Synthesis and stereoselective dealkylation of N-chiral quarternary N-alkyl galanthaminium halides

Article abstract of DOI:10.1016/S0957-4166(03)00116-2

The synthesis of N-chiral galanthaminium halides and their stereoselective dealkylation is described. The stereochemistry of two key compounds was determined by X-ray structure analysis.

Full text of DOI:10.1016/S0957-4166(03)00116-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 675–681
Synthesis and stereoselective dealkylation of N-chiral
quarternary N-alkyl galanthaminium halides
Manfred Hirnschall,a Matthias Treu,a Kurt Mereiter,b Christian Hametner,a Johannes Fro¨hlicha and
Ulrich Jordisa,*
aInstitute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163OC, A-1060 Vienna, Austria
bInstitute of Chemical Technologies and Analytics, Vienna University of Technology, Getreidemarkt 9, A-1060 Vienna, Austria
Received 17 October 2002; accepted 28 November 2002
Abstract—The synthesis of N-chiral galanthaminium halides and their stereoselective dealkylation is described. The stereochem-
istry of two key compounds was determined by X-ray structure analysis. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Galanthamine (Reminyl®, Nivalin®), which has been
introduced into the European market and approved by
the FDA for the treatment of Alzheimer’s disease, is a
reversible, competitive acetylcholinesterase inhibitor
and has also been found to allosterically modulate
nicotinic acetylcholine receptors.1,2 Attempts to develop
second generation galanthamine analogs have led to a
demand for a protocol which allows selective N-
demethylation of quarternary galanthaminium salts.
The crystal structures of two chiral galanthaminium
salts have been published.3 Surprisingly, literature on
the chemistry of chiral quarternary ammonium salts is
relatively scarce.
The N-chiral quarternary ammonium halides 4a–d and
ent-4b–ent-4c were prepared in 88–100% yields starting
either from (−)-galanthamine 1 or the appropriately
substituted (−)-galanthamine derivatives N-butylgalan-
thamine 28 and N-saccharinylbutylgalanthamine 39 by
treatment with an excess of alkylating agent in dry
DMF (see Scheme 1). As NMR techniques for structure
elucidation of quarternary galanthaminium derivatives
were not successful, the absolute stereochemistry of 4b
and ent-4b was determined by X-ray crystal analysis
(Figs. 1 and 2). For this purpose 4b was recrystallized
from ethanol/water yielding
a crystalline hydrate
4b·1.5H2O which was subjected to X-ray analysis at
T=297 and 213 K in view of a phase transition briefly
Cooke and Partman reported the demethylation of
quarternary ammonium salts by reaction with Super
Hydride®,4 whereas Fellows and co-workers employed
L-Selectride® as the reagent for the dealkylation of an
achiral benzyl ammonium derivative.5 Fleischhacker
and Richter reported the ring opening of a morphine
derivative on reaction with Super Hydride®.6 Manoha-
ran has described the N-demethylation of a quarternary
morphinium derivative.7
Based on these precedences, our strategy for the prepa-
ration of new N-substituted galanthamine derivatives
consisted of galanthamine alkylation followed by the
removal of the N-methyl substituent.
* Corresponding author. E-mail: ujordis@pop.tuwien.ac.at
Scheme 1. Synthesis of galanthaminium halides.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00116-2

676
M. Hirnschall et al. / Tetrahedron: Asymmetry 14 (2003) 675–681
the reaction conditions optimized for the model reac-
tion, loss of the least sterically hindered alkyl sub-
stituent was observed. The fact that substrates bearing
more sterically demanding substituents (4b, 4c) com-
pared to 4a underwent the dealkylation reaction only
with Super Hydride® but not with L-Selectride® can be
explained by the greater steric demand of the latter
reagent. On the other hand, high stereochemical prefer-
ences were observed only with the large saccharinyl-
butyl substituents of 4c and ent-4c but not with 4b or
ent-4b, which gave a mixture of dealkylated products A,
B, and C. When the saccharine derivative ent-4c was
employed for degradation, a concomitant reductive
ring-opening reaction at the saccharine moiety
occurred, leading to compound 6 (see Scheme 2 and
Table 1). These results exemplify the stereochemical
preference for the N-dealkylation of N-chiral quar-
ternary salts, but lack practical synthetic value for the
modification of the N-substituent of galanthamine.
3. Conclusion
In summary, we have prepared diastereomerically pure
quarternary galanthaminium derivatives and have
shown that treatment with L-Selectride® or Super
Hydride® under optimized conditions leads to cleavage
of the least sterically hindered alkyl moiety without a
ring opening side reaction. Although the aim of solving
the absolute stereochemistry of two representative com-
pounds by X-ray diffraction was initially considered
straightforward, complications caused by peculiar solid-
state structures and crystallography made the X-ray
analysis a challenge. Nevertheless, a case could be
found (4b·1.5H2O) where solid state packing require-
ments force the azepine ring of the galanthamine moi-
Figure 1. Thermal ellipsoid plots (20% ellipsoids) of the two
independent N-butylgalanthaminium cations with (a) chair
and (b) boat conformation of the azepine ring in the solid
state structure of 4b·1.5H2O at T=213 K. Iodide ions and
water molecules omitted.
described in Section 4. At 213 K 4b·1.5H2O contains
two independent N-butylgalanthaminium cations of
which one adopts the usual chair conformation for the
azepine ring (Fig. 1(a)), whereas the second stands out
by having this ring in the unusal boat conformation
(Fig. 1(b)). Ent-4b gave crystals suitable for X-ray
diffraction by crystallization from DMF forming
thereby the solvate ent-4b·DMF which was X-rayed at
T=223 K (see Section 4). This compound also contains
two independent galanthaminium cations but both of
which are similar and have the usual chair-conforma-
tion of the azepine ring (Fig. 2).
As the protocol given by Manoharan7 using sodium
thiophenolate led to side reactions without indication of
the formation of the desired products, borohydride
reagents were employed for the dealkylation experi-
ments. In a model reaction, dealkylation of methyl-
galanthaminium iodide 4a10 using L-Selectride® or
Super Hydride® (LiBHEt3) in dry THF at 65°C gave
rise to (−)-galanthamine in 90–100% yield. When N-chi-
ral galanthaminium starting materials were subjected to
Figure 2. Thermal ellipsoid plot (20% ellipsoids) of one of the
two independent but similar N-butylgalanthaminium cations
in the solid state structure of ent-4b·DMF at T=223 K.

M. Hirnschall et al. / Tetrahedron: Asymmetry 14 (2003) 675–681
677
Scheme 2. Dealkylation of galanthaminium halides.
Table 1. Dealkylation of galanthaminium halides 4a–d and ent-4b–ent-4c
Method I: L-Selectide®, THF, 65°C. Method II: Super Hydride®, THF, 65°C.
a
Isolated yield.
b Yield determined by HPLC.
c Yield estimated by TLC.
ety out of the favoured chair form and into the less
favourable boat conformation.
Perkin Elmer 241 polarimeter using a 1 dm cell with 1
ml cell volume. 1H and 13C NMR spectra were recorded
on a Bruker AC-200 or a Bruker Avance 400 FT NMR
spectrometer in CDCl3 or DMSO-d6 using tetra-
methylsilane as an internal standard. Thin layer chro-
matography (TLC) was performed on precoated plates
(Merck TLC aluminum sheets silica 60 F254) with detec-
tion by UV light or with phosphomolybdic acid in
aqueous EtOH and heating. All reactions were magnet-
4. Experimental
4.1. General
Melting points were measured on a Kofler hot stage
microscope. Optical rotations were determined on a

678
M. Hirnschall et al. / Tetrahedron: Asymmetry 14 (2003) 675–681
ically stirred under an argon atmosphere. All liquid
reagents were freshly distilled prior to use.
24 h/65°C; yield: 756 mg (88%); specific rotation:
20
[h]25089=−93.4, [h]52708=−98.9, [h]52406=−110.8, [h]
=
436
−185.9, [h]23605=−302.2 (c 0.109, H2O); mp 262–263°C.
Anal. calcd for C28H33BrN2O6S×0.5 H2O: C, 54.72;
H, 5.58; N, 4.56. Found: C, 54.73; H, 5.46; N, 4.74%.
1H NMR (DMSO-d6): l 8.36–8.28 (m, 1H), 8.16–8.00
(m, 3H), 6.89 (d, J=8.1 Hz, 1H), 6.78 (d, J=8.1 Hz,
1H), 6.25 (d, J=10.0 Hz, 1H), 5.90 (dd, J=10.2, 4.3
Hz, 1H), 5.04 (d, J=14.2 Hz, 1H), 4.65 (b, 1H),
4.53–4.38 (m, 2H), 4.11 (b, 1H), 3.83 (s, 3H), 3.70 (b,
1H), 3.35 (s, 7H), 2.85–2.75 (m, 2H), 2.38–1.72 (m,
7H); 13C NMR (DMSO-d6): l 158.6 (s) 146.5 (s),
145.4 (s), 136.7 (s), 135.8 (d), 135.3 (d) 132.7 (s),
130.0 (d), 126.4 (s), 125.1 (d), 123.7 (d), 121.5 (d),
118.2 (d), 112.2 (d), 86.5 (d), 59.9 (t), 59.4 (d), 55.6
(q), 45.9 (s), 38.0 (t), 35.7 (t), 30.7 (t), 25.1 (t), 19.1
(t).
4.2. Preparation of N-alkylgalanthaminium halides.
General procedure
A solution of the tertiary amine in dry DMF (5 mL/1
g amine) was treated with the alkylating agent (1.1
equiv.). The mixture was poured into EtOAc (50 mL/
1 ml DMF), the precipitate was collected by filtra-
tion, triturated with EtOAc and dried (50°C/50
mbar).
4.3. (4aS,6R,8aS,11S)-4a,5,9,10,11,12-Hexahydro-6-
hydroxy-3-methoxy-11,11-dimethyl-6H-benzo-
furo[3a,3,2-ef][2]benzazepinium iodide, 4a
Tertiary amine: (−)-galanthamine (7.00 g, 24.36
mmol); alkylating agent: MeI; reaction conditions: 30
min/25°C; yield: 10.39 g (99%); specific rotation:
4.6. (4aS,6R,8aS,11S)-4a,5,9,10,11,12-Hexahydro-6-
hydroxy-3-methoxy-11-methyl-11-(phenylmethyl)-6H-
benzofuro[3a,3,2-ef][2]benzazepinium bromide, 4d
20
436
[h]25089=−106.7, [h]52708=−110.9, [h]25406=−128.5, [h]
=
−227.3, [h]23605=−366.1 (c 0.165, H2O); mp 287–289°C
(lit.:10 286–291°C). 1H NMR (DMSO-d6): l 6.88 (d,
J=8.1 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H), 6.21 (d,
J=10.0 Hz, 1H), 5.90 (dd, J=10.2, 4.3 Hz, 1H), 5.07
(d, J=14.2 Hz, 1H), 4.65 (b, 1H), 4.53–4.38 (m, 2H),
4.09 (b, 1H), 3.85 (s, 3H), 3.70–3.55 (m, 1H), 3.38 (s,
6H), 2.95–2.78 (m, 2H), 2.42–1.80 (m, 3H); 13C NMR
(DMSO-d6): l 146.5 (s), 145.3 (s), 132.6 (s), 131.0 (s),
125.5 (d), 123.5 (d), 117.5 (t), 112.2 (d), 86.5 (d), 62.2
(t), 59.5 (t), 55.7 (q), 32.2 (t).
Tertiary amine: (−)-galanthamine (1.00 g, 3.48 mmol);
alkylating agent: benzyl bromide; reaction conditions:
12 h/25°C; yield: 1.40 g (88%); specific rotation:
20
436
[h]25089=−96.15, [h]52708=−100.0, [h]25406=−113.9, [h]
=
−197.1, [h]23605=−314.4 (c 0.208, H2O); mp 169–170°C
(lit.:10 192°C). H NMR (DMSO-d6): l 7.76–7.64 (m,
1
2H), 7.60–7.43 (m, 3H), 6.91–6.75 (m, 2H), 6.26 (d,
J=10.0, 1H), 5.88 (dd, J=10.0, 4.1 Hz, 1H), 5.33–
4.99 (m, 3H), 4.76–4.55 (m, 2H), 4.28–3.98 (m, 2H),
3.37 (s, 3H), 3.61–3.35 (m, 2H), 2.78 (s, 3H), 2.37–
1.74 (m, 3H); 13C NMR (DMSO-d6): 162.7 (s), 146.4
(s), 145.3 (s), 133.5 (d), 132.8 (s), 130.4 (d), 128.8 (d),
128.0 (s), 125.2 (d), 123.8 (d), 118.1 (s), 112.1 (d),
86.5 (d), 59.4 (q), 59.1 (t), 55.6 (q), 45.9 (s), 35.8 (t),
31.8 (t), 31.2 (t), 30.7 (t).
4.4. (4aS,6R,8aS,11S)-11-Butyl-4a,5,9,10,11,12-hexahy-
dro-6-hydroxy-3-methoxy-11-methyl-6H-benzo-
furo[3a,3,2-ef][2]benzazepinium iodide, 4b
Tertiary amine: (−)-galanthamine (5.00 g, 17.40
mmol); alkylating agent: BuI; reaction conditions: 24
20
h/65°C; yield: 8.17 g (99%); specific rotation: [h]
=
589
−114.9, [h]25078=−119.5, [h]52406=−136.2, [h]24306=−235.6,
[h]23065=−375.9 (c 0.174, H2O); mp 188–190°C. Anal.
calcd for C21H30INO3×0.5 H2O: C, 52.51; H, 6.50; N,
4.7. (4aS,6R,8aS,11R)-11-Butyl-4a,5,9,10,11,12-hexahy-
dro-6-hydroxy-3-methoxy-11-methyl-6H-benzo-
furo[3a,3,2-ef][2]benzazepinium iodide, ent-4b
1
2.92. Found: C, 52.13; H, 6.19; N, 3.23%. H NMR
(DMSO-d6): l 6.88 (d, J=8.1 Hz, 1H), 6.78 (d, J=
8.1 Hz, 1H), 6.25 (d, J=10.0 Hz, 1H), 5.90 (dd, J=
10.2, 4.3 Hz, 1H), 5.06 (d, J=14.2 Hz, 1H), 4.65 (b,
1H), 4.53–4.38 (m, 2H), 4.09 (b, 1H), 3.85 (s, 3H),
3.70–3.55 (m, 2H), 3.38 (s, 5H), 2.85–2.75 (m, 2H),
2.42–2.05 (m, 3H), 2.00–1.80 (m, 3H), 1.41 (sextet,
J=7.4 Hz, 2H), 1.02 (t, J=7.4 Hz, 3H); 13C NMR
(DMSO-d6): l 146.4 (s), 145.3 (s), 132.6 (s), 130.0 (s),
125.5 (d), 123.7 (d), 118.5 (t),112.5 (d), 86.4 (d), 59.8
(t), 59.4 (t), 55.6 (q), 45.9 (t), 35.7 (t), 30.7 (t), 23.7
(t), 19.4 (t), 13.5 (q).
Tertiary amine: (4aS,6R,8aS)-11-butyl-4a,5,9,10,11,12-
hexahydro-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benz-
azepine-6-ol (1.00 g, 3.04 mmol); alkylating agent:
MeI; reaction conditions: 20 min/25°C; yield: 1.35 g
(94%); specific rotation: [h]25809=−122.7, [h]52078=−131.0,
[h]25046=−147.45, [h]42306=−242.2, [h]23605=−381.4 (c
0.121, H2O); mp 224–226°C. Anal. calcd for
C21H30INO3×0.25 H2O: C, 53.00; H, 6.46; N, 2.94.
Found: C, 52.74; H, 6.16; N, 2.92%. 1H NMR
(DMSO-d6): l 6.82–6.76 (m, 2H), 6.25 (d, J=10.0
Hz, 1H), 5.90 (dd, J=10.2, 4.3 Hz, 1H), 5.10 (d,
J=14.2 Hz, 1H), 4.61 (b, 1H), 4.55–4.33 (m, 2H),
4.12 (b, 1H), 3.88 (s, 3H), 3.70–3.55 (m, 2H), 3.38 (s,
5H), 2.92–2.80 (m, 2H), 2.42–1.95 (m, 3H), 1.90–1.75
(m, 3H), 1.40 (sextet, J=7.4 Hz, 2H), 1.05 (t, J=7.4
Hz, 3H); 13C NMR (DMSO-d6): l 146.3 (s), 145.5 (s),
132.7 (s), 130.0 (s), 125.5 (d), 123.3 (d), 118.5
(t),112.3 (d), 86.4 (d), 59.6 (t), 59.3 (t), 55.6 (q), 45.9
(t), 35.3 (t), 30.5 (t), 23.9 (t), 19.4 (t), 13.5 (q).
4.5. (4aS,6R,8aS,11S)-4a,5,9,10,11,12-Hexahydro-6-
hydroxy-3-methoxy-11-methyl-11-[4-(1,1,3-trioxo-2H-
1,2-benzoisothiazolyl)butyl]-6H-benzofuro[3a,3,2-e,f]-
[2]benzazepinium bromide, 4c
Tertiary amine: (−)-galanthamine (400 mg, 1.39
mmol); alkylating agent: 2-(4-bromobutyl)-1,2-benzo-
isothiazol-3(2H)-one, 1,1-dioxide; reaction conditions:

M. Hirnschall et al. / Tetrahedron: Asymmetry 14 (2003) 675–681
679
4.8. (4aS,6R,8aS,11R)-4a,5,9,10,11,12-Hexahydro-6-
hydroxy-3-methoxy-11-methyl-11-[4-(1,1,3-trioxo-2H-
1,2-benzoisothiazolyl)butyl]-6H-benzofuro[3a,3,2-e,f][2]-
benzazepinium iodide, ent-4c
mainly inserted in idealized positions and rode on the
atoms to which they were bonded. Crucial hydrogen
atoms (OH, H2O) were refined in x,y,z using distance
restraints.
Tertiary amine: 2-[4-[(4aS,6R,8aS)-5,6,9,10,11,12-hex-
ahydro-6-hydroxy-3-methoxy-4aH-benzofuro[3a,3,2-e,f]-
[2]benzazepine-11-yl]butyl]-1,2-benzoisothiazol-3(2H)-
one, 1,1-dioxide (750 mg, 1.47 mmol); alkylating agent:
MeI; reaction conditions: 20 min/25°C; yield: 920 mg
(96%); specific rotation: [h]25809=−104. 9, [h]52078=−109.8,
[h]52406=−126.0, [h]42306=−213.0, [h]32605=−291.9 (c 0.123,
H2O); mp. 177–179°C. Anal. calcd for C28H33IN2O6S*
0.25 H2O: C, 51.18; H, 5.14; N, 4.26. Found: C, 50.90;
Crystal data for 4b·1.5H2O at T=297 K:
C21H33INO4.5=C21H30NO+3·I−·1.5H2O,
Mr=498.38,
yellow prism of 0.64×0.23×0.18 mm obtained from
ethanol/water 10:1 by solvent evaporation, monoclinic,
,
,
space group C2 (no. 5), a=25.109(6) A, b=8.809(2) A,
3
,
,
c=10.446(3) A, i=93.22(1)°, V=2306.9(10) A , Z=4,
Dx=1.435 Mg/m−3, v=1.415 mm−1, T=297(2) K.
15139 reflections with q<25° were measured, corrected
for absorption, and merged to 4080 unique reflections,
Rint=0.023. Final refinement: 259 parameters, R1=
1
H, 5.05; N, 4.48%. H NMR (DMSO-d6): l 8.32–8.23
2
2 2
(m, 1H), 8.15–7.95 (m, 3H), 6.92–6.70 (m, 2H), 6.27 (d,
J=9.0 Hz, 1H), 5.90 (dd, J=9.7, 4.1 Hz, 1H), 5.12 (d,
J=14.1 Hz, 1H), 4.68 (b, 1H), 4.60–4.37 (m, 2H), 4.09
(b, 1H), 3.71 (s, 3H), 3.70 (b, 1H), 3.67 (b, 2H), 3.38 (s,
3H), 3.30 (s, 2H), 3.15 (b, 2H), 2.45–2.01 (m, 3H),
1.92–1.51 (m, 5H); 13C NMR (DMSO-d6): l 158.6 (s)
146.4 (s), 145.2 (s), 136.5 (s), 135.8 (d), 135.3 (d) 132.7
(s), 129.9 (d), 126.2 (s), 125.0 (d), 123.3 (d), 121.4 (d),
117.9 (d), 111.9 (d), 86.3 (d), 59.4 (t), 55.5 (q), 53.1 (q),
45.9 (s), 38.0 (t), 35.8 (t), 30.8 (t), 24.8 (t), 18.7 (t).
SꢀꢀFoꢀ−ꢀFcꢀꢀ/SꢀFoꢀ=0.034,
wR2=[S(w(Fo −Fc ) )/
S(w(Fo ) )]1/2=0.084, and S=1.07 for all reflections;
2 2
R1=0.033 for the 3988 observed data [I>2|(I)].13
,
Selected bond distances and angles (A, °): O1ꢀC2
1.370(5), O1ꢀC15 1.457(5), O2ꢀC3 1.350(6), O2ꢀC16
1.445(7), O3ꢀC13 1.447(6), NꢀC7 1.535(5), NꢀC8
1.484(10), NꢀC17 1.450(7), NꢀC18 1.520(5), C1ꢀC2
1.382(5), C1ꢀC6 1.397(6), C1ꢀC10 1.503(5), C2ꢀC3
1.397(6), C3ꢀC4 1.384(7), C4ꢀC5 1.399(7), C5ꢀC6
1.386(7), C6ꢀC7 1.528(7), C8ꢀC9 1.303(9), C9ꢀC10
1.545(6), C10ꢀC11 1.509(6), C10ꢀC15 1.538(6),
C11ꢀC12 1.322(7), C12ꢀC13 1.459(9), C13ꢀC14
1.499(9), C14ꢀC15 1.511(6), C18ꢀC19 1.494(6),
C19ꢀC20 1.483(8), C20ꢀC21 1.478(9); C6ꢀC7ꢀNꢀC8
71.6(8), C7ꢀNꢀC8ꢀC9 −51(2), NꢀC8ꢀC9ꢀC10 39(2).
4.9. Dealkylation of galanthaminium derivatives.
General procedure
Method A: to 4a (500 mg, 1.16 mmol) in dry THF (8
mL) L-Selectride® (1 M in dry THF, 2.9 mL, 2.9 mmol)
was added over a period of 30 min at 65°C and stirred
for 5 h at this temperature. 2N HCl (20 mL) was added
dropwise, and the mixture was concentrated in vacuo to
a volume of 20 mL and washed with EtOAc (2×20 mL,
discard). The pH of the solution was adjusted to 9
using conc. NH4OH, and the aqueous layer was
extracted with CH2Cl2 (5×15 mL). The combined
organic layer was washed with water (2×20 mL) and
brine (1×20 mL), dried (Na2SO4), filtered and concen-
trated in vacuo. The residue was purified by MPLC (10
g SiO2, CHCl3:MeOH:conc. NH4OH=94:5:1). Yield:
colorless solid (300 mg, 90%). The identity of the
obtained substance with an authentic sample of galan-
thamine was confirmed by TLC, HPLC and NMR.
Method B: When Super Hydride® was used under the
same conditions, a quantitative yield was obtained.
The compound has the N-butyl group in an equatorial
orientation relative to the azepine ring. There is one
water molecule in special position on a two-fold axis,
which donates hydrogen bonds to two symmetry equiv-
alent further water molecules in general position. This
second water molecule donates one hydrogen bond to
the iodide ion and one to the galanthamine OH group,
which in turn forms a bifurcated hydrogen bond to
O(1) (intramolecular) and O(2) (intermolecular).
Unusually large anisotropic displacement parameters of
atoms N, C(8), and C(9) (same crystallographic atom
designation as shown in Figs. 1 and 2) indicated a
disorder of the azepine ring with a chair/boat confor-
mation ambiguity. Therefore, a low temperature X-ray
diffraction study was carried out showing that there is
phase transition which resolved this disorder as subse-
quently described.
Crystal data for 4b·1.5H2O at T=213 K:
4.10. X-Ray structure determinations of 4b·1.5H2O
and ent-4b·DMF
C21H33INO4.5=C21H30NO+3·I−·1.5H2O,
Mr=498.38,
same crystal as before, monoclinic, space group P21
,
,
(no. 14), a=24.951(8) A, b=8.717(3) A, c=10.384(4)
3
,
,
General: X-ray data collection was carried out with a
Bruker AXS Smart CCD area detector diffractometer,
graphite monochromatized Mo Ka radiation from a
A, i=93.10(1)°, V=2255(1) A , Z=4, Dx=1.447 Mg/
m−3, v=1.447 mm−1, T=213(2) K. 33064 reflections
with q<30° measured, corrected for absorption, and
merged to 12652 unique reflections, Rint=0.030. Final
refinement: 555 parameters, R1=SꢀꢀFoꢀ−ꢀFcꢀꢀ/SꢀFoꢀ=
,
sealed X-ray tube, u(Mo-Ka)=0.71073 A, and a
Bruker AXS Kryoflex cooling unit. Data treatment and
reduction was carried out with Bruker AXS pro-
grams.11 The structures were solved with direct methods
using program SHELXS97 and were refined on F2
using program SHELXL97.12 All non-hydrogen atoms
were refined anisotropically. Hydrogen atoms were
0.047, wR2=[S(w(Fo −Fc ) )/S(w(Fo ) )]1/2=0.108, and
S=1.06 for all reflections; R1=0.041 for the 6548
observed data [I>2|(I)].13 There are two crystallo-
graphically independent molecules with following bond
2
2 2
2 2
,
distances and selected angles (A and °; first/second

680
M. Hirnschall et al. / Tetrahedron: Asymmetry 14 (2003) 675–681
molecule): O1ꢀC2 1.356(4)/1.368(4), O1ꢀC15 1.458(4)/
1.469(4), O2ꢀC3 1.354(4)/1.360(5), O2ꢀC16 1.436(5)/
The structure contains two crystallographically inde-
pendent galanthaminium cations (Fig. 2) with essen-
tially agreeing dimensions and chair-type conformation
of the azepine rings. Selected bond distances and angles
1.439(5),
O3ꢀC13
1.436(5)/1.446(6),
N1ꢀC7
1.527(4)/1.504(11), N1ꢀC8 1.567(5)/1.552(10), N1ꢀC17
1.462(5)/1.478(9), N1ꢀC18 1.513(4)/1.537(9), C1ꢀC2
1.385(4)/1.384(4), C1ꢀC6 1.386(4)/1.381(5), C1ꢀC10
1.500(4)/1.500(5), C2ꢀC3 1.389(5)/1.391(4), C3ꢀC4
1.398(6)/1.378(6), C4ꢀC5 1.395(6)/1.399(6), C5ꢀC6
1.391(5)/1.383(6), C6ꢀC7 1.487(5)/1.492(5), C8ꢀC9
1.492(5)/1.512(8), C9ꢀC10 1.539(4)/1.552(6), C10ꢀC11
1.513(4)/1.509(5), C10ꢀC15 1.545(5)/1.529(5), C11ꢀC12
1.322(5)/1.319(6), C12ꢀC13 1.471(6)/1.462(8), C13ꢀC14
1.506(6)/1.501(8), C14ꢀC15 1.505(5)/1.509(5), C18ꢀC19
1.498(5)/1.500(5), C19ꢀC20 1.462(6)/1.509(6), C20ꢀC21
,
(A and °; first/second moiety): O1ꢀC2 1.367(5)/1.360(5),
O1ꢀC15 1.467(5)/1.472(5), O2ꢀC3 1.364(5)/1.378(6),
O3ꢀC13 1.433(5)/1.442(5), O2ꢀC16 1.425(6)/1.425(6),
NꢀC7 1.521(5)/1.517(5), NꢀC8 1.521(5)/1.515(5),
NꢀC17 1.521(5)/1.534(5), NꢀC18 1.521(5)/1.522(5),
C1ꢀC2 1.388(6)/1.390(6), C1ꢀC6 1.392(6)/1.407(6),
C1ꢀC10 1.521(6)/1.510(6), C2ꢀC3 1.403(6)/1.397(6),
C3ꢀC4 1.390(6)/1.383(6), C4ꢀC5 1.397(6)/1.411(6),
C5ꢀC6 1.404(6)/1.391(6), C6ꢀC7 1.501(6)/1.501(6),
C8ꢀC9 1.523(6)/1.529(6), C9ꢀC10 1.547(6)/1.531(6),
C10ꢀC11 1.512(6)/1.524(6), C10ꢀC15 1.555(5)/1.558(5),
C11ꢀC12 1.336(6)/1.327(6), C12ꢀC13 1.508(6)/1.516(6),
C13ꢀC14 1.518(7)/1.514(7), C14ꢀC15 1.520(6)/1.516(6),
C18ꢀC19 1.512(7)/1.517(6), C19ꢀC20 1.526(7)/1.520(7),
C20ꢀC21 1.482(14)/1.515(8), C6ꢀC7ꢀNꢀC8 74.9(5)/
73.9(4), C7ꢀNꢀC8ꢀC9 −72.6(5)/73.0(4), NꢀC8ꢀC9ꢀC10
72.0(5)/72.0(5); hydrogen bonds O3“I 3.533(4)/
3.550(4).
1.505(7)/1.507(7);
C7ꢀN1ꢀC8ꢀC9
69.0(3)/−87.2(7).
C6ꢀC7ꢀN1ꢀC8
−69.3(3)/39.6(7),
76.7(4)/50.9(8),
N1ꢀC8ꢀC9ꢀC10
Compared with the structure at room temperature
which adopts space group C2 (see above), the low
temperature structure of 4b·1.5H2O adopts space group
P21 with all previous unit cell base vectors retained. In
comparison to room temperature a desymmetrisation of
the structure takes place, which leads to two crystallo-
graphically independent N-butylgalanthamine moieties,
two independent iodide ions, and three independent
water molecules whereas the basic architecture of the
room temperature structure remains unchanged (P21 is
a maximal non-isomorphic subgroup of space group
C2; C-centering and two-fold axes vanish on transition
to P21). Most interesting result of this transformation
is, that the two independent galanthaminium cations in
the low temperature structure differ in conformation of
the azepine rings. The molecule shown in Fig. 1(a)
adopts the usual chair conformation whereas the sec-
ond one shown in Fig. 1(b) exhibits the unusual boat
conformation. Such boat conformation by now has
been reported only for two galanthamine type com-
pounds that bear –(C(7)ꢁO)ꢀN(1)R- instead of the
groups –C(7)H2ꢀN(1)R- or –C(7)H2ꢀN(1)R2- in the
azepine rings.14 It should be mentioned here that in the
213 K structure of 4b·1.5H2O about 1/3 of the
molecules shown in Fig. 1(b) (boat conformation) is by
disorder still replaced by molecules with chair confor-
mation. In view of the phase transition from room
temperature to 213 K it is expected that this amount of
chair-type molecules replacing those shown in Fig. 1(b)
decreases at temperatures below 213 K.
The structure of ent-4b·DMF is pseudosymmetric by
deviating moderately from a monoclinic one with 21
axes parallel to the crystallographic a-axis and space
group P2111. The deviation of the real unit cell angle
i=95.36° from 90° is however significant and appears
to be caused by the two independent DMF solvent
molecules, which differ notably in their spatial orienta-
tions and thermal displacements.
Acknowledgements
The authors thank Sanochemia Pharmazeutika AG for
their financial support and donation of chemicals.
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M. Hirnschall et al. / Tetrahedron: Asymmetry 14 (2003) 675–681
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