Efficient synthesis of (±)-γ-lycorane employing stereoselective conjugate addition to nitroolefin

Article abstract of DOI:10.1016/j.tetlet.2004.02.096

(±)-γ-Lycorane 3 was synthesized in 52% overall yield via seven steps from 5 by employing the highly stereoselective nitro-Michael cyclization of 5 to 9 and diastereoselective conjugate addition of aryllithium to a nitroolefin 10 as two key steps.

Full text of DOI:10.1016/j.tetlet.2004.02.096

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3043–3045
Efficient synthesis of ( )-c-lycorane employing stereoselective
conjugate addition to nitroolefin
Tomohisa Yasuhara,a Emi Osafune,a Katsumi Nishimura,b Mitsuaki Yamashita,b
Ken-ichi Yamada,b Osamu Muraokaa and Kiyoshi Tomiokab,*
aSchool of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan
bGraduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 3 February 2004; revised 17 February 2004; accepted 19 February 2004
Abstract—( )-c-Lycorane 3 was synthesized in 52% overall yield via seven steps from 5 by employing the highly stereoselective
nitro-Michael cyclization of 5 to 9 and diastereoselective conjugate addition of aryllithium to a nitroolefin 10 as two key steps.
Ó 2004 Elsevier Ltd. All rights reserved.
We have been involved in the asymmetric synthesis of
1;2
1
2
biologically active lycorine alkaloids 1–4 through the
Ar
Ar
conjugate addition to nitroolefin3;4 and cyclization
technology (Fig. 1). Deoxygenated skeletons of 4, a- and
b-lycoranes 1 and 2,5;6 were successfully synthesized by
employing the chemoselective conjugate addition of 3,4-
methylenedioxyphenyllithium to 6, obtained from 5, and
subsequent stereoselective cyclization of 7 to 8 (Scheme
1).7 Since all stereoisomers are necessary to fully evalu-
ate biological activity of lycorine alkaloids, further study
was focused on the stereoselective synthesis of c-lyco-
rane 3.8 We describe herein that the conjugate addition
of the aryllithium to a nitroolefin 10 gave highly stereo-
selectively all cis-11, which was then converted to 3.
NO2 CO2R
NO2 CO2R
NO2 CO2R
6
7
8
HO
NO2 CO2R
3
5
HO
Ar
NO2 CO2R
NO2 CO2R
NO2 CO2R
R = t-Bu
9
10
11
Scheme 1. Cyclization and conjugate addition to nitroolefins giving 1,
2, and 3.
at the b-position of a nitro group, cyclization of 5 was
expected to give 9, which is convertible to a nitroolefin
10 (Scheme 1). If the aryllithium addition to 10 takes
place cis to an acetate moiety, subsequent protonation
of a lithium nitronate intermediate takes place from the
less hindered face to give all cis-11 bearing the requisite
stereochemistry for 3.
Since the intramolecular nitro-Michael addition-type
cyclization of 7 was sterically controlled by the chirality
OH
HO
H
N
R
H
N
H
H
O
O
O
O
O
O
A w-hydroxy-x-nitro-a; b-enoate 5 was prepared by
employing the reported nitro-aldol procedures9;10 in four
steps and 65% overall yield from tetrahydropyran-2-ol.7
Intramolecular nitro-Michael cyclization of 5 with
2equiv of cesium fluoride and 0.1 equiv of myristyl-
trimethylammonium bromide11 in THF at room tem-
H
H
H
N
α-Lycorane (1) R = α-H
β-Lycorane (2) R = β-H
γ-Lycorane (3)
Lycorine (4)
Figure 1. Lycoranes 1–3 and lycorine 4.
perature for 24 h gave highly stereoselectively
a
separable diastereomeric mixture of 9 as colorless cubes
of mp 89–90 °C in 84% yield and 9a as a pale yellow oil
in 4% yield (Scheme 2).
Keywords: Alkaloid; Synthesis; Nitroolefin; Addition.
* Corresponding author. Tel.: +81-75-753-4553; fax: +81-75-753-4604;
e-mail: tomioka@pharm.kyoto-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.096

3044
T. Yasuhara et al. / Tetrahedron Letters 45 (2004) 3043–3045
CsF
Zn powder
H
H
n-C13H27NMe3Br
10% HCl
t
NaOMe
H
O
CO2 Bu
CO2tBu
Ar
11
Ar
H
HO
N
THF
rt, 24 h
EtOH
rt, 1 d
99%
MeOH
rt, 3 d
99%
N
H
NH2
NO2 CO2t Bu
O
HO
H
O
H
16
17
5
12
δ
4.49
δ
4.10
J = 2.3, 11.7 Hz
J = 4.9, 9.7, 10.2 Hz
H
N
H
H
BH3-THF
37% formalin
O
O
H
Ar
H
H
H
H
THF
reflux, 2 h
99%
CO2tBu
6N HCl/MeOH
rt, 3 h
N
+
NO2
H
CO2tBu
NO2
71%
γ-lycorane 3
HO
18
H
OH
9 84%
9a 4%
δ
4.25
δ
4.45-4.46
Scheme 4. Total synthesis of ( )-c-lycorane 3.
J = 9.7, 11.1 Hz
multiplet
PCC
Reaction of 10 with 1.5 equiv of 3,4-methy-
lenedioxyphenyllithium, generated by treating the
corresponding bromide with butyllithium at )78 °C for
15 min in THF, and subsequent protonation with aq
ammonium chloride gave an adduct 1116 as a sole
product in 95% yield with perfect diastereoselectivity
(Scheme 3). A pseudo-axially oriented acetate moiety in
14 due to the Að1;2Þ strain17 directed the axial addition of
aryllithium to an olefin in 10. Coordination of a lithium
cation to the carbonyl oxygen of the ester 14 may also
direct the cis-addition of aryllithium reagent. Proton-
ation of the resulting lithium nitronate takes place
stereoselectively from the less hindered face of 15 bear-
ing both axial aryl and acetate groups.18
MS4A
NaBH4
9
9
+
9a
O
CH2Cl2
rt, 16 h
93%
MeOH
0 °C, 4 h
49%
24%
NO2 CO2tBu
13
Scheme 2. Stereoselective nitro-Michael Cyclization of 5 to 9.
1
The stereochemistry of 9 was determined by H NMR
(Scheme 2). Coupling constants of methine protons
indicate that all substituents on a cyclohexane ring are
equatorial in 9. However, the stereochemistry of 9a was
hard to determine due to the complicated multiplicity of
the methine proton attached by a hydroxyl group. PCC
oxidation of 9 followed by sodium borohydride reduc-
tion of 13 afforded a mixture of 9 in 49% yield and 9a in
24% yield, confirming 9a as the epimer of 9 at the carbon
attached by a hydroxy group. Preferred approach of an
enoate moiety to a nitronate anti to a polarized HO–C
bond in 12 is the controlling factor of the highly stereo-
selective cyclization.12
Reduction of a nitro group of 11 with zinc powder in
10% aq HCl/ethanol19 at room temperature for 1 d gave
an amine 16 in 99% yield (Scheme 4). Treatment of 16
with sodium methoxide in methanol at room tempera-
ture for 3 d afforded a lactam 17 quantitatively, which is
the established intermediate8b for the synthesis of 3.
Then, the total synthesis of 3 was accomplished in high
overall yield according to the reported sequence8b
through borane–THF reduction and the Pictet–Spen-
gler-type cyclization. Spectroscopic data and the melting
point20 of synthetic ( )-c-lycorane 3 were identical with
those reported.8
Dehydration of 9 to 10 with methanesulfonyl chloride-
triethylamine13 and trifluoroacetic anhydride-triethyl-
amine,9 which were effective methods for preparation of
aliphatic nitroolefin 6 from 5, was unsuccessful. Treat-
ment with acetic anhydride-4-N,N-dimethylaminopyr-
idine-Al2O3,14 gave an acetylated product without
formation of 10. Fortunately, attempted conversion of
an equatorial hydroxyl group to an axial one under the
Mitsunobu conditions,15 diethyl azodicarboxylate-
triphenylphosphine-formic acid for 10 min at room
temperature, smoothly afforded 10 in an excellently high
yield of 94% (Scheme 3).
In conclusion, we have succeeded in the stereoselective
synthesis of c-lycorane 3 through a stereoselective
intramolecular nitro-Michael cyclization of w-hydroxy-
x-nitro-a; b-enoate 5, and perfectly diastereoselective
cis-conjugate addition of aryllithium to a cyclic nitro-
olefin 10 in high overall yield of 52% from 5 via seven
steps. Syntheses of a-, b-, and c-lycoranes from the same
starting material 5 would be the basis for the further
studies toward development of optically active lycorine-
based pharmaceuticals.
Li
O
O
DEAD, PPh3
HCO2H
O
H
N
H
C
C
O
9
ax'
THF
THF
rt, 10 min
94%
–78 °C, 10 min
O
Li
O
t
tBu
O
NO2 CO2 Bu
O
10
14
H
Acknowledgements
H
OLi
H
N
O
NO2
H
This research was partially supported by the 21st
Century Center of Excellence Program ÔKnowledge
Information Infrastructure for Genome ScienceÕ, a
Grant-in-Aid for Scientific Research on Priority Areas
(A) ÔExploitation of Multi-Element Cyclic MoleculesÕ,
H
tBuO2C
Ar
tBuO2C
Ar
15
11 95%
Scheme 3. Dehydration of 9 under the Mitsunobu conditions and
diastereoselective conjugate addition giving 11.

T. Yasuhara et al. / Tetrahedron Letters 45 (2004) 3043–3045
3045
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from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan, and a grant from JSPS.
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