Total synthesis of (-)-galanthamine and (-)-lycoramine via catalytic asymmetric hydrogenation and intramolecular reductive Heck cyclization

Article abstract of DOI:10.1021/ol300913g

A synthetic strategy featuring efficient ruthenium-catalyzed asymmetric hydrogenation of racemic α-aryloxy cyclic ketone via dynamic kinetic resolution and palladium-catalyzed intramolecular reductive Heck cyclization has been developed for the asymmetric total synthesis of (-)-galanthamine (20.1%, 12 steps) and (-)-lycoramine (40.2%, 10 steps)

Full text of DOI:10.1021/ol300913g

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2714–2717
Total Synthesis of (À)-Galanthamine and
(À)-Lycoramine via Catalytic Asymmetric
Hydrogenation and Intramolecular
Reductive Heck Cyclization
Ji-Qiang Chen, Jian-Hua Xie,* Deng-Hui Bao, Sheng Liu, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, China
jhxie@nankai.edu.cn; qlzhou@nankai.edu.cn
Received April 9, 2012
ABSTRACT
A synthetic strategy featuring efficient ruthenium-catalyzed asymmetric hydrogenation of racemic R-aryloxy cyclic ketone via dynamic kinetic
resolution and palladium-catalyzed intramolecular reductive Heck cyclization has been developed for the asymmetric total synthesis of
(À)-galanthamine (20.1%, 12 steps) and (À)-lycoramine (40.2%, 10 steps)
The galanthamine-type alkaloids including (À)-ga-
lanthamine (1) and (À)-lycoramine (2) (Figure 1), isolated
from the bulbs of different species of the Amaryllidaceae
family, have attractedmuchattentionof syntheticchemists
because of their intriguing structures and potent biological
activities.1 (À)-Galanthamine (1) is a selective, reversible,
and competitive acetylcholinesterase inhibitor and has
been used in the early treatment of Alzheimer’s disease.2
(À)-Lycoramine (2) has a similar, albeit less potent, activ-
ity as an acetylcholinesterase inhibitor and an allosteric
potentiating ligand.3 Because of the limited supplies of
these alkaloids from natural sources, a number of synthetic
strategies have been developed for the syntheses of ga-
lanthamine and its analogues since Barton and Kirby
initiatively reported the total synthesis of galanthamine
in the early 1960s.4 However, most of the reported syn-
thetic strategies provided the alkaloids in racemic form.5
Figure 1. Representative galanthamine-type alkaloids and their
core structure.
(1) Cordell, G. A., Ed. The Alkaloids: Chemistry and Biology;
Amsterdam; Elsevier 2010 Vol. 68,.
(2) Sramek, J. J.; Frackiewicz, J. E.; Cutler, N. R. Expert Opin.
(5) For recent reviews on the synthesis of galanthamine and its
analogues, see: (a) Marco-Contelles, J.; do Carmo Carreiras, M.;
Investig. Drugs 2000, 9, 2393.
(3) Han, S.; Sweeney, J. E.; Bachman, E. S.; Schweiger, E. J.; Forloni,
G.; Coye, J. T.; Davis, B. M.; Joullie, M. M. Eur. J. Med. Chem. 1992,
27, 673.
(4) (a) Barton, D. H. R.; Kirby, G. W. J. Chem. Soc. 1962, 806. (b)
Barton, D. H. R.; Kirby, G. W.; Taylor, J. B. J. Chem. Soc. 1962, 4545.
Rodrıguez, C.; Villarroya, M.; Garcıa, A. G. Chem. Rev. 2006, 106,
´ ´
116. (b) Marco-Contelles, J.; Perez-Mayoral, E.; van Nhien, A. N.;
Postel, D. Targets Heterocycl. Syst. 2007, 11, 365. (c) Zhong, J. Nat.
Prod. Rep. 2009, 26, 363. (d) Fang, L.; Gou, S.; Zhang, Y. Chin. J. Org.
Chem. 2011, 31, 286.
r
10.1021/ol300913g
Published on Web 05/21/2012
2012 American Chemical Society

Galanthamine-type alkaloids feature a unique tricyclic
benzofuran core structure with a chiral arylated-quatern-
ary carbon center, and the enantioselective construction of
this sterically congested quaternary carbon center is a
major challenge in the synthesis of these alkaloids. Thus,
a number of strategies have been developed to construct
the chiral arylated-quaternary carbon center for the synth-
esis of galanthamine-type alkaloids by means of phenolic
oxidative coupling,6 intramolecular Heck reaction,7
Claisen rearrangement,8 BrichÀCope sequence,9 phenolic
oxidative coupling and crystallization-induced chiral con-
version,10 and organocatalyzed Michael addition.11 How-
ever, although being one of the most promising methods
for the synthesis of chiral compounds, the asymmetric
catalysis has been rarely used for the enentioselective
synthesis of galanthamine-type alkaloids, and the reported
catalytic asymmetric syntheses of (À)-galanthamine (1)
and (À)-lycoramine (2) were not very efficient.7,11
from R,β-unsaturated ester (S)-4 containing an R-haloge-
nated phenoxyl group via an intramolecular reductive
Heck cyclization. The R,β-unsaturated ester (S)-4 could
be easily prepared from R-aryloxy cyclohexanone (S)-5 via
a HornerÀWadsworthÀEmmons reaction, and the opti-
cally pure (S)-5 could be obtained by ruthenium-catalyzed
asymmetric hydrogenation of rac-5 via DKR13 followed
by a Swern oxidation.
Scheme 1. Synthetic Strategy for (À)-Galanthamine (1) and
(À)-Lycoramine (2)
During the study on the catalytic asymmetric synthesis
of chiral natural products, we found that the intramo-
lecular reductive Heck reaction is a convenient access to
the construction of tricyclic dihydrobenzofuran ring with a
quaternary stereocenter.12 This intramolecular reductive
Heck reaction combining with the asymmetric hydrogena-
tion of R-aryloxy cyclic ketone via a dynamic kinetic
resolution (DKR), recently developed in our laboratory,13
provides a highly efficient strategy for the enantioselective
synthesis of (À)-galanthamine (1, 20.1%, 12 steps) and
(À)-lycoramine (2, 40.2%, 10 steps).
Since Larock14 and Trost7a,c had reported that the
intramolecular Heck reaction of aryl allyl ethers often
suffers from a competitive palladium-catalyzed ionization
of the aryloxy group, producing a phenol, the prevention
of this unwanted side reaction inevitably became one of the
Our strategy is outlined in Scheme 1. We expected that
the target molecules 1 and 2 could be synthesized from
ester (S,R)-3 via formation of the seven-memberedaza ring
through several steps including amidation and Pictet-
Spengler cyclization. The ester (S,R)-3 could be obtained
Table 1. Palladium-Catalyzed Cyclization of rac-4 to rac-3a
(6) (a) Tomioka, K.; Shimizu, K.; Yamada, S.; Koga, K. Hetero-
cycles 1977, 6, 1752. (b) Shimizu, K.; Tomioka, K.; Yamada, S.; Koga,
K. Heterocycles 1977, 8, 277. (c) Kodama, S.; Hamashima, Y.; Nishide,
K.; Node, M. Angew. Chem., Int. Ed. 2004, 43, 2659. (d) Node, M.;
Kodama, S.; Hamashima, Y.; Katoh, T.; Nishide, K.; Kajimoto, T.
Chem. Pharm. Bull. 2006, 54, 1662.
(7) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 11262.
(b) Trost, B. M.; Tang, W. Angew. Chem., Int. Ed. 2002, 41, 2759. (c)
Trost, B. M.; Tang, W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 14785.
Catalytic asymmetric synthesis of (À)-galanthamine (10 steps, 8%
overall yield).
(8) (a) Tanimoto, H.; Kato, T.; Chida, N. Tetrahedron Lett. 2007, 48,
6267. (b) Kato, T.; Tanimoto, H.; Yamada, H.; Chida, N. Heterocycles
2010, 82, 563.
(9) Malachowski, W. P.; Paul, T.; Phounsavath, S. J. Org. Chem.
2007, 72, 6792.
reductive
reagent
(equiv)
temp time yieldb
entry
1
X
[Pd]
(°C)
(h)
(%)
Br Pd(OAc)2
Br Pd(OAc)2
Br Pd(OAc)2
HCO2H (2.0)/
Et3N (2.5)
80
10
20
(10) Magnus, P.; Sane, N.; Fauber, B. P.; Lynch, V. J. Am. Chem.
Soc. 2009, 131, 16045.
2
3
HCO2H (2.0)/
Et3N (2.5)
100
120
10
10
40
32
(11) Chen, P.; Bao, X.; Zhang, L.-F.; Ding, M.; Han, X.-J.; Li, J.;
Zhang, G.-B.; Tu, Y.-Q.; Fan, C.-A. Angew. Chem., Int. Ed. 2011, 50,
8186. Catalytic asymmetric synthesis of (À)-galanthamine (16 steps,
2.8% overall yield) and (À)-lycoramine (14 steps, 8.1% overall yield).
(12) Reviews for reductive Heck reaction, see: (a) Oestreich, M., Ed.
The MizorokiÀ-Heck Reaction; Wiley: Chichester, 2009. (b) Link, J. T.;
Overman, L. E. Metal-catalyzed Cross Coupling Reaction; Diederick, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998, Chapter 6. (c) Tsuji, J.
Palladium Reagent and Catalysts. Innovation in Organic Synthesis; John
Wiley: New York, 1995. Selected papers for intramolecular reductive Heck
reaction for the construction of dihydrobenzofuran ring: (d) Trost, B. M.;
Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003, 125, 13155. (e) Trost,
B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2002, 124, 11616.
(13) Bai, W.-J.; Xie, J.-H.; Li, Y.-L.; Liu, S.; Zhou, Q.-L. Adv. Synth.
Catal. 2010, 352, 81.
HCO2H (2.0)/
Et3N (2.5)
4
5
Br Pd(OAc)2
Br Pd2(dba)3
HCO2Na (2.0)
HCO2Na (2.0)
100
80
10
3
43
49
CHCl3
3
6c
I
Pd2(dba)3
HCO2Na (2.0)
60
3
95
CHCl3
3
a Reaction conditions: 10 mmol of rac-4, 5 mol % of Pd catalyst,
10 mol % of PPh3, DMF as solvent. b Isolated yield. c Without PPh3.
Org. Lett., Vol. 14, No. 11, 2012
2715

major challenges of our synthetic strategy. We first evalu-
ate the intramolecular reductive Heck cyclization of rac-4a
(X = Br), which was prepared in good yield (67%, two
steps) from 2-bromo-6-methoxyphenol and 7-bromo-1,4-
dioxaspiro[4.5]decan-8-one15 (see the Supporting Infor-
mation). When the reaction was performed in the presence
of 5 mol % of Pd(OAc)2, 10 mol % of PPh3, 2.0 equiv of
HCO2H, and 2.5 equiv of Et3N at 80 °C in DMF for 10 h,
rac-4a was cyclized to rac-3 in 20% yield accompanied by a
significant amount of ionization product, 2-bromo-6-
methoxyphenol (Table 1, entry 1). Increasing the reaction
temperature led to a higher yield of rac-3, but still lower
than 40% (entries 2 and 3). Use of HCO2Na (2 equiv),
instead of HCO2H/Et3N, as a reductive reagent resulted in
a slight improvement of yield to 49% (entry 5). Fortu-
nately, when the iodinated R,β-unsaturated ester rac-4b
(X = I) was subjected to the reaction the ionization of
aryloxy group was strongly suppressed and the desired
reductive Heck cyclization product rac-3 was obtained in
95% yield under milder conditions (60 °C, 3 h) (entry 6).16
This palladium-catalyzed intramolecular reductive Heck
RuCl2-(S)-SDP/(R,R)-DPEN,17 rac-5b (obtained from the
reaction of 2-iodo-6-methoxyphenol with 7-bromo-1,4-
dioxaspiro[4.5]decan-8-one in 75% yield, see the Supporting
Information) was hydrogenated to chiral β-aryloxy cyclo-
hexanol (S,R)-6 in high yield (99%) with excellent enan-
tioselectivity (97% ee) and cis-selectivity (cis/trans > 99:1)
(Scheme 3), indicating that the ethylene ketal group in the
substrate has a negligible effect to the reaction. The β-
aryloxy cyclohexanol (S,R)-6 was then converted into R-
aryloxy cyclohexanone (S)-5b in 95% yield without loss of
its optical purity by Swern oxidation. Subsequently, a con-
densation of (S)-5b with ethyl 2-(dimethoxy-phosphoryl)
Scheme 3. Enantioselective Synthesis of (S,R)-3 (DMSO =
Dimethyl Sulfoxide)
Scheme 2. Palladium-Catalyzed Cyclization of rac-7 and rac-8
cyclization is also highly efficient for the cyclization
of rac-7 and rac-8, the analogues of rac-4 derived from
R-(2-iodophenoxy)cycloalkanones with five or seven-
membered ring to the corresponding benzofurans rac-9
(93%) and rac-10 (84%) in high yields (Scheme 2).
acetate by a Horner-Wadsworth-Emmons reaction gave
R,β-unsaturated esters (S)-4b in 96% yield with (E)-con-
figuration as the major isomer (Z/E ≈ 1:5). The Z,E-
mixture of (S)-4b was then submitted to the palladium-
catalyzed intramolecular reductive Heck cyclization to
give (S,R)-3 in 95% yield.
With ester (S,R)-3 in hand, we then focused our atten-
tion on its conversion into (À)-galanthamine (1) and (À)-
lycoramine (2). As shown in Scheme 4, the ester (S,R)-3
was hydrolyzed with sodium hydroxide in methanol/
H2O, followed by activation with ethyl chloroformate
(ClCO2Et) in the presence of triethylamine at À15 °C
and amidation with aqueous methylamine (MeNH2) to
offer amide (S,R)-11 in 83% yield (2 steps). Subsequent
Pictet-Spengler cyclization of (S,R)-11 with paraformalde-
hyde furnished the tetracyclic intermediate (S,R)-12
with a seven-membered azepine ring in 89% yield.18 The
intermediate (S,R)-12 was then subjected to a selective
Naturally, after the establishment of a highly efficient
intramolecular reductive Heck cyclization to create the
tricyclic benzofuran core structure of galanthamine-type
alkaloids, we then tried the synthesis of (S,R)-3 in optically
pure form. To address this topic, the enantioselective
synthesis of the optically pure R-aryloxy cyclohexanone
(S)-5b is the key. Recently, we developed a highly efficient
ruthenium-catalyzed asymmetric hydrogenation of race-
mic R-aryloxy cyclohexanones via DKR, producing chiral
β-aryloxy cycloalkanols in excellent enantioselectivity.13
This provides an method for us to try the synthesis of
the optically pure R-aryloxy cyclohexanone (S)-5b with
a bulky ethylene ketal group at the 4-position of the
cyclohexane ring. By using chiral ruthenium catalyst
(14) Larock, R. C.; Stinn, D. E. Tetrahedron Lett. 1988, 29, 4687.
(15) Lauktien, G.; Volk, F.-J.; Frahm, A.-W. Tetrahedron: Asymme-
try 1997, 8, 3457.
(17) (a) Xie, J.-H.; Wang, L.-X.; Zhu, S.-F.; Fu, Y.; Fan, B.-M.;
Duan, H.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125, 4404. (b) Xie,
J.-H.; Liu, S.; Huo, X.-H.; Cheng, X.; Duan, H.-F.; Fan, B.-M.; Wang,
L.-X.; Zhou, Q.-L. J. Org. Chem. 2005, 70, 2967.
(18) Guillou, C.; Beunard, J.-L.; Gras, E.; Thal, C. Angew. Chem.,
Int. Ed. 2001, 40, 4745.
(16) Ester rac-3 can also be synthesized in 65% yield by using radical
cyclization (AIBN, n-Bu3SnH, benezene, reflux, 3 h). However, the use
of toxic metal tin compound made the radical cyclization less applicable.
Selected papers for radical cyclization: (a) Parker, K. A.; Fokas, D.
J. Org. Chem. 2006, 71, 449. (b) Parker, K. A.; Kim, H.-J. J. Org. Chem.
1992, 57, 752.
2716
Org. Lett., Vol. 14, No. 11, 2012

reduction of the ketone group to the hydroxyl using
K-Selectride and a further reduction of the amide motif
to amine with triethoxysilane ((EtO)3SiH) in the presence
of Zn(OAc)2 as a catalyst19 to give (À)-lycoramine (2) in
84.6% yield (2 steps).20 The NMR spectroscopic data
and the optical rotation ([R]2D0 = À102 (c 0.35, EtOH),
lit. [R]2D0 = À100 (c 0.35, EtOH),9 [R]2D0 = À92.7 (c 0.35,
EtOH)11) of our synthetic (À)-lycoramine are identical to
those reported in the previous synthesis. Thus, enantiose-
lective synthesis of (À)-lycoramine was achieved in 40.2%
overall yield over 10 steps from the commercially available
2-iodo-6-methoxyphenol via a ruthenium-catalyzed asym-
metric hydrogenation and a palladium-catalyzed intra-
molecular reductive Heck cyclization as the key steps.
synthesis of (À)-galanthamine (1) was thus accomplished
in 12 steps with 20.1% overall yield.
Scheme 5. Enantioselective Synthesis of (À)-Galanthamine (1)
(TBSOTf = tert-Butyldimethylsilyl
Trifluoromethanesulfonate)
Scheme 4. Enantioselective Synthesis of (À)-Lycoramine (2)
(K-Selectride = Potassium Tri-sec-butyl Borohydride)
In conclusion, we have developed highly efficient en-
antioselective syntheses of (À)-galanthamine (1) and (À)-
lycoramine (2) based on a ruthenium-catalyzed asymmetric
hydrogenation and a palladium-catalyzed intramolec-
ular reductive Heck cyclization as the key steps. The (À)-
galanthamine (1) was synthesized in twelve steps with
20.1% overall yield and the (À)-lycoramine (2) was synthe-
sized in ten steps with 40.2% overall yield from commer-
cially available starting materials. These high yielding
syntheses of (À)-galanthamine and (À)-lycoramine have
good reproducibility. These results demonstrated that this
catalytic enantioselective synthetic strategy is efficient for
the asymmetric construction of the polycyclic benzofuran
ring systems bearing an all-carbon quaternary center and
has high potential for application to the syntheses of other
galanthamine-type, morphine-type, and lunarine-type bio-
logically significant alkaloids.
The enantioselective synthesis of (À)-galanthamine (1) is
outlined in Scheme 5. Using the procedure of SaegusaÀIto
oxidation,21 the tetracyclic intermediate (S,R)-12 was trea-
ted with TBSOTf, followed by palladium-mediated oxida-
tion to provide the desired enone (S,S)-14 in 51% yield
(two steps).22 The (S,S)-14 was then reduced sequentially
with K-Selectride and (EtO)3SiH/Zn(OAc)2 to yield
(À)-galanthamine (1) in 83% yield. The data of NMR
spectroscopy and optical rotation of our synthetic
(À)-galanthamine (1) are identical to those reported
in the literature ([R]2D0 = À119.5 (c 0.30, EtOH), lit.6c
[R]2D0 = À121.7 (c 0.30, EtOH)). The enantioselective
Acknowledgment. We thank the National Natural
Science Foundation of China, the National Basic Research
Program of China (973 Program) (2012CB821600), the
“111” project (B06005) of the Ministry of Education of
China, and the Program for New Century Excellent Ta-
lents in University (NCET-08-0292) for financial support.
(19) Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem.
Soc. 2010, 132, 1770.
(20) The reduction of the amide group of (S,S,R)-9 with LiAlH4 gave
Supporting Information Available. Experimental pro-
cedures, characterization data for the products, and
HPLC spectra for (S)-5b and (S,R)-6. This material is
available free of charge via the Internet at http://pubs.acs.
org.
2 in 81% yield.
(21) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(22) For improving the transformation of (S,R)-12 to (S,S)-14 other
methods, such as DDQ oxidation of silyl enol ester, treatment with
PhSeCl and oxidation with H2O2, and bromination followed with
elimination of HBr, have also been tried; however, the desired product
was obtained in very low yields.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
2717