Total synthesis of oxyfagaronine, phenolic benzo[c]phenanthridine and general synthetic way of 2,3,7,8- and 2,3,8,9-tetrasubstituted benzo[c]phenanthridine alkaloids

Article abstract of DOI:10.1248/cpb.54.476

Benzo[c]phenanthridine alkaloids such as oxynitidine, oxysanguinarine, oxyavicine and phenolic oxyfagaronine were synthesized from easily available starting benzonitriles 5 and toluamides 6 using a lithiated toluamidebenzonitrile cycloaddition reaction. T

Full text of DOI:10.1248/cpb.54.476

476
Chem. Pharm. Bull. 54(4) 476—480 (2006)
Vol. 54, No. 4
Total Synthesis of Oxyfagaronine, Phenolic Benzo[c]phenanthridine and
General Synthetic Way of 2,3,7,8- and 2,3,8,9-Tetrasubstituted
Benzo[c]phenanthridine Alkaloids
Thanh Nguyen LE and Won-Jea CHO*
College of Pharmacy and Research Institute of Drug Development, Chonnam National University; Yong-Bong dong, Buk-
gu, Kwangju 500–757, South Korea. Received September 30, 2005; accepted December 5, 2005
Benzo[c]phenanthridine alkaloids such as oxynitidine, oxysanguinarine, oxyavicine and phenolic oxyfagaro-
nine were synthesized from easily available starting benzonitriles 5 and toluamides 6 using a lithiated toluamide-
benzonitrile cycloaddition reaction. The coupling reaction provided 3-arylisoquinolinones that were transformed
to the benzo[c]phenanthridones. This method is highly efficient and could be useful for preparing diverse substi-
tuted aromatic benzo[c]phenanthridine compounds on a multi gram scale.
Key words oxyfagaronine; oxynitidine; oxysanguinarine; oxyavicine; benzo[c]phenanthridine; cycloaddition
Benzo[c]phenanthridines are isoquinoline alkaloids, many Results and Discussion
of which have various biological activities.1—4) Sanguinarine
The benzonitriles 5a, b were easily prepared from the ac-
displays antibacterial5,6) and antifungal7) activities while niti- etal bromides in four steps. For the synthesis of oxyfagaro-
dine and fagaronine have been investigated as potential anti- nine, the hydroxyl group at ring A was protected by benzyl
tumor and antiviral agents.8—12) Hence, much attention has group. The bromides 1a, b were converted to benzonitriles
been focused on the development of facile synthetic method- 2a, b in 67% and 81% yield, respectively. The Resenmund-
ology of benzo[c]phenanthridines.3,13—16) The approaches to von Braun reaction was performed using DMF instead of
these alkaloids via 3-arylisoquinoline intermediates such as pyridine as a solvent.25) The acetal groups of 2a, b were re-
homophthalic ester and homophthalic-imine condensation,17) moved by 5% HCl to afford aldehydes 3a, b, which were then
phenyl ethyl isocyanate cyclization18) and imine-toluamide19) reduced with NaBH4. Alcohol groups were protected by
condensation were reported. However, the limited application MOM group to provide the desired benzonitriles 5a, b in ex-
of diverse substitutions on the aromatic rings of benzo[c]- cellent yields as outlined in Chart 2.
phenanthridine is a barrier for broadening the utility of these
methods.
For the synthesis of oxysanguinarine, oxyavicine, and
oxynitidine, the substituted N,N-diethyl o-toluamides 6a—
We have synthesized the benzo[c]phenanthridine skele- c24) were deprotonated with n-BuLi and then treated with
ton20,21) and recently reported the preliminary synthesis of benzonitrile 5a. In this cycloaddition reaction, the starting N-
benzo[c]phenanthridine alkaloids, including oxynitidine, methyl o-toluamide was modified to N,N-diethyl toluamides
oxysanguinarine22) and oxychelerythrine.23) An alternative because the coupling reaction with benzonitriles that were
method to benzo[c]phenanthridine and protoberberine alka- protected with benzyl or methoxybenzyl gave lower yields
loids was also documented.24) Both syntheses involved the due to a weak solubility in THF. The cycloaddition reaction
cycloaddition reaction of lithiated o-toluamides with ben- between N,N-diethyl toluamides 6a—c and MOM-protected
zonitriles to prepare substituted 3-arylisoquinolinones, which
could be transformed to benzo[c]phenanthridine alkaloids
via an intramolecular enamide ring formation reaction. The
advantage of this our strategy is easy access to the starting
materials, which will be useful for preparing alkaloids with
various substituents. Here we report our progress in synthe-
sizing oxynitidine, oxysanguinarine, oxyavicine, and pheno-
Chart 1. Retrosynthetic Pathway of Benzo[c]phenanthridines
lic oxyfagaronine using the former procedure (Fig. 1).
Retrosynthetic consideration of benzo[c]phenanthridine
shows that the coupling of benzonitrile with o-toluamide
might produce 3-arylisoquinolinone, which could be con-
verted to an aldehyde. One more C extension can be intro-
duced by the Wittig reaction and the B ring of benzo[c]-
phenanthridine could be constructed by an intramolecular
ring closure as shown in Chart 1.
Fig. 1. Structure of Benzo[c]phenanthridine Alkaloids
Chart 2. Synthesis of Benzonitriles 5a, b
© 2006 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: wjcho@jnu.ac.kr

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477
Chart 3. Synthesis of Oxysanguinarine, Oxyavicine, Oxynitidine, and Oxyfagaronine
benzonitrile 5a produced 3-arylisoquinolinones 7a—c in tween toluamide 6c and benzonitrile 5b was carried out to
50—59% yield. These compounds were treated with MeI in give 3-arylisoquinolinone 7d in 30% yield. The consecutive
the presence of 60% NaH to give compounds 8a—c. The N-methylation, deprotection with 10% HCl, oxidation with
MOM group was removed by reflux with 10% HCl and the PDC, and the Wittig reaction followed by hydrolysis pro-
obtained alcohols were oxidized with PDC to afford aldehy- duced the benzo[c]phenanthridine compound 13d. Since
des 10a—c. The Wittig reactions were carried out with these compound 13d was converted to fagaronine29) we have ac-
aldehydes to yield mixture of cis/trans isomers. Without sep- complished the formal synthesis of fagaronine. The oxyfaga-
arating the cis/trans mixture of 11a—c, they were hydrolyzed ronine 14 was easily prepared from compound 13d by a hy-
with 10% HCl to give natural benzo[c]phenanthridines: oxy- drogenation reaction in the presence of 5% Pd/C, which was
sanguinarine (13a), oxyavicine (13b) and oxynitidine (13c) identical with the authentic sample provided by Prof. T.
in 75—89% yield. We postulated that acidic hydrolysis of the Ishikawa.30)
terminal methoxy vinyl group yielded the aldehyde and the
consecutive intramolecular enamide-aldehyde cyclization Conclusion
also occurred to form the B ring of benzo[c]phenanthridones
In conclusion, we succeeded in synthesizing four natural
as shown in Chart 3.26,27) The consecutive dehydration and benzo[c]phenanthridine alkaloids with diverse substituted
deprotonation reaction of intermediates 12a—c would easily patterns. The present synthesis shows that our method could
occur thus producing a fully aromatized ring system of be applied for the synthesis of both 2,3,7,8- and 2,3,8,9-sub-
benzo[c]phenanthridines 13a—c. Oxysanguinarine (13a), stituted alkaloids including phenolic alkaloid. This method-
which is a 2,3,7,8-tetraoxygenated alkaloid was prepared in ology could be applied to the synthesis of other substituted
20.7% overall yield and the 2,3,8,9-tetraoxygenated alka- aromatized benzo[c]phenanthridines and would provide sim-
loids, oxyavicine (13b) and oxynitidine (13c), were obtained ple multi-gram scale preparation of these compounds.
in 20.5% and 19.6% overall yield, respectively.
Experimental
We chose phenolic benzo[c]phenanthridine, fagaronine, as
a next target to determine the generality of our method. Faga-
Melting points were determined on an Electrothermal IA9200 melting
point apparatus and are uncorrected. Nuclear magnetic resonance spectra
(1H-NMR) were recorded on a Varian 300 spectrometer, using TMS as the
internal standard; chemical shifts are reported in parts per million and sig-
nals are quoted as s (singlet), d (doublet), t (triplet), q (quartet), and m (mul-
tiplet). IR spectra were recorded on a Perkin-Elmer 783 spectrometer and a
Nicolet instrument using KBr pellets. Mass spectra were analyzed on Varian
MS 1200. Elemental analyses were performed on a CaHo Erba elemental
analyzer. Solvents were routinely distilled prior to use. Anhydrous THF was
distilled from sodium-benzophenone. Column chromatography was per-
ronine contains a hydroxyl group at ring A, which made the
total synthesis of this alkaloids more difficult because a suit-
able protective group was needed.28) In our approach, the
phenol was protected with a conventional benzyl group29)
and benzonitrile 5b was obtained from the starting material
1b in 55% overall yield.
For the synthesis of fagaronine, the coupling reaction be-

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Vol. 54, No. 4
formed on Merck silica gel 60 (70—230 mesh). TLC was carried out using
plates coated with silicagel 60F 254 purchased from Merck Co. Reagents
of o-toluamide 6 (4.7 mmol) and benzonitrile 5 (5.4 mmol) in dry THF
(10 ml) were added drop-wise. The reaction mixture was stirred at the same
were obtained from commercial suppliers and were used without purifica- temperature for 4 h. The reaction solution was quenched with water and ex-
tion. tracted and dried over sodium sulfate. After removing the solvent, the
6-[1,3]Dioxolan-2-yl-benzo[1,3]dioxole-5-carbonitrile (2a) A mixture residue was separated by column chromatography with n-hexane–ethyl ac-
of 6-bromopiperonal ethylene acetal25) (15 g, 55 mmol), CuCN (5.91 g,
66 mmol) in DMF (20 ml) was refluxed for 3 h. The hot and dark reaction
etate (1 : 1) to afford compound 7.
7-(6-Methoxymethoxymethylbenzo[1,3]dioxol-5-yl)-8H-[1,3]diox-
mixture was poured into a warm solution of sodium cyanide (10 g) in water. olo[4,5-h]isoquinolin-9-one (7a) Yellow solid (59%). mp 151—153 °C;
After the mixture was shaken well, the mixture was extracted with benzene IR (KBr) cmꢀ1: 3400 (NH), 1665 (CO). 1H-NMR (300 MHz, CDCl3) d: 9.38
(60 ml). The combined extract was concentrated and purified by column (s, 1H), 7.18 (d, Jꢂ8.2 Hz, 1H), 7.04 (d, Jꢂ8.2 Hz, 1H), 6.94 (s, 1H), 6.93
chromatography to give benzonitrile compound 2a as a white needles (8.3 g, (s, 1H), 6.39 (s, 1H), 6.23 (s, 2H), 6.04 (s, 2H), 4.77 (s, 2H), 4.45 (s, 2H),
1
67%). mp 92—93 °C. IR (cmꢀ1): 2220 (CN). H-NMR (CDCl3) d: 7.07 (s,
3.51 (s, 3H). EI-MS: m/z 383 (Mꢁ, 17). Anal. Calcd for C20H17 NO7: C,
62.66; H, 4.47; N, 3.65. Found: C, 62.36; H, 4.46; N, 3.68.
1H); 7.05 (s, 1H); 6.08 (s, 2H); 5.92 (s, 1H); 4.23—4.05 (m, 4H).
4-Benzyloxy-2-[1,3]dioxolan-2-yl-5-methoxybenzonitrile (2b) The pro-
cedure described for compound 2a was used with acetal 1b (9.1 g, 25 mmol),
CuCN (2.7 g, 30 mmol) in DMF (20 ml) to afford compound 5b as a bright
yellow solid (6.3 g, 81%). mp 142—144 °C. IR (cmꢀ1): 2220 (CN). 1H-
7-(6-Methoxymethoxymethylbenzo[1,3]dioxol-5-yl)-6H-[1,3]diox-
olo[4,5-g]isoquinolin-5-one (7b) Solid (56%). mp 183—185 °C. IR (KBr)
1
cmꢀ1: 3400 (NH), 1657 (CO). H-NMR (300 MHz, CDCl3) d: 9.68 (s, 1H),
7.75 (s, 1H), 6.96 (s, 1H), 6.95 (s, 1H), 6.89 (s, 1H), 6.41 (s, 1H), 6.09 (s,
NMR (CDCl3) d 7.43—7.33 (m, 5H), 7.13 (s, 3H), 7.12 (s, 1H); 5.92 (s, 2H), 6.04 (s, 2H), 4.78 (s, 2H), 4.46 (s, 2H), 3.42 (s, 3H). EI-MS: m/z 383
1H), 5.19 (s, 2H), 4.19—4.05 (m, 4H), 3.90 (s, 3H). EI-MS: m/z 311 (Mꢁ, (Mꢁ, 12). Anal. Calcd for C20H17NO7: C, 62.66; H, 4.47; N, 3.65. Found: C,
100). Anal. Calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C, 62.78; H, 4.37; N, 3.78.
69.74; H, 5.30; N, 4.55.
6,7-Dimethoxy-3-(6-methoxymethoxymethylbenzo[1,3]dioxol-5-yl)-
6-Formylbenzo[1,3]dioxole-5-carbonitrile (3a) The cyano acetal 2a
(8.3 g, 37 mmol) in 5% HCl (25 ml) was warmed at 50—60 °C for 15 min.
The solid was collected, washed with water and dried to give aldehyde 3a as
a pale yellow solid (6.57 g, 100%). mp 160—162 °C. IR (cmꢀ1): 2230 (CN).
1H-NMR (CDCl3) d: 10.24 (s, 1H), 7.44 (s, 1H), 7.44 (s, 1H), 6.20 (s, 2H).
2H-isoquinolin-1-one (7c) Yellow solid (50%). mp 151—154.5 °C. IR
(KBr) cmꢀ1: 3400 (NH), 1657 (CO). 1H-NMR (300 MHz, CDCl3) d: 9.62 (s,
1H), 7.78 (s, 1H), 6.97 (s, 1H), 6.95 (s, 1H), 6.92 (s, 1H), 6.44 (s, 1H), 6.06
(s, 2H), 4.80 (s, 2H), 4.46 (s, 2H), 4.02 (s, 3H), 4.01 (s, 3H), 3.44 (s, 3H).
EI-MS: m/z 399 (Mꢁ, 75). Anal. Calcd for C21H21NO7: C, 63.15; H, 5.30; N,
4-Benzyloxy-2-formyl-5-methoxybenzonitrile (3b) The procedure de- 3.51. Found: C, 63.35; H, 5.25; N, 3.43.
scribed for aldehyde 3a was used with acetal 2b (5.6 g, 18 mmol) in 5% HCl
3-(4-Benzyloxy-5-methoxy-2-methoxymethoxymethylphenyl)-6,7-
(25 ml) to give aldehyde 3b as a pale yellow solid (4 g, 83%). mp 153— dimethoxy-2H-isoquinolin-1-one (7d) Yellow oil (30%). IR (cmꢀ1): 3400
1
156 °C. IR (cmꢀ1): 2230 (CN). H-NMR (CDCl3) d: 10.23 (s, 1H), 7.54 (s, (NH), 1657 (CO). 1H-NMR (300 MHz, CDCl3) d: 9.85 (s, 1H), 7.77 (s, 1H),
1H), 7.46—7.36 (m, 5H), 7.19 (s, 1H); 5.24 (s, 2H), 3.99 (s, 3H). EI-MS:
7.48—7.32 (m, 5H), 7.00 (s, 1H), 6.93 (s, 1H), 6.86 (s, 1H), 6.50 (s, 1H),
m/z 267 (Mꢁ, 100). Anal. Calcd for C16H13NO3: C, 71.90; H, 4.90; N, 5.24. 5.22 (s, 2H), 4.73 (s, 2H), 4.47 (s, 2H), 4.02 (s, 3H), 4.00 (s, 3H), 3.87 (s,
Found: C, 71.70; H, 4.64; N, 5.35.
3H), 3.38 (s, 3H). EI-MS: m/z 491 (Mꢁ, 4). HR-MS-EI (Calcd for
C28H29NO7): 491.1904. Found: 491.1906.
General Procedure for the Preparation of 8a—d To the solution of
compound 7 (3.9 mmol) in THF (20 ml) at 0 °C under nitrogen was added
6-Hydroxymethylbenzo[1,3]dioxole-5-carbonitrile (4a) To a solution
of aldehyde 3a (4.02 g, 23 mmol) in acetic acid (30 ml) was added NaBH4
(1.71 g, 45 mmol) at room temperature. After stirring the reaction for 2 h,
acetic acid was removed in vacuo to give the residue which was poured into NaH dispersion 60% (10 mmol). The resulting mixture was stirred at the
water and extracted with ethyl acetate. The organic layer was washed with same temperature for 1 h. After the ice bath was removed, the reaction mix-
water, brine and dried over sodium sulfate. The solvent was evaporated off ture was added methyl iodide (10 mmol) in THF (5 ml) and warmed up to
and the residue was purified by column chromatography with n-hexane– 60 °C. The reaction was quenched with water and extracted with ethyl ac-
ethyl acetate (2 : 1) to give the alcohol 4a as a white solid (3.81 g, 94%). mp
etate. The combined ethyl acetate extracts were washed with water, brine
1
152—154 °C. IR (KBr) cmꢀ1: 3400 (OH), 2230 (CN). H-NMR (CDCl3): d and dried over anhydrous sodium sulfate. After removing the solvent, the
7.21 (s, 1H), 6.85 (s, 1H), 6.13 (s, 2H), 5.19 (s, 2H). EI-MS: m/z 177 (Mꢁ, residue was separated by column chromatography on silica gel with n-
100). Anal. Calcd for C9H7NO3: C, 61.02; H, 3.98; N, 7.91. Found: C, 61.22; hexane–ethyl acetate (2 : 1) to give compound 8.
H, 3.89; N, 7.82.
7-(6-Methoxymethoxymethylbenzo[1,3]dioxol-5-yl)-8-methyl-8H-
4-Benzyloxy-2-hydroxymethyl-5-methoxybenzonitrile (4b) The pro-
cedure described for compound 4a was used with aldehyde 3b (4.02 g,
[1,3]dioxolo[4,5-h]isoquinolin-9-one (8a) Oil (90 %). IR (cmꢀ1): 1655
1
(CO). H-NMR (300 MHz, CDCl3) d: 7.17 (d, Jꢂ8.2 Hz, 1H), 7.03 (s, 1H),
15 mmol) in acetic acid (20 ml) and NaBH4 (1.14 g, 30 mmol) to give alco- 6.95 (d, Jꢂ8.2 Hz, 1H), 6.72 (s, 1H), 6.31 (s, 1H), 6.24 (m, 2H), 6.04 (m,
hol 4b as a yellow solid (3.57 g, 88%). mp 139—141 °C. IR (cmꢀ1): 2230
2H), 4.57 (s, 2H), 4.35 (q, 2H), 3.25 (s, 3H), 3.24 (s, 3H). EI-MS: m/z 397
1
(CN). H-NMR (CDCl3) d: 7.45—7.33 (m, 5H), 7.13 (s, 1H), 7.06 (s, 1H); (Mꢁ, 23). HR-MS-EI (Calcd for C21H19NO7): 397.1204. Found: 397.1205.
5.20 (s, 2H), 4.79 (s, 2H), 3.89 (s, 3H). EI-MS m/z 269 (Mꢁ, 100). Anal.
Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20; O, 17.82.
7-(6-Methoxymethoxymethylbenzo[1,3]dioxol-5-yl)-6-methyl-6H-
[1,3]dioxolo[4,5-g]isoquinolin-5-one (8b) Oil (89%). IR (cmꢀ1): 1650
(CO). 1H-NMR (300 MHz, CDCl3) d: 7.79 (s, 1H), 7.03 (s, 1H), 6.80 (s,
6-Methoxymethoxymethylbenzo[1,3]dioxole-5-carbonitrile (5a) To a
solution of 4a (4.3 g, 24 mmol) in CH2Cl2 (30 ml) were added diisopropy- 1H), 6.72 (s, 1H), 6.30 (s, 1H), 6.08 (s, 2H), 6.04 (s, 2H), 4.55 (d, 2H), 4.31
lethylamine (DIPEA) (6.46 g, 50 mmol) and chloromethyl methyl ether (q, 2H), 3.29 (s, 3H), 3.24 (s, 3H). EI-MS: m/z 397 (Mꢁ, 23). HR-MS-EI
(4.02 g, 50 mmol) at 0 °C. The reaction mixture was stirred over night, and
CH2Cl2 was evaporated off to give the residue, which was purified by col-
(Calcd for C21H19NO7): 397.1204. Found: 397.1202.
6,7-Dimethoxy-3-(6-methoxymethoxymethylbenzo[1,3]dioxol-5-yl)-2-
umn chromatography with n-hexane–ethyl acetate (4 : 1) to give benzonitrile methyl-2H-isoquinolin-1-one (8c) Solid (78%). mp 58.2—62.3 °C. IR
1
5a as a yellow oil (4.88 g, 92%). IR (neat) cmꢀ1: 2230 (CN), 1300—1000 (KBr) cmꢀ1: 1650 (CO). H-NMR (300 MHz, CDCl3) d: 7.82 (s, 1H), 7.04
(C–O). 1H-NMR (CDCl3) d: 7.02 (s, 1H), 7.01 (s, 1H), 6.07 (s, 2H), 4.74 (s, (s, 1H), 6.82 (s, 1H), 6.73 (s, 1H), 6.34 (s, 1H), 6.06 (s, 2H), 4.55 (m, 2H),
2H), 4.67 (s, 2H), 3.43 (s, 3H). EI-MS: m/z 221 (Mꢁ, 30). Anal. Calcd for 4.34 (m, 2H), 4.03 (s, 3H), 3.98 (s, 3H), 3.31 (s, 3H), 3.24 (s, 3H). EI-MS:
C11H11NO4: C, 59.73; H, 5.01; N, 6.33. Found: C, 59.78; H, 5.06; N, 6.13.
4-Benzyloxy-5-methoxy-2-methoxymethoxymethylbenzonitrile
m/z 413 (Mꢁ, 80). Anal. Calcd for C22H23NO7: C, 63.91; H, 5.61; N, 3.39.
(5b) Found: C, 63.99; H, 5.55; N, 3.40.
The procedure described for compound 5a was used with alcohol 4b (4.4 g,
3-(4-Benzyloxy-5-methoxy-2-methoxymethoxymethylphenyl)-6,7-
16 mmol), diisopropylethylamine (DIPEA) (3.9 g, 30 mmol) and chlorom- dimethoxy-2-methyl-2H-isoquinolin-1-one (8d) Oil (70%). IR (cmꢀ1):
ethyl methyl ether (2.5 g, 30 mmol) to give benzonitrile 5b as a yellow solid 1650 (CO). 1H-NMR (300 MHz, CDCl3) d: 7.83 (s, 1H), 7.50—7.32 (m,
(4.75 g, 93%). mp 75.5—76.5 °C; IR (cmꢀ1): 2230 (CN), 1300—1000 5H), 7.12 (s, 1H), 6.83 (s, 1H), 6.79 (s, 1H), 6.37 (s, 1H), 5.22 (s, 2H), 4.73
(C–O). 1H-NMR (CDCl3) d: 7.42—7.38 (m, 5H), 7.08 (s, 1H), 7.05 (s, 1H); (s, 2H), 4.47 (s, 2H), 4.02 (s, 3H), 3.97 (s, 3H), 3.88 (s, 3H), 3.33 (s, 3H),
5.21 (s, 2H), 4.73 (s, 2H), 4.69 (s, 2H), 3.89 (s, 3H), 3.38 (s, 3H). EI-MS m/z 3.19 (s, 3H). EI-MS: m/z 505 (Mꢁ, 24). HR-MS-EI (Calcd for C29H31NO7):
313 (Mꢁ, 60). Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. 505.2107. Found: 505.2108.
Found: C, 68.68; H, 6.35; N, 4.20.
General Procedure for the Preparation of 7a—d Dry THF (10 ml)
General Procedure for the Preparation of 9a—d To the solution of
compound 8 (3.5 mmol) in THF (15 ml) was added 10% HCl (10 ml) and the
was added n-BuLi (7.5 mmol) at ꢀ40 °C. After the addition was completed, reaction was refluxed for 3 h. The reaction mixture was poured into water
the solution was stirred till the temperature fell at ꢀ70 °C and the solution and extracted with ethyl acetate. The ethyl acetate extracts were washed with

April 2006
479
water, brine and dried over anhydrous sodium sulfate. After removing the
solvent, the residue was separated by column chromatography on silica gel
with n-hexane–ethyl acetate (1 : 2) to give an alcohol 9.
NMR (300 MHz, CDCl3) d (cis): 7.70 (s, 1H), 7.18 (d, Jꢂ8.2 Hz, 1 H), 6.95
(d, Jꢂ8.2 Hz, 1H), 6.70 (s, 1H), 6.31 (s, 1H), 6.23 (s, 2H), 6.01 (s, 2H), 5.98
(d, Jꢂ7.1 Hz, 1H), 4.85 (d, Jꢂ7.1 Hz, 1H), 3.75 (s, 3H), 3.23 (s, 3H). d
(trans): 7.18 (d, Jꢂ8.2 Hz, 1H), 6.95 (d, Jꢂ8.2 Hz, 1H), 6.92 (d, Jꢂ12.8 Hz,
1H), 6.89 (s, 1H), 6.70 (s, 1H), 6.30 (s, 1H), 6.23 (s, 2H), 6.01 (s, 2H), 5.47
(d, Jꢂ12.8 Hz, 1H), 3.48 (s, 3H), 3.23 (s, 3H).
7-(6-Hydroxymethyl-benzo[1,3]dioxol-5-yl)-8-methyl-8H-[1,3]diox-
olo[4,5-h]-isoquinolin-9-one (9a) Yellow solid (80%). mp 227—230 °C.
1
IR (cmꢀ1): 3300 (OH), 1654 (CO). H-NMR (300 MHz, CDCl3) d: 7.16 (d,
Jꢂ8.2 Hz, 1H), 7.10 (s, 1H), 6.95 (d, Jꢂ8.2 Hz, 1H), 6.70 (s, 1H), 6.31 (s,
1H), 6.22 (m, 2H), 6.04 (m, 2H), 4.44 (s, 2H), 3.22 (s, 3H); EI-MS: m/z 353
(Mꢁ, 25). Anal. Calcd for C19H15NO6: C, 64.59; H, 4.28; N, 3.96. Found: C,
64.68; H, 4.45; N, 3.94.
7-(6-Hydroxymethylbenzo[1,3]dioxol-5-yl)-6-methyl-6H-[1,3]diox-
olo[4,5-g]-isoquinolin-5-one (9b) Solid (65%). mp 217—219 °C. IR
(KBr) cmꢀ1: 3300 (OH), 1641 (CO). 1H-NMR (300 MHz, CDCl3) d: 7.70 (s,
1H), 7.09 (s, 1H), 6.78 (s, 1H), 6.69 (s, 1H), 6.30 (s, 1H), 6.07 (s, 2H), 6.04
(s, 2H), 4.43 (s, 2H), 3.25 (s, 3H), 2.49 (s, 1H). EI-MS: m/z 353 (Mꢁ, 24).
Anal. Calcd for C19H15NO6: C, 64.59; H, 4.28; N, 3.96. Found: C, 64.78; H,
4.27; N, 3.86.
3-(6-Hydroxymethylbenzo[1,3]dioxol-5-yl)-6,7-dimethoxy-2-methyl-
2H-isoquinolin-1-one (9c) White solid (86%). mp 171.5—173.5 °C. IR
(KBr) cmꢀ1: 3300 (OH), 1641 (CO). 1H-NMR (300 MHz, CDCl3) d: 7.78 (s,
1H), 7.10 (s, 1H), 6.81 (s, 1H), 6.71 (s, 1H), 6.35 (s, 1H), 6.05 (s, 2H), 4.45
(m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.29 (s, 3H). EI-MS: m/z 369 (Mꢁ, 74).
Anal. Calcd for C20H19NO6: C, 65.03; H, 5.18; N, 3.79. Found: C, 65.23; H,
5.16; N, 3.77.
3-(4-Benzyloxy-2-hydroxymethyl-5-methoxyphenyl)-6,7-dimethoxy-
2-methyl-2H-isoquinolin-1-one (9d) Yellow solid (65%). mp 181—
183.5 °C. IR (cmꢀ1): 3300 (OH), 1641 (CO). 1H-NMR (300 MHz, CDCl3) d:
7.81 (s, 1H), 7.48—7.40 (m, 5H), 7.17 (s, 1H), 6.82 (s, 1H), 6.77 (s, 1H),
6.37 (s, 1H), 5.22 (s, 2H), 4.46 (s, 2H), 4.02 (s, 3H), 3.97 (s, 3H), 3.88 (s,
3H), 3.29 (s, 3H). EI-MS: m/z 461 (Mꢁ, 54). Anal. Calcd for C27H27NO6: C,
70.27; H, 5.90; N, 3.04. Found: C, 70.47; H, 5.64; N, 3.00.
7-[6-(2-Methoxyvinyl)benzo[1,3]dioxol-5-yl]-6-methyl-6H-[1,3]diox-
olo[4,5-g]isoquinolin-5-one (11b) cis/trans (1 : 2). Brown oil (57%). 1H-
NMR (300 MHz, CDCl3) d (cis): 7.80 (s, 1H), 7.71 (s, 1H), 6.81 (s, 1H),
6.69 (s, 1H), 6.30 (s, 1H), 6.08 (s, 2H), 6.01 (s, 2H), 5.97 (d, Jꢂ7.1 Hz, 1H),
4.81 (d, Jꢂ7.1 Hz, 1H), 3.75 (s, 3H), 3.29 (s, 3H). d (trans): 7.80 (s, 1H),
6.90 (s, 1H), 6.88 (d, Jꢂ12.8 Hz, 1H), 6.82 (s, 1H), 6.69 (s, 1H), 6.30 (s,
1H), 6.09 (s, 2H), 6.01 (s, 2H), 5.44 (d, Jꢂ12.8 Hz, 1H), 3.47 (s, 3H), 3.29
(s, 3H).
6,7-Dimethoxy-3-[6-(2-methoxyvinyl)benzo[1,3]dioxol-5-yl]-2-methyl-
1
2H-isoquinolin-1-one (11c) cis/trans (1.5 : 1). Brown oil (70%). H-NMR
(300 MHz, CDCl3) d (cis): 7.80 (s, 1H), 7.71 (s, 1H), 6.83 (s, 1H), 6.70 (s,
1H), 6.34 (s, 1H), 6.01 (s, 2H), 5.97 (d, Jꢂ7.2 Hz, 1H), 4.83 (d, Jꢂ7.2 Hz,
1H), 4.03 (s, 3H), 3.98 (s, 3H), 3.75 (s, 3H), 3.29 (s, 3H). d (trans): 7.80 (s,
1H), 6.91 (s, 1H), 6.90 (d, Jꢂ12.8 Hz, 1H), 6.86 (s, 1H), 6.70 (s, 1H), 6.35
(s, 1H), 6.01 (s, 2H), 5.45 (d, Jꢂ12.8 Hz, 1H), 4.03 (s, 3H), 3.98 (s, 3H),
3.46 (s, 3H), 3.29 (s, 3H).
3-[4-Benzyloxy-5-methoxy-2-(2-methoxyvinyl)phenyl]-6,7-dimethoxy-
2-methyl-2H-isoquinolin-1-one (11d) cis/trans (1 : 1). Brown oil (65%).
1H-NMR (300 MHz, CDCl3) d (cis): 7.83 (s, 1H), 7.60 (s, 1H), 7.51—7.35
(m, 5H), 6.85 (s, 1H), 6.74 (s, 1H), 6.36 (s, 1H), 5.96 (d, Jꢂ7.1 Hz, 1H),
5.25 (s, 2H), 4.81 (d, Jꢂ7.1 Hz, 1H), 4.03 (s, 3H), 3.98 (s, 3H), 3.87 (s, 3H),
3.69 (s, 3H), 3.30 (s, 3H). d (trans): 7.83 (s, 1H), 7.60 (s, 1H), 7.51—7.35
(m, 5H), 6.94 (s, 1H), 6.85 (s, 1H), 6.78 (d, Jꢂ12.8 Hz, 1H), 6.74 (s, 1H),
6.36 (s, 1H), 5.44 (d, Jꢂ12.8 Hz, 1H), 4.03 (s, 3H), 3.98 (s, 3H), 3.87 (s,
3H), 3.45 (s, 3H), 3.30 (s, 3H).
General Procedure for the Preparation of 10a—d Reaction mixture of
alcohol 9 (2.1 mmol) and PDC (4.2 mmol) in CH2Cl2 (30 ml) was stirred for
2 h. Reaction mixture was filtered and washed with CH2Cl2. The solvent was
evaporated off and the residue was separated by column chromatography on
silica gel with n-hexane–ethyl acetate (2 : 1) to afford the aldehyde 10.
6-(8-Methyl-9-oxo-8,9-dihydro-[1,3]dioxolo[4,5-h]isoquinolin-7-
yl)benzo[1,3]dioxole-5-carbaldehyde (10a) Solid (68%). mp 234—
236 °C. IR (cmꢀ1): 1700, 1654 (CꢂO). 1H-NMR (300 MHz, CDCl3) d: 9.79
(s, 1H), 7.46 (s, 1H), 7.18 (d, Jꢂ8.2 Hz, 1H), 6.95 (d, Jꢂ8.2 Hz, 1H), 6.85
(s, 1H), 6.35 (s, 1H), 6.25 (s, 2H), 6.15 (s, 2H), 3.28 (s, 3H). EI-MS: m/z
351 (Mꢁ, 100). Anal. Calcd for C19H13NO6: C, 64.96; H, 3.73; N, 3.99.
Found: C, 64.88; H, 3.76; N, 3.89.
6-(6-Methyl-5-oxo-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquinolin-7-
yl)benzo[1,3]dioxole-5-carbaldehyde (10b) Solid (79%). mp ꢃ300 °C.
IR (cmꢀ1): 1700, 1640 (CꢂO). 1H-NMR (300 MHz, CDCl3) d: 9.75 (s, 1H),
7.80 (s, 1H), 7.47 (s, 1H), 6.83 (s, 1H), 6.82 (s, 1H), 6.34 (s, 1H), 6.17 (s,
2H), 6.10 (s, 2H), 3.34 (s, 3H). EI-MS: m/z 351 (Mꢁ, 100). Anal. Calcd for
C19H13NO6: C, 64.96; H, 3.73; N, 3.99. Found: C, 64.98; H, 3.77; N, 3.95.
6-(6,7-Dimethoxy-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-
yl)benzo[1,3]dioxole-5-carbaldehyde (10c) Solid (99%). mp 209.5—
212 °C. IR (cmꢀ1): 1700, 1640 (CꢂO). 1H-NMR (300 MHz, CDCl3): d 9.77
(s, 1H), 7.83 (s, 1H), 7.48 (s, 1H), 6.84 (s, 1H), 6.84 (s, 1H), 6.39 (s, 1H),
6.17 (s, 2H), 4.04 (s, 3H), 3.99 (s, 3H), 3.37 (s, 3H). EI-MS: m/z 367 (Mꢁ,
100); Anal. Calcd for C20H17NO6: C, 65.39; H, 4.66; N, 3.81. Found: C,
65.58; H, 4.67; N, 3.80.
5-Benzyloxy-2-(6,7-dimethoxy-2-methyl-1-oxo-1,2-dihydroisoquinolin-
3-yl)-4-methoxybenzaldehyde (10d) Solid (86%). mp 205—207 °C. IR
(cmꢀ1): 1700, 1640 (CꢂO). 1H-NMR (300 MHz, CDCl3) d: 9.80 (s, 1H,
CHO), 7.84 (s, 1H), 7.60 (s, 1H), 7.51—7.35 (m, 5H), 6.86 (s, 1H), 6.84 (s,
1H), 6.41 (s, 1H), 5.25 (s, 2H), 4.04 (s, 3H), 3.98 (s, 3H), 3.97 (s, 3H), 3.35
(s, 3H). EI-MS: m/z 459 (Mꢁ, 11), 91 (100). Anal. Calcd for C27H25NO6: C,
70.58; H, 5.48; N, 3.05. Found: C, 70.88; H, 5.38; N, 3.25.
General Procedure for the Preparation of 11a—d To the solution of
(methoxymethyl)triphenylphosphonium chloride (3 mmol) in dry THF
(15 ml) was added n-BuLi (3.2 mmol) at 0 °C and solution was stirred at
0 °C for 1 h. The reaction mixture was added aldehyde 10 (0.60 mmol) in
THF (10 ml) and was stirred at room temperature for 3 h. The reaction was
quenched with water and extracted with ethyl acetate. The organic layers
were washed with water, brine and dried over sodium sulfate. After remov-
ing the solvent, the residue was separated by column chromatography with
n-hexane–ethyl acetate (3 : 1) to afford mixture of cis/trans isomer 11.
7-[6-(2-Methoxyvinyl)benzo[1,3]dioxol-5-yl]-8-methyl-8H-[1,3]diox-
olo[4,5-h]isoquinolin-9-one (11a) cis/trans (1 : 1). Brown oil (66%). 1H-
General Procedure for the Preparation of 13a—d The reaction mix-
ture of cis/trans isomers 11 (0.4 mmol) in methanol (20 ml) and 10% HCl
(5 ml) was refluxed for 3 h. The methanol was removed by evaporation, reac-
tion mixture was poured into water and extracted with ethyl acetate. The
ethyl acetate extracts were washed with water, brine and dried over anhy-
drous sodium sulfate. After removing the solvent, the residue was separated
by column chromatography on silica gel with n-hexane–ethyl acetate (1 : 2)
to give 13.
Oxysanguinarine (13a) White solid (85%). mp 360—362 °C (lit.31) mp
366—368 °C). IR (cmꢀ1): 1652 (CꢂO). 1H-NMR (300 MHz, CDCl3) d:
7.99 (d, Jꢂ8.6 Hz, 1H), 7.76 (d, Jꢂ9.6 Hz, 1H), 7.56 (s, 1H), 7.52 (d, Jꢂ
8.6 Hz, 1H), 7.23 (d, Jꢂ9.6 Hz, 1H), 7.16 (s, 1H), 6.27 (s, 2H), 6.10 (s, 2H),
3.90 (s, 3H). EI-MS m/z. 347 (Mꢁ, 100%). Anal. Calcd for C20H13NO5: C,
69.16; H, 3.77; N, 4.03. Found: C, 69.36; H, 3.95; N, 4.13.
Oxyavicine (13b) Solid (75%). mp 279—282 °C (lit.32) mp 276—
277 °C, lit.33) mp 278—283 °C). IR (cmꢀ1): 1631 (CO). 1H-NMR (300 MHz,
CDCl3) d: 7.92 (d, Jꢂ8.6 Hz, 1H), 7.89 (s, 1H), 7.63 (s, 1H), 7.61 (s, 1H),
7.56 (d, Jꢂ8.6 Hz, 1H), 7.18 (s, 1H), 6.13 (s, 2H), 6.10 (s, 2H), 3.97 (s, 3H).
EI-MS m/z. 347 (Mꢁ, 61%). Anal. Calcd for C20H13NO5: C, 69.16; H, 3.77;
N, 4.03. Found: C, 69.24; H, 3.69; N, 4.14.
Oxynitidine (13c) Solid (88%). mp 284—285 °C (lit.17) mp 280—
283 °C, lit.26,27) mp 284—285 °C). IR (cmꢀ1): 1642 (CO). 1H-NMR
(300 MHz, CDCl3) d: 8.00 (d, Jꢂ9.0 Hz, 1H), 7.93 (s, 1H), 7.65 (s, 1H),
7.60 (s, 1H), 7.57 (d, Jꢂ8.8 Hz, 1H), 7.19 (s, 1H), 6.11 (s, 2H), 4.11 (s, 3H),
4.04 (s, 3H), 3.99 (s, 3H). EI-MS m/z. 363 (Mꢁ, 100%). Anal. Calcd for
C21H17NO5: C, 69.41; H, 4.72; N, 3.85. Found: C, 69.44; H, 4.62; N, 3.76.
2-Benzyloxy-3,8,9-trimethoxy-5-methyl-5H-benzo[c]phenanthridin-6-
one (13d) Solid (70%). mp 219—221 °C (lit.28) mp 227—229 °C). IR
(cmꢀ1): 1649 (CO). 1H-NMR (300 MHz, CDCl3) d: 8.00 (d, Jꢂ9.0 Hz, 1H),
7.93 (s, 1H), 7.63 (s, 1H), 7.59 (s, 1H), 7.56—7.36 (m, 5H), 7.50 (d, Jꢂ
9.0 Hz, 1H), 7.23 (s, 1H), 5.31 (s, 2H), 4.10 (s, 3H); 4.06 (s, 3H), 4.05 (s,
3H), 4.04 (s, 3H). EI-MS, m/z 455 (Mꢁ, 22). Anal. Calcd for C28H25NO5: C,
73.83; H, 5.53; N, 3.08. Found: C, 73.65; H, 5.67; N, 3.34.
Oxyfagaronine (14) The mixture of compound 13d (40 mg, 0.088
mmol) and 5% Pd/C (20 mg) in EtOH (10 ml) was treated with hydrogen gas
at 70 psi for 5 h using Parr apparatus. The reaction mixture was filtered off
and the filtrate was evaporated to give the residue which was purified by col-
umn chromatography to give 14 (oxyfagaronine) as a white solid (20 mg,
62%). mp 273—275 °C (lit.30) mp 273—275 °C). IR (cmꢀ1): 1649 (CO). 1H-
NMR (300 MHz, CDCl3) d: 8.00 (d, Jꢂ9.0 Hz, 1H), 7.93 (s, 1H), 7.63 (s,
1H), 7.62 (s, 1H), 7.56 (d, Jꢂ9.0 Hz, 1H), 7.33 (s, 1H), 4.11 (s, 3H), 4.06 (s,
3H), 4.05 (s, 3H), 4.05 (s, 3H). EI-MS, m/z 365 (Mꢁ, 85). Anal. Calcd for
C21H19NO5: C, 69.03; H, 5.24; N, 3.83. Found: C, 69.25; H, 5.45; N, 3.58.

480
Vol. 54, No. 4
Acknowledgements This work was supported by Korea Research Foun- 15) Harayama T., Akamatsu H., Okamura K., Miyagoe T., Akiyama T.,
dation Grant (KRF-2002-015-EP0142). We are grateful to Prof. Tsutomu
Ishikawa of Chiba University in Japan for providing authentic oxyfagaro-
nine.
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