Syntheses of the antibiotic alkaloids renierone, mimocin, renierol, renierol acetate, renierol propionate, and 7-methoxy-1,6-dimethylisoquinoline-5, 8-dione

Article abstract of DOI:10.1016/j.tet.2004.02.010

The total synthesis of renierone, mimocin, renierol, renierol acetate, renierol propionate, and 7-methoxy-1,6-dimethylisoquinoline-5,8-dione was successfully achieved by the regioselective oxidation of 5-oxygenated isoquinoline. The synthetic method of the 5-oxygenated isoquinoline is based on the thermal electrocyclic reaction of 1-azahexatriene system involving the benzene 1,2-bond.

Full text of DOI:10.1016/j.tet.2004.02.010

Tetrahedron 60 (2004) 2943–2952
Syntheses of the antibiotic alkaloids renierone, mimocin, renierol,
renierol acetate, renierol propionate, and
7-methoxy-1,6-dimethylisoquinoline-5,8-dione
Nagako Kuwabara, Hiroyuki Hayashi, Noriko Hiramatsu, Tominari Choshi, Teppei Kumemura,
*
Junko Nobuhiro and Satoshi Hibino
Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University,
Fukuyama, Hiroshima 729-0292, Japan
Received 29 January 2004; revised 6 February 2004; accepted 6 February 2004
Abstract—The total synthesis of renierone, mimocin, renierol, renierol acetate, renierol propionate, and 7-methoxy-1,6-dimethylisoquino-
line-5,8-dione was successfully achieved by the regioselective oxidation of 5-oxygenated isoquinoline. The synthetic method of the
5-oxygenated isoquinoline is based on the thermal electrocyclic reaction of 1-azahexatriene system involving the benzene 1,2-bond.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Many naturally occurring isoquinoline-5,8-diones have
been isolated both from marine sponges and from
Actinomycetes.1 The isoquinolinequinones possess signifi-
cant biological activity,2 which suggests their potential
value as promising structures for the development of new
pharmaceuticals. In 1979, renierone (1) was isolated from
the major metabolite of Reniera sp.3 Mimocin (2), isolated
from a metabolite of Streptomyces lavendulae, contains a
pyruvamide side chain in place of the angelate ester side
chain of 1.4 Renierol (3) was isolated from the hard blue
sponge Xestospongia caycedoi.6 Further studies of the
metabolites of Reniera sp. have resulted in the isolation of
7-methoxy-1,6-dimethylisoquinoline-5,8-dione (4),3b,5
which was also found in a blue Philippine marine sponge
of the genus Xestospongia sp.6 In addition, renierol acetate
(5) and renierol propionate (6) were isolated from the
marine sponge Xestospongia sp. and its associated nudi-
branch Jorunna funebris7 (Scheme 1).
Scheme 1.
were reported by the Kubo group.2d,7c,9a,c 7-Methoxy-1,6-
Synthetic studies of these antibiotic alkaloids have been
dimethyl-5,8-dihydro-isoquinoline-5,8-dione (4) was syn-
thesized by the groups of Kubo,9a,c Liebskind,12 and
Molina.13 Among these efforts, two regioselective syntheses
of the isoquinoline-5,8-dione system have been reported
that employ either the oxidation of an 8-aminoisoquinoline
derivative with Fremy’s salt (Kubo group)2d,9 or the
oxidative demethylation of a 5,7,8-trimethoxyisoquinoline
derivative with Ag2O (Liebskind group).12 However, it
remains difficult to estimate the regioselectivity of oxidative
demethylation from the 5,7,8-trimethoxyisoquinoline to
conducted by five groups. The total synthesis of renierone
(1) was established by the groups of Danishefsky8 and
Kubo.2d,9 Mimocin (2) was totally synthesized by the
groups of Matsuo10 and Kubo.11 The total syntheses of
renierol (3), renierol acetate (5), and renierol propionate (5)
Keywords: Antibiotic alkaloids; Isoquinoline-5,8-diones; Electrocyclic
reaction; Azahexatriene system.
*
Corresponding author. Tel.: þ81-84-936-2111; fax: þ81-84-936-2024;
e-mail address: hibino@fupharm.fukuyama-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.010

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N. Kuwabara et al. / Tetrahedron 60 (2004) 2943–2952
either the isoquinoline-5,8-dione or isoquinoline-7,8-dione
using the above synthetic works.
because it has been shown to be advantageous over other
approaches due to the cleanliness of the reaction associated
with the loss of water.16 As shown in a retro-synthetic
analysis (Scheme 1), we initially planned the synthesis of
the common precursor, 5-oxygenated 7-methoxy-6-methyl-
isoquinoline (7), in order to achieve the regioselective
syntheses of six isoquinoline-5,8-dione antibiotic alkaloids.
Namely, a required precursor (7) would be obtained by a
thermal electrocyclic reaction of o-alkenylbenzketoxime (8)
as a 1-aza-6p-electron system, which would be derived
from the known 2,4-dimethoxy-3-methylbenzaldehyde
(9).18
In the course of our studies directed towards the synthesis of
biologically active, condensed nitrogen-containing hetero-
cyclic compounds including natural products based on the
electrocyclic reaction of a 6p-electron system,14 we
developed thermal electrocyclic reactions using either
hexatriene14c,15 or azahexatriene14c,16 systems incorporat-
ing one double bond of the aromatic or heteroaromatic ring.
Recently, we preliminarily reported the total syntheses of
renierol (3), renierol acetate (5), and renierol propionate (6)
based on the application of our methodology.17 In this
paper, we describe the details of these former studies17 and
the additional total syntheses of renierone (1), mimocin (2),
and 7-methoxy-1,6-dimethylisoquinoline-5,8-dione (6). All
of these alkaloids have a common skeleton, 1-hydroxy-
methyl (or methyl)-7-methoxy-6-methylisoquinoline-5,8-
dione, and they differ only in terms of the side chain at
C-1 of the isoquinoline ring. There are several classical
methods currently used for the synthesis of this type of
isoquinoline, e.g., the Bischler-Napieralski reaction. How-
ever, we adopted our methodology for the present syntheses,
2. Results and discussion
For the preparation of a required precursor (7), we began as
follows (Scheme 2). The benzaldehyde (9) was treated with
boron tribromide to produce the 2-hydroxybenzaldehyde
(10) (88%), which was converted into the benzyl ether (11)
(99%). The benzaldehyde (11) was subjected to the
Baeyer–Villiger reaction with m-chloroperbenzoic acid
(mCPBA) to give the phenol (12) (88%). The Duff reaction
Scheme 2.

N. Kuwabara et al. / Tetrahedron 60 (2004) 2943–2952
2945
of 12 was carried out by hexamethylenetetramine in acetic
acid to yield the 2-hydroxybenzaldehyde (13) (53%), which
was treated with trifluoromethanesulfonic anhydride (Tf2O)
to yield the triflate (14) (81%). The cross-coupling reaction
of 14 with vinyl tributyltin in the presence of palladium
dichlorobistriphenylphosphine [PdCl2(PPh3)2] gave the
o-ethenylbenzaldehyde (15) (90%). The Grignard reaction
of 15 with dimethylisopropyloxysilylmethylmagnesium
chloride,19 followed by treatment with potassium fluoride
and 30% hydrogen peroxide, afforded the 1,2-diol (16)
(87%). Selective protection of 16 with tert-butyldimethyl-
silyl chloride (TBDMSCl) produced the TBDMS ether (17)
(92%), which was oxidized with pyridinium chlorochromate
(PCC) to obtain the ketone (18). Subsequent treatment of
18 with hydroxylamine afforded the ketoxime (19) as a
1-azahexatriene system (8) (57%), which was subjected to a
thermal electrocyclic reaction in o-dichlorobenzene at
180 8C to furnish the desired 5-benzyloxyisoquinoline (20)
(42%). Although the electrocyclic reaction of the highly
substituted substrate (19) also proceeded, the yield of 20
was only marginally better than that of the simple
o-alkenylbenzaldoxime.20 Deprotection of the TBDMS
group of 20 was carried out using tetrabutylammonium
fluoride (TBAF) to provide the expected 5-benzyloxy-1-
hydroxymethylisoquinoline (21) as the common precursor,
5-oxygenated isoquinoline (7), with the appropriate sub-
stitutents (Scheme 2).
2,4,6-trichlorobenzoyl chloride, acetic anhydride, and
propionic anhydride, respectively. For the conversion of
21 into the 1-methylisoquinoline (26), 1-hydroxymethyl-
isoquinoline (21) was tosylated by treatment with phenyl-
lithium, followed by the addition of p-toluenesulfonyl
chloride (p-TsCl) (64%). Subsequent reduction of the
tosylate (25) with lithium triethylborane (LiEt3BH)9
afforded the 1-methylisoquinoline (26) (85%). Furthermore,
the nucleophilic substitution reaction of tosyloxymethyl-
isoquinoline (25) was carried out by sodium azide to
obtain the azide derivative (27) (81%), which was treated
with triphenylphosphine (PPh3) in situ, followed by the
addition of pyruvoyl chloride,22 prepared from pyruvic acid
and a,a-dichloromethyl methyl ether at 50 8C,23 to furnish
the 1-pyruvoylaminomethylisoquinoline (28) (45%). Thus,
all of the side chains at the C-1 position of these
isoquinoline-5,8-dione alkaloids (1–6) could be arranged
(Scheme 3).
The sequential cleavage of the benzyl groups of 21, 23, 24,
26, and 28 was carried out by 10% Pd–C and hydrogen in
ethanol to give the phenols (29–33) in excellent yields
(91–99%). However, these conditions could not be utilized
for 22 because of the reduction of the alkene of the C-1 side
chain. Debenzylation of 5-benzyloxyisoquinoline (22)
successfully proceeded using Fuji’s conditions of
BF3·Et2O and Me2S in dichloromethane24 to obtain the
phenol (34) (98%) (Scheme 4).
For the next step, the 1-hydroxymethylisoquinoline (21)
was converted to the corresponding esters; angelate (22)
(78%), acetate (23) (83%), and propionate (24) (80%) by
treatment of 21 with phenyllithium, followed by the
addition of the mixed anhydride21 of angelic acid with
At the final stage, the oxidation of all of the 5-hydroxy-
isoquinolines (29–34) was attempted using two types of
oxidizing agents, ceric ammonium nitrate (CAN; Method
A),25 and a combination of salcomine with oxygen (Method
Scheme 3.

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N. Kuwabara et al. / Tetrahedron 60 (2004) 2943–2952
Scheme 4.
Table 1. Oxidation of phenols to isoquinoline-5,8-diones
Phenols compounds No.
R
Quinones compounds No.
Oxidizing agents
CAN (%)a
SalcomineþO2 (%)b
29
30
31
32
33
34
OH
3
5
6
4
2
1
52
91
87
81
79
90
78
96
99
85
85
95
OCOMe
OCOEt
H
NHCOCOMe
a
Method A.
Method B.
b
B)26 to exclusively provide the corresponding isoquinoline-
5,8-diones (1–6) in excellent yields, as shown in Table 1. It
was demonstrated that both oxidizing agents produced
similar results for the same substrate. The physical data for
these isoquinoline-5,8-dione derivatives (1–6) were con-
sistent with those of natural3–7 and synthetic2d,8–13products
in all respects.
4. Experimental
4.1. General
Melting points were measured with a Yanagimoto micro
melting point apparatus and are uncorrected. IR spectra
were recorded with a Horiba FT-720 spectrophotometer. 1H
NMR spectra were taken by JEOL PMX60Si and JNM
AL-300 spectrometers using SiMe4 as an internal standard.
Mass spectra (MS) and high-resolution mass spectra
(HRMS) were recorded on Shimadzu QP-5050 and GC–
MS 9020DF spectrometers (EI). Silica gel (60–100 mesh,
Merck Art 7734) was used for the column chromatography.
3. Conclusions
The total syntheses of the isoquinolinequinone antibiotics,
renierone (1), mimocin (2), renierol (3), renierol acetate (5),
renierol propionate (6), and 7-methoxy-1,6-dimethyliso-
quinoline-5,8-dione (4) were newly established through the
construction of 5-oxygenated isoquinoline (7) based on the
thermal electrocyclic reaction of 1-aza-6p-electron system
(8), followed by the regioselective oxidation with both
oxidizing agents. Based on this result, it was found that the
5-oxygenated isoquinoline (7) is an effective precursor of
isoquinoline-5,8-diones (1–6).
4.1.1. 2-Hydroxy-4-methoxy-3-methylbenzaldehyde
(10). A solution of benzaldehyde 9 (6 g, 33.3 mmol) in
CH2Cl2 (30 mL) was slowly added to a stirred solution of
BBr3 (3.7 mL, 40 mmol) in CH2Cl2 (40 mL) at 278 8C
under N2 atmosphere. After gradually being warmed to rt,
the mixture was quenched with water, and then the mixture
was extracted with EtOAc. The EtOAc layer was washed
with water and brine, dried over Na2SO4, and concentrated.

N. Kuwabara et al. / Tetrahedron 60 (2004) 2943–2952
2947
The residue was purified by column chromatography (silica
gel, 100 g) using EtOAc–hexane (1:9 v/v) as an eluent to
give the phenol 10 (4.6 g, 83%), mp 60.5–61.5 8C (Et2O).
4.1.5. 3-Benzyloxy-5-methoxy-4-methyl-2-(trifluoro-
methylsulfonyloxy)benzaldehyde (14). Tf2O (93 mL,
0.55 mmol) was added to an ice-cooled solution of
benzaldehyde 13 (100 mg, 0.37 mmol), and pyridine
(59 mL, 0.73 mmol) in CH2Cl2 (10 mL) under N2 atmos-
phere. After being stirred at the same temperature for 1 h, an
aqueous NaHCO3 solution (saturated) was added to the
reactant, and then the mixture was extracted with CH2Cl2.
The CH2Cl2 layer was washed with water and brine, dried
over Na2SO4, and concentrated. The residue was purified by
column chromatography (silica gel, 20 g) using EtOAc–
hexane (1:9 v/v) as an eluent to give the triflate 14 (120 mg,
1
IR (KBr) n: 3400, 1638 cm21; H NMR (CDCl3) d: 2.05
(3H, s), 3.92 (3H, s), 6.56 (1H, d, J¼9 Hz), 7.37 (1H, d,
J¼9 Hz), 9.71 (1H, s), 11.44 (1H, s); MS m/z: 166 (Mþ).
Anal. Calcd for C9H10O3: C, 65.05; H, 6.07. Found: C,
65.36; H, 6.35.
4.1.2. 2-Benzyloxy-4-methoxy-3-methylbenzaldehyde
(11). A mixture of phenol 10 (6 g, 54.2 mmol), benzyl
bromide (6.4 mL, 54.2 mmol) and K2CO3 (10 g,
72.2 mmol) in DMF (60 mL) was heated at 60 8C for 4 h
under N2 atmosphere. After being cooled to an ambient
temperature, the mixture was quenched with water, and then
the mixture was extracted with EtOAc. The EtOAc layer
was washed with water and brine, dried over Na2SO4, and
concentrated. The residue was purified by column chroma-
tography (silica gel, 100 g) using EtOAc–hexane (1:9 v/v)
as an eluent to give the benzyl ether 11 (9.2 g, 99%), mp
1
81%), mp 72–73 8C (Et2O). IR (KBr) n: 1711 cm21; H
NMR (CDCl3) d: 2.13 (3H, s), 3.89 (3H, s), 4.96 (2H, s),
7.17 (1H, s), 7.32–7.45 (5H, m), 10.18 (1H, s); MS m/z: 404
(Mþ). Anal. Calcd for C17H15F3O6S: C, 50.50; H, 3.74.
Found: C, 50.75; H, 3.90.
4.1.6. 3-Benzyloxy-2-ethenyl-5-methoxy-4-methyl-
benzaldehyde (15). A mixture of the triflate 14 (843 mg,
2.08 mmol), vinyl n-tributyltin (913 mL, 3.13 mmol),
Et4NCl (345 mg, 2.08 mmol) and PdCl2(PPh3)2 in DMF
(5 mL) was heated at 110 8C for 1.5 h under Ar atmosphere.
After being cooled to an ambient temperature, an aqueous
KF solution (30%) was added to the reactant, and then the
mixture was stirred at rt for 30 min. The mixture was filtered
through a pad of Celite, and the filtrate was extracted with
EtOAc. The EtOAc layer was washed with water and brine,
dried over Na2SO4, and concentrated. The residue was
purified by column chromatography (silica gel, 30 g) using
EtOAc–hexane (1:9 v/v) as an eluent to give the
benzaldehyde 15 (530 mg, 90%), mp 87–87.5 8C (Et2O).
IR (KBr) n: 1684 cm21; 1H NMR (CDCl3) d: 2.22 (3H, s),
3.90 (3H, s), 4.81 (2H, s), 5.35 (1H, d, J¼18 Hz), 5.72 (1H,
d, J¼12 Hz), 7.03 (1H, d, J¼12, 18 Hz), 7.35–7.47 (6H, m),
10.18 (1H, s); MS m/z: 282 (Mþ). Anal. Calcd for
C18H18O3: C, 76.57; H, 6.43. Found: C, 76.88; H, 6.59.
1
57.5–58.5 8C (Et2O). IR (KBr) n: 1680 cm21; H NMR
(CDCl3) d: 2.19 (3H, s), 3.92 (3H, s), 4.95 (2H, s), 6.77 (1H,
d, J¼9 Hz), 7.75 (1H, d, J¼9 Hz), 10.13 (1H, s); MS m/z:
256 (Mþ). Anal. Calcd for C16H16O3: C, 74.98; H, 6.29.
Found: C, 75.23; H, 6.52.
4.1.3. 2-Benzyloxy-4-methoxy-3-methylphenol (12). A
mixture of benzaldehyde 11 (250 mg, 0.98 mmol), and
mCPBA (252 mg, 1.46 mmol) in CH2Cl2 (15 mL) was
heated at 60 8C for 1 h under N2 atmosphere. After being
cooled to an ambient temperature, the mixture was
quenched with water, and then the mixture was extracted
with EtOAc. The EtOAc layer was washed with aqueous
NaHCO3 solution, water and brine, dried over Na2SO4, and
concentrated. A solution of the residue in EtOH (5 mL) was
added an aqueous KOH solution (10%, 5 mL), and then
stirred at rt for 1 h. The mixture was acidified with 1 M HCl,
which was extracted with EtOAc. The EtOAc layer was
washed with water and brine, dried over Na2SO4, and
evaporated in vacuo. The residue was purified by column
chromatography (silica gel, 30 g) using EtOAc–hexane (1:9
v/v) as an eluent to give the oily phenol 12 (209 mg, 88%).
4.1.7. 1-(3-Benzyloxy-2-ethenyl-5-methoxy-4-methyl-
phenyl)ethane-1,2-diol (16). A solution of the benzal-
dehyde 15 (60 mg, 0.21 mmol) in THF (3 mL) was added to
the Grignard reagent [prepared from chloromethyldimethyl-
isopropoxysilane (191 mL, 1.06 mmol), 1,2-dibromoethane
(20 mL, 0.23 mmol), and Mg (26 mg, 1.06 mmol) in THF
(2 mL) according to the Tamao’s procedure19] under N2
atmosphere. After being stirred at rt for 2 h, the mixture was
quenched with an aqueous NH4Cl solution (10%), and then
the mixture was extracted with Et2O. The organic layer was
dried over Na2SO4, and concentrated at 0 8C. A solution of
H2O2 (28%, 216 mL, 1.19 mmol) was added to the mixture
of the residue, KHCO3 (64 mg, 0.64 mmol), and KF (37 mg,
0.64 mmol) in THF (2 mL) and MeOH (2 mL). After being
stirred at rt for 3 h, an aqueous Na2S2O3 solution (50%) was
added slowly to the mixture. Et2O was added to the mixture,
which was filtered through a pad of Celite. The filtrate was
extracted with EtOAc. The organic layer was washed with
water and brine, dried over Na2SO4, and concentrated. The
residue was purified by column chromatography (silica gel,
20 g) using EtOAc–hexane (1:9 v/v) as an eluent to give the
diol 16 (58 mg, 87%), mp 79–80 8C (Et2O). IR (KBr) n:
1
IR (neat) n: 3528 cm21; H NMR (CDCl3) d: 2.22 (3H, s),
3.79 (3H, s), 4.88 (2H, s), 6.55 (1H, d, J¼9 Hz), 6.74 (1H, d,
J¼9 Hz), 7.45–7.55 (5H, m); MS m/z: 244 (Mþ). HRMS
calcd for C15H16O3: 244.1099; observed: 244.1105.
4.1.4. 3-Benzyloxy-2-hydroxy-5-methoxy-4-methyl-
benzaldehyde (13). Hexamethyltetramine (688 mg,
4.91 mmol) was added to a solution of the phenol 12
(200 mg, 0.82 mmol) in AcOH (10 mL), which was heated
at 110 8C for 3 h. After being cooled to an ambient
temperature, the solution was quenched with water, and
then the mixture was extracted with EtOAc. The EtOAc
layer was washed with water and brine, dried over Na2SO4,
and concentrated. The residue was purified by column
chromatography (silica gel, 30 g) using EtOAc–hexane (1:9
v/v) as an eluent to give the benzaldehyde 13 (118 mg,
53%), mp 73–74 8C (Et2O). IR (KBr) n: 3528, 1653 cm21
;
1H NMR (CDCl3) d: 2.13 (3H, s), 3.82 (3H, s), 5.09 (2H, s),
6.70 (1H, s), 7.32–7.49 (5H, m), 9.83 (1H, s); MS m/z: 272
(Mþ). Anal. Calcd for C16H16O4: C, 70.57; H, 5.92. Found:
C, 70.85; H, 6.18.
1
3279 cm21; H NMR (CDCl3) d: 2.09 (3H, s), 3.50–3.67
(2H, m), 3.84 (3H, s), 4.72 (2H, s), 5.07–5.11 (1H, m), 5.50
(1H, dd, J¼2, 12 Hz), 5.55 (1H, dd, J¼2, 18 Hz), 6.82 (1H,

2948
N. Kuwabara et al. / Tetrahedron 60 (2004) 2943–2952
d, J¼12, 18 Hz), 6.97 (1H, s), 7.28–7.43 (5H, m); MS m/z:
314 (Mþ). Anal. Calcd for C19H22O4: C, 72.59; H, 7.05.
Found: C, 72.81; H, 7.32.
7.33–7.47 (5H, m); MS m/z: 441 (Mþ). HRMS calcd for
C25H35NO4Si: 441.2335; observed: 441.2321.
4.1.11. 1-(tert-Butyldimethylsilyloxymethyl)-5-benzyl-
oxy-7-methoxy-6-methylisoquinoline (20). A solution of
the oxime 19 (141 mg, 0.32 mmol) in o-dichlorobenzene
(5 mL) was heated at 180 8C for 1 h. After being cooled to
an ambient temperature, the solvent was evaporated. The
residue was purified by column chromatography (silica gel,
20 g) using EtOAc–hexane (1:9 v/v) as an eluent to give the
4.1.8. 1-(3-Benzyloxy-2-ethenyl-5-methoxy-4-methyl-
phenyl)-2-(tert-butyldimethylsilyloxy)ethanol (17). tert-
Butyldimethylsilyl chloride (57 mg, 0.38 mmol) was added
to a solution of the diol 16 (100 mg, 0.32 mmol) and
imidazole (65 mg, 0.96 mmol) in DMF (10 mL) at rt under
N2 atmosphere. The mixture was stirred at the same
temperature for 1 h. After being quenched with water, the
mixture was extracted with EtOAc. The EtOAc layer was
washed with an aqueous NaHCO3 solution (saturated),
water, and brine, dried over Na2SO4, and concentrated. The
residue was purified by column chromatography (silica gel,
20 g) using EtOAc–hexane (1:9 v/v) as an eluent to give the
alcohol 17 (126 mg, 92%), mp 68.5–69.5 8C (Et2O). IR
(KBr) n: 3470 cm21; 1H NMR (CDCl3) d: 0.08 (6H, s), 0.92
(9H, s), 2.15 (3H, s), 3.48 (1H, d, J¼9 Hz), 3.78 (1H, dd,
J¼3, 9 Hz), 3.86 (3H, s), 4.68 (1H, d, J¼11 Hz), 4.76 (1H,
d, J¼11 Hz), 5.08 (1H, dd, J¼3, 9 Hz), 5.50 (1H, dd, J¼2,
12 Hz), 5.57 (1H, dd, J¼2, 18 Hz), 6.75 (1H, dd, J¼12,
18 Hz), 6.95 (1H, s), 7.32–7.46 (5H, m); MS m/z: 428 (Mþ).
Anal. Calcd for C25H36O4Si: C, 70.05; H, 8.47. Found: C,
70.29; H, 8.68.
1
oily isoquinoline 20 (66 mg, 49%). H NMR (CDCl3) d:
0.07 (6H, s), 0.90 (9H, s), 2.34 (3H, s), 3.98 (3H, s), 4.98
(2H, s), 5.22 (2H, s), 7.38–7.55 (6H, m), 7.74 (1H, d,
J¼6 Hz), 8.29 (1H, dd, J¼6 Hz); MS m/z: 423 (Mþ). HRMS
calcd for C25H33NO3Si: 463.2230; observed: 463.2228.
4.1.12. 5-Benzyloxy-1-hydroxymethyl-7-methoxy-6-
methylisoquinoline (21). A solution of TBAF (1.0 M in
THF, 107 mL, 0.11 mmol) was added to an ice-cooled
solution of the isoquinoline 20 (45.5 mg, 0.11 mmol) in
THF (3 mL). After being stirred at rt for 1 h, the reaction
mixture was treated with water. The mixture was extracted
with EtOAc. The EtOAc layer was washed with water and
brine, dried over Na2SO4, and concentrated. The residue
was purified by column chromatography (silica gel, 20 g)
using EtOAc–hexane (3:7 v/v) as an eluent to give the
alcohol 21 (30 mg, 89%), mp 144.5–146.5 8C (Et2O). IR
(KBr) n: 3350 cm21; 1H NMR (CDCl3) d: 2.34 (3H, s), 3.98
(3H, s), 4.98 (2H, s), 5.15 (2H, s), 6.85 (1H, s), 7.36–7.54
(5H, m), 7.74 (1H, d, J¼6 Hz), 8.33 (1H, dd, J¼6 Hz); MS
m/z: 309 (Mþ). Anal. Calcd for C19H19NO3: C, 73.77; H,
6.19; N, 4.53. Found: C, 73.97; H, 6.35; N, 4.49.
4.1.9. 2-Benzyloxy-4-[a-(tert-butyldimethylsilyloxy)-
acetyl]-3-ethenyl-6-methoxytoluene (18). A solution of
the alcohol 17 (432 mg, 2.02 mmol) in CH2Cl2 (5 mL) was
added to an ice-cooled mixture of PCC (434 mg,
2.02 mmol) and Celite (800 mg) in CH2Cl2 under N2
atmosphere. After being stirred at rt for 10 h, the reaction
mixture was diluted with Et2O, and then the mixture was
filtrated through a pad of Celite. The filtrate was
concentrated, and the residue was purified by column
chromatography (silica gel, 30 g) using EtOAc–hexane (1:9
v/v) as an eluent to give the oily ketone 18 (365 mg, 85%).
4.1.13. (5-Benzyloxy-7-methoxy-6-methylisoquinol-1-
yl)methyl angelate (22). A solution of PhLi (0.88 M in
cyclohexane–Et2O, 771 mL, 0.68 mmol) was added drop-
wise to an ice-cooled solution of the alcohol 21 (100 mg,
0.32 mmol) in dioxane (5 mL) and Et2O (5 mL) under N2
atmosphere. After being stirred at the same temperature for
10 min, the mixed anhydride (angelic 2,4,6-trichloro-
benzoic anhydride) [prepared from 2,4,6-trichlorobenzoyl
chloride (202 mL, 1.29 mmol), triethylamine (244 mL,
1.62 mmol) and angelic acid (136 mg, 1.36 mmol) in
toluene (10 mL) under N2 atmosphere, according to the
Greene’s procedure21] was added to the mixture. After
being stirred at rt for 12 h, the mixture was quenched with
water, which was extracted with EtOAc. The organic layer
was washed with water and brine, dried over Na2SO4, and
concentrated. The residue was purified by column chroma-
tography (silica gel, 20 g) using EtOAc–hexane (1:9 v/v) as
an eluent to give the oily ester 22 (98 mg, 78%). IR (neat) n:
1
IR (neat) n: 1750 cm21; H NMR (CDCl3) d: 0.08 (6H, s),
0.88 (9H, s), 2.17 (3H, s), 3.83 (3H, s), 4.56 (2H, s), 4.75
(2H, s), 5.41 (1H, dd, J¼1.5, 12 Hz), 5.39 (1H, dd, J¼1.5,
18 Hz), 6.62 (1H, s), 6.96 (1H, dd, J¼12, 18 Hz), 7.30–7.45
(5H, m); MS m/z: 426 (Mþ). HRMS calcd for C25H34O4Si:
426.2226; observed: 426.2233.
4.1.10. 2-Benzyloxy-4-[2-(tert-butyldimethylsilyloxy)-1-
(hydroxyimino)ethyl]-3-ethenyl-6-methoxytoluene (19).
A mixture of the ketone 18 (240 mg, 0.56 mmol), NH2-
OH·HCl (196 mg, 2.82 mmol) and AcONa (231 mg,
2.82 mmol) in EtOH (10 mL) were heated at 85 8C for
1 h. After being cooled to an ambient temperature, the
mixture was concentrated. The water was added to the
resulting residue, and then the mixture was extracted with
EtOAc. The EtOAc layer was washed with water and brine,
dried over Na2SO4, and concentrated. The residue was
purified by column chromatography (silica gel, 30 g) using
EtOAc–hexane (1:9 v/v) as an eluent to give the gummy
oxime 19 (141 mg, 57%). IR (neat) n: 3250, 1750 cm21; 1H
NMR (CDCl3) d: 20.06 (4H, s), 20.04 (2H, s), 0.71 (6H, s),
0.83 (3, s), 2.16 (2/3H, s), 2.17 (1/3H, s), 3.82 (3H, s), 4.73
(4/3H, s), 4.74 (2/3H, s), 5.31 (1/3H, dd, J¼2, 12 Hz), 5.36
(2/3H, dd, J¼2, 12 Hz), 5.61 (2/3H, dd, J¼2, 18 Hz), 5.69
(1/3H, dd, J¼2, 18 Hz), 6.49 (1/3H, s), 6.59 (2/3H, s), 6.75
(1/3H, dd, J¼12, 18 Hz), 6.84 (2/3H, dd, J¼12, 18 Hz),
1717 cm21
;
1H NMR (CDCl3) d: 1.90 (3H, dq, J¼1.5,
1.5 Hz), 1.98 (3H, dq, J¼1.5, 7.2 Hz), 2.34 (3H, s), 3.95
(3H, s), 4.98 (2H, s), 5.77 (2H, s), 6.09 (1H, qq, J¼1.5,
7.2 Hz), 7.20 (1H, s), 7.36–7.54 (5H, m), 7.81 (1H, d,
J¼5.5 Hz), 8.40 (1H, d, J¼5.5 Hz); MS m/z: 391 (Mþ).
HRMS calcd for C24H25NO4: 391.1784; observed:
391.1795.
4.1.14. (5-Benzyloxy-7-methoxy-6-methylisoquinol-1-
yl)methyl acetate (23). A solution of PhLi (0.88 M in
cyclohexane–Et2O, 154 mL, 0.14 mmol) was added drop-
wise to an ice-cooled solution of the alcohol 21 (20 mg,

N. Kuwabara et al. / Tetrahedron 60 (2004) 2943–2952
2949
0.06 mmol) in dioxane (2 mL) and Et2O (2 mL) under N2
atmosphere. After being stirred at the same temperature for
10 min, (MeCO)2O (7 mL, 0.07 mmol) was added to the
mixture. The mixture was stirred at ambient temperature for
30 min, which was quenched with water. The mixture was
extracted with EtOAc. The organic layer was washed with
water and brine, dried over Na2SO4, and concentrated. The
residue was purified by column chromatography (silica gel,
20 g) using EtOAc–hexane (1:9 v/v) as an eluent to give the
acetate 23 (19 mg, 83%), mp 112.5–113.5 8C (Et2O). IR
(KBr) n: 1744 cm21; 1H NMR (CDCl3) d: 2.17 (3H, s), 2.34
(3H, s), 3.98 (3H, s), 4.97 (2H, s), 5.70 (2H, s), 7.15 (1H, s),
7.38–7.54 (5H, m), 7.80 (1H, d, J¼6 Hz), 8.40 (1H, d,
J¼6 Hz); MS m/z: 351 (Mþ). Anal. Calcd for C21H21NO4:
C, 71.78; H, 6.02; N, 3.99. Found: C, 71.98; H, 4.30; N,
3.86.
for 1 h. After being cooled to an ambient temperature, the
mixture was diluted with water. The mixture was extracted
with EtOAc. The organic layer was washed with water and
brine, dried over Na2SO4, and concentrated. The residue
was purified by column chromatography (silica gel, 30 g)
using EtOAc–hexane (1:9 v/v) as an eluent to give the azide
27 (67 mg, 81%), mp 82–83 8C (Et2O). IR (KBr) n: 2100,
1250 cm21; 1H NMR (CDCl3) d: 2.34 (3H, s), 3.99 (3H, s),
4.86 (2H, s), 4.97 (2H, s), 7.10 (1H, s), 7.36–7.53 (5H, m),
7.79 (1H, d, J¼6 Hz), 8.36 (1H, d, J¼6 Hz); MS m/z: 334
(Mþ). Anal. Calcd for C19H18N4O2: C, 68.25; H, 5.43; N,
16.76. Found: C, 68.46; H, 5.54; N, 16.63.
4.1.19. 5-Benzyloxy-7-methoxy-6-methyl-1-(pyruvoyl-
aminomethyl)isoquinoline (28). A solution of PPh3
(54 mg, 0.21 mmol) in benzene (3 mL) was added dropwise
to a solution of the azide 27 (63 mg, 0.19 mmol) in benzene
(2 mL) under N2 atmosphere, and then the solution was
stirred at rt for 12 h. The pyruvoyl chloride [prepared from
pyruvic acid (52 mL, 0.75 mmol) and a,a-dichloromethyl
methyl ether (68 mL, 0.75 mmol) at 50 8C for 30 min22] was
added dropwise to the ice-cooled solution. After being
stirred at rt for 5 min, an aqueous NaHCO3 solution
(saturated, 30 mL) and MeOH (10 mL) was added to the
ice-cooled mixture, which was stirred at the same
temperature for 1 h. The mixture was diluted with water,
and then the mixture was extracted with EtOAc. The organic
layer was washed with water and brine, dried over Na2SO4,
and concentrated. The residue was purified by column
chromatography (silica gel, 30 g) using EtOAc–hexane (1:9
v/v) as an eluent to give the amide 28 (33 mg, 45%), mp
4.1.15. (5-Benzyloxy-7-methoxy-6-methylisoquinol-1-
yl)methyl propionate (24). The same procedure as above
was carried out using the alcohol 21 (50 mg, 0.16 mmol),
PhLi (0.88 M in cyclohexane–Et2O, 386 mL, 0.34 mmol)
and (EtCO)2O (23 mL, 0.18 mmol) to give the propionate 24
(47.5 mg, 80%), mp 97.5–98.5 8C (Et2O). IR (KBr) n:
1734 cm21; 1H NMR (CDCl3) d: 1.18 (3H, t, J¼8 Hz), 2.34
(3H, s), 2.44 (2H, q, J¼8 Hz), 3.97 (3H, s), 4.97 (2H, s),
5.70 (2H, s), 7.15 (1H, s), 7.37–7.54 (5H, m), 7.80 (1H, d,
J¼6 Hz), 8.39 (1H, d, J¼6 Hz); MS m/z: 365 (Mþ). Anal.
Calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C,
72.59; H, 6.33; N, 3.74.
4.1.16. 5-Benzyloxy-7-methoxy-6-methyl-1-(4-toluene-
sulfonyloxymethyl)isoquinoline (25). The same procedure
as above was carried out using the alcohol 21 (77 mg,
0.33 mmol), PhLi (0.88 M in cyclohexane–Et2O, 830 mL,
0.73 mmol) and p-TsCl (69 mg, 0.36 mmol) to give the oily
tosylate 25 (82 mg, 64%). IR (neat) n: 1371, 1177 cm21; 1H
NMR (CDCl3) d: 2.26 (3H, s), 2.36 (3H, s), 3.95 (3H, s),
4.88 (2H, s), 5.50 (2H, s), 7.22–7.72 (10H, m), 7.75 (1H, d,
J¼6 Hz), 8.20 (1H, d, J¼6 Hz); MS m/z: 463 (Mþ). HRMS
calcd for C26H25NO5S: 463.1453; observed: 463.1466.
1
129.5–131 8C (Et2O). IR (KBr) n: 1674 cm21; H NMR
(CDCl3) d: 2.34 (3H, s), 2.55 (3H, s), 400 (3H, s), 4.97 (2H,
s), 4.99 (2H, s), 7.04 (1H, s), 7.36–7.53 (5H, m), 7.76 (1H,
d, J¼6 Hz), 8.34 (1H, d, J¼6 Hz), 8.90 (1H, br s),; MS m/z:
378 (Mþ). Anal. Calcd for C22H22N2O4: C, 69.83; H, 5.86;
N, 7.40. Found: C, 69.98; H, 5.97; N, 7.36.
4.1.20. 5-Hydroxy-1-hydroxymethyl-7-methoxy-6-
methylisoquinoline (29). A mixture of the alcohol 21
(52 mg, 0.19 mmol) and 10% Pd–C (10 mg) in EtOH
(15 mL) was stirred at rt for 2 h under H2 atmosphere. The
reaction mixture was filtered through a pad of Celite, the
filtrate was concentrated. The residue was purified by
column chromatography (silica gel, 30 g) using EtOAc–
hexane (3:7 v/v) as an eluent to give the 5-hydroxyisoquino-
line 29 (19 mg, 99%), mp 189.5–190 8C (MeOH). IR (KBr)
n: 3017 cm21; 1H NMR (CDCl3) d: 2.28 (3H, s), 3.98 (3H,
s), 5.09 (2H, s), 7.13 (1H, s), 7.93 (1H, d, J¼6 Hz), 8.19
(1H, d, J¼6 Hz); MS m/z: 219 (Mþ). Anal. Calcd for
C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.88; H,
6.15; N, 6.22.
4.1.17. 5-Benzyloxy-1,6-dimethyl-7-methoxyisoquinoline
(26). A solution of LiEt3BH (1.0 M in THF, 470 mL,
0.48 mmol) was added dropwise to an ice-cooled solution of
the tosylate 25 (110 mg, 0.24 mmol) in THF (1 mL). After
being stirred at the same temperature for 10 min, the
reaction mixture was quenched with water. The mixture was
extracted with EtOAc. The organic layer was washed with
water and brine, dried over Na2SO4, and concentrated. The
residue was purified by column chromatography (silica gel,
30 g) using EtOAc–hexane (1:9 v/v) as an eluent to give the
1-methylisoquinoline 26 (59 mg, 85%), mp 123–124 8C
(Et2O). 1H NMR (CDCl3) d: 2.34 (3H, s), 2.92 (3H, s), 4.00
(3H, s), 4.97 (2H, s), 7.09 (1H, s), 7.39–7.55 (5H, m), 7.67
(1H, d, J¼6 Hz), 8.27 (1H, d, J¼6 Hz); MS m/z: 293 (Mþ).
Anal. Calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77.
Found: C, 77.93; H, 6.49; N, 4.65.
4.1.21. (5-Hydroxy-7-methoxy-6-methylisoquinol-1-
yl)methyl acetate (30). The same procedure as above was
carried out using the acetate 23 (20 mg, 0.057 mmol) and
10% Pd–C (10 mg) to give the 5-hydroxyisoquinoline 30
(14.5 mg, 98%), mp 204–205 8C (benzene). IR (KBr) n:
1736 cm21; 1H NMR (CDCl3) d: 2.16 (3H, s), 2.23 (3H, s),
3.96 (3H, s), 5.68 (2H, s), 6.95 (1H, s), 7.86 (1H, d,
J¼6 Hz), 8.40 (1H, d, J¼6 Hz); MS m/z: 261 (Mþ), 218.
Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36.
Found: C, 64.56; H, 5.98; N, 5.19.
4.1.18. 1-Azidomethyl-5-benzyloxy-7-methoxy-6-
methylisoquinoline (27). A solution of NaN3 (24 mg,
0.37 mmol) in water (3 mL) was added dropwise to an ice-
cooled solution of the tosylate 25 (115 mg, 0.25 mmol) in
dioxane (15 mL), and then the mixture was stirred at 60 8C

2950
N. Kuwabara et al. / Tetrahedron 60 (2004) 2943–2952
4.1.22. (5-Hydroxy-7-methoxy-6-methylisoquinol-1-
yl)methyl propionate (31). The same procedure as above
was carried out using the propionate 24 (42 mg, 0.11 mmol)
and 10% Pd–C (10 mg) to give the 5-hydroxyisoquinoline
31 (31 mg, 98%), mp 167.5–168 8C (benzene). IR (KBr) n:
neutralized with an aqueous NaHCO3 solution (saturated).
The mixture was extracted with EtOAc. The organic layer
was washed with water and brine, dried over Na2SO4, and
concentrated. The residue was purified by column chroma-
tography (silica gel, 30 g) using EtOAc–hexane (3:7 v/v) as
an eluent to give renierone 1 (15.5 mg, 90%), mp 92–
92.5 8C (Et2O) (lit.,3a 91.5–92.5 8C). IR (KBr) n: 1707,
1666, 1647 cm21; 1H NMR (CDCl3) d: 1.83 (3H, dq, J¼1.5,
1.5 Hz), 1.90 (3H, dq, J¼1.5, 7.3 Hz), 2.09 (3H, s), 4.14
(3H, s), 5.76 (2H, s), 6.09 (1H, qq, J¼1.5, 7.3 Hz), 7.86 (1H,
d, J¼5 Hz), 8.92 (1H, d, J¼5 Hz); MS m/z: 315 (Mþ), 83.
3450, 1736 cm21 1H NMR (CDCl3) d: 1.17 (3H, t,
;
J¼8 Hz), 2.30 (3H, s), 2.42 (1H, q, J¼8 Hz), 3.94 (3H, s),
5.68 (2H, s), 6.95 (1H, s), 7.87 (1H, d, J¼6 Hz), 8.37 (1H, d,
J¼6 Hz); MS m/z: 275 (Mþ), 218. Anal. Calcd for
C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.75;
H, 6.34; N, 4.93.
4.1.23. 5-Hydroxy-7-methoxy-1,6-dimethylisoquinoline
(32). The same procedure as above was carried out using
the 1-methylisoquinoline 26 (52 mg, 0.12 mmol) and 10%
Pd–C (10 mg) to give the 5-hydroxyisoquinoline 32
(33 mg, 91%), mp 238–240 8C (decomp.) (benzene). IR
(KBr) n: 3439 cm21; 1H NMR (CDCl3) d: 2.22 (3H, s), 2.78
(3H, s), 3.89 (3H, s), 6.80 (1H, s), 7.73 (1H, d, J¼6 Hz),
8.07 (1H, d, J¼6 Hz); MS m/z: 203 (Mþ). Anal. Calcd for
C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 71.14; H,
6.56; N, 6.73.
Method B. A stirred solution of the phenol 34 (17.3 mg,
0.057 mmol) and salcomine (3.6 mg, 0.011 mmol) in DMF
(5 mL) was bubbled with oxygen at rt for 2 h. The reaction
mixture was diluted with water, and then the mixture was
extracted with EtOAc. The organic layer was washed with
water and brine, dried over Na2SO4, and concentrated. The
residue was purified by column chromatography (silica gel,
20 g) using EtOAc–hexane (3:7 v/v) as an eluent to give
renierone 1 (17.2 mg, 95%).
4.1.27. Mimocin (2). Method A. The same procedure as
above was carried out using the amide 33 (15.7 mg,
0.055 mmol) and CAN (149 mg, 0.27 mmol) to give
mimocin 2 (13 mg, 79%), mp 189–191 8C (decomp.)
(Et2O) (lit.,4 189–191 8C). IR (KBr) n: 3391, 1722, 1684,
1665 cm21; 1H NMR (CDCl3) d: 2.10 (3H, s), 2.53 (3H, s),
4.17 (3H, s), 5.10 (2H, d, J¼5.1 Hz), 8.62 (1H, br s), 8.94
(1H, d, J¼5 Hz); MS m/z: 302 (Mþ).
4.1.24. 5-Hydroxy-7-methoxy-6-methyl-1-(pyruvoyl-
aminomethyl)isoquinoline (33). The same procedure as
above was carried out using the 1-methylisoquinoline 28
(62 mg, 0.16 mmol) and 10% Pd–C (10 mg) to give the
5-hydroxyisoquinoline 33 (42 mg, 91%), mp 174.5–
1
175.5 8C (Et2O). IR (KBr) n: 3302, 1676 cm21; H NMR
(CDCl3) d: 2.30 (3H, s), 2.55 (3H, s), 3.97 (3H, s), 4.95 (2H,
d, J¼4 Hz), 6.84 (1H, s), 7.82 (1H, d, J¼6 Hz), 8.33 (1H, d,
J¼6 Hz), 8.75–8.85 (1H, br s); MS m/z: 288 (Mþ), 202.
Anal. Calcd for C15H16N2O4: C, 62.49; H, 5.59; N, 9.72.
Found: C, 62.68; H, 5.80; N, 9.62.
Method B. The same procedure as above was carried out
using the amide 33 (14.8 mg, 0.051 mmol) and salcomine
(3.2 mg, 0.01 mmol) with O2 to give mimocin 2 (13.2 mg,
85%).
4.1.25. (5-Hydroxy-7-methoxy-6-methylisoquinol-1-
yl)methyl angelate (34). BF3·Et2O (214 mL, 1.69 mmol)
and Me2S (170 mL, 2.32 mmol) were added dropwise to an
ice-cooled solution of the angelate 28 (33 mg, 0.084 mmol)
in CH2Cl2 (8 mL), and then the mixture was stirred at rt for
12 h. In Addition, BF3·Et2O (214 mL, 1.69 mmol) and Me2S
(170 mL, 2.32 mmol) were added to an ice-cooled mixture,
which was stirred at rt for 6 h. The mixture was quenched
with water, which was extracted with EtOAc. The organic
layer was washed with water and brine, dried over Na2SO4,
and concentrated. The residue was purified by column
chromatography (silica gel, 20 g) using EtOAc–hexane (3:7
v/v) as an eluent to give the 5-hydroxyisoquinoline 34
(25 mg, 96%), mp 154–155 8C (Et2O). IR (KBr) n:
4.1.28. Renierol (3). Method A. The same procedure as
above was carried out using the 1-hydroxymethylisoquino-
line 29 (11 mg, 0.05 mmol) and CAN (143 mg, 0.26 mmol)
to give renierol 3 (6.2 mg, 52%), mp 128–130 8C (Et2O)
(lit.,9c 131–133 8C). IR (KBr) n: 1674 cm21 1H NMR
;
(CDCl3) d: 2.10 (3H, s), 4.15 (3H, s), 4.48 (1H, br s), 5.20
(2H, s), 7.92 (1H, d, J¼5 Hz), 8.84 (1H, d, J¼5 Hz); MS
m/z: 233 (Mþ), 233.
Method B. The same procedure as above was carried out
using the 1-hydroxymethylisoquinoline 29 (11 mg,
0.05 mmol) and salcomine (3 mg, 0.01 mmol) with O2 to
give renierol 3 (9.1 mg, 78%).
1719 cm21
;
1H NMR (CDCl3) d: 1.26 (3H, dq, J¼1.5,
1.5 Hz), 1.75 (3H, dq, J¼1.5, 7.2 Hz), 1.84 (3H, s), 2.29
(3H, s), 3.92 (3H, s), 5.72 (2H, s), 6.90 (1H, qq, J¼1.5,
7.2 Hz), 7.00 (1H, s), 7.86 (1H, d, J¼6 Hz), 8.38 (1H, d,
J¼6 Hz); MS m/z: 301 (Mþ), 218. Anal. Calcd for
C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.97;
H, 6.58; N, 4.51.
4.1.29. 7-Methoxy-1,6-dimethylisoquinoline-5,8-dione
(4). Method A. The same procedure as above was carried
out using the 1-methylisoquinoline 32 (17.2 mg, 0.084
mmol) and CAN (231 mg, 0.42 mmol) to give the com-
pound 4 (14.9 mg, 81%), mp 186–188.5 8C (Et2O) (lit.,3b
188–190 8C). IR (KBr) n: 1668, 1628, 1570 cm21; 1H NMR
(CDCl3) d: 2.08 (3H, s), 2.98 (3H, s), 4.14 (3H, s), 7.80 (1H,
d, J¼5 Hz), 8.84 (1H, d, J¼5 Hz); MS m/z: 217 (Mþ).
4.1.26. Renierone (1). Method A. A solution of CAN
(150 mg, 0.27 mmol) of CH3CN (2 mL) and H2O (1 mL)
was added dropwise to an ice-cooled solution of the phenol
34 (16.5 mg, 0.055 mmol) of CH3CN (2 mL) and H2O
(1 mL). After being stirred at the same temperature for
30 min, the mixture was diluted with water, which was
Method B. The same procedure as above was carried out
using the 1-methylisoquinoline 32 (15.8 mg, 0.078 mmol)
and salcomine (4.9 mg, 0.016 mmol) with O2 to give the
compound 4 (14.3 mg, 85%).

N. Kuwabara et al. / Tetrahedron 60 (2004) 2943–2952
2951
3. (a) McIntire, D. E.; Faulkner, D. J.; Engen, D. V.; Clardy, J.
Tetrahedron Lett. 1979, 20, 4163–4166. (b) Flinke, J. M.
J. Am. Chem. Soc. 1982, 104, 265–269.
4.1.30. Renierol acetate (5). Method A. The same
procedure as above was carried out using the acetate 30
(3.9 mg, 0.015 mmol) and CAN (41 mg, 0.075 mmol) to
give renierol acetate 5 (2.4 mg, 91%), mp 108–109 8C
(Et2O) (lit.,7c 118–119 8C). IR (KBr) n: 1749, 1674,
4. Kubo, A.; Nakahara, S.; Iwata, R.; Takahashi, K.; Arai, T.
Tetrahedron Lett. 1980, 21, 3207–3208.
1
1651 cm21; H NMR (CDCl3) d: 2.09 (3H, s), 2.23 (3H,
5. McKee, T.; Ireland, C. M. J. Nat. Prod. 1987, 50, 754–756.
6. Edrada, R. A.; Proksch, P.; Wray, V.; Christ, R.; Witte, L.;
Van Soest, R. W. M. J. Nat. Prod. 1996, 59, 973–976.
7. (a) de Silva, E. D.; Glavita, N. K. 16th IUPAC International
Symposium on the Chemistry of Natural Products; Kyoto,
May 1988, Abstract Pa 8, p 610. (b) Glavita, N. K. University
of Hawaii, PhD Dissertation. (c) Kitahara, Y.; Nakahara, S.;
Numata, R.; Inaba, K.; Kubo, A. Chem. Pharm. Bull. 1985, 33,
823–830.
s), 4.15 (3H, s), 5.71 (2H, s), 7.89 (1H, d, J¼5 Hz), 8.94
(1H, d, J¼5 Hz); MS m/z: 275 (Mþ), 233.
Method B. The same procedure as above was carried out
using the acetate 30 (8.3 mg, 0.032 mmol) and salcomine
(2 mg, 0.0064 mmol) with O2 to give renierol acetate 5
(8.4 mg, 96%).
4.1.31. Renierol propionate (6). Method A. The same
procedure as above was carried out using the propionate 31
(5.3 mg, 0.019 mmol) and CAN (53 mg, 0.097 mmol) to
give renierol propionate 6 (4.9 mg, 87%), mp 88–90 8C
(Et2O) (lit.,2d 89–90 8C). IR (KBr) n: 2960, 1751, 1672,
8. Danishefsky, S.; Berman, E.; Cvetovich, R.; Minamikawa, J.
Tetrahedron Lett. 1980, 21, 4819–4822.
9. (a) Kubo, A.; Nakahara, S. Chem. Pharm. Bull. 1981, 29,
595–596. (b) Kubo, A.; Nakahara, S.; Inaba, K.; Kitahara, Y.
Chem. Pharm. Bull. 1985, 33, 2582–2584. (c) Kubo, A.;
Nakahara, S.; Inaba, K.; Kitahara, Y. Chem. Pharm. Bull.
1986, 34, 4056–4068.
1653, 1614 cm21 1H NMR (CDCl3) d: 1.22 (3H, d,
;
J¼7.5 Hz), 2.09 (3H, s), 2.52 (2H, d, J¼7.5 Hz), 4.15
(3H, s), 5.71 (2H, s), 7.88 (1H, d, J¼5 Hz), 8.92 (1H, d,
J¼5 Hz); MS m/z: 289 (Mþ), 233.
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Method B. The same procedure as above was carried out
using the propionate 31 (7.4 mg, 0.027 mmol) and salco-
mine (3 mg, 0.096 mmol) with O2 to give renierol
propionate 6 (7.7 mg, 99%).
11. Kubo, A.; Kitahara, Y.; Nakahara, S.; Iwata, R.; Numata, R.
Chem. Pharm. Bull. 1988, 36, 4355–4363.
12. Iyer, S.; Liebskind, S. J. Am. Chem. Soc. 1987, 109,
2759–2770.
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14. (a) Okamura, W. H.; de Lera, A. R. Comprehensive organic
synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.;
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(b) Kawasaki, T.; Sakamoto, M. J. Indian Chem. Soc. 1994,
71, 443–457. (c) Hibino, S.; Sugino, E. Advances in nitrogen
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Acknowledgements
This work was in part supported by a Grant-in-Aid for
Scientific research of the Ministry of Education, Science,
Sports, and Culture of Japan. We would like to thank
Professor A. Kubo, Meiji Pharmaceutical University for the
information of renierol acetate and renierol propinate.
15. (a) Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama, C.; Sugino,
E.; Hibino, S. Tetrahedron Lett. 1996, 37, 2593–2596.
(b) Choshi, T.; Sada, T.; Fujimoto, H.; Nagayama, C.; Sugino,
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