A facile method for the synthesis of glaucine and norglaucine from boldine

Article abstract of DOI:10.1081/SCC-120014988

A large-scale preparation of glaucine was achieved by reacting boldine with trimethylphenylammonium chloride and potassium t-butoxide in high yield. Treatment of glaucine with 30% H202, subsequent with hydrated ferrous sulfate, afforded norglaucine in an overall yield of 40%.

Full text of DOI:10.1081/SCC-120014988

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A FACILE METHOD FOR THE SYNTHESIS OF GLAUCINE
AND NORGLAUCINE FROM BOLDINE
Wei-Jan Huang a , Chung-Hsiung Chen a , Om V. Singh a , Su-Lin Lee a & Shoei-Sheng Lee b
a School of Pharmacy , College of Medicine , National Taiwan University , 1 Jen-Ai Road, Sec.
1 Taipei, Taiwan, 100, Republic of China
b School of Pharmacy , College of Medicine , National Taiwan University , 1 Jen-Ai Road, Sec.
1 Taipei, Taiwan, 100, Republic of China
Published online: 16 Aug 2006.
To cite this article: Wei-Jan Huang , Chung-Hsiung Chen , Om V. Singh , Su-Lin Lee & Shoei-Sheng Lee (2002) A FACILE
METHOD FOR THE SYNTHESIS OF GLAUCINE AND NORGLAUCINE FROM BOLDINE, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:23, 3681-3686, DOI: 10.1081/SCC-120014988
To link to this article: http://dx.doi.org/10.1081/SCC-120014988
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 23, pp. 3681–3686, 2002
A FACILE METHOD FOR THE SYNTHESIS
OF GLAUCINE AND NORGLAUCINE
FROM BOLDINE
Wei-Jan Huang, Chung-Hsiung Chen, Om V. Singh,
*
Su-Lin Lee, and Shoei-Sheng Lee
School of Pharmacy, College of Medicine,
National Taiwan University, 1 Jen-Ai Road,
Sec. 1 Taipei, Taiwan 100, Republic of China
ABSTRACT
A large-scale preparation of glaucine was achieved by reacting
boldine with trimethylphenylammonium chloride and potas-
sium t-butoxide in high yield. Treatment of glaucine with
30% H2O2, subsequent with hydrated ferrous sulfate, afforded
norglaucine in an overall yield of 40%.
Key Words: Glaucine; Norglaucine; Large-scale preparation
The aporphine alkaloid (þ)-glaucine (1,2,9,10-tetramethoxyaporphine, 2)
is the direct intermediate for the preparation of the anti-arrhythmic
agent (þ)-thaliporphine (1-hydroxy-2,9,10-trimethoxyaporphine)[1] and was
recently demonstrated to be a potent antiinflammatory agent.[2] Various N-
substitutions in the morphine have arisen distinct biological activities. For
example, nalorphine (N-allyl) is an antagonist of morphine (N-methyl).
*Corresponding author. E-mail: shoeilee@ha.mc.ntu.edu.tw
3681
DOI: 10.1081/SCC-120014988
Copyright & 2002 by Marcel Dekker, Inc.
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3682
HUANG ET AL.
These stimulated our interest to develop a practical method to prepare 2 and
its N-homologues for further pharmacological studies. The total synthesis of
(þ)-glaucine has been achieved by asymmetric synthesis but in low yield.[3]
The homologues of 2 could be prepared from (þ)-norglaucine (3) simply by
reductive N-alkylation. Compound 3, however, is a minor natural product. In
this communication, we report a facile large-scale semisynthesis of 2 from the
commercially available (þ)-boldine (2,9-dihydroxy-1,10-dimethoxyapor-
phine, 1) and an efficient N-demethylation method for the preparation of 3
from 2.
Treatment of 1 with the conventional O-methylation reagents for the
phenolic group such as methyl iodide[4] and dimethylsulfate[5] under basic
conditions afforded quaternary ammonium salt predominantly for 1 being
a tertiary amine. Although 2 had been prepared by treatment of 1 with diazo-
methane,[6] this method is not practical on a large-scale preparation because
of the incomplete reaction and the explosive and toxic properties of this
reagent. Treatment of 1 with another useful O-methylation reagent used in
the alkaloid chemistry, trimethylphenylammonium chloride,[7] in presence of
potassium carbonate in dry dimethylformamide at 90ꢀC under nitrogen
atmosphere afforded 2 in good yields. But the scale could be only up to ca
2 g level. Beyond that we found that the reaction was incomplete despite of the
presence of much excess of this O-methylated reagent. Many attempts have
been made to improve this situation and finally we found that displacement of
the relatively weak base by potassium t-butoxide solved this problem. Thus 1
yielded 2 in 87% on a preparative scale (up to 50 g) (Sch. 1). Separation of the
product 2 from the accompanied N,N-dimethylaniline, obtained from the N-
demethylation of the reagent, was performed on a molecular sieving chroma-
tography (Sephadex LH-20, MeOH), from which 2 eluted out first, followed
by the aniline. This separation method was found to be much easier than silica
gel column chromatography.
N-Demethylation of glaucine (2) with commonly used reagents for
some alkaloids such as cyanogen bromide,[8] ethyl chloroformate[9] and
diethyl diazodicarboxylate[10] failed to afford norglaucine (3). These
reactions produced a Hofmann degradation product, secoglaucine (5), in
high yield. Till now, only one method, i.e., using liquid sulfur dioxide and
subsequent acid-catalyzed hydrolysis, has been reported to convert the
aporphine N-oxides, e.g., N-methylovigerine N-oxide, into the corresponding
noraporphines.[11] The yield, however, was poor and several other products
including the 6,6a-secoaporphine were produced. After several attempts,
we found that the following method could give 3 in an acceptable yield.
Treatment of 2 with 30% H2O2 in methanol at room temperature gave
glaucine N-oxide (4) as a diastereomeric mixture in ratio (1.7 : 1) (determined
by 1H-NMR) in 88% yield. Subsequent reaction of 4 with hydrated ferrous

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SYNTHESIS OF GLAUCINE AND NORGLAUCINE
3683
Scheme 1.
sulfate in methanol at 10ꢀC afforded norglaucine (3) in 52% yield, along with
5 (13%). This reagent (FeSO4) and the related one, ferrous chloride, have been
reported for the conversion of common tertiary amine N-oxides into
secondary amines.[8] We also observed that only 5 was obtained if the reaction
temperature raised to 50ꢀC or the reagent was changed to ferrous chloride.
This work demonstrated a practical semisynthesis of glaucine (2) from
boldine (1), and a facile method for the preparation of norglaucine (3) from
2 by N-demethylation. This breakthrough facilitates to a great extent the
synthesis of O-methylaporphines from the corresponding phenolic alkaloids
and for the preparation of N-noraporphines, key intermediates for the
synthesis of the N-homologues.
EXPERIMENTAL
General
Melting points were taken in open capillaries on Fisher-Johns melting
point apparatus and are uncorrected. The physical data of the compounds
were obtained by the following instruments: [a]D: JASCO DIP-181 Digital

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3684
HUANG ET AL.
polarimeter; IR(KBr disc): JASCO IRReport-100 spectrophotometer; UV
(MeOH): Hitachi 150–20 spectrophotometer; NMR: Bruker AMX400 spec-
trometer and EIMS: JEOL JMS-SX 102 mass spectrometer operating at
70 ev. TLC (silica gel) was developed with CHCl3-MeOH (98 : 2), saturated
with NH4OHaq and visualized under UV at 254 nm and by Dragendorff ’s
spray reagent.
(Q)-Glaucine (2): To a solution of boldine (1; 45.0 g, 137.6 mmol) and
trimethylphenylammonium chloride (82.6 g, 481.7 mmol) in dry DMF
(500 mL) was added potassium t-butoxide (56.9 g, 481.7 mmol) and the
suspension was heated to 90ꢀC under N2 for 16 h. After removal of the organic
solvent, the residue was dissolved in CHCl3 (500 mL) and washed with 5%
sodium hydroxide solution (250 mL Â 2) followed by H2O (250 mL Â 3). The
organic layer was dried over anhydrous sodium sulfate and evaporated under
reduced pressure. The residue was purified by passing through a Sephadex
LH-20 column (500 g) using, MeOH as eluent to afford (þ)-glaucine (2)
25
(42.5 g, 87%); m.p. 112–114ꢀC (lit.[12] 117–118ꢀC); ½ꢀŠ þ 120 (c 1, MeOH)
D
[lit.[12] 115 (c 0.4, MeOH)]; 1H NMR(CDCl 3, 400 MHz): ꢁ 8.06 (1H, s, H-11),
6.75 (1H, s, H-8), 6.56 (1H, s, H-3), 3.91 (3H, s, 9-OMe), 3.88 (3H, s, 10-
OMe), 3.86 (3H, s, 2-OMe), 3.64 (3H, s, 1-OMe), 2.53 (s, N-Me); FAB MS:
m/z (rel. int. %) [MþH]þ 356 (100), 325 (10), 154 (45), 136 (35).
Glaucine N-oxide (4): To a solution of 2 (3.1 g, 8.73 mmol) in methanol
(100 mL) was added 30% H2O2 (50 mL) and the reaction mixture were
stirred at room temperature. After completion of reaction (ca 24 h), as
monitored by tlc, the excess H2O2 was quenched by 10% Pd-C (150 mg)
at ice bath for 2 h. The reaction mixture was filtered and the filtrate was
evaporated to remove methanol. The residue suspended in brine (50 mL)
was extracted with CHCl3 (50 mL Â 3). The CHCl3 layer after washing with
water (25 mL Â 3) and drying over Na2SO4 was condensed under reduced
pressure to give a residue, which was purified on a silica gel column (50 g),
eluted with 0–10% MeOH in CHCl3, to afford glaucine N-oxide (4) (2.84 g,
88%); m.p 90–92ꢀC (lit.[13] 95–97ꢀC); 1H NMR(CDCl 3, 400 MHz): ꢁ 8.02 &
7.97 (1H, s, H-11), 6.87 & 6.82 (1H, s, H-8), 6.63 & 6.58 (1H, s, H-3), 4.42 &
4.22 (1H, dd, J ¼ 3.3 & 13.6 Hz, H-7), 3.90 & 3.89 (3H, s, OMe), 3.87 & 3.86
(3H, s, OMe), 3.84 (3H, s, OMe), 3.67 & 3.59 (3H, s, OMe), 3.52 & 3.15
(3H, s, N-Me).
Treatment of Glaucine N-Oxide with Hydrated Ferrous Sulfate—
Synthesis of Norglaucine and Secoglaucine
To a solution of 4 (378 mg, 1.02 mmol) in methanol (20 mL) was added
FeSO4.7H2O (690 mg, 2.48 mmol) at 10ꢀC while stirring. After 12 h reaction,

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SYNTHESIS OF GLAUCINE AND NORGLAUCINE
3685
saturated aqueous NaHCO3 (10 mL) was added to the reaction mixture and
the suspension was stirred at room temperature for 30 min and then
extracted with chloroform (50 mL Â 3). The combined chloroform layer
was washed with water (25 mL Â 3), brine and dried over Na2SO4. After
removal of the organic solvent under reduced pressure, the residue was
chromatographed over a silica gel column, eluted with 0–1% MeOH in
CHCl3,to afford norglaucine (3) (190 mg, 52%) and secoglaucine (5)
(50 mg, 13%).
25
D
(Q)Norglaucine (3): ½ꢀŠ þ 80 (c 1, MeOH); 1H NMR(CDCl
,
3
400 MHz): ꢁ 8.09 (1H, s, H-11), 6.72 (1H, s, H-8), 6.58 (1H, s, H-3), 3.89
(3H, s, 9-OMe), 3.87 (3H, s, 10-OMe), 3.86 (3H, s, 2-OMe), 3.81 (1H, dd,
J ¼ 5.2 & 13.2 Hz, H-7), 3.64 (3H, s, 1-OMe); EIMS (70 eV): m/z (rel. int. %)
341 Mþ (34), 328 (100).
Secoglaucine (5): M.p. 113–114ꢀC (lit[14] 112–114ꢀC), 1H NMR
(MeOH-d4, 400 MHz): ꢁ 9.21 (1H, s, H-5), 7.80 (1H, d, J ¼ 9.1 Hz, H-10),
7.58 (1H, d, J ¼ 9.1 Hz, H-9), 7.32 (1H, s, H-8), 7.29 (1H, s, H-2), 4.01 (6H, s,
6 & 5-OMe), 3.97 (3H, s, 4-OMe), 3.90 (3H, s, 3-OMe), 3.28 (2H, t,
J ¼ H-11), 2.92 (2H, t, J ¼ 7.4 Hz, H-12), 2.45 (3H, N-Me).
ACKNOWLEDGMENTS
This work was supported by the National Science Council, Taiwan,
R.O.C., under the grant NSC89-2320-B-002-272. A postdoctoral fellowship
(NSC89-2811-B-002-0137) to OVS from NSC is also acknowledged.
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Received in the USA November 25, 2001