Carbocyclic galanthamin analogs: 4a,5,9,10,11,12-Hexahydro-6H-1283 benzo[b]cyclohepta[cd]benzofurans

Article abstract of DOI:10.1002/jhet.5570390626

The synthesis of a novel unnatural carbocyclic analog of the acetylcholine esterase inhibitor galanthamine with a K₃[Fe(CN)₆] promoted oxidative tandem cyclization as the key step is reported.

Full text of DOI:10.1002/jhet.5570390626

Nov-Dec 2002
Carbocyclic Galanthamin analogs: 4a,5,9,10,11,12-Hexahydro-6H-
benzo[b]cyclohepta[cd]benzofurans
1283
a
b
a
a
Matthias Treu, Kurt Mereiter, Christian Hametner, Johannes Fröhlich,
a
and Ulrich Jordis*
a
Institute of Applied Synthetic Chemistry, Vienna University of Technology
Getreidemarkt 9, A-1060 Vienna, Austria
ujordis@pop.tuwien.ac.at
Institute of Chemical Technologies and Analytics, Vienna University of Technology,
b
Getreidemarkt 9,A-1060 Vienna, Austria
Received April 23, 2002
The synthesis of a novel unnatural carbocyclic analog of the acetylcholine esterase inhibitor galanthamine
with a K3[Fe(CN)6] promoted oxidative tandem cyclization as the key step is reported.
J. Heterocyclic Chem., 39, 1283(2002).
Scheme 1
Introduction.
Galanthamine [1] - a natural product which can be iso-
lated from caucasian snowdrops - is a selective, reversible
acetylcholine esterase inhibitor [2] and is one of the few
drugs approved for the treatment of Alzheimer's disease
[3]. As an acetylcholine esterase (AChE) inhibitor, galan-
thamine was shown to elevate the level of acetylcholine in
the brain. Galanthamine also exerts a second mechanism
of action. This involves an allosteric potentiation of the
nAChR function (APL) via a new class of noncompetitive
cholinergic agonist binding sites [4]. The aim of this work
was to prepare an isomer to galanthamine with the amine
functionality as substituent instead of the benzazepine sub-
structure. The key intermediate 4a,5,9,10,11,12-hexahy-
dro-6H-benzo[b]cyclohepta[cd]benzofuran derivative (10)
should be available by the extension of the tandem cycliza-
tion [1] to the novel precursor 9 and be elaborated into the
target structure 13.
was converted into the alkyl iodide (4) under Appelt con-
ditions with a 79% yield (see Scheme 1).
1-Bromo-2-chloromethyl-5-methoxy-4-(1-methyl-
ethoxy)benzene (5) [6] was converted into the nitrile (6)
using freshly ground KCN in DMSO with a 95% yield. As
attempts to use NaH and NaNH for the deprotonation of 6
2
failed, LDA was used as the base for linking 4 to 6. The
nitrile (7), which was obtained in a yield of 71%, was con-
verted into the amide (8) by treatment with KOH in aque-
ous ethanol with an 84% yield. Cleavage of the isopropyl
protecting group was performed using BCl as lewis acid
3
Results and Discussion.
in dry CH Cl and gave the diphenol (9) in a 99% yield
2
2
For the construction of the key intermediate of 10, 3-(4-
hydroxyphenyl)propionic acid (1) was reacted with iso-
propyl bromide in presence of potassium carbonate to give
the ester (2) [5] in 94% yield, which was subsequently
reduced using lithium aluminum hydride in dry THF. The
resulting alcohol (3), which was obtained in 99% yield,
(see Scheme 2).
Tandem cyclization [7] of 9 by vigorous stirring of a sus-
pension of the starting material in CHCl with an aqueous
3
solution of K [Fe(CN) ] and potassium carbonate afforded
3
6
the 4a,5,9,10,11,12-hexahydro-6H-benzo[b]cyclohepta-
[cd]benzofuran derivative (10) as a mixture of diastereo-
Scheme 2

1284
M. Treu, K. Mereiter, C. Hametner, J. Fröhlich, and U. Jordis
Vol. 39
meric amides (10a and 10b), the isomerization of 10b into
10a after separation of the isomers by MPLC was
observed via TLC and H-NMR spectroscopy.
for a better understanding of binding mechanisms of
galanthamine itself.
1
Conclusion.
Stereoselective reduction of the ketone (10a) gave rise
to the allyl alcohol (11) with a yield of 83%. X-ray analy-
sis of 10a and 11 proved that no inversion at C-12 had
taken place. (see Figures 1 and 2).
The use of phenyliodisyl bis(trifluoroacetate) (PIFA)
[8,9] allowed the transformation of the amide (11) into the
amine (12) with a 58% yield in the presence of the allyl
alcohol substructure. The final debromination by treating
12 with a freshly prepared copper-zinc-couple [10] in the
In summary we have extended the applicability of tan-
dem cyclization by phenol oxidation towards the synthesis
of members of the 4a,5,9,10,11,12-hexahydro-6H-
benzo[b]cyclohepta[cd]benzofuran ring system and have
thus provided access to novel unnatural analogs of the
anti-Alzheimer drug galanthamine.
EXPERIMENTAL
presence of CaCl afforded the unnatural galanthamine
2
analog (13) as a colorless solid with a yield of 78% (see
Scheme 3).
General.
The fact that 13 displayed no noticeable acetylcholine-
(AChE) or butyrylcholine esterase (BuChE) inhibition was
quite surprising. This information is intended to be used
Melting points were determined on a Kofler melting point
1
apparatus. H and 13C NMR-spectra were recorded on a Bruker
AC-200 (200 MHz) pulse Fourier-transform NMR spectrometer
Scheme 3
Figure 1. View of the two independent molecules present in the crystal structure of 10a (20% ellipsoids, crystallographic atom numbering) and a super-
position plot of the two (second molecule shown by broken lines; positional differences: r.m.s. 0.15 Å, O2-O2' 0.35 Å, O3-O3' 0.44 Å).

Nov-Dec 2002
Carbocyclic Galanthamin analogs
1285
reduced pressure. The residue was purified by kugelrohr distilla-
tion (139 - 142 °C/0.025 mbar). Yield: colorless oil (70.8 g, 94%).
TLC: petroleum ether:EtOAc = 9:1, Rf = 0.8; 1H NMR (CDCl3):
d 7.10 (d, J = 9.5 Hz, 2H), 6.81 (d, J = 9.5 Hz, 2H), 4.99 (septet,
J = 6.3 Hz, 1H), 4.48 (septet, J = 6.3 Hz, 1H), 2.87 (t, J = 7.9 Hz,
2H), 2.54 (t, J = 7.9 Hz, 2H), 1.20 (d, J = 6.3 Hz, 6H), 1.31 (d, J=
6.3 Hz, 6H); 13C NMR (CDCl3): d 172.4 (s), 156.2 (s), 132.4 (s),
129.1 (d), 115.8 (d), 69.7 (d), 67.4 (d), 36.4 (t), 30.1 (t), 22.0 (q),
21.7 (q).
Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.84;
H, 8.75.
4-(1-Methylethoxy)benzenepropanol (3).
Compound 2 (10.0 g, 39.9 mmol) in dry THF (100 mL) was
added to a suspension of LiAlH4 (3.04 g, 80 mmol) in dry THF
(100 mL) at 0 °C over 30 minutes and stirred at ambient temper-
ature for 12 hours. Water (30 mL) was added, followed by con-
centrated HCl until the solution became clear. The mixture was
partitioned between water (30 mL) and Et2O (60 mL); the aque-
ous layer was extracted with Et2O (2 x 20 mL), and the combined
organic layer was washed with 2 N HCl (3 x 100 mL), water (1 x
100 mL), saturated NaHCO3 (2 x 100 mL) and brine (1 x 100
mL), dried over Na2SO4, filtered and concentrated under reduced
pressure. Yield: colorless crystals (7.04 g, 99%), mp. 36 – 38 °C.
TLC: petroleum ether : EtOAc = 4:1, Rf = 0.25. 1H NMR
(CDCl3): d 7.10 (d, J = 9.5 Hz, 2H), 6.82 (d, J = 9.5 Hz, 2H),
4.50 (septet, J = 6.3 Hz, 1H), 3.68 (t, J = 7.9 Hz, 2H), 2.66 (t, J =
7.9 Hz, 2H), 2.0 (b, 1H), 1.93 - 1.78 (m, 2H), 1.32 (d, J = 6.3 Hz,
6H); 13C NMR (CDCl3): d 155.9 (s), 133.7 (s), 129.2 (d), 115.9
(d), 69.9 (d), 62.0 (t), 34.3 (t), 31.1 (t), 22.0 (q).
1
Figure 2. Molecular structure of 11 in crystalline 11•~ / C H OH (20%
2
2 5
ellipsoids) seen in two views (crystallographic atom numbering).
in CDCl3 or DMSO-d6 using tetramethylsilane as an internal
standard. Thin layer chromatography (TLC) was performed on
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 performed with
magnetic stirring under an argon atmosphere. MPLC (medium
pressure liquid 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 97:3, solvent B: 20 mM CCl3COOH:
MeCN 97:3, flow rate: 0.5 mL/min, injection volume: 1 µL,
gradient: see Table 1.
Anal. Calcd for C12H18O2: C, 74.19; H, 9.34. Found: C, 73.93;
H, 9.07.
1-(3-Iodopropyl)-4-(1-methylethoxy)benzene (4).
A mixture of triphenylphosphine (13.1 g, 49.9 mmol), iodine
(19.9 g, 78.4 mmol) and imidazole (4.0 g, 58.8 mmol) in dry
CH2Cl2 (250 mL) was stirred at ambient temperature for 20 min-
utes. At 15 °C, 3 (8.74 g, 45.0 mmol) in CH2Cl2 (100 mL) was
added and stirred at ambient temperature for 12 hours. The mix-
ture was then partitioned between water (300 mL) and CH2Cl2
(150 mL). The aqueous layer was extracted with CH2Cl2 (2 x 50
mL), and the combined organic layer was washed with water (1 x
100 mL), 10% CuSO4 (2 x 200 mL), water (1 x 200 mL), satu-
rated NaHSO3 (2 x 200 mL) and brine (1 x 200 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure. The
residue was slurried in iPr2O (200 mL) and filtered. The filtrate
was concentrated in vacuo and purified by MPLC (500 g SiO2,
petroleum ether:EtOAc = 95:5). Yield: colorless oil (10.9 g,
Table 1
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
1
79%). TLC: petroleum ether:EtOAc = 4:1, Rf = 0.9. H NMR
(CDCl3): d 7.11 (d, J = 9.5 Hz, 2H), 6.82 (d, J = 9.5 Hz, 2H),
4.53 (septet, J = 6.3 Hz, 1H), 3.18 (t, J = 7.9 Hz, 2H), 2.67 (t, J =
7.9 Hz, 2H), 2.10 (Quintett, J = 7.9 Hz, 2H), 1.35 (d, J = 6.3 Hz,
6H); 13C NMR (CDCl3): d 156.2 (s), 132.2 (s), 129.4 (d), 115.9
(d), 69.8 (d), 35.2 (t), 35.0 (t), 22.1 (q), 6.5 (t).
4-(1-Methylethoxy)benzenepropanoic Acid, (1-Methyl)ethyl
Ester (2).
A mixture of 4-hydroxybenzenepropanoic acid (1) (50.0 g, 300
mmol), potassium carbonate (210 g, 1.5 mol, anhydrous, freshly
ground) and 2-bromopropane (221 g, 1.8 mol) in dry DMF (500
mL) was stirred at 60 °C for 24 hours. The mixture was filtered
and evaporatedin vacuo. The residue was partitioned between 2 N
NaOH (500 mL) and Et2O (500 mL), and the aqueous layer was
extracted with Et2O (2 x 100 mL). The combined organic layer
was washed with 2 N NaOH (2 x 200 mL), water (2 x 500 mL)
and brine (1 x 500 mL), dried over Na2SO4, and evaporated under
Anal. Calcd for C12H17IO: C, 47.39; H, 5.63. Found: C, 47.37;
H, 5.41.
2-Bromo-4-methoxy-5-(1-methylethoxy)benzeneacetonitrile (6).
A mixture of 1-bromo-2-(chloromethyl)-5-methoxy-4-(1-
methylethoxy)benzene (5) (7.00 g, 23.8 mmol) and potassium
cyanide (1.70 g, 26.1 mmol, freshly ground) in dry DMSO (70

1286
M. Treu, K. Mereiter, C. Hametner, J. Fröhlich, and U. Jordis
Vol. 39
mL) was stirred at ambient temperature for 12 hours. Water (700
mL) was added, and the mixture was extracted with Et2O (3 x
150 mL). The combined organic layer was washed with water (5
x 150 mL) and brine (1 x 200 mL), dried over Na2SO4, filtered
and concentrated in vacuo. The residue was triturated with iPr2O
(2 x 15 mL). Yield: colorless crystals (6.46 g, 95%); mp. 92 - 94
°C. TLC: petroleum ether:EtOAc = 4:1, Rf = 0.55. 1H NMR
(CDCl3): d 7.02 (s, 1H), 6.97 (s, 1H), 4.50 (septet, J = 6.3 Hz,
1H), 3.81 (s, 3H), 3.72 (s, 2H), 1.36 (d, J = 6.3 Hz, 6H); 13C
NMR (CDCl3): d 150.8 (s), 147.1 (s), 121.5 (s), 117.3 (s), 116.7
(d), 116.3 (d), 113.9 (s), 72.1 (d), 56.2 (q), 24.2 (t), 21.9 (q).
Anal. Calcd for C12H14BrNO2: C, 50.72; H, 4.97; N, 4.93.
Found: C, 50.73; H, 4.84; N, 4.89.
The residue was dissolved in dry THF (100 mL), and NH3 was
bubbled through the stirred solution for 2 hours. The mixture was
concentrated and partitioned between water (100 mL) and Et2O
(100 mL). The aqueous layer was extracted with Et2O (3 x 50
mL). The combined organic layer was washed with water (3 x 150
mL) and brine (1 x 200 mL), dried over Na2SO4, filtered and con-
centrated in vacuo. The residue was added to the fraction with the
lower Rf, and the solvent was removed under reduced pressure.
The residue was triturated with iPr2O (2 x 50 mL). Yield: color-
less crystals, (26.0 g, 83.5%), mp. 183 - 185 °C. TLC: petroleum
ether: Et2O = 1:4, Rf = 0.45. 1H NMR (CDCl3): d 7.01 (d, J = 8.9
Hz, 2H), 6.98 (s, 1H), 6.92 (s, 1H), 6.75 (d, J = 8.9 Hz, 2H), 5.98
(b, 1H), 5.52 (b, 1H), 4.47 (septet, J = 6.3 Hz, 2H), 3.91 (t, J = 7.0
Hz, 1H), 3.82 (s, 3H), 2.74 - 2.40 (m, 2H), 2.22 - 2.00 (m, 1H),
1.91 - 1.36 (m, 3H), 1.35 - 1.22 (m, 6H); 13C NMR (CDCl3): d
175.2 (s), 155.8 (s), 149.9 (s), 147.0 (s), 133.9 (s), 130.8 (s), 129.1
(d), 115.7 (d), 114.8 (d), 114.7 (d), 71.4 (d), 69.7 (d), 56.0 (q), 49.7
(d), 34.6 (t), 31.9 (t), 29.1 (t), 22.0 (q), 21.8 (q), 21.7 (q).
a -[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]4-(1-methyl-
ethoxy)benzenepentanenitrile (7).
n-Butyllithium (12.7 mL, 27.5 mmol, 2.2 M in hexane) was
added to a solution of diisopropylamine (3.55 g, 35.08 mmol) in
dry THF (50 mL) at - 78 C° over a period of 15 minutes. The
mixture was allowed to warm up to – 30 °C, stirred for 30 min-
utes and then cooled to - 78 C°. Compound 6 in dry THF (100
mL) was added, stirred for 20 minutes, warmed up to ambient
temperature and stirred for an additional 60 minutes. The mixture
was cooled to – 78 °C, then 4 in dry THF (50 mL) was added over
15 minutes and stirred for 45 minutes. Saturated NH4Cl (50 mL)
was added, the mixture was allowed to warm up to ambient tem-
perature and partitioned between 2 N HCl (200 mL) and Et2O
(200 mL). The aqueous layer was extracted with Et2O (3 x 50
mL). The combined organic layer was washed with water (5 x
150 mL), saturated NaHCO3 (1 x 200 mL) and brine (1 x 200
mL), dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by MPLC (1000 g SiO2, petroleum
ether:EtOAc = 98:2). Yield: colorless crystals (11.46 g, 71%),
mp. 63 - 65 °C. TLC: petroleum ether: Et2O = 1:4, Rf = 0.85. 1H
NMR (CDCl3): d 7.06 (d, J = 7.9 Hz, 2H), 7.01 (s, 1H), 7.02 (s,
1H), 6.82 (d, J = 7.9 Hz, 2H), 4.51 (septet, J = 6.3 Hz, 2H), 4.20
(t, J = 7.0 Hz, 1H), 3.82 (s, 3H), 2.68 - 2.56 (m, 2H), 1.99 - 1.68
(m, 4H), 1.31 (d, J = 6.3 Hz, 6H), 1.36 (d, J = 6.3 Hz, 6H); 13C
NMR (CDCl3): d 156.1 (s), 150.7 (s), 147.2 (s), 133.0 (s), 129.2
(d), 127.1 (s), 120.5 (s), 116.2 (s), 115.9 (d), 115.5 (d),113.2 (s),
72.0 (d), 69.8 (d), 56.2 (q), 36.5 (t), 34.1 (d), 33.9 (t), 28.6 (t),
22.0 (q), 21.9 (q), 21.8 (q).
Anal. Calcd for C24H32BrO4: C, 60.25; H, 6.74; N, 2.93.
Found: C, 60.00; H, 6.49; N, 2.80.
a -[2-Bromo-5-hydroxy-4-methoxyphenyl]-4-hydroxybenzene-
pentanamide (9).
To 8 (24.0 g, 50.2 mmol) in dry CH2Cl2 (300 mL) BCl3 (150
mL, 150 mmol, 1 M in CH2Cl2) was added at -78 °C and stirred
at ambient temperature for 4 hours. Water (200 mL) was added
dropwise, and the mixture was concentrated to 150 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
crystals (19.7 g, 99%), mp. 183 - 184 °C. TLC: EtOAc, Rf = 0.7.
1H NMR (DMSO-d6): d 9.25 (s, 1H), 9.13 (s, 1H), 7.32 (s, 1H),
7.04 (s, 1H), 7.02 (s, 1H), 6.93 (d, J = 7.6 Hz, 2H), 6.91 (s, 1H),
6.66 (d, J = 7.6 Hz, 2H), 3.81 - 3.61 (m, 1H), 3.71 (s, 3H), 2.58 -
2.38 (m, 2H), 1.95 - 1.68 (m, 1H), 1.65 - 1.38 (m, 3H); 13C NMR
(DMSO-d6): d 174.1 (s), 155.3 (s), 147.2 (s), 146.1 (s), 132.1 (s),
129.1 (d), 115.7 (d), 115.4 (d), 115.1 (d), 111.8 (s), 55.9 (q), 49.1
(d), 34.2 (t), 29.6 (t), 26.9 (t).
Anal. Calcd for C18H20BrNO4: C, 54.84; H, 5.11; N, 3.55.
Found: C, 54.56; H, 5.40; N, 3.25.
1-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxo-6H-
benzo[b]cyclohepta[cd]benzofuran-12-carboxamide (10).
Anal. Calcd for C24H30BrNO3: C, 62.61; H, 6.57; N, 3.04.
Found: C, 62.32; H, 6.31; N, 2.97.
To a suspension of 9 (3.00 g, 7.61 mmol) in CHCl3 (300 mL) a
mixture of K3[Fe(CN)6] (13.2 g, 40.0 mmol) and K2CO3 (7.50 g,
53.1 mmol) in water (75 mL) was added at once and stirred vig-
orously using a mechanical stirrer at ambient temperature for 45
minutes. The mixture was filtered using diatomaceous earth, and
the filtrate was washed with water (3 x 200 mL) and brine (200
mL), dried over Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography (SiO2,
CHCl3: MeOH = 96:4). Yield of diastereomer with the higher Rf:
colorless crystals (0.24 g, 8%), mp. 257 - 258 °C (dec.). TLC:
EtOAc, Rf = 0.6. 1H NMR (DMSO-d6): d 7.57 (s, 1H), 7.48 (d, J
= 14.5 Hz, 1H), 7.14 (s, 2H), 5.89 (d, J = 14.5 Hz, 1H), 4.66 (s,
1H), 4.32 (s, 1H), 4.01 (q, J = 7.7 Hz, 1H), 3.78 (s, 3H), 3.02 (d,
J = 19.6 Hz, 1H), 2.79 (d, J = 19.6 Hz, 1H), 2.52 (d, J = 16.5 Hz,
1H), 2.16 (d, J = 16.5 Hz, 1H), 1.96 - 1.67 (m, 2H), 1.14 (t, J =
7.7 Hz, 1H); 13C NMR (DMSO-d6): d 195.6 (s), 174.6 (s), 149.5
(d), 147.9 (s), 144.4 (s), 133.6 (s), 130.6 (s), 126.5 (d), 117.5 (s),
117.1 (d), 88.4 (d), 56.8 (q), 52.1 (s), 51.6 (d), 37.9 (t), 36.6 (t),
33.3 (t), 21.5 (t).
a -[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]-4-(1-methyl-
ethoxy)benzenepentaamide (8).
Compound 7 (30.0 g, 65.2 mmol) in EtOH (600 mL) was
treated with KOH (60.0 g, 1.07 mol) in water and refluxed for 6
hours. The mixture was concentrated under reduced pressure, and
the residue was partitioned between 2 N HCl (200 mL) and Et2O
(300 mL). The aqueous layer was extracted with Et2O (3 x 75
mL). The combined organic layer was washed with water (3 x 200
mL), saturated NaHCO3 (1 x 200 mL) and brine (1 x 200 mL),
dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by MPLC (1000 g SiO2, petroleum ether:
Et2O = 1:2) giving two fractions. The fraction eluted first (the acid
8, X = COOH) was collected, concentrated in vacuo, dissolved in
dry CH2Cl2 (100 mL), cooled to 0 °C and treated with oxalyl
chloride (3 mL) in presence of a catalytic amount of DMF. The
mixture was stirred for 2 hours and then evaporated to dryness.

Nov-Dec 2002
Carbocyclic Galanthamin analogs
1287
Anal. Calcd for C18H18BrNO4: C, 55.12; H, 4.63; N, 3.57.
Found: C, 55.15; H, 4.71; N, 3.38.
The diastereomer with the lower Rf 10b which was formed as
a minor byproduct was observed via TLC and NMR spec-
troscopy to isomerize to 10a.
Anal. Calcd for C18H18BrNO4: C, 55.12; H, 4.63; N, 3.57.
Found: C, 55.10; H, 4.59; N, 3.46.
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 invacuo. The crude
product was purified by flash chromatography (50 g SiO2,
EtOAc). Yield: colorless solid (798 mg, 83%), mp. 200 - 202 °C.
TLC: EtOAc, Rf = 0.45. 1H NMR (CDCl3/DMSO-d6): d 6.97 (s,
1H), 6.79 (b, 1H), 6.49 (b, 1H), 6.12 (d, J = 11.4 Hz, 1H), 5.83
(dd, J = 11.4 Hz, J = 5.1 Hz, 1H), 4.42 (s, 1H), 4.31 - 4.21 (m,
1H), 3.78 (s, 3H), 3.42 - 3.18 (m, 2H), 2.68 - 2.29 (m, 2H), 2.14 -
1.38 (m, 5H); 13C NMR (CDCl3/DMSO-d6): d 173.4 (s), 146.3
(s), 143.6 (s), 134.2 (s), 128.8 (d), 128.6 (d), 126.8 (s), 116.1 (s),
115.6 (d), 87.1 (d), 60.1 (q), 55.6 (d), 50.1 (s), 49.5 (d), 37.5 (t),
31.0 (t), 29.8 (t), 20.3 (t).
X-Ray Structure Determination of 10a.
Crystal data: C18H18BrNO4, Mr = 392.24, monoclinic, space
group P21/n (no. 14), a = 15.447(6) Å, b = 12.289(5) Å, c =
17.426(7) Å, = 99.55(1)°, V = 3262(2) Å3, Z = 8, Dx = 1.597
Mg/m-3, (Mo-Ka ) = 0.71073 Å, = 2.54 mm-1, T = 297(2) K.
X-ray data collection with a Bruker SMART CCD area detector
diffractometer and graphite monochromatized Mo Ka radiation.
46429 reflections with q < 30.0° were measured, corrected for LP
Anal. Calcd for C18H20BrNO4: C, 54.84; H, 5.11; N, 3.55.
Found: C, 54.67; H, 5.10; N, 3.46.
and absorption, and merged to 9457 unique reflections, Rint
=
X-Ray Structure Determination of 11 in the Form of the Solvate
11•~1/2C2H5OH.
0.030. Structure solved with direct methods, structure refinement
on F2 using program SHELXL97 [11]. All non-hydrogen atoms
were refined anisotropically. Hydrogen atoms had isotropic tem-
perature factors and resided on the atoms to which they were
Crystal data: C19H23BrNO4.5 (C18H20BrNO4•1/2C2H5OH,
idealized), Mr = 417.29, monoclinic, space group C2/c (no. 15), a
= 24.820(9) Å, b = 11.447(5) Å, c = 17.097(7) Å, = 131.14(1)°,
V = 3658(3) Å3, Z = 8, Dx = 1.515 Mg/m-3, (Mo-Ka ) = 0.71073
Å, = 2.27 mm-1, T = 297(2) K. A colorless prism (0.64 x 0.38 x
0.32 mm) obtained from ethanol on slow evaporation (uptake of
moisture likely) was used for X-ray data collection with a Bruker
SMART CCD diffractometer and graphite monochromatized Mo
Ka radiation. 21449 reflections with q < 30.0° were measured,
corrected for LP and absorption, and merged to 5223 unique
reflections, Rint = 0.019. Structure solved with direct methods,
structure refinement on F2 using program SHELXL97 [11]. All
non-hydrogen atoms were refined anisotropically. Hydrogen
atoms had isotropic temperature factors and resided on the atoms
to which they were bonded, except for the hydroxyl H-atom that
was refined without restraints. Three solvent peaks – C(1s),
C(2s), and C(3s), attributed to the presence of disordered ethanol
and possibly some water – were refined in coordinates, site occu-
pation factors, and anisotropic thermal parameters. The final
refinement varied 253 parameters and converged at R1 = S||Fo|-
bonded. The final refinement varied 442 parameters and con-
2
verged at R1 = S||Fo|-|Fc||/S|Fo| = 0.056, wR2 = [S(w(Fo
-
2 2
Fc ) )/S(w(Fo2)2)]? = 0.083, and S = 0.97 for the 9457 unique
reflections; R1 = 0.032 for the 6493 observed data [I>2 (I)] [12].
The molecular structure of 10a in the crystalline state is shown
in Figure 1. The compound contains two crystallographically
independent molecules the tetracyclic cores of which agree well
in conformation, bond lengths, and bond angles whereas terminal
atoms and groups show moderate (carbonyl oxygen O3, carbox-
amide group) to significant differences (methoxy group). The ori-
entation of the methoxy group in the first molecule corresponds
to what is usually observed in narwedine- and galanthamine-like
compounds (e.g. compound 11, Figure 2), whereas the "upward"
orientation of the methoxy group of the second molecule is
uncommon [13]. All differences between the two molecules are
attributable to crystal packing and van-der-Waal forces assisted
by intermolecular hydrogen bonds between the NH2-groups as
donors and the C=O groups of O(3) and O(4) of both molecules
as acceptors (four bonds with N Æ O distances from 2.884 to
3.014 Å). Bond distances are (Å; first/second molecule; all
e.s.d.'s 0.002-0.003 Å): Br-C5 1.907/1.912, O1-C2 1.365/1.375,
O1-C15 1.461/1.454, O2-C3 1.367/1.367, O2-C16 1.403/1.410,
O3-C13 1.219/1.231, O4-C17 1.226/1.229, N-C17 1.330/1.337,
C1-C2 1.389/1.397, C1-C6 1.396/1.393, C1-C10 1.535/1.535,
C2-C3 1.376/1.380, C3-C4 1.374/1.384, C4-C5 1.397/1.380, C5-
C6 1.399/1.406, C6-C7 1.521/1.512, C7-C17 1.525/1.528, C7-
C7A 1.550/1.545, C7A-C8 1.511/1.514, C8-C9 1.531/1.519, C9-
C10 1.532/1.534, C10-C11 1.506/1.508, C10-C15 1.539/1.536,
C11-C12 1.324/1.339, C12-C13 1.462/1.448, C13-C14
1.491/1.493, C14-C15 1.504/1.509.
2 2
|Fc||/S|Fo| = 0.038, wR2 = [S(w(Fo2-Fc ) )/S(w(Fo2)2)]? = 0.075,
and S = 1.06 for all 5223 unique reflections; R1 = 0.028 for the
4146 observed data [I>2 (I)] [12].
The molecular structure of 11 in its crystalline solvate
11•~1/2C2H5OH is shown in Figure 2. The compound contains
between eight symmetry equivalent molecules of 11 per unit cell
four cavities occupied by disordered ethanol solvent molecules
(about one per cavity). A partial replacement of ethanol by water
cannot be ruled out. Each cavity has a solvent accessible volume
of about 100 Å3 and a scattering power of ca. 27 electrons closely
corresponding to the idealized chemical formula 11•~1/2C2H5OH
with 26 electrons solvent scattering power per cavity (= 13 elec-
trons or 1/2C2H5OH per molecule of 11). Compound 11 adopts a
conformation agreeing well with galanthamine and its derivatives
[13]. Bond distances (Å; all e.s.d.'s ~0.002 Å): Br-C5 1.909, O1-
C2 1.373, O1-C15 1.468, O2-C3 1.364, O2-C16 1.420, O3-C13
1.440, O4-C17 1.227, N-C17 1.329, C1-C2 1.380, C1-C6 1.403,
C1-C10 1.530, C2-C3 1.389, C3-C4 1.383, C4-C5 1.394, C5-C6
1.394, C6-C7 1.517, C7-C17 1.532, C7-C7A 1.542, C7A-C8
1.521, C8-C9 1.520, C9-C10 1.527, C10-C11 1.518, C10-C15
1.543, C11-C12 1.323, C12-C13 1.490, C13-C14 1.510, C14-
C15 1.506. Torsion angles (°): C16-O2-C3-C2 -176.8, C6-C7-
(4a ,6 ,8a ,12R*)-1-Bromo-4a,5,9,10,11,12-hexahydro-6-
hydroxy-3-methoxy-6H-benzo[b]cyclohepta[cd]benzofuran-12-
carboxamide (11).
To a suspension of 10a (600 mg, 1.52 mmol) in dry THF (5
mL) L-Selectride® (4.6 mL, 4.6 mmol, 1 M in THF) was added
dropwise at - 5 °C within 15 minutes and stirred at room temper-
ature for 4 hours. The mixture was hydrolyzed with water (3 mL)
and then concentrated in vacuo. The residue was partitioned
between EtOAc (30 mL) and 2 N HCl (20 mL). The aqueous

1288
M. Treu, K. Mereiter, C. Hametner, J. Fröhlich, and U. Jordis
Vol. 39
C17-N 175.8. Hydrogen bonds: O3 Æ O1 = 2.937 Å (intramolec-
ular), N Æ O1 = 3.075 Å (intermolecular), and N Æ O4 = 2.886
Å (intermolecular).
121.9 (d), 109.9 (d), 87.7 (d), 61.1 (d), 54.8 (q), 48.5 (s), 37.0 (t),
34.4 (t), 29.0 (t), 25.8 (t), 16.9 (t). HPLC/MS m/z (relative inten-
sity): NI: 287.1 (17%), 286.1 (54%), 285.2 (8%), 284.2 (36%),
279.2 (5%), 268.2 (28%), 266.1 (5%), 265.1 (8%), 253.1 (6%),
252.2 (18%), 251.2 (100%), 247.1 (5%), 240.2 (6%), 237.1
(10%), 236.1 (24%); PI: 272.0 (19%), 270.9 (100%), 270.0
(13%), 253.9 (11%), 253.0 (15%).
(4a ,6 ,8a ,12R*)-12-Amino-1-bromo-4a,5,9,10,11,12-hexahy-
dro-3-methoxy-6H-benzo[b]cyclohepta[cd]benzofuran-6-ol (12).
To bis(trifluoracetoxy)iodobenzene (PIFA, 300 mg, 0.76
mmol) in MeCN (1.5 mL, HPLC grade) water (1.5 mL, HPLC
grade) was added. Within 2 hours 11 was added and stirred at
ambient temperature for 24 hours. The reaction solution was con-
centrated in vacuo, dissolved in CHCl3 (5 mL), filtered and puri-
fied by flash chromatography (30 g SiO2, CHCl3:MeOH:concen-
trated NH3 = 96:3:1). Yield: colorless foam (161 mg, 58%), mp.
156 - 159 °C. TLC: CHCl3:MeOH:conc. NH3 = 89:10:1, Rf =
Acknowledgements.
The authors wish to thank Sanochemia Pharmazeutika AG for
their financial support and donation of chemicals.
REFERENCES AND NOTES
1
0.6. H NMR (MeOH-d4): d 7.08 (s, 1H), 6.41 (d, J = 14.5 Hz,
[1] B. Küenburg, L. Czollner, J. Fröhlich, and U. Jordis, Org.
Process Res. Dev., 3, 425 (1999).
[2] L. J. Scott and K. L. Goa, Drugs, 60, 1095 (2000).
[3] A. Nordberg and A. L. Svensson, Drug Safety, 19, 465
(1998).
[4] A. Maelicke, Dementia Geriatr. Cognit. Disord., 11, 11
(2000).
[5] S. B. Garber, J. S. Kingsbury, B. L. Gray, and A. H.
Hoveyda, J. Am. Chem. Soc., 122, 8168 (2000).
[6] M. Treu, U. Jordis, and K. Mereiter, Heterocycles, 55, 1727
(2001).
[7] D. H. R. Barton and G. W. Kirby, Proc. Chem. Soc., 392
(1960).
[8] G. M. Loudon, A. S. Radhakrishna, M. R. Almond, J. K.
Blodgett, and R. H. Boutin, J. Org. Chem., 49, 4272 (1984).
[9] R. H. Boutin and G. M. Loudon, J. Org. Chem., 49, 4277
(1984).
1H), 5.83 (dd, J = 14.5 Hz, J = 5.1 Hz, 1H), 4.72 (s, 1H), 4.58 (s,
1H), 4.13 (t, J = 3.6 Hz, 1H), 3.82 (s, 3H), 2.49 (d, J = 17.2 Hz,
1H), 2.45 - 2.07 (m, 4H), 1.92 - 1.58 (m, 4H); 13C NMR (MeOH-
d4): d 147.2 (s), 144.7 (s), 134.5 (s), 133.3 (s), 130.9 (d), 126.4
(d), 116.6 (d), 115.5 (s), 87.8 (d), 61.2 (d), 57.3 (q), 54.0 (d), 48.6
(s), 38.3 (t), 35.2 (t), 30.1 (t), 17.9 (t). HPLC/MS m/z (relative
intensity): NI: 366.1 (44%), 364.1 (100%), 349.1 (34%), 329.2
(37%) ; PI: 349.9 (98%), 348.8 (100%), 347.7 (16%), 332.8
(42%), 331.8 (38%).
Anal. Calcd for C17H20BrNO2•0.66H2O: C, 54.02; H, 5.68; N,
3.71. Found: C, 53.93; H, 5.52; N, 3.60.
(4a ,6 ,8a ,12R*)-12-Amino-4a,5,9,10,11,12-hexahydro-3-
methoxy-6H-benzo[b]cyclohepta[cd]benzofuran-6-ol (13).
A suspension of zinc powder (500 mg) and Cu(I)I (500 mg) in
water (4 mL)/EtOH (4 mL) was sonicated under argon for 45
minutes. Compound 12 (70 mg, 0.19 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
purified by flash chromatography (30 g SiO2, CHCl3:MeOH:
concentrated NH3 = 96:3:1). Yield: colorless crystals (42 mg,
78%), mp. 158 - 160 °C. TLC: CHCl3:MeOH:concentrated NH3
[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 10a and 11•~1/2C2H5OH
(excluding structure factors) have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no CCDC
172274 and 172275. 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. Soc.
Chim. Fr., 769 (1990); [c] R. Matusch, M. Kreh, and U. Mueller, Helv.
Chim. Acta, 77, 1611 (1994); [d] O. M. Peeters, N. M. Blaton, and C. J.
De Ranter, Acta Crystallogr., Sect. C (Cr.Str.Comm.), 53, 1284 (1997).
1
= 89:10:1, Rf = 0.55. H NMR (CDCl3): d 6.81 - 6.61 (m, 3H),
6.97 (dd, J = 14 Hz, J = 4 Hz, 1H), 4.44 (s, 1H), 4.30 (s, 1H),
4.24 (t, J = 3Hz, 1H), 3.85 (s, 3H), 2.63 (dd, J = 17 Hz, J = 6 Hz,
1H), 2.40 (q, J = 15 Hz, 1H), 2.19 - 2.08 (m, 1H), 2.02 (dd, J =
18 Hz, J = 4 Hz, 1H), 1.97 - 1.52 (m, 7 H);13C NMR (CDCl3): d
145.4 (s), 143.2 (s), 134.1 (s), 132.6 (s), 129.9 (d), 125.4 (d),