Radical-initiated cyclization as a key step for the synthesis of oxoprotoberberine alkaloids

Article abstract of DOI:10.1016/j.tetlet.2009.05.095

The oxoprotoberberine alkaloids 1a-d have been synthesized efficiently from the enamide derivatives 2a-d by a radical-initiated cyclization reaction utilizing n-Bu₃SnH/AIBN and CuCl. The enamide derivatives 2a-d were prepared from phenylethylam

Full text of DOI:10.1016/j.tetlet.2009.05.095

Tetrahedron Letters 50 (2009) 4558–4562
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Radical-initiated cyclization as a key step for the synthesis
of oxoprotoberberine alkaloids
a
a
a
b
Chih-Shone Lee a, , Tsung-Ching Yu , Jian-Wen Luo , Yen-Yao Cheng , Che-Ping Chuang
*
a Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan, ROC
b Department of Chemistry, National Cheng Kung University, Tainan 70101, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxoprotoberberine alkaloids 1a–d have been synthesized efficiently from the enamide derivatives
2a–d by a radical-initiated cyclization reaction utilizing n-Bu3SnH/AIBN and CuCl. The enamide deriva-
tives 2a–d were prepared from phenylethylamine analogues 5a–b, followed by acylation with acetic
anhydride, Bischler–Napieralski cyclization with POCl3 and benzoylation with the corresponding bromo-
benzoyl chloride, respectively.
Received 27 December 2008
Revised 23 May 2009
Accepted 27 May 2009
Available online 30 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Oxoprotoberberine
Radical-initiated cyclization
Protoberberines and relative analogues, 8-oxoprotoberberines
(Fig. 1) are important group of isoquinoline alkaloids that possess
a variety of pharmacological activities.1,2 Many of them are found
in medicinal plants of the genera Berberis and Coptis,3,4 which have
been used in China and Japan for centuries as a folk medicine in
treatment of jaundice, dysentery, diarrhoea and hypertension.
Oxoprotoberberine alkaloids with ortho-diphenolic substitution
on Ring D are found to exhibit cytotoxic, antioxidant and dopami-
nergic activities.5 8-Oxoberberine (1e), a derivative of tetrahydrob-
erberine, exerted antiarrhythmic activity and negative
chronotropic actions on rat atrial preparations in our previous
studies.6 Recently, oxoprotoberberine alkaloids isolated from the
stems of Cocculus orbiculatus7 were also reported to inhibit basal
and TPA-mediated PGE2 level.8
The enamide intermediates 2a–d can be readily synthesized by treat-
ing dihyroisoquinolines 4a–bwithavarietyofbenzoylchloride deriv-
atives. The formation of enamides 2a–d could offer a flexible
synthetic approach to a range of oxoprotoberberine analogues. Sub-
stitutions on ring A or D are easily introduced using appropriate
precursors.
The requisite dihydroisoquinolines 4a–b can be prepared from
commercially available phenylethylamines 5a–b (Scheme 2).
Treatment of phenylethylamines 5a–b with acetic anhydride gave
the N-acetylated products 6a–b. Subsequent Bischler–Napieralski
cyclization12 employing POCl3 in toluene afforded dihydroisoquin-
olines 4a–b in good yields.
The bromobenzoyl chloride derivatives, prepared from the cor-
responding benzoic acids 3a–c with SOCl2, were added to the dihy-
Many synthetic routes to the biologically active protoberberine or
oxoprotoberberine alkaloids have been investigated for a long
time.9,10 Most of these synthetic strategies for oxoprotoberberine
alkaloids involved the construction of protoberberine first, and fol-
lowed by oxidative conversion in the reaction sequence. Herein we
try to develop a facile synthesis of oxoprotoberberine alkaloids (1a–
d) for further biological investigations. The retrosynthetic analysis
to construct oxoprotoberberines is shown in Scheme 1. This synthetic
strategy involved an intramolecular radical-initiated cyclization. The
choice for the preparation of key intermediate enamides 2a–d was
based on our previous study on a one-pot reductive-cyclization syn-
thesis of rutaecarpine. A key precursor of enamide with isomerized
exocyclicdouble bond was formed during the benzoylation process.11
R1
N
O
R2
R5
R4
R3
1a-e
1a : R1 = R2 = R3 = R4 = OMe, R = H
1b : R1 = R2 = OMe, R3 = R4 = R55 = H
1c : R1 = R4 = OMe, R2 = R3 = R5 = H
1d : R1 = OMe, R2 = R3 = R4 = R5 = H
1e : R1 = R2 = -OCH2O-, R4 = R5 = OMe, R3 = H
* Corresponding author. Tel.: +886 7 525 3947; fax: +886 7 525 3908.
E-mail address: shonle@faculty.nsysu.edu.tw (C.-S. Lee).
Figure 1. Oxoprotoberberine analogues.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.095

C.-S. Lee et al. / Tetrahedron Letters 50 (2009) 4558–4562
4559
R1
R2
R1
R2
R1
R2
R1
R2
N
O
N
O
N
NH2
Br
5a-b
4a-b
R4
R4
5a : R1 = R2 = OMe
5b : R1 = OMe, R2 = H
R3
R3
2a-d
1a-d
1a : R1 = R2 = R3 = R4 = OMe
1b : R1 = R2 = OMe, R3 = R4 = H
1c : R1 = R4 = OMe, R2 = R3= H
1d : R1 = OMe, R2 = R3 = R4 = H
O
R4
R3
OH
Br
3a-c
3a : R3 = R4 = OMe
3b : R3 = R4 = H
3c : R3 = H, R4 = OMe
Scheme 1. Retrosynthetic analysis of 1a–d.
R1
R1
R1
R2
Ac2O, TEA
POCl3
HN
N
NH2
DCM
toluene
R1
R2
R2
R2
O
N
O
4a-b
5a-b
6a-b
Br
5a : R1 = R2 = OMe
5b : R1 = OMe, R2 = H
TEA, DCM
R4
O
O
R3
R4
R4
R3
2a-d
Cl
OH
SOCl2
DCM
R3
Br
Br
2a : R1 = R2 = R3 = R4 = OMe, 86%
2b : R1 = R2 = OMe, R3 = R4 = H, 93%
2c : R1 = R4 = OMe, R2 = R3 = H, 88%
2d : R1 = OMe, R2 = R3 = R4 = H, 84%
3a-c
3a : R3 = R4 = OMe
3b : R3 = R4 = H
3c : R3 = H, R4 = OMe
Scheme 2. Synthesis of enamide derivatives 2a–d.
Table 1
Radical cyclization reaction of enamide 2a
MeO
MeO
MeO
MeO
MeO
N
N
O
N
O
O
nBu3SnH, AIBN
MeO
+
Br
(eq. 1)
OMe
OMe
MeO
OMe
OMe
OMe
7
2a
1a
Entry
Compound
Solvent
nBu3SnH (equiv)
AIBN (equiv)
Product ratio (7: 1a)
Yield (7+1a) (%)
1
2
3
4
5
6
2a
2a
2a
2a
2a
2a
Benzene
Benzene
Benzene
Benzene
Toluene
Toluene
2
3
2
2
2
2
0.1
0.1
0.2
0.5
0.2
0.4
6:1
6:1
4:1
1:3
4:1
1:3
46
44
48
32
38
30
droisoquinolines 4a–b to afford the requisite benzoylated enamide
derivatives 2a–d in good yields. Bromobenzoic acid derivatives
3a–c are either commercially available or prepared according to
the known procedures from benzaldehyde derivatives.13,14
We then took enamide 2a to investigate the possibility of an
intramolecular radical cyclization reaction (Table 1). The reaction
solution was stirred in benzene or toluene at reflux under high
dilution by adding n-Bu3SnH/AIBN via syringe pump. Numerous

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C.-S. Lee et al. / Tetrahedron Letters 50 (2009) 4558–4562
reaction conditions have been examined in the ring cyclization
process. Sequential radical cyclization reaction and spontaneous
oxidation of dehydrogenation process afforded 7 and 1a as mixture
of adducts. The desired products in this reaction process could be
accomplished by adding n-Bu3SnH and AIBN in a 5 h period under
reflux in benzene (Table 1). The ratio of reaction adducts mixture 7
and 1a was determined by signal integration of 1H NMR of these
two compounds.
The synthetic studies in Table 1 showed that radical cyclization
of enamides 2a could afford oxoprotoberberine 1a and its C13-13a
saturated adduct 7 in moderate yield. Slow addition of 2 equiv
n-Bu3SnH and 0.2 equiv AIBN to a benzene solution of 2a–d under
reflux condition for 5 h generated 8-oxoprotoberberines 1a–d and
related C13-13a saturated adducts in 48% yields (Table 1, entry 3).
Alternatively, the radical cyclization mixtures were not purified.
Subsequent dehydrogenation of the mixtures with DDQ gave oxo-
protoberberines 1a–d (Scheme 3). To our knowledge, there are
only limited reports regarding the synthesis of oxoportoberberines
using n-Bu3SnH/AIBN-initiated reaction in moderate yields as we
have achieved.15 We then tried to reexamine the cyclization path-
way to optimize the yield of oxoprotoberberine alkaloids.
Literature search showed that copper(I)-mediated halogen
atom transfer radical cyclizations have attracted considerable re-
search interest for years.16 Recently, more copper(I)-mediated ac-
tive reactions have been developed to facilitate the cyclization of
monobromoderivatives.17 Therefore, we envisaged the possibility
of activating an intramolecular 6-endo ring cyclizations during
the construction of oxoprotoberberines. We found that utilization
of CuCl with n-Bu3SnH/AIBN during this cyclization reaction pro-
cess dramatically increased the yield of 8-oxoprotoberberine 1a
with minor amount of C13-13a saturated adduct 7 (Table 2). The
addition of 2 equiv CuCl in n-Bu3SnH/AIBN radical-initiated cycli-
zation reaction afforded a clean ring-cyclized 8-oxoprotoberberine
1a as the only product in 75% yield (Table 2, entry 3). However,
R1
R1
N
O
N
O
R2
R2
1. nBu3SnH, AIBN
benzene
Br
2. DDQ, benzene
R4
R4
R3
R3
1a-d
2a-d
2a : R1 = R2 = R3 = R4 = OMe
1a : R1 = R2 = R3 = R4 = OMe, 58%
1b : R1 = R2 = OMe, R3 = R4 = H, 56%
1c : R1 = R4 = OMe, R2 = R3 = H, 45%
1d : R1 = OMe, R2 = R3 = R4 = H, 66%
2b : R1 = R2 = OMe, R3 = R4 = H
2c : R1 = R4 = OMe, R2 = R3 = H
2d : R1 = OMe, R2 = R3 = R4 = H
Scheme 3. Synthesis of 1a–d.
Table 2
Cu(I)-mediated radical cyclization
MeO
MeO
MeO
MeO
MeO
N
N
O
N
O
O
nBu3SnH, AIBN
MeO
+
(eq. 2)
Br
CuCl, benzene
OMe
MeO
OMe
OMe
OMe
OMe
7
2a
1a
Entry
Compound
Solvent
nBu3SnH (equiv)
AIBN (equiv)
CuCl (equiv)
Product ratio (7: 1a)
Yield (7+1a) (%)
1
2
3
2a
2a
2a
Benzene
Benzene
Benzene
2
2
2
0.2
0.2
0.2
1
1.5
2
1: 2
1: 3
Only 1a
50
56
75
R1
R2
R1
R2
O
R4
R3
N
N
O
O
Cl
2 eq. nBu3SnH,
0.2 eq. AIBN, benzene
R1
R2
Br
Br
TEA, DCM
N
R4
R4
2 eq. CuCl
R3
R3
4a-b
2a-d
1a-d
4a : R1 = R2 = OMe
4b : R1 = OMe, R2 = H
1a : R1 = R2 = R3 = R4 = OMe, 75%
1b : R1 = R2 = OMe, R3 = R4 = H, 78%
1c : R1 = R4 = OMe, R2 = R3 = H, 82%
1d : R1 = OMe, R2 = R3 = R4 = H. 78%
2a : R1 = R2 = R3 = R4 = OMe, 86%
2b : R1 = R2 = OMe, R3 = R4 = H, 93%
2c : R1 = R4 = OMe, R2 = R3 = H, 88%
2d : R1 = OMe, R2 = R3 = R4 = H, 84%
Scheme 4. Toal synthesis of 1a–d.

C.-S. Lee et al. / Tetrahedron Letters 50 (2009) 4558–4562
4561
Chung, J. G. Anticancer Res. 2005, 25, 4149; (d) Yu, H. H.; Kim, K. J.; Cha, J. D.;
Kim, H. K.; Lee, Y. E.; Choi, N. Y.; You, Y. O. J. Med. Food 2005, 8, 454; (e)
Letasiova, S.; Jantova, S.; Cipak, L.; Muckova, M. Cancer Lett. 2006, 239, 254; (f)
Qin, Y.; Pang, J. Y.; Chen, W. H.; Cai, Z.; Jiang, Z. H. Bioorg. Med. Chem 2006, 14,
25–32; (g) Ball, A. R.; Casadei, G.; Samosorn, S.; Bremner, J. B.; Ausubel, F. M.;
Moy, T. I.; Lewis, K. Chem. Biol. 2006, 1, 594–600; (h) Hsieh, Y. S.; Kuo, W. H.;
Lin, T. W.; Chang, H. R.; Lin, T. H.; Chen, P. N.; Chu, S. C. J. Agric. Food Chem. 2007,
55, 10437–10445.
R1
R2
R1
R2
N
N
O
O
Br
nBu3Sn
R4
R4
2. (a) González, M. C.; Zafra-Polo, M. C.; Amparo-Blázquez, M.; Serrano, A.; Cortes,
D. J. Nat. Prod. 1997, 60, 108–110; (b) Gentry, E. J.; Jampani, H. B.; Keshavarz-
Shokri, A.; Morton, M. D.; Velde, D. V.; Telikepalli, H.; Mitscher, L. A. J. Nat. Prod.
1998, 61, 1187–1193; (c) Yan, M. H.; Cheng, P.; Jiang, Z. Y.; Ma, Y. B.; Zhang, X.
M.; Zhang, F. X.; Yang, L. M.; Zheng, Y. T.; Chen, J. J. J. Nat. Prod. 2008, 71, 760–
763.
R3
R3
8a-d
2a-d
ˇ
ˇ
ˇ
3. Marek, R.; Seckárová, P.; Hulová, D.; Marek, J.; Dostál, J.; Sklenár, V. J. Nat. Prod.
2003, 66, 481–486.
R1
R2
R1
R2
4. (a) Iwasa, K.; Lee, D. U.; Kang, S. I.; Wiegrebe, W. J. Nat. Prod 1998, 61, 1150–
1153; (b) Chae, S. H.; Jeong, I. H.; Choi, D. H.; Oh, J. W.; Ahn, Y. J. J. Agric. Food
Chem. 1999, 47, 934–938; (c) Lee, H. S. J. Agric. Food Chem. 2002, 50, 7013–7016.
5. (a) Dai, J. R.; Chai, H.; Pezzuto, J. M.; Kinghorn, A. D.; Tsauri, S.; Padmawinata, K.
Phytother. Res. 1993, 7, 290–294; (b) Cortes, D.; Arbaoui, J.; Protais, P. Nat. Prod.
Lett. 1993, 3, 233–238.
6. (a) Chi, J. F.; Chu, S. H.; Lee, C. S.; Chou, N. K.; Su, M. J. Br. J. Pharmacol 1996, 118,
503–512; (b) Chi, J. F.; Chu, S. H.; Lee, C. S.; Su, M. J. Can. J. Cardiol. 1997, 13,
1103–1110.
N
N
O
O
Cu+
- e-
H
R4
R4
R3
R3
7. Chang, F. R.; Wu, Y. C. J. Nat. Prod 2005, 68, 1056.
10a-d
9a-d
8. Kuo, C. L.; Chi, C. W.; Liu, T. Y. Cancer Lett. 2004, 203, 127–137.
9. (a) Dai-Ho, G.; Mariano, P. S. J. Org. Chem 1987, 52, 704–706; (b) Chrzanowska,
M. J. Nat. Prod. 1995, 58, 401–407; (c) Sotomayor, N.; Domnguez, E.; Lete, E. J.
Org. Chem. 1996, 61, 4062–4072.
- H+
10. (a) Chakravarti, S. N.; Perkin, W. H. J. Chem. Soc. 1929, 196–201; (b) Chakravarti,
S. N. J. Indian. Chem. Soc. 1932, 577–579; (c) Lenz, G. R. J. Org. Chem. 1974, 39,
2846–2851; (d) Dorn, C. R.; Koszyk, F. J.; Lenz, G. R. J. Org. Chem. 1984, 49,
2642–2644; (e) Saa, C.; Guitian, E.; Castedo, L.; Suan, R.; Saa, J. M. J. Org. Chem.
1986, 51, 2781–2784; (f) Cobas, A.; Guitian, E.; Castedo, L. J. Org. Chem. 1992,
57, 6765–6769; (g) Venkov, A. P.; Ivanov, I. I. Tetrahedron. 1996, 52, 12299–
12308; (h) Warrener, R. N.; Liu, L.; Russell, R. A. Chem. Commun. 1997, 2173–
2174; (i) Bombrun, A.; Sageot, O. Tetrahedron Lett. 1997, 38, 1057–1060; (j)
Singh, K. N. Tetrahedron Lett. 1998, 39, 4391–4392; (k) Orito, K.; Miyazawa, M.;
Kanbayashi, R.; Tokuda, M.; Suginome, H. J. Org. Chem. 1999, 64, 6583–6596; (l)
Rodriguez, G.; Castedo, L.; Dominguez, D.; Saa, C.; Adam, W.; Saha-Möller, C. R.
J. Org. Chem. 1999, 64, 877–883; (m) Orito, K.; Satoh, Y.; Nishizawa, H.; Harada,
R.; Tokuda, M. Org. Lett. 2000, 2, 2535–2537; (n) Suau, R.; Lopez-Romero, J. M.;
Ruiz, A.; Rico, R. Tetrahedron 2000, 56, 993–998; (o) Huang, W. J.; Singh, O. V.;
Chen, C. H.; Chiou, S. Y.; Lee, S. S. Helv. Chim. Acta. 2002, 85, 1069–1078; (p)
Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341–3370; (q)
Le, T. N.; Gang, S. G.; Cho, W. J. J. Org. Chem. 2004, 69, 2768–2772; (r) Li, W. D.;
Yang, H. Tetrahedron 2005, 61, 5037–5042; (s) Le, T. N.; Cho, W. J. Bull. Korean
Chem. Soc 2007, 28, 763–766; (t) Grycová, L.; Dostál, J.; Marek, R.
Phytochemistry 2007, 68, 150–175; (u) Majumdar, K. C.; Basu, P. K.;
Chattopadhyay, S. K. Tetrahedron 2007, 63, 793–826; (v) Tomasevich, L. L.;
Kennedy, N. M.; Zitelli, S. M.; Hull, R. T.; Gillen, C. R.; Lam, S. K.; Baker, N. J.;
Rohanna, J. C.; Conley, J. M.; Guerra, M. L.; Starr, M. L.; Sever, J. B.; Carroll, P. J.;
Leonard, M. S. Tetrahedron Lett. 2007, 48, 599–602; (w) Le, T. N.; Cho, W. J.
Chem. Pharm. Bull. 2008, 56, 1026–1029; (x) Chang, J. K.; Chang, N. C.
Tetrahedron 2008, 64, 3483–3487.
R1
R2
N
O
R4
R3
1a-d
Scheme 5. Cu(I)-mediated radical cyclization.
treating 1 or 1.5 equiv of CuCl in n-Bu3SnH/AIBN radical-initiated
cyclization generated a mixture of 7 and 1a with only 50–56% of
the ring-closure adducts (Table 2, entries 1 and 2). Presumably
Cu(I) could activate this n-Bu3SnH/AIBN-initiated radical reaction,
and also accomplished a Cu(I)-oxidation during the cyclization
process. As shown in Scheme 4, this radical cyclization reaction
using n-Bu3SnH/AIBN and 2 equiv of CuCl yielded the desired 8-
oxoprotoberberine alkaloids 1a–d with good yields.18
In conclusion, we have developed a new method for the synthe-
sis of 8-oxoprotoberberines 1a–d. These 8-oxoprotoberberines
were formed presumably via the 6-endo cyclization of radical
intermediates 8a–d and subsequent Cu(I) oxidation of 10a–d
(Scheme 5). The Cu(I)-mediated n-Bu3SnH/AIBN radical cyclization
process is feasible to afford the oxoprotoberberine. Thus, the meth-
odology applying CuCl to radical-initiated cyclization for the
synthesis of alkaloids is noteworthy.
11. Lee, C. S.; Liu, C. K.; Chiang, Y. L.; Cheng, Y. Y. Tetrahedron Lett 2008, 49, 481–
484.
12. (a) Bischler, A.; Napieralski, B. Chem. Ber 1893, 26, 1903; (b) Fodor, G.; Gal, J.;
Phillips, B. A. Angew. Chem., Int. Ed. Engl 1972, 11, 919.
13. Eck, J. C.; Marvel, C. S. In Organic Syntheses; Blatt, A. H., Ed.; Collective Volume
II; John Wiley & Sons: New York, 1943; p 74.
14. Shriner, R. L.; Kleiderer, E. C. In Organic Syntheses; Blatt, A. H., Ed.; Collective
Volume II; John Wiley & Sons: New York, 1943; p 538.
15. (a) Uemura, M.; Nishimura, H.; Hayashi, Y. Tetrahedron Lett. 1990, 31, 2319–
2322; (b) Takano, S.; Suzuki, M.; Ogasawara, K. Heterocycles 1990, 31, 1151–
1156; (c) Nimgirawath, S.; Ponghusabun, O. Aust. J. Chem 1994, 47, 951–955.
16. (a) Clark, A. J.; Battle, G. M.; Bridge, A. Tetrahedron Lett. 2001, 42, 1999–2001;
(b) Bryans, J. S.; Chessum, N. E. A.; Huther, N.; Parsons, A. F.; Ghelfi, F.
Tetrahedron 2003, 59, 6221–6231; (c) Clark, A. J.; Geden, J. V.; Thom, S. J. Org.
Chem 2006, 71, 1471–1479; (d) Clark, A. J.; Geden, J. V.; Thom, S.; Wilson, P. J.
Org. Chem 2007, 72, 5923–5926.
17. Clark, A. J.; Wilson, P. Tetrahedron Lett 2008, 49, 4848–4850.
18. 8-Oxopseudopalmatine (1a): mp 197–198 °C (lit.10g mp 198–199 °C). IR (KBr,
cmÀ1) 1645; 1H NMR (300 MHz, CDCl3) d 2.95 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H),
3.99 (s, 3H), 4.02 (s, 3H), 4.02 (s, 3H), 4.37 (t, J = 6.3 Hz, 2H), 6.75 (s, 1H), 6.84 (s,
1H), 6.95 (s, 1H), 7.25 (s, 1H), 7.81 (s, 1H); 13C NMR (75 MHz, CDCl3) d 28.16,
39.75, 56.03 (2C), 56.21 (2C), 101.06, 105.95, 107.78, 107.91, 110.59, 118.61,
122.57, 128.42, 132.16, 136.19, 148.48, 149.03, 150.16, 153.53, 161.42; LRMS
(EI, 70 eV) m/z (%) 367 (M+, 100%). 2,3-dimethoxy-8-oxoberberine (1b): mp 190–
191 °C (lit.10m mp 188–189 °C). IR (KBr, cmÀ1) 1643; 1H NMR (300 MHz, CDCl3)
d 2.95 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 4.00 (s, 3H), 4.37 (t, J = 6.3 Hz, 2H), 6.75 (s,
1H), 6.89 (s, 1H), 7.29 (s, 1H), 7.44 (t, J = 6.9 Hz, 1H), 7.55–7.66 (m, 2H), 8.43 (d,
J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 28.11, 39.73, 56.03, 56.27, 101.42,
107.96, 110.52, 122.33, 124.57, 125.89, 126.15, 127.97, 128.74, 132.22, 136.67,
137.42, 148.50, 150.40, 162.21; LRMS (EI, 70 eV) m/z (%) 307 (M+, 100%). 3,10-
Acknowledgement
We thank National Science Council, ROC for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.095.
References and notes
1. (a) Iwasa, K.; Moriyasu, M.; Yamori, T.; Turuo, T.; Lee, D. U.; Wiegrebe, W. J. Nat.
Prod. 2001, 64, 896–898; (b) Morel, C.; Stermitz, F. R.; Tegos, G.; Lewis, K. J.
Agric. Food Chem. 2003, 51, 5677–5679; (c) Lin, C. C.; Kao, S. T.; Chen, G. W.;

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C.-S. Lee et al. / Tetrahedron Letters 50 (2009) 4558–4562
Dimethoxy-8-oxoberberine (1c): mp 187 °C. (lit.10a mp 180 °C). IR (CHCl3, cmÀ1
)
Methoxy-8-oxoberberine (1d): mp 145–146 °C (lit.10b mp 143 °C). IR (KBr, cmÀ1
)
1643; 1H NMR (300 MHz, CDCl3) d 2.97 (t, J = 6.3 Hz, 2H), 3.86 (s, 3H), 4.37 (t,
J = 6.3 Hz, 2H), 6.77 (d, J = 2.4 Hz, 1H), 6.87–6.90 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H),
7.53 (d, J = 7.5 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 8.42 (d,
J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 28.82, 39.57, 55.39, 101.32, 112.61,
113.62, 122.86, 124.45, 125.91, 126.04, 126.60, 127.91, 132.16, 136.77, 137.08,
137.44, 160.47, 162.16; LRMS (EI, 70 eV) m/z (%) 277 (M+, 97.75%).
1644; 1H NMR (300 MHz, CDCl3) d 2.98 (t, J = 6.0 Hz, 2H), 3.86 (s, 3H), 3.94 (s,
3H), 4.38 (t, J = 6.0 Hz, 2H), 6.77 (d, J = 2.7 Hz, 1H), 6.87–6.90 (m, 2H), 7.24 (dd,
J = 8.7, 2.7 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.82 (d,
J = 2.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 28.86, 39.77, 55.39, 55.64, 101.28,
107.57, 112.58, 113.59, 123.08, 125.52, 126.27, 127.62 (2C), 130.96, 135.30,
136.68, 158.32, 160.17, 161.77; LRMS (EI, 70 eV) m/z (%) 307 (M+, 100%). 3-