Novel synthetic route to the tricyclic core of (±)-galanthamine

Article abstract of DOI:10.1016/j.tetlet.2009.06.055

In this Letter, we describe the novel synthetic approach to the tricyclic core of (±)-galanthamine from the easily available starting material isovanillin.

Full text of DOI:10.1016/j.tetlet.2009.06.055

Tetrahedron Letters 50 (2009) 4882–4884
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Tetrahedron Letters
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Novel synthetic route to the tricyclic core of ( )-galanthamine
*
S. Chandrasekhar , Debjit Basu, M. Sailu, S. Kotamraju
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, we describe the novel synthetic approach to the tricyclic core of ( )-galanthamine from the
easily available starting material isovanillin.
Received 2 May 2009
Revised 8 June 2009
Accepted 10 June 2009
Available online 14 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
(À)-Galanthamine (1a), an alkaloid isolated from the bulbs of
different Amaryllidaceae species and Caucasian snowdrop,1 is a
selective, reversible competitive acetyl cholinesterase (AChE)
inhibitor that has been approved for the symptomatic treatment
of Alzheimer’s disease.2 It has also been tested for use in anesthe-
siology,3 from facial nerve paralysis to schizophrenia.4 Galantha-
mine is a structural analog of lycoramine (1c), being devoid of
the double bond, which inhibits the formation of the peptide bond
in protein synthesis5 and is related to the structure of morphine
(1d) and other simplified analogs (e.g., morphinan, benzomorphan,
and 4-phenylpiperidine derivatives) which are used for the treat-
ment of pain.6 Therefore, the compound containing simplified
galanthamine-like skeleton may be of interest for the development
of novel AChE inhibitors and the development of further analogs of
morphine. Despite considerable effort to construct galanthamine
analogs having enhanced efficacy,7 there is no report which de-
scribes the synthesis of analog 1b which is devoid of C ring
(Fig. 1). Hence, this leaves the opportunity to explore this void
and add to the structure–activity relationship of galanthamine.
We have used diversity-oriented synthesis to construct the analog
of the galanthamine, with the goal of discovering new molecules
having biological effects beyond those previously associated with
the natural product.
In the past decades, several elegant total syntheses of 1a have
been reported,8 with the key transformations involved in the con-
struction of the tricyclic benzofuran core with a sterically con-
gested quaternary carbon, which was shared by galanthamine-
type and morphine-type alkaloids (Fig. 1). In constructing the basic
skeleton, many synthetic strategies, such as biomimetic phenolic
oxidative coupling,9 photochemical reaction,10 semipinacol rear-
rangement,11 radical cyclization,12 intramolecular Heck reaction,13
intermolecular alkylation,14 and arylation15 had been utilized.
However, our novel synthetic approach to the galanthamine skele-
ton offers a range of functionalities for diversity-generating reac-
tions and synthesis of different analogs.
The synthesis commenced with the commercially available
3-hydroxy-4-methoxy benzaldehyde (isovanillin) 2. The phenolic
hydroxyl group of 2 was protected as its allyl ether 3. This was fol-
lowed by a Claisen rearrangement of 3, by heating to 200 °C for 4 h,
in a solvent-free condition to obtain the rearranged product 4. The
phenol 4 was protected as its TBS-ether 5, which was followed by
reduction of the aldehyde functionality using sodium borohydride
in methanol to obtain the alcohol 6. The hydroxyl group of com-
pound 6 was protected as its methoxymethylether to afford the
compound 7.
The osmium tetraoxide, sodium metaperiodate, 2,6-lutidine-
promoted oxidative cleavage of the olefin 7 gave the aldehyde 8
which was transformed into its nitrile product 9 using hydroxyl-
amine hydrochloride and pyridine followed by the addition of cop-
per sulfate, triethylamine, and DCC with CH2Cl2 as solvent. The
next objective was the sequential alkylation adjacent to the nitrile
functionality. Accordingly, the homoallyl functionality was substi-
H
O
N
N
O
D
D
OH
C
H
A
O
B
O
A
B
O
O
O
tricyclic core of galanthamine (1b)
(-) Galanthamine (1a)
HO
N
OH
O
N
O
H
H
HO
O
Morphine (1d)
Lycoramine (1c)
* Corresponding author. Tel.: +91 040 27193210; fax: +91 040 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.055

S. Chandrasekhar et al. / Tetrahedron Letters 50 (2009) 4882–4884
4883
MOMO
RO
CHO
O
CHO
O
CHO
O
CHO
a
c
b
d, e
f
CHO
OTBS
g
OTBS
OH
O
OH
OTBS
O
5
O
O
R= H, 6
3
4
2
8
R= MOM, 7
O
O
MOMO
MOMO
O
MOMO
MOMO
O
O
MOMO
CN
l
j
i
k
CN
h
CN
CN
CN
OTBS
OTBS
OTBS
OTBS
OTBS
O
O
9
O
O
12
O
O
10
11
13
COOMe
COOMe
MOMO
HO
HO
N3
O
O
O
O
m
o
p
n
1b
O
O
O
O
O
O
O
O
O
O
O
O
14
17
15
16
Scheme 1. Reagent and conditions: (a) Allyl bromide, K2CO3, acetone, 4 h, 96%; (b) 200 °C, 6 h, 85%; (c) TBSCl, imidazole, CH2Cl2, 4 h, 90%; (d) NaBH4, MeOH, 85%; (e) MOMCl,
DIPEA, CH2Cl2, 8 h, 85%; (f) OsO4, 2,6-lutidine, NaIO4, 1,4-dioxane/water, 28 h, 81%; (g) NH2OHÁHCl, pyridine, then CuSO4, Et3N, DCC, CH2Cl2, 5 h, 87%; (h) homoallyl bromide,
LDA, DMPU, THF, À78 °C, 2 h, 93%; (i) PdCl2, CuCl, O2, DMF/H2O, 12 h, 92%; (j) ethyleneglycol, pTSA, benzene, 80 °C, 6 h, 88%; (k) allyl bromide, LDA, DMPU, THF, À78 °C, 2 h,
94%; (l) (i) 3 N KOH, C2H5OH, reflux, 0.5 h; (ii) aq solution of NaHSO4 till pH 5, 86% for two steps; (m) 4 N HCl–THF, 2 h, 94%; (n) (i) O3, CH2Cl, À78 °C, 5 min, then (CH3)2S; (ii)
NaClO2, NaH2PO4, 2-methyl-2-butene, acetonitrile–water, 56% for two steps; CH2N2, (C2H5)2O, 5 min, quantative; (o) DPPA, DBU, toluene, 80 °C, 18 h, 92%; (p) Zn, NH4Cl,
EtOH, 80 °C, 5 min, 26%.
tuted on treating 9 with lithiumdiisopropyl amide and homoallyl
bromide in THF at À78 °C to obtain the homoallyl-substituted
product 10. The compound 10 was then subjected to Wacker oxi-
dation to obtain the keto derivative 11 in high yield. The ketone
functionality of 11 was protected as 1,3-dioxolane 12 using ethyl-
ene glycol and catalytic amount of p-TSA. Next, the allyl function-
ality was introduced by treating 12 with lithiumdiisopropyl amine
and allyl bromide in THF–DMPU as solvent at À78 °C to obtain the
key intermediate 13. Having successfully synthesized the struc-
tural backbone, the next objective was to construct the B and C
rings of galanthamine. Accordingly, the compound 13 was heated
at reflux for 0.5 h in 3 N KOH–EtOH, and then on acidifying the
reaction mixture to pH 5, the product lactone 14 was obtained in
good yield. The methoxymethylether (MOM) group of the com-
pound 14 was removed using 4 N HCl. Pleasingly, the reaction con-
ditions also led to the desired 1,3-dioxolane deprotection of the
ketone. Next, it was desired to functionalize the olefin moiety.
Accordingly, the olefin 15 was subjected to ozonolysis and the
crude aldehyde was then transformed to the corresponding acid
using NaH2PO4, NaClO2, and 2-methyl-2-butene in 56% yield in
two steps. Next, the acid was esterified by diazomethane to its
methylester 16 in quantitative yield. The azide functionality was
introduced by substituting the primary alcohol of 17, using
diphenylphosphoryl azide (DPPA) and DBU in toluene. The seven-
membered azapine ring was constructed by reducing the azide
functionality, using zinc and ammonium chloride, to its amine
which spontaneously cyclized to form the amide 1b in moderate
yield (Scheme 1).16
Figure 2.
with isovanillin. The final product, galanthamine devoid of C ring
was shown to have AChE inhibitory activity by 40% as compared
to galanthamine (55%) at the same concentration. The total synthe-
sis of galanthamine and the synthesis of more galanthamine ana-
logs are presently being actively pursued in our laboratory.
Acknowledgments
We thank CSIR New Delhi, for the research fellowship to Debjit
Basu and DST, New Delhi, for financial assistance (GAP-0154). We
also thank Dr. Rene Gree of University of Rennes for useful sugges-
tions. This work has been the part of Indo-French Joint Laboratory
for sustainable chemistry at interface.
The acetyl cholinesterase (AChE) inhibitory activity of tricyclic
core of galanthamine (1b) was measured in vitro by comparing
with (À)-galanthamine (1a) using Ellman assay.17 It was observed
that, compound 1b at 0.5 lM concentration inhibited AChE activity
References and notes
by 40% as compared to 55% inhibition by 1a, a known AChE inhib-
itor at the same concentration. The values shown in Figure 2 are
from three independent experiments.
In summary, a non-biomimetic synthetic route to the novel
galanthamine analog, devoid of C ring, was established starting
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2-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-3-methoxy-6-[(methoxymethoxy)methyl]-
benzylcyanide (9): 1H NMR (300 MHz, CDCl3): d 6.88 (d, J = 8.3 Hz, 1H), 6.76 (d,
J = 8.3 Hz, 1H), 4.60 (s, 2H), 4.58 (s, 2H), 3.80 (s, 5H), 3.38 (s, 2H), 1.03 (s, 9H), 0.22
(s, 6H); 13C NMR (75 MHz, CDCl3): d 149.8, 143.5, 128.5, 122.8, 121.2, 117.8,
110.4, 95.1, 67.3, 55.5, 54.7, 29.6, 26.0, 14.7, À3.75; HRMS (ESI): Calcd for
C18H29NO4NaSi: 374.1763 [M+Na]+, Found: 374.1758 [M+Na]+; IR (KBr): mmax
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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.
2932, 2248, 1497, 1030, 833 cmÀ1
.
1-2-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-3-methoxy-6-[(methoxymethoxy)methyl]phenyl-
4-pentenyl cyanide (10): 1H NMR (300 MHz, CDCl3): d 6.94 (d, J = 8.3 Hz, 1H), 6.76 (d,
J = 8.3 Hz, 1H), 5.80–5.69(m, 1H), 5.13–5.00(m, 2H), 4.75–4.56(m, 5H), 3.79(s, 3H,), 3.39
(s, 3H), 2.38–1.73 (m, 4H), 0.99 (s, 9H), 0.24 (s, 6H); 13C NMR (75 MHz, CDCl3): d 149.3,
142.7, 136.4, 128.4, 125.5, 123.4, 120.5, 116.1, 110.4, 95.5, 66.8, 55.5, 54.6, 31.8, 31.6,
28.0, 26.2, 19.1, À3.0; HRMS (ESI): Calcd for C22H35NO4NaSi: 428.2233 [M+Na]+, Found:
428.2241 [M+Na]+; IR (KBr): max 3432, 2931, 2238, 1743, 1494, 758 cmÀ1
m .
1-2-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-3-methoxy-6-[(methoxymethoxy)methyl]phenyl-
4-oxopentyl cyanide (11): 1H NMR (300 MHz, CDCl3): d 6.93 (d, J = 8.3 Hz, 1H), 6.76 (d,
J = 8.3 Hz, 1H), 4.74–4.51 (m, 5H), 3.80 (s, 3H), 3.39 (s, 3H), 2.66–2.15 (m, 4H), 2.13 (s,
3H), 0.99 (s, 9H), 0.24 (s, 6H); 13C NMR (75 MHz, CDCl3): d 206.4, 149.3, 124.8, 123.4,
120.3, 110.5, 115.1, 95.4, 95.3, 66.7, 55.5, 54.5, 42.9, 40.5, 29.9, 27.6, 27.2, 26.3, À3.0;
HRMS (ESI): Calcd for C22H35NO5NaSi: 444.2182 [M+Na]+, Found: 444.2176 [M+Na]+;IR
8. (a) Satcharoen, V.; McLean, N. J.; Kemp, S. C.; Nicholas, P. C.; Brown, R. Org. Lett.
2007, 9, 1867; (b) Marco-Contelles, J.; Carreiras, M. C.; Rodr´ıguez, C.; Villarroya,
´
116; (c) Trost, B. M.; Tang, W.; Toste, F. D.
(KBr): m .
max 2933, 2238, 1718, 1495, 840 cmÀ1
M.; Garcı, A. G. Chem. Rev. 2006, 106,
J. Am. Chem. Soc. 2005, 127, 14785; (d) Kodama, S.; Hamashima, Y.; Nishide, K.;
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M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 11262; (h) Czollner, L.; Frantsits, W.;
Bernhard, K.; Hedenig, U.; Johannes, F.; Jordis, U. Tetrahedron Lett. 1998, 39,
2087; (i) Krikorian, D.; Vlahov, R.; Parushdev, S.; Chinova, M.; Vlahov, I.
Tetrahedron Lett. 1984, 25, 2969.
1-2-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-3-methoxy-6-[(methoxymethoxy)methyl]phenyl-
1-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-3-butenyl cyanide (13): 1H NMR (300 MHz,
CDCl3): d 6.90 (d, J = 8.3 Hz, 1H), 6.72 (d, J = 8.3 Hz, 1H), 5.83–5.69 (m, 1H), 5.19–5.07
(m, 2H), 4.90–4.78 (q, J = 12.0, 13.5 Hz, 2H) 4.65 (s, 2H), 3.89–3.80 (s, 4H), 3.77 (s, 3H,),
3.38 (s, 3H), 2.75–2.63 (m, 2H), 2.05–1.45 (m, 4H), 1.27 (s, 3H), 0.95 (s, 9H), 0.27 (s, 6H);
13C NMR (75 MHz, CDCl3): d 149.0, 143.2, 133.0, 129.1, 124.4, 124.0, 119.0, 109.4, 95.3,
68.4, 64.4, 55.5, 54.2, 46.4, 42.1, 36.8, 34.8, 32.8, 27.1, 26.3, 23.8, 19.9, À1.4; HRMS (ESI):
Calcd for C27H43NO6NaSi: 528.2757 [M+Na]+, Found: 528.2770 [M+Na]+; IR (KBr): mmax
9. (a) Krikorian, D.; Tarpanov, V.; Parushdev, S.; Mechkarov, P. Synth. Commun.
2000, 30, 2833; (b) Barton, D. H. R.; Kirby, G. W. J. Chem. Soc. (C) 1969, 2602; (c)
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1513.
2933, 2887, 2237, 1477 cmÀ1
.
3-Allyl-7-methoxy-4-[(methoxymethoxy)methyl]-3-[2-(2-methyl-1,3-dioxolan-2-
yl)ethyl]2,3-dihydrobenzo[b] furan-2-one (14): 1H NMR (300 MHz, CDCl3): d 7.14
(d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 5.38–5.24 (m, 1H), 5.05–4.88 (m, 2H),
4.68 (s, 2H) 4.62–4.52 (q, J = 7.3, 11.8 Hz, 2H), 3.91 (s, 3H,), 3.88–3.76 (m, 4H),
2.88–2.66 (m, 2H), 2.21–2.10 (m, 2H), 1.43–1.12 (m, 5H); 13C NMR (75 MHz,
CDCl3): d 178.4, 143.8, 141.5, 131.4, 127.9, 126.0, 125.9, 119.4, 112.1, 109.0, 95.4,
65.2, 64.4, 56.1, 55.5, 54.2, 42.1, 34.0, 31.6, 29.6, 23.5; ESI (MS): m/z 415 [M+Na]+;
IR (KBr): m .
max 2930, 1750, 1223 cmÀ1
Methyl2-[4-(hydroxymethyl)-7-methoxy-2-oxo-3-(3-oxobutyl)-2,3-dihydrobenzo-
[b]furan-3-yl]acetate (16): 1H NMR (300 MHz, CDCl3): d 7.09 (d, J = 8.3 Hz, 1H),
6.92 (d, J = 8.3 Hz, 1H), 4.64 (s, 2H), 3.96 (s, 3H), 3.50 (s, 3H), 3.43–3.13 (m, 2H),
2.65–1.99 (m, 4H,),1.88 (s, 3H); 13C NMR (75 MHz, CDCl3): d 207.2, 177.9, 170.1,
143.0, 140.6, 130.8, 126.1, 124.9, 119.1, 112.0, 60.6, 55.6, 53.3, 41.0, 38.1, 30.4,
29.5; ESI (MS): m/z 336 [M+H]+; IR (KBr): mmax 3449, 2925, 1801, 1736,
15. Ackland, D. J.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. 1 1987, 2695.
16. Spectral data of selected new compounds: 3-(allyloxy)-4-methoxybenzaldehyde
(3): 1H NMR (300 MHz, CDCl3): d 9.84 (s, 1H), 7.48–7.40 (m, 2H), 7.00 (d,
J = 8.3 Hz, 1H), 6.16–6.03 (m, 1H), 5.48–5.29 (m, 2H), 4.68 (d, J = 5.2 Hz, 2H), 3.96
(s, 3H); 13C NMR (75 MHz, CDCl3): d 190.6, 154.6, 148.3, 132.3, 129.7, 126.6,
118.3, 110.6, 110.4, 69.5, 55.9; HRMS (ESI): Calcd for C11H13O3: 193.0864
1287 cmÀ1
.
1-[7-Methoxy-3-(2-methoxy-2-oxoethyl)-2-oxo-3-(3-oxobutyl)-2,3-dihydrobenzo-
[b]furan-4-yl]methyl-1,2-triazadien-2-ium (17): 1H NMR (300 MHz, CDCl3): d 7.05
(d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.32–4.19 (q, J = 13.7, 10.7 Hz, 2H), 3.96
[M+H]+, Found: 193.0861 [M+H]+; IR (KBr): max 1685, 1589, 1267 cmÀ1
m .
2-Allyl-3-[1-(tert-butyl)-1,1-dimethylsilyl]oxy-4-methoxybenzaldehyde (5): 1H
NMR (300 MHz, CDCl3): 10.01 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 6.83 (d,
(s, 3H,), 3.50 (s, 3H), 3.20 (d, J = 3.0 Hz, 2H), 2.43–1.96 (m, 4H), 1.94 (s, 3H); 13
C
d
NMR (75 MHz, CDCl3): d 205.9, 177.8, 169.4, 144.4, 142.5, 127.1, 126.6, 123.2,
112.8, 56.2, 52.0, 50.8, 49.5, 41.5, 37.5, 31.0, 29.8; HRMS (ESI): Calcd for
C17H19N3O6: 379.1621 [M+NH4]+, Found: 379.1616 [M+NH4]+; IR (KBr): mmax
J = 8.3 Hz, 1H), 6.01–5.88 (m, 1H), 5.00–4.81 (m, 2H), 3.87 (s, 3H), 3.86 (d,
J = 7.5 Hz, 2H), 0.99 (s, 9H), 0.17 (s, 6H); 13C NMR (75 MHz, CDCl3): d 191.0, 154.3,
142.9, 136.7, 132.8, 128.1, 125.9, 115.1, 108.8, 54.6, 28.5, 25.9, 18.76, À3.9;
HRMS (ESI): Calcd for C17H27O3Si: 307.1729 [M+H]+, Found: 307.1732 [M+H]+; IR
3430, 2923, 2106, 1803, 1734, 1193 cmÀ1
.
3-Methoxy-9a-(3-oxobutyl)-1,6,7,8,9,9a-hexahydro-2-oxa-7-azabenzo[cd]azulene-
1,8-dione (1b): 1H NMR (300 MHz, CDCl3): d 6.94 (d, J = 8.0 Hz, 1H), 6.83 (d,
J = 8.0 Hz, 1H), 6.14 (br s, 1H), 4.71–4.68 (m, 2H), 3.89 (s, 3H), 2.30–2.34 (m, 2H),
2.19–1.96 (m, 4H), 1.79 (s, 3H); 13C NMR (75 MHz, CDCl3): d 206.0, 177.8, 172.8,
147.5, 144.8, 126.7, 123.2, 113.0, 111.2, 56.2, 52.1, 50.9, 49.3, 37.54, 29.6, 26.1;
HRMS (ESI): Calcd for C16H17NO5: 326.1004 [M+Na]+, Found: 326.0999 [M+Na]+;
(KBr): m .
max 2929, 1680, 1584, 1292, 833 cmÀ1
2-Allyl-6-methoxy-3-[(methoxymethoxy)methyl] phenoxy(tert-butyl)dimethylsilane
(7): 1H NMR (300 MHz, CDCl3): d 6.87 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H),
5.93–5.82 (m, 1H), 4.95–4.80 (m, 2H), 4.60 (s, 2H), 4.46 (s, 2H), 3.78 (s, 3H), 3.52–
3.47 (m, 2H), 3.37 (s, 3H), 1.01 (s, 9H), 0.19 (s, 6H); 13C NMR (75 MHz, CDCl3): d
149.6, 143.0, 136.6, 129.7, 129.0, 122.1, 114.5, 108.7, 95.4, 67.1, 55.3, 54.6, 30.3,
26.2, 18.9, À3.7; HRMS (ESI): Calcd for C19H32O4NaSi: 375.1967 [M+Na]+, Found:
IR (KBr): m .
max 3432, 2923, 1803, 1735, 1632 cmÀ1
17. (a) Ellman, G. L.; Courtney, K. D.; Andres, V., Jr.; Featherstone, R. M. Biochem.
Pharmacol. 1961, 7, 88; (b) Decker, M. Eur. J. Med. Chem. 2005, 40, 305.
375.1959 [M+Na]+; IR (KBr): max 2932, 2857, 1492, 1442, 1285 cmÀ1
m .