Synthesis of novel 5-oxaprotoberberines as bioisosteres of protoberberines

Article abstract of DOI:10.1016/j.tetlet.2014.01.020

5-Oxaprotoberberinones and 5-oxaprotoberberinium were synthesized as bioisosteres of protoberberines. 5-Oxaprotoberberinones were prepared by linking phenol with the isoquinolone ring of 3-phenolisoquinolones by methyleneoxy bridge, while the quaternary 5-oxaprotoberberinium salt was synthesized by reduction and oxidation of the lactam moiety of 5-oxaprotoberberinone.

Full text of DOI:10.1016/j.tetlet.2014.01.020

Tetrahedron Letters 55 (2014) 1366–1369
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel 5-oxaprotoberberines as bioisosteres
of protoberberines
⇑
Yifeng Jin, Daulat Bikram Khadka, Su Hui Yang, Chao Zhao, Won-Jea Cho
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
5-Oxaprotoberberinones and 5-oxaprotoberberinium were synthesized as bioisosteres of protoberbe-
rines. 5-Oxaprotoberberinones were prepared by linking phenol with the isoquinolone ring of 3-pheno-
lisoquinolones by methyleneoxy bridge, while the quaternary 5-oxaprotoberberinium salt was
synthesized by reduction and oxidation of the lactam moiety of 5-oxaprotoberberinone.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 28 November 2013
Revised 2 January 2014
Accepted 7 January 2014
Available online 13 January 2014
Keywords:
Protoberberine
Bioisostere
5-Oxaprotoberberinium
5-Oxaprotberberin-8-one
Introduction
N
O
O
O
O
O
Protoberberines are important natural isoquinoline alkaloids.
They have been found in several medicinal plant families such as
Papaveraceae,1 Ranunculaceae,2 Berberidaceae,3 and Fumariaceae.4
Fascinated by the diverse pharmacological activities such as anti-
fungal,5 antitumor,6 and antidiabetic7 properties, scientists have
concentrated on the synthesis and derivatization of protoberberine
alkaloids for decades. Structural modifications have mainly
focused on functional groups radiating out from central tetracyclic
protoberberinium quaternary salt,3 tetrahydroprotoberberine,8 or
dihydroprotoberberine to alter physiochemical and pharmacologi-
cal properties. However, variation of the units of the protoberber-
ine scaffold is limited.
B
N
A
MeO
MeO
MeO
MeO
D
C
R1
N
N
NMe2
Me
R
O
O
1
2
3
OMe
OMe
R2
A
MeO
MeO
R1
D
C
O
B
N
O
N
4
5
Figure 1. Nitidine (1), dibenzo[c,h][1,6]naphthyridinones 2, 12-oxobenzo[c]phe-
nanthridinone 3, coralyne (4), and 5-oxaprotoberberinone 5.
Changes in the skeleton of natural alkaloids have proved benefi-
cial. Series of modifications of nitidine (benzo[c]phenanthridine
alkaloid) (1) to dibenzo[c,h][1,6]naphthyridinones 2 show that
replacement of C12 to N12 is essential for interaction with topoiso-
merase I (topo I; an enzyme necessary for relaxing supercoiled
DNA) and is responsible for remarkable (20- and 130-fold) in-
creases in topo I inhibitory and cytotoxicity effects.9 Likewise, the
activities are preserved when the N12 is replaced by O12 as in
12-oxobenzo[c]phenanthridinone 3.10 Interestingly, coralyne (4)
(a synthetic protoberberine), which differs from nitidine with re-
spect to the position of ring B, targets topo I and possesses cytotoxic
effects. Similar pharmacological activities have also been observed
in indeno[1,2-c]isoquinolines and isoindolo[2,1-b]isoquinolinones
OMe
OMe
O
OH
O
OMe
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
5
O8
O
O
6
7
8
Figure 2. Natural protoberberines: 8-oxypseudoberberine (6), 8-oxypseudopalm-
atine (7), and cerasonine (8).
with a five-membered B ring.11 Thus, it can be expected that 5-oxa-
protoberberines, which share structural homology with the chem-
ical compounds mentioned earlier, possess topo I inhibitory and
cytotoxic activities or pharmacological properties unique to their
⇑
Corresponding author. Tel.: +82 62 530 2933; fax: +82 62 530 2911.
E-mail address: wjcho@chonnam.ac.kr (W.-J. Cho).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2014.01.020

Y. Jin et al. / Tetrahedron Letters 55 (2014) 1366–1369
1367
R2
R2
NH OPG
[H], [O]
R2
OPG
12
R1
R1
R1
+
N
O
N O
SN2
NEt
2 NC
O
O
O
coupling reaction
10
9
5
11
Scheme 1. Retrosynthesis of protoberberinium 9 and 5-oxaprotoberberin-8-ones 5.
R5
O
R5
R5
R4
R4
R4
R1
R1
R5
R1
R1
R2
R3
R2
R3
R4
R2
R3
R2
R3
i
ii
iii
+
NEt2
N
NH OR
NH OH
NC
O
O
OR
O
O
11
12
10a-m
13a-m
5a-m
R1 R2
R3
H
H
H
CH3
R
R4 R5
11a
11b
11c
11d
11e
11f
H
CH3
H
H
H
CH3
H
12a
MOM
H
H
H
H
12b PMB
12c MOM
OCH2O
H
H
H
H
CH3 CH3
OCH3OCH3
OCH3 OBn
11g
Scheme 2. Synthesis of 5-oxaprotoberberin-8-ones 5. Reagents and conditions: (i) n-BuLi, dry THF, ꢀ78 °C; (ii) 10% HCl or TFA, THF, reflux; (iii) CH2I2, K2CO3, DMF, 100 °C.
Table 1
Table 2
Synthesis of 3-arylisoquinolones 10
5-Oxaprotoberberinones 5
R5
O
Compound no.
R1
R2
R3
R
R4
R5
Yield (%)
R4
R1
R2
R3
10a
10b
10c
10d
10e
10f
10g
10h
10i
H
CH3
H
H
H
H
H
H
CH3
H
H
H
H
H
H
CH3
CH3
OCH3
OBn
H
H
H
CH3
CH3
OCH3
MOM
PMB
MOM
MOM
PMB
H
H
H
H
H
H
H
H
H
H
H
H
H
H
63
41
43
51
42
40
41
40
54
43
48
44
54
N
CH3
H
CH3
OCH3
OCH3
H
H
CH3
H
O
Compound no. R1
R2
R3
R4 R5 Yield (%) Mp (°C)
PMB
MOM
MOM
MOM
MOM
MOM
MOM
MOM
5a
5b
5c
5d
5e
5f
H
CH3
H
H
H
H
H
H
H
H
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
50
41
20
44
37
20
27
58
26
46
46
20
22
176.5–177.2
165.0–166.3
181.4–182.2
151.2–153.1
174.8–176.5
205.2–208.6
192.9–193.5
211.5–212.3
219.7–222.3
237.2–238.9
230.8–232.5
258.4–260.4
266.4–268.8
OCH2O
OCH2O
OCH2O
OCH2O
OCH2O
OCH2O
CH3
H
CH3
10j
10k
10l
H
H
H
CH3
OCH3
H
OCH3 OCH3
OCH3 OBn
10m
5g
5h
5i
H
H
CH3
H
H
H
H
H
H
CH3
CH3
OCH2O
OCH2O
OCH2O
OCH2O
OCH2O
5j
CH3
H
CH3
5k
5l
H
H
parent natural protoberberine. Based on this rationale, we herein
disclose design and synthesis of 5-oxaprotoberberinones and
5-oxaprotoberberinium (see Fig. 1).
5m
H
OCH3 OCH3 OCH2O
Results and discussion
OH
OH
O
OH
CN
OMOM
CN
O
O
O
O
O
i
ii
iii
O
O
CHO
The total synthesis of natural 8-oxyprotobeberines as 8-oxy-
pseudoberberine (6), 8-oxypseudopalmatine (7)12 and cerasonine
(8),13 as reported by our research group, principally involves: (1)
formation of 3-arylisoquinolone by cycloaddition of lithiated tol-
uamides and benzonitriles as initial precursor, and (2) closure of
the B ring as final step (Fig. 2). Based on the strategy, synthesis
of novel protoberberine bioisosteres, 5-oxaprotoberberin-8-ones
5, was envisioned as shown in Scheme 1.
14
15
16
12c
Scheme 3. Synthesis of compound 12c. Reagents and conditions: (i) hexamethy-
lenetetramine, TFA, reflux, 53% yield; (ii) nitroethane, NaOAc, CH3COOH, reflux, 86%
yield; (iii) MOMCl, DIPEA, CH2Cl2, rt, 98% yield.
Oxaprotoberberinones 5 can be prepared from phenolic iso-
quinolines 10 by intramolecular cyclization. The phenolic com-
pounds 10 in turn can be derived from coupling of lithiated
toluamides 11 and 2-cyanophenols 12. Furthermore, protoberberi-
nium 9 can be expected to be synthesized by reduction and oxida-
tion of 5-oxaprotoberberinone 5.14,15
2'
N3H O
1
1''
2''
O
O
3''
Figure 3. Structure of compound 17.
Synthesis of 5-oxaprotoberberin-8-ones 5 was initiated with
lithiated toluamide-benzonitrile cycloaddition (Scheme 2).16
Varieties of o-toluamides 11 were treated with n-BuLi to form
dianion, which in turn reacted with MOM (methoxymethyl) or
PMB (p-methoxybenzyl) protected o-cyanophenols 12 yielding
3-aryisoquinolones 10 (Table 1). MOM/PMB groups of 10 were
deprotected under acidic conditions (10% HCl/trifluoroacetic acid)

1368
Y. Jin et al. / Tetrahedron Letters 55 (2014) 1366–1369
Figure 4. HMBC (600 MHz, CDCl3) of compound 17. The arrow represents correlation between H100 and C20.
to give phenols 13 with yield ranging from 34% to 92%. Finally the
methylene bridge between amide and hydroxyl groups of com-
pound 13 was formed by SN2 reaction with diiodomethane and
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to yield 5-oxaproto-
berberinium chloride
9 after treatment with concentrated
hydrochloric acid.21
K2CO3 as base to afford desired 5-oxaprotoberberinones
5
(Table 2).17
Conclusion
The o-toluamides 11a–g and o-cyanophenols 12a,b were pre-
pared according to synthetic methods reported previously,10,18
while cyanophenol 12c was synthesized as described in Scheme 3.
Benzaldehyde 15 was obtained from sesamol (14) by Duff reac-
tion.19 Aldehyde 15 was converted to cyanophenol 16 by refluxing
the compound along with nitroethane,20 sodium acetate, and ace-
tic acid. Finally, the hydroxyl group was protected by MOM to give
compound 12c.
In summary, we have established an easy and efficient synthetic
route to novel 5-oxaprotoberberinium and 5-oxaprotoberberinon-
es with heterocyclic B ring as bioisosteres of protoberberines.
5-Oxaprotoberberinones were synthesized by three reactions
starting with toluamides and benzonitriles. Cyclization of ring B
took place at the final step by two consecutive SN2 reactions with
priority to the phenol –OH followed by N2 of isoquinolone.
Protoberberinium salt was formed by reduction of the lactam ring
of oxaprotoberberinone and aromatization of the ring by DDQ.
Adaptation of this approach and the use of diversely functionalized
toluamides and benzonitriles should allow the formation of
synthetic analogs of various natural protoberberines with
important pharmacological properties.
To investigate the precedence of two nucleophilic groups during
formation of ring B of protoberberine 5, phenolic compound 13a
was treated with chloroacetone in the presence of K2CO3 as base.
As
a result, 3-[2-(2-oxo-propoxy)phenyl]-2H-isoquinolin-1-one
17 was formed (Fig. 3). The structure of compound 17 was deter-
mined by 1D 1H, 13C NMR and 2D 1H–13C heteronuclear multiple
1
bond coherence (HMBC) spectra. H NMR showed H100 proton sig-
nals at d = 4.75, H300 protons at d = 2.25 and aromatic protons at
Acknowledgment
13
d = 8.38–6.69. C NMR revealed that C20 appeared at d = 154.6
and carbonyl carbon C200 at d = 204.7. Importantly, HMBC cross
peak of H100 protons and C20 corroborated that the acetone group
was attached to the 3-phenol rather than to N2 of the isoquinolone
moiety, which indicates that the phenolic –OH is more nucleophilic
than the lactam group of isoquinolone (see Fig 4).
This work was supported by Korea Research Foundation Grant
(NRF-2011-0015551).
Supplementary data
Furthermore, oxaprotoberberinone 5a was reduced by lithium
aluminum hydride to give 7H-5-oxa-6a-aza-benzo[a]anthracene
18 (Scheme 4). Finally, compound 18 was oxidized by
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
01.020.
References and notes
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ii
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ˇ
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LiAlH4, THF, MeOH, 43% yield; (ii) DDQ, 5% NaOH, benzene, c-HCl, 65% yield.

Y. Jin et al. / Tetrahedron Letters 55 (2014) 1366–1369
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21. All synthesized compounds were fully characterized by spectroscopy. Selected
data for key compounds: Compound 10a; 1H NMR (300 MHz, CDCl3) d: 9.60
(bs, 1H), 8.40 (d, J = 7.9 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.58 (d, J = 7.9 Hz, 2H),
7.48 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.14 (t,
J = 7.9 Hz, 1H), 6.71 (s, 1H), 5.28 (s, 2H), 3.47 (s, 3H). Compound 13a; 1H NMR
(300 MHz, CDCl3) d: 12.60 (s, 1H), 11.68 (s, 1H), 8.52 (d, J = 8.1 Hz, 1H), 7.76–
7.66 (m, 3H), 7.57–7.51 (m, 1H), 7.35–7.31 (m, 2H), 7.09 (s, 1H), 7.02–6.97 (m,
1H). Compound 5a; Mp: 176.5–177.2 °C. 1H NMR (300 MHz, CDCl3) d: 8.43 (dt,
J = 7.8, 0.6 Hz, 1H), 7.81 (dd, J = 7.8, 1.5 Hz, 1H), 7.70–7.64 (m, 1H), 7.58 (d,
J = 7.5 Hz, 1H), 7.51–7.45 (m, 1H), 7.41–7.35 (m, 1H), 7.18 (td, J = 7.8, 1.2 Hz,
1H), 7.11 (dd, J = 7.8, 0.9 Hz, 1H), 6.93 (s, 1H), 5.93 (s, 2H). 13C NMR (125 MHz,
CDCl3) d: 159.8, 153.8, 149.9, 149.7, 149.0, 144.3, 132.5, 132.2, 118.6, 111.9,
107.8, 106.2, 102.4, 101.8, 99.2, 71.9. MS (ESI) m/z = 250 (M+H)+. Compound
17; 1H NMR (300 MHz, CDCl3) d: 10.05 (s, 1H), 8.41 (d, J = 8.1 Hz, 1H), 7.69–
7.57 (m, 3H), 7.51–7.37 (m, 2H), 7.12 (td, J = 7.8, 1.2 Hz, 1H), 6.69 (s, 1H), 4.78
(s, 2H), 2.27 (s, 3H). 13C NMR (150 MHz, CDCl3) d: 204.7, 162.9, 154.7, 138.2,
138.0, 132.5, 130.9, 130.5, 127.4, 126.5, 126.3, 125.1, 123.7, 122.4, 112.4, 106.0,
73.0, 26.5. MS (ESI) m/z = 294 (M+H)+. Compound 9; 1H NMR (300 MHz, D2O) d:
9.73 (s, 2H), 8.85 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.22 (t,
J = 7.8 Hz, 1H), 8.00 (t, J = 8.1 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 7.8 Hz,
1H), 7.34 (d, J = 8.4 Hz, 1H), 6.39 (s, 2H). 13C NMR (125 MHz, D2O) d: 153.1,
146.5, 139.2, 137.8, 135.8, 134.1, 131.2, 130.3, 127.5, 125.9, 125.3, 125.2, 120.1,
117.6, 116.4, 82.3. MS (ESI) m/z = 235 (M+H)+.
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