Syntheses of Norphysostigmine and Norphenserine
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2899
added. The mixture was extracted with AcOEt (2 × 300 mL).
The combined AcOEt layers were washed with brine (200 mL)
and H2O (200 mL) and dried over Na2SO4. After the removal
of solvent, the residue was flashed chromatographed (CH2Cl2/
MeOH ) 20/1) to give 3 (13.3 g, 82.9%) as a colorless oil: 1H
NMR (CDCl3) δ 7.40-6.70 (m, 9H, Ar-H), 5.20 (s, 2H, Ph-CH2),
3.80 (s, 3H, O-CH3), 3.70 (s, 3H, O-CH3); CI-MS (NH3) m/z 339
(MH+). Anal. (C20H22N2O3) C, H, N.
and extracted into CH2Cl2 (3 × 100 mL). The extract was dried
over Na2SO4 and evaporated in vacuo. The residue was
chromatographed on silica gel (CH2Cl2/MeOH ) 10:1) to give
1.82 g of (+)-(3aR) richer base [(-)- and (+)-7] which was
dissolved in THF (6 mL) and mixed with a solution of ditoluyl-
L-tartaric acid (2.22 g, 0.0057 mol) in THF (6 mL). Crystal-
lization gradually occurred, and filtration gave 3.3 g of a
crystalline salt which was dissolved in THF (50 mL) and left
overnight to yield 1.65 g (19.2%) of ditoluyl-L-tartrate of (+)-
(3aR)-8-benzyl-1,3a-dimethyl-1,2,3,3a,8,8a-hexhydro-5-meth-
oxypyrrolo[2,3-b]indole [(+)-7] as white crystals: mp 173-174
1-Ben zyl-1,3-d ih yd r o-5-m eth oxy-3-[2′-[(m eth oxyca r bo-
n yl)a m in o]eth yl]-2H-in d ol-2-on e (4). Compound 3 (13.3 g,
39.3 mmol) was dissolved in DMSO (15 mL). After addition
of concentrated HCl (36%, 90 mL) dropwise, the solution
became dark green and then stirred at room temperature for
1 h. H2O (300 mL) was added, and the mixture was neutral-
ized with NaHCO3 and extracted with AcOEt (2 × 200 mL).
The combined AcOEt layers were washed with an aqueous
solution of NaHCO3 (5%), dried over Na2SO4, and evaporated
in vacuo to give a syrup which was recrystallized from AcOEt/
hexane to give 4 (10.5 g, 77.5%) as white crystals: mp 112-
°C; [R]20 +4.76° (c ) 0.5, EtOH). Anal. (C40H42N2O9) C, H,
D
N.
(-)-(3a S)-8-Ben zyl-1,3a -d im eth yl-1,2,3,3a ,8,8a -h exa h y-
d r o-5-m eth oxyp yr r olo[2,3-b]in d ole [(-)-7]. Dibenzoyltar-
trate (1 g) of compound (-)-7 was dissolved in H2O (40 mL),
basified by Na2CO3, and extracted by CH2Cl2 to give the base
of compound (-)-7 (460 mg, 100%) as white crystals: mp 39-
40 °C; [R]D -87.1° (c ) 1, EtOH); 100% ee, estimated by HPLC
analysis with a Chiracel OD column.26 Anal. (C20H24N2O) C,
H, N.
(+)-(3a R)-8-Ben zyl-1,3a -d im eth yl-1,2,3,3a ,8,8a -h exa h y-
d r o-5-m eth oxyp yr r olo[2,3-b]in d ole [(+)-7]. Ditoluyl-L-tar-
trate (1.04 g) of compound (+)-7 was dissolved in H2O (40 mL),
basified by Na2CO3, and extracted by CH2Cl2 to give the base
of compound (+)-7 (455 mg, 98%) as white crystals: mp 39-
40 °C; [R]D +87.0° (c ) 1, EtOH); 99% ee, estimated by HPLC
analysis on a Chiracel OD column.26 Anal. (C20H24N2O) C,
H, N.
(-)-(3a S)-8-Ben zyl-1,3a -d im eth yl-1,2,3,3a ,8,8a -h exa h y-
d r op yr r olo[2,3-b]in d ol-5-ol [(-)-8]. Compound (-)-7 (460
mg, 1.49 mmol) was dissolved in CHCl3 (10 mL), and BBr3
(99.9%) (0.5 mL) was added dropwise for 5 min with stirring.
The mixture was stirred at room temperature for 4 h, and
MeOH (10 mL) was added slowly. After removal of solvent
under vacuo, the residue was dissolved in H2O (20 mL),
basified with NaHCO3, and extracted with ether (3 × 20 mL).
After evaporation of solvent the residue was flash chromato-
graphed (CH2Cl2/MeOH ) 20:1) to give (-)-8 (420 mg, 95.5%)
as a light pink foam: [R]D -102.7° (c ) 0.95, EtOH); 1H NMR
(CDCl3) δ 7.33-7.23 (m, 5H, benzyl-Ar-H), 6.67 (d, J ) 2.6
Hz, 1H, C4-H), 6.57 (dd, J ) 2.6, 8.4 Hz, 1H, C6-H), 6.23 (d,
J ) 8.4 Hz, 1H), 5.12 (bs, 1H, NH), 4.51 and 4.36 (AB, J )
16.6 Hz, 2H, Ph-CH2), 4.27 (s, C8a-H), 2.73-2.46 (m, 2H, C2-
H2), 2.43 (s, 3H, N1-CH3), 2.03-1.73 (m, 2H, C2-H2), 1.43 (s,
3H, C3a-CH3); CI-MS (NH3) m/z 295 (MH+). Anal. (C19H22N2O)
C, H, N.
(+)-(3a R)-8-Ben zyl-1,3a -d im eth yl-1,2,3,3a ,8,8a -h exa h y-
d r op yr r olo[2,3-b]in d ol-5-ol [(+)-8]. According to the pro-
cedure for making compound (-)-8, from compound (+)-7 (392
mg, 1.27 mmol), 340 mg (91.1%) of compound (+)-8 was
obtained as a gum: [R]D +102.1° (c ) 0.2, EtOH); 1H NMR
and MS were identical with that of compound (-)-8. Anal.
(C19H22N2O‚1/6H2O) C, H, N.
(-)-(3a S)-8-Ben zyl-1,3a -d im eth yl-1,2,3,3a ,8,8a -h exa h y-
d r op yr r olo[2,3-b]in d ol-5-yl N-Meth ylca r ba m a te [(-)-9].
Compound (-)-8 (145 mg, 0.49 mmol) was dissolved in ether
(10 mL), and Na (1 mg) was added. The mixture was stirred
at room temperature for 1 min; then methyl isocyanate (28.1
mg, 0.49 mmol) was added. The mixture was stirred at room
temperature for 10 min. After the removal of solvent, the
residue was chromatographed (CH2Cl2/MeOH ) 20/1) to give
(-)-9 (127 mg, 70.8%) as white crystals: mp 79-81 °C; [R]D
-86.3° (c ) 0.7, EtOH); 1H NMR (CDCl3) δ 7.37-7.26 (m, 5H,
benzyl-Ar-H), 6.82 (d, J ) 2.2 Hz, 1H, C4-H), 6.74 (dd, J )
2.2, 8.5 Hz, 1H, C6-H), 6.24 (d, J ) 8.5 Hz, 1H, C7-H), 4.90 (d,
J ) 3.9 Hz, 1H), 4.55 and 4.41 (AB, J ) 16.6 Hz, 2H, Ph-CH2),
4.36 (s, 1H, C8a-H), 2.94 (d, J ) 3.9 Hz, 3H, NH-CH3), 2.80-
2.75 (m, 2H, C1-H2), 2.45 (s, 3H, N1-CH3), 2.05-2.00 (m, 2H,
C2-H2), 1.44 (s, 3H, C3a-CH3); CI-MS (NH3) m/z 352 (MH+).
Anal. (C21H25N3O2) C, H, N.
1
113 °C; H NMR (CDCl3) δ 7.34-7.16 (m, 5H, benzyl-Ar-H),
6.68-6.56 (m, 3H, Ar-H), 5.33 (bs, 1H, NH), 4.90 (s, 2H, Ph-
CH2), 5.33 (broad, NH), 3.75 (s, 3H, O-CH3), 3.68 (s, 3H,
O-CH3), 3.55 (m, 1H, C3-H), 3.45 (m, 2H, C2’-H2), 2.15 (m, 2H,
C1’-H2); CI-MS (NH3) m/z 355 (MH+). Anal. (C20H22N2O4) C,
H, N.
1-Ben zyl-1,3-d ih yd r o-5-m eth oxy-3-m eth yl-3-[2′-[(m eth -
oxyca r bon yl)a m in o]eth yl]-2H-in d ol-2-on e (5). Compound
4 (10.2 g, 28.7 mmol) was dissolved in CH2Cl2 (230 mL), and
20% NaOH (115 mL), benzyltrimethylammonium bromide
(BTMAB) (1.15 g, 5.75 mmol), and MeI (8.1 g, 56 mmol) were
added. The mixture was stirred vigorously at room temper-
ature under N2 for 2 h; then H2O (300 mL) was added. The
mixture was extracted with CH2Cl2 (3 × 300 mL). The
combined CH2Cl2 layers were dried over Na2SO4. After the
removal of solvent in vacuo, the residue was chromatographed
(CH2Cl2/MeOH ) 20/1) to give 5 (10.0 g, 94.9%) as a foam: 1H
NMR (CDCl3) δ 7.34-7.16 (m, 5H, benzyl-Ar-H), 6.81 (d, J )
2.5 Hz, 1H, C4-H), 6.67 (dd, J ) 2.5, 8.8 Hz, 1H, C5-H), 6.62
(d, J ) 8.3 Hz, 1H, C7-H), 4.93 and 4.84 (AB, J ) 15.6 Hz,
2H, Ph-CH2), 4.75 (bs, 1H, NH), 3.76 (s, 3H, O-CH3), 3.59 (s,
3H, O-CH3), 3.10-2.80 (m, 2H, C2’-H2), 2.30-1.90 (m, 2H, C1’-
H2), 1.42 (s, 3H, C3-CH3); CI-MS (NH3) m/z 369 (MH+). Anal.
(C21H24N2O4) C, H, N.
8-Ben zyl-1,3a-dim eth yl-1,2,3,3a,8,8a-h exah ydr o-5-m eth -
oxyp yr r olo[2,3-b]in d ole (6). Compound 5 (9.0 g, 24.42
mmol) was dissolved in dry benzene (120 mL), and 17.12 g
(60%) (50 mmol) of Red-Al was added at 0 °C. The mixture
was stirried at room temperature for 5 h; then the reaction
mixture was cooled again in an ice bath, and H2SO4 (10%) (120
mL) was added. After stirring for a while, the organic layer
was separated. The aqueous solution was basified with Na2-
CO3, extracted by CH2Cl2 (3 × 200 mL), dried over Na2SO4,
and evaporated under reduced presssure. The residue was
flash chromatographed (CH2Cl2/MeOH ) 20/1) to give 6 (5.66
g, 75.3%) as white crystals: mp 79-80 °C; 1H NMR (CDCl3) δ
7.33-7.23 (m, 5H, benzyl-Ar-H), 6.67 (d, J ) 2.6 Hz, 1H, C4-
H), 6.57 (dd, J ) 2.6, 8.4 Hz, 1H, C6-H), 6.23 (d, J ) 8.4 Hz,
1H, C7-H), 4.51 and 4.36 (AB, J ) 16.6 Hz, 2H, Ph-CH2), 4.27
(s, 1H, C8a-H), 3.75 (s, 3H, O-CH3), 2.73-2.46 (m, 2H, C2-
H2), 2.43 (s, 3H, N-CH3), 2.03-1.73 (m, 2H, C3-H2), 1.43 (s,
3H, C3a-CH3); CI-MS (NH3) m/z 309 (MH+). Anal. (C20H24N2O)
C, H, N.
R esolu t ion of 8-Ben zyl-1,3a -d im et h yl-1,2,3,3a ,8,8a -
h exa h yd r o-5-m eth oxyp yr r olo[2,3-b]in d ole (6). Compound
6 (3.84 g, 0.0124 mol) was dissolved in THF (12 mL), and
dibenzoyl-D-tartaric acid (5.37 g, 0.015 mol) was dissolved in
THF (12 mL) also. The two solutions were mixed together,
and crystallization gradually occurred. After filtration, 5.34
g of the crystalline salt of dibenzoyl-D-tartrate was obtained.
The salt was dissolved in THF (50 mL) and left overnight to
yield 2.68 g (32.5%) of dibenzoyl-D-tartrate of (-)-(3aS)-8-
benzyl-1,3a-dimethyl-1,2,3,3a,8,8a-hexahydro-5-methoxypyr-
rolo[2,3-b]indole [(-)-7] as white crystals: mp 126-127 °C;
(-)-(3a S)-8-Ben zyl-1,3a -d im eth yl-1,2,3,3a ,8,8a -h exa h y-
d r op yr r olo[2,3-b]in d ol-5-yl N-P h en ylca r ba m a te [(-)-10].
Compound (-)-8 (215 mg, 0.73 mmol) was dissolved in ether
(10 mL), and Na metal (1 mg) was added. The mixture was
stirred at room temperature for 1 min; then phenyl isocyanate
[R]20 -5.26° (c ) 0.5, EtOH). Anal. (C38H38N2O9) C, H, N.
D
Combined mother liquor was evaporated in vacuo; the
residue was dissolved in H2O (40 mL), basified with Na2CO3,