Synthesis of thalprzewalskiinone, a revision of structure

Article abstract of DOI:10.1021/np0101200

A direct comparison of the spectral data for synthetic 2-methyl-6,7-dimethoxy-3′-methoxy-4′-hydroxyoxobenzylisoquinoline iodide (1) and its positional isomer 2-methyl-6,7-dimethoxy-3′-hydroxy-4′-methoxyoxobenzylisoquinoline iodide (2) with the data obtain

Full text of DOI:10.1021/np0101200

J . Nat. Prod. 2001, 64, 823-826
823
Syn th esis of Th a lp r zew a lsk iin on e, a Revision of Str u ctu r e
Tawfeq A. Al-Howiriny,† Michael A. Zemaitis,† Cong-yuan Gao,‡ Chad E. Hadden,§ Gary E. Martin,§
Fu-tyan Lin, and Paul L. Schiff, J r.*,†
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261,
Department of Spectral Analysis, Beijing Medical University, Beijing, 100083, People’s Republic of China, Pharmaceutical
Development, Pharmacia Corporation, Kalamazoo, Michigan 49001, and Department of Chemistry, Faculty of Arts and
Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
Received March 2, 2001
A direct comparison of the spectral data for synthetic 2-methyl-6,7-dimethoxy-3′-methoxy-4′-hydroxy-
oxobenzylisoquinoline iodide (1) and its positional isomer 2-methyl-6,7-dimethoxy-3′-hydroxy-4′-meth-
oxyoxobenzylisoquinoline iodide (2) with the data obtained for the oxobenzylisoquinoline alkaloid
thalprzewalskiinone revealed that the original structural assignment of the alkaloid as 1 was in error.
These results mandate the revision of structure of thalprzewalskiinone to 2-methyl-6,7-dimethoxy-3′-
hydroxy-4′-methoxyoxobenzylisoquinoline iodide (2).
In 1999, a new oxobenzylisoquinoline alkaloid, thalprze-
walskiinone, was isolated from the roots of the ancient
Chinese medicinal herb Thalictrum przewalskii Maxim.
(Ranunculaceae).1 The structure of this quaternary alkaloid
was assigned as 2-methyl-6,7-dimethoxy-3′-methoxy-4′-
hydroxyoxobenzylisoquinoline iodide (1) on the basis of a
consideration of the available spectral data.1 However,
since it was not possible to exclude that thalprzewalskii-
none might correspond to the positional isomer of 1,
2-methyl-6,7-dimethoxy-3′-hydroxy-4′-methoxyoxobenzyl-
isoquinoline (2), it was decided to undertake a synthesis
of both oxobenzylisoquinolines 1 and 2 in order to unam-
biguously assign the structure of the natural isolate.
isoquinoline alkaloids rugosinone (6,7-methylenedioxy-2′-
hydroxy-3′,4′-dimethoxyoxobenzylisoquinoline)2 and thalmi-
crinone (5,6,7,4′-tetramethoxyoxobenzylisoquinoline).3 The
first part involved the preparation of the Reissert com-
pound 2-benzoyl-1-cyano-6,7-dimethoxy-1,2-dihydroisoquin-
oline (3) from 6,7-dimethoxyisoquinoline.2-5 This Reissert
compound served as the common top-half for each of the
two isomeric oxobenzylisoquinolines 1 and 2. The second
part involved coupling the Reissert anion (prepared via
treatment of Reissert compound 3 with NaH in DMF) with
the appropriate aldehyde (either O-benzylvanillin or O-
benzylisovanillin)6 to afford the respective carbinols 3′-
methoxy-4′-benzyloxyphenyl-1-(6,7-dimethoxyisoquinolyl)
carbinol (4) and 3′-benzyloxy-4′-methoxyphenyl-1-(6,7-
dimethoxyisoquinolyl) carbinol (5). These alcohols under-
went facile oxidation with chromic acid2,3 to yield the
respective ketones, 6,7-dimethoxy-3′-methoxy-4′-benzyloxy-
oxobenzylisoquinoline (6) and 6,7-dimethoxy-3′-benzyloxy-
4′-methoxyoxobenzylisoquinoline (7), which were subse-
quently debenzylated to 6,7-dimethoxy-3′-methoxy-4′-
hydroxyoxobenzylisoquinoline (8) and 6,7-dimethoxy-3′-
hydroxy-4′-methoxyoxobenzylisoquinoline (9), respectively,
on treatment with HCl/HOAc. Quaternization of tertiary
amines 8 and 9 with MeI in MeCN afforded the desired
compounds 1 and 2, respectively.
A consideration of the UV spectral data (MeOH) for
oxobenzylisoquinolines 1 and 2 with thalprzewalskiinone
showed great similarity, as seen in Table 1. All three
compounds had UV spectral maxima at 256, 302, and 326-
327 nm. However, in the presence of strong alkali (0.1 N
methanolic NaOH), compound 1 displayed an intense
bathochromic shift (+52 nm) of the 327 nm band to 379
nm, consistent with the presence of the phenolic hydroxy
group at C-4′ (para to the carbonyl carbon).7 A review of
the UV spectra of several known phenolic oxobenzyliso-
quinoline alkaloids is likewise consistent with these ob-
servations. The UV spectrum of gandharamine (6,7-
dimethoxy-4′-hydroxyoxobenzylisoquinoline) showed ab-
sorption maxima at 255 nm (log ꢀ 4.07) and 316 (3.65) nm,
with the addition of strong alkali producing a pronounced
bathochromic shift (+49 nm) of the latter band to 365 (3.89)
nm.8 Furthermore, the UV spectrum of longifolonine (6-
methoxy-7-hydroxy-4′-hydroxyoxobenzyl-3,4-dihydroiso-
quinoline) was characterized by absorption maxima at 231
and 295 nm, with the addition of strong base also resulting
The synthesis of these two compounds was accomplished
in a conventional, two-part manner using well-established
chemistry as described in the synthesis of the oxobenzyl-
* To whom correspondence should be addressed. Tel: (412) 648-8462.
Fax: (412) 383-7436. E-mail: pschiff+@pitt.edu.
† School of Pharmacy, University of Pittsburgh.
‡ Beijing Medical University.
§ Pharmacia Corporation.
Department of Chemistry, University of Pittsburgh.
10.1021/np0101200 CCC: $20.00
© 2001 American Chemical Society and American Society of Pharmacognosy
Published on Web 05/31/2001

824 J ournal of Natural Products, 2001, Vol. 64, No. 6
Notes
Ta ble 1. MP and UV Spectral Data (nm/log ꢀ) for Compounds
1 and 2 Iodides and Thalprzewalskiinone Iodide
natural
thalprzewalskiinone
1
2
iodide1
mp
174-175 °C 196-197 °C amorphous residue
(Me2CO)
(Me2CO)
UV (MeOH)
220 (4.43)
256 (4.57)
302 (4.04)
327 (4.17)
256 (4.59)
256 (4.54)
302 (4.05)
327 (4.11)
255 (4.57)
256 (4.38)
302 (3.89)
326 (3.94)
255 (4.55)
UV (MeOH +
0.1 N methanolic
NaOH)
323 (4.05)
379 (4.23)
318 (4.11)
317 (3.95)
allows a much closer agreement between the carbon
chemical shift of the 4′-OCH3 in phenol 2 (δ 57.7) and the
methoxy in thalprzewalskiinone (δ 56.2) (+1.5 Hz) than
between the 3′-OCH3 in phenol 1 (δ 60.4) and the methoxy
in thalprzewalskiinone (δ 56.2) (+4.2 Hz). The chemical
shift of C-5′ in phenol 1 was δ 133.2 and that of the same
carbon in phenol 2 was δ 127.3. The chemical shift of C-5′
in thalprzewalskiinone (δ 127.0) is characterized by sig-
nificantly more agreement with that of phenol 2 (+0.3 Hz)
than that of phenol 1 (+6.2 Hz). Similarly, the chemical
shift of C-6′ in phenol 1 was δ 120.6, and that of the same
carbon in phenol 2 was δ 113.8. Thus, the chemical shift
of C-6′ in thalprzewalskiinone (δ 112.4) is found to be much
more in agreement with that of phenol 2 (+1.4 Hz) than
that of phenol 1 (+8.2 Hz). These magnetic resonance
spectral considerations are complimentary to the previous
ultraviolet data and mandate the revision of structure of
thalprzewalskiinone to 2-methyl-6,7-dimethoxy-3′-hydroxy-
4′-methoxyoxobenzylisoquinoline iodide (2).
in a pronounced shift (+50 nm) of the latter band to 345
nm.7 By contrast, both compound 2 and natural thalprze-
walskiinone underwent only a weak bathochromic shift
(+15-16 nm) of the 302 nm band to 317-318 nm. This
weak shift is characteristic of the presence of the phenolic
hydroxy group in compound 1 at C-3′ (meta to the carbonyl
carbon).9
Therefore, a comparison of the UV absorption band shift
behavior of isomers 1 and 2 in strongly alkaline medium
with thalprzewalskiinone iodide prompts us to conclude
that thalprzewalskiinone is identical to 2.
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. The UV spectra
were obtained in MeOH on a Hewlett-Packard HP-845 UV-
vis spectrophotometer. The IR spectra were measured on a
Nicolet Impact 410 spectrophotometer as liquid films on KBr
disks. Melting points were determined on a Fisher-J ohns hot-
1
13
stage apparatus and are uncorrected. H and NMR spectra
were recorded in CDCl3 or CD3OD on a Bruker model WH-
300 spectrometer operating at 300 and 75 MHz, respectively.
The HSQC and HMBC experiments were performed in DMSO-
d6 on Varian INOVA spectrometers operating at a proton
observation frequency of 399.803, 499.791, and 599.754 MHz.
These instruments were equipped with a Nalorac MIDTG
microdual obtained from Nalorac Cryogenics Corp, Martinez,
CA. MS analysis was performed on an Extrel ELQ400 quad-
rupole mass spectrometer equipped with a DCI Probe HP
direct probe from Vacumetrics Inc. or on a Hewlett-Packard
5971A mass spectrometer. High-resolution mass spectra were
recorded on a Fisons VG Autospec spectrometer or a Fison VG
Analytical 70-G spectrometer. FABMS was obtained using VG
Analytical 70-G or Fisons VG Autospec spectrometer with
m-nitrobenzyl alcohol (MNBA) as the matrix. Si gel was used
for column chromatography, and TLC was performed using 5
× 20 cm precoated TLC sheets of silica gel 60 F254, 0.2 mm
layer thickness (E. Merck). Chemicals were purchased from
Aldrich Chemical Co. Organic solvents such as Et2O, CH2Cl2,
and CHCl3 that were used in partitioning procedures were
dried over anhydrous Na2SO4 and filtered prior to evaporation.
P r ep a r a tion of 1-Cya n o-2-ben zoyl-6,7-d im eth oxyiso-
qu in olin e (3). To 6,7-dimethoxyisoquinoline2-4 (5.0 g, 0.026
mol) in CH2Cl2 (300 mL) was added a solution of KCN (13.6 g,
0.209 mol) in H2O (60 mL). Benzoyl chloride (13.6 g, 11.25 mL,
0.097 mol) was added over 30 min under N2 and the mixture
allowed to stand at room temperature for 1 h. An additional
With regard to the magnetic resonance spectral data, it
may be reasonably anticipated that any significant differ-
ences in chemical shifts between positional isomers 1 and
2 would affect the following: first, the multiplicity and
chemical shift of the H-2′, H-5′, and H-6′ protons; second,
the chemical shift of the protons found on the C-3′ or C-4′
aromatic methoxy group; and third, the carbon chemical
shifts of the C-2′, C-3′, C-4′, C-5′, and C-6′ atoms.
The 1H NMR spectrum of phenol 1 revealed the presence
of H-6′ as a one-proton doublet at δ 6.85 (J ) 6.6 Hz), while
the same proton was observed as a one-proton doublet at
δ 7.02 (J )8.4 Hz) in phenol 2. The H-6′ proton was found
at δ 7.06 in thalprzewalskiinone,1 being much closer in
chemical shift to that of phenol 2 (+0.04 Hz) than to that
of phenol 1 (+0.21 Hz). This distinct difference in the
chemical shift of H-6′ is another compelling piece of
evidence in support of the identity of thalprzewalskiinone
as phenol 2. The chemical shift of C-3′ in phenol 1 was δ
155.9, and that of the same carbon in phenol 2 was δ 149.4.
Although the C-4′ in thalprzewalskiinone was originally
assigned the chemical shift of δ 147.6,1 reversing the C-3′
and C-4′ assignments is consistent with the results of the
synthesis and the ultraviolet spectral data. Thus, the
reassignment of the signal at δ 147.6 to C-3′ allows a
significantly closer agreement with phenol 2 (+1.8 Hz) than
with phenol 1 (+8.3 Hz). Similarly, this reassignment

Notes
J ournal of Natural Products, 2001, Vol. 64, No. 6 825
quantity of KCN (6.8 g, 0.105 mol) in H2O (30 mL) was added
and the mixture kept at room temperature for an additional
4 h. The CH2Cl2 layer was separated, partitioned consecutively
with H2O (2 × 100 mL), 2 M HCl (2 × 100 mL), 2 M NaOH (2
× 100 mL), and water (2 × 100 mL), and evaporated to
dryness. The resulting residue was crystallized from MeOH
as colorless needles (3.5 g, 42% yield) of 1-cyano-2-benzoyl-
6,7-dimethoxyisoquinoline (3): mp 182-183 °C; UV (MeOH)
λmax (log ꢀ) 226 (4.51), 250 (sh) (4.30), 312 (4.01) nm; IR (KBr)
νmax 2240, 1665, 1630, 1603, 1580, 1515, 1452, 1425, 1345,
1′′), 134.2 (C-4a), 130.1 (C-1′), 128.8 (C-2′′ and C-6′′), 128.2 (C-
4′′), 127.2 (C-3′′ and C-5′′), 126.8 (C-6′), 122.9 (C-8a), 121.4 (C-
4), 112.4 and 112.1 (C-2′ and C-5′), 104.9 and 104.2 (C-5 and
C-8), 70.9 (OCH2), 56.2 (OCH3), 56.2 (OCH3), 56.2 (OCH3);
EIMS m/z 429 [M+] (9), 338 (14), 188 (13), 91 (100).
P r ep a r a tion of 6,7-Dim eth oxy-3′-m eth oxy-4′-h yd r oxy-
oxoben zylisoqu in olin e (8). A solution of 6,7-dimethoxy-3′-
methoxy-4′-benzyloxyoxobenzylisoquinoline (6) (280 mg, 0.652
mmol) in HCl-HOAc (1:1) (20 mL) was refluxed for 2 h. The
solution was cooled, diluted with H2O (40 mL), alkalinized with
NH4OH to pH 8-9, and extracted with Et2O (3 × 50 mL). The
combined Et2O extracts were evaporated to a white residue,
which on crystallization from MeOH afforded 6,7-dimethoxy-
3′-methoxy-4′-hydroxyoxobenzylisoquinoline (8) as white cubic
crystals (140 mg, 64% yield): mp 179-180 °C; UV (MeOH)
λmax (log ꢀ) 240 (4.46), 315 (3.85) nm; UV (MeOH + 2 drops of
0.1 N NaOH) λmax (log ꢀ) 369 (3.88); IR (KBr) νmax 3453, 1650,
1581, 1506, 1488, 1432, 1410, 1286, 1231, 1160, 1138, 1052,
1027, 865, 732 cm-1; 1H NMR (DMSO-d6, 500 MHz) δ 3.78 (3H,
s, OCH3), 3.81 (3H, s, 3H, OCH3), 3.94 (3H, s, OCH3), 6.82 (1H,
d, J ) 8.5 Hz, H-5′), 7.15 (1H, dd, J ) 8.5 Hz, J ) 2.0 Hz,
H-6′), 7.25 (1H, s, H-8), 7.46 (1H, s, H-5), 7.55 (1H, d, J ) 2.0
Hz, H-2′), 7.82 (1H, d, J ) 5.5 Hz, H-4) 8.38 (1H, d, J ) 5.0
Hz, H-3); 13C NMR (CDCl3, 75 MHz) δ 193.5 (CdO), 154 (C-
1), 153.1 (C-7), 151.1 (C-6), 149.7 (C-3′), 148.2 (C-4′), 140.2 (C-
3), 133.8 (C-4a), 128.4 (C-1′), 127.3 (C-6′), 122.1 (C-8a), 121.4
(C-4), 115.3 (C-5′), 112.9 (C-2′), 105.9 (C-5), 103.7 (C-8), 56.2
(OCH3), 55.9 (OCH3), 55.8 (OCH3); HREIMS m/z 339.1091 [M+]
(calcd for C19H17O5N, 339.1106), 151.0393 (calcd for C8H7O3,
151.0395).
1285, 1231, 1146, 1107 cm-1 1H NMR (CDCl3, 400 MHz) δ
;
3.93 (3H, s, OCH3), 3.95 (3H, s, OCH3), 6.01 (1H, d, J ) 7.5
Hz, H-4), 6.52 (1H, s, H-1), 6.73 (1H, s, H-8), 6.86 (1H, s, H-5),
7.54 (5H, m, 5ArH), 8.11 (1H, d, J ) 7.15 Hz, H-3); 13C NMR
(CDCl3, 75 MHz) δ 168.8 (CdO), 150.3 and 149.2 (C-6 and C-7),
133.7 (C-1′), 132.3 and 132.0 (C-3 and C-4′), 130.2 (C-2′), 129.2
(C-3′), 128.7 and 128.4 (C-5′ and C-6′), 124.5 (C-4a), 123.5 (C-
8a), 116.6 (CtN), 110.0 (C-4), 109.6 and 108.7 (C-5 and C-8),
56.3 (OCH3), 56.1 (OCH3), 44.8 (C-1); EIMS m/z 320 [M]+ (27),
215 (7), 189 (25), 146 (5), 105 (100), 77 (43).
P r ep a r a tion of 3′-Meth oxy-4′-ben zyloxyp h en yl-1-(6,7-
d im eth oxyisoqu in olyl)ca r bin ol (4). To NaH (100 mg, 4.2
mmol) suspended in DMF (10 mL) at -10° was added 1-cyano-
2-benzoyl-6,7-dimethoxyisoquinoline (3) (1.0 g, 3.12 mmol) in
DMF (15 mL) over a period of 5 min under N2. After 5 min,
O-benzylvanillin (822 mg, 3.4 mmol) in DMF (10 mL) was
added over 10 min at -10 °C. The mixture was stirred for 2 h
at 0 °C and then allowed to stand at room temperature for an
additional 2 h. The mixture was treated with MeOH (50 mL)
and then evaporated. The residue was dissolved in C6H6 (40
mL), partitioned with H2O (2 × 30 mL), and evaporated. The
resulting residue, consisting primarily of the benzoate ester
of 4, was dissolved in EtOH (25 mL) and hydrolyzed with KOH
(0.2 g) in H2O (10 mL) under reflux for 3 h. The solution was
cooled and evaporated to dryness, and the resulting residue
was partitioned with Et2O (3 × 30 mL). The combined Et2O
extracts were evaporated to afford a white residue, which upon
crystallization from MeOH afforded 3′-methoxy-4′-benzyloxy-
phenyl-1-(6,7-dimethoxyisoquinolyl)carbinol (4) (500 mg, 37%
yield). The alcohol 4 had a mp of 142-143 °C; UV (MeOH)
P r ep a r a tion of 2-Meth yl-6,7-d im eth oxy-3′-m eth oxy-4′-
h yd r oxyoxoben zylisoqu in olin e Iod id e (1). To 6,7-dimeth-
oxy-3′-methoxy-4′-hydroxyoxobenzylisoquinoline (8) (40 mg,
0.118 mmol) in CH3CN (10 mL) was added CH3I (1 mL). The
solution was refluxed for 12 h, cooled, and evaporated to a
yellow residue (49 mg). Treatment of the residue with Me2CO
afforded 2-methyl-6,7-dimethoxy-3′-methoxy-4′-hydroxyoxo-
benzylisoquinoline iodide (1) as yellow crystals (40 mg, 72%
yield): mp 174-175 °C; UV (MeOH) λmax (log ꢀ) 220 (4.43),
256 (4.57), 302 (4.04), 327 (4.17) nm; UV (MeOH + 2 drops of
0.1 N NaOH) λmax (log ꢀ) 323 (4.05), 3.79 (4.23) nm; IR (KBr)
λmax (log ꢀ) 238 (4.68), 278 (3.88), 313 (3.73), 326 (3.72) nm; IR
(KBr) νmax 3500-3200, 1617, 1593, 1510, 1480, 1460, 1407,
1270, 1234, 1159, 1136, 1020 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 3.72 (6H, s, 2-OCH3), 4.01 (3H, s, OCH3), 5.10 (2H, s, OCH2),
6.23 (1H, s, H-R), 6.67 (1H, d, J ) 8 Hz, H-8′), 6.77 (1H, d, J
) 8 Hz, H-6′), 6.92 (1H, s, H-8), 7.09 (1H, s, H-2′), 7.20 (1H, s,
H-5), 7.33 (5H, m, ArH), 7.63 (1H, d, J ) 5.8 Hz, H-4), 8.44
(1H, d, J ) 5.8 Hz, H-3); 13C NMR (CDCl3, 75 MHz) δ 156.5
(OCH3, C-6), 152.9 (OCH3, C-7), 150.0 (C-1 and C-4′), 147.8
(C-3′), 138.2 (C-3), 137.0 and 136.5 (C-1′ and C-1′′), 133.8 (C-
4a), 128.5 (C-2′′ and C-6′′), 127.8 (C-4′′), 127.2 (C-3′′ and C-5′′),
121.0 (C-6′), 120.2 and 120.0 (C-4 and C-8a), 113.8 (C-2′), 111.1
(C-5′), 105.3 (C-5), 103.4 (C-8), 72.5 (C-R), 70.9 (OCH2), 56.1
(OCH3), 56.0 (OCH3), 55.9 (OCH3); EIMS m/z 431 [M+] (100),
416 (10), 340 (27), 324 (8), 188 (25), 91 (19).
νmax 3420,1655, 1583, 1514, 1494, 1430, 1289, 1231, 1164, 1025,
994, 875, 755 cm-1; 1H NMR (DMSO-d6, 600 MHz,) δ 3.71 (3H,
s, OCH3, C-7), 3.85 (3H, s, OCH3, C-3′), 4.06 (3H, s, OCH3,
C-6), 4.13 (3H, s, NCH3), 6.85 (1H, d, J ) 6.6 Hz, H-6′), 6.88
(1H, s, H-8), 7.15 (1H, br s, H-5′), 7.61 (1H, br s, H-2′), 7.85
(1H, s, H-5), 8.42 (1H, d, J ) 6.6 Hz, H-4) 8.66 (1H, d, J ) 7.2
Hz, H-3), 10.94 (1H, s, OH); 13CNMR δ 190.0 (CdO), 162.3
(C-6), 158.1 (C-7), 155.9 (C-3′), 154.7 (C-1), 153.9 (C-4′), 141.2
(C-4a), 141.1 (C-3), 133.2 (C-5′), 130.3 (C-1′), 128.4 (C-4), 126.1
(C-8a), 120.6 (C-6′), 115.9 (C-2′), 111.1 (C-5), 108.7 (C-8), 61.6
(C-6) (OCH3), 60.8 (C-7) (OCH3), 60.4 (C-3′) (OCH3), 50.1
(NCH3); HREIMS m/z 353.1247 [M+ - HI] (calcd for C20H19O5N,
353.1263), 339.1100 (calcd for C19H17O5N, 339.1106).′′
P r ep a r a tion of 3′-Ben zyloxy-4′-m eth oxyp h en yl-1-(6,7-
d im eth oxyisoqu in olyl)ca r bin ol (5). To NaH (100 mg, 4.2
mmol) suspended in DMF (10 mL) at -10 °C was added
1-cyano-2-benzoyl-6,7-dimethoxyisoquinoline (3) (1.0 g, 3.12
mmol) in DMF (15 mL) over a period of 5 min under N2. After
5 min, O-benzylisovanillin (822 mg, 3.4 mmol) in DMF (10 mL)
was added over 10 min at -10 °C. The mixture was stirred
for 2 h at 0 °C and then allowed to stand at room temperature
for an additional 2 h. The mixture was treated with MeOH
(50 mL) and then evaporated to a residue that was dissolved
in C6H6 (40 mL), partitioned with H2O (2 × 30 mL), and
evaporated. The resulting residue, consisting primarily of the
benzoate ester of 5, was dissolved in EtOH (25 mL) and
hydrolyzed by KOH (0.2 g) in H2O (10 mL) under reflux for 3
h. The solution was cooled and evaporated to dryness, and the
resulting residue was treated with Et2O (3 × 30 mL). The
combined Et2O extracts were evaporated to a white residue,
which upon crystallization from MeOH afforded 3′-benzyloxy-
4′-methoxyphenyl-1-(6,7-dimethoxyisoquinolyl)carbinol (5) (430
mg, 32% yield): mp of 140-141 °C; UV (MeOH) λmax 239 (4.68),
278 (3.88), 313 (3.72), 326 (3.57) nm; IR (KBr) νmax 3437, 1622,
P r epar ation of 6,7-Dim eth oxy-3′-m eth oxy-4′-ben zyloxy-
oxoben zylisoqu in olin e (6). To 3′-methoxy-4′-benzyloxyphe-
nyl-1-(6,7-dimethoxyisoquinolyl)carbinol (4) (400 mg, 0.92
mmol) in HOAc (5 mL) was added a solution of Na2CrO4 (620
mg, 3.78 mmol) in HOAc (5 mL). The mixture was heated for
3 min on a steam bath, diluted with H2O (50 mL), alkalinized
with NH4OH to pH 8-9, and partitioned with Et2O (3 × 50
mL). The Et2O extracts were combined and evaporated, and
the resulting residue was treated with MeOH to afford 6,7-
dimethoxy-3′-methoxy-4′-benzyloxyoxobenzylisoquinoline (6)
as yellow crystals (303 mg, 75% yield): mp 170 °C; UV (MeOH)
λ
max (log ꢀ) 237 (4.49), 280 (3.99), 326 (3.97) nm; IR (KBr) νmax
1655, 1591, 1505, 1477, 1415, 1267, 1235, 1157, 1137, 1032,
861, 753 cm-1 1H NMR (CDCl3, 400 MHz) δ 3.95 (3H, s,
;
OCH3), 3.98 (3H, s, OCH3), 4.08 (3H, s, OCH3), 5.24 (2H, s,
OCH2), 6.87 (1H, d, J ) 8.4 Hz, H-5′), 7.17 (1H, s, H-8), 7.35
(6H, m, H-6′ and 5ArH), 7.48 (1H, s, H-5), 7.73 (2H, d, J ) 1.5
Hz, H-4 and H-2′), 8.45 (1H, d, J ) 5.2 Hz, H-3); 13C NMR
(CDCl3, 75 MHz) δ 193.8 (CdO), 153.6 and 153.4 (C-6 and C-7),
153.1 (C-1), 151.2 (C-4′), 149.6 (C-3′), 139.8 (C-3), 136.3 (C-

826 J ournal of Natural Products, 2001, Vol. 64, No. 6
Notes
1570, 1510, 1481, 1434, 1406, 1272, 1235, 1158, 1138, 1022,
(1H, s, H-5), 7.80 (1H, d, J ) 5.6 Hz, H-4), 8.35 (1H, d, J ) 5.6
Hz, H-3); 13C NMR δ 195.1 (CdO), 155.5 (C-1), 154.4 (C-7),
154.3 (C-4′), 152.2 (C-6), 147.8 (C-3′), 141.9 (C-3), 134.8 (C-
4a), 130.5 (C-1′), 125.5 (C-6′), 123.2 (C-8a), 122.5 (C-4), 117.8
(C-2′), 112.8 (C-5′), 107.1 (C-5), 104.7 (C-8), 57.3 (OCH3), 57.2
(OCH3), 56.9 (OCH3); HREIMS m/z 339.1091 [M+] (calcd for
C19H17O5N, 339.1106), 188.0709 (calcd for C11H10O2N, 188.0711),
151.0393 (calcd for C8H7O3, 151.0395).
963, 754 cm-1 1H NMR (CDCl3, 400 MHz) δ 3.72 (3H, s,
;
OCH3), 3.83 (3H, s, OCH3), 4.02 (3H, s, OCH3), 5.03 (2H, s,
OCH2), 6.22 (1H, s, 1H, H-′), 6.81 (1H, d, J ) 8.2 Hz, H-5′),
6.86 (1H, s, H-8), 6.95 (1H, dd, J ) 8.2 Hz and 1.9 Hz, H-6′),
7.08 (2H, s, H-2′ and H-5), 7.29 (5H, m, ArH), 7.56 (1H, d, J )
5.8 Hz, H-4), 8.40 (1H, d, J ) 5.8 Hz, H-3); 13C NMR NMR
(CDCl3, 75 MHz) δ 156.4 (C-6), 152.9 (C-7), 149.9 (C-1), 149.4
(C-4′), 148.4 (C-3′), 138.2 (C-3), 136.9 (C-1′′), 135.9 (C-1′), 133.7
(C-4a), 128.4 (C-2′′ and C-6′′), 127.7 (C-4′′), 127.3 (C-3′′ and
C-5′′), 120.9 (C-6′), 120.8 (C-8a), 119.9 (C-4), 113.4 (C-2′), 111.6
(C-5′), 105.2 (C-5), 103.3 (C-8), 72.4 (C-R), 70.9 (OCH2), 56.1
(OCH3), 56.0 (OCH3), 55.8 (OCH3); EIMS m/z 431 [M+] (88),
416 (5), 340 (70), 324 (85), 310 (24), 280 (33), 218 (47), 188
(80), 91 (100).
P r ep a r a tion of 2-Meth yl-6,7-d im eth oxy-3′-h yd r oxy-4′-
m eth oxyoxoben zylisoqu in olin e Iod id e (2). To 6,7-dimeth-
oxy-3′-hydroxy-4′-methoxyoxobenzylisoquinoline (9) (30 mg,
0.088 mmol) in CH3CN (10 mL) was added CH3I (1 mL). The
solution was refluxed for 12 h, cooled, and evaporated to a
yellow residue (42 mg). Treatment of the residue with Me2CO
afforded 2-methyl-6,7-dimethoxy-3′-hydroxy-4′-methoxyoxo-
benzylisoquinoline iodide (2) as yellow crystals (33 mg, 77%
yield): mp 196-197 °C; UV (MeOH) λmax 256 (4.54), 302 (4.05),
327 (4.11) nm; UV (MeOH + 2 drops of 0.1 N NaOH) λmax (log
ꢀ) 318 (4.11) nm; IR (KBr) νmax 3500-3300,1655, 1511, 1498,
P r ep a r a tion of 6,7-Dim eth oxy-3′-ben zyloxy-4′-m eth -
oxyoxoben zylisoqu in olin e (7). To 3′-benzyloxy-4′-methoxy-
phenyl-1-(6,7-dimethoxyisoquinolyl) carbinol (5) (400 mg, 0.92
mmol) in HOAc (5 mL) was added a solution of Na2CrO4 (620
mg, 3.78 mmol) in HOAc (5 mL). The mixture was heated for
3 min on a steam bath, diluted with H2O (50 mL), alkalinized
with NH4OH to pH 8-9, and partitioned with Et2O (3 × 50
mL). The Et2O extracts were combined, partitioned with H2O
(3 × 100 mL), and evaporated. Treatment of the resulting
residue with MeOH afforded 6,7-dimethoxy-3′-benzyloxy-4′-
methoxyoxobenzylisoquinoline (7) as crystals (320 mg, 80%
yield): mp 158-159 °C; UV (MeOH) λmax 238 (4.52), 282(3.86),
326 (3.85) nm; IR (KBr) νmax 1655, 1591, 1578, 1505, 1480,
1
1434, 1290, 1164, 1144, 1015, 995 cm-1; H NMR (DMSO-d6,
400 MHz) δ 3.70 (3H, s, OCH3, C-7), 3.86 (3H, s, OCH3, C-4′),
4.05 (3H, s, OCH3, C-6), 4.11 (3H, s, NCH3), 6.85 (1H, s, H-8),
7.02 (1H, d, J ) 8.4 Hz, H-6′), 7.21 (1H, br s, H-5′), 7.40 (1H,
br s, H-2′), 7.85 (1H, s, H-5), 8.41 (1H, d, J ) 6.8 Hz, H-4)
8.65 (1H, d, J ) 6.4 Hz, H-3), 9.87 (1H, s, OH); 13C NMR δ
188.1 (CdO), 159.2 (C-6), 157.0 (C-4′), 154.5 (C-7), 150.9 (C-
1), 149.4 (C-3′), 137.9 (C-4a), 137.9 (C-3), 128.1 (C-1′), 127.3
(C-5′), 125.3 (C-4), 122.9 (C-8a), 116.2 (C-2′), 113.8 (C-6′), 108.0
(C-5), 105.5 (C-8), 58.6 (C-6) (OCH3), 57.8 (C-7) (OCH3), 57.7
(C-4′) (OCH3), 47.0 (NCH3); HREIMS m/z 353.1271 [M+ - HI]
(calcd for C20H19O5N, 353.1263), 339.1102 (calcd for C19H17O5N,
339.1106), 150.9995 (calcd for C8H7O3, 150.9991).
1
1434, 1268, 1234, 1157, 1138, 1020, 861, 753 cm-1; H NMR
(CDCl3, 400 MHz) δ 3.93 (6H, s, OCH3), 4.05 (3H, s, OCH3),
5.18 (2H, s, OCH2), 6.90 (1H, d, J ) 8.4 Hz, H-5′), 7.13 (1H, s,
H-8), 7.35 (6H, m, H-6′ and 5ArH), 7.48 (1H, s, H-5), 7.64 (1H,
d, J ) 5.4 Hz, H-4), 7.70 (1H, d, J ) 1.8 Hz, H-2′), 8.42 (1H,
d, J ) 5.4 Hz, H-3); 13C NMR NMR (CDCl3, 75 MHz) δ 193.8
(CdO), 154.4 (C-1), 153.7 (C-7), 153.3 (C-6), 151.0 (C-4′), 148.1
(C-3′), 139.9 (C-3), 136.5 (C-1′′), 134.0 (C-4a), 129.7 (C-1′), 128.6
(C-2′′ and C-6′′), 128.0 (C-4′′), 127.5 (C-3′′ and C-5′′), 126.9 (C-
6′), 122.8 (C-8a), 121.2 (C-4), 114.6 (C-2′), 110.4 (C-5′), 104.8
and 104.1 (C-5 and C-8), 70.9 (OCH2), 56.2 (OCH3), 56.2
(OCH3), 56.1 (OCH3); EIMS m/z 429 [M+] (35), 400 (20), 338
(100), 324 (40), 308 (37), 296 (25), 188 (36), 152 (33), 91 (61).
P r ep a r a tion of 6,7-Dim eth oxy-3′-h yd r oxy-4′-m eth oxy-
oxoben zylisoqu in olin e (9). A solution of 6,7-dimethoxy-3′-
benzyloxy-4′-methoxyoxobenzylisoquinoline (7) (300 mg, 0.70
mmol) in of HCl-HOAc (1:1) (20 mL) was refluxed for 2 h.
The solution was cooled, diluted with H2O (40 mL), alkalinized
with NH4OH to pH 8-9, and extracted with Et2O (3 × 50 mL).
The combined Et2O extracts were evaporated to a residue that
upon crystallization from MeOH afforded 6,7-dimethoxy-3′-
hydroxy-4′-methoxyoxobenzylisoquinoline (9) as pale yellow
crystals (180 mg, 76% yield): mp 150-151 °C; UV (MeOH)
Ack n ow led gm en t. The authors gratefully acknowledge
the partial financial support of King Saud University (TAA).
Su p p or tin g In for m a tion Ava ila ble: Tables of the proton and
carbon chemical shift assignments and long-range connectivities
observed in the GHMBC spectra of compounds 1 and 2. This material
is available free of charge via the Internet at http://pubs.acs.org.
Refer en ces a n d Notes
(1) Al-Rehaily, A. J .; Sharaf, M. H. M.; Zemaitis, M. J .; Gao, C.-Y.; Martin,
G. E.; Chadden, C. E.; Thamann, T. J .; Lin, F.-T.; Schiff, P. L., J r. J .
Nat. Prod. 1999, 62, 146-148.
(2) Cheng, H. Y.; Doskotch, R. W. J . Nat. Prod. 1980, 43, 151-156.
(3) Al-Khalil, S.; Schiff, P. L., J r. J . Nat. Prod. 1985, 48, 989-991.
(4) Birch, A. J .; J ackson, A. H.; Shannon, P. V. R. J . Chem. Soc., Perkin
Trans. 1 1974, 2190-2194.
(5) Birch, A. J .; J ackson, A, H.; Shannon, P. V. R. J . Chem. Soc., Perkin
Trans. 1 1974, 2185-2189.
(6) Schiff, P. L., J r. The Isolation and Characterization of the Alkaloids
of Thalictrum minus L. var. adiantifolium Hort. Ph.D. Dissertation,
The Ohio State University, Columbus, OH, 1967; p 163.
(7) Bick, I. R. C.; Sevenet, T.; Sinchai, W.; Skelton, B.; White, A. H. Aust.
J . Chem. 1981, 34, 195-207.
(8) Abu Zarga, M. H.; Miana, G. A.; Shamma, M. Heterocycles 1982, 18,
63-65.
(9) Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrophotometric
Identification of Organic Compounds, 5th ed.; J ohn Wiley & Sons:
New York, 1991; p 181.
λ
max 238 (4.45), 280 (3.78), 329 (3.78) nm; UV (MeOH + 2 drops
of 0.1 N NaOH) λmax (log ꢀ) 288 (3.79), 332 (3.80) nm; IR (KBr)
νmax 3500-3350,1655, 1606, 1506, 1483, 1437, 1271, 1234,
1157, 1134, 859, 755 cm-1; H NMR (DMSO-d6, 400 MHz) δ
1
3.74 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.91 (3H, s, OCH3),
6.97 (1H, d, J ) 8.0 Hz, H-5′), 7.18 (1H, s, H-8), 7.20 (1H, dd,
J ) 8.8 and 2.4 Hz, H-6′), 7.29 (1H, d, J ) 2,4 Hz, H-2′), 7.44
NP0101200