1

Total Synthesis of Dimeric HPI Alkaloids

Xianfu Shen, Yongyun Zhou, Yongkai Xi, Jingfeng Zhao, and Hongbin Zhang*

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, P. R. China.

Email: zhanghb@ynu.edu.cn

Supporting Information

Copies of 1H and 13C spectra of new compounds Corresponding author: Professor Hongbin Zhang Key Laboratory of Medicinal Chemistry for Natural Resource Ministry of Education School of Chemical Science and Technology Yunnan University Kunming, Yunnan 650091 P. R. China. Fax: 86-871-5035538

2

Supporting information for

Total Synthesis of Dimeric HPI Alkaloids

Xianfu Shen, Yongyun Zhou, Yongkai Xi, Jingfeng Zhao, and Hongbin Zhang*

Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Chemical Science and Technology,

Yunnan University, Kunming, Yunnan 650091, P. R. China

Fax: 86-871-5035538. E-mail: zhanghb@ynu.edu.cn

Crystal data for compound 23: C70H72F2N4O10S4•C4H8O2, M = 1383.66, orthorhombic, a =

10.1404(9) Å, b = 25.087(2) Å, c = 27.663(3) Å, α = 90.00°, β = 90.00°, γ = 90.00°, V = 7037.4(11)

Å3, T = 100(2) K, space group P212121, Z = 4, μ(MoKα) = 0.205 mm-1, 70275 reflections measured,

17497 independent reflections (Rint = 0.0645). The final R1 values were 0.0434 (I > 2σ(I)). The final

wR(F2) values were 0.0969 (I > 2σ(I)). The final R1 values were 0.0596 (all data). The final wR(F2)

values were 0.1063 (all data). The goodness of fit on F2 was 1.030. Flack parameter = 0.03(4).

View of the molecules in an asymmetric unit.

Displacement ellipsoids are drawn at the 30% probability level.

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View of a molecule of zhb_s3 with the atom-labelling scheme.

Displacement ellipsoids are drawn at the 30% probability level.

Sulfinamide (13a’ + 13b’: 3.59g, 3.9 mmol) was dissolved in methanol (60 mL). To this mixture was added an

aqueous solution of HCl (4N, 2.9 mL, 11.7 mmol, 3 eq.). The resulting mixture was allowed to stir at room

temperature under nitrogen for 1 h. The reaction mixture was then treated with saturated aqueous solution of sodium

bicarbonate (~50 mL) and concentrated under reduced pressure. The mixture was diluted with water (100 mL) and

extracted with dichloromethane (3 50 mL), the combined organic phases were dried over anhydrous Na2SO4.

After removal of the solvent, the residue was chromatographed on silica gel (Dichloromethane : Methanol = 20 : 1)

to afford the amine (24) (2.63g, 95%) as white foam.*1 The diamine was dissolved in methanol (20 mL) and HCl

(2N, 5.6 mL, 11.1 mmol, 3.0 eq.) was added. This solution was allowed to crystallize at room temperature. The

needle-like crystals were collected and subjected to HPLC analysis (a 1:1 mixture of C3R-C3’R and C3S-C3’S

enantiomers). The mother liquid was then treated with saturated aqueous solution of sodium bicarbonate to pH = 8,

NO

ON

Bn

Bn

NH

HN

Bn

Bn

24

24: (3R,3'R)-1,1'-dibenzyl-3,3'-bis(2-(benzylamino)ethyl)-[3,3'-biindoline]-2,2(3R,3'R)-1,1'-dibenzyl-3,3'-bis(2-(benzylamino)ethyl)-[3,3'-biindoline]-2,2'-dione

NO

ON

Bn

Bn

N

N

Bn

Bn

S

S

OO C48H46N4O2

Mol. Wt.: 710.90

13a'

4

and extracted with dichloromethane (3). The combined organic phases were dried over anhydrous Na2SO4. After

removal of the solvents, the enantiomeric pure product 24 was obtained (1.60 g, 61%) as a pale yellow syrup.*2

24: [α]20D +171 (c 0.12, MeOH). ee = 99.1%. Rf: 0.40 (CH2Cl2: MeOH: Et3N= 20: 1 : 0.01). FTIR (KBr, thin film)

cm1: 3426, 2967, 1701, 1611, 1456, 1365, 1174, 1047, 746, 700. 1H-NMR (400 MHz, CDCl3), δ (ppm): 7.32-7.16

(29H, m), 7.10 (22H, d, J = 7.2 Hz), 7.04 (21H, d, J = 7.2 Hz), 6.97 (21H, t, J = 7.6 Hz), 6.71 (21H, t, J = 7.6

Hz), 6.39 (21H, d, J = 7.6 Hz), 5.03 (21H, d, J = 15.6 Hz), 4.45 (21H, d, J = 15.6 Hz), 3.60 (21H, d, J = 13.6

Hz), 3.53 (21H, d, J = 13.6 Hz), 3.26 (21H, ddd, J = 5.6, 6.0, 13.2 Hz), 2.64 (21H, ddd, J = 7.6, 8.0, 13.2 Hz),

2.27-2.17 (22H, m). 13C-NMR (100 MHz, CDCl3), δ (ppm): 178.03, 143.09, 140.31, 135.85, 128.68, 128.32,

128.06, 128.01, 127.85, 127.58, 126.74, 124.12, 121.76, 108.52, 55.14, 53.65, 45.41, 44.12, 29.22. EI-MS m/z (%) :

710 (M+, 2%), 577 (1), 356 (4), 344 (2), 262 (3), 236 (4), 223 (4), 134 (8), 118 (12), 106 (21), 91 (100). HRMS m/z

Found: 710.3622, Calcd. for C48H46N4O2 (M)+: 710.3621.

(13a’ racemic )*1 Chiral HPLC analysis: 25 ºC; column: DAICEL Chiralcel OD-H (0.46 cm Φ × 25 cm); mobile

phase: hexane / iso-propanol 85 / 15; flow rate: 0.500 mL/min; detection, UV 254 nm; tR1 = 48.247 min, Area =

39.4094; tR2 = 53.887 min, Area = 60.5906.

(24)*2 Chiral HPLC analysis: 25 ºC; column: DAICEL Chiralcel OD-H (0.46 cm Φ × 25 cm); mobile phase: hexane

/ iso-propanol 85/ 15; flow rate: 0.500 mL/min; detection, UV 254 nm; tR1 = 50.183 min, Area = 0.4883; tR2 =

52.932 min, Area = 99.5117.

To a solution of sulfinamide 21b (2.42 g, 2.5 mmol) in methanol (50 mL) was added an aqueous solution of HCl

(4N, 1.88 mL, 7.5 mmol, 3 eq.). The resulting mixture was allowed to stir at room temperature for 1 h. The reaction

mixture was then treated with saturated aqueous solution of sodium bicarbonate (until pH = 8) and concentrated

under reduced pressure. The mixture was diluted with water (80 mL) and extracted with dichloromethane (3 50

mL), the combined organic phases were dried over anhydrous Na2SO4. After removal of the solvent, the residue was

chromatographed on silica gel (Petroleum ether 60-90 ºC: ethyl acetate = 2:1) to afford the amine (28) (1.81 g, 95%)

as a pale yellow syrup.

28 C52H50N4O2

Mol. Wt.: 762.98N O

O N

Bn

Bn

N

N

Bn

Bn

S

S

O

O

N O

O N

Bn

Bn

NH

Bn

HN

Bn

28: (3S,3'S)-1,1'-dibenzyl-3,3'-bis((S)-2-(benzylamino)but-3-en-1-yl)-[3,3'-biindoline]-2,2'-dione

21b

5

[α]20D 241 (c 0.18, CHCl3). ee = 99.8%, Rf: 0.65 (Petroleum ether: ethyl acetate = 2:1). FTIR (KBr, thin film)

cm1: 3454, 3061, 2921, 1699, 1609, 1485, 1361, 742. 1H-NMR (400 MHz, CDCl3), δ (ppm): 7.23-7.15 (25H, m),

7.11-7.04 (23H, m), 6.98 (21H, t, J = 6.8 Hz), 6.97 (21H, d, J = 7.2 Hz), 6.72-6.66 (22H, m), 6.61 (21H, t, J =

7.2 Hz), 6.35 (21H, t, J = 8.0 Hz), 5.52 (21H, ddd, J = 8.4, 10.0, 17.2 Hz), 5.00 (21H, d, J = 10.0 Hz), 4.75

(21H, d, J = 17.2 Hz), 4.48 (21H, d, J = 15.6 Hz), 4.42 (21H, d, J = 15.6 Hz), 3.50 (21H, d, J = 13.2 Hz), 3.33

(21H, dd, J = 4.0, 13.6 Hz), 3.01 (21H, d, J = 13.2 Hz), 2.54 (21H, ddd, J = 4.0, 8.6, 10.8 Hz), 2.40 (21H, dd, J

= 10.8, 13.6 Hz), 0.91 (21H, brs). 13C-NMR (100 MHz, CDCl3), δ (ppm): 179.28, 143.86, 140.53, 140.01, 136.12,

128.44, 128.07, 128.02, 127.87, 127.70, 127.31, 126.32, 124.88, 121.36, 115.53, 108.44, 57.58, 54.78, 50.31, 44.45,

34.85. +TOF-MS m/z (%) : 763 (M++1, 100%), 382 (15), 275 (2), 236 (20). HRMS m/z Found: 763.4015, Calcd.

for C52H51N4O2 (M+H)+: 763.4012.

(28 racemic ) Chiral HPLC analysis: 25 ºC; column: DAICEL Chiralcel AD-H (0.46 cm Φ × 25 cm); mobile phase:

hexane / iso-propanol 90 / 10; flow rate: 0.600 mL/min; detection, UV 254 nm; tR1 = 11.693 min, Area = 49.2003;

tR2 = 24.015 min, Area = 50.7997.

(28) Chiral HPLC analysis: 25 ºC; column: DAICEL Chiralcel AD-H (0.46 cm Φ × 25 cm); mobile phase: hexane /

iso-propanol 90 / 10; flow rate: 0.600 mL/min; detection, UV 254 nm; tR1 = 11.769 min, Area = 0.1004; tR2 =

24.349 min, Area = 99.8996.

To a solution of amine 31 (74 mg, 0.2 mmol) and FMOC-(S)-MePhe-OH (200 mg, 0.5 mmol, 2.5 eq.) in anhydrous

DMF (3 ml) was added Et3N (0.14 mL, 1 mmol, 5.0 eq.) and O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-

tetramethyluronium hexafluorophosphate (HATU, 190 mg, 0.5 mmol, 2.5 eq.) at 0 ºC. The resulting mixture was

then stirred at room temperature for 12 h. The mixture was then treated with an aqueous solution of LiCl (5%, ca. 10

mL). After stirring for 5 minutes, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3

20 mL). The combined organic phases were washed with 5% aqueous solution of LiCl (5 mL) and dried over

anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure to afford the product (32,

198 mg, 87%) which was used directly in the next step without further purification.

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[α]20D 265 (c 0.40, CHCl3). Rf: 0.48 (Petroleum ether: ethyl acetate = 3:1). HRMS m/z Found: 1137.5271, Calcd.

for C74H69N4O6 (M+H)+: 1137.5279.

1H-NMR (400 MHz, CDCl3), δ (ppm): 7.45 (22H, d, J = 7.2 Hz), 7.36 (22H, t, J = 7.2 Hz), 7.33-7.24 (24H, m),

7.14-7.08 (22H, m), 6.81 (21H, t, J = 7.6 Hz), 6.59 (21H, d, J = 7.2 Hz), 6.49 (21H, t, J = 7.6 Hz), 6.25 (21H,

d, J = 8.0 Hz), 5.02 (21H, d, J = 15.6 Hz), 4.72-4.55 (21H, m), 4.48-4.32 (21H, m), 4.27 (21H, d, J = 15.6 Hz),

3.27-3.14 (21H, m), 2.69-2.54 (21H, m), 2.46-2.31 (22H, m), 1.41 (29H, s). 13C-NMR (100 MHz, CDCl3), δ

(ppm): 176.32, 142.37, 136.18, 135.44, 129.09, 128.91, 128.65, 128.49, 127.87, 127.78, 127.65, 126.38, 123.56,

122.11, 108.57, 61.60, 54.13, 51.89, 43.90, 43.43, 27.04, 24.96.

Synthesis of compound 19a: A mixture of tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, FW 915.72, 46.0 mg,

0.05 mmol, 0.025 eq.], triphenylphosphine (FW 262.29, 52 mg, 0.2 mmol, 0.1 eq.) and bromoanilide 12b (541 mg,

1.0 mmol) in anhydrous toluene (20 mL) was degassed and purged with argon (3 times). To this mixture, a

solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 2 mL, 2 mmol, 2.0 eq.) was added and the resulting

mixture was stirred at 80 °C (oil bath) under argon for 6 h. After cooling to room temperature then 0 °C, powdered

NH4Cl (107 mg, 2 mmol) was added. After stirring at 0 °C for 60 min, the mixture was diluted with water (5 mL).

The aqueous phase was extracted with ethyl acetate (3 30 mL). The combined organic phases were dried over

anhydrous Na2SO4. After removal of the solvents, the residue was chromatographed on silica gel (Petroleum ether

60-90 ºC: ethyl acetate = 2:1) to afford the major product (19a, 280 mg, 61%) as pale yellow syrup, Further elution

afforded the minor product (19, 133 mg, 28%) as a yellow solid.

19a: Rf: 0.54 (Petroleum ether: ethyl acetate = 2:1). 1H-NMR (as a mixture of rotamers, 300 MHz, CDCl3), δ (ppm):

7.39-6.87 (13H, m), 6.67 (1H, d, J = 7.8 Hz), 4.87 (1H, d, J = 15.6 Hz ), 4.80 (1H, d, J = 15.6 Hz ), 4.39-4.07 (2H,

m), 3.45 ( 1H, t, J = 6.0 Hz), 3.31-3.10 (1H, m), 3.09-2.82 (1H, m), 2.33-2.04 (1H, m), 1.22 (4.5H, s), 1.20 (4.5H, s). 13C-NMR ((rotamer in brackets, 75 MHz, CDCl3), δ (ppm):177.08, 143.26, 137.12, 135.85, 128.79, 128.63, 128.02,

127.62, 127.54, 127.30, 123.75, 122.48, 109.08, 58.46 ( 58.30), 51.34, 45.86 (45.29), 43.75, 43.34, 29.48 (29.30),

23.48 (23.40). HRMS m/z Found: 460.2168, Calcd. for C28H32N2NaO3S (M)+: 460.2200.

Synthesis of compound 19: A solution of amine 19a (184 mg, 0.4 mmol) in anhydrous toluene (5 mL) was degassed

and purged with argon (3 times). To this solution, lithium bis(trimethylsilyl)amide (1.0 M in THF, 0.48 mL, 0.48

7

mmol, 1.2 eq.) was added and the resulting mixture was stirred at 0 °C under argon for 0.5 h. A solution of

anhydrous t-BuOOH (3.0 M in toluene, 0.16 mL, 0.48 mmol, 1.2 eq.) was added and the reaction mixture was

stirred at 0 °C under argon for another 0.5 h. Saturated aqueous solution of NH4Cl (1 mL) was then added. After 10

min, the resulting mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 5 mL). After removal

of the solvents, the residue was chromatographed on silica gel (Petroleum ether 60-90 ºC: ethyl acetate = 2:1) to

afford the product (19, 166 mg, 87%) as a yellow solid.

19: m.p.: 125-127 ºC. Rf: 0.54 (Petroleum ether: ethyl acetate = 1:1). FTIR (KBr, thin film) cm1: 3321, 3057, 2958,

2866, 1722, 1611, 1460, 1359, 1273, 1174, 1068, 928, 743, 704, 633, 596, 464. 1H-NMR (as a mixture of rotamers,

400 MHz, CDCl3), δ (ppm): 7.30-7.11 (12H, m), 7.08 (0.5H, t, J = 7.6 Hz), 7.07 (0.5H, t, J = 7.6 Hz), 6.92 (0.5H, t,

J = 7.6 Hz), 6.91 (0.5H, t, J = 7.6 Hz), 6.61 (0.5H, d, J = 7.6 Hz), 6.60 (0.5H, d, J = 7.6 Hz), 5.07 (0.5H, s), 5.04

(0.5H, s), 4.86 (0.5H, d, J = 15.6 Hz), 4.83 (0.5H, d, J = 15.6 Hz), 4.61 (0.5H, d, J = 15.6 Hz), 4.59 (0.5H, d, J =

15.6 Hz), 4.19 (0.5H, d, J = 15.2 Hz), 4.17 (0.5H, d, J = 15.2 Hz), 4.02 (0.5H, d, J = 15.2 Hz), 4.01 (0.5H, d, J =

15.2 Hz), 3.10-2.95 (1H, m), 2.93-2.70 (1H, m), 2.38-2.18 (2H, m), 1.10 (4.5H, s), 1.09 (4.5H, s). 13C-NMR

(rotamer in brackets, 100 MHz, CDCl3), δ (ppm): 177.54, 141.86, 136.62 (136.56), 135.29, 129.86 (129.80), 129.21,

128.60, 128.36 (128.30), 127.41 (127.20), 127.03 (127.00), 123.73 (123.68), 122.88, 109.24, 74.75 (74.71), 57.97,

51.24, 43.46, 42.72, 36.55 (36.43), 23.09. HRMS m/z Found: 499.2028, Calcd. for C28H32N2NaO3S (M+Na)+:

499.2031.

8

10NH

O

Br

OH

9

11Br

N OOH

Ph

10

11

13BrN

O

Ph

N

S

O

H

12

13

Br

N O

Ph

NS

O

Ph

14

Br

N O

Ph

NS

O

Ph

15

16

17

18

19

20

21

I

N O

Ph

NS

O

Ph

22

N O

Ph

NS

O

Bn

23

24

25

N

O

O

N

Bn

Bn

N

N

S

SO

O

13a: Major 13b: Minor

+

Ph

Ph

unseparatable mixture

N

O

O

N

Bn

Bn

N

N

S

SO

O

Ph

Ph

26

27

28

29

30

31

32

33

34

35

36

37

38

39

N

O

O

N

Bn

Bn

HN

NH

Bn

Bn

40

N

O

O

N

Bn

Bn

HN

NH

Bn

Bn

41

42

43

44

45

46

47

48

49

N

O

O

N

Bn

Bn

HN

NH

Bn

Bn

+N

O

O

N

Bn

Bn

HN

NH

Bn

Bn

50

51

52

53