMS (ESI): Calcd for

C26H48NaO7Si2 [M+Na]+ 551.2831, found 551.2830.

OO

OTBS

OH

TBSO

OMe

6

OO

OTBS

OPMB

TBSO

OMe16

OO

OBn

OPMB

TBSO

OMe15

OO

OTBS

O

TBSO

OMe

18

OMe

Total Synthesis of (�)-Episilvestrol and (�)-Silvestrol Supporting Information Page 3

Dioxane 19: Colourless oil; [!]23

D +2.46 (c 1.14, CH2Cl2); IR (thin

film) "max 2953, 2929, 1726, 1605, 1594, 1493, 1463 cm-1

; 1H NMR

(500 MHz, CDCl3) # 0.03 (s, 3H), 0.04 (s, 3H), 0.90 (s, 9H), 3.54 (s,

3H), 3.57-3.60 (m, 1H), 3.76 (s, 3H), 3.72-3.77 (m, 2H), 3.82 (t, J = 10.5 Hz, 1H), 3.87 (dd, J = 11,

3 Hz), 4.01 (td, J = 9, 3 Hz, 1H), 4.61 (d, J = 2 Hz, 1H), 4.65 (ABq, J = 11.0 Hz, 2H,), 5.16 (d, J =

2 Hz, 1H), 6.58-6.66 (m, 3H), 7.16 (t, J = 8 Hz, 1H), 7.26-7.35 (m, 5H); 13

C NMR (125 NMR) # -

5.5, 18.3, 25.9, 55.2, 55.4, 60.2, 61.7, 72.5, 73.2, 79.0, 95.1, 96.3, 103.4, 108.5, 108.5, 127.7, 127.9,

128.3, 130.0, 138.2, 158.1, 160.6; HRMS (ESI): Calcd for C26H48NaO7Si2 [M+Na]+ 551.2831,

found 551.2831.

Flavanone 20: Pale yellow solid; m.p. 175-177 °C; IR (CH2Cl2) "max 3332,

2974, 2928, 2891, 2832, 1708, 1642, 1449, 1274 cm-1

; 1H NMR (400 MHz,

d6-DMSO) # 2.72 (dd, 1H, J = 17.2, 2.8 Hz), 3.32 (dd, 1H, J = 17.2, 12.9

Hz), 5.17 (s, 2H), 5.48 (dd, 1H, J = 12.9, 2.8 Hz), 6.16 (ABq, J = 1.2 Hz, 2H), 6.80 (d, J = 8.5 Hz,

2H), 7.29-7.45 (m, 7H), 9.60 (s, 1H), 12.10 (s, 1H); 13

C NMR (126 MHz, d6-DMSO) # 42.1, 69.8,

78.7, 94.5, 95.5, 102.7, 115.2, 127.7, 128.1, 128.3, 128.5, 128.7, 136.2, 157.8, 162.9, 163.2, 166.4,

196.9; HRMS (ESI): Calcd for C22H17O5 [M�H+]� 361.1076, found 361.1074.

Flavone 22: Yellow solid; m.p. 143-145 °C; IR (CH2Cl2) "max 3468, 2937,

1637, 1601, 1511, 1422, 1256 cm-1

; 1H NMR (500 MHz, CDCl3) # 3.88 (s,

3H), 3.95 (s, 3H), 5.16 (s, 2H), 6.46 (d, J = 1.2 Hz, 1H), 6.66 (d, J = 1.2

Hz, 1H), 6.72 (s, 1H), 7.00 (d, 2H, J = 8.7 Hz), 7.35-7.48 (m, 5H), 7.83 (d, 2H, J = 8.7 Hz); 13

C

NMR (126 MHz, CDCl3) # 55.2, 56.1, 70.2, 93.5, 96.3, 107.1, 108.9,114.0, 123.3, 127.2, 127.4,

128.1, 128.5, 135.6, 159.3, 160.5, 161.8, 162.7, 177.2. HRMS (ESI): Calcd for C24H20NaO5

[M+Na]+ 411.1203, found 411.1202.

3-Hydroxyflavone 23: Orange amorphous solid; IR (CH2Cl2) "max 3347,

2938, 1729, 1618, 1512, 1488, 1257 cm-1

; 1H NMR (500 MHz, CDCl3)

# 3.88 (s, 3H), 3.97 (s, 3H), 5.15 (s, 2H), 6.43 (d, J = 2 Hz, 1H), 6.63 (d, J

= 2 Hz, 1H), 7.03 (d, J = 9 Hz, 2H), 7.38-7.47 (m, 5H). 8.16 (d, J = 9 Hz, 2H); 13

C NMR (125

MHz, CDCl3) # 55.4, 56.4, 70.6, 93.4, 96.1, 106.4, 114.0, 123.5, 127.6, 128.5, 128.8, 128.9, 135.6,

137.5, 142.3, 158.8, 160.6, 160.6, 163.4, 171.9; HRMS (ESI): Calcd for C24H21O6 [M+H]+

405.1333, found 427.1333.

OO

OTBS

TBSO

OMe

O

19

OMe

O

O

OMe

MeO

BnO

OH

23

O

O

OMe

OMe

BnO

22

O

O

OH

OH

BnO

20

Total Synthesis of (�)-Episilvestrol and (�)-Silvestrol Supporting Information Page 4

Endo isomer 27: Colourless oil; IR (CH2Cl2) !max 3493, 3064, 2932, 1745,

1599, 1514, 1498 cm-1; 1H NMR (500 MHz, CDCl3) " 1.85 (br s, 1H), 3.65 (s,

3H), 3.70 (s, 3H), 3.86 (s, 3H), 3.90 (dd, J = 14.3, 6.5 Hz, 1H), 4.31 (d, J =

14 Hz, 1H), 5.03 (d, J = 6 Hz, 1H), 5.08 (ABq, J = 14 Hz, 2H), 6.21 (d, J = 2

Hz, 1H), 6.36 (d, J = 2 Hz, 1H), 6.67 (d, J = 9 Hz, 2H), 6.87-6.88 (m, 2H), 7.02-7.06 (m, 3H), 7.11

(d, J = 9 Hz, 2H), 7.34-7.46 (m, 5H); 13

C NMR (125 MHz) " 50.5, 51.9, 55.0, 55.1, 55.7, 70.5,

79.5, 90.5, 93.3, 93.7, 101.9, 107.9, 112.7, 126.4, 126.5, 127.5, 127.7, 127.8, 128.1, 128.7, 129.0,

136.5, 136.9, 157.0, 158.7, 160.8, 163.2, 170.5; HRMS (ESI): Calcd for C34H32NaO8 [M+Na]+

591.1989, found 591.1990.

Exo isomer: Colourless oil; IR (CH2Cl2) !max 3491, 3034, 2951, 1734, 1599,

1513, 1435 cm-1; 1H NMR (500 MHz, CDCl3) " 3.26 (dd, J = 12.5, 10.5 Hz,

1H), 3.63 (s, 3H), 3.80 (s, 3H), 3.81 (s, 3H), 4.04 (d, J = 13 Hz, 1H), 4.79 (d,

J = 10.5 Hz, 1H), 5.03 (ABq, J = 14 Hz, 2H), 6.17 (d, J = 1.5 Hz, 1H), 6.22

(d, J = 1.5 Hz, 1H), 6.90 (d, J = 9 Hz, 2H), 6.96-6.97 (m, 2H), 7.16-7.19 (m, 3H), 7.36 (d, J = 8.5

Hz, 2H), 7.39-7.45 (m, 5H); 13

C NMR (125 MHz) " 50.7, 52.1, 54.7, 55.2, 55.7, 70.5, 83.8, 89.6,

91.2, 93.3, 99.3, 105.2, 113.5, 127.2, 127.6, 127.9, 128.2, 128.3, 128.7, 129.0, 134.8, 136.4, 157.8,

159.3 161.9, 163.1, 173.0; HRMS (ESI): Calcd for C34H32NaO8 [M+Na]+ 591.1989, found

591.1990.

Phenol ±7: Colourless solid; IR (CH2Cl2) !max 3467, 1729, 1514, 1439, 1251,

1150, 1117 cm-1; 1H NMR (500 MHz, d6-acetone) " 2.89 (brs, 1H), 3.56 (s,

3H), 3.66 (s, 3H), 3.83 (s, 3H), 3.95 (dd, J = 14, 6.5 Hz, 1H), 4.29 (d, J = 14

Hz, 1H), 4.93 (d, J = 6.5 Hz, 1H), 6.12 (d, J = 2 Hz, 1H), 6.17 (d, J = 2 Hz,

1H), 6.63 (d, J = 9 Hz, 2H), 6.91 (d, J = 7 Hz, 2H), 6.99-7.05 (m, 3H), 7.13 (d, J = 9 Hz, 2H); 13

C

NMR (125 MHz, , d6-acetone) " 51.6, 51.7, 55.3, 55.8, 56.0, 80.9, 92.0, 93.4, 94.6, 102.7, 108.5,

113.0, 126.9, 128.3, 128.9, 129.0, 130.1, 139.3, 158.9, 159.4, 161.9, 162.2, 170.9; HRMS (ESI):

Calcd for C27H26NaO8 [M+Na]+ 501.1520, found 501.1520.

1,4-Dioxane 28: Colourless oil; [#]23

D �34.2 (c 0.065, CH2Cl2);

HPLC (5 µm SiO2, 10x250 mm, 50% EtOAc/petrol) Rt = 10.48

min; IR (CH2Cl2) !max 3505, 2953, 2929, 1604, 1515, 1498, 1464,

1252 cm-1

; 1H NMR (400 MHz, CDCl3) " -0.03 (s, 3H), 0.02 (s,

3H), 0.09 (s, 3H), 0.12 (s, 3H), 0.82 (s, 9H), 0.89 (s, 9H), 3.48 (s, 3H), 3.54 (dd, J = 10.5, 5.3 Hz ,

O

OMe

MeO

HO

HO

HO CO2Me

±7

O

OMe

MeO

BnO

HO

HO CO2Me

exo

O

OMe

MeO

BnO

HO

HO CO2Me

27

O

OMe

CO2MeMeO

OO

OTBS

O

TBSO

OMe

HO

HO

28

Total Synthesis of (�)-Episilvestrol and (�)-Silvestrol Supporting Information Page 5

1H), 3.62 (dd, J = 10.5, 4.3 Hz, 1H), 3.65 (s, 3H), 3.71 (s, 3H), 3.71-3.74 (m, 1H), 3.81-3.83 (m,

1H), 3.86 (s, 3H), 3.93 (dd, J = 14.1, 6.5 Hz , 1H), 4.00 (t, J = 11.2 Hz , 1H), 4.20-4.21 (m, 1H),

4.34 (d, J = 14.2 Hz, 1H), 4.58 (s, 1H), 5.01 (d, J = 6.4 Hz, 1H), 5.26 (s, 1H), 6.28 (s, 1H), 6.43 (s,

1H), 6.67 (d, J = 8 Hz, 2H), 6.90 (d, J = 7.2 Hz, 2H), 7.05-7.07 (m, 3H), 7.11 (d, J = 8 Hz, 2H);

13C NMR (200 MHz, CDCl3) ! �5.5, �5.4, �4.9, �4.3, 18.1, 18.2, 25.8, 25.8, 50.4, 52.1, 54.8, 54.9,

55.1, 55.7, 59.7, 64.5, 67.6, 73.9, 79.5, 92.3, 93.5, 93.6, 93.9, 95.3, 101.8, 108.7, 112.6, 126.2,

126.5, 128.5, 128.5, 128.9, 136.8, 156.8, 158.6, 160.6, 160.7, 170.5; HRMS (ESI): Calcd for

C46H66NaO13Si2 [M+Na]+ 905.3934, found 905.3951.

1,4-Dioxane 5: Colourless oil; ["]23

D �113.9 (c 0.015, CH2Cl2);

HPLC (5 µm SiO2, 10x250 mm, 50% EtOAc/petrol) Rt = 10.10

min; IR (CH2Cl2) #max 3505, 2953, 2929, 2856, 1748, 1602, 1515,

1498, 1435, 1252 cm-1

; 1

H NMR (400 MHz, CDCl3) ! -0.11 (s,

3H), -0.04 (s, 3H,), 0.07 (s, 3H), 0.10 (s, 3H), 0.82 (s, 9H), 0.89 (s, 9H), 3.47 (dd, J = 10.5, 5.4 Hz,

1H,), 3.49 (s, 3H), 3.61 (dd, J = 10.5, 3.5 Hz, 1H), 3.64 (s, 3H), 3.68-3.71 (m, 1H), 3.72 (s, 3H),

3.74-3.75 (m, 1H), 3.87 (s, 3H), 3.89 (dd, J = 14.2, 6.3 Hz , 1H), 3.98 (t, J = 11.3 Hz , 1H), 4.15-

4.17 (m, 1H), 4.27 (d, J = 14.1 Hz, 1H), 4.59 (s, 1H), 5.05 (d, J = 6.4 Hz, 1H), 5.27 (s, 1H), 6.28 (s,

1H), 6.45 (s, 1H), 6.68 (d, J = 8 Hz, 2H), 6.84-6.85 (m, 2H), 7.05-7.07 (m, 3H), 7.11 (d, J = 8.3

Hz, 2H); 13

C NMR (200 MHz, CDCl3) ! �5.5, �5.5, �4.9, �4.2, 18.1, 18.2, 25.8, 25.8, 50.4, 52.0,

54.9, 55.0, 55.1, 55.8, 59.8, 64.7, 67.6, 74.1, 79.6, 92.4, 93.7, 94.0, 94.0, 95.4, 101.8, 109.1, 112.7,

126.2, 126.6, 127.7, 127.8, 129.0, 136.8, 156.9, 158.8, 160.6, 160.7, 170.4; HRMS (ESI): Calcd for

C46H66NaO13Si2 [M+Na]+ 905.3934, found 905.3951.

Episilvestrol (2): Colourless solid; IR (CH2Cl2) #max 3494, 2923,

2850, 1730, 1606, 1515, 1457 cm-1

; ["]25

D �91.3 (c 0.03, CHCl3);

lit.[1]

["]20

D � 94.5 (c 0.43, CHCl3); 1H NMR (800 MHz, CDCl3) !

3.51 (s, 3H), 3.62 (dd, J = 10.6, 4.9 Hz, 1H), 3.65 (s, 3H), 3.68 (m,

1H), 3.71 (s, 3H), 3.79 (dd, J = 11.0, 2.2 Hz, 1H), 3.87 (s, 3H), 3.91 (dd, J = 14.1, 6.8 Hz , 1H),

4.03 (t, J = 11.4 Hz , 1H), 4.13 (dd, J = 10.9, 5.2, 2.8, 1H), 4.29 (d, J = 14.0 Hz, 1H), 4.61 (s, 1H),

5.04 (d, J = 6.6 Hz, 1H), 5.29 (s, 1H), 6.30 (d, J = 2.0 Hz, 1H), 6.45 (d, J = 2.0 Hz, 1H), 6.68 (d, J

= 8.8 Hz, 2H), 6.86-6.88 (m, 2H), 7.05-7.07 (m, 3H), 7.11 (d, J = 8.8 Hz, 2H); 13

C NMR (200

MHz, CDCl3) ! 50.3, 52.1, 55.1, 55.1, 55.1, 55.9, 59.7, 62.5, 67.6, 71.5, 79.6, 92.9, 93.5, 93.7,

94.4, 95.3, 102.0, 109.3, 112.8, 126.2, 126.7, 127.8, 127.8, 128.9, 136.7, 157.1, 158.8, 160.0,

160.5, 170.7; HRMS (ESI): Calcd for C34H38NaO13 [M+Na]+ 677.2205, found 677.2212. See

Figure 1 and Table 1 for comparison of NMR data with natural 2.

O

OMe

CO2MeMeO

OO

OH

O

HO

OMe

HO

HO

2

O

OMe

CO2MeMeO

OO

OTBS

O

TBSO

OMe

HO

HO

5

Total Synthesis of (�)-Episilvestrol and (�)-Silvestrol Supporting Information Page 6

Isomer 29: Colourless solid; [!]24

D �23.9 (c 0.09, CHCl3); IR

(CH2Cl2) "max 3439, 2918, 2849, 1732, 1609, 1514, 1452 cm-1

; 1H

NMR (400 MHz, CDCl3) # 3.51 (s, 3H), 3.61-3.63 (m, 1H), 3.65 (s,

3H), 3.66-3.71 (m, 2H), 3.71 (s, 3H), 3.78 (dd, J = 11.6, 2.8 Hz, 1H),

3.87 (s, 3H), 3.90 (dd, J = 14.4, 6.8 Hz , 1H), 4.03 (t, J = 11.2 Hz , 1H), 4.11-4.15 (m, 1H), 4.30 (d,

J = 14.4 Hz, 1H), 4.61 (s, 1H), 5.02 (dd, J = 6.8, 1.6 Hz, 1H), 5.30 (s, 1H), 6.29 (d, J = 1.6 Hz, 1H),

6.46 (d, J = 1.6 Hz, 1H), 6.68 (d, J = 8.8 Hz, 2H), 6.86-6.88 (m, 2H), 7.05-7.08 (m, 3H), 7.10 (d, J

= 8.8 Hz, 2H); 13

C NMR (200 MHz, CDCl3) # 50.3, 52.1, 55.1, 55.1, 55.1, 55.9, 59.7, 62.5, 67.6,

71.5, 79.6, 92.9, 93.5, 93.7, 94.4, 95.3, 102.0, 109.3, 112.8, 126.2, 126.7, 127.8, 127.8, 128.9,

136.7, 157.1, 158.8, 160.0, 160.5, 170.7; HRMS (ESI): Calcd for C34H38NaO13 [M+Na]+ 677.2205,

found 677.2212. See Figure 1 for comparison of 13

C NMR chemical shift differences with natural 2.

Bis-p-nitrobenzoate ester: Colourless oil; [!]20

D �41.4 (c 1.34,

CH2Cl2); 1H NMR (400 MHz, CDCl3) # 3.48 (s 3H), 3.65 (s, 3H),

3.63-3.71 (m, 3H), 3.71 (3H, s), 3.85 (s, 3H), 3.81-3.88 (m, 2H),

4.05 (t, J = 11.2 Hz, 1H), 4.13 (d, J =14.0 Hz, 1H), 4.52-4.68 (m,

3H), 4.64 (s, 1H), 5.02 (d, J = 6.8 Hz, 1H), 5.38 (s, 1H), 5.61 (dt, J = 3.2, 6.8 Hz, 1H), 6.25 (d, J =

2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H), 6.78-6.80 (m, 2H), 7.02-7.06 (m,

5H), 7.94 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 8.8 Hz, 2H), 8.28 (ABq, J = 8.8 Hz, 4H). 13

C NMR (100

MHz, CDCl3) # 29.7, 50.1, 52.0, 54.8, 55.1, 55.3, 55.8, 58.6, 60.4, 62.37, 66.3, 70.6, 77.2, 79.6,

92.7, 93.4, 93.4, 95.4, 101.9, 110.0, 112.7, 123.6, 123.8, 126.0, 126.6, 127.7, 127.7, 128.9, 130.6,

131.0, 134.1, 134.2, 136.6, 150.5, 150.9, 156.9, 158.8, 159.9, 160.5, 164.0, 164.0, 170.2. HRMS

(ESI): Calcd for C48H44N2NaO19 [M + Na]

+ 975.2436, found 975.2429.

Silvestrol (1): Colourless solid; [!]25

D � 142.6 (c 0.155, CHCl3); IR

(CH2Cl2) 3482, 2948, 2839, 1743, 1603, 1514, 1453, 1298, 1216

cm-1

; 1H NMR (400 MHz, CDCl3) # 3.50 (s, 3H), 3.57 (dd, J = 11.6,

2.4 Hz, 1H), 3.60-3.67 (m, 3H), 3.65 (s, 3H), 3.71 (s, 3H), 3.87 (s,

3H), 3.90 (dd, J = 14, 6.8 Hz , 1H), 4.15 (t, J = 11.6 Hz , 1H), 4.25 (brd, J = 11.6 Hz, 1H), 4.29 (d,

J = 14 Hz, 1H), 4.60 (s, 1H), 5.04 (dd, J = 6.4, 1.6 Hz, 1H), 5.31 (s, 1H), 6.28 (d, J = 2 Hz, 1H),

6.44 (d, J = 2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 2H), 6.84-6.87 (m, 2H), 7.05-7.07 (m, 3H), 7.10 (d, J =

8.8 Hz, 2H); 13

C NMR (100 MHz, CDCl3) # 50.4, 52.1, 55.1, 55.1, 55.1, 55.9, 59.0, 63.4, 68.4,

70.6, 79.6, 92.8, 93.5, 93.9, 94.1, 95.2, 102.0, 109.5, 112.8, 126.1, 126.6, 127.8, 127.8, 129.0,

136.7, 157.1, 158.8, 160.1, 160.6, 170.6; HRMS (ESI): Calcd for C34H38NaO13 [M+Na]+ 677.2205,

found 677.2208.

O

OMe

CO2MeMeO

OO

OPNB

O

PNBO

OMe

HO

HO

O

OMe

CO2MeMeO

OO

OH

O

HO

OMe

HO

HO

1

O

OMe

CO2MeMeO

OO

OH

O

HO

OMe

HO

HO

29

Total Synthesis of (�)-Episilvestrol and (�)-Silvestrol Supporting Information Page 7

Figure 1: 13

C NMR (200 MHz, CDCl3) chemical shift differences between natural 2 and

synthetic 2 and isomer 29. 13C NMR chemical shift differences

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1 2 3 3a 4a 5 6 7 8 8a 8b 1'

2', 6

'

3', 5

' 4' 1''

2'',

6''

3'',

5''

4''

1'''

2'''

3'''

4'''

5'''

6'''

2CO

2OM

e

8OM

e

4'O

Me

2"'O

Me

Carbon

∆δ

29

2

Table 1: 1H NMR (800 MHz, CDCl3) data for natural and synthetic episilvestrol (2).

Position Natural 2 !, mult., (J) Synthetic 2 !, mult., (J) 1 5.04, d (6.6) 5.04, d (6.7) 2 3.90, dd (14.1, 6.8) 3.91, dd (14.1, 6.8) 3 4.29, d (14.0) 4.29, d (14.0) 5 6.45, d (2.0) 6.45, d (2.0) 7 6.29, d (2.0) 6.30, d (2.0)

2', 6' 7.11, d (8.8) 7.11, d (8.9) 3', 5' 6.68, d (8.8) 6.69, d (8.9) ArH 6.86-6.87, m 6.86-6.88, m

ArH 7.05-7.07, m 7.05-7.07, m

1''' 5.29, s 5.29, s 2''' 4.61, s 4.61, s

3'''eq 3.79, dd (11.5, 2.1) 3.79 (11.0, 2.2) 3"'ax 4.03, t (11.4) 4.03, t (11.4) 4''' 4.13, ddd (10.9, 5.2, 2.7) 4.13, ddd (10.9, 5.2, 2.8) 5''' 3.68, m 3.69, m

6''' 3.73, m 3.73, m

6"' 3.62, dd (10.7, 4.2)* 3.62 dd (10.6, 4.9)* 2-OMe 3.66, s 3.65, s 8-OMe 3.88, s 3.87, s 4'-OMe 3.71, s 3.71, s 2'"-OMe 3.51, s 3.51, s

*Assigned as H5"' by Kinghorn et. al.[1]

Reference

[1] B. Y. Hwang, B.-N. Su, H. M. Chai, Q., L. B. S. Kardono, J. J. Afriastini, S. Riswan, B. D. Santarsiero, A. D.

Mesecar, R. Wild, C. R. Fairchild, G. D. Vite, W. C. Rose, N. R. Farnsworth, G. A. Cordell, J. M. Pezzuto, S. M.

Swanson, A. D. Kinghorn, J. Org. Chem. 2004, 69, 3350; Correction: J. Org. Chem. 2004, 69, 6156.