One-step conversion of galanthamine to lycoraminone: A novel hydride- transfer reaction

Full text of DOI:10.1021/jo980271g

J . Org. Chem. 1998, 63, 4535-4538
4535
Sch em e 1a
On e-Step Con ver sion of Ga la n th a m in e to
Lycor a m in on e: A Novel Hyd r id e-Tr a n sfer
Rea ction
Thomas B. K. Lee,† Keith E. Goehring, and
Zhenkun Ma*
Hoechst Marion Roussel, Inc.,
Bridgewater, New J ersey 08807-0800
Received February 17, 1998
Galanthamine (1) and its structurally related com-
pounds such as lycoramine (2) are members of the
Amaryllidaceae family of alkaloids that have been known
for more than 4 decades.1 There were relatively few
publications in the early years, and they were mainly
focused on the structure identification2 and the total
synthesis of these alkaloids.3 Since 1986, galanthamine
research was stimulated by the discovery of its acetyl-
choline esterase inhibition activity and its potential
clinical application for the treatment of Alzheimer’s
disease. Recent work has been focused on its practical
synthesis, mechanism of action, pharmacological profile,
and structure-activity relationships.4 In the past few
years, a variety of galanthamine derivatives have been
synthesized in order to improve potency and to reduce
side effects.4a
During our development of novel pharmaceuticals for
the treatment of Alzheimer’s disease, we observed that
galanthamine (1) was converted to lycoraminone (3) in
a single step. This transformation normally requires a
two-step process involving the oxidation of the allylic
alcohol and the reduction of the olefin double bond.4a
Thus, when 1 was treated with potassium hydride (KH)
in toluene in the presence of hexamethylphosphoramide
(HMPA) at 60 °C for 4 h, 3 was obtained in 85% yield.5
The structure of 3 was confirmed by Swern oxidation of
1 to narwedine (4) followed by catalytic hydrogenation
of 4 to 3. This reaction represents a novel redox process
such that within the same molecule one functional group
a
Conditions: (a) NaBD4, CH3OD; (b) KH, HMPA, toluene, 80
°C, 5 h; (c) D2, Pd-C, toluene; (d) DMSO, (COCl)2, CH2Cl2, then
KOH, CH3OH.
* To whom correspondence should be addressed. Current address:
Infectious Diseases Research, Abbott Laboratories, 100 Abbott Park
Rd, Abbott Park, IL 60064.
† Current address: Pharmaceutical Process Development, Roche
Carolina, Inc., 6173 E. Old Marion Highway, Florence, SC 29506-
9300.
(1) For references, see: Dictionary of Natural Products; Chapman
& Hall: London, 1994; p 2493.
(2) (a) Barton, D. H. R.; Kirby, G. W. J . Chem. Soc. 1962, 806. (b)
Kobayashi, S.; Shingu, T.; Uyeo, S. Chem. Ind. 1956, 177. (c) Williams,
D. J .; Rogers, D. Proc. Chem. Soc., London 1964, 357.
(3) See ref 2a and (a) Kametani, T.; Shishido, K.; Hayashi, E.; Seino,
C.; Kohno, T.; Shibuya, S.; Fukumoto, K. J . Org. Chem. 1971, 36, 1295.
(b) Fuganti, C.; Ghiringhelli, D.; Grasselli, P.; Mazza, M. Tetrahedron
Lett. 1974, 2261. (c) Schultz, A. G.; Yee, Y. K.; Berger, M. H. J . Am.
Chem. Soc. 1977, 99, 8066. (d) Sanchez, I. H.; Siria, J . J .; Lopez, F. J .;
Larraza, M. I.; Flores, H. J . J . Org. Chem. 1984, 49, 157. (e) Ackland,
D. J .; Pinhey, J . T. J . Chem. Soc., Perkin Trans. 1 1987, 2695. (f)
Szewezyk, J .; Lewin, A. H.; Carroll, F. I. J . Heterocycl. Chem. 1988,
25, 1809. (g) Shieh, W.-C.; Carlson, J . A. J . Org. Chem. 1994, 59, 5463.
(h) Chaplin, D. A.; Fraser, N.; Tiffin, P. D. Tetrahedron Lett. 1997, 38,
7931.
(4) For reviews, see: (a) Bores, G. M.; Kosley, R. W. Drugs Future
1996, 21, 621. (b) Mucke, H. A. M. Drugs Today 1997, 33, 251.
(5) The counterion has a large effect on the reaction. When LiH was
used, no reaction occurred. NaH provided reaction product but required
a higher temperature. For a similar counterion effect, see: Wilson, S.
R.; Mao, D. T.; J ernberg, K. M.; Ezmirly, S. T. Tetrahedron Lett. 1977,
2559.
(-OH) is being oxidized and another functional group
(-CdC-) is being reduced. Because of the great mecha-
nistic interest and synthetic potential of such reactions,
we decided to further elucidate the stereochemical course
and the reaction mechanism of this transformation.
Deuterium-labeled galanthamine (1-d ) was thus pre-
pared to probe the reaction process (Scheme 1). Reduc-
S0022-3263(98)00271-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/29/1998

4536 J . Org. Chem., Vol. 63, No. 13, 1998
Ta ble 1. 1H a n d 13C Ch em ica l Sh ifts of Com p ou n d 3 a n d 3-d a
Notes
3
3-d
position
δ C-13
δ H-1
δ C-13
δ H-1
1
2
208.8
35.6
208.8
35.6
a: 2.09 (ddd, J ) 18.0, 15.0, 4.0 Hz)
e: 2.34 (ddd, J ) 18.0, 4.0, 3.6 Hz)
a: 1.79 (ddd, J ) 15.0, 15.0, 3.6 Hz)
e: 2.40 (ddd, J ) 15.0, 4.0, 4.0 Hz)
a: 2.08 (dd, J ) 18.0, 15.0 Hz)
e: 2.33 (dd, J ) 18.0, 3.6 Hz)
a: 1.78 (br dd, J ) 15.0, 3.6 Hz)
3
29.5
29.3 (t)b
4
5
47.5
36.2
47.4
36.2
a: 2.26 (ddd, J ) 13.5, 13.5, 3.0 Hz)
e: 1.66 (br d, J ) 13.5 Hz)
a: 3.28 (br dd, J ) 13.5, 13.5 Hz)
e: 3.15 (br d, J ) 13.5 Hz)
a: 4.16 (d, J ) 17.5 Hz)
a: 2.25 (ddd, 13.5, J ) 13.5, 3.0 Hz)
e: 1.62 (br dd, J ) 13.5, 3.0 Hz)
a: 3.24 (br dd, J ) 13.5, 13.5 Hz)
e: 3.12 (br d, J ) 13.5 Hz)
a: 4.12 (d, J ) 17.5 Hz)
e: 3.67 (d, J ) 17.5 Hz)
6
7
54.0
59.8
54.0
59.8
e: 3.70 (d, J ) 17.5 Hz)
8
9
131.7
111.0
122.3
143.7
129.0
146.7
88.3
131.7
111.0
122.3
143.7
129.0
146.7
88.3
6.66 (AB q) with 10
6.69 (AB q) with 9
6.65 (AB q) with 10
6.69 (AB q) with 9
10
11
12
13
14
15
4.78 (dd, J ) 3.3, 2.7 Hz)
a: 2.65 (dd, J ) 20.0, 2.7 Hz)
e: 3.03 (dd, J ) 20.0, 3.3 Hz)
2.37 (s)
4.78 (dd, J ) 3.4, 2.7 Hz)
a: 2.65 (dd, J ) 20.0, 2.7 Hz)
e: 3.03 (dd, J ) 20.0, 3.3 Hz)
2.40 (s)
40.1
40.1
16
17
41.9
55.9
41.9
55.9
3.85 (s)
3.85 (s)
a
b
a, axial proton; e, equatorial proton. Triplet and reduced intensity.
tion of 4 with sodium borodeuteride provided deuterium-
labeled galanthamine (1-d ) and epi-galanthamine (1-d ′)
in an 87:13 ratio. Compound 1-d was isolated and then
subjected to rearrangement conditions (KH/HMPA/
toluene, 80 °C, 5 h)6 to provide deuterium-labeled lyc-
oraminone (3-d ).7 All protons and carbons in compound
3 were assigned by COSY and HETCOR experiments
through H-H correlation, H-C correlation, and coupling
constants (Table 1). The 1H NMR spectrum of 3-d
indicated that the peak at 2.40 ppm corresponding to the
equatorial proton at the 3-position was completely absent.
Meanwhile the peak at 1.79 ppm corresponding to the
axial proton at the 3-position remained undiminished.
The 13C NMR spectrum of 3-d showed that the peak at
29.5 ppm, corresponding to the 3-carbon, was signifi-
cantly reduced and was split into a triplet. These data
indicated that the deuterium has moved completely to
the 3-position. This conclusion was further confirmed by
synthesis (Scheme 1). Catalytic deuteration of 1 provided
deuterium-labeled lycoramine (2-d 2). Swern oxidation
followed by deuterium exchange provided a mixture of
3-d and its C-3 diastereomer.
respectively. Only two conformations, i and ii, in which
the 14-proton is gauche to both of the 15-protons, are
consistent with these coupling constants. The NOEs
between protons 3a-15a, 3a-5e, 3a-6a, and 5e-15a
indicated that ii is the most favored conformation.9 Of
the four possible conformations, only ii is consistent with
all the NOE data. On the basis of NMR experiments,
the absolute structure of 3-d was then determined to be
as shown in Scheme 1.
1
The H NMR data for compound 3-d revealed that the
deuterium was completely transferred to the equatorial
position on the 3-carbon, and this conclusion was further
supported by the deuterium NMR experiments. The
deuterium NMR spectrum of 3-d showed only a single
peak at 2.39 ppm and no detectable amount of deuterium
at any other position indicating a stereospecific reaction.
To determine the absolute stereochemistry of 3-d , a
NOESY experiment was performed. There are four
possible conformations for the six-membered ring in
compound 3.8 The coupling constants between the 14-
proton and the two 15-protons are 2.7 and 3.3 Hz,
The transformation from 1 to 3 represents a formal
antarafacial 1,3-hydrogen-transfer reaction process. Con-
servation of orbital symmetry suggests10 that a thermally
allowed 1,3-hydrogen-transfer reaction requires an ant-
arafacial process, and the stereochemistry of the reaction
product (3-d ) is in agreement with that. Theoretically,
lycoraminone (3-d ) can be formed via an antarafacial 1,3-
hydrogen transfer reaction from galanthamine alkoxide
(5-d ) to enolate (6-d ) as shown in Scheme 2. However,
(6) The deuterium-labeled compound 1-d reacted substantially
slower than the unlabeled compound 1.
(8) For conformations of galanthamine, see: Vlahov, R.; Krikorian,
D.; Spassov, G.; Chinova, M.; Vlahov, I.; Parushev, S.; Snatzke, G.;
Ernst, L.; Kieslich, K.; Abraham, W.; Sheldrick, W. S. Tetrahedron
1989, 45, 3329.
(9) Molecular mechanics calculations indicated that ii is about 2.30
kcal/mol more stable than i.
(7) Under the same conditions, 1-d ′ and the simple 2-cyclohexen-
1-ol failed to give hydride-transfer products. The coordination between
potassium and the ring oxygen and the methoxy oxygen in compound
1-d may play a key role in this reaction. Such coordination is not
possible in 1-d ′. For a crown ether-promoted anionic rearrangement,
see: Bhupathy, M.; Cohen, T. J . Am. Chem. Soc. 1983, 105, 6978.
(10) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital
Symmetry; Academic Press: New York, 1970.

Notes
J . Org. Chem., Vol. 63, No. 13, 1998 4537
Sch em e 2
molecular hydride-transfer reaction. In the same reac-
tion, one part of the molecule was reduced while another
part of the molecule was oxidized. This transformation
represents one of the most efficient and economical
processes in that one functional group (-OH) was
oxidized by another functional group (-CdC-) of the
same molecule.
Exp er im en ta l Section
Galanthamine (1) was prepared in 99% purity from com-
mercial galanthamine hydrobromide.12 All reactions were car-
ried out in an air-tight flask with nitrogen purge except as
otherwise indicated. Reactions were monitored by high-
performance liquid chromatography (HPLC) on a Bondclone 10
C18 column with 20:80:0.5:0.5 acetonitrile-H2O-triethylamine-
acetic acid solution as eluting solvent (1.5 mL/min).
Sch em e 3
P r ep a r a tion of Na r w ed in e (4). To a stirred solution of
oxalyl chloride (6.96 mL, 80.0 mmol) in CH2Cl2 (175 mL) at -60
°C was added a solution of DMSO (12 mL) in CH2Cl2 (36 mL)
over 5 min. The reaction mixture was allowed to warm to -50
°C, and a solution of galanthamine (1) (10.0 g, 34.8 mmol) in
CH2Cl2 (40 mL) was introduced over 5 min. After the reaction
mixture had been stirred at -55 to -40 °C for 30 min, Et3N (50
mL) was added over 20 min, and the mixture stirred for an
additional 5 min. The reaction mixture was then allowed to
warm to room temperature, and the reaction was quenched with
iced water. The mixture was extracted with CHCl3 (50 mL),
and the organic phase was then washed with water (50 mL) and
brine (50 mL) and dried over Na2SO4. After filtration and
concentration, an off-white solid was obtained. The crude
product was purified by flash column chromatography (silica gel,
1:9 MeOH-CH2Cl2) to give narwedine (4) (8.82 g, 88%) as a
white solid: mp 186-188 °C (lit.2a mp 187-189 °C); HPLC
retention time 5.12 min; 1H NMR (200 MHz, CDCl3) δ 6.96 (dd,
1H, J ) 10.4, 2.0 Hz), 6.71 (d, 1H, J ) 8.0 Hz), 6.64 (d, 1H, J )
8.0 Hz), 6.22 (d, 1H, J ) 10.4 Hz), 4.73 (m, 1H), 4.09 (d, 1H, J
) 15.6 Hz), 3.83 (s, 3H), 3.73 (d, 1H, J ) 15.6 Hz), 3.15-3.32
(m, 3H), 2.75 (dd, 1H, J ) 17.2, 4.0 Hz), 2.44 (s, 3H), 2.27 (ddd,
1H, J ) 14.0, 12.4, 4.0 Hz), 1.85 (ddd, 1H, J ) 14.0, 4.0, 2.4
Hz).
P r ep a r a tion of Lycor a m in on e (3). Narwedine (4) (1.42 g,
5.00 mmol) was dissolved in EtOAc (100 mL), and 10% Pd-C
(300 mg) was then added under nitrogen. The system was
flushed with hydrogen three times and hydrogenated at atmo-
spheric pressure for 20 h. The catalyst was removed by
filtration, and the solvent was evaporated. The crude product
was purified by flash column chromatography (silica gel, 1:9
MeOH-CH2Cl2) to provide lycoraminone (3) (1.31 g, 92%) as a
such a 1,3-antarafacial process suffers a severe steric
distortion which makes the necessary transition state
highly unfavorable. In fact, such a reaction has never
been observed.11 With that in mind, all the experimental
evidence we observed so far supports a Meerwien-
Ponndorf-Verley/Oppenauer-like intermolecular hydride-
transfer reaction as shown in Scheme 3. The trace
amount of narwedine (4) that exists in the starting
material or is being generated during the reaction
initiates a chain process in which alkoxide (5) transfers
a hydride from its 1-position to the 3-position of 4
stereospecifically. During this process 4 is regenerated
and 6 is produced, which is converted to 3 upon aqueous
workup. Unlike the Meerwein-Ponndorf-Verley/Op-
penauer reaction, the hydride from the alkoxide is
transferred to the â-carbon of the R,â-unsaturated ketone
instead of the carbonyl carbon.
1
white foam: HPLC retention time 4.84 min; for H and 13C NMR,
see Table 1; IR (KBr) 3050, 1725 cm-1; MS m/z (relative
intensity) 288 (13), 287 (M+, 85), 286 (100), 272 (2), 258 (3), 244
(5), 230 (8), 218 (19), 202 (34), 187 (17).
Rea ction of Ga la n th a m in e (1). To a suspension of KH (60
mg, 1.50 mmol) in toluene (5.0 mL) under nitrogen at room
temperature was added a solution of galanthamine (1) (287 mg,
1.00 mmol) in toluene (5.0 mL) over 5 min. HMPA (1.0 mL)
was then introduced, and the reaction mixture was stirred at
60 °C for 4 h. The reaction mixture was taken up in EtOAc (50
mL), washed with water (2 × 50 mL) and brine (50 mL), and
dried over Na2SO4. After the solvent was evaporated, lycorami-
none (3) (240 mg, 84%) was obtained as an off-white foam:
HPLC retention time 4.77 min; 1H NMR and MS identical to
those of lycoraminone obtained above (see Table 1).
P r ep a r a t ion of Deu t er iu m -La b eled Ga la n t h a m in e (1-
d ). To a stirred solution of narwedine (4) (1.42 g, 5.00 mmol) in
CH3OD (40 mL) at 0 °C under nitrogen was added NaBD4 (837
mg, 20.0 mmol) in small portions over 1 h. The ice bath was
removed, and the reaction mixture was stirred for an additional
10 min at 0-10 °C. Brine (100 mL) was added, and the resulting
mixture was extracted with CH2Cl2 (100 mL). The organic phase
was dried over Na2SO4 and evaporated to give a white foam.
In conclusion, galanthamine (1) was converted to
lycoraminone (3) in a single step through a novel inter-
(11) A formal antarafacial [1,3]-alkyl transfer in an anti-7-nor-
bornenol system was reported but was believed to proceed through a
fragmentation-recombination pathway; see: Paquette, L. A.; Pierre,
F.; Cottrell, C. E. J . Am. Chem. Soc. 1987, 109, 5731. Paquette, L. A.;
DeRussy, D. T. Tetrahedron 1988, 44, 3139.
(12) Carroll, P.; Furst, G. T.; Han, S. Y.; J oullie, M. Bull Soc. Chim.
Fr. 1990, 127, 769.

4538 J . Org. Chem., Vol. 63, No. 13, 1998
Notes
Flash column chromatography (silica gel, 1:9 MeOH-CH2Cl2)
provided 1-d (520 mg, 37%) as a white foam: HPLC retention
time 3.73 min; H NMR (200 MHz, CDCl3) δ 6.64 (AB q, 2H, J
) 8.2 Hz), 6.03 (AB q, 2H, J ) 10.2 Hz), 4.61 (m, 1H), 4.10 (d,
1H, J ) 15.4 Hz), 3.83 (s, 3H), 3.68 (d, 1H, J ) 15.4 Hz), 3.27
(m, 1H), 3.05 (m, 1H), 2.65 (m, 1H), 2.40 (s, 3H), 1.95-2.17 (m,
2H), 1.58 (m, 1H); MS (EI) m/z (relative intensity) 289 (60), 288
(69), 287 (51), 245 (17), 216 (91).
product obtained was purified by flash column chromatography
(silica gel, 1:4 MeOH-CH2Cl2) to provide 3-d (150 mg, 52%) as
a white foam: HPLC retention time 4.77 min; for 1H NMR, see
1
2
Table 1; H NMR (500 MHz, CHCl3) δ 2.39 (br s); MS (EI) m/z
(relative intensity) 290 (13), 289 (53), 288 (M+, 100), 287 (66),
273 (2), 259 (3), 245 (4), 231 (7), 219 (15), 203 (37), 188 (14).
Ack n ow led gm en t. We thank Mr. J ason B. Karns
for technical assistance in obtaining two-dimensional
NMR spectra, Dr. Dorothea Kominos for performing
molecular modeling, and Dr. Raymond W. Kosley for
helpful discussion.
1H NMR (200 MHz, CDCl3) for galanthamine (1): δ 6.64 (AB
q, 2H, J ) 8.2 Hz), 6.03 (m, 2H), 4.61 (m, 1H), 4.15 (m, 1H),
4.10 (d, 1H, J ) 15.6 Hz), 3.83 (s, 3H), 3.68 (d, 1H, J ) 15.6
Hz), 3.26 (m, 1H), 3.04 (m, 1H), 2.66 (m, 1H), 2.40 (s, 3H), 1.95-
2.17 (m, 2H), 1.57 (m, 1H).
Rea ction of Deu ter iu m -La beled Ga la n th a m in e (1-d ). To
a suspension of KH (60 mg, 1.50 mmol) in toluene (5.0 mL) under
nitrogen at room temperature was added a solution of deuterium-
labeled galanthamine (1-d ) (288 mg, 1.00 mmol) in toluene (5.0
mL) over 5 min. HMPA (1.0 mL) was then introduced, and the
reaction mixture was stirred at 60 °C for 2 h and then at 80 °C
for 6 h. The reaction mixture was taken up in EtOAc (50 mL),
washed with water (2 × 50 mL) and brine (50 mL), and dried
over Na2SO4. After the solvent was evaporated, the crude
Su p p or tin g In for m a tion Ava ila ble: Various NMR spec-
tra for compounds 3 and 3-d (13 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O980271G