A divergent route to 9,10-oxygenated tetrahydroprotoberberine and 8-oxoprotoberberine alkaloids: Synthesis of (±)-isocorypalmine and oxypalmatine

Article abstract of DOI:10.1016/j.tet.2015.01.004

A new route, which is germane to the synthesis of 9,10-oxygenated tetrahydroprotoberberines and 8-oxoprotoberberines is described. The route features the use of a diester (14) generated from reaction of dimethylmalonate with an aryl halide in the presence of n-butyllithium. The amide 17 prepared in subsequent steps is a versatile precursor for the synthesis of tetrahydroprotoberberine and 8-oxoprotoberberine scaffolds using standard high-yielding reactions. In this manner, (±)-isocorypalmine and oxypalmatine have been synthesized in 23% and 22% yields, respectively.

Full text of DOI:10.1016/j.tet.2015.01.004

Tetrahedron 71 (2015) 1227e1231
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journal homepage: www.elsevier.com/locate/tet
A divergent route to 9,10-oxygenated tetrahydroprotoberberine and
8-oxoprotoberberine alkaloids: synthesis of (ꢀ)-isocorypalmine
and oxypalmatine
,
,b,
Satish Gadhiya a b, Shashikanth Ponnala a, Wayne W. Harding a
*
a Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA
b The Graduate Center, City University of New York, 365 5th Avenue, NY 10016, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route, which is germane to the synthesis of 9,10-oxygenated tetrahydroprotoberberines and
8-oxoprotoberberines is described. The route features the use of a diester (14) generated from reaction of
dimethylmalonate with an aryl halide in the presence of n-butyllithium. The amide 17 prepared in
Received 10 November 2014
Received in revised form 2 January 2015
Accepted 5 January 2015
subsequent steps is
a versatile precursor for the synthesis of tetrahydroprotoberberine and
Available online 9 January 2015
8-oxoprotoberberine scaffolds using standard high-yielding reactions. In this manner, (ꢀ)-iso-
corypalmine and oxypalmatine have been synthesized in 23% and 22% yields, respectively.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
THPB
Tetrahydroprotoberberine
Isocorypalmine
Oxypalmatine
8-Oxoprotoberberine
1. Introduction
The tetracyclic tetrahydroprotoberberine (THPB) alkaloids are
a sub-group of isoquinoline alkaloids that have displayed in-
teresting biological activities, for example, as antimicrobial,1,2 an-
titumor,3,4 antifungal,5 and anti-cholinesterase agents.6,7 There
have also been several reports on THPBs as central nervous system
receptor (particularly dopamine receptor) ligands with potential as
antipsychotic agents.8e10 The core tetracyclic nucleus of naturally
occurring THPBs is usually decorated with hydroxyl or alkoxyl
substituents in the aromatic A and D rings.
The THPB (ꢁ)-isocorypalmine (ICP, 1, Fig. 1) is a natural product
that has been isolated from a number of Corydalis species.11,3
(ꢁ)-ICP was recently reported to reduce the rewarding effects of
cocaine in mice via acting on dopamine receptors.12 As such,
(ꢁ)-ICP is a promising molecule towards the development of anti-
cocaine therapeutics.
Fig. 1. Structures of (ꢁ)-ICP and oxypalmatine.
been most utilized owing to the relative ease with which the BTHIQ
precursors can be prepared. However, the Mannich method is non-
ideal for the synthesis of 9,10-oxygenated THPBs, since Mannich
reaction on the required BTHIQ substrate yields both the 9,10- (4)
and 10,11-oxygenated (5) THPBs (often giving the latter either
predominantly or exclusively).13,14
Use of bromine as a blocking group (at the incipient C12 position
of the THPB nucleus; 6) has been used to circumvent this problem.
However, this strategy lengthens the synthesis, is often low yield-
ing and may be less desirable for the synthesis of more structurally
rich THPBs.14e16
Several methods have been developed for the synthesis of the
THPB core. Among them, closure of ring C via a Mannich reaction on
a benzyltetrahydroisoquinoline (BTHIQ) substrate (3; Fig. 2) has
Enantioselective synthesis of THPBs has been accomplished via
reduction of intermediate BTHIQs with Noyori catalysts.10,17,18 Sun
et al. recently reported an enantioselective synthesis of several
9,10-oxygenated THPBs (including 1) via key lactone precursors
* Corresponding author. Tel.: þ1 212 772 5359; fax: þ1 212 772 5332; e-mail
address: whardi@hunter.cuny.edu (W.W. Harding).
http://dx.doi.org/10.1016/j.tet.2015.01.004
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

1228
S. Gadhiya et al. / Tetrahedron 71 (2015) 1227e1231
a benzyne intermediate generated from dehydrobromination of
13.23 Selective hydrolysis of the aliphatic ester group was accom-
plished with K2CO3 in refluxing H2O/MeOH to give acid 15. This acid
was coupled to readily available amine 1624 with carbon-
yldiimidazole (CDI) to provide key amide precursor 17.
BischlereNapieralski cyclization on amide 17 proved to be suc-
cessful with POCl3 as dehydrating agent and acetonitrile as solvent.
This cyclization was fortuitously accompanied by simultaneous
removal of the ethoxymethyl protecting group. Other dehydrating
conditions (neat POCl3, P2O5 or PCl5) and solvents (dichloro-
methane or toluene) were tried but gave inferior yields of imine
product. BischlereNapieralski cyclization was followed by imme-
diate reduction (due to instability of the intermediate imines of this
type) with NaBH4 to afford the 8-oxotetrahydroprotoberberine 18.
The C10 phenol of 18 was methylated to give 19. Reduction of the 8-
oxo group of 19 with LAH provided an intermediate tertiary amine,
which was subsequently heated with concentrated HCl, thus
effecting debenzylation to give (ꢀ)-ICP.
Fig. 2. Synthesis of 9,10-oxygenated THPBs.
typified by 7. Here, condensation of a phenethylamine with 7, gave
an amide.10 Further synthetic manipulations eventually trans-
formed the aromatic ring of 7 into ring D of the THPB core. How-
ever, the synthesis overall is lengthy (>10 steps) and preparation of
lactones, such as 7 is known to be problematic, particularly on large
scale.19,20
These troublesome issues with synthesis of 9,10-oxygenated
THPBs prompted an investigation into alternative routes to pre-
pare molecules with this structural feature. In this paper, we report
our efforts in this regard as applied to the synthesis of (ꢀ)-ICP. The
route described may also be modified to prepare oxidized 8-
oxoprotoberberine congenersdexemplified herein in our synthe-
sis of oxypalmatine (2).
The success of this route propelled us to investigate an analo-
gous asymmetric route to (ꢁ)-ICP. We presumed that this could be
easily accomplished by replacing NaBH4 as the reducing agent in
Scheme 1 (17 to 18) with Noyori’s asymmetric hydrogenation
method.25 The chiral 8-oxotetrahydroprotoberberine thus formed
(i.e., analogous to 18) would then be transformed to (ꢁ)-ICP by
using the identical sequence of reagents that was used in Scheme 1.
Thus, BischlereNapieralski cyclization on amide 17 was performed
as described in Scheme 1 (Scheme 2).
The imine formed was then subjected to Noyori’s asymmetric
hydrogenation conditions. To our surprise this did not yield the
desired chiral 8-oxotetrahydroprotoberberine 20. Instead the 8-
oxoprotoberberine 21 was produced. One possible cause for fail-
ure of the reduction is due to formation (and subsequent isomeri-
zation) of an acyl iminium ion formed from reaction of the imine
nitrogen (from BischlereNapieralski reaction) with the aryl ester
group. Another possibility is that when the imine derived from 17
(i.e., compound 22) is subjected to Noyori reduction conditions,
isomerization of the imine to an enamine precedes the cyclization
of ring C. Treatment of the 22 with triethylamine (the base used in
the Noyori reduction) gives 21. Presumably, the isomerization/cy-
clization steps occur at a faster rate than Noyori reduction.
Through this attempt to achieve an enantioselective synthesis of
(ꢁ)-ICP, it was recognized that naturally occurring 8-
oxoprotoberberines could be synthesized by variations of this
method. Previous syntheses of the 8-oxoprotoberberine skeleton
have required several synthetic steps and/or suffer from low-
yielding steps.26e30 Thus to demonstrate the pliability of the
route, compound 21 was transformed to the natural product oxy-
palmatine (2, Scheme 2) by removal of the C2 benzyl group fol-
lowed by Williamson ether methylation. Insofar as synthesis of
oxypalmatine is concerned, this method is comparable to published
methods in both yield and number of steps (seven steps and 22%
overall yield for the present synthesis; nine steps 10% yield for the
previous synthesis).31
2. Results and discussion
We envisaged that the 9,10-methoxylated THPB core (8) could
be prepared via the amide intermediate 9 (Fig. 3). This intermediate
in turn is derivable from the diester 10 (via amide coupling with the
corresponding aliphatic acid). Compound 10 we reasoned, would
serve as an easily reachable synthetic surrogate for the isochroman
7. The diester 10 would be prepared from aryl bromide 11.
3. Conclusions
Fig. 3. Retrosynthetic analysis to THPB core.
Herein, a new synthesis of (ꢀ)-ICP is delineated, which features
the use of the easily obtainable diester intermediate 14. (ꢀ)-ICP was
prepared in nine steps from readily available precursors in 23%
overall yield. The route is attractive due to its efficiency and practical
ease; no chromatographic purification was necessary for a number
of steps. The yield obtained is comparable to a reported synthesis of
(ꢀ)-ICP.32 However, enantioselective preparation of (ꢁ)-ICP by
modifications to this route remains to be optimized. The key amide
intermediate (17), that is, used for (ꢀ)-ICP synthesis can also be used
to prepare a 9,10-oxygenated-8-oxoprotoberberine core, and we
This general approach was applied to the synthesis of (ꢀ)-ICP as
depicted in Scheme 1. Commercially available bromo cresol 12 was
protected as the ethoxymethyl ether by reaction with chlor-
omethoxyethane affording 13 (We considered that the ethox-
ymethyl ether group could be selectively removed later so that
various C10 alkoxy analogs in addition to ICP itself could be pre-
pared). Thereafter reaction of 13 with n-butyllithium in the pres-
ence of dimethylmalonate gave diester 14.21,22 This reaction
presumably proceeds via nucleophilic attack of malonate anion on

S. Gadhiya et al. / Tetrahedron 71 (2015) 1227e1231
1229
Scheme 1. Synthesis of (ꢀ)-isocorypalmine (1).
Scheme 2. Synthesis of oxypalmatine (2).
adapted this method to prepare oxypalmatine (2). Hence, the route
examined here is a versatile one for the preparation of 9,10-
oxygenated THPBs as well as their 8-oxoprotoberberine analogs.
125 MHz, for 13C) using CDCl3 as solvent unless stated otherwise.
Tetramethylsilane (
0.00 ppm) served as an internal standard in 1H
NMR and CDCl3
77.0 ppm) in 13C NMR unless stated otherwise.
Chemical shift ( 0.00 ppm) values are reported in parts per million
d
(d
d
and coupling constants in Hertz (Hz). Splitting patterns are de-
scribed as singlet (s), doublet (d), triplet (t), and multiplet (m).
Reactions were monitored by TLC with Whatman Flexible TLC silica
gel G/UV 254 precoated plates (0.25 mm). TLC plates were visual-
ized by UV (254 nm) and by staining in an iodine chamber. Flash
column chromatography was performed with silica gel 60 (EMD
Chemicals, 230e400 mesh, 0.063 mm particle size).
4. Experimental section
4.1. General methods
All moisture-sensitive and oxygen-sensitive reactions were
carried out in flame-dried glassware under a nitrogen atmosphere.
Solvents and all other reagents were purchased at the highest
commercial quality from Aldrich and Fisher Scientific USA and used
without further purification, unless otherwise stated. Anhydrous
sodium sulfate was used as drying agent for work-up of reactions.
HRESIMS spectra were obtained using an Agilent 6520 QTOF in-
strument. 1H NMR and 13C NMR spectra were recorded using
Bruker DPX-500 spectrometer (operating at 500 MHz for 1H;
4.2. 4-Bromo-1-(ethoxymethoxy)-2-methoxybenzene (13)
Compound 12 (8.0 g, 39 mmol) and diisopropylethyl amine
(13.7 mL, 78.8 mmol) were stirred in DCM (100 mL) at 0 ꢂC for
15 min. Ethoxycholoromethyl ether (5.48 mL, 59.1 mmol) was

1230
S. Gadhiya et al. / Tetrahedron 71 (2015) 1227e1231
added dropwise to the solution at 0 ꢂC. The solution was allowed
to stir at rt for 1 h. The reaction mixture was washed with 0.1 N
HCl (120 mL). The organic layers were combined, dried over so-
dium sulfate, and evaporated to dryness to give 13 (10.1 g, 98%)
as a brownish oil. This product was used in the subsequent re-
action without any further purification: 1H NMR (CDCl3,
(7.0 g, 78%) as a brown oil: 1H NMR (CDCl3, 500 MHz)
d 7.43 (d,
J¼7 Hz, 2H), 7.37 (t, J¼8 Hz, 2H), 7.29 (t, J¼7 Hz, 1H), 7.18 (d, J¼9,
1H), 6.98 (d, J¼9 Hz, 1H), 6.74 (d, J¼8 Hz, 1H), 6.68 (d, J¼2 Hz, 1H),
6.50 (dd, J¼8, 2 Hz, 1H), 6.16 (t, J¼5 Hz, 1H), 5.25 (s, 2H), 5.11 (s,
2H), 3.88 (s, 6H), 3.84 (s, 3H), 3.75 (q, J¼7 Hz, 2H), 3.40e3.39 (m,
3H), 2.67 (t, J¼7 Hz, 2H), 1.23 (t, J¼7 Hz, 3H); 13C NMR (CDCl3,
500 MHz)
d
7.06e7.00 (m, 3H), 5.26 (s, 2H), 3.86 (s, 3H), 3.76 (q,
125 MHz) d 170.3, 168.4, 149.7, 149.6, 147.3, 146.7, 137.4, 132.1,
J¼7 Hz, 2H), 1.22 (t, J¼7 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
128.8, 128.5, 128.5, 127.8, 127.3, 127.3, 126.8, 126.1, 120.6, 118.5,
114.2, 112.4, 93.8, 71.1, 64.7, 61.6, 55.9, 52.6, 41.2, 40.9, 35.2, 15.1;
HRMS (ESI) m/z calcd for C30H35NO8 ([MþNa]þ), 560.2255, found
560.2260.
d
150.5, 145.9, 123.6, 117.7, 115.2, 114.4, 94.2, 64.5, 56.1, 15.1; HRMS
(ESI) m/z calcd for
C
10H13BrO3 ([MþNa]þ), 282.9940, found
282.9942.
4.3. Methyl 3-(ethoxymethoxy)-2-methoxy-6-(20-methoxy-20-
oxoethyl) benzoate (14)
4.6. 2-(Benzyloxy)-10-hydroxy-3,9-dimethoxy-5,6,13,13a-tet-
rahydro-8H-isoquinolino[3,2-a]isoquinolin-8-one (18)
Diisopropylamine (11.5 mL, 84.3 mmol) was stirred in dry THF
(100 mL) at ꢁ78 ꢂC in an oven-dried round bottom flask for
15 min. n-Butyllithium (2.5 M in hexane, 100 mL) was added and
the solution was allowed to stir at ꢁ78 ꢂC for 30 min. Dime-
thylmalonate (18.9 mL, 164 mmol) in 60 mL dry THF was added.
The solution was stirred at ꢁ78 ꢂC for 1 h and a solution of 13
(10.0 g, 38.3 mmol) in 50 mL dry THF was added. After 45 min, the
reaction mixture was quenched with a saturated solution of am-
monium chloride. THF was evaporated and the crude mixture was
extracted with dichloromethane (4ꢃ100 mL). The solvent was
reduced in vacuo and the crude product was purified via flash
chromatography on silica gel (10% acetone/hexanes) to afford
compound 14 (6.5 g, 54%) as a yellowish oil: 1H NMR (CDCl3,
Compound 17 (5.0 g, 9.3 mmol) and POCl3 (6.95 mL, 74.4 mmol)
were refluxed in 60 mL acetonitrile for 3 h. The solvent was evap-
orated and the residue was dissolved in 120 mL DCM. The resulting
solution was washed with sodium bicarbonate and then dried over
sodium sulfate. The organic solvent was removed in vacuo and
methanol (100 mL) was added. Sodium borohydride (1.4 g,
37 mmol) was added at 0 ꢂC and the mixture allowed to stir for 6 h.
The reaction was quenched with water and methanol was evapo-
rated. The residue was extracted with DCM (3ꢃ80 mL). The organic
layer was dried, filtered, and evaporated to dryness to afford 18
(3.2 g, 79%). It was used in the next step without further purifica-
tion: 1H NMR (CDCl3, 500 MHz)
d
7.44 (d, J¼7 Hz, 2H), 7.37 (t,
J¼8 Hz, 2H), 7.29 (t, J¼7 Hz, 1H), 7.06 (d, J¼10 Hz, 1H), 6.84 (d,
J¼10 Hz, 1H), 6.71 (s, 1H), 6.68 (s, 1H), 6.01 (s, 1H), 5.15 (s, 2H), 4.99
(d, J¼10 Hz, 1H), 4.68 (dd, J¼16, 4 Hz, 1H), 4.00 (s, 3H), 3.90 (s, 3H),
500 MHz)
d
7.20 (d, J¼9 Hz, 1H), 6.96 (d, J¼9 Hz, 1H), 5.26 (s, 2H),
3.90 (s, 3H), 3.89 (s, 3H), 3.75 (q, J¼7 Hz, 2H), 3.68 (s, 3H), 3.62 (s,
2H), 1.23 (t, J¼7 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d
171.5, 167.6,
2.93e2.70 (m, 5H); 13C NMR (CDCl3, 125 MHz)
d 162.6, 149.0, 148.8,
149.8, 147.6, 129.0, 126.5, 125.6, 118.0, 93.8, 64.6, 61.7, 52.2, 52.1,
38.4, 15.1; HRMS (ESI) m/z calcd for C15H20O7 ([MþNa]þ), 315.1101,
found 315.1104.
147.3, 146.9, 137.0, 130.7, 128.6, 128.6, 128.1, 127.9, 127.5, 127.4, 127.4,
122.8, 121.5, 118.1, 112.6, 111.9, 71.6, 62.4, 56.1, 54.9, 38.9, 38.3, 29.4;
HRMS (ESI) m/z calcd for C26H25NO5 ([MþH]þ), 432.1805, found
432.1809.
4.4. 2-[40-(Ethoxymethoxy)-30-methoxy-20-(methox-
ycarbonyl)phenyl]acetic acid (15)
4.7. 2-(Benzyloxy)-3,9,10-trimethoxy-5,8,13,13a-tetrahydro-
6H-isoquinolino[3,2-a]isoquinoline (19)
Compound 14 (5.8 g, 18 mmol) and potassium carbonate (5.1 g,
37 mmol) were refluxed in
a
1:1 water/methanol mixture
Compound 18 (0.03 g, 0.07 mmol) was dissolved in 5 mL DMF.
Potassium carbonate (0.02 g, 0.1 mmol) and methyl iodide
(0.013 mL, 0.21 mmol) were added and reaction mixture was stirred
at rt for 6 h. DMF was evaporated and 0.1 N HCl (15 mL) was added.
The crude mixture was extracted with dichloromethane (3ꢃ20 mL).
The combined organic layer was dried and concentrated to yield 19
(0.027 g, 91%), which was used in the next step without further
(150 mL) for 1 h. The methanol was evaporated and the crude
mixture was acidified with 0.1 N HCl. The solution was extracted
with ethyl acetate (3ꢃ100 mL) and dried over sodium sulfate.
Filtration and evaporation of the ethyl acetate extract afforded 15
(5.2 g, 95%) as a yellowish oil. This was used in the next step
without purification: 1H NMR (CDCl3, 500 MHz)
d
7.21 (dd, J¼8,
3 Hz, 1H), 6.97 (dd, J¼8, 3 Hz, 1H), 5.26 (d, J¼2 Hz, 2H), 3.90 (d,
purification: 1H NMR (CDCl3, 500 MHz)
d
7.46 (t, J¼7 Hz, 2H), 7.38 (t,
J¼4 Hz, 3H), 3.88 (d, J¼2 Hz, 3H), 3.76 (q, J¼2 Hz, 2H), 3.64 (s, 2H),
J¼7 Hz, 2H), 7.31 (t, J¼7 Hz,1H), 6.83 (d, J¼9 Hz,1H), 6.78 (d, J¼8 Hz,
1H), 6.75 (s, 1H), 6.64 (s, 1H), 5.14 (s, 2H), 4.20 (d, J¼16 Hz, 1H), 3.88
(s, 3H), 3.85 (s, 6H), 3.53e3.46 (m, 2H), 3.20e3.07 (m, 3H),
1.27e1.21 (m, 3H); 13C NMR (CDCl3, 125 MHz)
d 171.1, 168.8, 150.0,
147.9, 128.3, 126.6, 125.4, 118.5, 93.7, 64.6, 61.7, 52.7, 38.9, 15.1;
HRMS (ESI) m/z calcd for C14H18O7 ([MþNa]þ), 321.0945, found
321.0948.
2.75e2.60 (m, 3H); 13C NMR (CDCl3, 125 MHz)
d 162.7, 152.1, 150.9,
148.0, 147.9, 137.0, 131.7, 128.6, 128.6, 127.9, 127.7, 127.6, 127.3, 127.3,
123.9, 122.0, 118.1, 111.4, 109.1, 71.4, 61.7, 56.2, 55.97, 54.9, 39.3, 38.2,
29.5; HRMS (ESI) m/z calcd for C27H27NO5 ([MþH]þ), 446.1962,
found 446.1968.
4.5. Methyl 6-{20-[(400-(benzyloxy)-300-methoxyphenethyl)
amino]-20-oxoethyl}-3-(ethoxymethoxy)-2-methoxybenzoate
(17)
4.8. ( )-Isocorypalmine [( 1)]
Compound 15 (5.0 g, 17 mmol) was dissolved in 60 mL THF and
stirred at
0
ꢂC for 15 min. 1,10-Carbonyldiimidazole (2.7 g,
Compound 19 (0.02 g, 0.05 mmol) in 5 mL THF was added to
a suspension of lithium aluminum hydride (0.005 g, 0.1 mmol) and
the reaction mixture allowed to heat at reflux for 1 h. The reaction
mixture was allowed to cool to rt and excess of lithium aluminum
hydride was quenched with water. THF was evaporated and the
crude mixture was extracted with dichloromethane (4ꢃ10 mL). The
organic layer was evaporated and the resulting crude product was
refluxed in a mixture of methanol (5 mL) and concentrated
17 mmol) was added portion-wise to the solution at 0 ꢂC and the
mixture allowed to stir at rt for 1 h. A solution of 16 (4.3 g,
17 mmol) in 60 mL THF was added to the above reaction mixture
at 0 ꢂC and allowed to stir overnight at rt. THF was evaporated and
the residue was dissolved in 150 mL dichloromethane and washed
with sodium bicarbonate and 0.1 N HCl consecutively. The organic
layer was dried, filtered, and concentrated in vacuo to afford 17

S. Gadhiya et al. / Tetrahedron 71 (2015) 1227e1231
1231
hydrochloric acid (3 mL) for 3 h. Methanol was evaporated and the
resulting mixture was basified with ammonia solution, and
extracted with dichloromethane (3ꢃ10 mL). The combined organic
layer was dried, filtered, and concentrated to give the crude prod-
uct, which was purified by flash column chromatography on silica
gel (2%e5% MeOH/DCM) to give (ꢀ)-isocorypalmine (0.012 g, 81%);
mp: 216e221 ꢂC (lit.33 219e222 ꢂC); 1H NMR (CDCl3, 500 MHz)
107.5, 100.9, 61.6, 56.9, 56.24, 56.0, 39.4, 28.2; HRMS (ESI) m/z
calcd for C21H21NO5 ([MþH]þ), 368.1492, found 368.1497.
Acknowledgements
This publication was made possible by Grant Numbers
1SC1GM092282 and G12RR003037 from the National Institutes of
Health. Its contents are solely the responsibility of the authors and
do not necessarily represent the official views of the NIH or its
divisions.
d
6.87 (d, J¼8 Hz, 1H), 6.83 (s, 1H), 6.78 (d, J¼8 Hz, 1H), 6.60 (s, 1H),
4.24 (d, J¼16 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 6H), 3.55e3.51 (m, 2H),
3.28e3.14 (m, 3H), 2.81 (dd, J¼16,12 Hz,1H), 2.68e2.61 (m, 2H); 13
C
NMR (CDCl3, 125 MHz)
d 150.2, 145.1, 145.0, 143.9, 130.6, 128.7,
127.9,126.1,123.9,111.3,110.9,110.6, 60.2, 59.2, 55.9, 55.9, 54.0, 51.6,
Supplementary data
36.3, 29.7; HRMS (ESI) m/z calcd for
C
20H23NO4 ([MþH]þ),
342.1700, found 342.1704.
NMR spectra for all new compounds. Supplementary data re-
lated to this article can be found at http://dx.doi.org/10.1016/
j.tet.2015.01.004.
4.9. 2-(Benzyloxy)-10-hydroxy-3,9-dimethoxy-5,6-dihydro-
8H-isoquinolino[3,2-a]isoquinolin-8-one: (21)
References and notes
Compound 17 (0.2 g, 0.4 mmol) and POCl3 (0.28 mL, 3.0 mmol)
were refluxed in 10 mL acetonitrile for 3 h. The solvent was
evaporated and the residue was dissolved in 25 mL DCM. The
resulting solution was washed with sodium bicarbonate and then
dried over sodium sulfate. The organic solvent was removed in
vacuo and the residues were dissolved in 10 mL dry DCM. Trie-
thylamine (1.6 mL, 0.10 mmol) was added to the solution and
allowed to stir at rt for 2 h. The reaction mixture was washed with
0.1 N HCl and extracted with DCM (3ꢃ15 mL). The combined or-
ganic layer was evaporated and concentrated to yield 21 (0.11 g,
70%), which was used in the next step without further purifica-
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d
159.7, 151.0, 147.7, 147.6, 145.5, 136.9, 135.3, 132.2, 129.0, 128.5,
128.5, 127.9, 127.4, 127.4, 122.9, 122.3, 121.1, 118.1, 111.3, 111.0, 101.4,
71.9, 62.6, 56.0, 39.4, 28.2; HRMS (ESI) m/z calcd for C26H23NO5
([MþH]þ), 430.1649, found 430.1652.
4.10. Oxypalmatine (2)
Compound 21 (0.015 g, 0.033 mmol) was refluxed in a mixture
of methanol (10 mL) and concentrated HCl (5 mL) for 3 h. Meth-
anol was evaporated and the resultant mixture was basified with
ammonia solution, and extracted with dichloromethane
(3ꢃ10 mL). The combined organic layer was dried and concen-
trated to give a crude product, which was used in the next step
without further purification. Crude residues were dissolved in
5 mL DMF. Potassium carbonate (0.014 g, 0.10 mmol) and methyl
iodide (0.013 mL, 0.20 mmol) were added and reaction mixture
was stirred at rt for 6 h. DMF was evaporated and 0.1 N HCl
(10 mL) was added. The crude mixture was extracted with
dichloromethane (3ꢃ10 mL). The combined organic layer was
dried the crude product was purified by flash column chroma-
tography on silica gel (1%e3% methanol/dichloromethane) to yield
oxypalmatine (2) (0.01 g, 79%); mp: 178e185 ꢂC (lit.31
181e183 ꢂC); 1H NMR (CDCl3, 500 MHz)
d
7.33 (d, J¼9 Hz, 1H),
7.3 (d, J¼9 Hz, 1H), 7.23 (s, 1H), 6.76 (s, 1H), 6.73 (s, 1H), 4.32 (t,
J¼6 Hz, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 2.93
(t, J¼6 Hz, 2H); 13C NMR (CDCl3, 125 MHz)
d 160.3, 151.4, 150.1,
149.6, 148.4, 135.6, 132.4, 128.5, 122.3, 122.1, 119.4, 118.9, 110.5,