Stereocontrolled synthesis of (-)-galanthamine

Article abstract of DOI:10.1021/ol070255i

An enantiosetective synthesis of (-)-galanthamine has been realized in 11 linear steps starting from isovanillin. A Mitsunobu aryl ether forming reaction was used to assemble the galanthamine backbone, which was stitched together using enyne ring-closing metathesis, Heck, and N-alkylatton reactions affording the tetracyclic ring system. Control of relative and absolute stereochemistry was derived from an easily accessible enantiomerically enriched propargylic alcohol 13.

Full text of DOI:10.1021/ol070255i

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1867-1869
Stereocontrolled Synthesis of
)-Galanthamine
(−
Vachiraporn Satcharoen,†,§ Neville J. McLean,† Stephen C. Kemp,†
Nicholas P. Camp,‡ and Richard C. D. Brown*,†
School of Chemistry, UniVersity of Southampton, Highfield, Southampton SO17 1BJ,
U.K., and Eli Lilly Research Centre, Erl Wood Manor, Sunninghill Road, Windlesham,
Surrey, GU20 6PH, U.K.
rcb1@soton.ac.uk
Received February 1, 2007
ABSTRACT
An enantioselective synthesis of (−)-galanthamine has been realized in 11 linear steps starting from isovanillin. A Mitsunobu aryl ether forming
reaction was used to assemble the galanthamine backbone, which was stitched together using enyne ring-closing metathesis, Heck, and
N-alkylation reactions affording the tetracyclic ring system. Control of relative and absolute stereochemistry was derived from an easily
accessible enantiomerically enriched propargylic alcohol 13.
Galanthamine (1) is an Amaryllidaceae alkaloid,1,2 which is
in clinical use for the symptomatic treatment of Alzheimer’s
disease.3 (-)-Galanthamine displays competitive reversible
inhibition of acetylcholine esterase (AChE) and allosteric
potentiation of nicotinic acetylcholine receptors.4,5 These
effects are believed to be associated with the therapeutic
effect of the drug. (-)-Galanthamine is relatively expensive
to obtain from natural sources, leading to the development
of a synthetic process for its commercial production. This
process utilizes oxidative phenolic coupling and crystalliza-
tion-induced chiral conversion as key steps6-8 and is effective
for the synthesis of the natural product but somewhat limited
in terms of analogue synthesis due to the requirement of
electron-rich aryl groups. Alternative synthetic routes to
galanthamine and structurally related alkaloids have been
reported,1,3,9-11 including an asymmetric total synthesis.12
Recognition of the benefits of a synthetic route to
galanthamine with the potential to create structural analogues
not available through the oxidative coupling approach3,12,13
stimulated our initial synthetic efforts toward the natural
product. Analysis of (-)-galanthamine (1) led us to consider
a diene of general structure 2 as a key intermediate, which
contains suitable functionality for the closure of the two
† University of Southampton.
‡ Eli Lilly.
§ Present address: Department of Chemistry, Faculty of Science,
Ramkhamhaeng University, Bangkok 10240, Thailand.
(1) (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) Jin, Z. Nat. Prod. Rep. 2003, 20, 606-614.
(2) Proskurnina, N. F.; Yakovleva, L. P. Zh. Obshch. Khim. 1952, 22,
1899-1900.
(6) For detailed discussion of the synthesis of galanthamine by oxidative
phenolic coupling, see refs 1b and 3. For the first example of this approach,
see: (a) Barton, D. H. R.; Kirby, G. W. J. Chem. Soc. 1962, 806-817. For
stereoselective oxidative coupling approaches, see: (b) Shimizu, K.;
Tomioka, K.; Yamada, S. I.; Koga, K. Chem. Pharm. Bull. 1978, 26, 3765-
3771. (c) Kodama, S.; Hamashima, Y.; Nishide, K.; Node, M. Angew.
Chem., Int. Ed. 2004, 43, 2659-2661.
(7) Ku¨enburg, B.; Czollner, L.; Fro¨hlich, J.; Jordis, U. Org. Process Res.
DeV. 1999, 3, 425-431.
(8) Total spontaneous resolution of (-)- or (+)-narwedine: Shieh, W.-
C.; Carlson, J. A. J. Org. Chem. 1994, 59, 5463-5465.
(3) For a recent review of the synthesis and pharmacology of galan-
thamine: Marco-Contelles, J.; Carreiras, M. D.; Rodriguez, C.; Villarroya,
M.; Garcia, A. G. Chem. ReV. 2006, 106, 116-133.
(4) Nordberg, A.; Svensson, A.-L. Drug Safety 1998, 19, 465-480.
(5) (a) Lilienfield, S. CNS Drug ReV. 2002, 8, 159-176. (b) Popa, R.
V.; Pereira, E. F. R.; Lopes, C.; Maelicke, A.; Albuquerque, E. X. J. Mol.
Neurosci. 2006, 30, 227-232. (c) Maelicke, A.; Albuquerque, E. X. Eur.
J. Pharmacol. 2000, 393, 165-170.
10.1021/ol070255i CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/13/2007

Our initial investigations, using a racemic propargylic
alcohol (()-4a17 and phenol 5,18 established the enyne RCM
reaction as a highly chemoselective means to create the
vinylcyclohexene 7 (Scheme 2). However, it transpired that
Scheme 1. Proposed Synthetic Route to (-)-Galanthamine
Scheme 2. Synthesis of a Racemic ABD Ring System
heterocyclic C and D rings (Scheme 1). Formation of the D
ring, and corresponding quaternary stereogenic center, would
be achieved by application of the Heck strategy introduced
by Fels and Parsons.11,12 The proposal centered on the use
of an enyne ring-closing metathesis (RCM) reaction to create
the vinyl-substituted cyclohexene ring within a structure
containing all of the carbon atoms required in the final
target.14 Joining the two fragments would be effected through
Mitsunobu coupling of a phenol 3 with an enantiomerically
enriched propargylic alcohol 4a,15 readily available through
asymmetric ketone reduction. Ultimately, we imagined that
such an approach could be adapted to incorporate the
galanthamine allylic hydroxyl group within the fragment
4b.16
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2953. (b) Misaka, Y.; Mizutani, T.; Sekido, M.; Uyeo, S. J. Chem. Soc.
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(10) Racemic syntheses (narwedine): (a) Holton, R. A.; Sibi, M. P.;
Murphy, W. S. J. Am. Chem. Soc. 1988, 110, 314-316. (Galanthamine):
(b) Guillou, C.; Beunard, J. L.; Gras, E.; Thal, C. Angew. Chem., Int. Ed.
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S.; Wang, A.; Fan, C.-A.; Wang, M. Org. Lett. 2006, 8, 1823-1825.
(11) Synthetic approaches/formal syntheses: (a) Parsons, P. J.; Charles,
M. D.; Harvey, D. M.; Sumoreeah, L. R.; Shell, A.; Spoors, G.; Gill, A.
L.; Smith, S. Tetrahedron Lett. 2001, 42, 2209-2211. (b) Pilger, C.;
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127, 14785-14803.
Pd-catalyzed arylation of the diene 7 did not provide the
desired product and instead favored C-C bond formation
at the less sterically encumbered end of the 1,3-diene system,
affording diene 8.19 Presumably, the intermediacy of a π-allyl
palladium species also favors the observed regioselectivity.
The required C-C bond formation was realized by selective
hydration of the less-substituted olefin prior to the Heck
reaction, securing the tricyclic ABD system 11 in high overall
yield.11,12,20,21
Although the ultimately successful route to the tricycle
11 came at the expense of additional functional group
interconversions and protecting group manipulations, it was
easy to envisage its adaptation to provide a streamlined
asymmetric synthesis of galanthamine. Accordingly, the
(16) For the synthesis of protected 4b, see: Smith, A. B.; Ott, G. R. J.
Am. Chem. Soc. 1998, 120, 3935-3948.
(13) For some examples of galanthamine analogues, see: (a) Bores, G.
M.; Kosley, R. W. J. Drugs Future 1996, 21, 621-635. (b) Poschalko, A.;
Welzig, S.; Treu, M.; Nerdinger, S.; Mereiter, K.; Jordis, U. Tetrahedron
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D. R. J. Med. Chem. 1992, 35, 466-479.
(19) For a discussion of intermolecular palladium-catalyzed diene
arylation, see: Heck, R. F. Palladium Reagents in Organic Syntheses;
Academic Press: New York, 1985; pp 223-227.
(14) Enyne metathesis: (a) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004,
104, 1317-1382. (b) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1-18.
(15) Kiankarimi, M.; Lowe, R.; McCarthy, J. R.; Whitten, J. P.
Tetrahedron Lett. 1999, 40, 4497-4500.
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Org. Lett., Vol. 9, No. 10, 2007

protected aminomethyl group was introduced into the aryl
fragment 3 (Scheme 3). Mitsunobu coupling of 3 with the
The remaining steps to complete the total synthesis of (-)-
galanthamine were carried out without protection of the
primary hydroxyl group. An intramolecular Heck reaction
of 17 led to successful formation of the central heterocyclic
five-membered D ring in an acceptable yield. Trost’s
procedure was then applied to install the allylic hydroxyl
group into 19,12 leading to an excess of the desired R-dia-
stereoisomer (dr ) 4.8:1 estimated by 1H NMR). Separation
of the diastereoisomers was not possible at this stage, so the
mixture of epimers was taken through the remaining two
steps. Activation of the 1° hydroxyl group was achieved
through mesylation. Although some bismesylation was also
observed under the conditions employed, no attempt was
made to optimize this reaction. Finally, the azepine B ring
formation was achieved in a one-pot process by sequential
treatment with TFA and neutralization with NaHCO3 (aq).
Thus (-)-galanthamine and its epimer 19 were obtained after
separation by column chromatography.22
Scheme 3. Asymmetric Synthesis of (-)-Galanthamine
In conclusion, an enantioselective synthesis of (-)-
galanthamine has been described from commercially avail-
able materials in 11 linear steps (11 steps from isovanillin
or 5-hexenoic acid, 14 steps in total). Control of absolute
stereochemistry was achieved through an asymmetric reduc-
tion of a propargylic ketone. An efficient enyne metathesis
reaction was used to close the B ring while generating the
requisite functionality later used in the formation of the D
and C rings.
Acknowledgment. The authors thank The Royal Society
(R.C.D.B., University Research Fellowship), Eli Lilly (S.C.K.,
studentship), The University of Southampton (V.S., student-
ship), and the EPSRC (S.C.K. and N.J.M., studentships) for
financial support.
Supporting Information Available: Procedures and
spectroscopic and analytical data for compounds 1, 3, 4a,
1
6-11, and 13-19. Copies of H and 13C NMR spectra for
enantiomerically enriched propargylic alcohol 13 delivered
the aryl ether 14. The enyne 15 (92% ee, HPLC), obtained
after TMS deprotection of 14, underwent an efficient RCM
reaction in the presence of 3 mol % of the first-generation
Grubbs’ catalyst (12) at ambient temperature to give diene
16. Hydroboration and oxidation of 16 was unaffected by
the presence of the carbamate group, allowing access to the
homoallylic alcohol 17 in excellent yield (91%).
compounds 1, 3, 6-11, and 13-19. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL070255I
(22) Spectroscopic and physical data for synthetic (-)-galanthamine were
consistent with those reported in the literature: ref 12 for 1H and 13C NMR.
Melting point and [R]D: ref 8 and: Kobayashi, S.; Yuasa, K.; Sato, K.;
Imakura, Y.; Shingu, T. Heterocycles 1982, 19, 1219-1222.
Org. Lett., Vol. 9, No. 10, 2007
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