Chemistry of renieramycins. Part 4. Synthesis of a simple natural marine product, 6-hydroxy-7-methoxyisoquinolinemethanol

Article abstract of DOI:10.1248/cpb.52.282

6-Hydroxy-7-methoxyisoquinolinemethanol (15) and mimosamycin (1) were recently isolated from a marine sponge, Haliclona sp. The former was prepared in ten steps from vanillin (22) in 26% overall yield using an isopropyl for phenol protection.

Full text of DOI:10.1248/cpb.52.282

282
Notes
Chem. Pharm. Bull. 52(2) 282—286 (2004)
Vol. 52, No. 2
Chemistry of Renieramycins. Part 4. Synthesis of a Simple Natural
Marine Product, 6-Hydroxy-7-methoxyisoquinolinemethanol
*
Naoki SAITO, Chieko TANAKA, Tomoo SATOMI, Chigusa OYAMA, and Akinori KUBO
Meiji Pharmaceutical University; 2–522–1 Noshio, Kiyose, Tokyo 204–8588, Japan.
Received September 29, 2003; accepted November 4, 2003
6-Hydroxy-7-methoxyisoquinolinemethanol (15) and mimosamycin (1) were recently isolated from a marine
sponge, Haliclona sp. The former was prepared in ten steps from vanillin (22) in 26% overall yield using an iso-
propyl for phenol protection.
Key words Pomeranz–Fritsch synthesis; phenol; marine natural product; isoquinoline; isopropyl protecting group
During the past two decades, mimosamycin (1) and re- tive deprotection could be achieved by using TiCl4 at room
nierone (2) and its derivatives (3—14) have been isolated temperature, leaving methoxyl-substituted arenas unaf-
from marine sponges belonging to genera Reniera,1—3) fected.19,20) According to the procedure of Rozwadowska and
Xestospongia,4—7) Cribrochalina,8,9) Haliclona,10—12) and Pet- Brozda,21) a two-phase system composed of the starting ma-
rosia,13,14) as well as a nudibranch, Jorunna funebris.15—17) terial 16 with potassium cyanide and benzoyl chloride in
Recently, 1 and 6-hydroxy-7-methoxyisoquinolinemethanol dichloromethane and water gave the Reissert compound 17
(15) were isolated from the cytotoxic fractions of an aqueous in 75% yield, which, upon treatment with formalin in the
extract of a marine sponge Haliclona sp., and the structure of presence of a phase transfer catalyst, benzyltriethylammo-
15 was established by conventional spectroscopic methods, nium chloride (TEBA), in 50% aqueous NaOH and aceto-
particularly, nuclear Overhauser enhancement (NOE) experi- nitrile at room temperature afforded [7-methoxy-6-(1-
ments.12) In the course of our chemical studies of these nat- methylethoxy)-1-isoquinolyl]methanol (18) in 91% yield.
ural marine products, we have been interested in the structure
The direct conversion of 18 into the final goal 15 under a
of 15 because the biosynthetic pathway of this natural prod- variety of conditions was unsuccessful. It was difficult to re-
uct may be different from those of 2—14. We describe herein move the inorganic materials from the crude products be-
the five-steps synthesis of 15 from known compound 16.18)
cause of the poor solubility of 15 in organic solvents. Ac-
To establish the practical synthesis of 15, it is important to cordingly, a sequence of reactions was examined. Treatment
select a protecting group for the phenol. We chose an iso- of 18 with acetic anhydride and triethylamine in
propyl group to protect the phenolic function because selec- dichloromethane afforded acetate 19 in quantitative yield,
Fig. 1
To whom correspondence should be addressed. e-mail: naoki@my-pharm.ac.jp
© 2004 Pharmaceutical Society of Japan

February 2004
283
Table 1. NMR Data for Diacetates 21 and 27
Compound 21
Compound 27
C no.
13C
1H mult., J (Hz)
HMBC
NOESY
13C
1H mult., J (Hz)
HMBC
NOESY
1
3
4
5
6
7
8
9
152.6 s
140.7 d
120.8 d
119.9 d
144.1 s
151.5 s
104.2 d
126.0 s
132.1 s
65.5 t
153.6 s
142.5 d
120.2 d
106.3 d
153.8 s
141.5 s
117.8 d
122.1 s
136.6 s
65.5 t
8.44 d (5.6)
7.56 d (5.6)
7.52 s
C-1, C-4, C-10
C-3, C-5, C-9
C-4, C-6, C-7, C-9
4-H
3-H
8.45 d (5.6)
7.55 d (5.6)
7.18 s
C-1, C-4, C-10
C-3, C-5, C-9
C-4, C-6, C-7, C-9
4-H
3-H, 5-H
4-H, OCH3
7.48 s
C-1, C-6, C-7, C-10
OCH3, 11-H2
8-H
7.77 s
C-6, C-7, C-10
11-H2
8-H
10
11
13
14
16
17
OCH3
5.70 s
2.16 s
C-1, C-9, C-13
C-13
5.61 s
2.15 s
C-1, C-9, C-13
C-13
170.8 s
20.9 q
168.6 s
20.6 q
170.7 s
20.9 q
168.9 s
20.6 q
2.39 s
3.98 s
C-16
C-6
2.39 s
3.98 s
C-16
C-6
56.1 q
8-H
56.6 q
5-H
Fig. 2
which upon treatment with TiCl4 gave phenol 20 in 67%
yield. After hydrolyzing 20 with 10% aqueous LiOH and
chloroform, the pH of the mixture was brought to 6—7 using
acetic acid, and the reaction mixture was concentrated in
vacuo to give a residue that was subjected to purification by
silica gel column chromatography to afford a solid, the re-
crystallization of which from ethanol gave 6-hydroxy-7-
methoxyisoquinolinemethanol (15) in 73% yield. Thus, we
succeeded in preparing the structure reported for the natural
product, but the properties of the 1H- and 13C-NMR spectrum
could not be identical with those reported in the literature.
All the proton and carbon 13 signals of 15 reported by
Rashid and co-workers12) revealed a distinct upfield shift
comparable to synthetic 15. However, the spectral data of
Fig. 3
synthetic 15 in dimethylsulfoxide (DMSO)-d6 with two drops correlation (HMBC) NMR experiments and NOE (Fig. 2).
of trifluoroacetic acid (TFA)-d was in excellent agreement These spectra clearly showed that acetates 21 and 27 were
with the reported data of 15. This result indicates that the re- identical.
ported sample may be produced in the form of a salt during
In summary, we succeeded in the practical synthesis of a
simple natural marine product 15 from vanillin (22) in 26%
the extraction and isolation procedure.22)
Finally, the fully assigned 13C-NMR signals for diacetates overall yield. There are scant data on the biosynthesis of sim-
21 and 2723) that were obtained by acetylation of 15 and 30 ple natural marine products 3—14; however, it is interesting
with acetic anhydride in pyridine were recorded (Table 1). that they have often been isolated, together with their dimeric
Unambiguous assignment was made possible by long-range analogues. He and Faulkner suggested that renieramycin-type
1H–13C connectivity, which was determined through a series compounds (such as 31a) underwent oxidative cleavage
1
of H detected two-dimensional heteronuclear multiple bond degradation to give mimosamycin (1) and renierone (2).3)

284
Vol. 52, No. 2
Thus, we believe that it may be possible to discover a new Jϭ6.3 Hz, OCH), 5.13 (2H, s, CH2OH), 7.06, 7.11 (each 1H, s, ArH), 7.43
(1H, d, Jϭ5.9 Hz, 4-H), 8.31 (1H, d, Jϭ5.9 Hz, 3-H). 13C-NMR d: 21.7 (q,
type of renieramycin compound, such as 32.
CH(CH3)2), 56.1 (q, OCH3), 61.3 (t, CH2), 71.1 (d, OCH), 101.6 (d), 107.5
(d), 119.1 (d), 120.4 (s), 132.8 (s), 139.0 (d), 151.2 (s), 151.4 (s), 154.7 (s).
IR (KBr) cmϪ1: 3250, 3000, 1480, 1280, 1240, 1210, 1170. MS m/z (%):
Experimental
247 (Mϩ, 70), 205 (43), 204 (100), 190 (36), 176 (77), 175 (2), 174 (11),
All melting points were determined with a Yanagimoto micromelting
point apparatus and are uncorrected. IR spectra were obtained with a Hitachi
260-10 IR Fourier-transform spectrometer. H-NMR spectra were recorded
162 (15), 161 (18), 133 (14). Anal. Calcd for C14H17NO3: C, 67.99; H, 6.93;
N, 5.66. Found: C, 67.74; H, 6.92; N, 5.37.
1
at 270 MHz on a JEOL JNM-EX 270 spectrometer and at 300 MHz on a
JEOL-AL300 spectrometer. 13C-NMR spectra were recorded at 67.5 MHz
[multiplicity determined from off-resonance decoupled or distortionless en-
hancement by polarization transfer (DEPT) spectra]. NMR spectra were
measured in CDCl3, and chemical shifts were recorded in dH values relative
to (CH3)4Si as the internal standard. Mass spectra were recorded on a JMS-
700 instrument with a direct inlet system operating at 70 eV. Elemental
analyses were conducted on YANACO MT-6 CHN CORDER elemental ana-
lyzers.
N-Benzoyl-1-cyano-7-methoxy-6-(1-methylethoxy)-1,2-dihydroiso-
quinoline (17) Benzoyl chloride (3.48 ml, 30 mmol) was added dropwise
for 5 min to a stirred solution of 16 (1.09 g, 5 mmol) in dichloromethane
(10 ml) and KCN (2.61 g, 40 mmol) in water (10 ml). The mixture was
stirred for an additional 2 h, diluted with water (30 ml), and extracted with
chloroform (30 mlϫ3). The combined extracts were washed with brine
(30 ml), dried, and concentrated in vacuo to give a residue, the recrystalliza-
tion of which from ethyl acetate–ether gave 17 (1.30 g, 74.7%) as colorless
prisms, mp 131—134 °C. 1H-NMR d: 1.39 (6H, d, Jϭ5.9 Hz, CH(CH3)2),
3.90 (3H, s, OCH3), 4.56 (1H, sept, Jϭ5.9 Hz, OCH), 5.96 (1H, d,
Jϭ7.6 Hz, 3-H), 6.50 (2H, br s, 1-H and 4-H), 6.74, 6.86 (each 1H, s, ArH),
7.43—7.75 (5H, m). 13C-NMR d: 21.9 (q, CH(CH3)2), 44.8 (d, 1-H), 56.2 (q,
OCH3), 71.7 (d, OCH), 110.3 (d), 112.8 (d), 116.6 (s, CN), 123.3 (s), 124.2
(d), 128.6 (d), 128.8 (d), 129.1 (d), 130.5 (s), 131.8 (d), 148.6 (s), 150.5 (s),
168.7 (s, CO). IR (KBr) cmϪ1: 1680, 1640, 1520, 1450, 1350, 1240, 1110.
MS m/z (%): 348 (Mϩ, 2), 217 (33), 176 (11), 175 (100), 160 (24), 132 (30),
131 (15), 105 (27), 77 (14). High-resolution MS Calcd for C21H20N2O3:
348.1479. Found: 348.1474.
[7-Methoxy-6-(1-methylethoxy)-1-isoquinolyl]methanol (18) Forma-
lin (1.04 ml) was added dropwise for 5 min to a stirred solution of 17
(1.392 g, 4 mmol), TEBA (120 mg, 0.528 mmol), and 50% aqueous NaOH
(2 ml) in acetonitrile (28 ml), and the mixture was stirred at room tempera-
ture for 18 h. The reaction mixture was diluted with dichloromethane
(100 ml) and extracted with 1% HCl solution (100 mlϫ3). The combined
aqueous layer was rendered alkaline with NH4OH, and extracted with chlo-
roform (150 mlϫ3). The combined extracts were washed with brine
(100 ml), dried, and concentrated in vacuo to give a solid (950 mg), the re-
crystallization of which from ethyl acetate gave 18 (895.4 mg, 90.6%) as
colorless prisms, mp 109—112 °C. 1H-NMR d: 1.48 (6H, d, Jϭ6.3 Hz,
CH(CH3)2), 3.40—3.80 (1H, br s, OH), 4.00 (3H, s, OCH3), 4.78 (1H, sept,
[7-Methoxy-6-(1-methylethoxy)-1-isoquinolyl]methyl Acetate (19)
Acetic anhydride (189 ml, 2 mmol) was added to a stirred solution of 18
(247 mg, 1 mmol) and triethylamine (278 ml, 2 mmol) in dry
dichloromethane (10 ml), and the mixture was stirred for 4 h at room tem-
perature. The mixture was diluted with brine (30 ml), then extracted with
dichloromethane (30 mlϫ3). The combined extracts were washed with 5%
aqueous NaHCO3, dried, and concentrated in vacuo to give a residue
(348.1 mg). Chromatography on
a silica gel (10 g) column with
hexane–ethyl acetate (2 : 1) as the eluent gave 19 (288.6 mg, 100%) as a
solid. When this sample was left to stand in a refrigerator for a couple of
days, colorless crystals were obtained, mp 68.5—69 °C. 1H-NMR d: 1.48
(6H, d, Jϭ5.9 Hz, CH(CH3)2), 2.15 (3H, s, COCH3), 4.00 (3H, s, OCH3),
4.78 (1H, sept, Jϭ5.9 Hz, OCH), 5.66 (2H, s, CH2OH), 7.09, 7.36 (each 1H,
s, ArH), 7.48 (1H, d, Jϭ5.6 Hz, 4-H), 8.36 (1H, d, Jϭ5.6 Hz, 3-H). 13C-
NMR d: 20.9 (q, COCH3), 21.7 (q, CH(CH3)2), 56.1 (q, OCH3), 65.7 (t,
CH2), 71.1 (d, OCH), 103.1 (d), 107.2 (d), 120.1 (d), 122.6 (s), 133.4 (s),
140.8 (d), 151.3 (s), 151.8 (s), 151.8 (s), 170.9 (s, CO). IR (KBr) cmϪ1
:
1720. MS m/z (%): 289 (Mϩ, 24), 246 (17), 205 (24), 204 (100). Anal. Calcd
for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C, 66.32; H, 6.70; N,
4.57.
(6-Hydroxy-7-methoxy-1-isoquinolyl)methanol Acetate (20) A stirred
solution of 19 (578.0 mg, 2 mmol) in dry dichloromethane (4 ml) was cooled
in ice water and a dichloromethane solution of TiCl4 (1.0 M, 6 ml, 6 mmol)
was added dropwise for 5 min. This mixture was then stirred at room tem-
perature for 68 h. The reaction mixture was poured into water (100 ml), and
the pH was brought to 6—7 with 5% NaHCO3 solution. Then, the mixture
was extracted with chloroform (100 mlϫ3). The combined extracts were
washed with brine (100 ml), dried, and concentrated in vacuo to give a solid
(406 mg), the recrystallization of which from acetone gave 20 (327.6 mg,
66.5%) as colorless prisms, mp 192—193 °C. 1H-NMR d: 2.14 (3H, s,
COCH3), 4.05 (3H, s, OCH3), 5.69 (2H, s, CH2OH), 7.25, 7.40 (each 1H, s,
ArH), 7.49 (1H, d, Jϭ5.6 Hz, 4-H), 8.36 (1H, d, Jϭ5.6 Hz, 3-H). 13C-NMR
d: 20.9 (q, COCH3), 56.1 (q, OCH3), 65.5 (t, CH2), 102.5 (d), 108.7 (d),
120.3 (d), 122.6 (s), 134.0 (s), 140.4 (d), 148.7 (s), 150.0 (s), 151.9 (s),
170.9 (s, CO). IR (KBr) cmϪ1: 3200, 1740. MS m/z (%): 247 (Mϩ, 24), 205
(22), 204 (100), 190 (9). Anal. Calcd for C13H13NO4: C, 63.15; H, 5.30; N,
5.67. Found: C, 63.37; H, 5.49; N, 5.37.
6-Hydroxy-7-methoxyisoquinolinemethanol (15)
A 10% aqueous
LiOH solution (0.5 ml) was added to a stirred solution of 20 (74.1 mg,
Chart 1

February 2004
285
0.3 mmol) in chloroform (5 ml), and the mixture was stirred at room temper-
ature for 2 h. After the pH of the mixture was brought to 6—7 with acetic
acid, the mixture was concentrated in vacuo to give a residue (151.3 mg).
Chromatography on a silica gel (4 g) column with chloroform–methanol
(40 : 1) as the eluent gave 1a (44.7 mg, 72.7%) as a white powder, the recrys-
tallization of which from ethanol gave 15 as colorless needles, mp 202—
Jϭ8.1, 1.8 Hz, 6-H), 6.84 (1H, d, Jϭ8.1 Hz, 5-H), 6.87 (1H, d, Jϭ1.8 Hz, 2-
H).
4) A solution of 25 (20.33 g, 72 mmol) and triethylamine (15.1 ml,
108 mmol) in dry dichloromethane (90 ml) was cooled with ice water, and a
solution of p-toluenesulfonyl chloride (20.6 g, 108 mmol) in dry
dichloromethane (60 ml) was added dropwise over 10 min. The mixture was
stirred at room temperature for 20 h at room temperature. The organic layer
was washed with 10% aqueous NaOH (300 ml), and then water (200 ml),
dried, and concentrated in vacuo to give a residue (37.7 g). The chromatog-
raphy of this residue on a silica gel (300 g) column with hexane–ethyl ac-
etate (5 : 1) as the eluent gave 26 (31.43 g, 100%) as a colorless oil. 1H-NMR
d: 1.34 (6H, d, Jϭ5.9 Hz, CH(CH3)2), 2.42 (3H, s, ArCH3), 3.21 (2H, d,
Jϭ5.3 Hz, NCH2CH), 3.26 (6H, s, CH(OCH3)2), 3.72 (3H, s, OCH3), 4.36
(1H, t, Jϭ5.3 Hz, CH2CH), 4.40 (2H, s, ArCH2N), 4.48 (1H, sept, Jϭ5.9 Hz,
OCH), 6.67—6.71 (2H, m, 2-H, 6-H), 6.77 (1H, d, Jϭ7.9 Hz, 5-H), 7.30,
7.74 (each 2H, d, Jϭ8.3 Hz, CH3–C6H4–). IR (neat) cmϪ1: 1345, 1170. MS
m/z (%): 437 (Mϩ, 11), 282 (10), 179 (15), 137 (47), 75 (100). High-resolu-
tion MS Calcd for C22H31NO6S: 437.1872. Found: 437.1877.
5) A solution of 26 (21.85 g, 50 mmol) in dioxane (500 ml) was treated
with 6 N HCl (37 ml), then the mixture was heated under reflux for 1 h. The
mixture was diluted with water (1000 ml), rendered alkaline with 4%
NH4OH solution, and extracted with ether (500 mlϫ3). The combined ex-
tracts were washed with brine (300 ml), dried, and concentrated in vacuo to
give a solid, the recrystallization of which from ether gave 16 (7.06 g,
65.1%) as colorless prisms, mp 111—113 °C. 1H-NMR d: 1.48 (6H, d,
Jϭ5.9 Hz, CH(CH3)2), 4.00 (3H, s, OCH3), 4.77 (1H, sept, Jϭ5.9 Hz, OCH),
7.05, 7.19 (each 1H, s, ArH), 7.47 (1H, d, Jϭ5.6 Hz, 4-H), 8.36 (1H, d,
Jϭ5.6 Hz, 3-H), 9.02 (1H, s, 1-H). 13C-NMR d: 21.7 (q, CH(CH3)2), 56.0 (q,
OCH3), 71.1 (d, OCH), 105.4 (d), 106.6 (d), 119.1 (d), 124.5 (s), 132.5 (s),
141.6 (d), 149.8 (d), 151.1 (s), 151.4 (s). IR (KBr) cmϪ1: 1630, 1500, 1470,
1440, 1420, 1340, 1250, 1220, 1140, 1120, 930, 860. MS m/z (%): 217 (Mϩ,
11), 176 (11), 175 (100), 160 (24), 132 (30). Anal. Calcd for C13H15NO2: C,
71.86; H, 6.96; N, 6.45. Found: C, 71.83; H, 7.01; N. 6.26.
1
204 °C. H-NMR d (DMSO-d6): 3.94 (3H, s, OCH3), 4.95 (2H, s, CH2OH),
7.17 (1H, s, ArH), 7.44 (1H, d, Jϭ5.6 Hz, 4-H), 7.52 (1H, s, ArH), 8.14 (1H,
d, Jϭ5.6 Hz, 3-H). 13C-NMR d (DMSO-d6): 55.6 (q, OCH3), 63.3 (t, CH2),
103.9 (d, C-8), 108.4 (d, C-5), 118.5 (d. C-4), 121.0 (s, C-9), 133.0 (s, C-10),
1
139.2 (d. C-3), 149.8 (s, C-1), 151.6 (s, C-7), 156.7 (s, C-6). . H-NMR d
(DMSO-d6ϩtwo drops of TFA-d): 4.02 (3H, s, OCH3), 5.38 (2H, s,
CH2OH), 7.52 (1H, s, 5-H), 7.60 (1H, s, 8-H), 8.04 (1H, d, Jϭ5.9 Hz, 4-H),
8.20 (1H, d, Jϭ5.9 Hz, 3-H). 13C-NMR d (DMSO-d6ϩtwo drops of TFA-d):
56.4 (q, OCH3), 58.4 (t, CH2), 104.9 (d, C-8), 109.3 (d, C-5), 119.0 (s, C-9),
121.2 (d. C-4), 128.7 (d. C-3), 135.9 (s, C-10), 152.0 (s, C-7), 154.7 (s, C-1),
157.0 (s, C-6). IR (KBr) cmϪ1: 3400, 3050, 1625, 1575, 1470, 1455, 1440,
1380, 1325, 1255, 1215. MS m/z (%): 205 (Mϩ, 100), 204 (76), 190 (24),
176 (59), 175 (20), 174 (13), 162 (20), 161 (30), 160 (11), 133 (21), 132
(19). High-resolution MS Calcd for C11H11NO3: 205.0739. Found: 205.0741.
(6-Acetyloxy-7-methoxy-1-isoquinolyl)methanol Acetate (21) From
15: Acetic anhydride (0.2 ml, 2.12 mmol) was added to a stirred solution of
15 (52.6 mg, 0.257 mmol) in dry pyridine (1.0 ml), and the mixture was
stirred for 2 h at room temperature. After dilution with water (10 ml), the
mixture was extracted with chloroform (10 mlϫ3). The combined extracts
were washed with 5% NaHCO3 (10 ml), dried, and concentrated in vacuo to
give a residue (80.0 mg), the recrystallization of which from ethyl acetate
gave 21 (72.0 mg, 97.0%) as colorless prisms. From 20: Acetic anhydride
(76 ml, 0.8 mmol) was added to a stirred solution of 20 (98.8 mg, 0.4 mmol)
and triethylamine (111 ml, 0.8 mmol) in dry dichloromethane (4 ml), and the
mixture was stirred for 15 h at room temperature. The mixture was diluted
with brine (20 ml) and extracted with dichloromethane (20 mlϫ3). The com-
bined extracts were washed with 5% aqueous NaHCO3, dried, and concen-
trated in vacuo to give a residue (120.0 mg), the recrystallization of which
from ethyl acetate–ether gave 21 (90.8 mg, 78.5%) as colorless prisms, mp
95—96.5 °C. 1H-NMR (CDCl3) and 13C-NMR (CDCl3): see Table 1. 1H-
NMR d (CDCl3ϩCF3COOD): 2.28 (3H, s, COCH3), 2.42 (3H, s, COCH3),
4.05 (3H, s, OCH3), 6.00 (2H, s, CH2), 7.60 (1H, s), 7.75 (1H, s), 7.97 (1H,
d, Jϭ5.6 Hz), 8.60 (1H, d, Jϭ5.6 Hz). IR (KBr) cmϪ1: 1760. 1740. MS m/z
(%): 289 (Mϩ, 20), 247 (15), 246 (11), 205 (33), 204 (100), 190 (6). Anal.
Calcd for C15H15NO5·1/4H2O: C, 61.32; H, 5.32; N, 4.77. Found: C, 61.29;
H, 5.18; N, 4.53.
Acknowledgments This research was partially supported by a Grant-in-
Aid for Scientific Research (B) (No. 14370725) from the Ministry of Educa-
tion, Culture, Sports, Science and Technology (MEXT), Japan. We thank the
Japan Society for the Promotion of Science (JSPS) for supporting the col-
laboration between Thai and Japanese researchers in this work. We would
also like to thank T. Kozeki and S. Kubota of the Analytical Center of this
University for MS and NMR measurements, and for elemental analysis.
7-Methoxy-6-(1-methylethoxy)isoquinoline (16) (Modified Pomer-
anz–Fritsch Isoquinoline Synthesis) 1) A mixture of vanillin (22)
(15.2 g, 0.1 mol), isopropyl bromide (14.1 ml, 0.15 mol), and anhydrous
K2CO3 (20.7 g, 0.15 mol) in DMF (100 ml) was heated at 80 °C for 1 h. The
reaction mixture was diluted with water (200 ml) and extracted with ether
(200 mlϫ3). The combined extracts were washed with brine (200 ml) and
concentrated in vacuo to give a residue (26.7 g), the chromatography of
which on a silica gel (200 g) column with hexane–ethyl acetate as an eluent
gave 4-isopropyl-3-methoxybenzaldehyde (23) (19.4 g, 100%) as a colorless
oil. 1H-NMR d: 1.43 (6H, d, Jϭ6.3 Hz, CH(CH3)2), 3.92 (3H, s, OCH3),
4.69 (1H, sept, Jϭ6.3 Hz, OCH), 6.98 (1H, d, Jϭ7.9 Hz, 5-H), 7.41 (1H, d,
Jϭ2 Hz, 2-H), 7.43 (1H, dd, Jϭ7.9, 2.0 Hz, 6-H), 9.84 (1H, s, CHO). IR
(neat) cmϪ1: 1670. MS m/z (%): 194 (Mϩ, 26), 152 (100), 151 (95). High-
resolution MS Calcd for C11H14O3: 194.0934. Found: 194.0941.
References and Notes
1) Sponge Reniera sp. (Mexico): McIntyre D. E., Faulkner D. J., Van
Engen D., Clardy J., Tetrahedron Lett., 1979, 4163—4166 (1979).
2) Sponge Reniera sp. (Mexico): Frincke J. M., Faulkner D. J., J. Am.
Chem. Soc., 104, 265—269 (1982).
3) Sponge Reniera sp. (Palau): He H., Faulkner D. J., J. Org. Chem., 54,
5822—5824 (1989).
4) Sponge Xestospongia caycedoi (Fiji): McKee T. C., Ireland C. M., J.
Nat. Prod., 50, 754—756 (1987).
5) Sponge Xestospongia caycedoi (Fiji): Davidson B. S., Tetrahedron
Lett., 33, 3721—3724 (1992).
6) Sponge Xestospongia sp. (Philippines): Edrada R. A., Proksch P.,
Wray V., Christ R., Writte L., Soest R. W. N., J. Nat. Prod., 59, 973—
976 (1996).
2) Aminoacetaldehyde dimethylacetal (8.55 ml, 78.7 mmol) was added
to a solution of 23 (14.02 g, 72.0 mmol) in benzene (500 ml). This mixture
was refluxed in a Dean–Stark apparatus for 1 h. Removal of the solvent in
vacuo gave the required Schiff’s base 24 (21.2 g, 100%) as a pale yellow oil,
which was used without further purification. 1H-NMR d: 1.39 (6H, d,
Jϭ6.1 Hz, CH(CH3)2), 3.42 (6H, s, CH(OCH3)2), 3.75 (2H, d, Jϭ5.3 Hz,
CH2CH), 3.91 (3H, s, OCH3), 4.60 (1H, sept, Jϭ6.1 Hz, OCH), 4.67 (1H, t,
Jϭ5.3 Hz, CH2CH), 6.89 (1H, d, Jϭ8.5 Hz, 5-H), 7.15 (1H, dd, Jϭ8.5,
1.8 Hz, 6-H), 7.44 (1H, d, Jϭ1.8 Hz, 2-H), 8.18 (1H, s, CHϭN).
7) Sponge Xestospongia sp. (Thailand): Suwanborirux K., Amnuoypol
S., Plubrukarn A., Pummangura S., Kubo A., Tanaka C., Saito N., J.
Nat. Prod., 66, 1441—1446 (2003).
8) Sponge Cribrochalina sp. (the Republic of Maldives): Pettit G. R.,
Collins J. C., Herald D. L., Doubek D. L., Boyd M. R., Schmidt J. M.,
Hooper J. N. A., Tackett L. P., Can. J. Chem., 70, 1170—1175 (1992).
9) Sponge Cribrochalina sp. (the Republic of Maldives): Pettit G. R.,
Knight J. C., Collins J. C., Herald D. L., Pettit R. K., Boyd M. R.,
Young V. G., J. Nat. Prod., 63, 793—798 (2000).
3) Schiff’s base 24 (20.18 g, 72.0 mmol) was dissolved in methanol
(500 ml), and NaBH4 (2.99 g, 79.0 mmol) was added in portions with stir-
ring. The mixture was stirred for 20 h, diluted with water (150 ml), and ex-
tracted with chloroform (300 mlϫ3). The combined extracts were washed
with brine (300 ml), dried, and concentrated in vacuo to give am amine 25
10) Sponge Haliclona cribricutis DENDY (India): Parameswaran P. S.,
Kamat S. Y., Chandramohan D., Nair S., Das B., “Oceanography of
the Indian Ocean,” ed. by Desai B. N., Oxford & IBH Inc., New Delhi,
1992, p. 417.
11) Sponge Haliclona cribricutis DENDY (India): Parameswaran P. S., Naik
C. G., Kamat S. Y., Pramanik B. N., Indian J. Chem., 37B, 1258—
1263 (1998).
1
(20.33 g, 100%), which was used without further purification. H-NMR d:
1.35 (6H, d, Jϭ6.1 Hz, CH(CH3)2), 2.75 (2H, d, Jϭ5.5 Hz, NCH2CH), 3.37
(6H, s, CH(OCH3)2), 3.74 (2H, s, ArCH2N), 3.85 (3H, s, OCH3), 4.48 (1H,
sept, Jϭ6.1 Hz, OCH), 4.49 (1H, t, Jϭ5.5 Hz, CH2CH), 6.80 (1H, dd,
12) Sponge Haliclona sp. (Philippines): Rashid M. A., Gustafson K. P.,
Boyd M. R., J. Nat. Prod., 64, 1249—1250 (2001).

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Vol. 52, No. 2
13) Sponge Petrosia similes (India): Venkateswarlu Y., Reddy M. V. R., 19) Banwell M. G., Flynn R. L., Stewart S. G., J. Org. Chem., 63, 9139—
Srinivas K. V. N. S., Rao J. V., Indian J. Chem., 32B, 704 (1993). 9144 (1998).
14) Sponge Petrosia similes (India): Ramesh P., Reddy S., Venkateswarlu 20) Saito N., Tachi M., Seki R., Sugawara Y., Takeuchi E., Kubo A., Synth.
Y., J. Nat. Prod., 62, 780—781 (1999). Commun., 30, 2404—2421 (2000).
15) Nudibranch Jorunna funebris (India): de Silva E. D., Gulavita N. K., 21) Rozwadowska M. D., Brozda D., Pharmazie, 39, 387—388 (1984).
Abstracts of Papers. 16th IUPAC International Symposium on the 22) The crude fraction was separated and purified to obtain 15 by
Chemistry of Natural Products, Kyoto, May, 1988, p. 610.
16) Nudibranch Jorunna funebris (India): Karuso P., “Bioorganic Marine
Chemistry,” Vol. 1, ed. by Scheuer P. J., Springer Inc., Berlin, 1987,
pp. 31—60.
17) Nudibranch Jorunna funebris (India): Fontana A., Cavaliere P.,
Wahidulla S., Naik C. G., Cimino G., Tetrahedron, 56, 7305—7308
(2000).
18) Compound 16 is already known, but details of the experiment could
not be obtained from the literature [Servin A. L., Wicek D., Oryszczyn
M. P., Jacquot C., Lussiana J. P., Christinaki H., Viel C., Xenobiotica,
17, 1381—1391 (1987)]. Thus, according to modified Pomeranz–
Fritsch isoquinoline synthesis,24) compound 16 was prepared from
vanillin (22) via 4-isopropyl-3-methylbenzaldehyde (23)19) in five
steps with 65% overall yield (see: Experimental).
Sephadex LH 20 and C18 HPLC column using a methanol–water con-
taining 0.1% TFA graduation. Furthermore, a sample of 21 could not
be purified, because natural 15 was available only in minute
quantities.12) Therefore, the reported derivative 21 may also be re-
tained in the form of a TFA salt.
23) In a similar way, (7-acetoxy-6-methoxy-1-isoquinolyl)methanol ac-
etate (27) was prepared from isovanillin (28) via 29 and 30 in 11%
overall yield. 30: mp 181—183 °C (from acetone). 1H-NMR d
(CD3OD): 4.04 (3H, s, OCH3), 5.09 (2H, s, CH2), 7.13, 7.37 (each 1H,
s, ArH), 7.54 (1H, d, Jϭ5.0 Hz, 4-H), 8.17 (1H, d, Jϭ5.0 Hz, 3-H). IR
(KBr) cmϪ1: 3250, 1480, 1420, 1340, 1280. MS m/z (%): 205 (Mϩ,
100), 204 (70), 176 (56), 175 (14), 161 (9). High-resolution MS Calcd
for C11H11NO3: 205.0739. Found: 205.0741. 27: mp 114—115 °C
(from ethyl acetate–ether). 1H- and 13C-NMR data: see Table 1. IR
(KBr) cmϪ1: 1760, 1730, 1370, 1270, 1210. MS m/z (%): 289 (Mϩ,
11), 247 (25), 205 (30), 204 (100). Anal. Calcd for C15H15NO5: C,
62.28; H, 5.23; N, 4.84. Found: C, 62.09; H, 5.39; N, 4.75.
24) Birch A. J., Jackson A. H., Shannon R. V. R., J. Chem. Soc., Perkin
Trans. 1, 1974, 2185—2190 (1974).