Total synthesis of (-)-lycorine and (-)-2-epi-lycorine by asymmetric conjugate addition cascade

Article abstract of DOI:10.1021/ol9003564

Total syntheses of (-)-lycorine and (-)-2-epi-lycorine were accomplished using chiral ligand-controlled asymmetric cascade conjugate addition methodology, which enables the formation of two C-C bonds and three stereogenic centers in one pot to give synthe

Full text of DOI:10.1021/ol9003564

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1631-1633
Total Synthesis of (-)-Lycorine and
(-)-2-epi-Lycorine by Asymmetric
Conjugate Addition Cascade
Ken-ichi Yamada, Mitsuaki Yamashita, Takaaki Sumiyoshi, Katsumi Nishimura,
and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received February 18, 2009
ABSTRACT
Total syntheses of (-)-lycorine and (-)-2-epi-lycorine were accomplished using chiral ligand-controlled asymmetric cascade conjugate addition
methodology, which enables the formation of two C-C bonds and three stereogenic centers in one pot to give synthetically useful chiral
cyclohexane derivatives.
The Amaryllidaceae alkaloids are ideal candidates for
clinically useful pharmaceuticals, such as galantamine for
Alzheimer’s disease.1 (-)-Lycorine (1), a potent emetic first
isolated in 1877, is the most abundant Amaryllidaceae
alkaloid.2 Recent studies revealed that lycorine has other
interesting biologic activities, including antiviral activity and
apoptosis induction.3,4 Since its structure was determined by
Uyeo in 1935,5 it has attracted the attention of synthetic
chemists, and many synthetic studies, including total syn-
theses, have been reported.6 Only one asymmetric synthesis,
however, has been reported to date.7 Herein, we report the
asymmetric synthesis of lycorine (1) and the first total
synthesis of 2-epi-lycorine (2) using a chiral ligand-
controlled8 asymmetric cascade conjugate addition reaction.
In our strategy, chiral ligand 3 mediates an asymmetric
conjugate addition reaction9 of aryllithium 4 with a sym-
(6) (a) Tsuda, Y.; Sano, T.; Taga, J.; Isobe, K.; Toda, J.; Irie, H.; Tanaka,
H.; Takagi, S.; Yamaki, M.; Murata, M. J. Chem. Soc., Chem. Commun.
1975, 933. (b) Møller, O.; Steinberg, E.-M.; Torssell, K. Acta Chem. Scand.,
Sect. B 1978, 32, 98. (c) Umezawa, B.; Hoshino, O.; Sawaki, S.; Sashida,
H.; Mori, K. Heterocycles 1979, 12, 1475. (d) Martin, S. F.; Tu, C. -y. J.
Org. Chem. 1981, 46, 3764. (e) Boeckman, R. K., Jr.; Goldstein, S. W.;
Walters, M. A. J. Am. Chem. Soc. 1988, 110, 8250. (f) Hoshino, O.; Ishizaki,
M.; Kamei, K.; Taguchi, M.; Nagao, T.; Iwaoka, K.; Sawaki, S.; Umezawa,
B.; Iitaka, Y. J. Chem. Soc., Perkin Trans. 1 1995, 571.
(1) (a) Zarotsky, V.; Sramek, J. J.; Cutler, N. R. Am. J. Health-Syst.
Pharm. 2003, 60, 446. (b) WHO Drug Info. 1998, 12, 205.
(2) Cook, J. W.; Loudon, J. D. In The Alkaloids; Manske, R. H. F.,
Holmes, H. L., Eds; Academic Press: New York, 1952; Vol. 2, p 331.
(3) (a) Liu, J.; Li, Y.; Tang, L.-J.; Zhang, G.-P.; Hu, W.-X. Biomed.
Pharmacother. 2007, 61, 229. (b) Liu, J.; Hua, W.-X.; He, L.-F.; Ye, M.;
Li, Y. FEBS Lett. 2004, 578, 245
(4) For a review of the biological effects of lycorine and related
Amaryllidaceae alkaloids, see: Ghosal, S.; Saini, K. S.; Razdan, S.
.
(7) Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J. Am. Chem. Soc.
1996, 118, 6210.
Phytochemistry 1985, 24, 2141
.
(8) Tomioka, K. Synthesis 1990, 541.
(5) Kondo, H.; Uyeo, S. Chem. Ber. 1935, 68, 1756.
(9) Asano, Y.; Iida, A.; Tomioka, K. Tetrahedron Lett. 1997, 38, 8973.
10.1021/ol9003564 CCC: $40.75
Published on Web 02/25/2009
2009 American Chemical Society

metric Michael acceptor 5 that has two enoate moieties,
which enantioselectively affords enolate 6 (Scheme 1). The
The presence of chlorotrimethylsilane improved the enan-
tioselectivity, and a 9:1 mixture of 7 with 92% ee and its
isomer was obtained in 97% yield.13 It is noteworthy that
chiral ligand 3 was quantitatively recovered without loss of
optical purity and was therefore reusable.
Scheme 1. Retrosynthetic Analysis of (-)-Lycorine (1)
With the key intermediate 7 in hand, the total synthesis
of lycorine was explored. Reaction of the 9:1 mixture of 7
and its isomer in refluxing ethanolic HCl removed the tert-
butyl and the trimethylsilyl groups, accompanied by esteri-
fication of the less hindered carboxylic acid moiety, to give,
after reketalization, monocarboxylic acid 8 as a single
diastereomer, which was easily separated from the diethyl
ester derived from the isomer of 7 (Scheme 2). Introduction
of a nitrogen atom using diphenylphosphoryl azide (DPPA)14
efficiently proceeded to form carbamate 9. Recrystallization
of 9 from hexane afforded enantiomerically pure (>99% ee)
9 in 88% yield. Ring construction by reductive alkylation
of the nitrogen functionality, followed by treatment with ethyl
chloroformate, gave carbamate 10, which was subjected to
a Bischler-Napieralski reaction, affording 11 in high yield
(Scheme 3).
subsequent diastereoselective intramolecular Michael addition
of 6 gives cyclohexane 7 bearing three adjacent stereogenic
centers. The lycorine skeleton, therefore, derives from 7 via
Curtius rearrangement and a Bischler-Napieralski reaction.
A toluene solution of enoate 5 was added to a solution of
ortho-TMS-substituted aryllithium 4,10 prepared from the
corresponding aryl bromide11 and tert-butyllithium in the
presence of chiral ligand 3 in toluene at -78 °C. In contrast
to the related reaction of ω-nitroethenylalkenoate,12 the
desired cascade reaction proceeded within 0.5 h at -78 °C
to give a 9:1 mixture of cyclization products all-trans 7 with
88% ee and its trans-cis isomer in 98% combined yield
(Scheme 2). The relative and absolute configurations of 7
Scheme 3
.
Total Syntheses of (-)-Lycorine (1) and
(-)-2-epi-Lycorine (2)
Scheme 2. Asymmetric Conjugate Addition Cascade and
Introduction of Nitrogen Functionality
and its isomer were confirmed by the conversion of 7 into
(-)-lycorine (1) (vide infra).
(10) A TMS substituent often improves enantioselectivity in chiral
ligand-controlled asymmetric addition reactions of lithiated nucleophiles:
(a) Sakai, T.; Doi, H.; Kawamoto, Y.; Yamada, K.; Tomioka, K. Tetrahedron
Lett. 2004, 45, 9261. (b) Yamashita, M.; Yamada, K.; Tomioka, K. J. Am.
Chem. Soc. 2004, 126, 1954. (c) Nishimura, K.; Ono, M.; Nagaoka, Y.;
Tomioka, K. J. Am. Chem. Soc. 1997, 119, 12974.
(11) Mattson, R. J.; Sloan, C. P.; Lockhart, C. C.; Catt, J. D.; Gao, Q.;
Huang, S. J. Org. Chem. 1999, 64, 8004.
The first total synthesis of (-)-2-epi-lycorine (2) was
achieved from 11. Ketone 11 was converted into TIPS enol
(12) Yasuhara, T.; Nishimura, K.; Yamashita, M.; Fukuyama, N.;
Yamada, K.; Muraoka, O.; Tomioka, K. Org. Lett. 2003, 5, 1123.
1632
Org. Lett., Vol. 11, No. 7, 2009

ethers 12 and 13 in 58% and 41% yield, respectively.
Although the regioselectivity of this enol formation was not
high (3:2), the separated undesired regioisomer 13 was
readily converted back into 11 for recycling by treatment
with aqueous hydrogen fluoride in acetonitrile: thus, 11 was
converted into 12 in 80% yield by repeating these transfor-
mations twice. This poor selectivity would be desirable if a
3-oxygenated derivative of lycorine were the target. In the
same manner, 13 would be obtained from 11 in 63% yield
by recycling 12 instead of 13. The oxidation of 12 by
Magnus’ procedure15 gave m-chlorobenzoate 14. Dehydro-
genation at the 3,12-position of 14 was regioselectively
realized through phenylselenylation of the corresponding
TMS enol ether to give enone 15 in 52% yield in three steps.
Luche’s reduction of 15 stereoselectively afforded allylic
alcohol 16. The subsequent LAH reduction furnished 2,
which was purified and characterized after conversion to
known di-O-acetyl derivative 17 in 47% yield from 16. The
sign of the specific rotation of 17 was identical to that
previously reported,16 and the melting point and spectro-
scopic data were consistent with those of an authentic sample
prepared by a previously reported procedure.16
rotation, 1H and 13C NMR, MS, and IR data were consistent
with those previously reported,7 as well as those of an
authentic sample prepared by a previously reported proce-
dure.16
In summary, we achieved total syntheses of (-)-lycorine
and (-)-2-epi-lycorine using our chiral ligand-controlled
asymmetric cascade conjugate addition methodology. This
methodology enables the formation of two C-C bonds and
three stereogenic centers in one pot to give synthetically
useful chiral cyclohexane derivatives. The synthetic strategy
is flexible, and applicable for other natural and unnatural
lycorine derivatives. Importantly, the chiral ligand could be
recycled, and the one-pot reactions are economically and
ecologically beneficial.
Acknowledgment. We thank Prof. Toshio Yokoi of Kobe
Gakuin University for providing a natural sample of (-)-
lycorine and JSPS and MEXT, Japan, for financial support
(the 21st Century COE Program “Knowledge Information
Infrastructure for Genome Science”, a Grant-in-Aid for
Scientific Research on Priority Areas “Advanced Molecular
Transformations”, and a Grant-in-Aid for Scientific Re-
search).
Although an attempted re face-selective reduction17 of 15
toward (-)-lycorine (1) failed, inversion of the stereochem-
istry of allylic alcohol 16 was accomplished by a modified
Mitsunobu reaction18 to give 1 after LAH reduction. The
1H and 13C NMR spectra, and the TLC behavior were
identical to those of an authentic sample. Synthesized 1 was
purified at the stage of di-O-acetyl derivative 18 (52% yield
from 16), whose TLC behavior, melting point, specific
Supporting Information Available: Experimental details,
characterization data of new compounds, and HPLC traces
of 7 and 9. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL9003564
(16) Nakagawa, Y.; Uyeo, S. J. Chem. Soc. 1959, 3736.
(17) (a) Noyori, R.; Tomiono, L.; Tanimoto, Y.; Nishizawa, M. J. Am.
Chem. Soc. 1984, 106, 6709. (b) Corey, E. J.; Bakshi, R. K. Tetrahedron
Lett. 1990, 31, 611.
(13) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am.
Chem. Soc. 2003, 125, 2886.
(14) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151.
(15) Magnus, P.; Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341.
(18) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
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