Stereoselective syntheses of galanthamine and its stereoisomers by complementary Luche and L-selectride reductions

Article abstract of DOI:10.1016/j.tetasy.2013.11.016

A diastereodivergent approach for the stereoselective syntheses of all four stereoisomers of galanthamine, (-)-galanthamine 1, (+)-galanthamine 2, (-)-epigalanthamine 3, and (+)-epigalanthamine 4, from (±)-narwedine 5 is reported. Thus (±)-narwedine 5 was resolved by dynamic kinetic resolution to obtain enantiomerically pure (-)-narwedine 6 and (+)-narwedine 7. Each enantiomerically pure isomer of narwedine was subjected to Luche and L-selectride reactions to obtain all four isomers of galanthamine. In these reactions, the (-)-galanthamine 1 and (+)-galanthamine 2 isomers were obtained with an enantiomeric purity of >99.5%, whereas (-)-epigalanthamine 3 and (+)-epigalanthamine 4 are obtained with a chiral purity of >97%. The axial hydride attack by the Luche reduction and the equatorial hydride attack by the L-selectride reduction on the cyclic enone system are explored in the stereoselective synthesis of the galanthamine isomers and thus it was demonstrated that the stereoselective synthesis involving the Luche and L-selectride reductions are complementary in yielding enantiomeric stereogenic centers from a prochiral carbonyl group on the cyclic enone system.

Full text of DOI:10.1016/j.tetasy.2013.11.016

Tetrahedron: Asymmetry 25 (2014) 117–124
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Tetrahedron: Asymmetry
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Stereoselective syntheses of galanthamine and its stereoisomers by
complementary Luche and L-selectride reductions
Ganala Naga Trinadhachari a,b, Anand Gopalkrishna Kamat a, Korupolu Raghu Babu b,
Paul Douglas Sanasi b, Koilpillai Joseph Prabahar a,
⇑
a Chemical Research and Development, APL Research Center, Aurobindo Pharma Ltd, Survey No. 71 & 72, Indrakaran (V), Sangareddy (M), Medak Dist 502329, Andhra Pradesh, India
b Department of Engineering Chemistry, A.U. College of Engineering, Andhra University, Visakhapatnam 530003, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 September 2013
Accepted 28 November 2013
A diastereodivergent approach for the stereoselective syntheses of all four stereoisomers of galantha-
mine, (ꢀ)-galanthamine 1, (+)-galanthamine 2, (ꢀ)-epigalanthamine 3, and (+)-epigalanthamine 4, from
( )-narwedine 5 is reported. Thus ( )-narwedine 5 was resolved by dynamic kinetic resolution to obtain
enantiomerically pure (ꢀ)-narwedine 6 and (+)-narwedine 7. Each enantiomerically pure isomer of
narwedine was subjected to Luche and L-selectride reactions to obtain all four isomers of galanthamine.
In these reactions, the (ꢀ)-galanthamine 1 and (+)-galanthamine 2 isomers were obtained with an enan-
tiomeric purity of >99.5%, whereas (ꢀ)-epigalanthamine 3 and (+)-epigalanthamine 4 are obtained with a
chiral purity of >97%. The axial hydride attack by the Luche reduction and the equatorial hydride attack
by the L-selectride reduction on the cyclic enone system are explored in the stereoselective synthesis of
the galanthamine isomers and thus it was demonstrated that the stereoselective synthesis involving the
Luche and L-selectride reductions are complementary in yielding enantiomeric stereogenic centers from
a prochiral carbonyl group on the cyclic enone system.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
H
OH
H
OH
(S)
(R)
(
)
R
Galanthamine 1 is a tertiary alkaloid, which is chemically
known as (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-
methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-ol. The naturally
occurring and therapeutically active isomer is (ꢀ)-galanthamine 1,
which has a configuration of (4aS,6R,8aS) and has been approved
for the treatment of mild to moderate Alzheimer’s disease. The
chemical structures of galanthamine 1 and its stereoisomers 2, 3,
and 4 are shown in Figure 1.1
(R)
(S)
(S)
O
O
N
N
CH3
CH3
H3CO
H3CO
2
1
(4aR,6S,8aR)
(4aS,6R,8aS)
(-)-galanthamine
(+)-galanthamine
Thefirst successful synthesisof (ꢀ)-galanthamine 1 was reported
by Barton and Kirby in 1962 in which ( )-narwedine 5 was resolved
to obtain (ꢀ)-narwedine 6, which was then reduced with lithium
aluminum hydride to obtain a mixture of (ꢀ)-galanthamine 1 and
(ꢀ)-epigalanthamine 3. Barton also reported on the reduction of
(+)-narwedine 7 with LiAlH4 toobtain a mixtureof (+)-galanthamine
2 and (+)-epigalanthamine 4. The residue obtained after the reduc-
tion was subjected to chromatographic separation to obtain both
(+)-galanthamine 2 (36% yield) and (+)-epigalanthamine 4 (25%
yield), which indicates that the selectivity of the LiAlH4 reduction
of (+)-narwedine 7 favors the formation of (+) galanthamine 2 rather
than (+)-epigalanthamine 4 in a ratio of 1.4:1.2 Szewczyk et al. pre-
H
OH
H
OH
(S)
(R)
(R)
(S)
(S)
( )
R
O
O
N
N
CH3
CH3
H3CO
H3CO
4
3
(4aR,6R,8aR)
(4aS,6S,8aS)
(-)-epigalanthamine
(+)-epigalanthamine
Figure 1. Structures of the galanthamine stereoisomers.
pared (ꢀ)-galanthamine 1 and (+)-galanthamine 2 from 1-bromo-
⇑
Corresponding author. Tel.: +91 9885327333.
E-mail address: joseph.prabahar@gmail.com (K.J. Prabahar).
11-formyl-nornarwedine; this synthetic approach involved
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.11.016

118
G. N. Trinadhachari et al. / Tetrahedron: Asymmetry 25 (2014) 117–124
(1S)-(ꢀ)-camphanic chloride as a resolving agent and fractional
crystallization from methanol to obtain (ꢀ)-galanthamine 1 and
(+)-galanthamine 2.3 Many other synthetic routes for the
preparation of (ꢀ)-galanthamine have also been reported in the lit-
erature.4–8 Valhov et al. prepared (ꢀ)-epigalanthamine 3 via micro-
bial reductive transformations of 1-bromo narwedine-12-one to a
(ꢀ)-epigalanthamine derivative with an isolated yield of 50% pure
product, which was further reduced with lithium aluminum hydride
to obtain (ꢀ)-epigalanthamine 3 in 92% yield. The selectivity ob-
tained here is due to the microbial reductive transformation and
not because of the LiAlH4 reduction.9 Tomioka et al. synthesized
approach. In a continuation of our interests in synthesizing tertiary
alkaloids, we herein report the synthesis of the galanthamine
isomers in a diastereodivergent synthetic approach.
2. Results and discussion
The synthesis of all four stereoisomers of galanthamine in a dia-
stereodivergent approach is shown in Scheme 1. Herein we chose
( )-narwedine 5 as a key starting material for the synthesis of the
galanthamine isomers. This approach involves two critical synthetic
stages; the first is the kinetic dynamic resolution of ( )-narwedine 5
and the second is the reduction of the narwedine isomers by com-
plementary stereoselective reduction reactions to give all four iso-
mers of galanthamine with an enantiomeric purity of >97%. The
resolution of ( )-narwedine 5 to obtain (ꢀ)-narwedine 6 was first
reported by Barton.2 Shieh et al. explained the mechanism of this ki-
netic dynamic resolution process of ( )-narwedine 5 with a retro-
Michael ring opening and ring closing dienone system.12 It has also
been reported that either (ꢀ)-narwedine 6 or (+)-galanthamine 2
can be used to induce the resolution to produce (ꢀ)-narwedine 6
as a single pure isomer.12,13 The resolution was reported to be
(+)-galanthamine 2 from L
-tyrosine in seven steps.10 Dyer et al. pre-
pared a 1:1 mixture of (+)-galanthamine 2 and (+)-epigalanthamine
4 by reducing (+)-narwedine 7 with lithium aluminum hydride in
the presence of N-methylephedrine and N-ethyl-2-aminopyridine.
This clearly signifies that there is no selectivity during the reduction,
hence the selectivity is almost equal with regard to the formation of
both diastereoisomers. Flash chromatography of this 1:1 mixture
yielded (+)-galanthamine 2 (98% ee, 30% yield) and (+)-epigalanth-
amine 4 (95% ee, 26% yield).11 To the best of our knowledge, there
is no report that prepares all four isomers in a diastereodivergent
O
6
5
7
8
10
12
4 O
11
9
N
CH3
3
1
H3CO
2
5
triethylamine
/
triethylamine
/
(-)-narwedine seed
(+)-Narwedine seed
O
O
(S)
(R)
(S)
(R)
O
O
N
N
CH3
CH3
H3CO
H3CO
(-)-narwedine
(+)-narwedine
[(4aS,8aS)-isomer]
[(4aR,8aR)-isomer]
6
7
1) NaBH4 / CeCl3
2) purification
from acetone
1) NaBH4 / CeCl3
2) purification
from acetone
L-selectride
L
-selectride
H
OH
H
OH
H
OH
H
OH
(R)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(
)
S
(S)
(
)
R
(R)
O
O
O
O
N
N
N
N
CH3
CH3
CH3
CH3
H3CO
H3CO
H3CO
H3CO
(-)-galanthamine
(-)-epigalanthamine
(+)-galanthamine
(+)-epigalanthamine
1
3
2
4
Scheme 1. The synthesis of all four stereoisomers of galanthamine 1, 2, 3, and 4.

G. N. Trinadhachari et al. / Tetrahedron: Asymmetry 25 (2014) 117–124
119
carried out with an appropriate enantiomerically pure enantiomer
seeding a supersaturated ethanolic solution of ( )-narwedine 5 in
the presence or absence of triethylamine. The resolution was
achieved by stirring the mixture at 40 °C for 12 h to 7 days.12–16
We carried out the kinetic dynamic resolution of ( )-narwedine 5
by following the reported procedures and observed that these re-
ported procedures were inconsistent in yielding an impure (ꢀ)-nar-
wedine 6 isomer, which was contaminated with the undesired
enantiomer, (+)-narwedine 7. For the successful synthesis of enan-
tiomerically pure galanthamine isomers, the resolution process of
( )-narwedine 5 should consistently yield the narwedine isomers
with high enantiomeric purity. We presume that the resolution time
and temperature play an important role in yielding the narwedine
isomers with a higher enantiomeric purity. Hence we decided to
optimize these two key parameters in the kinetic dynamic resolu-
tion of ( )-narwedine 5.
To investigate this kinetic dynamic resolution process of ( )-
narwedine 5, we monitored the resolution process of ( )-narwe-
dine 5 by analyzing aliquots at different stages by chiral HPLC
methods. As expected, we observed that prior to adding the seed
of (ꢀ)-narwedine, the ethanolic solution of ( )-narwedine 5 at
reflux temperature contains both stereoisomers (ꢀ)-narwedine 6
and (+)-narwedine 7 in almost equal amounts in an equilibrium
state. The resolution mixture was cooled to 72–73 °C and (ꢀ)-
narwedine 6 was added as a seed. (ꢀ)-Narwedine 6 started to crys-
tallize from the solution after the addition of the (ꢀ)-narwedine 6
seed and the mixture was slowly cooled to room temperature over
a period of 4 h. During this process, aliquots of the resolution slurry
were collected at different temperatures. The aliquots collected at
different temperatures were filtered and the solids were analyzed
by chiral HPLC to check the contents for (+)-narwedine 6 and
(ꢀ)-narwedine 7. The results obtained by the kinetic dynamic
resolution of ( )-narwedine 5 to obtain (ꢀ)-narwedine 6 at
different temperature are summarized in Table 1.
process in order to check the content of (+)-and (ꢀ)-narwedine
after seeding and cooling the reaction. In this experiment, aliquots
of the slurry collected at different intervals were filtered and the
filtered solids as well as mother liquors were analyzed by chiral
HPLC method. The results obtained from this resolution study at
different intervals of time are given in Table 2.
The above experimental results showed that the filtrates
obtained from the aliquots contain a racemic mixture of narwe-
dine. It was also concluded that stirring the resolution mixture
for 3ꢀ4 h at 40ꢀ42 °C was required to obtain an enantiomerically
pure product with very good yield. Based on these studies, we
summarized this kinetic dynamic resolution of ( )-narwedine 5
to obtain a pure enantiomer of (ꢀ)-narwedine 6 as follows: ( )-
narwedine 5 is dissolved in aqueous ethanol solution containing
triethylamine at 75–80 °C to obtain a saturated solution and cooled
to 70–73 °C. (ꢀ)-Narwedine 6 seed crystals were added at 70–
73 °C. This resolution mixture was then gradually cooled to 40–
42 °C and stirring was continued at 40–42 °C for 3–4 h to obtain
enantiomerically pure (ꢀ)-narwedine 6. The slurry mass was
cooled to 25–30 °C and filtered to obtain (ꢀ)-narwedine 6 with
an enantiomeric purity of >99.5% and purity of >99.5% (by HPLC).
The resolution of (+)-narwedine
7 from ( )-narwedine 5
requires (+)-narwedine 7 seed crystals, which were prepared by
the resolution of ( )-narwedine 5 by using (ꢀ)-galanthamine 1 as
the seed, as reported in the literature.2,13 Thereafter, (+)-narwedine
7 was successfully prepared by seeding the ethanolic solution of
( )-narwedine 5 containing triethylamine at 70–73 °C with (+)-
narwedine 7 seed crystals; the resolution process was continued
as described for the preparation of (ꢀ)-narwedine.
Our next goal was to prepare all four stereoisomers of galantha-
mine diastereoselectively from enantiomerically pure narwedine
isomers. The prochiral carbonyl group of narwedine has to be
reduced diastereoselectively to obtain all fours isomers of galan-
thamine. Hence we evaluated two complementary reducing
agents, which could either predominantly facilitate an axial hy-
dride attack to yield an equatorial alcohol or facilitate equatorial
hydride attack to give an axial alcohol.17
The initial solution of narwedine and the filtrates obtained from
the aliquots collected at different temperatures during the resolu-
tion process, contain a racemic mixture of narwedine. It is well
known that narwedine in solution exists as a racemic mixture
and while crystallizing out from the solution, it separates out as
enantiomerically pure (ꢀ)-narwedine 6. Herein we have shown
that the resolution of narwedine to obtain (ꢀ)-narwedine 6 isomer
can be achieved in a shorter time period.
It was reported in the literature18 that the bulk of the reagent
appears to dictate the hydride approach from the less sterically
hindered face to facilitate an equatorial hydride attack to yield
an axial alcohol; thus (ꢀ)-narwedine 6 was reduced with L-select-
ride to yield exclusively (ꢀ)-galanthamine 1.12,13 Sodium borohy-
dride could facilitate axial attack19 and thus initially, we carried
out the reduction reaction of (ꢀ)-narwedine 6 with sodium
borohydride in methanol solvent and anticipated the product as
Secondly, since the reported procedures12–15 for this resolution
recommend an optimized temperature of approximately 40 °C, we
studied this resolution at 40–42 °C at different intervals of the
Table 1
Resolution of ( )-narwedine 5 at different temperatures
Content of isomersa
O
O
(
)
R
(S)
(S)
(R)
O
O
N
N
CH3
CH3
H3CO
H3CO
Particulars
Time (h)
After dissolution at 75 °C and before addition of seed
0
1
2
3
4
49.43
99.28
99.60
99.47
99.76
50.57
0.72
0.40
0.53
0.24
Solid obtained from the aliquot of slurry collected at 60 °C and filtered
Solid obtained from the aliquot of slurry collected at 50 °C and filtered
Solid obtained from the aliquot of slurry collected at 40 °C and filtered
Solid obtained from the aliquot of slurry collected at 25 °C and filtered
Reaction conditions: ( )-Narwedine 5 was dissolved in aqueous ethanol containing triethylamine at reflux and seeded with (ꢀ)-narwedine at 72–73 °C and then cooled to
25 °C over a 4 h period.
a
Chromatographic purity (by chiral HPLC, by area normalization).

120
G. N. Trinadhachari et al. / Tetrahedron: Asymmetry 25 (2014) 117–124
Table 2
Resolution process of ( )-narwedine 5 at different intervals of time at 40–42 °C
Content of isomersa
O
O
(S)
(R)
(S)
(R)
O
O
N
N
CH3
CH3
H3CO
H3CO
Particulars
Crystallized solid after cooling to 40 °C in 3–4 h period
Mother liquor at 40 °C
Crystallized solid after stirring at 40–42 °C for 1 h
Mother liquor at 40–42 °C for 1 h
Crystallized solid after stirring at 40–42 °C for 2 h
Mother liquor at 40–42 °C for 2 h
Crystallized solid after stirring at 40–42 °C for 3 h
Mother liquor at 40–42 °C for 3 h
99.12
49.83
99.40
49.31
99.61
48.87
99.74
49.89
99.77
0.88
50.17
0.60
50.69
0.39
51.13
0.26
50.11
0.23
Final filtered solid after cooling to 25–30 °C in 1–2 h period
Reaction conditions: ( )-Narwedine 5 was dissolved in aqueous ethanol containing triethylamine at reflux and seeded with (ꢀ)-narwedine 6 at 72–73 °C and further cooled to
40–42 °C over a 3–4 h period. The reaction mass was then stirred for 3–4 h after cooling (during which time aliquots were taken), then finally cooled to 25–30 °C and filtered.
a
Chromatographic purity (by chiral HPLC, by area normalization).
predominantly being (ꢀ)-epigalanthamine 3 and lycoramine 8.20
However this reaction gave a mixture of ( )-galanthamine 1 and
2, ( )-epigalanthamine 3 and 4 and lycoramine 8 (Scheme 2).
The formation of lycoramine 8 was anticipated due to the conju-
gate reduction of the C-7 double bond. However, the reduction of
(ꢀ)-narwedine 6 in yielding ( )-galanthamine and ( )-epigalanth-
amine has not been understood. Similar results were obtained when
(+)-narwedine 7 was reduced with sodium borohydride in metha-
nol, in which the formation of a ( )-galanthamine and ( )-epiga-
lanthamine racemic mixture was observed instead of the expected
product of predominantly (+)-epigalanthamine 4. We decided to
evaluate the enantiomeric purity of the (ꢀ)-narwedine 6 isomer
while it was suspended in a protic solvent. Therefore, (ꢀ)-narwedine
6 was suspended in methanol at 25–30 °C and stirred at this temper-
ature for 1 h. Aliquots were drawn from the slurry mass after 15 min
and 1 h and filtered. The filtrates, as well as the solids, were analyzed
for (ꢀ)-narwedine 6 and (+)-narwedine 7 contents by chiral HPLC
and we found that the amount of (+)-narwedine 7 slightly increases
in the solid sample. However, the solution contained a racemic
mixture of narwedine. The results from this experiment are shown
in Table 3.
When (ꢀ)-narwedine 6 was suspended in a protic solvent, the
chirality remained intact as long as (ꢀ)-narwedine 6 existed as a
solid and thus no significant racemization occurred. However,
racemization of (ꢀ)-narwedine 6 occurs spontaneously when it is
dissolved in a protic solvent. (+)-Narwedine 7 also behaves in a
similar way in methanol. Hence it was understood that the racemi-
zation of the narwedine isomer, which occurred spontaneously due
to the dissolution during the reduction reaction of narwedine with
sodium borohydride in methanol, and further reduction of racemic
narwedine resulted in the formation of ( )-galanthamine and
( )-epigalanthamine.
We also studied the stability of a homogenous solution of enan-
tiopure (ꢀ)-narwedine 6 in methylene chloride and methanol sol-
vent mixture in the presence and absence of cerium (III) chloride.
Enantiopure (ꢀ)-narwedine 6 in a solvent mixture of methylene
chloride and methanol (1:1 v/v) was stirred at ꢀ50 °C and aliquots
were analyzed by chiral HPLC at different intervals. We observed
O
(S)
(S)
O
N
CH3
H3CO
6
NaBH4 / methanol
H
OH
OH
H
H
OH
(S)
(S)
(
)
R
and the (R,S,R)-
and the (R,R,R)-
(S)
(S)
(S)
enantiomer
enantiomer
O
O
O
+
+
N
N
N
CH3
CH3
CH3
H3CO
H3CO
H3CO
3 and 4
1 and 2
8
Scheme 2. Reduction of (ꢀ)-narwedine with sodium borohydride in the absence of CeCl3.

G. N. Trinadhachari et al. / Tetrahedron: Asymmetry 25 (2014) 117–124
121
Table 3
Stability of (ꢀ)-narwedine 6 in methanol solvent
Content of isomersa
O
O
(
)
R
(S)
(S)
(R)
O
O
N
N
CH3
CH3
H3CO
H3CO
Particulars
Time
Input (ꢀ)-narwedine 6
—
99.95
99.71
53.31
99.80
49.66
00.05
0.29
46.69
0.20
Analysis of the solid obtained after filtration of slurry
Analysis of the filtrate obtained after filtration of slurry
Analysis of the solid obtained after filtration of slurry
Analysis of the filtrate obtained after filtration of slurry
15 min
15 min
1 h
1 h
50.36
a
Chromatographic purity (by chiral HPLC, by area normalization).
that spontaneous racemization of (ꢀ)-narwedine 6 occurred in the
absence of cerium (III) chloride, whereas the chirality of (ꢀ)-nar-
wedine 6 remained intact in the homogenous solution containing
cerium (III) chloride (Luche condition). These experimental results
are summarized in Tables 4 and 5.
isomers. The Luche reduction has advantages such as it being
regiospecific to facilitate 1,2-reduction of cyclic enones and thus
formation of the 1,4-reduction product, lycoramine 8 can be con-
trolled. The Luche reduction also favors an axial hydride attack
and so facilitates the formation of a predominantly equatorial alco-
hol.19,21 The Luche reduction was carried with sodium borohydride
in the presence of cerium (III) chloride to reduce (ꢀ)-narwedine 6;
this reaction was also carried out in different solvents such as tet-
rahydrofuran, methanol, methylene chloride and acetonitrile and
mixtures of solvents such as tetrahydrofuran and methanol (1:1),
methylene chloride and methanol (1:1). It was observed that the
reduction of (ꢀ)-narwedine 6 with sodium borohydride in the
presence of cerium (III) chloride in a mixture of methylene chloride
and methanol (1:1) predominantly yielded an equatorial alcohol,
(ꢀ)-epigalanthamine 3 along with a lesser amount of axial alcohol,
(ꢀ)-galanthamine 1. We also studied the effect of temperature on
the stereoselectivity of the Luche reduction of (ꢀ)-narwedine 6.
Thus, the Luche reaction of (ꢀ)-narwedine 6 was carried out with
sodium borohydride in the presence of cerium (III) chloride at dif-
ferent temperatures and the results are given in Table 6.
In order to achieve a diastereoselective reduction, we decided to
carry out a Luche reaction for the reduction of the narwedine
Table 4
The stability of (ꢀ)-narwedine 6 in a methanol and methylene chloride solution at
ꢀ50 °C
Content of isomersa
O
O
(
)
R
(S)
(S)
(R)
O
O
N
N
CH3
CH3
H3CO
H3CO
The balance of material in all cases comprised of the sum of all
of the other peaks observed in the chromatogram.
Time
Initial
15 min
1 h
99.73
71.23
63.94
60.62
0.27
28.77
36.06
39.38
The above studies showed that when the Luche reduction of
(ꢀ)-narwedine 6 was carried out at ꢀ55 to ꢀ50 °C, effective diaste-
reoselectivity was observed and this yielded the desired equatorial
alcohol, (ꢀ)-epigalanthamine 3 (ꢁ83%) along with axial alcohol
(ꢀ)-galanthamine 1 (ꢁ14%). The diastereoselectivity of this reac-
tion was observed to be ꢁ6:1. This crude product was further puri-
fied by stirring with acetone at reflux temperature to obtain the
desired equatorial alcohol, (ꢀ)-epigalanthamine 3 with an enantio-
meric purity of >97%. It was also found that (ꢀ)-epigalanthamine 3
had a chromatographic purity of >96% (by HPLC) and a specific
rotation of ꢀ230 (c 1, CHCl3).
2 h
a
Chromatographic purity (by chiral HPLC, by area normalization).
Table 5
The stability of (ꢀ)-narwedine 6 in a methanol and methylene chloride solution at
ꢀ50 °C in the presence of CeCl3ꢂ7H2O
Similarly, (+)-narwedine 7 was subjected to a Luche reduction
with sodium borohydride in the presence of cerium (III) chloride
at ꢀ55 to ꢀ50 °C to give ꢁ83% of the equatorial alcohol (+)-epiga-
lanthamine 4 along with ꢁ14% of the axial alcohol (+)-galantha-
mine 2; purification of this crude product by stirring with
acetone at reflux temperature afforded the desired stereoisomer
of the equatorial alcohol, (+)-epigalanthamine 4, which showed a
purity of >96% (by HPLC), enantiomeric purity of >97% (by HPLC)
and a specific rotation of +232 (c 1, CHCl3).
Content of isomersa
O
O
(S)
(R)
(S)
(R)
O
O
N
N
CH3
CH3
H3CO
H3CO
Time
The diastereoselectivity of the Luche reduction increases at a
lower temperature (ꢀ55 to ꢀ50 °C) which is due to the ligation
of the cerium ion with the carbonyl group, which means that the
protic solvent is more effective at a low temperature and thus
predominantly yields the equatorial alcohol, epigalanthamine.
Initial
15 min
1 h
99.73
99.19
99.13
99.11
0.27
0.81
0.87
0.89
2 h
a
Chromatographic purity (by chiral HPLC, by area normalization).

122
G. N. Trinadhachari et al. / Tetrahedron: Asymmetry 25 (2014) 117–124
Table 6
The effect of temperature on the formation of equatorial and axial alcohols during the reduction of (ꢀ)-narwedine 6 with sodium borohydride in the presence of CeCl3ꢂ7H2O
% of producta
Enone
Equatorial alcohol
Axial alcohol
C-7 reduced product
O
H
H
H
OH
OH
OH
Lycoramine
(-)-Narwedine
(-)-Epigalanthamine
(-)-Galanthamine
8
Temperature
Quantity of NaBH4 used (m. eq.)
5
3
1a
Without CeCl3ꢂ7H2O
25–30 °C
1.20
1.20
1.50
1.80
2.10
2.30
2.50
2.70
3.00
0.02
0.60
0.14
0.65
0.71
0.53
0.03
0.02
2.25
34.78
60.18
61.62
69.70
71.55
73.47
82.87
81.50
73.90
38.48
38.32
37.27
29.14
24.59
24.01
13.94
14.50
18.85
24.60
0.46
0.44
0.23
0.16
0.12
10–15 °C
0–5 °C
ꢀ15 to ꢀ10 °C
ꢀ30 to ꢀ25 °C
ꢀ55 to ꢀ50 °C
ꢀ65 to ꢀ60 °C
ꢀ75 to ꢀ70 °C
Not detected
1.94
1.05
Reaction conditions: a 0.10 M solution of enone 5 in a 1:1 mixture of methanol and methylene chloride; 1.0 m. eq. of CeCl3.
a
Chromatographic purity (by HPLC, by area normalization).
Secondly, the ligation of the cerium ion with the carbonyl group
through methanol completely prevents the racemization of narwe-
dine and thus controls the formation of the other isomers of galan-
thamine as observed when narwedine was reduced with sodium
borohydride in the absence of cerium (III) chloride. Thirdly, the
Luche reduction is regiospecific in favoring 1,2-reduction, and thus
controlled the formation of lycoramine 8. Thus Luche reduction of
the narwedine isomers is better in yielding their respective epiga-
lanthamine isomers with high enantiomeric purity than other
reducing agents such as lithium aluminum hydride, sodium boro-
hydride and so on.
4. Experimental
4.1. General
Starting material, ( )-narwedine 5 was prepared by following
the literature,22 L-selectride was procured from BASF. Other re-
agents and solvents were obtained from commercial suppliers
and used without further purification. Narwedine and narwedine
salts are classified as moderate to severe sensitizing agents and,
after prolonged exposure, cause severe allergic skin reactions.5
For this reason, suitable personal protective equipment should be
used while handling. Melting points were determined on a Polmon
MP96 capillary melting point apparatus and are uncorrected. 1H
NMR spectra were recorded on a Bruker 300 MHz spectrometer
and 13C NMR spectra were recorded on a Bruker 100 MHz spec-
trometer in DMSO-d6 or CDCl3, chemical shift data are reported
in ppm from the internal standard TMS. The reaction monitoring
and chromatographic purities of samples were analyzed qualita-
tively by High Performance Liquid Chromatography (HPLC) on a
Waters 2695 with a 2996 PDA detector using Phenomenex Gemini
Diastereoselective reduction of (ꢀ)-narwedine 6 was carried
out with L-selectride in tetrahydrofuran at ꢀ50 to ꢀ45 °C to exclu-
sively produce axial alcohol (ꢀ)-galanthamine 1. After the reaction
was completed, the reaction was quenched with hydrogen perox-
ide and the excess peroxide was destroyed with sodium sulfite.
After aqueous work-up of the reaction, (ꢀ)-galanthamine base
was obtained and then treated with hydrobromic acid in aqueous
ethanol to give the desired product, (ꢀ)-galanthamine hydrobro-
mide 1 with a chromatographic purity of >99.7% (by HPLC) and
an enantiomeric purity of >99.9% (by HPLC). The specific rotation
of this axial alcohol 1 was ꢀ96.5 (c 0.1, water).
C18 column (250 mm ꢃ 4.6 mm, 5
l). The enantiomeric purity of
the narwedine and galanthamine isomers were analyzed on a
Similarly the diastereoselective reduction of (+)-narwedine 7
with L-selectride in tetrahydrofuran at ꢀ50 to ꢀ45 °C gave the
axial alcohol, (+)-galanthamine 2, which is the enantiomer of
(ꢀ)-galanthamine 1 with the chromatographic purity of >99% (by
HPLC) and an enantiomeric purity of >99.5% (by HPLC). The specific
rotation of this axial alcohol 2 was +97.7 (c 0.1, water).
Waters 2695 with a 2996 PDA detector using Chiralpak AD-H
(250 mm ꢃ 4.6 mm, 5
l) column, respectively. High Resolution
Mass spectra (HRMS) were taken on Xevo G2 Q TOF HRMS instru-
ment with electrospray ionization (positive) mode in units of mass
(m/z). The IR spectra were recorded using KBr pellets on Perkin–El-
mer FTIR (spectrum one) spectrophotometer.
3. Conclusion
4.2. (4aS,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-
methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one [(ꢀ)-
narwedine] 6
In conclusion, we have developed an efficient diastereodiver-
gent approach for the synthesis of all four stereoisomers of galan-
thamine from ( )-narwedine 5. The resolution of ( )-narwedine 5
was optimized to obtain narwedine isomers with an enantiomeric
purity of >99.7%. Luche and L-selectride reduction of the cyclic
enone system have been demonstrated as being complementary
to yield the axial and equatorial alcohols, meaning that epigalanth-
amine isomers were prepared with an enantiomeric purity of >97%
and galanthamine isomers were prepared with an enantiomeric
purity of >99.5%.
( )-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-ben-
zofuro[3a,3,2-ef][2]benzazepin-6-one [( )-narwedine]
5 (75 g,
0.263 mol) was dissolved in a mixture of demineralised water
(57 mL), ethanol (1090 mL), and triethylamine (127.5 mL) at 75–
80 °C. The reaction mixture was cooled to 70–73 °C and (ꢀ)-narwe-
dine (1.5 g) was added as seed to the dissolved solution. The result-
ing mixture was gradually cooled to 40–42 °C and stirred at the
same temperature for 3 h. The completion of the resolution was

G. N. Trinadhachari et al. / Tetrahedron: Asymmetry 25 (2014) 117–124
123
monitored by qualitative chiral HPLC analysis. Thereafter, the slur-
ry was cooled to 25–30 °C, the product filtered and dried at 55–
65 °C under reduced pressure to give (ꢀ)-narwedine 6 as a cream
crystalline powder (67.5 g, 90%). Chromatographic purity: 99.92%
(by HPLC); enantiomeric purity: 99.95% (by HPLC); mp: 190–
1H), 2.04 (dd, J = 15.6, 5.1 Hz, 2H), 2.23 (dd, J = 15.6 Hz, 1H),
2.49 (s, 3H), 2.97 (brs, 2H), 3.34 (m, 1H), 3.76 (s, 3H), 3.82 (brs,
1H), 4.09 (s, 1H), 4.48 (m, 2H), 4.59 (s, 1H), 4.78 (d, J = 14.1 Hz,
1H), 5.87 (dd, J = 6, 3 Hz, 1H), 6.12 (d, J = 9 Hz, 1H), 6.79 and
6.85 (2d, J = 8.4, 8.4 Hz, 2H), 9.82 (2brs, 1H); dC (100 MHz,
DMSO-d6): 30.9 (2ꢃCH2), 35.1 (CH3), 46.4 (CH2), 55.6 (OCH3),
59.4 (CH2), 86.4 (CH), 111.9 (CH), 120.4, 122.8 (CH), 125.4 (CH),
129.8 (CH), 132.8, 144.8, 146.3; HRMS (ESI+): m/z 288.1608
[M+H]+.
192 °C; ½a 2D5
ꢄ
¼ ꢀ409:1 (c 1, CHCl3); IR(KBr) (cmꢀ1): 1682 (C@O),
1620 (C@C), 1507, 1439; dH (300 MHz, DMSO-d6): 1.81 and 2.12
(dd, J = 14.1, 3.0 Hz, 2H), 2.28 (s, 3H), 2.76 and 2.96 (dd, J = 2.1,
2.1 Hz, 2H) 3.01 and 3.18 (dd, J = 3.3, 13.2 Hz, 2H), 3.60 and 4.13
(dd, J = 15.6, 15.3 Hz, 2H), 3.71 (s, 3H), 4.71(brs, 1H), 5.90 (d,
J = 9 Hz, 1H), 6.63 and 6.76 (2d, J = 9, 6 Hz, 2H), 7.14 (d, J = 9 Hz,
1H); HRMS (ESI+): [M+H]+ m/z 286.1453.
4.5. (4aR,6S,8aR)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-
methyl-6H-benzofuro[3a,3,2-ef][2] benzazepine-6-ol [(+)-
galanthamine] 2
4.3. (4aR,8aR)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-
6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one [(+)-narwedine] 7
Lithium tri-sec-butyl borohydride [L-selectride] (1 molar solu-
tion in THF, 67 mL) was added dropwise to a suspension of
(4aR,8aR)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-
benzofuro[3a,3,2-ef][2]benzazepin-6-one, [(+)-narwedine] 7 (10 g,
0.0351 mol) in THF (200 mL) at ꢀ50 to ꢀ45 °C for 1 h after which
the reaction mixture was stirred at ꢀ50 to ꢀ45 °C for 3 h. The com-
pletion of the reaction was monitored by qualitative HPLC analysis.
The reaction mixture was quenched by adding aqueous hydrogen
peroxide (40% w/w, 17 g, 1.3 mol) and the excess peroxide was de-
stroyed by stirring the reaction with an aqueous sodium sulfite
solution. The reaction mixture was concentrated under reduced
pressure and the product was extracted into toluene (250 mL).
The organic extract was concentrated under reduced pressure at
50–55 °C to obtain (+)-galanthamine base 2, which was dissolved
in a mixture of ethanol (40 mL) and DM water (10 mL). Aqueous
hydrobromic acid (48% w/w, 6.22 g, 0.0878 mol) was added to
the (+)-galanthamine base solution and stirred at 15–20 °C for
2 h to obtain (+)-galanthamine as its hydrobromide salt. The prod-
uct was filtered and dried under vacuum at 50–55 °C to obtain (+)-
galanthamine hydrobromide 2 as a white crystalline powder (11 g,
85.4% yield). Chromatographic purity: 99.08% (by HPLC); enantio-
( )-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-ben-
zofuro[3a,3,2-ef][2]benzazepin-6-one [( )-narwedine]
5 (50 g,
0.333 mol) was dissolved in a mixture of demineralised water
(38 mL), ethanol (1381 mL), and triethylamine (85 mL) at 75–
80 °C. Thereafter the reaction mass was cooled to 70–73 °C and
(+)-narwedine (1 g) was added as a seed to the solution. The result-
ing mixture was gradually cooled to 40–42 °C and stirred at the
same temperature for 3 h. The completion of the resolution was
monitored by qualitative chiral HPLC analysis. The slurry mass
was further cooled to 25–30 °C, the product filtered and dried at
55–65 °C under reduced pressure to give (+)-narwedine 7 as a
cream crystalline powder (45 g, 90% yield). Chromatographic pur-
ity: 99.89% (by HPLC); enantiomeric purity: 99.77% (by HPLC);
mp: 190–191 °C; ½a D25
ꢄ
¼ þ412:3 (c 1, CHCl3); IR(KBr) (cmꢀ1):
1681 (C@O), 1619 (C@C), 1507, 1439; dH (300 MHz, DMSO-d6):
1.80 and 2.13 (dd, J = 13.8, 2.7 Hz, 2H), 2.27 (s, 3H), 2.75 and
3.01 (dd, J = 2.4, 3.3 Hz, 2H) 3.07 and 3.18 (dd, J = 3.6, 13.8 Hz,
2H), 3.59 and 4.12 (dd, J = 15.3, 15.6 Hz, 2H), 3.71 (s, 3H),
4.71(brs, 1H), 5.89 (d, J = 10.2 Hz, 1H), 6.63 and 6.75 (2d, J = 8.1,
8.1 Hz, 2H), 7.14 (d, J = 10 Hz, 1H); HRMS (ESI+): m/z 286.1474
[M+H]+.
meric purity: 99.60% (by HPLC); mp: 244 °C (dec); ½a D25
¼ þ97:7
ꢄ
(c 0.1, water); IR (KBr) (cmꢀ1): 3561, 3043, 3022, 2946, 2923,
2620, 2482, 1625, 1513, 1466, 1438, 1282, 1068; dH (300 MHz,
DMSO-d6): 1.97–2.28 (2dd, J = 14.1, 10.8, 10 Hz, 4H), 2.56 (s, 1H),
2.98 (brs, 2H), 3.57 (d, J = 14.7 Hz, 1H), 3.77 (brs, 4H), 4.10
(s, 1H), 4.37 and 4.80 (2m, 2H), 4.58 and 4.65 (2m, 2H), 5.90 (dd,
J = 6, 3 Hz, 1H), 6.12 (d, J = 9 Hz, 1H), 6.78 and 6.85 (2d, J = 8.1,
8.1 Hz, 2H), 9.81 and 10.54 (2brs, 1H); dC (100 MHz, DMSO-d6):
30.9 (2ꢃCH2), 34.8 (CH3), 46.2 (CH2), 55.6 (OCH3), 59.4 (CH2),
86.4 (CH), 111.9 (CH), 120.6, 122.5 (CH), 125.12 (CH), 130.0 (CH),
133.0, 145.0, 146.5; HRMS (ESI+): m/z 288.1609 [M+H]+.
4.4. (4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-
6H-benzofuro[3a,3,2-ef][2] benzazepine-6-ol hydrobromide [(ꢀ)-
galanthamine hydrobromide] 1
Lithium tri-sec-butyl borohydride (L-selectride), (1 molar solu-
tion in THF, 360.8 mL) was added dropwise to a suspension of
(4aS,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-
benzofuro[3a,3,2-ef][2]benzazepin-6-one, [(ꢀ)-narwedine] 6 (50 g,
0.175 mol) in THF (1000 mL) at ꢀ50 to ꢀ45 °C for 1 h after which
the reaction mixture was stirred at ꢀ50 to ꢀ45 °C for 3 h. The com-
pletion of the reaction was monitored by qualitative HPLC analysis.
Next, the reaction mixture was quenched by adding aqueous
hydrogen peroxide (40% w/w, 85 g, 1 mol) and the excess peroxide
was destroyed by stirring the reaction with an aqueous sodium
sulfite solution. The reaction mixture was concentrated under re-
duced pressure and the product was extracted into toluene
(1250 mL). The organic extract was concentrated under reduced
pressure at 50–55 °C to obtain (ꢀ)-galanthamine base as an oily
mass, which was dissolved in a mixture of ethanol (200 mL) and
DM water (50 mL). Aqueous hydrobromic acid (48% w/w, 31.09 g,
0.185 mol) was then added to the (ꢀ)-galanthamine base solution
and stirred at 15–20 °C for 2 h. The product was filtered and dried
under vacuum at 50–55 °C to obtain (ꢀ)-galanthamine 1 as a
hydrobromide salt as white crystalline powder (55 g, 85.4% yield).
Chromatographic purity: 99.85% (by HPLC); enantiomeric purity:
4.6. (4aS,6S,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-
methyl-6H-benzofuro[3a,3,2-ef][2] benzezapine-6-ol [(ꢀ)-
epigalanthamine] 3
A mixture of (4aS,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-
11-methyl-6H-benzofuro[3a,3,2-ef][2]benzezapin-6-one [(ꢀ)-nar-
wedine]
6 (10 g, 0.035 mol), cerium chloride heptahydrate
(13.07 g, 0.035 mol) in methylene chloride–methanol (1:1 v/v,
300 mL) was stirred at ꢀ55 to ꢀ50 °C for 30 min after which sodium
borohydride (3.33 g, 0.088 mol) was added in portions at ꢀ55 to
ꢀ50 °C over a period of 30 min. The reaction mixture was stirred
at ꢀ55 to ꢀ50 °C for 2 h and the completion of the reaction was
monitored by qualitative HPLC analysis. Water (10 mL) was then
added to the reaction mixture and the temperature was raised to
25–30 °C. The reaction mixture was concentrated under reduced
pressure and the concentrated mass was stirred with chloroform
(100 mL). The inorganic residue was removed by filtration. The fil-
trate was washed with water (60 mL) and the organic layer was con-
centrated under reduced pressure. The crude product was stirred
100% (by HPLC); mp: 253 °C (dec); ½a D25
¼ ꢀ96:5 (c 0.1, water);
ꢄ
IR(KBr) (cmꢀ1): 3561, 3043,3022, 2946, 2922, 2619, 2482, 1625,
1512, 1465, 1439, 1282, 1068; dH (300 MHz, DMSO-d6): 1.90 (brs,

124
G. N. Trinadhachari et al. / Tetrahedron: Asymmetry 25 (2014) 117–124
with acetone (50 mL) at reflux temperature. The slurry mass was
cooled to 25–30 °C, filtered and dried at 45–50 °C under reduced
pressure to yield (ꢀ)-epigalanthamine 3 as a white crystalline pow-
der (6.85 g, 68% yield). Chromatographic purity: 96.49% (by HPLC);
enantiomeric purity: 97.71% (by HPLC); mp: 181–182 °C;
ful to the entire Analytical Research Department for their valuable
analytical support of this work.
References
½
a 2D5
ꢄ
¼ ꢀ229:9 (c 1, CHCl3); IR (KBr, cmꢀ1): 3151, 3031, 3011,
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2945, 2916, 1623, 1508, 1459, 1445, 1436, 1272, 1053; dH
(300 MHz, CDCl3): 1.61–1.75 (m, 2H), 2.18 and 2.75 (dd, J = 12, 12
Hz, 2H), 2.36 (s, 3H), 3.07 and 3.22 (dd, J = 12.9, 12.1 Hz, 2H),
3.59 and 4.05 (dd, J = 15.3, 15 Hz, 2H), 3.83 (s, 3H), 4.60 (m, 2H),
5.79 (d, J = 10.2 Hz, 1H), 6.05 (d, J = 11.7 Hz, 2H), 6.55 and 6.62
(2d, J = 8.1, 8.1 Hz, 2H); dC (100 MHz, CDCl3): 32.3 (2ꢃCH2), 34.1
(CH3), 41.6 (CH2), 48.0, 53.8 (CH2), 55.8 (OCH3), 60.1 (CH2), 62.7
(CH), 88.4 (CH), 110.8 (CH), 121.5, 126.2 (CH), 128.9 (CH), 131.9
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4.7. (4aR,6R,8aR)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-
methyl-6H-benzofuro[3a,3,2-ef][2] benzezapine-6-ol [(+)-
epigalanthamine] 4
A mixture of [4aR,8aR]-4a,5,9,10,11,12-hexahydro-3-methoxy-
11-methyl-6H-benzofuro[3a,3,2-ef][2]benzezapin-6-one, [(+)-nar-
wedine]
7 (10 g, 0.035 mol), cerium chloride heptahydrate
(13.07 g, 0.035 mol) in methylene chloride–methanol (1:1 v/v,
300 mL) was stirred at ꢀ55 to ꢀ50 °C for 30 min and sodium boro-
hydride (3.33 g, 0.088 mol) was added in portions at ꢀ55 to ꢀ50 °C
over period of 30 min. The reaction mixture was stirred at ꢀ55 to
ꢀ50 °C for 2 h and the completion of the reaction was monitored
by qualitative HPLC analysis. Water (10 mL) was then added to
the reaction mixture and the temperature was raised to 25–
30 °C. The mixture was concentrated under reduced pressure and
the concentrated mass was stirred with chloroform (100 mL). The
inorganic residue was removed by filtration. The filtrate was
washed with water (60 mL) and the organic layer was concen-
trated under reduced pressure. The crude product was stirred with
acetone (50 mL) at reflux temperature and then cooled to 25–30 °C.
The product slurry was stirred for 1 h, filtered and dried at 45–
50 °C under reduced pressure to yield (+)-epigalanthamine 4 as a
white crystalline powder (6.95 g, 69% yield). Chromatographic pur-
ity: 96.66% (by HPLC); enantiomeric purity: 97.06% (by HPLC); mp:
182–183 °C; ½a 2D5
ꢄ
¼ þ232:6 (c 1, CHCl3);IR (KBr) (cmꢀ1): 3151,
3031, 3011, 2945, 2916, 1624, 1508, 1460, 1445, 1436, 1272,
1070; dH (300 MHz, CDCl3): 1.63–1.76 (m, 2H), 2.15 and 2.76 (dd,
J = 12, 12 Hz, 2H), 2.37 (s, 3H), 3.03 and 3.22 (dd, J = 15, 15 Hz,
2H), 3.60 and 4.10 (dd, J = 15, 15 Hz, 2H), 3.84 (s, 3H), 4.60 (m,
2H), 5.79 (d, J = 12 Hz, 1H), 6.05 (d, J = 9 Hz, 2H), 6.55 and 6.62
(2d, J = 9, 9 Hz, 2H); dC (100 MHz, CDCl3): 32.3 (2ꢃCH2), 34.1
(CH3), 41.7 (CH2), 48.1, 53.8 (CH2), 55.8 (OCH3), 60.2 (CH2), 62.9
(CH), 88.4 (CH), 110.8 (CH), 121.5, 126.3 (CH), 128.9 (CH), 131.8
(CH), 132.9, 143.8, 146.6; HRMS (ESI+): m/z 288.1616 [M+H]+.
22. (a) Prabahar, K. J.; Trinadhachari, G. N.; Naveen, K. P.; Lakshmi, U. V.; Ramesh,
D.; Sivakumaran, M. European Patent (Aurobindo Pharma Ltd, Hyderabad,
India; Process for the preparation of galanthamine hydrobromide) EP 2009015
B1; Jan 11, 2012, Chem. Abstr. 150, 77837.; (b) Trinadhachari, G. N.; Kamat, A.
G.; Prabahar, K. J.; Handa, V. K.; Satyasrinu, K. N. V.; Raghubabu, K.; Douglas, P.
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Acknowledgements
Authors thank the management of Aurobindo Pharma Ltd,
Hyderabad for permission to publish this work. Authors are grate-