Formal total synthesis of (-)-emetine using catalytic asymmetric allylation of cyclic imines as a key step

Article abstract of DOI:10.1021/ol0530326

Catalytic asymmetric allylation of 3,4-dihydro-6,7-dimethoxyisoquinoline was carried out using allyltrimethoxysilane in the presence of Cu(I) and tol-BINAP. The allyl adduct thus obtained was transformed to a chiral synthetic intermediate for (-)-emetine in good yield. The procedure was applied to the total synthesis of ent-emetine.

Full text of DOI:10.1021/ol0530326

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1295-1297
Formal Total Synthesis of (−)-Emetine
Using Catalytic Asymmetric Allylation of
Cyclic Imines as a Key Step
Takashi Itoh,* Michiko Miyazaki, Hiromi Fukuoka, Kazuhiro Nagata, and
Akio Ohsawa
School of Pharmaceutical Sciences, Showa UniVersity, 1-5-8 Hatanodai,
Shinagawa-ku, Tokyo 142-8555, Japan
itoh-t@pharm.showa-u.ac.jp
Received December 14, 2005
ABSTRACT
Catalytic asymmetric allylation of 3,4-dihydro-6,7-dimethoxyisoquinoline was carried out using allyltrimethoxysilane in the presence of Cu(I)
and tol-BINAP. The allyl adduct thus obtained was transformed to a chiral synthetic intermediate for (−)-emetine in good yield. The procedure
was applied to the total synthesis of ent-emetine.
Isoquinoline alkaloids1 have long attracted much attention
due to their biological activities, which involve recent
discoveries for R-glucosidase2 and Parkinson’s disease.3 Most
of these compounds have a common characteristic in their
structures; that is, they have a chiral center at the C-1 position
of the isoquinoline nucleus. Thus, the formation of the chiral
center is a crucial step for general synthetic methods of
isoquinoline alkaloids.
underwent diastereoselective addition with allyltributyltin and
silyl enol ethers to give 1-substituted tetrahydroisoquinoline
derivatives in a stereoselective manner.7 These results
prompted us to investigate a catalytic process for the reaction,
and it was found that 3,4-dihydro-6,7-dimethoxyisoquinoline
(1) was a substrate for the addition of allyltrimethoxysilane
in the presence of a catalytic amount of Cu(I) salt and a
chiral phosphine ligand to give 1-allyl-1,2,3,4-tetrahydro-
6,7-dimethoxyisoquinoline (2) in good yield and moderate
stereoselectivity. The enantiomeric excess was further in-
creased by recrystallization in the presence of dibenzoyl
tartaric acid to afford a pure enantiomer. The allyl adduct
thus obtained was transformed to a key intermediate for the
total synthesis of (-)-emetine in short steps, and the ent-
There are, however, only a few methods4-6 for constructing
a chiral 1-substituted tetrahydroisoquinoline nucleus in high
stereoselectivity.
In the course of our research for the asymmetric synthesis
of isoquinoline alkaloids, we have found that N-acyliso-
quinolinium salts with a chiral center in the acyl group
(4) Meyers, A. I.; Dickman, D. A.; Boes, M. Tetrahedron 1987, 43, 5095
and references therein.
(5) (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 4916. (b) Noyori, R.; Hashiguchi, S. Acc. Chem.
Res. 1997, 30, 97.
(1) (a) Rozwadowska, M. D. Heterocycles 1994, 39, 903. (b) Chrza-
nowska, M.; Rozwadowska, M. D. Chem. ReV. 2004, 104, 3341.
(2) Takada, K.; Uehara, T.; Nakao, Y.; Matsunaga, S.; van Soest, R. W.
M.; Fusetani, N. J. Am. Chem. Soc. 2004, 126, 187.
(3) (a) Nagatsu, T. Neurosci. Res. 1997, 29, 99. (b) Sano, T. J. Synth.
Org. Chem. Jpn. 1999, 57, 136. (c) Yamakawa, T.; Ohta, S. Biochem.
Biophys. Res. Commun. 1997, 236, 676. (d) Thull, U.; Kneubuler, S.;
Gaillard, P.; Carrupt, P. A.; Testa, B.; Altomare, C.; Carotti, A.; Jenner,
P.; McNaught, K. St. P. Biochem. Pharmacol. 1995, 50, 869.
(6) (a) Taylor, M. S.; Jacobsen, E. N.J. Am. Chem. Soc. 2004, 126, 10558.
(b) Tayler, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2005, 44, 2.
(7) Itoh, T.; Nagata, K.; Miyazaki, M.; Kameoka, K.; Ohsawa, A.
Tetrahedron 2001, 57, 8827 and references therein.
10.1021/ol0530326 CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/02/2006

emetine was synthesized by the same method. This paper
describes these results.
With a practical amount of compound 2 in hand, we
decided to functionalize the obtained allyl group. After the
protection of an amino group of 2, reaction of 3 with various
monosubstituted alkenes using the second-generation Grubbs’
catalyst was carried out, and it was found that the cross-
metathesis products were obtained in high yields and good
stereoselectivity.13 Without the Boc protecting group, the
metathesis reaction did not proceed.
Although there are a few papers on the catalytic asym-
metric allylation of imines,8 there has been no report
concerning the catalytic allylation of cyclic imines.9 Although
Yamamoto et al. recently reported a general method for the
allylation of various kinds of imines, they showed the
incompatibility of cyclic imines to their reaction system.8d
Recently, a new allylation reaction of ketones and aldehydes
has been published by Shibasaki et al.10 using allyltrimethox-
ysilane and a catalytic amount of Cu(I) salt. We applied their
reaction system to the allylation of 6,7-dimethoxy-3,4-
dihydroisoquinoline and found that the reaction proceeded
in a stereoselective manner as shown in Table 1.
By using the ethyl acrylate, sufficient stereoselectivity was
obtained to give an adequate amount of a functionalized (E)-
alkene derivative 4 (Scheme 1).
Scheme 1
Table 1
yield of ee of 212
entry solvent
chiral ligand
time
2 (%)
(%)
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
DMF
ether
20 h
1 d
1 d
72
91
35
78
31
21
37
35
(R)-tol-BINAP
(R)-BINAP
(R,R)-DIPAMP
71 (S)
71 (S)
5
21 (S)
50 (S)
47 (S)
67 (S)
1 d
The deprotection of 4 followed by Michael addition of 5
with methyl vinyl ketone afforded an N-(3-oxobutyl) deriva-
tive, which was then cyclized to 6 in a completely diaste-
reoselective manner (Scheme 2). In our first plan, the acetyl
group would be transformed to the corresponding ethyl group
according to the reported method,14 but our attempt to reduce
the keto group to give 7 resulted in a very low yield under
various conditions.15
(R,R)-CHIRAPHOS 1 d
(R)-tol-BINAP
(R)-tol-BINAP
1 d
1 d
1 d
dioxane (R)-tol-BINAP
Various phosphine derivatives were investigated as chiral
ligands, and it was found that tol-BINAP in THF at room
temperature afforded the best result for the present reaction.
The yield of 2 was lowered to 21% by the reaction at 10 °C
without an increase of the ee, and the reaction did not proceed
at 0 °C. Other allylation reagents such as allyltributyltin
afforded a racemic product. Although the stereoselectivity
is moderate, this is the first example that a cyclic imine is
adopted as a catalytic allylation reaction.
The product 2 thus obtained was treated with (-)-
dibenzoyl-L-tartaric acid to form a mixture of the diastere-
omeric salts, which was recrystallized from acetonitrile/H2O
(20:1) to give optically pure 2 (97% ee) in 67% yield based
on the starting material.11
Thus, we changed the synthetic procedure as follows
(Scheme 3). Although Michael addition of acrolein to
compound 5 resulted in a complex mixture of the products,
slowing the addition of acrolein considerably improved the
reaction yield to a practical level. That is, the addition of
acrolein to 5 over 5 h followed by treatment with pyrrolidine
afforded a ring-closing product 8 in good yield and complete
stereoselectivity. Although the compound 8 was obtained at
first as its epimer at the C-3 position (according to emetine
numbering), the epimeric compound rapidly isomerized to
8 under the reaction conditions. The formyl derivative 8 thus
(11) With three times of careful recrystallization, the tartrate salt of
racemic 2 afforded the enantiomeric 2 in 97% ee.
(12) The absolute configuration of the compound 2 was determined by
the transformation to the known compound 10.
(13) Nagata, K.; Itoh, T.; Fukuoka, H.; Nakamura, S.; Ohsawa, A.
Heterocycles 2005, 65, 1283.
(14) Hirai, Y.; Terada, T.; Hasegawa, A.; Yamazaki, T. Chem. Pharm.
Bull. 1998, 36, 1343.
(15) Other than the reported method that used ethanedithiol-TFA
followed by Raney Ni, several reduction systems were tested which involve
various variants of Wolff-Kishner or Clemmensen reduction, but the
product 7 was not obtained in more than 7% yield.
(8) (a) Nakamura, H.; Nakamura, K.; Yamamoto, Y.J. Am. Chem. Soc.
1998, 120, 4242. (b) Fang, X.; Johannsen, M.; Yao, S.; Gathergood, N.;
Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 1999, 64, 4844. (c) Gastner,
T.; Ishitani, H.; Akiyama, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2001,
40, 1896. (d) Fernandes, R. A.; Stimac, A.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 14133.
(9) There are a few reports which claimed the asymmetric allylation using
a stoichiometrical amount of chiral compound; see: Nakamura, M.; Hirai,
A.; Nakamura, E. J. Am. Chem. Soc. 1996, 118, 8489 and references therein.
(10) Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2002, 124, 6536.
1296
Org. Lett., Vol. 8, No. 7, 2006

method gives a better way of obtaining the important
intermediate 10, which can also be transformed to several
alkaloids such as psychotrine17 and tubulosine.18
The final stage of the total synthesis of (-)-emetine (11)
was accomplished according to Tietze’s method16 in three
steps (Scheme 4).
Scheme 2
Scheme 4
obtained underwent the Wittig reaction with methyltri-
phenylphosphonium bromide followed by treatment with
methanol to give alkene 9. A catalytic hydrogenation of 9
resulted in the formation of compound 10, which was re-
ported by Tietze16 as an intermediate for the synthesis of
(-)-emetine. Thus, the stereoselectivity of the present
reaction was proved to be consistent with that of the natural
product.
Using the present procedure, we obtained ent-emetine
((+)-emetine) in overall yield of 8.5% from 1and (S)-tol-
BINAP.
In this paper, we have described asymmetric formal total
synthesis of (-)-emetine and the synthesis of (+)-emetine
in a completely stereoselective manner. In the key step,
catalytic allylation was carried out to introduce an allyl group
at the C-1 position of the isoquinoline nucleus using tol-
BINAP as a chiral source. The application of the allyl adduct
2 to the total synthesis of other isoquinoline alkaloids and
the biological activity of ent-emetine are now under inves-
tigation.
In our synthesis, the overall yield of 10 was 21.5% in 8
steps from the starting material 1. Since the reported
synthesis16 afforded 10 in 3.2% yield via 12 steps, the present
Scheme 3
Supporting Information Available: Detailed experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0530326
(16) Tietze, L. F.; Rackelmann, N.; Sekar, G. Angew. Chem., Int. Ed.
2003, 42, 4254.
(17) (a) Battersby, A. R.; Turner, J. C. J. Chem. Soc. 1960, 717. (b)
Teitel, S.; Brossi, A. J. Am. Chem. Soc. 1966, 88, 4068. (c) Fujii, T.; Ohba,
M.; Yonemitsu, O.; Ban, Y. Chem. Phar. Bull. 1982, 30, 598. (d) Fujii, T.;
Yamada, K.; Minami, S.; Yoshifuji, S.; Ohba, M. Chem. Pharm. Bull. 1983,
31, 2583. (e) Fujii, T.; Ohba, M. Chem. Pharm. Bull. 1985, 33, 144. (f)
Fujii, T.; Ohba, M. Chem. Pharm. Bull. 1985, 33, 583.
(18) (a) Brauchli, P.; Deulofeu, V.; Budzikiewicz, H.; Djerassi, C. J.
Am. Chem. Soc. 1964, 86, 1895. (b) Openshaw, H. T.; Robson, N. C.;
Whittaker, N. J. Chem. Soc. 1969, 101. (c) Kametani, T.; Suzuki, Y.; Ihara,
M. Can. J. Chem. 1979, 57, 1679. (d) Ihara, M.; Yasui, K.; Taniguchi, N.;
Fukumoto, K. J. Chem. Soc. 1990, 1469. (e) Tietze, L. F.; Rackelmann,
N.; Muller, I. Chem. Eur. J. 2004, 10, 2722.
Org. Lett., Vol. 8, No. 7, 2006
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