Syntheses of the seco benzyltetrahydroisoquinoline alkaloids polysignine and methoxypolysignine

Article abstract of DOI:10.1071/ch00023

The structures previously assigned to the seco benzyltetrahydroisoquinoline alkaloids polysignine (1) and methoxypolysignine (2) have been confirmed by total syntheses in which the key step involved cleavage of the C 1-N bonds in the corresponding N-methylbenzyltetrahydroisoquinolines. CSIRO 2000.

Full text of DOI:10.1071/ch00023

C S I R O P U B L I S H I N G
Australian Journal
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Volume 53, 2000
© CSIRO 2000
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Aust. J. Chem., 2000, 53, 523–525
Syntheses of the Seco Benzyltetrahydroisoquinoline
Alkaloids Polysignine and Methoxypolysignine*
Surachai Nimgirawath
Department of Chemistry, Faculty of Science,
Silpakorn University, Nakorn Pathom 73000, Thailand.
The structures previously assigned to the seco benzyltetrahydroisoquinoline alkaloids polysignine (1) and methoxy-
polysignine (2) have been confirmed by total syntheses in which the key step involved cleavage of the C 1–N bonds
in the corresponding N-methylbenzyltetrahydroisoquinolines.
Keywords. Alkaloid; isoquinoline; synthesis.
The isoquinoline alkaloids comprise many bioactive prin-
ciples of medicinal importance. These include benzyliso-
quinoline, benzyltetrahydroisoquinoline, bisbenzyliso-
quinoline, morphinandienone, aporphine, protoberberine,
benzophenanthridine and phenanthrene alkaloids.
Although all these alkaloids possess the isoquinoline ring
as a common feature, simple seco benzyltetrahydroisoquino-
line alkaloids in which the isoquinoline ring is opened at the
C 1–N bond are extremely rare. To date only two examples
of such alkaloids have been found to occur naturally. These
are polysignine (1) and methoxypolysignine (2) found in the
bark of a Malaysian annonaceous plant, Polyalthia insignis.1
Because of the interesting structural features of these
alkaloids from a biogenetic point of view and also our inter-
est in the ring-opening reactions of benzyltetrahydroiso-
quinolines, we decided to undertake simple syntheses of
these alkaloids and now report a confirmation by total syn-
theses of the structures previously assigned to polysignine
(1) and methoxypolysignine (2).
Eschweiler–Clark methylation of the readily accessible
tetrahydroisoquinolines (3)2 and (4)3 afforded in excellent
yields (5) and (6) which on treatment with methyl chlorofor-
mate and triethylamine gave carbamates (7) and (8). The
structures assigned to these (E)-stilbenes were supported by
the coupling constants (15.8 and 16.0 Hz respectively) of the
two olefinic protons in (7) and (8). The 1H n.m.r. spectrum of
(7) measured at 295 K was complex and was only well
resolved when measurement was made at 325 K, and proton
assignments were made possible by proton-decoupling
experiments. On the other hand, the 13C n.m.r. spectrum of
(7) gave rise to resonance signals due to hindered rotation
around the amide bond. For example, C␣ gave rise to two
signals at ␦ 31.1 for one conformer and ␦ 31.9 for the other
conformer while C␤ also gave rise to two signals at ␦ 50.2
and 51.0 respectively. Similar phenomena were observed in
the 13C n.m.r. spectrum of (8). Catalytic hydrogenation of (7)
and (8) afforded in excellent yields the carbamates (9) and
(10) in which the phenomena of hindered rotation around the
amide bond were also evident from the 13C n.m.r. spectra.
Finally, lithium aluminium hydride reduction of (9) and (10)
gave respectively polysignine (1) and methoxypolysignine
1
(2). The H and 13C spectral data of the synthetic alkaloids
are identical in all respects with those recorded for the
natural alkaloids.
Experimental
Melting points were determined on a Stuart MP-2 apparatus and are
uncorrected. Ultraviolet spectra were recorded on methanol solutions
with a Shimadzu 240 spectrophotometer. Infrared spectra were
recorded on Nujol mulls or liquid films with a Jasco IRA-1 spec-
trophotometer. 1H and 13C magnetic resonance spectra were recorded on
(D)chloroform solutions at 60 MHz with a Varian EM360A spectrome-
* Dedicated to Professor W. C. Taylor, on the occasion of the 70th anniversary of his birthday, for his contributions to the advancement of organic
chemistry in developing countries.
Manuscript received 14 February 2000
© CSIRO 2000
10.1071/CH00023
0004-9425/00/060523

524
Short Communications
ter or at 400 MHz for 1H and 100 MHz for 13C with a Varian
Inova 400 MHz or a Bruker AVANCE 400 MHz spectrometer.
Tetramethylsilane was used as the internal standard. 13C n.m.r. spectra
were interpreted with the aid of DEPT spectra. Low-resolution mass
spectra were run on a Hewlett Packard 5989B spectrometer and high-
resolution mass spectra on a Kratos Concept ISQ mass spectrometer.
Elemental microanalyses were performed with a Perkin–Elmer 2400
elemental analyser.
1H n.m.r. (400 MHz) ␦ 7.39, d, J 16 Hz, C=CH; 7.31, s, ArH; 7.14, s,
ArH; 7.12–6.98, m, 2×ArH; 6.87, d, J 8 Hz, ArH; 6.86, d, J 16 Hz,
HC=C; 4.01, s, OCH3; 3.93, s, OCH3; 3.89, s, OCH3; 3.88, s, OCH3;
3.62, s, COOCH3; 3.42, t, J 7.2 Hz, CH2; 2.96, t, J 7.2 Hz, CH2; 2.84,
br s, NCH3. 13C n.m.r. (100 MHz) ␦ 156.7 (C), 149.2 (C), 148.7 (C),
148.6 (C), 147.9 (C), 130.9 (C), 129.2 (C), 129.0 (C), 128.1 (CH), 123.5
(CH), 120.0 (CH), 119.0 (CH), 113.0 (CH), 110.9 (CH), 108.1 (CH),
55.9 (CH3), 55.6 (CH3), 52.3 (CH3), 51.2 (CH2), 50.2 (CH2), 35.0
(CH3), 31.8 (CH2), 31.2 (CH2). Mass spectrum m/z 415 (M+, 59%), 384
(2), 326 (79), 282 (65), 264 (47), 233 (10), 204 (54), 175 (70), 151
(100), 102 (100), 69 (15), 58 (68).
6,7-Dimethoxy-1-(4-methoxybenzyl)-2-methyl-1,2,3,4-
tetrahydroisoquinoline (5)
Formaldehyde (37%, 68 ml) was added portionwise to a stirred solu-
tion of the isoquinoline (3)2 (26.7 g) in methanol (500 ml) and stirring
was continued for 2 h. Sodium borohydride (20 g) was added portion-
wise and the mixture was stirred for 5 h. Removal of most of the
methanol gave a residue which was shaken with water (300 ml) and
chloroform (300 ml). The chloroform layer was worked up as usual to
give the isoquinoline (5) as colourless prisms (25.2 g, 90%) from
Methyl N-[2-(4,5-Dimethoxy-2-[2-(4-
methoxyphenyl)ethyl]phenyl)ethyl]-N-methylcarbamate (9)
A solution of the carbamate (7) (4 g) in methanol (400 ml) was
hydrogenated at 40–50 psi in the presence of 10% Pd/C (0.4 g). Uptake
of hydrogen ceased after about 2 h. The catalyst was filtered off, and the
solvent removed in vacuum to give a residue which was recrystallized
from ethanol at –10o to give colourless prisms of the carbamate (9) (3.9
g, 97.0%), m.p. 62–63o (Found: C, 68.0; H, 7.7; N, 3.5. C22H29NO5
requires C, 68.2; H, 7.5; N, 3.6%). ␭max 230, 275 nm; log⑀ 3.61, 3.59.
1
benzene/hexane, m.p. 60–61o (lit.4 62–62.5o). H n.m.r. (60 MHz) ␦
6.97, d, J 8 Hz, 2×ArH; 6.70, d, J 8 Hz, 2×ArH; 6.48, s, ArH; 5.92, s,
ArH; 4.85–4.50, m, H 1; 3.80, s, OCH3; 3.73, s, OCH3; 3.52, s, OCH3;
3.37–2.50, m, 3×CH2; 2.50, s, NCH3.
␯
max
1690 (COOCH3), 1610, 1584, 1512, 1315, 1300, 1255, 1220,
1200, 1188, 1110, 1095, 1040, 995, 860, 835, 770 cm–1. 1H n.m.r. (400
MHz) ␦ 7.08, d, J 8.4 Hz, 2×ArH; 6.82, d, J 8.4 Hz, 2×ArH; 6.70–6.55,
m, 3×ArH; 3.86, s, OCH3; 3.78, s, 2×OCH3; 3.70 and 3.61, 2×br s,
COOCH3 of both conformers; 3.43–3.28, m, CH2N; 2.90–2.68, m, 3×
CH2; 2.82, br s, NCH3. 13C n.m.r. (100 MHz) ␦ 157.9 (C), 156.7 (C),
147.3 (C), 147.1 (C), 133.7 (C), 132 (C), 129.3 (CH), 128.4 (CH), 113.7
(CH), 112.9 (CH), 112.8 (CH), 55.9 (CH3), 55.8 (CH3), 55.2 (CH3),
52.4 (CH3), 50.8 (CH2), 50.4 (CH2), 37.0 (CH2), 35.0 (CH3), 34.5
(CH2), 31.1 (CH2), 30.3 (CH2). Mass spectrum m/z 387 (M+, 18%), 308
(4), 285 (6), 266 (31), 234 (52), 219 (3), 179 (13), 164 (25), 121 (100),
102 (92), 77 (41), 58 (75).
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-
tetrahydroisoquinoline (6)
In a similar manner, the isoquinoline (6) was obtained in 86.6%
yield as colourless prisms, m.p. 113–114o (lit.3 114–115o). 1H n.m.r. (60
MHz) ␦ 6.90–6.40, m, 4×ArH; 6.03, s, ArH; 4.85–4.50, m, H 1; 3.82, s,
2×OCH3; 3.76, s, OCH3, 3.55, s, OCH3; 3.45–2.50, m, 3×CH2; 2.52, s,
NCH3.
Methyl N-[2-(4,5-Dimethoxy-2-[2-(4-
methoxyphenyl)ethenyl]phenyl)ethyl]-N-methylcarbamate (7)
Methyl chloroformate (20 g) was added dropwise to a stirred solu-
tion of the isoquinoline (5) (19 g) and triethylamine (20 g) in chloro-
form (200 ml) at 0–10o. The mixture was then stirred at 10–15o for 5 h.
Water (200 ml) was added and the chloroform layer was washed with 3
M HCl (3×80 ml), water (2×50 ml), brine then dried. Removal of the
solvent in vacuum gave a residue which was recrystallized from ethanol
at –10o to give colourless prisms of the carbamate (7) (14.5 g, 64.8%),
m.p.109–110o (Found: C, 68.4; H, 7.1; N, 3.5. C22H27NO5 requires C,
Methyl N-[2-(2-[2-(3,4-Dimethoxyphenyl)ethyl]-4,5-
dimethylphenyl)ethyl]-N-methylcarbamate (10)
A solution of the carbamate (8) (5 g) in methanol (400 ml) was
hydrogenated at 40–50 psi in the presence of 10% Pd/C (0.4 g) for 6 h.
The catalyst was filtered off and the solvent removed in vacuum to give
a residue which was recrystallized from ethanol at –10o to give colour-
less prisms of the carbamate (10) (4.7 g, 93.6%), m.p. 89–90o (Found:
C, 66.4; H, 7.4; N, 3.2. C23H31NO6 requires C, 66.2; H, 7.5; N, 3.4%).
68.6; H, 7.1; N, 3.6%). ␭ 212, 292, 336 nm; log⑀ 4.44, 4.29, 4.33.
max
␯
1690 (COOCH3), 1605, 1570, 1513, 1505, 1328, 1315, 1265,
max
␭max 228, 278 nm; log⑀ 4.25, 3.83. ␯max 1690 (COOCH3), 1610, 1590,
1242, 1205, 1175, 1130, 1100, 1047, 1000, 974, 965, 882, 854, 842,
830, 820, 768 cm–1. 1H n.m.r. (400 MHz, 325 K) ␦ 7.47, d, J 8 Hz,
2×ArH; 7.22, d, J 15.8 Hz, C=CH; 7.11, s, ArH; 6.91, d, J 8 Hz, 2×ArH;
6.87, d, J 15.8 Hz, HC=C; 6.69, s, ArH; 3.93, s, OCH3; 3.89, s, OCH3;
3.83, s, OCH3; 3.66, s, COOCH3; 3.44, t, J 7.2 Hz, CH2; 2.95, t, J 7.2
Hz, CH2; 2.86, br s, NCH3. 13C n.m.r. (100 MHz) ␦ 159.1 (C), 156.7 (C),
148.6 (C), 147.9 (C), 130.5 (C), 129.4 (C), 129.0 (C),128.2 (CH), 128.0
(CH), 127.5 (CH), 123.4 (CH), 114.1 (CH), 113.1 (CH), 108.4 (CH),
108.3 (CH), 55.9 (CH3), 55.2 (CH3), 52.6 (CH3), 52.4 (CH3), 51.0
(CH2), 50.2 (CH2), 35.0 (CH3), 31.9 (CH2), 31.1 (CH2). Mass spectrum
m/z 385 (M+, 60%), 354 (2), 310 (7), 283 (88), 252 (64), 237 (24), 204
(28), 175 (27), 145 (36), 121 (83), 102 (100), 69 (12), 58 (57).
1514, 1310, 1260, 1220, 1205, 1160, 1135, 1100, 1028, 1000, 875, 808,
768 cm–1. 1H n.m.r. (400 MHz) ␦ 6.80–6.58, m, 5×ArH; 3.84, s, OCH3;
3.82, s, 2×OCH3; 3.80, s, OCH3; 3.68 and 3.60, 2×br s, COOCH3 of
both conformers; 3.42–3.28, m, CH2N; 2.92–2.68, m, 3×CH2; 2.82, br
s, NCH3. 13C n.m.r. (100 MHz) ␦ 156.7 (C), 156.3 (C), 148.7 (C), 147.3
(C), 147.2 (C), 134.3 (C), 132.0 (C), 128.6 (C), 120.3 (CH), 112.9
(CH), 111.9 (CH), 111.2 (CH), 55.9 (CH3), 55.8 (CH3), 55.7 (CH3), 52.4
(CH3), 50.9 (CH2), 50.3 (CH2), 37.5 (CH2), 35.0 (CH3), 34.4 (CH2),
31.0 (CH2), 30.4 (CH2). Mass spectrum m/z 417 (M+, 14%), 328 (4),
296 (6), 266 (34), 234 (51), 179 (20), 151 (85), 102 (89), 69 (40), 58
(100).
Polysignine (1)
Methyl N-[2-(2-[2-(3,4-Dimethoxyphenyl)ethenyl]-4,5-dimethoxy-
phenyl)ethyl]-N-methylcarbamate (8)
A mixture of the carbamate (9) (2.2 g) and lithium aluminium
hydride (1.0 g) in dry tetrahydrofuran (30 ml) was refluxed for 3 h.
Water (10 ml) was added dropwise followed by dilute ammonium
hydroxide (5 ml). Chloroform extraction afforded polysignine (1) as a
Methyl chloroformate (10 g) was added dropwise to a stirred solu-
tion of the isoquinoline (6) (9.5 g) and triethylamine (10 g) in chloro-
form (100 ml) at 0–10o. The mixture was then stirred at 10–15o for 5 h.
Water (100 ml) was added and the chloroform layer was washed with 3
M HCl (3×50 ml), water (2×50 ml), brine then dried. Removal of the
solvent in vacuum gave a residue which was recrystallized from ethanol
at –10o to give colourless prisms of the carbamate (8) (9.4 g, 85.0%),
m.p. 139–140o (Found: C, 66.3; H, 7.0; N, 3.2. C23H29NO6 requires C,
66.5; H, 7.0; N, 3.4%). ␭max 217, 292sh, 336 nm; log⑀ 4.32, 4.19, 4.36.
pale yellow oil (1.2 g, 61.5%) (Found: M+, 343.2145. Calc. for
12
C
21
1H2914N16O3: M+, 343.2149). ␭ 228, 278 nm; log⑀ 3.61, 3.59.
max
␯
2980–2880, 2860, 2830, 1615, 1585, 1532, 1470, 1462, 1455,
max
1400, 1350, 1250, 1215, 1170, 1140, 1110, 1100, 1040, 825, 770 cm–1.
1H n.m.r. (400 MHz) ␦ 7.07, d, J 8.8 Hz, 2×ArH; 6.82, d, J 8.8 Hz,
2×ArH; 6.67, s, ArH; 6.58, s, ArH; 3.86, s, OCH3; 3.80, s, OCH3; 3.78,
s, OCH3 ; 2.82, br s, 2×CH2 ; 2.76–2.65, m, CH2; 2.41–2.39, m, CH2N;
2.30, s, NCH3. 13C n.m.r. (100 MHz) ␦ 158.0 (C), 147.2 (C), 133.8 (C),
␯
max 1690 (COOCH3), 1605, 1585, 1515, 1328, 1310, 1300, 1264, 1238,
1205, 1185, 1160, 1140, 1100, 1040, 1024, 1004, 964, 865, 768 cm–1.

Short Communications
525
131.8 (C), 129.9 (C), 129.9 (CH), 113.8 (CH), 112.9 (CH), 61.4 (CH2),
55.9 (CH3), 55.3 (CH3), 45.5 (CH3), 37.3 (CH2), 34.9 (CH2), 30.8
(CH2). Mass spectrum m/z 343 (M+, 1%), 298 (1), 164 (3), 121 (12), 69
(22), 58 (100).
Acknowledgments
The author is extremely grateful to Professor W. C. Taylor
for kindly carrying out variable-temperature measurements
1
of the H n.m.r. spectra, proton assignments of carbamates
(7) and (8) as well as measuring the DEPT spectra of carba-
mates (7)–(10). Mr Jim Hutton, Dr Evan Peacock and Dr
Noel Davies of the Central Science Laboratory, Tasmania
University, are thanked for the n.m.r. spectra and high-
resolution mass spectra. Mrs Panit Vedkanchana and
Mr Witoon Ngow of the Silpakorn University Scientific and
Technological Research Equipment Centre are also thanked
for kindly measuring the low-resolution mass spectra.
Methoxypolysignine (2)
A mixture of the carbamate (10) (2.0 g) and lithium aluminium
hydride (1.0 g) in dry tetrahydrofuran (30 ml) was refluxed for 3 h.
Similar workup as above afforded methoxypolysignine (2) as a
pale yellow oil (1.2 g, 67%) (Found: M+, 373.2251. Calc. for
12
C
22
1H3114N16O4: M+, 373.2254). ␭ 228, 278 nm; log⑀ 4.08, 3.76.
max
␯
2980–2880, 2860, 2830, 1610, 1580, 1538, 1530, 1515, 1505,
max
1470, 1464, 1450, 1422, 1415, 1300–1170, 1160, 1140, 1100, 1030,
855, 805, 765 cm–1. 1H n.m.r. (400 MHz) ␦ 6.76, d, J 8.4 Hz, ArH; 6.70,
dd, J 8 and 2 Hz, ArH; 6.67, s, ArH; 6.65, d J 2 Hz, ArH; 6.62, s, ArH;
3.86, s, 2×OCH3; 3.83, s, OCH3; 3.80, s, OCH3; 2.84, br s, 2×CH2;
2.76–2.65, m, CH2; 2.41–2.39, m, CH2N; 2.30, s, NCH3. 13C n.m.r. (100
MHz) ␦ 148.7 (C), 147.5 (C), 147.1 (C), 134.3 (C), 131.6 (C), 129.9
(C), 120.3 (CH), 112.9 (CH), 111.8 (CH), 111.2 (CH), 61.3 (CH2), 55.9
(CH3), 45.3(CH3), 37.7 (CH2), 34.7 (CH2), 30.7 (CH2). Mass spectrum
m/z 373 (M+, 4%), 328 (1), 206 (2), 177 (1), 151 (5), 121 (2), 91 (3), 58
(100).
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Lee, K-H., Chuah, C.-H., and Goh, S.-H., Tetrahedron Lett., 1997,
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Coomes, R. M., Falck, J. R., Williams, D. K., and Stermitz, F. R., J.
Org. Chem., 1973, 38, 3701.
Craig, L. E., and Tarbell, D. S., J. Am. Chem. Soc., 1948, 70, 2783.
Tomita, M., and Yamaguchi, H., Pharm. Bull. (Jpn), 1953, 1, 1
3
4
(Chem. Abstr., 1954, 48, 12132g).