Synthesis of the reported protoberberine gusanlung D

Article abstract of DOI:10.1055/s-0028-1088050

Starting from homopiperonylamine or phenethylamine with homophthalic anhydride or 3,4-methylenedioxyhomophthalic acid, respectively, facile syntheses of the reported structures of (±)-gusanlung D and (±)- isogusanlung D were accomplished via regioselectiv

Full text of DOI:10.1055/s-0028-1088050

PAPER
1667
Synthesis of the Reported Protoberberine Gusanlung D
S
ynthesis of th
r
e
R
epor
a
ted Protobe
s
rberine
G
u
a
sanlung
D
d B. Wakchaure, Srinivasan Easwar, Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India
E-mail: np.argade@ncl.res.in
Received 15 January 2009; revised 21 January 2009
During the past several years, we have been using cyclic
anhydrides as potential precursors for the synthesis of
structurally interesting and biologically important natural
and unnatural products.10 As the unconjugated carbonyl
Abstract: Starting from homopiperonylamine or phenethylamine
with homophthalic anhydride or 3,4-methylenedioxyhomophthalic
acid, respectively, facile syntheses of the reported structures of
( )-gusanlung D and ( )-isogusanlung D were accomplished via
regioselective reductive dehydration of the corresponding homoph- group in the homophthalic anhydride/imide can be regio-
thalimides followed by an intramolecular acid-catalyzed or radical
selectively explored, we reasoned that homophthalic an-
cyclization pathway. Starting from the corresponding suitably
hydride or imide would be the most appropriate building
ortho-halogenated homophthalimides, the syntheses of dehydrogu-
block for the synthesis of protoberberine alkaloids. Herein
sanlung and dehydroisogusanlung D were completed via regiose-
we report a general strategy for the synthesis of protober-
lective reductive dehydration followed by an intramolecular Heck
berine alkaloids starting from homophthalic anhydride or
imide, to synthesize the reported ( )-gusanlung D (1), ( )-
isogusanlung D (3), dehydrogusanlung D (2), and dehy-
droisogusanlung D (4) by three different modes of in-
tramolecular cyclization (Schemes 1 and 2).
coupling reaction as the key steps. The analytical and spectral data
obtained for all four synthetic compounds differed from the report-
ed data for natural gusanlung D, and therefore the structural assign-
ment of the natural product needs to be revised.
Key words: homophthalic anhydride, homopiperonyl amine, re-
ductive dehydration, Heck reaction, gusanlung D
The regioselective ring opening of homophthalic anhy-
dride (6) at the more reactive unconjugated carbonyl with
homopiperonylamine (5) in a diethyl ether–tetrahydrofu-
ran mixture at room temperature exclusively furnished
benzoic acid 7 in 92% yield (Scheme 1). An attempted
preparation of the corresponding isoquinoline-
1,3(2H,4H)-dione 9 by dehydration of 7 induced by acetic
anhydride–sodium acetate resulted instead in the forma-
tion of 3-hydroxyisoquinolin-1(2H)-one 8 bearing an a-
acyl substituent in 76% yield (Scheme 1), formed due to
the highly acidic nature of the a-methylene protons of
such systems. A singlet signal at d = 11.05 and the corre-
sponding absence of a methylene proton signal in the 1H
NMR spectrum of the above product clearly revealed that
the product existed exclusively as the enol 8, which is sta-
bilized by conjugation of the double bond with the carbo-
nyl group and the phenyl ring as well as by intramolecular
hydrogen bonding. Ultimately, acid 7 on treatment with
hexamethyldisilazane–zinc(II) chloride11 gave the desired
Protoberberine alkaloids make up an important class of
natural products that contain a tetracyclic ring skeleton
with an isoquinoline core1 possessing anti-inflammatory,
antimicrobial, antileukemic, and antitumor activities.2
Many elegant achiral and chiral synthetic routes to proto-
berberines have been reported in the literature.2,3 The iso-
lation of (–)-gusanlung
D
(2,3-methylenedioxy-8-
oxoberberine, 1; Scheme 1) from the stem of Acangelisia
gusanlung was reported in 1995 by Zhong et al.; this is the
first optically active protoberberine unoxygenated at ring
D.4 Well before the isolation of gusanlung D, Kesser et al.
from India reported its racemic synthesis via the genera-
tion and trapping of a-oxo-o-quinodimethanes.5 Unfortu-
nately, the analytical and spectral data reported for the
natural and synthetic gusanlung D were not in agreement
with one other.4,5 Padwa and Waterson reported a neat ap-
proach to berberine derivative ( )-1 by taking advantage
of a Pummerer/Mannich-induced cyclization cascade.6
Recently, Reimann et al. reported the synthesis of ( )-gu-
sanlung D from the Reissert compounds.7 Very recently,
Chang and Chang reported the synthesis of ( )-gusanlung
D via dehydrogusanlung D (2; Scheme 1), by taking ad-
vantage of ring-closing metathesis.8 Chrzanowska et al.
reported the first asymmetric synthesis of both (+)- and
(–)-gusanlung D, indicating the possibility of consider-
able contamination of the natural product with dehydro-
gusanlung D (2).9
isoquinoline-1,3(2H,4H)-dione
9
in 90% yield
(Scheme 1).
We envisaged a regioselective reduction of the unconju-
gated carbonyl in imide 9 to provide the corresponding
hydroxylactam, which upon intramolecular cyclization
would provide us with the desired racemic protoberberine
( )-1 (Scheme 1). Interestingly, when we carried out the
sodium borohydride reduction of 9 under the conditions
reported by Speckamp et al.,12 the expected hydroxylac-
tam formed as an intermediate, directly furnishing the iso-
quinolin-1(2H)-one 10 in 72% yield by an in situ
dehydration. The formation of 10 constitutes a formal
synthesis of ( )-gusanlung D (1), since 10 is a known pre-
cursor that can be easily transformed into the protober-
berine, as demonstrated by Padwa and Waterson.6 We
employed their acid-catalyzed cyclization conditions to
SYNTHESIS 2009, No. 10, pp 1667–1672
x
x.
x
x
.
2
0
0
9
Advanced online publication: 20.04.2009
DOI: 10.1055/s-0028-1088050; Art ID: Z00909SS
© Georg Thieme Verlag Stuttgart · New York

1668
P. B. Wakchaure et al.
PAPER
O
O
O
O
O
COOH
O
i
ii
O
HN
O
O
N
NH2+
92%
76%
O
H
O
O
7
O
6
8
5
iii
(90%)
I
O
O
O
iv
vi
O
N
O
O
N
O
N
O
O
O
72%
86%
O
10
9
11
v
68%
viii
vii
78%
63%
I
O
O
O
N
viii
X
ix
72%
O
O
N
O
N
O
O
O
12
dehydrogusanlung D (2)
rac-gusanlung D (1)
Scheme 1 Reagents and conditions: (i) Et2O–THF (4:1), r.t., 2 h (92%); (ii) Ac2O, NaOAc, 60 °C, 3 h (76%); (iii) HMDS, ZnCl2, benzene,
2.5 h (90%); (iv) (a) NaBH4, EtOH, 0 °C, 6 h; (b) H+/HCl, r.t., 12 h (72%); (v) concd HCl, r.t., 48 h (68%); (vi) I2, AgO2CCF3, CHCl3, r.t., 8 h
(86%); (vii) (a) NaBH4, EtOH, 0 °C, 6 h; (b) H+/HCl, r.t., 12 h (78%); (viii) AIBN, Bu3SnH, benzene, reflux, 6 h (63%); (ix) Pd(OAc)2, tetra-
methylguanidine, NaOAc, DMF, 110 °C, 20 h (72%).
convert enamide 10 into ( )-gusanlung D (1) in 68% yield Towards this end, a very selective iodination of imide 9 by
(Scheme 1). However, the analytical and spectral data for iodine–silver trifluoroacetate was used, affording isoquin-
compound 1 synthesized by us did not match those report- oline-1,3(2H,4H)-dione 11 in 86% yield (Scheme 1). As
ed for the isolated natural product, but were in full agree- expected, the sodium borohydride reduction of 11, under
ment with those reported in the earlier syntheses.5–9 the Speckamp et al. conditions as before, furnished iso-
Chrzanowska et al. had opined that the discrepancy could quinolin-1(2H)-one 12 in 78% yield. Compound 12 could
have arisen due to a possible contamination of the isolated potentially serve as a precursor to both ( )-gusanlung D
natural product with a considerable amount of the corre- (1), through an intramolecular radical cyclization, as well
sponding oxidized product dehydrogusanlung D (2),8 as dehydrogusanlung D (2), via an intramolecular Heck
formed during the isolation process. Therefore, we coupling reaction (Scheme 1).13 Unfortunately, our at-
planned to synthesize dehydrolactam 12 by a route that tempts at intramolecular radical cyclization of 12 using
had the potential to deliver ( )-gusanlung D (1) as well.
the standard conditions consisting of azoisobutyronitrile
i
ii
O
N
O
O
N
N
O
X
92%
98%
3
15a
14a
O
O
O
COOH
COOH
O
O
O
O
O
iii
rac-isogusanlung D (3)
80%
13
Br
Br
O
N
O
O
N
O
N
i
ii
iv
94%
98%
74%
14b
15b
O
O
O
O
O
O
dehydroisogusanlung D (4)
Scheme 2 Reagents and conditions: (i) Ph(CH2)2NH2 (for 14a) or 2-BrC6H4(CH2)2NH2 (for 14b), 1,2-dichlorobenzene, 180 °C, 3 h (92/94%);
(ii) (a) NaBH4, EtOH, 0 °C, 6 h; (b) H+/HCl, r.t., 12 h (98%); (iii) AIBN, Bu3SnH, benzene, reflux, 2 h (80%); (iv) Pd(OAc)2, TBAB, K2CO3,
DMF, 120 °C, 24 h (74%).
Synthesis 2009, No. 10, 1667–1672 © Thieme Stuttgart · New York

PAPER
Synthesis of the Reported Protoberberine Gusanlung D
1669
1
and tributyltin hydride failed to deliver the protoberberine Melting points are uncorrected. H NMR spectra of samples in
CDCl3 and DMSO-d6 with TMS as an internal standard were re-
( )-1; we ended up instead with the dehalogenated prod-
uct 10 in 63% yield (Scheme 1). We were, nevertheless,
corded on 200- and 400-MHz spectrometers. 13C NMR spectra were
recorded on 200-, 400- and 500-MHz NMR spectrometers (at 50,
successful in carrying out a palladium(II) acetate–tetra-
100, and 125 MHz, respectively, for 13C). IR spectra were recorded
methylguanidine induced14 intramolecular Heck coupling
on an FT-IR spectrometer. Column chromatographic separations
of isoquinolin-1(2H)-one 12, and obtained the desired de-
hydrogusanlung D (2) in 72% yield (Scheme 1). The ana-
lytical and spectral data obtained for 2 were in complete
agreement with the reported data.8 However, a compari-
son of the analytical and spectral data of compound 2 with
those of gusanlung D (1) and those reported for the iso-
lated natural product ruled out the possibility that the iso-
lated product could have been contaminated with a
considerable amount of 2.
were done on silica gel (60–120, 230–300 mesh). Commercially
available homophthalic anhydride (6), 2-bromophenethylamine,
HMDS, ZnCl2, silver trifluoroacetate, Bu3SnH, and Pd(OAc)2 were
used.
2-(2-{[2-(1,3-Benzodioxol-5-yl)ethyl]amino}-2-oxoethyl)benzo-
ic Acid (7)
A soln of homopiperonylamine (5; 2.48 g, 15.00 mmol) in Et2O (15
mL) was added dropwise over 15 min to a constantly stirring soln
of homophthalic anhydride (6; 2.43 g, 15.00 mmol) in a mixture of
Et2O–THF (4:1, 15 mL). The reaction mixture was stirred for 2 h at
r.t. and the precipitated crystalline product was filtered, washed
with Et2O (30 mL), and dried in vacuo; this gave 7.
Yield: 4.52 g (92%); mp 155–157 °C (Lit.17 158–159 °C).
IR (CHCl3): 3346, 1700, 1694 cm–1.
At this stage, on the basis of the 1H NMR data for reported
natural 1 (a singlet at d = 7.35 for one of the aromatic pro-
tons), we felt that there is a possibility that the isolated
natural product could be the isomeric compound 3 (peri
interaction with the carbonyl group), and we planned to
synthesize both ( )-isogusanlung D (3) and dehydroiso- 1H NMR (200 MHz, DMSO-d6): d = 2.64 (t, J = 7 Hz, 2 H), 3.26 (q,
J = 7 Hz, 2 H), 3.86 (s, 2 H), 5.97 (s, 2 H), 6.65 (dd, J = 8, 2 Hz, 1
gusanlung D (4) (Scheme 2). The thermal double dehy-
H), 6.80 (s, 1 H), 6.82 (d, J = 10 Hz, 1 H), 7.26 (dd, J = 10, 2 Hz, 1
drative condensation of phenethylamine or 2-
H), 7.36 (dt, J = 8, 2 Hz, 1 H), 7.49 (dt, J = 8, 2 Hz, 1 H), 7.86 (dd,
bromophenethylamine with 3,4-methylenedioxyhomoph-
J = 8, 2 Hz, 1 H), 7.98 (t, J = 6 Hz, 1 H).
13C NMR (50 MHz, DMSO-d6): d = 35.2, 40.8, 40.9, 100.9, 108.4,
thalic acid 1315 gave the corresponding imides 14a and
14b, respectively, in high yields (Scheme 2). The regiose-
109.4, 121.9, 127.0, 130.5, 131.6, 131.9 (2 C), 133.6, 137.2, 145.8,
lective reductive dehydration of both the imides 14a and
147.5, 169.0, 170.5.
14b provided the required isoquinolinone derivatives 15a
and 15b, respectively, in 98% yield. All our attempts to
induce acid-catalyzed intramolecular cyclization of 15a to
Anal. Calcd for C18H17NO5: C, 66.05; H, 5.23; N, 4.28. Found: C,
65.96; H, 5.11; N, 4.35.
form ( )-isogusanlung D (3) met with failure, because of
4-Acetyl-2-[2-(1,3-benzodioxol-5-yl)ethyl]-3-hydroxyisoquino-
the absence of any activating group on phenyl ring, re-
quired to force such type of cyclizations. However, treat-
ment of aryl bromide 15b with azoisobutyronitrile–
tributyltin hydride resulted in intramolecular radical cy-
clization,16 to furnish the desired ( )-isogusanlung D (3)
in 74% yield, while Heck coupling of 15b gave the corre-
sponding dehydroisogusanlung D (4) in 80% yield
(Scheme 2). Unfortunately, in this case too, the obtained
analytical and spectral data for 3 and 4 did not match the
data reported for the natural product 1.
lin-1(2H)-one (8)
A stirred mixture of 7 (490 mg, 1.50 mmol) in Ac2O (10 mL) and
fused NaOAc (20 mg, 0.24 mmol) was heated at 60 °C for 3 h. The
mixture was allowed to reach r.t. and was then poured into ice-cold
H2O. The precipitate that formed was filtered, washed with an ex-
cess of H2O, and vacuum-dried; this gave 8.
Yield: 400 mg (76%); mp 112–114 °C.
IR (CHCl3): 3311, 1739, 1648 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.57 (s, 3 H), 2.88 (t, J = 7 Hz, 2
H), 3.73 (app q, J = 7 Hz, 2 H), 5.92 (s, 2 H), 6.60–6.80 (m, 3 H),
7.10–7.25 (m, 1 H), 7.50–7.70 (m, 2 H), 8.16 (d, J = 8 Hz, 1 H),
11.05 (bs, 1 H).
13C NMR (50 MHz, CDCl3): d = 31.0, 35.5, 42.7, 92.4, 100.8, 108.2,
108.9, 114.8, 121.6, 123.3, 123.4, 130.2, 131.5, 134.8, 138.7, 146.2,
147.7, 158.6, 160.9, 194.2.
In summary, we have developed a general approach to
protoberberine alkaloids starting from homophthalic an-
hydride, and accomplished a facile synthesis of the
claimed gusanlung D and isogusanlung D via an efficient
regioselective reductive dehydration followed by acid-
catalyzed or radical-induced intramolecular cyclizations,
respectively. Similarly, the synthesis of the corresponding
dehydrogusanlung D and dehydroisogusanlung D were
completed by taking advantage of an elegant intramolec-
ular Heck coupling reaction. Unfortunately, the analytical
and spectral data obtained for all four berberine analogues
did not concur with the reported data of the natural prod-
uct. At this point, we feel that revision of the reported
structural assignment of gusanlung D needs to be under-
taken, and that it would be more appropriate to re-estab-
lish the actual structure of the natural product gusanlung
D on the basis of X-ray crystallographic analysis.
Anal. Calcd for C20H17NO5: C, 68.37; H, 4.88; N, 3.99. Found: C,
68.57; H, 4.93; N, 4.05.
2-[2-(1,3-Benzodioxol-5-yl)ethyl]isoquinoline-1,3(2H,4H)-di-
one (9)
To a stirred suspension of 7 (3.92 g, 12.00 mmol) in anhyd benzene
(30 mL) was added ZnCl2 (1.64 g, 12.00 mmol) and the mixture was
heated at 80 °C. To this mixture was slowly added a soln of HMDS
(3.75 mL, 18.00 mmol) in anhyd benzene (15 mL) over 20 min. The
mixture was refluxed for an additional 2 h, then cooled to r.t. and
poured into 1 N HCl (30 mL). The aqueous phase was extracted
with EtOAc (3 × 30 mL) and the combined organic layer was
washed with 5% aq NaHCO3 (3 × 20 mL) and brine (25 mL), and
dried (Na2SO4). Concentration of the organic layer in vacuo fol-
Synthesis 2009, No. 10, 1667–1672 © Thieme Stuttgart · New York

1670
P. B. Wakchaure et al.
PAPER
lowed by purification of the residue by column chromatography
(silica gel, PE–EtOAc, 4:1) gave pure 9.
2-[2-(6-Iodo-1,3-benzodioxol-5-yl)ethyl]isoquinolin-1(2H)-one
(12)
Compound 12 was prepared from 11 (1.09 g, 2.51 mmol) by the
same procedure as described above for the preparation of 10 from 9.
Yield: 3.34 g (90%); mp 158–159 °C (Lit.17 156–157 °C).
IR (CHCl3): 1709, 1662, 1607 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.75–2.90 (m, 2 H), 4.03 (s, 2 H),
4.05–4.25 (m, 2 H), 5.92 (s, 2 H), 6.65–6.85 (m, 3 H), 7.28 (d, J = 8
Hz, 1 H), 7.45 (t, J = 8 Hz, 1 H), 7.60 (dt, J = 8, 2 Hz, 1 H), 8.22 (d,
J = 8 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 33.7, 36.3, 41.6, 100.7, 108.1,
109.3, 121.7, 125.2, 127.0, 127.6, 129.0, 132.2, 133.5, 134.0, 146.0,
147.5, 164.6, 169.7.
Yield: 819 mg (78%); mp 165–167 °C.
IR (CHCl3): 1651, 1626, 1599 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.14 (t, J = 8 Hz, 2 H), 4.15 (t,
J = 8 Hz, 2 H), 5.94 (s, 2 H), 6.43 (d, J = 8 Hz, 1 H), 6.75 (s, 1 H),
6.94 (d, J = 6 Hz, 1 H), 7.24 (s, 1 H), 7.40–7.70 (m, 3 H), 8.46 (dd,
J = 8, 2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 39.6, 49.6, 87.8, 101.6, 105.9,
110.2, 118.6, 125.9, 126.1, 126.8, 127.7, 131.7, 132.1, 134.0, 137.0,
147.4, 148.7, 162.1.
Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C,
70.02; H, 4.81; N, 4.59.
Anal. Calcd for C18H14INO3: C, 51.57; H, 3.37; N, 3.34. Found: C,
51.42; H, 3.48; N, 3.29.
2-[2-(1,3-Benzodioxol-5-yl)ethyl]isoquinolin-1(2H)-one (10)
Excess NaBH4 (304 mg, 8.00 mmol) was added to a stirred soln of
9 (309 mg, 1.00 mmol) in EtOH (10 mL) at 0 °C. The mixture was
stirred under inert atmosphere for 6 h at 0 °C while 2–3 drops of 2
N HCl in EtOH were added at intervals of 20 min. The excess of
NaBH4 was then quenched at 0 °C by the addition of 2 N HCl in
EtOH until the mixture was acidic (pH 3). The mixture was then al-
lowed to warm to r.t. and stirred for a further 12 h. The EtOH was
removed by distillation under reduced pressure, the residue was di-
luted with H2O (20 mL), and the mixture was extracted with EtOAc
(3 × 25 mL). The combined organic layer was washed with H2O (20
mL), 5% aq NaHCO3 (20 mL), and brine (20 mL) and dried
(Na2SO4). Concentration of the organic layer in vacuo followed by
purification of the residue by column chromatography (silica gel,
PE–EtOAc, 4:1) gave 10.
6-Phenethyl[1,3]dioxolo[4,5-g]isoquinoline-5,7(6H,8H)-dione
(14a)
A stirring soln of Ph(CH2)2NH2 (108 mg, 0.89 mmol) and 13 (200
mg, 0.89 mmol) in 1,2-dichlorobenzene (10 mL) was refluxed at
180 °C for 3 h. After the mixture had cooled to r.t., it was loaded on
a silica gel column [PE (removal of 1,2-dichlorobenzene), then PE–
EtOAc, 4:1]; this furnished 14a as a yellow crystalline solid.
Yield: 253 mg (92%); mp 110–112 °C.
IR (CHCl3): 1711, 1665, 1622 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.84–2.96 (m, 2 H), 3.91 (s, 2 H),
4.12–4.23 (m, 2 H), 6.07 (s, 2 H), 6.65 (s, 1 H), 7.16–7.34 (m, 5 H),
7.59 (s, 1 H).
Yield: 211 mg (72%); mp 87–88 °C (Lit.6 90–91 °C).
IR (CHCl3): 1649, 1626 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.00 (t, J = 8 Hz, 2 H), 4.16 (t,
J = 8 Hz, 2 H), 5.93 (s, 2 H), 6.39 (d, J = 8 Hz, 1 H), 6.60–6.75 (m,
3 H), 6.81 (d, J = 8 Hz, 1 H), 7.40–7.55 (m, 2 H), 7.55–7.70 (m, 1
H), 8.45 (d, J = 8 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 34.9, 51.6, 100.8, 105.6, 108.3,
109.2, 121.8, 125.8, 126.1, 126.6, 127.6, 131.9 (2 C), 132.0, 137.0,
146.2, 147.7, 161.9.
13C NMR (50 MHz, CDCl3): d = 34.0, 36.4, 41.4, 102.0, 106.3,
107.8, 119.4, 126.4, 128.4, 128.9, 130.3, 138.6, 147.7, 152.5, 164.0,
169.7.
Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89; N, 4.53. Found: C,
70.02; H, 4.63; N, 4.40.
6-Phenethyl[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one (15a)
Compound 15a was prepared from 14a (150 mg, 0.49 mmol) by the
same procedure as described above for the preparation of 10 from 9.
Yield: 139 mg (98%); mp 107–109 °C.
IR (CHCl3): 1657, 1620, 1606 cm–1.
Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C,
73.59; H, 5.22; N, 4.59.
1H NMR (200 MHz, CDCl3): d = 3.07 (t, J = 8 Hz, 2 H), 4.18 (t,
J = 8 Hz, 2 H), 6.07 (s, 2 H), 6.25 (d, J = 8 Hz, 1 H), 6.70 (d, J = 8
Hz, 1 H), 6.82 (s, 1 H), 7.14–7.34 (m, 5 H), 7.80 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 35.3, 51.5, 101.6, 103.6, 105.5,
105.6, 121.7, 126.5, 128.6, 128.9, 130.7, 134.3, 138.3, 147.8, 151.7,
161.2.
2-[2-(6-Iodo-1,3-benzodioxol-5-yl)ethyl]isoquinoline-
1,3(2H,4H)-dione (11)
I2 (775 mg, 3.05 mmol) was added in small portions over 15 min to
a stirring soln of 9 (943 mg, 3.05 mmol) and AgO2CCF3 (674 mg,
3.05 mmol) in anhyd CHCl3 (15 mL). The mixture was stirred for a
further 8 h at r.t. The mixture was filtered, washed with CH2Cl2 (25
mL) and the filtrate was washed with 5% aq Na2S2O3 (10 mL), H2O
(20 mL), and brine (25 mL) and dried (Na2SO4). Concentration of
the organic layer in vacuo followed by purification of the residue by
column chromatography (silica gel, PE–EtOAc, 4:1) gave 11.
Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C,
73.68; H, 5.11; N, 4.97.
6-(2-Bromophenethyl)[1,3]dioxolo[4,5-g]isoquinoline-
5,7(6H,8H)-dione (14b)
Compound 14b was prepared from 2-BrC6H4(CH2)2NH2 (446 mg,
2.23 mmol) and 13 (500 mg, 2.23 mmol) by the same procedure as
described above for the preparation of 14a from 13 and
Ph(CH2)2NH2.
Yield: 1.14 g (86%); mp 217–219 °C.
IR (CHCl3): 1701, 1668, 1609 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.90–3.10 (m, 2 H), 4.04 (s, 2 H),
4.10–4.25 (m, 2 H), 5.95 (s, 2 H), 6.85 (s, 1 H), 7.22 (s, 1 H), 7.25–
7.35 (m, 1 H), 7.45 (t, J = 8 Hz, 1 H), 7.60 (dt, J = 8, 2 Hz, 1 H),
8.22 (dd, J = 8, 2 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 36.4, 38.6, 40.2, 87.7, 101.5, 109.7,
118.6, 125.3, 127.1, 127.7, 129.1, 133.6, 134.1, 135.0, 147.2, 148.5,
164.7, 169.8.
Yield: 814 mg (94%); mp 134–136 °C.
IR (CHCl3): 1709, 1665, 1657, 1649, 1618 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.00–3.15 (m, 2 H), 3.90 (s, 2 H),
4.15–4.30 (m, 2 H), 6.06 (s, 2 H), 6.65 (s, 1 H), 7.00–7.32 (m, 3 H),
7.53 (dd, J = 8, 2 Hz, 1 H), 7.58 (s, 1 H).
Anal. Calcd for C18H14INO4: C, 49.68; H, 3.24; N, 3.22. Found: C,
49.53; H, 3.15; N, 3.10.
Synthesis 2009, No. 10, 1667–1672 © Thieme Stuttgart · New York

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Synthesis of the Reported Protoberberine Gusanlung D
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13C NMR (50 MHz, CDCl3): d = 34.1, 36.4, 39.6, 102.0, 106.3,
107.7, 119.3, 124.6, 127.4, 128.1, 130.2, 130.9, 132.7, 138.2, 147.6,
152.4, 163.9, 169.7.
H), 7.43 (t, J = 8 Hz, 1 H), 7.53 (d, J = 8 Hz, 1 H), 7.62 (t, J = 8 Hz,
1 H), 8.41 (d, J = 8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 28.5, 39.7, 101.5, 101.9, 105.0,
107.9, 123.7, 124.6, 126.0, 126.3, 127.9, 130.3, 132.3, 136.6, 137.4,
147.4, 148.7, 162.1.
Anal. Calcd for C18H14BrNO4: C, 55.69; H, 3.63; N, 3.61. Found: C,
55.55; H, 3.47; N, 3.80.
Anal. Calcd for C18H13NO3: C, 74.22; H, 4.50; N, 4.81. Found: C,
74.31; H, 4.47; N, 4.96.
6-(2-Bromophenethyl)[1,3]dioxolo[4,5-g]isoquinolin-5(6H)-one
(15b)
Compound 15b was prepared from 14b (600 mg, 1.54 mmol) by the
same procedure as described above for the preparation of 10 from 9.
5,6,14,14a-Tetrahydro-8H-[1,3]dioxolo[4,5-g]isoquino[2,1-
b]isoquinolin-8-one [( )-Isogusanlung D, 3]
Yield: 563 mg (98%); mp 153–155 °C.
IR (CHCl3): 1655, 1618, 1605 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.23 (t, J = 8 Hz, 2 H), 4.22 (t,
J = 8 Hz, 2 H), 6.08 (s, 2 H), 6.27 (d, J = 6 Hz, 1 H), 6.76 (d, J = 6
Hz, 1 H), 6.83 (s, 1 H), 7.04–7.21 (m, 3 H), 7.56 (d, J = 8 Hz, 1 H),
7.81 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 35.3, 49.2, 101.5, 103.5, 105.3,
105.5, 121.5, 124.3, 127.6, 128.3, 130.5, 131.3, 132.7, 134.2, 137.4,
147.6, 151.5, 161.1.
A soln of Bu3SnH (0.3 mL, 1.07 mmol) and AIBN (9 mg, 0.05
mmol) in benzene (5 mL) was added dropwise over 5 min to a con-
stantly stirring, refluxing soln of 15b (200 mg, 0.53 mmol) in ben-
zene (10 mL) under a N2 atmosphere. The mixture was refluxed for
an additional 2 h. Then the mixture was cooled to r.t. and the ben-
zene solvent was removed in vacuo. The residue thus obtained was
then dissolved in MeCN (20 mL) and washed with n-hexane (3 × 25
mL). Concentration of the MeCN layer in vacuo followed by puri-
fication of the residue by column chromatography (silica gel, PE–
EtOAc, 7:3) furnished pure 3 as a white crystalline solid.
Yield: 116 mg (74%); mp 157–159 °C.
IR (CHCl3): 1639, 1611 cm–1.
Anal. Calcd for C18H14BrNO3: C, 58.08; H, 3.79; N, 3.76. Found: C,
57.94; H, 3.65; N, 3.69.
1H NMR (400 MHz, CDCl3): d = 2.80–3.07 (m, 4 H), 3.14 (dd,
J = 12, 4 Hz, 1 H), 4.84–5.00 (m, 2 H), 6.02 (d, J = 4 Hz, 2 H), 6.69
(s, 1 H), 7.15–7.35 (m, 4 H), 7.59 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 29.6, 37.7, 38.5, 55.1, 101.4, 106.7,
108.3, 123.1, 125.8, 126.6, 126.7, 128.9, 132.8, 134.9, 135.7, 146.9,
150.4, 164.1.
5,6,13,13a-Tetrahydro-8H-[1,3]dioxolo[4,5-g]isoquino[3,2-
a]isoquinolin-8-one [( )-Gusanlung D, 1]
A soln of 10 (147 mg, 0.50 mmol) in concd HCl (5 mL) was stirred
at r.t. for 48 h. The mixture was then diluted with ice water (20 mL)
and extracted with EtOAc (3 × 10 mL). The combined organic layer
was washed successively with 5% aq NaHCO3 (20 mL) and brine
(20 mL) and dried (Na2SO4). Concentration of the organic layer in
vacuo followed by purification of the residue by column chroma-
tography (silica gel, PE–EtOAc, 4:1) gave ( )-gusanlung D (1).
Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C,
73.57; H, 5.05; N, 4.66.
Yield: 100 mg (68%); mp 194–196 °C [Lit.4 250–251 °C (natural),
5,6-Dihydro-8H-[1,3]dioxolo[4,5-g]isoquino[2,1-b]isoquinolin-
8-one (Dehydroisogusanlung D, 4)
Lit.9 195–197 °C (synthetic)].
K2CO3 (438 mg, 3.18 mmol), TBAB (346 mg, 1.07 mmol), and
Pd(OAc)2 (11 mg, 10 mol%) were added to a stirred soln of 15b
(200 mg, 0.53 mmol) in DMF (10 mL) at r.t. under a N2 atmosphere.
Then the mixture was heated at 120 °C for 24 h, before it was cooled
to r.t. and diluted with EtOAc (20 mL), washed with brine, and fi-
nally dried (Na2SO4). Concentration of the organic layer in vacuo
followed by purification of the residue by column chromatography
(silica gel, PE–EtOAc, 7:3) furnished compound 4 as a yellow crys-
talline solid.
IR (CHCl3): 1647 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.70–2.80 (m, 1 H), 2.85–3.05 (m,
3 H), 3.18 (dd, J = 16, 4 Hz, 1 H), 4.83 (dd, J = 13, 4 Hz, 1 H), 4.90–
5.00 (m, 1 H), 5.96 (s, 2 H), 6.67 (s, 1 H), 6.72 (s, 1 H), 7.24 (d, J = 8
Hz, 1 H), 7.39 (t, J = 8 Hz, 1 H), 7.46 (t, J = 8 Hz, 1 H), 8.13 (d,
J = 8 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 29.7, 38.1, 38.8, 55.3, 101.1,
105.9, 108.7, 126.9, 127.3, 128.5, 128.6, 128.9, 129.1, 131.8, 137.2,
146.6, 146.8, 164.6.
Yield: 125 mg (80%); mp 174–175 °C.
IR (CHCl3): 1649, 1605 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.95–3.05 (m, 2 H), 4.30–4.40 (m,
2 H), 6.07 (s, 2 H), 6.91 (s, 2 H), 7.20–7.40 (m, 3 H), 7.70–7.80 (m,
1 H), 7.79 (s, 1 H).
13C NMR (50 MHz, CDCl3): d = 28.2, 39.3, 101.4, 102.5, 103.5,
105.3, 120.2, 124.4, 127.1, 127.7, 128.8, 129.8, 133.5, 134.8, 135.8,
147.4, 151.5, 160.9.
Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C,
73.56; H, 5.28; N, 4.81.
5,6-Dihydro-8H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-
8-one (Dehydrogusanlung D, 2)
A soln of Pd(OAc)2 (0.5 mg, 0.25 mol%) and tetramethylguanidine
(1 mg, 1 mol%) in DMF (10 mL) was added to an argon-flushed
flask containing 12 (335 mg, 0.80 mmol) and NaOAc (98.5 mg,
1.20 mmol), and the mixture was stirred at 120 °C for 20 h. After
cooling to r.t., the mixture was poured into H2O (20 mL) and ex-
tracted with EtOAc (3 × 25 mL). The combined organic layer was
washed with brine (20 mL) and dried (Na2SO4). Concentration of
the organic layer in vacuo followed by purification of the residue by
column chromatography (silica gel, PE–EtOAc, 4:1) furnished 2.
Anal. Calcd for C18H13NO3: C, 74.22; H, 4.50; N, 4.81. Found: C,
74.37; H, 4.42; N, 4.89.
Acknowledgement
P.B.W. thanks CSIR, New Delhi and S.E. thanks UGC, New Delhi
for the awards of research fellowships. N.P.A. thanks Department
of Science and Technology, New Delhi, for financial support. We
thank Professor Albert Padwa for providing us the experimental de-
tails for the synthesis of ( )-1.
Yield: 168 mg (72%); mp 181–182 °C (Lit.8 183–184 °C).
IR (CHCl3): 1715, 1645, 1616 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.91 (t, J = 6 Hz, 2 H), 4.33 (t,
J = 6 Hz, 2 H), 6.01 (s, 2 H), 6.71 (s, 1 H), 6.83 (s, 1 H), 7.25 (s, 1
Synthesis 2009, No. 10, 1667–1672 © Thieme Stuttgart · New York

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P. B. Wakchaure et al.
PAPER
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Synthesis 2009, No. 10, 1667–1672 © Thieme Stuttgart · New York