Carbocyclic galanthamine analogs: Incorporating the phenethylamine motif

Article abstract of DOI:10.1002/jhet.5570390609

An unnatural analog of the anti-Alzheimer drug galanthamine bearing a phenethylamine moiety has been prepared as a racemic mixture using K₃[Fe(CN)₆] induced tandem cyclization techniques in the key step to form derivatives of a novel

Full text of DOI:10.1002/jhet.5570390609

Nov-Dec 2002
Carbocyclic Galanthamine Analogs: Incorporating
the Phenethylamine Motif
1167
a
b
a
Matthias Treu, Kurt Mereiter, Christian Hametner,
a
a
Johannes Fröhlich, and Ulrich Jordis*
a
Institute of Applied Synthetic Chemistry, Vienna University of Technology
Getreidemarkt 9, A-1060 Vienna, Austria
ujordis@pop.tuwien.ac.at
b
Institute of Chemical Technologies and Analytics, Vienna University of Technology, Getreidemarkt 9, A-
1060 Vienna, Austria
Received January 21, 2002
An unnatural analog of the anti-Alzheimer drug galanthamine bearing a phenethylamine moiety has been
prepared as a racemic mixture using K3[Fe(CN)6] induced tandem cyclization techniques in the key step to
form derivatives of a novel heterocyclic ring system.
J. Heterocyclic Chem., 39, 1167(2002).
Introduction.
sium carbonate to give the substituted malonic ester 4 in
82% yield. 4-Isopropyloxystyrene was detected as a minor
side product. Reacting 1-bromo-2-chloromethyl-5-
methoxy-4-(1-methylethoxy)benzene (5), available from
bromo-isovanilline in 3 steps [5], with 4 under the same
conditions gave 6 in 95% yield after purification by
Kugelrohr distillation. Ester cleavage and decarboxylation
under reduced pressure gave rise to the carboxylic acid (7),
which was obtained as colorless solid in 95% yield. The
conversion of 7 into the amide (8) was performed by suc-
cessive treatment with thionyl chloride in dry
dichloromethane and ammonia in dry formamide and gave
8 in 92% yield. Isopropyl ether cleavage of 8 using boron
trichloride in dry dichloromethane afforded the diphenol
(9) in 88% yield, which was then subjected to a
Phenethylamine is known to be the essential pharma-
cophore of a large number of CNS-active compounds. The
array of these drugs starts with amphetamine and related
designer drugs (e.g. ecstasy or 2C-B) and ends with com-
plex natural products like morphine, physostigmine or
lysergic acid diethyl amide (LSD). The first attempts to
incorporate the phenethylamine substructure into the core
of the anti-Alzheimer drug galanthamine [1,2] led to the
synthesis of (4aa ,6b,8aR*)-4a,5,9,10,11,12-hexahydro-3-
methoxy-10-methyl-6H-benzofuro[3a,3,2-ef][3]ben-
zazepine-6-ol (1), termed "isogalanthamine" [3]. The iso-
meric compound (2) was expected to show promising bio-
logical properties, and the tetracyclic ring system should
be accessible utilizing tandem cyclization by phenol oxi-
dation [3-7]. (see Table 1).
K [Fe(CN) ] induced tandem cyclization. After chromato-
3
6
graphic purification (4aR*,8aR*)-1-bromo-4a,5,9,10,
11,12-hexahydro-3-methoxy-6-oxo-6H-benzo[a]cyclo-
hepta[hi]benzofuran-11-carboxamide (10) was isolated as
a mixture of diastereomeric amides with a total yield of
19% and was used directly in the next reaction steps (see
Scheme 1).
Results and Discussion.
For the synthesis of the norbelladine analog (9) 1-(2-
bromoethyl)-4-(1-methylethoxy)benzene (3), which was
prepared starting from 4-hydroxyacetophenone [5], was
reacted with dimethyl malonate in the presence of potas-
Table 1: The Phenethylamine Motif

1168
M. Treu, K. Mereiter, C. Hametner, J. Fröhlich, and U. Jordis
Vol. 39
The cyclization product (10) was converted into the cor-
responding allyl alcohol (11) using L-Selectride in dry
phenyliodisyl bis(trifluoroacetate) (PIFA) [8,9] in acetoni-
trile/water as the selective oxidant led to the desired amine
(12) in 75% yield without formation of major byproducts.
After debromination using a freshly prepared copper-zinc-
couple [10] the diastereomeric galanthamine analogs 2a
and 2b were separated by medium pressure liquid chro-
matography (MPLC) (see Scheme 2) and were both
obtained as colorless solids.
®
tetrahydrofuran as the stereoselective reducing agent with
86% yield as a diastereomeric mixture (relative R- and S-
configuration at C-11) as confirmed by the corresponding
signals in NMR. Due to the presence of the cyclohexene
ring the degradation of the amide (11) required very mild
reaction conditions to avoid epoxide formation. Applying
Scheme 1
Scheme 2
Figure 1. Molecular structure of 11 (crystallographic atom numbering), the diastereomer with the lower R (20% ellipsoids). For crystallography see
f
experimental section.

Nov-Dec 2002
Carbocyclic Galanthamine Analogs:Incorporating the Phenethylamine Motif
1169
tioned between water (250 mL) and Et2O (250 mL). The aqueous
layer was extracted with Et2O (1 x 100 mL), the combined
organic layer was washed with water (3 x 200 mL) and brine (1 x
150 mL), dried over Na2SO4, filtered and concentrated in vacuo.
The excess of dimethylmalonate was removed by distillation
(160 °C/15 mbar), and the crude product was purified by
Kugelrohr distillation (140 °C/0.001 mbar). Yield: colorless oil
(18.9 g, 82%). TLC: petroleum ether:EtOAc = (90:10), Rf = 0.4.
1H NMR (CDCl3): d 7.08 (d, J = 10.0 Hz, 2H), 6.81 (d, J = 10.0
Hz, 2H), 4.50 (septet, J = 6.5 Hz, 1H), 3.71 (s, 6H), 3.32 (t, J =
7.5 Hz, 1H), 2.58 (t, J = 7.5 Hz, 2H), 2.19 (q, J = 7.5 Hz, 2H),
1.31 (d, J = 6.5 Hz, 6H); 13C NMR (CDCl3): d 169.8 (s), 156.3
(s), 132.3 (s), 129.4 (d), 115.9 (d), 69.9 (d), 52.5 (q), 50.8 (d),
32.4 (t), 30.6 (t), 22.1 (q).
For structural investigations the diastereomer with the
lower R of an analytical sample of 11 was isolated by
f
MPLC and crystallized from ethanol. X-ray diffraction
confirmed the relative R-configuration at C11 for this com-
pound. (see Figure 1).
Conclusion.
In summary, we have demonstrated that tandem cycliza-
tion by phenol oxidation can be successfully applied to
access new members of the galanthamine family.
Specifically we have prepared derivatives of the novel 6H-
benzo[a]cyclohepta[hi]benzofuran ring system. The bio-
logical data of these compounds should allow conclusions
on the binding mechanisms of galanthamine itself as well
as valuable insights into structure-activity-relationships
and will be published elsewhere.
2-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenylmethyl]-2-
[2-[4-(1-methylethoxy)-phenyl]ethyl]propanediacid Dimethyl
Ester (6).
Compound 4 (18.9 g, 64.2 mmol), 1-bromo-2-chloromethyl-5-
methoxy-4-(1-methylethoxy)benzene (5) [5] (18.9 g, 64.2 mmol)
and potassium carbonate (45.0 g, 321 mmol, anhydrous, freshly
ground) in dry DMF (300 mL) were stirred for 12 hours at 60 °C.
The suspension was filtered and concentrated, and the residue
was partitioned between water (250 mL) and Et2O (250 mL). The
aqueous layer was extracted with Et2O (1 x 100 mL), the com-
bined organic layer was washed with water (3 x 200 mL) and
brine (1 x 150 mL), dried over Na2SO4, filtered and concentrated
in vacuo. The crude product was purified by Kugelrohr distilla-
tion (160 °C/0.005 mbar). Yield: colorless oil (33.7 g, 95%).
TLC: petroleum ether: EtOAc = 90 : 10, Rf = 0.5; 1H NMR
(CDCl3): d 7.04 (s, 1H), 7.01 (d, J = 10.0 Hz, 2H), 6.79 (d, J =
10.0 Hz, 2H), 6.73 (s, 1H), 4.47 (septet, J = 6.5 Hz, 1H), 4.36
(septet, J = 6.5 Hz, 1H), 3.80 (s, 3H), 3.72 (s, 6H), 3.48 (s, 2H),
2.65 - 2.47 (m, 2H), 2.26 - 2.06 (m, 2H), 1.31 (d, J = 6.5 Hz,
12H); 13C NMR (CDCl3): d 171.4 (s), 156.1 (s), 149.8 (s), 146.2
(s), 133.0 (s), 129.3 (s), 129.1 (d), 118.2 (s), 116.2 (d), 116.0 (d),
115.8 (d), 71.6 (d), 69.7 (d), 58.7 (s), 55.9 (q), 52.3 (q), 37.4 (t),
34.5 (t), 29.9 (t), 22.0 (q), 21.9 (q).
EXPERIMENTAL
General.
Melting points were determined on a Kofler melting point
apparatus. H and 13C NMR-spectra were recorded on a Bruker
AC-200 (200 MHz) pulse Fourier-transform NMR spectrometer
in CDCl3 or DMSO-d6 using tetramethylsilane as an internal
standard. Thin layer chromatography (TLC) was performed on
1
precoated plates (Merck TLC aluminum sheets silica 60 F254
)
with detection by UV light or with phosphomolybdic acid in
aqueous EtOH by heating. All reactions were magnetically
stirred under an argon atmosphere. MPLC (medium pressure liq-
uid chromatography) was performed using SiO2 (Baker), a LC-
8A pump (Shimadzu), a SPD-6AV UV-detector (Shimadzu) and
Büchi glass columns. All the HPLC-MS data were obtained using
a HP1100 liquid chromatography system equipped with a diode
array detector (Hewlett-Packard) and a 1100 Series MSD with
Atmospheric Pressure Chemical Ionization Interface (APCI) in
positive and negative ion mode, scanning m/z 200 - 550. Column:
Merck Purospher RP18e, 5 µm, solvent A: MeCN:H2O (97:2),
solvent B: 20 mM CCl3COOH:MeCN (97:3), flow rate: 0.5
mL/min, injection volume: 1 µL. Gradient: see Table 2.
Anal. Calcd for C27H35BrO7: C, 58.81; H, 6.40. Found: C,
59.00; H, 6.26.
2-(2-Bromo-5-isoproxy-4-methoxybenzyl)-4-(4-isopropoxy-
phenyl)butyric Acid (7).
Compound 6 (33.7 g, 61.1 mmol) and KOH (17.5 g, 312
mmol) were stirred in EtOH (150 mL)/water (30 mL) under
reflux for 12 hours. The solution was concentrated to 30 mL in
vacuo, the pH was adjusted to less than 1 by the dropwise addi-
tion of concentrated HCl, and the mixture was partitioned
between water (250 mL) and Et2O (250 mL). The aqueous layer
was extracted with Et2O (2 x 100 mL), the combined organic
layer was washed with water (3 x 200 mL) and brine (1 x 150
mL), dried over Na2SO4, filtered and concentrated in vacuo. The
residue was decarboxylated using a Kugelrohr apparatus (30
minutes, 140 °C/0.005 mbar), and the formed carboxylic acid
was purified by subsequent distillation (150 °C/0.005 mbar).
Yield: colorless crystals (27.5 g, 94%); mp. 114 - 116 °C. TLC:
CHCl3:MeOH = 90:10, Rf =0.65; 1H NMR (DMSO-d6): d 7.09,
(s, 1H), 7.01 (d, J = 7.3 Hz, 2H), 6.80 (s, 1H), 6.78 (d, J = 7.3 Hz,
2H), 4.69 - 4.37 (m, 2H), 3.72 (s, 3H), 3.00 - 2.33 (m, 5H), 1.99 -
1.58 (m, 2H), 1.18 (d, J = 6.4 Hz, 12H); 13C NMR (DMSO-d6): d
176.0 (s), 155.6 (s), 149.3 (s), 145.8 (s), 133.1 (s), 130.3 (s),
Table 2. HPLC-gradient
Time
%A
%B
20.0
20.0
60.0
60.0
20.0
80.0
80.0
40.0
40.0
80.0
5.00
17.00
22.00
22.50
2-[2-[4-(1-Methylethoxy)phenyl]ethyl]propanedioic Acid
Dimethyl Ester (4).
1-(2-Bromoethyl)-4-(1-methylethoxy)benzene (3) [5] (19.0 g,
78.1 mmol), dimethyl malonate (40.0 g, 300 mmol) and potas-
sium carbonate (42.0 g, 300 mmol, anhydrous, freshly ground) in
dry DMF (400 mL) were stirred for 10 hours at 70 °C. The sus-
pension was filtered and concentrated, and the residue was parti-

1170
M. Treu, K. Mereiter, C. Hametner, J. Fröhlich, and U. Jordis
Vol. 39
129.1 (d), 118.1 (d), 116.0 (d), 115.5 (s), 114.1 (d), 70.6 (d), 69.0
(d), 55.8 (q), 44.9 (d), 33.5 (t), 31.9 (t), 21.9 (q), 21.8 (q).
Anal. Calcd for C24H31BrO5: C, 60.13; H, 6.52. Found: C,
60.38; H, 6.55.
1H), 3.23 (dd, J = 16.2 Hz, J = 3.0 Hz, 1H), 3.08 - 2.89 (m, 1H),
2.77 (dd, J = 16.2 Hz, J = 6.0 Hz, 1H), 2.62 - 1.70 (m, 5H); 13C
NMR (DMSO-d6): d 202.5 (s), 184.9 and 179.1 (s), 146.5 and
146.1 (d), 145.0 and 145.9 (s), 143.3 and 142.0 (s), 132.0 and
131.8 (s), 128.9 and 128.0 (s), 126.7 and 126.2 (d), 116.3 and
115.0 (s), 114.4 (d), 87.4 and 87.3 (d), 56.0 (q), 49.5 and 49.3 (s),
45.3 (d), 37.3 and 37.0 (t), 35.4 (t), 34.4 (t), 30.4 (t).
2-(2-Bromo-5-isoproxy-4-methoxybenzyl)-4-(4-isopropoxy-
phenyl)butyramide (8).
To 7 (10.0 g, 20.8 mmol) in dry CH2Cl2 (100 mL) thionyl
chloride (50 mL) was added within 15 minutes at 0 °C and stirred
for 2 hours at this temperature. The mixture was concentrated in
vacuo, and the residue was dissolved in dry formamide (15 mL),
treated with a saturated solution of NH3 in dry formamide (100
mL) at 0 °C and stirred for 1 hour at the same temperature. The
solution was poured into water (1500 mL), and the precipitate
was collected by filtration and triturated with water (4 x 400 mL).
Yield: colorless crystals (9.21 g, 92%); mp. 154 - 156 °C. TLC:
CHCl3: MeOH = 90:10, Rf = 0.7; 1H NMR (DMSO-d6): d 7.32
(s, 1H), 7.08, (s, 1H), 7.02 (d, J = 7.3 Hz, 2H), 6.83 (s, 1H), 6.80
(s, 1H), 6.78 (d, J = 7.3 Hz, 2H), 4.68 - 4.32 (m, 2H), 3.77 (s,
3H), 3.39 (s, 3H), 3.00 - 2.62 (m, 2H), 2.00 - 1.58 (m, 2H), 1.18
(d, J = 6.4 Hz, 12H); 13C NMR (DMSO-d6): d 175.8 (s), 155.5
(s), 149.1 (s), 145.8 (s), 133.5 (s), 130.9 (s), 129.9 (d), 118.1 (d),
115.8 (d), 115.5 (s), 114.1 (d), 70.9 (d), 69.0 (d), 55.8 (q), 45.9
(d), 34.2 (t), 32.1 (t), 21.9 (q), 21.8 (q).
Anal. Calcd for C18H18BrNO4: C, 55.12; H, 4.63; N, 3.57.
Found: C, 54.91; H, 4.66; N, 3.41.
(4a ,6 ,8aR*)-1-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-
6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-11-carbox-
amide (11).
To a suspension of 10 (860 mg, 2.19 mmol) in dry THF (5 mL)
L-Selectride® (6.6 mL, 6.6 mmol, 1 M in THF) was added drop-
wise at - 5 °C within 15 minutes and stirred for 4 hours at room
temperature. The mixture was hydrolyzed with water (3 mL) and
concentrated in vacuo. The residue was partitioned between
EtOAc (30 mL) and 2 N HCl (20 mL). The aqueous layer was
extracted with EtOAc (3 x 5 mL), the combined organic layer was
washed with 2 N HCl (2 x 25 mL), water (1 x 25 mL), saturated
NaHCO3 (1 x 25 mL) and brine (1 x 25 mL), dried over Na2SO4,
filtered and concentrated in vacuo. The crude product was purified
by flash chromatography (50 g SiO2, EtOAc). Yield: colorless
solid (741 mg, 86%). TLC: CHCl :MeOH = 90:10, Rf = 0.35 and
Anal. Calcd for C24H32BrNO4: C, 60.25; H, 6.74; N, 2.93.
Found: C, 59.99; H, 6.56; N, 2.82.
3
0.45;1H NMR (CDCl3): d 6.92 (s, 1H), 6.10 - 5.89 (m, 2H), 5.82 -
5.53 (m, 2H), 4.54 (s, 1H), 4.13 (s, 1H), 3.81 (s, 3H), 3.51 (d, J =
15.4 Hz, 1H), 3.05 (dd, J = 17.0 Hz, J = 6.5 Hz, 1H), 2.96 - 2.84
(m, 1H), 2.65 (d, J = 16.2 Hz, 1H), 2.83 (dd, J = 16.2 Hz, J = 6.5
Hz, 1H), 2.44 - 1.40 (m, 9H); 13C NMR (CDCl3): d 177.7 and
175.2 (s), 145.3 (s), 145.7 (s), 144.2 and 143.9 (s), 133.8 and 134.2
(s), 128.3 and 128.2 (d), 126.5 (d), 116.1 and 115.9 (s), 115.3 and
115.1 (d), 88.5 (d), 61.8 (d), 56.1 (q), 49.1 and 49.0 (s), 46.0 (d),
41.9 (t), 35.9 and 35.7 (t), 29.8 and 29.6 (t), 28.8 and 26.2 (t).
Anal. Calcd for C18H20BrNO4: C, 54.84; H, 5.11; N, 3.55.
Found: C, 54.84; H, 5.18; N, 3.43.
a -(2-Bromo-5-hydroxy-4-methoxyphenylmethyl)-4-hydroxy-
benzenebutaneamide (9).
To 8 (9.30 g, 19.4 mmol) in dry CH2Cl2 (150 mL) BCl3 (40
mL, 1.6 M in CH2Cl2) was added at -78 °C and stirred for 1 hour.
The solution was allowed to warm up to ambient temperature and
stirred for an additional 2 hours. Water (300 mL) was added drop-
wise, and the mixture was concentrated to 300 mL in vacuo. The
formed precipitate was collected by filtration and triturated with
water (6 x 200 mL) and iPr2O (2 x 40 mL). Yield: colorless crys-
tals (6.76 g, 88%); mp. 177 - 179 °C. TLC: CHCl3:MeOH =
X-Ray Analysis.
1
90:10, Rf = 0.4; H NMR (DMSO-d6): d 9.18 (s, 2H), 7.18 (s,
1H), 7.04, (s, 1H), 6.97 (d, J = 7.3 Hz, 2H), 6.72 (s, 1H), 6.65 (s,
1H), 6.66 (d, J = 7.3 Hz, 2H), 3.77 (s, 3H), 3.48 (s, 3H), 2.92 -
2.38 (m, 4H); 13C NMR (DMSO-d6): d 175.6 (s), 155.5 (s), 147.0
(s), 145.8 (s), 131.3 (s), 129.9 (s), 129.8 (d), 117.9 (s), 115.8 (d),
115.0 (d), 111.9 (d), 56.0 (q), 48.1 (d), 37.6 (t), 37.0 (t).
Anal. Calcd for C18H20NO4: C, 54.84; H, 5.11; N, 3.55.
Found: C, 54.55; H, 4.90; N, 3.28.
For X-ray analysis the diastereomer ((4a ,6 ,8a ,11R*)-1-
bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-
benzo[a]cyclohepta[hi]benzofuran-11-carboxamide) with the
lower Rf was isolated by MPLC and crystallized from EtOH.
Crystal Data.
C18H20BrNO4, Mr = 394.26, monoclinic, space group P21/c
(no. 14), a = 10.417(4) Å, b = 14.375(5) Å, c = 11.722(4) Å,
=
(4aR*,8aR*)-1-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-
oxo-6H-benzo[a]cyclohepta[hi]-benzofuran-11-carboxamide
(10).
107.57(1)°, V = 1673.4(10) Å3, Z = 4, Dx = 1.565 Mg/m-3, (Mo-
Ka ) = 0.71073 Å, = 2.48 mm-1, T = 297(2) K. X-ray data col-
lection with a Bruker SMART CCD area detector diffractometer
and graphite monochromatized Mo Ka radiation. 24015 reflec-
tions with q < 30.0° were measured, corrected for LP and absorp-
tion, and merged to 4813 unique reflections, Rint = 0.034.
Structure solved with direct methods, structure refinement on F2
using program SHELXL97 [11]. All non-hydrogen atoms were
refined anisotropically. Hydrogen atoms had isotropic tempera-
ture factors and rided on the atoms to which they were bonded
(exception: hydroxyl hydrogen H(3o), which was refined without
To a suspension of 9 (3.00 g, 7.61 mmol) in CHCl3 (300 mL)
K3[Fe(CN)6] (13.2 g, 40.0 mmol) and K2CO3 (7.50 g, 54 mmol)
in water (75 mL) were added at once and stirred vigorously using
a mechanical stirrer for 45 minutes at ambient temperature. The
mixture was filtered using diatomaceous earth, and the filtrate was
washed with water (3 x 100 mL) and brine (100 mL), dried over
Na2SO4, filtered and concentrated in vacuo. The crude product
was purified by flash chromatography (50 g SiO2, EtOAc). Yield:
colorless crystals (0.576 g, 19.2%); mp. 231 - 235 °C (dec.). TLC:
CHCl3:MeOH = 90:10, Rf =0.4 and 0.5; 1H NMR (CDCl3): d 7.00
(s, 1H); 6.86 (dd, J = 12.3 Hz, J = 1.0Hz, 1H), 6.06 (d, J = 1.0 Hz,
1H), 5.02 (bs, 2H), 4.70 (s, 1H), 3.82 (s, 3H), 3.62 (d, J = 16.2 Hz,
restraints). The final refinement varied 223 parameters and con-
2
verged at R1 = S||Fo|-|Fc||/S|Fo| = 0.050, wR2 = [S(w(Fo
-
2 2
2 2
Fc ) )/S(w(Fo ) )]? = 0.091, and S = 1.05 for the 4813 unique
reflections; R1 = 0.034 for the 3664 observed data [I>2 (I)] [12].

Nov-Dec 2002
Carbocyclic Galanthamine Analogs:Incorporating the Phenethylamine Motif
1171
The molecular structure of 11 in crystalline state is shown in
Figure 1. The tetracyclic core corresponds in bond lengths, bond
angles, and conformation well with galanthamine and derivatives
thereof, except for small bond geometry differences at C7A
which in the galanthamine family is a nitrogen atom [13].
Different from the galanthamine family where the N-bonded
methyl group or related substituents prefer the axial orientation
relative to the 7-membered ring (e.g. references [13b,13d])
although they are free to adopt also the equatorial orientation, the
axial orientation of the CONH2 group in 11 is stereochemically
fixed. Bond distances are (Å; all e.s.d.’s 0.002-0.003 Å): Br-C5
1.903, O1-C2 1.373, O1-C15 1.471, O2-C3 1.363, O2-C16
1.429, O3-C13 1.446, O4-C17 1.228, N-C17 1.337, C1-C2
1.384, C1-C6 1.401, C1-C10 1.523, C2-C3 1.392, C3-C4 1.383,
C4-C5 1.398, C5-C6 1.396, C6-C7 1.511, C7-C7A 1.531, C7A-
C8 1.538, C7A-C17 1.536, C8-C9 1.531, C9-C10 1.536, C10-
C11 1.510, C10-C15 1.550, C11-C12 1.318, C12-C13 1.501,
C13-C14 1.508, C14-C15 1.511. Hydrogen bonds: O3ÆO1
2.945 (intramolecular and distinctly bent), NÆO3 3.094 (inter-
molecular), NÆO4 2.989 (intermolecular).
4.14 (s, 1H), 3.82 (s, 3H), 3.57 (s, 1H), 3.22 (d,J = 16.2 Hz, 1H),
2.83 (dd, J = 16.2 Hz, J = 6.5 Hz, 1H), 2.24 - 1.60 (m, 9H); 13
C
NMR (CDCl3): d 146.2 (s), 144.3 (s), 133.6 (s), 128.4 (s), 128.1
(d), 127.2 (d), 124.8 (d), 111.9 (d), 89.0 (d), 62.6 (d), 56.3 (q)
49.0 (s), 48.3 (d, C-11), 41.8 (t, C-9), 32.5 (t, C-12), 30.4 (t,
C-10), 30.4 (t). HPLC/MS m/z (relative intensity): PI: 289.0
(11%), 288.0 (59%), 271.0 (29%), 269.9 (100%), 252.9 (10%).
(4a ,6 ,8a ,11R*)-11-Amino-4a,5,9,10,11,12-hexahydro-3-
methoxy-6H-benzo[a]cyclohepta[hi]benzofuran-6-ol (2b).
Compound 2b was obtained as colorless foam, yield 26 mg; 1H
NMR (CDCl3): d 6.70 - 6.58 (m, 2H), 6.07 - 5.91 (m, 2H), 4.54 (s,
1H), 4.12 (s, 1H), 3.82 (s, 3H), 2.99 (s, 1H), 2.86 (t, J = 15.0 Hz,
1H), 2.72 (d, J = 16.0 Hz, 1H), 2.63 (dd, J = 16.0 Hz, J = 3.3 Hz,
1H), 2.30 - 1.60 (m, 9H); 13C NMR (CDCl3): d 146.4 (s), 143.9 (s),
133.7 (s), 128.5 (s), 128.1 (d), 127.5 (d), 123.3 (d), 111.7 (d), 88.9
(d), 62.4 (d), 56.3 (q), 52.8 (d, C-11), 48.3 (s), 45.1 (t, C-9), 35.8 (t,
C-12), 35.6 (t, C-10), 30.4 (t). HPLC/MS m/z (relative intensity):
PI: 287.0 (5%), 272.0 (7%), 271.0 (46%), 270.0 (100%).
The total combined yield of compounds 2a and 2b, as colorless
foam, was 36 mg (59%).
(4a ,6 ,8aR*)-11-Amino-1-bromo-4a,5,9,10,11,12-hexahydro-3-
methoxy-6H-benzo[a]cyclohepta[hi]benzofuran-6-ol (12).
Acknowledgements.
To bis(trifluoracetoxy)iodobenzene (PIFA, 787 mg, 1.78
mmol) in MeCN (3.5 mL, HPLC grade) water (3.5 mL, HPLC
grade) was added. Compound 11 was added within 3 hours and
stirred at ambient temperature for 24 hours. The reaction solution
was concentrated in vacuo, dissolved in CHCl3 (5 mL), filtered
and purified by flash chromatography (30 g SiO2, CHCl3:
MeOH:conc. NH3 = 96: 3:1). Yield: colorless foam (490 mg,
75%). TLC: CHCl3: MeOH: conc. NH3 = 89:10:1, Rf =0.2 and
The authors wish to thank Sanochemia Pharmazeutika AG for
their financial support and donation of chemicals.
REFERENCES AND NOTES
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1
0.25. H NMR (MeOH-d4): d 7.07 (s, 1H), 6.12 - 5.87 (m, 2H),
5.82 - 5.53 (m, 2H), 4.53 (s, 1H), 4.14 (s, 1H), 3.80 (s, 3H), 3.59
(d, J = 20.0 Hz, 1H), 3.14 - 2.92 (m, 1H), 2.47 (d, J = 17.0 Hz,
1H), 2.16 (s, 3H), 2.01 - 2.62 (m, 2H); 13C NMR (MeOH-d4): d
148.3 and 148.2 (s), 146.5 and 146.1(s), 135.8 (s), 129.9 and
129.3 (s), 128.5 and 127.9 (d), 125.9 and 123.9(d), 118.4 and
118.1 (s), 116.9 and 116.0 (d), 118.4 and 118.0 (s), 116.8 and
116.0 (d), 89.0 and 88.9 (d), 62.4 and 62.3 (d), 57.2 (q), 50.6 and
50.4 (s), 49.8 (d), 38.5 (t), 36.0 and 35.0 (t), 31.8 and 31.0 (t),
31.4 and 28.3 (t). LC-MS: NI: 367.1 (21%), 366.1 (90%), 364.1
(100%), 362.1 (11%), 361.1 (10%), 348.2 (16%), 346.2 (6%); PI:
367.8 (18%), 365.9 (23%), 363.8 (6%), 351.8 (58%), 350.8
(10%), 349.9 (100%), 348.8 (63%), 347.9 (87%).
(4a ,6 ,8aR*)-11-Amino-4a,5,9,10,11,12-hexahydro-3-methoxy-
6H-benzo[a]cyclohepta[hi]benzofuran-6-ol (2).
[10] E. Erdik, Tetrahedron, 43, 2203 (1987).
[11] G. M. Sheldrick, SHELX97. Program system for crystal
structure determination. University of Göttingen, Germany, 1997.
[12] Complete crystallographic data of 11 (excluding structure
factors) have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication no CCDC 172748. Copies
of the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ (fax: +44 1223 336033, email:
deposit@ccdc.cam.ac.uk).
[13a] R. Roques and J. Lapasset, Acta Crystallogr., Sect. B, 32,
579 (1976); [b] P. Carroll, G. T. Furst, S. Y. Han, and M. Joullie, Bull.
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and C. J. De Ranter, Acta Crystallogr., Sect. C (Cr. Str. Comm.), 53,
1284 (1997).
Zinc powder (600 mg) and Cu(I)I (600 mg) in water (4
mL)/EtOH (4 mL) were sonicated for 45 minutes under argon. 12
(80 mg, 0.22 mmol) and CaCl2 (300 mg, 2.7 mmol) were added and
refluxed for 12 hours. Concentrated NH3 (1 mL) was added, and the
mixture was concentrated in vacuo. The residue was dissolved in
CHCl3 (15 mL), filtered and the isomers separated by flash chro-
matography (30 g SiO2, CHCl3:MeOH:conc. NH3 = 96:3:1).
(4a ,6 ,8a ,11R*)-11-Amino-4a,5,9,10,11,12-hexahydro-3-
methoxy-6H-benzo[a]cyclohepta[hi]benzofuran-6-ol (2a).
Compound 2a was obtained as colorless foam, yield 10 mg; 1H
NMR (CDCl3): d 6.73 - 6.62 (m, 2H), 6.05 (s, 2H), 4.62 (s, 1H),