Total synthesis of (S)-(-)-stepholidine using (S)-tert-butanesulfinylimine

Article abstract of DOI:10.3987/COM-10-12056

A new synthetic strategy of (S)-(-)-stepholidine, a promising antipsychotic drug candidate, is described. Nucleophilic addition of a laterally lithiated nitrile to a (S)-tert-butanesulfinylimine was used as the key step, which was complished in 94 % de and the main isomer was isolated in 52% yield. (S)-(-)-Stepholidine was prepared after another 5 steps, with an overall yield of 18.3% and > 98% ee. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-12056

HETEROCYCLES, Vol. 81, No. 11, 2010
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HETEROCYCLES, Vol. 81, No. 11, 2010, pp. 2581 - 2592. © The Japan Institute of Heterocyclic Chemistry
Received, 30th August, 2010, Accepted, 28th September, 2010, Published online, 30th September, 2010
DOI: 10.3987/COM-10-12056
TOTAL
SYNTHESIS
OF
(S)-(−)-STEPHOLIDINE
USING
(S)-TERT-BUTANESULFINYLIMINE
Jianjun Cheng, Liqiang Fu, Chenyu Ling, and Yushe Yang *
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai 201203, China
e-mail: ysyang@mail.shcnc.ac.cn
Abstract – A new synthetic strategy of (S)-(−)-stepholidine, a promising
antipsychotic drug candidate, is described. Nucleophilic addition of a laterally
lithiated nitrile to a (S)-tert-butanesulfinylimine was used as the key step, which
was complished in 94 % de and the main isomer was isolated in 52% yield. (S)-
(−)-Stepholidine was prepared after another 5 steps, with an overall yield of
18.3% and > 98% ee.
INTRODUCTION
Tetrahydroprotoberberines (THPBs) represent a large class of naturally occurring alkaloids which possess
a wide range of biological activities.1 Asymmetric syntheses of THPBs which mostly emphasize the
construction of chiral amines have attracted much attention these years.2 Among the diverse methods to
prepare chiral amines, addition of nucleophile to enantiopure sulfinimine has become a method of choice
since this methodology showed advantages in both enantioselectivity and substrate diversity (Figure 1).3,4
Addition of laterally lithiated amides or nitriles 1 to enantiopure sulfinimines 2 has been developed and
used in the syntheses of 6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (4),5 (−)-normalindine
(5),6 (S)-(−)-xylopinine (6),7 and (S)-(−)-O-methylbharatamine (7).8 Among them, 6 and 7 represent
typical structures of THPBs.
(S)-(−)-Stepholidine (l-SPD, 10), a prototypical member of THPBs, which is extracted from Stephanie
intermedi, a traditional Chinese herb, has attracted a great deal of attention since it was reported to display
a unique pharmacological profile toward the central nervous system.9 Clinical trials and animal studies
have demonstrated that l-SPD is a potential candidate for the treatment of schizophrenia and/or drug
abuse.10

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HETEROCYCLES, Vol. 81, No. 11, 2010
O
S
H
R3
N
R2
R2
N
2
R3
S
MeO
O
R1
NH
OMe Me
R1
X
X
1: X = C(O)NEt2, CN
3
4
MeO
MeO
MeO
MeO
H
N
N
H
H
N
N
Me
OMe
OMe
6
5
7
Figure 1. Addition of nucleophiles to enantiopure sulfinimines as a synthetic approach
Recently, we have reported the first enantioselective synthesis of l-SPD using Noyori’s enantioselective
reduction of cyclic imine as the key step.11 However, due to the high price of the Ru (II) catalyst and the
harsh conditions needed for the catalytic reduction, new and smooth method for producing this alkaloid is
still necessary. Herein, we report the synthesis of (S)-(−)-stepholidine 10 by applying chiral
(S)-N-tert-butanesulfinimine 8 and benzonitrile 9 as building blocks (Scheme 1), via a similar approach
for the synthesis of (S)-(−)-xylopinine. 7
O
CN
O
OPG
N
HO
O
Me
H
N
R1
S
O
PGO
PGO
O
OH
10
(S)-(-)-stepholidine
8
9
Scheme 1. New synthetic approach of (S)-(−)-stepholidine
RESULTS AND DISCUSSION
12
Phenylacetic acid 11 was prepared according to the reported method and used as starting material for
the synthesis of (S)-N-tert-butanesulfinimine (Scheme 2). Reduction of 11 with LiAlH4 afforded
phenethyl alcohol 12 in high yield, and bromination of 12 with NBS in DMF at room temperature gave
13 in almost quantitative yield. The alcohol group of 13 was protected as a silyl ether 14 and lithium
halogen exchange was accomplished using n-BuLi at -78 oC, which was quenched with anhydrous DMF
to give aldehyde 15. Sulfinimine 16 was prepared similarly according to Ellmans’ procedure with 15 and
(S)-tert-butanesulfinylamide in the presence of Ti(Oi-Pr)4 in 92% yield.13

HETEROCYCLES, Vol. 81, No. 11, 2010
2583
O
O
OH
O
OH
i
ii
iii
CO2H
i-PrO
i-PrO
i-PrO
Br
11
12
13
O
OTBS
O
OTBS
O
OTBS
v
iv
N
i-PrO
S
i-PrO
Br
i-PrO
CHO
O
14
15
16
Scheme 2. Reagents and conditions: (i) LiAlH4, THF, reflux 2 h, 98%; (ii) NBS, DMF, rt, 12 h, 98%; (iii)
o
TBSCl, imidazole, CH2Cl2, rt, 91%; (iv) n-BuLi, THF, DMF, -78 ~ 0 C, 93%; (v) (S)-tert-butane-
sulfinylamide, Ti(Oi-Pr)4, THF, reflux 4 h, 92%.
Synthesis of the requisite benzonitrile started from isopropyl ether of vanillin 17, as shown in Scheme 3.
Reductive amination of 17 afforded benzylic amine 18, treatment of which with n-BuLi and ClCO2Me
using reported method afforded 19 in high yield.14 Hydrogenation of the benzylic chloride followed by
hydrolyzation of the ester group gave benzoic acid 21, which was converted to amide 22 with oxalyl
chloride and ammonia. Dehydration of this amide was accomplished using cyanuric chloride, giving the
desired benzonitrile 23 in 95% yield.15
CO2Me
CO2Me
Me
O
CHO
O
iii
i
ii
N
O
O
Cl
i-PrO
i-PrO
i-PrO
i-PrO
17
18
19
20
O
NH2
Me
CO2H
Me
CN
v
iv
vi
O
O
Me
O
i-PrO
i-PrO
i-PrO
21
22
23
Scheme 3. Reagents and conditions: (i) a. Me2NH·HCl, Et3N, Ti(Oi-Pr)4, EtOH, rt, 12 h; b. NaBH4, 8 h,
o
82%; (ii) n-BuLi, THF, ClCO2Me, -78 ~ 0 C, 93%; (iii) H2, Pd/C, MeOH, 4 h, 97%; (iv) NaOH,
H2O-EtOH, reflux 2 h, 96%; (v) a. (COCl)2, reflux 2 h; b. NH4OH, 88%; (vi) cyanuric chloride, DMF, rt,
16 h, 95%.
With both 16 and 23 in hand, the key step was carried out, as shown in Scheme 4. Thus, benzonitrile 23
was treated with LDA at -78 oC to give a dark red solution of the laterally lithiated o-tolylnitrile. To this
solution was added 1.0 equiv of sulfinimine 16 and the reaction was quenched with aqueous NH4Cl after
0.5 h. It was reported that in the asymmetric synthesis of (S)-(−)-xylopinine (6), the addition of laterally

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HETEROCYCLES, Vol. 81, No. 11, 2010
lithiated derivative of o-tolunitrile to enantiopure sulfinimine derived from tert-butanesulfinamide lead to
complex mixture of products and the corresponding sulfinamide was not detected.7 Fortunately for us, the
addition of lithiated 23 to sulfinimine 16 gave the the corresponding sulfinamide in moderate yield and
97:3 dr, determined by LC-MS. The major isomer 24 was isolated by chromatography in 52% yield,
using CH2Cl2/CH3OH as the eluent. The reason for the low yield of this reaction is probably the
self-condensation of 23, and attempts to improve the yield of 24, such as changing the solvent, base or
reaction temperature failed (data not shown).
O
OTBS
O
OH
NH2
H
N
i-PrO
S
i-PrO
ii
i
O
16
+
23
i-PrO
CN
i-PrO
CN
O
O

25
O
OH
O
O
H
N
O
N
O
N
i-PrO
v
iv
i-PrO
i-PrO
iii
O
O
O
Oi-Pr
Oi-Pr
Oi-Pr
27
28
26
O
N
HO
vi
O
OH
10
o
Scheme 4. Reagents and conditions: (i) LDA, THF, -78 C, 52%; (ii) MeOH, conc. HCl, rt, 81%; (iii)
KOH, H2O-EtOH, reflux 20 h, 87%; (iv) TsCl, pyridine, rt, 8 h; NaH, THF, 0 oC, 2 h. 67% for 2 steps; (v)
LiAlH4, THF, reflux 2 h, 91%; (vi) BCl3, CH2Cl2, -78 oC, 82%.
Removal of the N-sulfinyl auxiliary along with the silyl protecting group of 24 was accomplished in one
step with hydrochloric acid to give the priamry amine 25 in 81% yield. Refluxing of 25 in aqueous KOH
for 20 h afforded the lactam 26, which was converted to its tosylate and treated with NaH to give 27.
Reduction of the lactam 27 was accomplished with LiAlH4 and the following deprotection of the
isopropyl groups using BCl3 in CH2Cl2 afforded the title compound 10 successfully, in an overall yield of
18.3% based on 16 and 23.
In conclusion, total synthesis of (S)-(−)-stepholidine 10, a protoberberine alkaloid, using addition of
laterally lithiated nitriles to enantiopure sulfinimine was reported. Enantiopure sulfinimine 16 was

HETEROCYCLES, Vol. 81, No. 11, 2010
2585
prepared in 5 steps and 76% overall yield from the known phenylacetic acid, and the requisite
benzonitrile 23 was prepared in 6 steps and 55% overall yield from isopropyl ether of vanillin. Addition
of lithiated 23 to sulfinimine 16 yielded the desired sulfinamide in 97:3 dr, and the desired isomer was
isolated in 52% yield. (S)-(−)-stepholidine was prepared after another 5 steps, with an overall yield of
18.3% and > 98% ee. Spectral properties, specific rotation of the title compound were in agreement with
the reported ones.11
EXPERIMENTAL
All solvents used were of analytical grade, purified and dried by standard methods prior to use. Melting
points (uncorrected) were determined on an X-4 melting point apparatus. EI-MS spectra were obtained on
a Finnigan MAT 95 mass spectrometer and ESI-MS spectra were obtained on a Kratos MS 80 mass
spectrometer. Column chromatography was performed on silica gel H (200-300 mesh), and the solvent
proportions were expressed on a volume/volume basis.
2-(4-Isopropoxy-3-methoxyphenyl)ethanol (12)
o
To a suspension of LiAlH4 (11.4 g, 0.30 mol) in anhydrous THF (500 mL) cooled at 0 C was added
dropwise a solution of 2-(4-isopropoxy-3-methoxyphenyl)acetic acid 6 (44.8 g, 0.20 mol) in the same
o
solvent (200 mL). The mixture was refluxed for 1 h and then cooled to 0 C again. Water (30 mL) was
added slowly followed by 10% aq. NaOH (30 mL), and water (100 mL). Then the mixture was filtered
and the filtrate was extracted with Et2O. The combined organic phase was dried over Na2SO4 and
concentrated in vacuo to yield a colorless oil 12 (41.2 g, 98%). 1H NMR (300 MHz, CDCl3): 6.84 (d, 1H,
J = 10.4 Hz), 6.76-6.70 (m, 2H), 4.51-4.43 (m, 1H), 3.86-3.76 (m, 5H), 2.80 (t, 2H, J = 6.6 Hz), 1.35 (d,
6H, J = 6.1 Hz); 13C NMR (100 MHz, CDCl3): 150.4, 145.9, 131.4, 120.9, 116.2, 112.9, 71.5, 63.7, 55.9,
38.7, 22.1 (×2). EI-MS: m/z (%) 137 (100), 168 (20), 210 (14); HRMS calcd for C12H18O3: 210.1256,
found: 210.1263.
2-(2-Bromo-4-isopropoxy-5-methoxyphenyl)ethanol (13)
o
A solution of 12 (44.2 g, 0.21 mol) in anhydrous DMF (200 mL) was cooled to 0 C, and NBS (41.1 g,
0.23 mol) was added portionwise. The mixture was stirred at room temperature overnight before saturated
aq. Na2S2O3 was added and the mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2
and washed with H2O, brine, dried over Na2SO4, then concentrated to give a brown oil, which was
1
purified by fast chromatography (EtOAc/petroleum ether = 1/3) to yield a yellow oil (59.3 g, 98%). H
NMR (400 MHz, CDCl3): 7.03 (s, 1H), 6.77 (s, 1H), 4.50–4.46 (m, 1H), 3.86 (t, 2H, J = 6.6 Hz), 3.83 (s,
3H), 2.94 (t, 2H, J = 6.6 Hz), 1.36 (d, 6H, J = 6.0 Hz); 13C NMR (100 MHz, CDCl3): 149.6, 146.6, 130.0,
119.7, 114.4, 114.2, 71.9, 62.2, 56.1, 39.0, 21.9 (×2); EI-MS: m/z (%) 215 (100), 217 (97), 246 (33), 248

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HETEROCYCLES, Vol. 81, No. 11, 2010
(31), 288 (18), 290 (17); HRMS: calcd for C12H17BrO3: 288.0361, found: 288.0356.
(2-Bromo-4-isopropoxy-5-methoxyphenethyloxy)(tert-butyl)dimethylsilane (14)
To a stirred solution of the alcohol 13 (10.4 g, 36 mmol) in anhydrous CH2Cl2 (200 mL) was added
imidazole (4.9 g, 72 mmol), followed by TBSCl (8.1 g, 54 mmol). The mixture was stirred at room
temperature for 1 h. CH2Cl2 (200 mL) was added and the organic phase was washed with H2O, brine,
dried over Na2SO4, concentrated and purified by chromatography (EtOAc/petroleum ether = 1/6) to yield
1
a yellow oil (13.9 g, 96%). H NMR (400 MHz, CDCl3): 7.03 (s, 1H), 6.78 (s, 1H), 4.51–4.42 (m, 1H),
3.86-3.74 (m, 5H), 2.87 (t, 2H, J = 6.7 Hz), 1.34 (d, 6H, J = 6.1 Hz), 0.86 (s, 9H), -0.03 (s, 6H); 13C NMR
(100 MHz, CDCl3): 149.4, 146.2, 130.8, 119.6, 114.8, 114.0, 71.8, 62.6, 55.9, 39.2, 25.8 (×3), 21.9 (×2),
18.2, -5.5 (×2); EI-MS: m/z (%) 73 (41), 223 (47), 345 (100), 347 (96), 402 (6), 404 (6); HRMS: calcd for
C18H31SiBrO3: 402.1226, found: 402.1218.
2-(2-(tert-Butyldimethylsilyloxy)ethyl)-5-isopropoxy-4-methoxybenzaldehyde (15)
A solution of 14 (8.07 g, 20 mmol) in anhydrous THF (200 mL) was cooled to -78 oC, and n-BuLi (1.6 M
in hexane, 16 mL) was added dropwise under N2 and the solution was stirred at the same temperature for
30 min before DMF (2.3 mL, 30 mmol) was added. Saturated aq. NH4Cl was added after another 30 min
and the mixture was warmed to room temperature. Water was added and the mixture was extracted with
Et2O. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by chromatography (ethyl acetate/petroleum ether = 1/4) to
1
give a yellow oil (6.4 g, 91%). H NMR (300 MHz, CDCl3): 10.15 (s, 1H), 7.39 (s, 1H), 6.74 (s, 1H),
4.47-4.58 (m, 1H), 3.91 (s, 3H), 3.83 (t, 2H, J = 6.3 Hz), 3.17 (t, 2H, J = 6.3 Hz), 1.37 (d, 6H, J = 6.0 Hz),
0.82 (s, 9H), 0.09 (s, 6H). 13C NMR (100 MHz, CDCl3): 190.4, 154.8, 145.9, 137.4, 127.4, 115.4, 114.2,
71.4, 64.4, 56.0, 34.9, 25.8 (×3), 21.9 (×2), 18.2, -5.6 (×2). EI-MS: m/z (%) 75 (31), 214 (31), 216 (31),
221 (32), 295 (100), 352 (1); HRMS: calcd for C19H32SiO4: 352.2070, found: 352.2081.
Condensation of aldehyde 15 with (S)-tert-butanesulfinylamide
To a solution of the benylaldehyde 15 (3.6 g, 10 mmol) in anhydrous THF (100 mL) was added
(S)-tert-butanesulfinylamide (1.27 g, 10.5 mmol), Ti(Oi-Pr)4 (7.4 mL, 25 mmol) under argon, and the
mixture was refluxed for 4 h before it was cooled to room temperature and water (10 mL) was added. The
mixture was filtered, and the filtrate cake was washed with THF. The filtrate was extracted with CH2Cl2,
and the combined extracts was washed with brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by chromatography (EtOAc/petroleum ether = 1/4) to yield a red thick
1
oil (3.8 g, 95%). [α]20 +41.5 (c 0.53, CHCl3); H NMR (300 MHz, CDCl3): 8.72 (s, 1H), 7.50 (s, 1H),
D
6.76 (s, 1H), 4.62-4.51 (m, 1H), 3.91 (s, 3H), 3.86-3.71 (m, 2H), 3.16-3.05 (m, 2H), 1.36 (d, 6H, J = 6.3

HETEROCYCLES, Vol. 81, No. 11, 2010
2587
13
Hz), 1.24 (s, 9H), 0.81 (s, 9H), -0.09 (s, 6H); C NMR (100 MHz, CDCl3): 160.2, 153.3, 145.7, 135.6,
124.7, 115.4, 114.2, 71.4, 64.2, 57.4, 55.8, 35.6, 25.8 (×3), 22.5 (×3), 21.9, 21.7, 18.2, -5.6 (×2); EI-MS:
m/z (%) 73 (65), 177 (100), 219 (63), 267 (72), 399 (84), 455 (3); HRMS: calcd for C23H41NO4SSi:
455.2526, found: 455.2558.
(4-Isopropoxy-3-methoxyphenyl)-N,N-dimethylmethanamine (18)
To an ice-cooled solution of isopropylvanillin 17 (77.7 g，0.40 mol) in EtOH (400 mL) was added Et3N
(112 mL, 0.80 mol), Me2NH•HCl (65.2 g, 0.80 mol), Ti(Oi-Pr)4 (238 mL, 0.80 mol) and the mixture was
stirred at 30 oC for 16 h. NaBH4 (24 g, 0.60 mol) was added and the stirring was continued for another 14
h. The mixture was poured into 3 N aqueous ammonia with ice (2 L) and filtered after 1 h standing at
room temperature. The filtrate cake was washed with CH2Cl2, and the filtrate was extracted with the same
solvent. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to yield
a colorless oil (73.2 g, 82%). 1H NMR (300 MHz, CDCl3): 6.86 (d, 1H, J = 2.0 Hz), 6.82 (d, 1H, J = 8.0
Hz), 6.76 (dd, 1H, J = 8.0, 2.0 Hz), 4.52-4.44 (m, 1H), 3.84 (s, 3H), 3.33 (s, 2H), 2.22 (s, 6H), 1.34(d, 6H,
J = 6.6 Hz); 13C NMR (300 MHz, CDCl3): 150.2, 146.2, 131.8, 121.1, 115.4, 112.7, 71.3, 64.2, 55.9, 45.2
(×2), 22.0 (×2); EI-MS: m/z (%) 137 (100), 138 (18), 163 (16), 180 (15), 223 (26); HRMS: calcd for
C13H21NO2: 223.1572, found: 223.1573.
Methyl 6-(chloromethyl)-3-isopropoxy-2-methoxybenzoate (19)
o
To a cooled (-10 C) solution of 18 (32.0 g, 0.14 mol) in anhydrous THF (300 mL) was added n-BuLi
(1.6 M in hexane, 100 mL) under argon and the stirring was continued for 1 h at the same temperature.
The solution was then cooled to -78 oC, and ClCO2Me (27.5 mL, 0.35 mol) was added. The mixture was
stirred for 15 min before it was warmed to room temperature and stirred overnight. With ice cooling,
water was added and the mixture was extracted with t-BuOMe. The combined extracts was washed with
brine, dried over Na2SO4, and concentrated to afford a red oil which was purified by chromatography
(EtOAc/petroleum ether = 1/6) to give the benzylic chlorine 19 as colorless oil (35.0 g, 92%).1H NMR
(300 MHz, CDCl3): 7.06 (d, 1H, J = 8.5 Hz), 6.90 (d, 1H, J = 8.5 Hz), 4.59-4.51 (m, 3H), 3.94 (s, 3H),
13
3.87 (s, 3H), 1.35 (d, 6H, J = 6.1 Hz); C NMR (100 MHz, CDCl3): 167.3, 151.2, 147.7, 128.9, 127.2,
125.5, 116.4, 71.1, 61.3, 52.4, 43.6, 21.9 (×2); EI- MS: m/z (%) 163 (81), 198 (100), 200 (34), 230 (42),
232 (13), 272 (41), 274 (14); HRMS: calcd for C13H17ClO4: 272.0815, found: 272.0818.
Methyl 3-isopropoxy-2-methoxy-6-methylbenzoate (20)
The benzylic chlorine 19 (17.5 g，64 mmol) was dissolved in MeOH (200 mL), and 10% Pd/C (1.8 g) was
added. The mixture was hydrogenated at 1 atm for 8 h at room temperature. Pd/C was filtered off and the
filtrate was concentrated under reduced pressure to give 20 as colorless oil (14.1 g, 92%). 1H NMR (300

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HETEROCYCLES, Vol. 81, No. 11, 2010
MHz, CDCl3): 6.85 (d, 1H, J = 8.6 Hz), 6.83 (d, 1H, J = 8.6 Hz), 4.53-4.42 (m, 1H), 3.90 (s, 3H), 3.85 (s,
13
3H), 2.21 (s, 3H), 1.32 (d, 6H, J = 6.1Hz); C NMR (100 MHz, CDCl3): 168.4, 148.4, 147.4, 129.3,
127.8, 125.3, 117.8, 71.5, 61.2, 52.0, 22.0 (×2), 18.4; EI-MS: m/z (%) 164 (100), 196 (48), 207 (14), 238
(30); HRMS: calcd for C13H18O4: 238.1205, found: 238.1200.
3-Isopropoxy-2-methoxy-6-methylbenzoic acid (21)
To a solution of the methyl ester 20 (7.9 g，33 mmol) in EtOH (100 mL) was added 20% aqueous NaOH
(100 mL) and the mixture was refluxed for 4 h. The solution was cooled to room temperature and EtOH
was removed under vacuo. The resultant basic solution was washed with Et2O, acidified with conc. HCl,
and extracted with EtOAc. The combined EtOAc was washed with brine, dried over Na2SO4 and
concentrated to yield a yellow solid (6.9 g, 94%). mp 61-62 oC; 1H NMR (300 MHz, CDCl3): 6.94 (d, 1H,
J = 8.4 Hz), 6.90 (d, 1H, J = 8.4 Hz), 4.53 (m, 1H), 3.95 (s, 3H), 2.40 (s, 3H), 1.36 (d, 6H, J = 6.0 Hz);
13C NMR (100 MHz, CDCl3): 170.1, 148.5, 148.2, 130.4, 126.5, 126.3, 118.6, 71.6, 61.7, 22.1 (×2), 19.9;
EI-MS: m/z (%) 121 (26), 135 (28), 136 (32), 164 (100), 165 (21), 182 (53), 207 (27), 224 (36); HRMS:
calcd for C12H16O4: 224.1049, found: 224.1049.
3-Isopropoxy-2-methoxy-6-methylbenzamide (22)
Benzoic acid 21 (10.0 g, 44.6 mmol) was dissolved in oxalyl chloride (50 mL) and refluxed for 2 h.
Oxalyl chloride was removed under reduced pressure and the residual benzoyl chloride was dissolved in
o
anhydrous Et2O (50 mL). Saturated aq. ammonia (100 mL) was stirred and cooled at 0 C, and the
solution of the benzoyl chloride was added dropwise. The resultant slurry was stirred at room temperature
for 1 h before n-hexane (100 mL) was added and the stirring was continued for 15 min. The mixture was
filtered and the solid was washed with water, petroleum ether, and dried to give the amide 22 (8.8 g,
1
88 %). mp 80-81 oC; H NMR (300 MHz, DMSO-d6): 7.69 (br, 1H), 7.40 (br, 1H), 6.91 (d, 1H, J = 8.5
Hz), 6.85 (d, 1H, J = 8.5 Hz), 4.59-4.51 (m, 1H), 3.74 (s, 3H), 2.16 (s, 3H), 1.27 (d, 6H, J = 6.2 Hz); 13C
NMR (100 MHz, DMSO-d6): 168.8, 148.1, 145.8, 134.1, 126.1, 125.0, 115.4, 70.1, 60.6, 21.9 (×2), 18.0;
EI-MS: m/z (%) 135 (48), 164 (100), 181 (78), 223 (62); HRMS: calcd for C12H17NO3: 223.1208, found:
223.1204.
3-Isopropoxy-2-methoxy-6-methylbenzonitrile (23)
To an ice-cooled solution of benzamide 22 (8.8 g, 39.4 mmol) in DMF (100 mL) was added cyanuric
chloride (18.4 g, 0.1 mol), and the slurry was stirred at room temperature for 16 h. Water was added
dropwise and the solvent was removed in vacuo. The residue was dissolved in EtOAc, washed with water,
brine, dried over Na2SO4, concentrated and the residue was purified by chromatography (EtOAc
/petroleum ether = 1/6) to give a colorless oil (7.7 g, 95%). 1H NMR (300 MHz, CDCl3): 7.01 (d, 1H, J =

HETEROCYCLES, Vol. 81, No. 11, 2010
2589
8.5 Hz), 6.90 (d, 1H, J = 8.5 Hz), 4.54-4.42 (m, 1H), 3.98 (s, 3H), 2.42 (s, 3H), 1.34 (d, 6H, J = 6.2 Hz);
13C NMR (100 MHz, CDCl3): 152.9, 148.3, 134.6, 125.0, 120.9, 115.5, 108.3, 72.0, 61.4, 22.0 (×2), 19.7;
EI-MS: m/z (%) 120 (26), 148 (26), 163 (100), 205 (15); HRMS: calcd for C12H15NO2: 205.1103, found:
205.1096.
Addition of lithiated nitrile 23 to sulfinimine 16
LDA (purchased from Acros Organics, 2 M in THF, 5.0 mL) was diluted with anhydrous THF (20 mL) at
o
-78 C under argon, and a solution of compound 23 (1.03 g, 5 mmol) in the same solvent (5 mL) was
added dropwise in 10 min. After the addition, the solution was stirred at -78 oC for 30 min, and a solution
of compound 16 (2.28 g, 5 mmol) in anhydrous THF (5 mL) was added in 10 min and the mixture was
stirred at -60 oC for 30 min. Sat. aq. NH4Cl (10 mL) was added dropwise and the mixture was warmed up
to room temperature and extracted with Et2O. The combined organic layer was washed with brine, dried
over Na2SO4, concentrated and purified by chromatography (CH2Cl2/MeOH = 100/1) to give the major
1
isomer as a brown thick oil (1.72 g, 52%). [α]20 +34.5 (c 0.80, CHCl3); H NMR (300 MHz, CDCl3):
D
6.99 (d, 1H, J = 8.5 Hz), 6.94 (s, 1H), 6.89 (d, 1H, J = 8.5 Hz), 6.68 (s, 1H), 4.78-4.70 (m, 1H), 4.56-4.42
(m, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.79-3.68 (m, 2H), 3.46 (d, 1H, J = 4.4 Hz), 3.34 (dd, 1H, J = 14.1,
6.6 Hz), 3.11 (dd, 1H, J = 14.1, 6.6 Hz), 2.84-2.66 (m, 2H), 1.38-1.28 (m, 12H), 1.11 (s, 9H), 0.84 (s, 9H),
-0.09 (s, 6H); 13C NMR (100 MHz, CDCl3): 152.7, 149.7, 149.1, 145.8, 134.2, 131.1, 129.8, 125.7, 120.2,
115.5, 114.8, 114.2, 109.0, 71.7 (×2), 64.0, 61.4, 56.1, 55.8, 55.7, 41.2, 35.4, 25.9 (×3), 22.4 (×3), 22.1
(×2), 21.9 (×2), 18.3, -5.3 (×2); ESI-MS: 683 (M + Na); HRMS: 683.3524 (C35H56N2O6NaSSi, M + Na).
The de determination of the crude product was carried out using LC-MS (LC column: C18, 5 μm, 0.46
cm × 25 cm, gradient eluent with MeCN/H2O from 10/90 to 90/10 in 20 min, and 90/10 after that), minor
isomer: RT1 = 26.6 min (3%); major isomer: RT2 = 27.0 min (97%).
(S)-6-(2-Amino-2-(2-(2-hydroxyethyl)-5-isopropoxy-4-methoxyphenyl)ethyl)-3-isopropoxy-2-methoxy-
benzonitrile (25)
To a solution of compound 24 (0.50 g, 0.82 mmol) in MeOH (20 mL) was added conc. HCl (1.0 mL) and
the mixture was stirred at room temperature for 2 h. MeOH was removed under reduced pressure and the
residue was basified with 10% aq. NaOH. The mixture was then extracted with CH2Cl2 and the combined
extracts was washed with brine, dried over Na2SO4 and concentrated to give a white solid (0.27 g, 81%).
mp 70-71 oC; [α]20D -4.7 (c 0.95, CHCl3); 1H NMR (300 MHz, CDCl3): 7.05 (s, 1H), 7.02 (d, 1H, J = 8.5
Hz), 6.92 (d, 1H, J = 8.5 Hz), 6.68 (s, 1H), 4.58-4.42 (m, 3H), 4.00 (s, 3H), 3.86-3.75 (m, 4H), 3.73-3.64
(m, 1H), 3.22-3.12 (m, 1H), 3.04-2.73 (m, 3H), 1.38-1.29 (m, 12H). 13C NMR (100 MHz, CDCl3): 153.0,
149.6, 149.2, 145.8, 135.1, 134.1, 130.2, 125.8, 120.1, 115.7, 113.8 (×2), 107.9, 71.7 (×2), 63.9, 61.5,

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HETEROCYCLES, Vol. 81, No. 11, 2010
55.9, 51.1, 43.1, 35.6, 22.1 (×4); ESI-MS: 443 (M + H); HRMS: 465.2363 (C25H34N2O5Na, M + Na).
ee determination: Chiralpak IA column (0.46 cm × 25 cm, 5 μm), mobile phase: hexane/i-PrOH/i-Pr2NH
= 80/20/0.1 (v/v/v), flow rate: 0.7 mL/min, UV 230 nm. RT1 = 12.6 min (R isomer, 0.6%); RT2 = 14.2 min (S
isomer, 99.4%).
(S)-3-(2-(2-Hydroxyethyl)-5-isopropoxy-4-methoxyphenyl)-7-isopropoxy-8-methoxy-3,4-dihydroiso-
quinolin-1(2H)-one (26)
To a solution of compound 25 (0.35 g, 0.79 mmol) in EtOH (15 mL) was added 20 % aqueous KOH (15
mL) and the mixture was refluxed for 12 h before it was cooled to room temperature, and EtOH was
removed under reduced pressure. The resultant mixture was extracted with CH2Cl2, and the combined
extracts was washed with brine, dried over Na2SO4, concentrated and purified by chromatography
(CH2Cl2/MeOH = 40/1) to give a light yellow foam (0.30 g, 87%). [α]20D -97.1 (c 0.51, CHCl3); 1H NMR
(300 MHz, CDCl3): 7.00 (d, 1H, J = 8.1 Hz), 6.86 (d, 1H, J = 8.1 Hz), 6.72 (s, 1H), 6.57 (s, 1H), 4.93 (dd,
1H, J = 11.6, 3.3 Hz), 4.53-4.45 (m, 2H), 3.90 (s, 3H), 3.86-3.75 (m, 5H), 3.17-3.06 (m, 1H), 2.92-2.76
(m, 3H), 1.36-1.24 (m, 12H); 13C NMR (100 MHz, CDCl3): 164.9, 152.1, 151.1, 150.0, 146.0, 132.0,
130.6, 129.4, 122.8, 122.5, 121.1, 114.1, 113.9, 72.2, 71.6, 63.5, 61.3, 56.0, 51.2, 37.1, 35.2, 22.2 (×4);
ESI-MS: 466 (M + Na); HRMS: 466.2210 (C25H33NO6Na, M + Na).
Intramolecular cyclization of 26
Compound 26 (130 mg, 0.29 mmol) was dissolved in anhydrous pyridine (10 mL), to which TsCl (95 mg,
0.5 mmol) was added and the mixture was stirred at room temperature overnight. Pyridine was removed
under reduced pressure, and the residue was dissolved in CH2Cl2, which was washed with water, brine,
dried over Na2SO4 and concentrated to yield an oil. The oil was dissolved in anhydrous THF (10 mL),
NaH (60% in mineral oil, 100 mg) was added, and the mixture was stirred for 2 h at room temperature
before it was cooled to 0 oC and water (10 mL) was added dropwise. The mixture was then extracted with
CH2Cl2, and the combined organic layer was washed with brine, dried over Na2SO4, concentrated and
purified by chromatography (EtOAc/petroleum ether = 1/2) to give a light yellow thick oil (90 mg, 72%).
[α]20D -247.9 (c 0.75, CHCl3); 1H NMR (300 MHz, CDCl3): 7.03 (d, 1H, J = 8.2 Hz), 6.92 (d, 1H, J = 8.2
Hz), 6.73 (s, 1H), 6.70 (s, 1H), 4.72 (dd, 1H, J = 13.0, 3.2 Hz), 4.60-4.43 (m, 2H), 4.02 (s, 3H), 3.87 (s,
13
3H), 3.04-2.72 (m, 6H), 1.42-1.31 (m, 12H); C NMR (100 MHz, CDCl3): 162.7, 151.8, 151.2, 149.4,
146.0, 131.7, 128.2, 127.6, 123.8, 121.9, 120.2, 114.3, 111.9, 72.0, 71.9, 61.3, 55.9, 54.8, 39.2, 38.1, 29.4,
22.1 (×4); ESI-MS: 448 (M + Na); HRMS: 448.2092 (C25H31NO5Na, M + Na).
14-(S)-3,9-Dimethoxyl-2,10-diisopropoxy-tetrahydroprotoberberine (28)
To a solution of compound 27 (108 mg, 0.25 mmol) in anhydrous THF (20 mL) was added LiAlH4 (20

HETEROCYCLES, Vol. 81, No. 11, 2010
2591
mg, 0.5 mmol), and the mixture was refluxed under an argon atmosphere for 2 h before it was cooled to 0
oC and water was added. The mixture was filtered, and the filtrate was extracted with CH2Cl2. The
combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by
chromatography (CH2Cl2/MeOH = 100/1) to yield a light yellow foam (94 mg, 91%). [α]20 -190.5 (c
D
1
0.66, CHCl3); H NMR (300 MHz, CDCl3): 6.87-6.78 (m, 3H), 6.63 (s, 1H), 4.57-4.46 (m, 2H), 4.24 (d,
1H, J = 15.9 Hz), 3.88 (s, 3H), 3.85 (s, 3H), 3.62-3.50 (m, 2H), 3.31-3.08 (m, 3H), 2.88-2.61 (m, 3H),
1.45-1.34 (m, 12H); 13C NMR (100 MHz, CDCl3): 148.9, 148.1, 146.4, 145.4, 129.6, 128.8, 128.0, 127.5,
123.7, 115.0, 113.9, 111.8, 71.8, 71.1, 60.0, 59.1, 55.8, 54.0, 51.4, 36.3, 29.1, 22.1 (×4); ESI-MS: 412 (M
+ H); HRMS: 412.2490 (C25H34NO4, M + H).
(S)-(−)-Stepholidine (10)
To a solution of compound 28 (140 mg, 0.34 mmol) in anhydrous CH2Cl2 (15 mL) cooled at -78 oC, BCl3
(1 M in CH2Cl2, 1.4 mL) was added dropwise under argon and the solution was stirred for 0.5 h at the
same temperature before it was warmed to room temperature and stirred overnight. The solution was
o
cooled to -78 C again, MeOH (10 mL) was added and the stirring was continued for 2 h at room
temperature. The mixture was then concentrated and the residue was dissolved in CH2Cl2 (20 mL) and
THF (10 mL), which was washed with saturated aq. NaHCO3, brine, dried over Na2SO4, concentrated
o
and recrystallized in MeOH to give the title compound (96 mg, > 98% ee, 86%). mp 127-128 C; [α]20
D
-279.4 (c 1.0, CH3OH); NMR, MS data were in accordance with previous report.11
ee determination: Chiralpak OJ-H column (0.46 cm × 25 cm, 5 μm), mobile phase: hexane/i-PrOH =
50/50 (v/v), flow rate: 0.7 mL/min, UV 230 nm. RT1 = 9.8 min (R isomer, 0.9%); RT2 = 17.2 min (S isomer,
99.1%).
ACKNOWLEDGEMENTS
This work was sponsored by the Key New Drug Creation and Manufacturing Program of the National
Science & Technology Major Project, China (No. 2009ZX09301-001, 2009ZX09102-023), and we thank
Shanghai institute of organic chemistry, Chinese academy of sciences, for the ee determination.
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