Total synthesis of (±)-galanthamine

Article abstract of DOI:10.1021/ol060339b

A practical and efficient total synthesis of (±)-galanthamine was achieved from commercially available materials through a novel approach, in which the construction of its core structure and the special allylic group were based on a successive semipinacol

Full text of DOI:10.1021/ol060339b

ORGANIC
LETTERS
Total Synthesis of (±
)-Galanthamine‡
2006
Vol. 8, No. 9
1823-1825
Xiang-Dong Hu, Yong Qiang Tu,* En Zhang, Shuanhu Gao, Shaohua Wang,
Aixia Wang, Chun-An Fan, and Min Wang
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou UniVersity, Lanzhou 730000, PRC
tuyq@lzu.edu.cn
Received February 8, 2006
ABSTRACT
A practical and efficient total synthesis of (
which the construction of its core structure and the special allylic alcohol group were based on a successive semipinacol rearrangement/
desilyation/cyclization and Saegusa Ito oxidation, respectively.
±)-galanthamine was achieved from commercially available materials through a novel approach, in
−
Galanthamine (1),1 the parent member of the galanthamine-
type Amaryllidaceae alkaloids, is a centrally acting competi-
tive and reversible inhibitor of acetylcholinesterase (Ache),
which significantly enhances cognitive functions of patients
suffering from Alzheimer’s disease and was first approved
in Austria and most recently in the rest of Europe and in the
United States for the treatment of Alzheimer’s disease.2 To
date, several elegant total syntheses of 1 were developed,3
in which the key transformations involved the construction
of two units: (i) the universal tricyclic benzofuran core A
with a sterically congested quaternary carbon, which was
shared by galanthamine-type and morphine-type alkaloids
(Figure 1), and (ii) the special C3 allylic alcohol moiety,
which is essential for its anticholinesterase activity.4 In
constructing the universal skeleton, many synthetic strategies,
such as biomimetic phenolic oxidative coupling,3a-n photo-
chemical reaction,5 radical cyclization,6 intramolecular Heck
reaction,3o-r semipinacol rearrangement,7 intermolecular
alkylation,8 and arylation,9 had been utilized. However, the
successful introduction of the allylic alcohol moiety only
relied on two protocols, biomimetic oxidative bisphenol
(3) (a) Barton, D. H. R.; Kirby, G. W. J. Chem. Soc. 1962, 806. (b)
Kametani, T.; Yamaki, K.; Yagi, H.; Fukumoto, K. J. Chem. Soc. D 1969,
425. (c) Kametani, T.; Yamaki, K.; Yagi, H.; Fukumoto, K. J. Chem. Soc.
C 1969, 2602. (d) Kametani, T.; Yamaki, K.; Terui, T. J. Heterocycl. Chem.
1973, 10, 35. (e) Shimizu, K.; Tomioka, K.; Yamada, S.; Koga, K.
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K. Chem. Pharm. Bull. 1978, 26, 3765. (g) Krikorian, D.; Vlahov, R.;
Parushev, S.; Chinova, M.; Vlahov, I.; Schaefer, H. J.; Duddeck, H.; Snatzke,
G. Tetrahedron Lett. 1984, 25, 2969. (h) Vlahov, R.; Krikorian, D.; Spassov,
G.; Chinova, M.; Vlahov, I.; Parushev, S.; Snatzke, G.; Ernst, L.; Kieslich,
K.; Abraham, W. R.; Sheldrick, W. S. Tetrahedron 1989, 45, 3329. (i)
Szewczyk, J.; Wilson, J. W.; Lewin, A. H.; Carroll, F. I. J. Heterocycl.
Chem. 1995, 32, 195. (j) Chaplin, D. A.; Fraser, N.; Tiffin, P. D. Tetrahedron
Lett. 1997, 38, 7931. (k) Czollner, L.; Frantsits, W.; Kenburg, B.; Hedenig,
U.; Frohlich, J.; Jordis, U. Tetrahedron Lett. 1998, 39, 2087. (l) Kita, Y.;
Arisawa, M.; Gyoten, M.; Nakajima, M.; Hamada, R.; Tohma, H.; Takada,
T. J. Org. Chem. 1998, 63, 6625. (m) Krikorian, D.; Tarpanov, V.; Parushev,
S.; Mechkarova, P. Synth. Commun. 2000, 30, 2833. (n) Node, M.; Kodama,
S.; Hamashima, Y.; Baba, T.; Hamamichi, N.; Nishide, K. Angew. Chem.,
Int. Ed. 2001, 40, 3060. (o) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc.
2000, 122, 11262. (p) Guillou, C.; Beunard, J.-L.; Gras, E.; Thal, C. Angew.
Chem., Int. Ed. 2001, 40, 4745. (q) Trost, B. M.; Tang, W. Angew. Chem.,
Int. Ed. 2002, 41, 2795. (r) Parsons, J. P.; Charles, M. D.; Harvey, D. M.;
Sumoreeah, L. R.; Shell, A.; Spoors, G.; Gill, A. L.; Smith, S. Tetrahedron
Lett. 2001, 42, 2209.
‡ The new approach to galanthamine is under application for the Chinese
Patent (No. 200610041682.6).
(1) For reviews, see: (a) Hoshino, O. In The Alkaloids; Cordell, G. A.,
Ed.; Academic Press: New York, 1998; Vol. 51, pp 323-424. (b) Martin,
S. F. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1987;
Vol. 30, pp 251-376. (c) Marco-Contelles, J.; Carreiras, M. D. C.;
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10.1021/ol060339b CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/31/2006

Scheme 1. Construction of Tricyclic Benzofuran 8
Figure 1. Representative galanthamine-type and morphine-type
alkaloids.
coupling and intramolecular Heck reaction. Because of the
outstanding biological activity but the limited supplies of
1,10 other practical and efficient synthetic approaches to 1
are still desirable.
On the basis of our preliminary efficient strategy, the
combination of the bromonium ion promoted semipinacol
rearrangement of allylic alcohol, and the desilyation/cycliza-
tion to the universal tricyclic benzofuran core A developed
in the total synthesis of Lycoramine,7 we established suc-
cessfully the allylic alcohol group of 1 by a key Saegusa-
Ito oxidation11 and accomplished its total synthesis.
Starting from the construction of the key core A, namely,
the corresponding intermediate 8 (Scheme 1), we prepared
the allylic alcohol 6 in 85% yield first through the modified
Shapiro reaction12 of hydrazone 4, obtained in 90% yield
from commercially available materials 2 and 3, with TBS-
protected o-vanillin 5. Because of our study on the construc-
tion of quarternary carbon with semipinacol rearrangement,13
the aldehyde 7, structurally featuring a sterically congested
quaternary carbon, was obtained readily in 95% yield by
treating 6 with NBS in CH2Cl2 at 0 °C. Then, the intramo-
lecular cyclization of 7 proceeded under DBU/DMSO at 95
°C, and the important aldehyde 8 was obtained in 90% yield.
Once we had established the core structure of the galan-
thamine, we turned our attention to the introduction of its
C3 allylic alcohol group. As demonstrated in Scheme 2, the
Scheme 2. Synthesis of Allylic Alcohol 13
(5) Schultz, A. G.; Yee, Y. K.; Berger, M. H. J. Am. Chem. Soc. 1977,
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Uyeo, S. J. Chem. Soc. C 1968, 2954. (c) Martin, S. F.; Garrison, P. J. J.
Org. Chem. 1981, 46, 3567. (d) Martin, S. F.; Garrison, P. J. J. Org. Chem.
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Flores, H. J. J. Org. Chem. 1984, 49, 157.
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2695.
(10) (a) Shieh, W.-C.; Carlson, J. A. J. Org. Chem. 1994, 59, 5463. (b)
Kueenburg, B.; Czollner, L.; Froehlich, J.; Jordis, U. Org. Process Res.
DeV. 1999, 3, 425.
(11) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(b) Gross, A. S.; Grieco, P. A.; Collins, J. L. J. Am. Chem. Soc. 1990, 112,
9436.
(12) (a) Chamberlin, A. R.; Stemke, J. E.; Thomas, B. F. J. Org. Chem.
1978, 43, 147. (b) Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res.
1983, 16, 55.
(13) (a) Hu, X.-D.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q. Angew. Chem.,
Int. Ed. 2004, 43, 1702 and references therein. (b) Wang, M.; Wang, B.
M.; Shi, L.; Tu, Y. Q.; Fan, C.-A.; Wang, S. H.; Hu, X. D.; Zhang, S. Y.
Chem. Commun. 2005, 5580.
carbonyl homologation of 8 was realized by a widely applied
Wittig reaction and smoothly gave rise to a mixture of vinyl
ethers 9 in 98% yield. When the hydrolysis of the glycol
protection moiety of 9 was carried out under the usual acidic
condition, it was very interesting that an unexpected in-
tramolecular exchange of the glycol protection proceeded
and ketone 10 was obtained but in poor yield. To our delight,
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Org. Lett., Vol. 8, No. 9, 2006

this transformation can be improved by the addition of glycol,
and 10 was obtained in 75% yield under the best result.
The efficient and elegant transformation of the protecting
group built a firm basis for the introduction of the C3-C4
double bond of 1. Following the regular operation of
Saegusa-Ito oxidation,11 10 was transformed into the
corresponding silyl enol ether 11 and was directly oxidized
by Pd(OAc)2 in acetonitrile. However, the expected enone
12 was not obtained. To our delight, through the protocol of
P. A. Grieco by the addition of Na2CO3, the enone 12 was
obtained in 63.5% yield over two steps reclaiming 10 in 17%
yield. The introduction of the C3-C4 double bond, which
was vital and had been accomplished with a (phSeO)2O
oxidation in 50% yield in the total synthesis of 1 reported
by the C. Guillou group,3p was achieved in 76.5% yield based
on the consumed ketone 10. Then, enone 12 was reduced
with L-selectride to give 13 in 93% yield.
Scheme 3. Total Synthesis of (()-Galanthamine 1
At the end, we are now in a position to apply the
experience gained from our studies to the synthesis of
Lycoramine. As shown in Scheme 3, after simple hydrolysis
and the protection operations of 13, aldehyde 15 was obtained
in 80% yield. Treatment of 15 with NBS in the presence of
a catalytic quantity of AIBN as a radical initiator resulted in
the crude acid bromide 15a,7,14 and then, without further
purification, the reaction mixture was directly treated with
an excess of dry methylamine gas prepared in situ (in the
meantime, the cleavage of the acetyl ester moiety took place
under this condition) to afford the expected amide 16 in 75%
overall yield in one pot. To construct the final cycle of 1,
the Pictet-Spengler reaction of 16 with para-formaldehyde
smoothly proceeded and gave the known lactam 173p in 82%
yield. Finally, reduction of 17 with LiAlH4 readily afforded
(()-1.
semipinacol rearrangement/desilyation/cyclization and the
modified Saegusa-Ito oxidation, respectively. Further work
on the asymmetric establishment of the universal basic
skeleton and the synthesis of morphine is underway in our
laboratory.
Acknowledgment. We are grateful for the financial
support of the NSFC (Nos. 30271488 and 20021001) and
the Chang Jiang Scholars Program.
In summary, a practical and efficient total synthesis of
(()-galanthamine 1 was achieved in 13 steps from the
commercially available 2 and 3 in an overall yield of 12%
through a novel approach, in which the construction of the
universal core structure and the successful introduction of
its special allylic alcohol succeeded from a successive
Supporting Information Available: Experimental pro-
cedures, spectroscopic and analytical data, and copies of
NMR spectra of the products. This material is available free
of charge via the Internet at http://pubs.acs.org.
(14) Marko’, I. E.; Mekhalfia, A. Tetrahedron Lett. 1990, 31, 7237.
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