An Efficient Palladium Mediated Synthesis of (±)-γ-Lycorane

Article abstract of DOI:10.1055/s-2003-42053

An intramolecular approach incorporating a Michael addition followed by a palladium-mediated arylation of ketone towards the synthesis of Amaryllidaceae alkaloid (±)-γ-lycorane was reported.

Full text of DOI:10.1055/s-2003-42053

2228
LETTER
An Efficient Palladium Mediated Synthesis of ( )-g-Lycorane
An
E
fficient Pa
h
lladium
M
ed
i
iatedS
h
ynthesis of
(
u
)-
g
-Lycoran
i
e
Shao, Jingbo Chen, Rong Huang, Chenying Wang, Liang Li, Hongbin Zhang*
School of Pharmacy, Yunnan University, Kunming, Yunnan 650091, P. R. China
Fax +86(871)5035538; E-mail: zhanghb@ynu.edu.cn
Received 21 July 2003
in our retrosythetic analysis in Scheme 1, one of the key
issues in our synthetic pathway is the palladium-mediated
arylation of ketone to afford the galathan ring system for
lycorine-type alkaloids.
Abstract: An intramolecular approach incorporating a Michael
addition followed by a palladium-mediated arylation of ketone
towards the synthesis of Amaryllidaceae alkaloid ( )-g-lycorane
was reported.
Key words: synthesis, ( )-g-lycorane, palladium, intramolecular
arylations, alkaloids
R1
R
Palladium mediated
arylation of ketone
N
O
C
N
Br
O
O
The lycorine-type alkaloids, which are characterized by
the presence of the galanthan (tetracyclic pyrro-
lo[d,e]phenanthridine) ring system, are an important class
of natural products isolated from the plants of the Amaryl-
lidaceae family.1 Many members of this group of alka-
loids exhibit potent biological activities including
antitumor,2 antiviral and insect antifeedant activities.3 The
pentacyclic structure as well as its interesting biological
activities have long attracted the attention of numerous re-
search groups. Synthetic efforts directed towards lycorine
(1) and g-lycorane (2) have generated a great deal of cre-
ative total synthesis and a wide variety of methodologies
(Figure 1).4 Recent examples in the synthesis of lycorine-
type alkaloids were documented in Padwa’s elegant in-
tramolecular [4+2] cycloaddition and rearrangement cas-
cade of furanyl carbamates,4b Zard’s radical cyclization of
xanthates5 and Tomioka’s nitro-Michael cyclization of
unsaturated esters.6
B
D
A
Lycorine-type alkaloid
O
O
Aminocyclization
NH2
O
NH
X
Br
NH2
O
O
O
X = Protecting group
Scheme 1 Retrosythetic analysis of lycorine-type alkaloids
Although palladium mediated arylation of ketones has
been well documented in the literature8 and has the poten-
tial to be used for the synthesis of complex natural prod-
ucts, few methodologies involving this powerful reaction
has been developed towards the synthesis of natural prod-
ucts.9 In order to demonstrate the efficiency of such an in-
tramolecular approach as depicted in Scheme 2, a
synthesis towards the less complicated lycorine-type alka-
loid, namely the ( )-g-lycorane was initiated.
OH
HO
H
N
H
H
O
O
O
O
H
H
N
γ-Lycorane (2)
Lycorine (1)
Figure 1 Representative lycorine-type alkaloids
Starting from commercially available 2-(4-methoxyphe-
nyl)-ethylamine, a Birch reduction furnished the diene 4
in 98% yield. The diene 4 was then treated with 6-bro-
mopiperonal followed by reduction with NaBH4 in etha-
nol afforded the secondary amine 5. After treatment with
4 N HCl in methanol at 35 °C, an intramolecular Michael
addition provided the octahydro-indol-6-one (6) in 80%
overall yield for the two reactions. It is noteworthy that
only cis-C,D-ring junction for the octahydro-indol-6-one
(6) was observed.10 The intramolecular arylation of com-
pound 6 was initially conducted in anhydrous THF with
Pd2(dba)3 and racemic BINAP in the presence of sodium
tert-butoxide. The reaction did proceed, however, in low
yield. To our delight, variation of the solvent to toluene
afforded the desire cyclization in 81% yield. The stereo-
As part of our ongoing program in pursuit of efficient
while flexible strategy for the synthesis of Amaryllidace-
ae alkaloids, we recently disclosed a highly stereoselec-
tive aminocyclization approach towards the synthesis of
the core N-heterocyclic center for a number of natural al-
kaloids.7 It appeared to us that lycorine-type alkaloids
such as lycorine and g-lycorane were the immediate target
by employing this aminocyclization protocol. As shown
SYNLETT 2003, No. 14, pp 2228–2230
0
6
.1
1
.2
0
0
3
Advanced online publication: 07.10.2003
DOI: 10.1055/s-2003-42053; Art ID: D18403ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
An Efficient Palladium Mediated Synthesis of ( )-g-Lycorane
2229
chemistry of this reaction is quite remarkable, cis-fused
B,C-ring junction was exclusively formed.11 The NOE
experiment for this compound was conducted and the
results were consistent with a cis-B,C,D-ring system.
In the literature,12 ketone 7 has already been converted
to ( )-g-lycorane, therefore a formal synthesis of ( )-g-
lycorane was completed.
References
(1) (a) Lewis, J. R. Nat. Prod. Rep. 2001, 18, 95. (b) Hoshino,
O. In The Alkaloids, Vol. 51; Cordell, G. A., Ed.; Academic
Press: New York, 1998, 323–424. (c) Martin, S. F. In The
Alkaloids, Vol. 30; Brossi, A., Ed.; Academic Press: New
York, 1987, 251–376.
(2) Tang, W.; Hemm, I.; Bertram, B. Planta Med. 2003, 69, 97;
and references cited therein.
(3) (a) Lewis, J. R. Nat. Prod. Rep. 1998, 15, 107. (b) Lewis, J.
R. Nat. Prod. Rep. 1994, 11, 329.
NH2
NH2
Na, NH3 (liq.)
(4) (a) Jin, Z.; Li, Z.; Huang, R. Nat. Prod. Rep. 2002, 19, 454.
(b) Padawa, A.; Brodney, M. A.; Lynch, S. M. J. Org. Chem.
2001, 66, 1716. (c) Banwell, M. G.; Harvey, J. E.; Hockless,
D. C. R.; Wu, A. W. J. Org. Chem. 2000, 65, 4241; and
references cited therein.
(5) Miranda, L. D.; Zard, S. Z. Org. Lett. 2002, 4, 1135.
(6) Yasuhara, T.; Nishimura, K.; Yamashita, M.; Fukuyama, N.;
Yamada, K.; Muraoka, O.; Tomioka, K. Org. Lett. 2003, 5,
1123.
(7) Shao, Z.; Chen, J.; Tu, Y.; Li, L.; Zhang, H. Chem. Commun.
2003, 1918.
(8) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 1261.
(9) To the best of our knowledge only one total synthesis
involving intramolecular arylation of ketone was made by:
Muratake, H.; Hayakawa, A.; Natsume, M. Chem. Pharm.
Bull. 2000, 48, 1558.
(10) Similar transformation has been used for the synthesis of
Aeruginosins in: (a) Valls, N.; Vallribera, M.; Carmeli, S.;
Bonjoch, J. Org. Lett. 2003, 5, 447. (b) Valls, N.; López-
Canet, M.; Vallribera, M.; Bonjoch, J. Chem.–Eur. J. 2001,
7, 3446.
(11) Compound 4: IR (KBr): nmax = 1696 (w), 1664 (m), 1389
(m), 1216 (s), 1173 (s)cm–1. 1H NMR (300 MHz, CDCl3):
d = 5.36 (1 H, s), 4.53 (1 H, s), 3.46 (3 H, s, OMe), 2.69 (2
H, t, J = 6.7 Hz), 2.67–2.62 (4 H, brs), 2.05 (2 H, t, J = 6.7
Hz), 1.26 (2 H, brs). 13C NMR (75 MHz, CDCl3): d = 153.23,
133.15, 119.52, 90.54, 54.05, 41.09, 40.17, 29.40. GC-MS:
m/z (%) = 153.4 (2) [M+], 152.3 (1), 138.4 (1), 136.4 (3),
135.3 (17), 125.5 (15), 123.7 (100), 121.4 (16), 120.3 (5),
109.4 (39), 108.3 (35), 105.2 (16), 103.2 (11), 91.3 (46), 79.4
(35), 77.3 (38). Compound 5: IR (KBr): nmax = 1665 (w),
1502 (w), 1477 (s), 1413 (w), 1390 (w), 1241 (s), 1216 (s),
1172 (m), 1038 (s) cm–1. 1H NMR (300 MHz, CDCl3): d =
6.96 (1 H, s), 6.87 (1 H, s), 5.93 (2 H, s), 5.43 (1 H, s), 4.58
(1 H, s), 3.74 (2 H, s), 3.52 (3 H, s, OMe), 2.80–2.60 (6 H,
m), 2.20 (2 H, t, J = 6.7 Hz). 13C NMR (75 MHz, CDCl3):
d = 153.31, 147.69, 147.61, 133.46, 133.01, 119.47, 114.38,
113.00, 110.39, 102.01, 90.65, 54.18, 53.91, 47.05, 37.36,
29.60, 29.51. GC-MS: m/z (%) = 364.4 (7) [M+ – 1], 362.4
(6) [M+ – 1], 284.4 (10), 244.2 (61), 242.2 (58), 216.3 (22),
215.0 (100), 213.1 (82), 182.9 (8), 162.4 (13), 157.2 (21),
155.2 (16), 136.5 (9), 135.2 (72), 124.4 (67), 123.3 (26),
121.4 (17), 108.4 (7), 105.4 (32). Compound 6: IR (KBr):
THF, EtOH (1:1)
–78 °C, 98%
O
O
(4)
1)
(3)
O
O
O
Br
EtOH, 50 °C
2) NaBH4,
EtOH, 0 °C
92% over
2 steps
H
N
N
Br
Br
O
O
(5)
1) 4 N HCl
O
O
O
O
MeOH, 35 °C, 48 h
O
O
O
O
2) K2CO3, MeOH
H2O, 25 °C, 80%
H
O
O
H
H
N
N
Br
(6)
Br
2 eq. t-BuONa
PhMe, 100 °C, 81%
5% Pd2(dba)3
10% BINAP
O
H
N
H
Ref. 12
(±)-γ-Lycorane (2)
O
O
(7)
H
Scheme 2 Formal synthesis of ( )-g-lycorane
In summary, we have developed a concise method to-
wards the synthesis of ( )-g-lycorane. A convenient four
step-sequence leaded to the ( )-a-dihydrocaronone in an
overall 58% yield. The intramolecular approach including
a Michael addition followed by a palladium mediated
arylation of ketone demonstrated herein represents a high-
ly efficient while stereoselective strategy and are valuable
for the preparation of lycorine related compounds. Syn-
thesis of lycorine by utilizing this protocol is in progress.
n
max = 1713 (s), 1503 (w), 1478 (s), 1411 (w), 1360 (m),
1223 (s) cm–1. 1H NMR (500 MHz, CDCl3): d = 6.92 (1 H,
s), 6.83 (1 H, s), 5.92 (1 H, d, J = 1.0 Hz), 5.91 (1 H, d,
J = 1.0 Hz), 3.76 (1 H, d, J = 13.8 Hz), 3.28 (1 H, d, J = 13.8
Hz), 2.91 (1 H, dd, J = 8.3, 17.0 Hz), 2.87 (1 H, dd, J = 4.3,
10.3 Hz), 2.55 (1 H, td, J = 4.2, 15.8 Hz), 2.52 (1 H, td,
J = 4.2, 15.8 Hz), 2.51 (1 H, dd, J = 4.3, 15.7 Hz), 2.44 (1 H,
ddd, J = 4.7, 10.3, 18.0 Hz), 2.18 (1 H, ddd, J = 4.5, 6.5, 18.0
Hz), 2.10 (1 H, dd, J = 9.7, 17.0 Hz), 2.02–1.90 (2 H, m),
1.76–1.68 (1 H, m), 1.55–1.45 (1 H, m). 13C NMR (75 MHz,
CDCl3): d = 212.74, 147.73, 147.53, 131.93, 114.33, 112.71,
110.71, 101.96, 62.20, 57.20, 53.50, 41.93, 36.48, 35.52,
29.83, 26.71. GC-MS: m/z (%) = 353.4 (37) [M+], 351.2 (42)
Acknowledgment
This work was partially supported by a Grant (20272049) from
National Natural Science Foundation of China and a Grant from the
foundation of the Chinese Ministry of Education for the promotion
of Excellent Young Scholar. We would like to thank the Internatio-
nal Cooperation Division of Yunnan provincial Science & Techno-
logy Department for partial financial support (2002GH04).
Synlett 2003, No. 14, 2228–2230 © Thieme Stuttgart · New York

2230
Z. Shao et al.
LETTER
[M+], 296.3 (45), 294.1 (54), 281.3 (6), 272.3 (8), 213.3
(100), 185.0 (11), 159.2 (8), 157.1 (34), 154.9 (15), 148.4
(11), 135.3 (47). Compound 7: IR (KBr): nmax = 2927 (w),
2788 (w), 1730 (m), 1715 (s), 1645 (w), 1503 (m), 1484 (s),
1448 (w), 1373 (w), 1241 (s), 1145 (w), 1100 (w), 1039 (s),
935 (m), 807 (m)cm–1. 1H NMR (500 MHz, CDCl3): d = 6.60
(1 H, s), 6.50 (1 H, s), 5.91 (1 H, d, J = 1.3 Hz), 5.90 (1 H, d,
J = 1.3 Hz), 3.99 (1 H, d, J = 14.5 Hz, PhCH), 3.46 (1 H, d,
J = 3.6 Hz), 3.28 (1 H, d, J = 14.5 Hz, PhCH), 3.22 (1 H, dd,
J = 7.9, 8.6 Hz), 2.83 (1 H, dd, J = 3.6, 7.8 Hz), 2.71–2.63 (1
H, m), 2.53 (1 H, ddd, J = 4.3, 10.8, 15.4 Hz), 2.39 (1 H, ddd,
J = 4.5, 6.5, 10.8 Hz), 2.22 (1 H, dd, J = 8.6, 17.4 Hz), 2.13–
2.03 (2 H, m), 1.85–1.76 (1 H, m), 1.69–1.60(1 H, m). 13
C
NMR (75 MHz, CDCl3): d = 209.84, 147.02, 146.04, 128.40,
125.04, 111.81, 106.42, 101.19, 64.39, 56.19, 54.12, 51.46,
36.59, 34.97, 29.35, 27.20. GC-MS: m/z (%) = 271.4 (64)
[M+], 270.4 (100), 255.5 (5), 254.4 (35), 243.4 (3), 242.4
(18), 241.4 (3), 228.4 (7), 225.4 (2), 215.4 (6), 214.4 (21),
212.3 (15), 207.3 (11), 200.4 (5), 188.4 (7), 187.4 (17), 184.4
(5), 174.3 (13), 173.3 (6), 162.4 (14), 154.3 (9), 148.3 (12),
147.3 (10), 130.4 (11), 116.4 (8), 115.3 (10), 106.4 (5), 102.3
(12), 91.4 (7), 89.3 (17), 78.3 (10), 77.4 (24).
(12) (a) Ueda, N.; Tokuyama, T.; Sakan, T. Bull. Chem. Soc. Jpn.
1966, 39, 2021. (b) Kotera, K. Tetrahedron 1961, 12, 248.
Synlett 2003, No. 14, 2228–2230 © Thieme Stuttgart · New York