Total synthesis of (±)-Galanthamine via a C3-selective stille coupling and IMDA cycloaddition cascade of 3,5-dibromo-2-pyrone

Article abstract of DOI:10.1021/ol100617u

Figure presented A new efficient synthetic route to (±)-galanthamine was devised by using a tandem C3-selective Stille coupling-IMDA cascade of 3,5-dibromo-2-pyrone as a key strategy.

Full text of DOI:10.1021/ol100617u

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2016-2018
Total Synthesis of (()-Galanthamine via
a C3-Selective Stille Coupling and IMDA
Cycloaddition Cascade of
3,5-Dibromo-2-pyrone
Jay Hyok Chang, Ho-Ung Kang, In-Hak Jung, and Cheon-Gyu Cho*
Department of Chemistry, Hanyang UniVersity, Seoul 133-791, Korea
ccho@hanyang.ac.kr
Received March 16, 2010
ABSTRACT
A new efficient synthetic route to (()-galanthamine was devised by using a tandem C3-selective Stille coupling-IMDA cascade of 3,5-dibromo-
2-pyrone as a key strategy.
Galanthamine (1, Figure 1), an alkaloid isolated from various
plant sources including the bulbs and flowers of the
Caucasian snowdrop (Galanthus woronowii), is a selective,
competitive, and reversible inhibitor of acetylcholinesterase
(Ache). It has also shown potent activity in allosteric
modulation of the neural nicotinic receptors to increase
acetylcholine release.1 Being marketed as a hydrobromide
salt under several brand names, galanthamine is a com-
mercially available prescription drug for the symptomatic
treatment of senile dementia of Alzheimer’s disease (AD)
patients.2 The inefficiency in its isolation from natural sources
has led to the development of effective synthetic methods
and strategies, mainly based on biomimetic oxidative phenol
coupling or an intramolecular Heck reaction.3
As part of our current study concerning the synthetic utility
of 3,5-dibromo-2-pyrone in target-oriented synthesis,4 we
have envisaged that the tricyclic core of galanthamine with
all required functional elements including the characteristic
quaternary benzylic carbon could be readily forged from
6-endo, the IMDA cycloaddition product of 7. The IMDA
precursor 7 is in turn attainable from the C3-selective Stille
coupling reaction of 2-pyrone 8 with the corresponding aryl
stannane 9 (Scheme 1).5 In forward direction, ester 5, the
lactone ring-opening product of IMDA product 6-endo, needs
to be homologated by one carbon to provide the key
intermediate 4. Connection of two terminal groups, amine
and aldehyde, would assemble the benzoazepin ring system.
Inversion of the stereochemistry of the secondary hydroxyl
group and the removal of the vinyl bromide would then
complete the total synthesis of (()-galanthamine.
Our synthetic study began with the preparation of aryltin
9 (Scheme 2). Installation of a vinyl ether group on
commercial phenol 10 was made by employing the Cu(II)-
promoted vinylation process reported by Blouin and co-
Figure 1. Galanthamine and its related congenors.
10.1021/ol100617u  2010 American Chemical Society
Published on Web 04/08/2010

from the intramolecular Diels-Alder reaction of the initially
formed coupling product 7 (Table 1).8
Scheme 1. Retrosynthesis of (()-Galanthamine
Table 1. Tandem Stille/IMDA Cascade
a
entry
catalyst
additive
conditions
yield (ratio)
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
none
CuI
toluene, 100 °C, 20 h trace
toluene, 90 °C, 6 h 10% (2:1)
CuBr toluene, 80 °C, 10 h 15% (2:1)
CuI
DMF, 90 °C, 16 h
DMF, 90 °C, 12 h
DMF, 95 °C, 11 h
DMF, 110 °C, 12 h
DMF, 95 °C, 12 h
DMF, 80 °C, 8 h
35% (2.5:1)
26% (2.5:1)
45% (2.5:1)
12% (1:4)
trace
CuIb
CuI
CuI
workers,6 which provided aryl vinyl ether 11 in 73% yield.
Despite the potential interference of the neighboring vinyl
ether function, the Pd-catalyzed stannylation7 of iodide 11
proceeded surprisingly well to afford aryltin 9 in 82% yield.
Alternatively, aryltin 9 could be made with a two-step
sequence composed of the aldehyde protection and lithi-
ation-stannylation-workup process in a more economical
way. The easy access to aryltin 9 allowed the C3-selective
Stille coupling reaction with 3,5-dibromo-2-pyrone toward
the synthesis of the IMDA precursor 7.
none
Pd(t-Bu3P)2 CuI
trace
a 5 mol % catalyst and 10 mol % additive. b 20 mol %.
A thorough screening of reaction conditions indicated that
this tandem Stille/IMDA cascade is quite sensitive to solvent,
temperature, and cocatalyst, but not much on Pd catalyst.
Shown in Table 1 is a partial list of our work. The best results
were obtained when the reaction was performed with 5 mol
% of Pd(PPh3)4 and 10 mol % of CuI in DMF at 95 °C (entry
6).9 DMF proved to be a better solvent than toluene. The
reactions without CuI provided only a trace of the IMDA
products regardless of the solvent type (entries 1 and 8). It
also turned out that 6-endo is thermally more labile than
6-exo, which accounts for the diminished product yield of
the reaction conducted at elevated temperature (110 °C, entry
Scheme 2
.
Preparation of Aryltin 9 and Coupling Reaction with
8
(2) (a) Popa, R. V.; Pereira, E. F. R.; Lopes, C.; Maelicke, A.;
Albuquerque, E. X. J. Mol. Neurosci. 2006, 393, 165. (b) Lilienfield, S.
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1823. (d) Trost, B. M.; Tang, W.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 14785. (e) Kodama, S.; Hamashima, Y.; Nishide, K.; Node, M. Angew.
Chem., Int. Ed. 2004, 43, 2659.
(4) For a recent review and selected articles, see: (a) Kim, H.-Y.; Cho,
C.-G. Prog. Heterocycl. Chem. 2007, 18, 1. (b) Tam, N. T.; Cho, C.-G.
Org. Lett. 2008, 10, 601. (c) Tam, N. T.; Chang, J.; Jung, E.-J.; Cho, C.-G.
J. Org. Chem. 2008, 73, 6258. (d) Shin, I.-J.; Choi, E.-S.; Cho, C.-G. Angew.
Chem., Int. Ed. 2007, 46, 2303. (e) Tam, N. T.; Cho, C.-G. Org. Lett. 2007,
9, 3319. (f) Shin, J.-T.; Hong, S.-C.; Shin, S.; Cho, C.-G. Org. Lett. 2006,
8, 3339. (g) Ryu, K.; Cho, Y.-S.; Cho, C.-G. Org. Lett. 2006, 8, 3343. (h)
Chung, S.-I.; Seo, J.; Cho, C.-G. J. Org. Chem. 2006, 71, 6701. (i) Shin,
J.-T.; Shin, S.; Cho, C.-G. Tetrahedron Lett. 2004, 45, 5857. (j) Pang,
S.-J.; Min, S.-H.; Lee, H.; Cho, C.-G. J. Org. Chem. 2003, 68, 10191.
(5) Kim, W.-S.; Kim, H.-J.; Cho, C.-G. J. Am. Chem. Soc. 2003, 125,
14288.
The actual coupling reaction afforded not the expected
2-pyrone 7, but tetracyclolactones 6-endo and 6-exo, resulting
(6) Blouin, M.; Frenette, R. J. Org. Chem. 2001, 66, 9043.
(7) Azizian, H.; Eaborn, C.; Pidcock, A. J. Organomet. Chem. 1981,
215, 49.
(1) For a recent review, see: (a) Marco-Contelles, J.; Carreiras, M. D. C.;
Rodriguez, C.; Villarroya, M.; Garcia, A. G. Chem. ReV. 2006, 106, 116.
(b) Jin, Z. Nat. Prod. Rep. 2003, 20, 606. (c) Hoshino, O. The Alkaloids;
Cordell, G. A., Ed.; Academic Press: New York, 1998; Vol. 51, pp
323-424. (d) Martin, S. F. The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1987; Vol. 30, pp 252-376.
(8) For a recent review, see: Deagostino, A.; Prandi, C.; Zavattraro, C.;
Venturello, P. Eur. J. Org. Chem. 2006, 11, 2463.
(9) There is a peculiar temperature effect in the regiochemical outcome.
A detailed account will be followed in due course.
Org. Lett., Vol. 12, No. 9, 2010
2017

7). The reaction at lower temperature also gave lower product
yield due to the increased formation of byproducts (entry
4).
Scheme 3. Synthesis of (()-Galanthamine
The stereochemistry of 6-endo and 6-exo was determined
1
primarily by comparing the H NMR chemical shifts and
coupling constants of the C5 and C6 protons of the isolated
6-endo and 6-exo products (Figure 2). The H6a of 6-endo
Figure 2.
1H NMR assignment of 6-endo and 6-exo.
appears at higher field than the H6a of 6-exo (2.27 vs 2.54
ppm) because of the anisotropic effect of the bridgehead
aromatic ring, generally observed in the series of similar
bicyclolactones.10
mediated debromination gave (()-narwedine 2 and the over-
reduction product (()-lycoraminone 19 in 55% and 20%
yield, respectively, from 18.12 Finally, the L-selectride
reduction of the ketone furnished (()-galanthamine 1 in 87%
yield.13 The hydride was delivered exclusively to the R-face
of the ketone 2 as the ꢀ-face is blocked by the flanking
benzofuran subunit.
Lactone ring opening of 6-endo with NaOMe and protec-
tion of the resultant secondary hydroxyl group as a MOM
ether furnished ester 14 in 84% yield over two steps. From
this point, we adapted the procedures elaborated by Trost
and co-workers for their synthesis of galanthamine,3d based
on the structural similarity with their tricyclic intermediate.
Nevertheless, an intensive optimization process was required
for the transformation of tricyclic ester 14 to the final target
in an acceptable total yield (see Supporting Information for
the details). The reductive amination reaction of aldehyde
14 under the modified reaction conditions gave the corre-
sponding secondary amine which was masked with the Boc
group in 62% total yield over two steps (Scheme 3).11
DIBAL reduction followed by oxidation provided aldehyde
16a. Subsequent Wittig olefination with methoxymethyl
phosphorus ylide furnished enol ether 17 as a mixture of
E/Z isomers in reasonable yield (46%). The acid-promoted
hydrolysis of the sterically hindered vinyl ether to aldehyde
became more tricky, due to the presence of the MOM ether
group. We found that the hydrolysis was best when reacted
with TFA at rt, which accompanied deblocking of both
N-Boc and MOM groups. Reduction of the resultant cyclic
hemiaminal with NaCNBH3 furnished tetracycle 18 in 79%
total yield from 17. Dess-Martin oxidation followed by Zn-
In summary, we have devised a new synthetic route to
(()-galanthamine from 3,5-dibromo-2-pyrone by using a C3-
selective Stille coupling/IMDA cascade as a key strategy.
Our novel strategy would be a valuable addition to the current
galanthamine synthesis predominated by the approaches
involving either oxidative phenol coupling or an intramo-
lecular Heck reaction.
Acknowledgment. Financial support was provided by the
grants from the National Research Foundation, KRF-2008-
313-C00467 and 2009-0080752. C.J.H. and K.H.-W. thank
the BK21 fellowship.
Supporting Information Available: Details of experi-
mental procedures and compound characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100617U
(10) Cho, C.-G.; Kim, Y.-W.; Lim, Y.-K.; Park, J.-S.; Lee, H.; Koo, S.
J. Org. Chem. 2002, 67, 290.
(11) Submission of 14 to the literature conditions using methylamine
hydrochloride in MeOH resulted in the formation of aromatic dimethyl
acetal. Use of MeNH2 dissolved in anhydrous MeOH was required to avoid
the problematic acetal formation in our case.
(12) Szewezyk, J.; Wilson, J. W.; Lewin, A. H.; Carroll, F. I. J. Het-
erocycl. Chem. 1995, 32, 195.
(13) Ku¨enburg, B.; Czollner, L.; Fro¨hlich, J.; Jordis, U. Org. Process
Res. DeV. 1999, 3, 425.
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Org. Lett., Vol. 12, No. 9, 2010