(±)-Heterocarpine, a hydroxymethylated isoquinoline alkaloid from Ceratocapnos heterocarpa

Article abstract of DOI:10.1016/S0031-9422(98)00198-8

Heterocarpine, a novel alkaloid from Ceratocapnos heterocarpa, has been characterised as (±)-1-hydroxymethyl-2-(3-hydroxy-4-methoxybenzyl)-7- hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline. The alkaloid was synthesized from the corresponding 3,4-dihydro isoquinoliniun salt. A key step in the process is the acid resin catalysed methanolysis of the 1- carbamoyl isoquinoline. The structural correlation of the hydroxymethylated alkaloids heterocarpine and malacitanine with their unsubstituted counterparts capnosine and caseamine, also present in the plant, might be of biosynthetic significance.

Full text of DOI:10.1016/S0031-9422(98)00198-8

Phytochemistry Vol. 49, No. 8, pp. 2551±2555, 1998
# 1998 Elsevier Science Ltd. All rights reserved
Printed in Great Britain
0031-9422/98/$ - see front matter
PII: S0031-9422(98)00198-8
( )-HETEROCARPINE, A HYDROXYMETHYLATED
ISOQUINOLINE ALKALOID FROM CERATOCAPNOS
HETEROCARPA
RAFAEL SUAU*, NATALIA POSADAS, M. VICTORIA SILVA and MARIA VALPUESTA
Departamento de Quõmica Organica, Facultad de Ciencias. Universidad de Malaga, 29071, Malaga,
Spain.
(Received 2 February 1998)
Key Word IndexÐCeratocapnos heterocarpa; Fumariaceae; heterocarpine; structure; syn-
thesis; isoquinoline alkaloids.
AbstractÐHeterocarpine, a novel alkaloid from Ceratocapnos heterocarpa, has been characterised as ( )-1-
The
hydroxymethyl-2-(3-hydroxy-4-methoxybenzyl)-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline.
alkaloid was synthesized from the corresponding 3,4-dihydro isoquinoliniun salt. A key step in the process
is the acid resin catalysed methanolysis of the 1-carbamoyl isoquinoline. The structural correlation of the
hydroxymethylated alkaloids heterocarpine and malacitanine with their unsubstituted counterparts capno-
sine and caseamine, also present in the plant, might be of biosynthetic signi®cance. # 1998 Elsevier Science
Ltd. All rights reserved
INTRODUCTION
RESULTS AND DISCUSSION
Optically inactive heterocarpine (1) was isolated
as an amorphous powder and analysed for
C19H23NO5. The UV spectrum of 1 was consistent
with an unconjugated tetrahydroisoquinoline (lmax
284 nm) with phenolic substituents (lmax+NaOH:
290 nm). The mass spectrum in the CI mode pro-
duced the expected [M + H]+ ion at m/z 346. The
EI-mass spectrum revealed two important features:
the absence of [M]+, a strong peak at [M±CH3O]+
(m/z 314.1387, C18H20NO4) was obtained instead,
and the splitting of the m/z 314 ion into two frag-
ments at m/z 178 (11%) and 137 (100%). These
peaks were assigned to tetrahydroisoquinolinium
and a benzyl ion respectively, both substituted with
one methoxy and one hydroxy group [13].
The biosynthesis of most types of isoquinoline alka-
loids depends on the oxygenation pattern of the 1-
benzylisoquinoline precursor. Thus, reticuline, oxy-
genated at positions 6,7 of the heterocyclic ring, is a
precursor for morphinans, aporphinoids and 2,3-
berbines [1, 2]. On the other hand, crassifoline [3],
oxygenated at positions 7,8, is associated with the
biosynthesis of cularines, quettamines and 1,2-ber-
bines. In previous papers [4±11], we reported that
Ceratocapnos heterocarpa is a particularly interest-
ing species by virtue of its ability to express both
metabolic pathways. It produces (either in the plant
or in in vitro cultures) a wide variety of types of iso-
quinoline alkaloids including isoquinolones, N-ben-
zylisoquinolines, cularines, berbines, protopines, Heterocarpine (1) reacted with diazomethane to
give O,O-dimethyl heterocarpine (2), which also
exhibited in the mass spectrum the ion[M-31]+ and
others at m/z 192 and 151.
aporphines, benzophenanthridines and ribasines [12].
In this paper, we report on the isolation of a new
alkaloid named heterocarpine (1), a phenolic N-ben-
zylisoquinoline bearing a hydroxymethyl group at
position 1, from C. heterocarpa. The structure of 1
was established spectroscopically and con®rmed by
total synthesis of heterocarpine and its O,O-
dimethyl derivative 2.
The 13C NMR spectrum of 1 revealed the pre-
sence of four aliphatic methylene groups. In ad-
dition to the expected C-3 and C-4 signals of the
tetrahydroisoquinoline nucleus (d 41.9 and 22.5), a
signal at d 56.7 was assigned to a benzyl carbon,
while a low ®eld one (d 63.5) suggested the presence
of a hydroxymethyl substituent that was tentatively
located at C-1 in accordance with a methine carbon
*Author to whom correspondence should be addressed.
2551

2552
R. SUAU et al.
used to synthesize solidaline, an 8-hydroxymethyl-
berberine alkaloid [15]. However, this methodology
was discounted since the irradiation of N-benzyl-
3,4-dihydro-isoquinolinium salts in methanol/HCl
does not stop at the addition stage because dehy-
dration is followed by photoreduction of the imi-
nium ion [16]. One other, particularly interesting,
approach to inserting a hydroxymethyl group uses
the electrophilicity of C-1 in isoquinolines or 3,4-
dihydroisoquinolines and the addition of hydroxy-
methyl anion equivalents or the cyanide ion [17],
which requires further manipulation of the func-
tionality. We chose this last strategy because of our
interest in the synthetic and cyclization potentials of
1-carbamoyl isoquinolines.
Conventional Bischler±Napieralski reactions were
used to prepare the starting 3,4-dihydroisoquino-
lines, which were alkylated with the corresponding
benzyl chlorides to a€ord the isoquinolinium chlor-
ides 3a and 3b. The cyanides 4a,b were obtained in
high yield when the reactions were conducted in
aqueous solutions [18]. Hydrolysis to the amide in
related systems has been reported [17] to proceed
with good yield by reaction in benzene/ethanol/
HCl. Under these conditions, however, we only
observed elimination of hydrogen cyanide.
Concentrated hydrochloric acid at a temperature
below 58 produced the carboxyamides 5a and 5b.
As expected, the concomitant removal of the pro-
tecting groups during the reaction of 4a was also
observed. Hydrolysis of the amide 5a to the car-
boxylic acid under acid or basic conditions [19, 20]
gave very low yields that were attributed to solubi-
lity problems. The alternative step going from the
amide to the ester was found to be very convenient.
The reaction was carried out by using the acid resin
Amberlite1 IR-120 in methanol [21]. Extraction of
6b from the resin was readily achieved with metha-
nol±pyridine (3:1), by contrast the extraction of 6a
required more basic conditions, i.e. methanol±
triethylamine (3:1). LiAlH4 reduction of 6a and 6b
a€orded ( )-heterocarpine (1) and O,O-dimethyl
heterocarpine (2) which were shown to be identical
to the natural compounds (TLC, IR, 1H and 13C
NMR, MS). The hydroxymethyl group at position
1 of the heterocyclic nucleus is a common structural
feature of isoquinoline alkaloids. Examples [22]
include simple isoquinolines (e.g. calycotomine),
signal at d 61.1; thus, the benzyl substituent must
be linked to the nitrogen atom. From the aromatic
part of the 1H NMR spectrum of 1, the OMe and
the OH groups on the isoquinoline nucleus were
assigned to positions 6 and 7 (two singlets for H-5
and H-8), also three protons in an ABX pattern
indicated 1,3,4-substitution of the benzyl unit. The
position of the substituents on the aromatic rings
was inferred from the 2D-COSY spectrum. The cor-
relation between the proton at d 6.67 (H-5) and the
high-®eld multiplet assigned to H-4 and a methoxy
group, indicated that 1 must be methoxylated at C-
6 and hydroxylated at C-7. In addition, an ortho
coupled proton (H-5') was found to be correlated
with the methoxy group at C-4'. On biosynthetic
grounds the hydroxy group was assigned to the
neighbouring carbon (C-3'). Consequently, hetero-
carpine (1) was tentatively characterized as ( )-1-
hydroxymethyl-2-(3'-hydroxy-4'-methoxybenzyl)-7-
hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline.
In order to con®rm this structure, a synthesis for 1
and 2 was developed. Most of the syntheses for
1,2,3,4-tetrahydroisoquinolines bearing a substituent
at position 1 introduce the substituent before the
heterocycle is formed, via the Pictet±Spengler or the
Bischler±Napieralski reaction. In the latter case,
however, the introduction of
a hydroxymethyl
group meets with some diculties that have been
partially resolved [14]. The most direct approach,
based on the photoaddition of methanol to isoqui-
nolinium salts via single electron transfer, has been

(
)-Heterocarpine, a hydroxymethylated isoquinoline alkaloid
2553
protoberberines (e.g. malacitanine, solidaline),
O,O-Dimethyl heterocarpine (2). To a soln of 1
benzophenanthridines (e.g. bocconoline), and the (25 mg) in Et2O (10 ml containing a few drops of
more complex quinocarcins [23] and MeOH) a large excess of a ethereal soln of CH2N2
ecteinascidins [24]. It is assumed that the additional was added. The mixture was allowed to stand at
carbon atom is introduced at the heterocycle form- room temp. for 24 hr and the solvent removed
ing step, pyruvate or glyoxylate being two potential under a N2 stream to give 2 as a white powder, mp
1
precursors [25].
95±978. IR nmax cm (KBr): 3417 (OH); 1H NMR
It is interesting to note that heterocarpine (1) and (CDCl3: d 6.88 (1 H, s, H-2'), 6.80 (2 H, s, H-6', H-
the C-1 unsubstituted N-benzylisoquinoline capno- 5'), 6.59 (1 H, s, H-5), 6.50 (1 H, s, H-8), 4.70 (1 H,
sine (7) occur concomitantly in Ceratocapnos br s, OH), 3.85 (6 H, s, 2 ÂOMe), 3.83, 3.81 (3 H
heterocarpa [8]. Moreover, the 1,2,10,11-substituted each, two s, 2Â OMe), 3.80±3.65 (3 H, m, 2 H,
berbine alkaloids ( )-malacitanine (8) [6] and ( )- CH2Ph), 3.70±3.60 (1 H, m, H-1), 3.65±3.45 (2 H,
caseamine (9) [4] have also been isolated from this m, CH2OH), 3.30±2.30 (4 H, m, H-3, H-4); 13C
source. Structurally, 8 can be considered the hydro- NMR (CDCl3): d 149.0, 148.3, 147.8, 147.6 (C-6,
xymethyl derivative of 9. This suggests that intro- C-7, C-3', C-4'), 130.9 (C-1'), 126.3, 125.4 (C-4a, C-
duction of this substituent at position 1 of the 8a), 121.1 (C-6'), 111.9, 111.6, 110.9, 110.3 (C-5, C-
isoquinoline nucleus might occur after the hetero- 8, C-2', C-5'), 63.6 (CH2OH), 60.9 (C-1), 56.9
cycle has been formed.
(CH2Ph), 55.9, 55.8, 55.7 (4 ÂOMe), 42.0 (C-3),
22.4 (C-4); EIMS m/z (rel. int.): 342 [M-31]+ (30),
192 (10), 151 (100). Found: C, 63.80; H, 7.61; N,
3.46. C21H27NO5.H2O requires C, 64.43; H, 7.47;
N, 3.58%.
EXPERIMENTAL
General
Mps: uncorr.; EIMS: direct inlet, 70 eV; CC:
Silica gel 60 (70±230 mesh); TLC: silica GF254
1H
Preparation of 1-cyano-1,2,3,4-tetrahydroisoquinoline
derivatives 4a,b.
;
The isoquinolinium salt 3a was prepared by
and 13C NMR: 200 and 50 MHz, respectively. reaction of 7-benzyloxy-6-methoxy-3,4-dihydro-
Proton chemical shifts are referred to the residual isoquinoline [8] and 3-benzyloxy-4-methoxybenzyl
CHCl3 (d 7.24) signal, and carbon chemical shifts chloride in MeCN at re¯ux temp for 4 hr, followed
to the solvent (13CDCl3 d 77). 1H and 13C NMR by removal of the solvent. Similar conditions were
signals were assigned from 2D COSY and DEPT used to prepare 3b from 6,7-dimethoxy-3,4-
expts.
dihydroisoquinoline [8] and 3,4-dimethoxybenzyl
( )-Heterocarpine (1), Acid-base fractionation of chloride.
the methanolic extract of Ceratocapnos heterocarpa
To a soln of the corresponding 3,4-dihydroisoqui-
(3 kg of air dried plant) a€orded an alkaloid frac- nolinium salts (3a,b, 1 mmol) in H2O (10±12 ml),
tion soluble in CHCl3±MeOH that was separated KCN±H2O (3 mmol) was added. The mixture was
CC [5]. The fraction eluted with EtOAc was further stirred at room temp. for 30 min, extracted with
puri®ed by prep. TLC (CHCl3±MeOH) to give het- CHCl3 (4 Â20 ml), dried over MgSO4 and the sol-
erocarpine (70 mg). Yellowish amorphous solid, mp vent evaporated.
105±1068, [a]D 08. UV lmax nm (log E) MeOH: 226 1-Cyano-2-(3-benzyloxy-4-methoxybenzyl)-7-ben-
(4.08), 284 (3.79); +NaOH: 240 (4.01), 290 (3.86); zyloxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline (4a).
1
IR
nmax cm
(KBr): 3386 (OH); 1H NMR Yield 88%, pale yellow powder, mp 60±658. IR
1
(acetone-d6): d 6.90 (1 H, d, J = 2.0 Hz, H-2'), 6.87
(1 H, d, J = 8.2 Hz, H-5'), 6.78 (1 H, dd, J = 2.0,
n
max cm (CHCl3): 2256 (CN); 1H NMR (CHCl3):
d
7.5±7.2 (10H, m, 2 ÂPh), 6.96 (1 H, d,
8.2 Hz, H-6'), 6.67 (1 H, s, H-5), 6.60 (1 H, s, H-8), J = 1.8 Hz, H-2'), 6.93 (1 H, dd, J = 8.0, 1.8 Hz,
3.82, 3.80 (3 H each, two s, 2 ÂOMe), 3.70 (2 H, s, H-6'), 6.84 (1 H, d, J = 8.0 Hz, H-5'), 6.62 (1 H, s,
CH2Ph), 3.68±3.50 (3 H, m, H-1, CH2OH), 3.30± H-5), 6.59 (1 H, s, H-8), 5.1, 5.05 (2 H each, two s,
2.35 (4 H, m, H-3, H-4); 13C NMR (CDCl3): d 2 ÂOCH2Ph), 4.42 (1 H, s, H-1), 3.87, 3.84 (3 H
146.1, 145.7, 145.6, 144.1 (C-6, C-7, C-3', C-4'), each, two s, 2Â OMe), 3.78 (1 H, d, J = 13.0 Hz,
131.1, 126.0, 125.5, (C-1', C-4a, C-8a), 120.6 (C-6'), H-a), 3.64 (1 H, d, J = 13.0 Hz, H-a'), 3.05±2.55 (4
115.3, 113.3, 110.9, 110.6 (C-5, C-8, C-2', C-5'), H, m, H-3, H-4); EIMS m/z (rel. int.): 494 [M-26]+
63.5 (CH2OH), 61.1 (C-1), 56.7 (CH2Ph), 55.9, 55.8 (1), 268 (11), 227 (32), 91 (100).
(2 ÂOMe), 41.9 (C-3), 22.5 (C-4); CIMS (CH4,
1-Cyano-2-(3,4-dimethoxybenzyl)-6,7-dimethoxy-
probe) m/z: 346 [M + H]+; EIMS m/z (rel int.): 1,2,3,4-tetrahydroisoquinoline (4b), Yield 91%, yel-
314 [M-31]+ (40), 178 (11), 137 (100); HRMS:[M± lowish oil, pure based on TLC (Lit.: mp 988 [20]).
1
CH3O]+ (found: 314.1387; C18H20NO4 requires: IR
nmax cm
(CHCl3): 2260 (CN); 1H NMR
314.1392). Found: C, 63.19; H, 6.59; N, 3.85. (CHCl3): d 6.92 (2 H, m, H-2', H-6'), 6.81 (1 H, d,
C19H23NO5.H2O requires: C, 62.80; H, 6.93; N, J = 8.6 Hz, H-5'), 6.59 (1 H, s, H-5), 6.55 (1 H, s,
3.85%.
H-8), 4.53 (1 H, s, H-1), 3.85, 3.84, 3.82, 3.79 (3 H

2554
R. SUAU et al.
each, four s, 4Â OMe), 3.85 (1 H, d, J = 12.8 Hz, J4eq,3ax=J4eq,3eq=3.6 Hz, H-4eq), 2.43 (1 H, dt,
H-a), 3.69 (1 H, d, J = 12.8 Hz, H-a'), 3.10±2.60 (4 J3ax,3eq=J3ax,4ax=11.0, J3ax,4eq=3.6 Hz, H-3ax); 13C
H, m, H-3, H-4); 13C NMR (CDCl3): d 149.1, NMR (CDCl3): d 176.1 (CO), 148.9, 148.4, 148.1,
149.0, 148.5, 147.7 (C-6, C-7, C-3', C-4'), 128.9, 147.4 (C-6, C-7, C-3', C-4'), 129.9, 126.1, 123.7,
126.7 (C-1', C-4a), 121.4 (C-6'), 121.2, 116.7 (C-8a, 121.1 (C-1', C-6', C-4a, C-8a), 112.1, 111.1, 110.9,
CN), 111.9, 111.4, 110.9, 109.5 (C-5, C-8, C-2', C- 109.8 (C-5, C-8, C-2', C-5'), 67.5 (C-1), 59.6
5'), 59.6 (CH2Ph), 55.9, 55.8 (4 ÂOMe), 53.8 (C-1), (CH2Ph), 55.9, 55.8 (4Â OMe), 46.5 (C-3), 28.1 (C-
46.6 (C-3), 28.1 (C-4); EIMS m/z (rel. int.): 368 4); EIMS m/z (rel. int.): 342 [M-44]+ (27), 151
[M]+ (1), 151 (100).
(100); CIMS (CH4, probe) m/z: 387 [M + H]+.
Synthesis of heterocarpine (1)
Preparation of 1-carbamoyl derivatives 5a,b
A mixture of the 1-carboxamide derivative 5a,
(210 mg, 0.75 mmol) in MeOH (10 ml) and
Amberlite1 IR-120 resin(2.5 g, thoroughly rinsed
with MeOH) was gently stirred in a tightly capped
¯ask at 658 for 14 hr. The mixture was cooled and
the resin ®ltered and washed once with MeOH. The
Amberlite was suspended in a mixture of MeOH±
Et3N (3:1) and shaken at room temp. for 48 hr.
Solvent evaporation gave a yellowish syrup that
solidi®ed on standing. The solid was ground with
Et2O to obtain a white solid that was characterized
as the 1-methoxycarbonyl derivative 6a and used
without further puri®cation (190 mg, 68%); mp
A cooled (08) mixture of the corresponding 1-
cyano derivative (4a,b 1 mmol) and conc. HCl
(4 ml) was stirred to complete dissolution and the
soln allowed to stand at 48 for 36±48 hr. The mix-
ture was made alkaline (pH 8±9) with conc. ammo-
nia, extracted with CHCl3 (3Â20 ml) and dried
(MgSO4). The extracts were concentrated to a€ord
a solid residue that was puri®ed by recrystallization.
1-Carbamoyl-2-(3-hydroxy-4-methoxybenzyl)-7-
hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline
(5a). Yield 76%, white solid, mp 218±2208
1
(Me2CO). IR nmax cm
(KBr): 3430, 3300±3200
(OH, NH), 1684 (Amide I); 1H NMR (CDCl3): d
7.09 (1 H, s, H-8), 6.90 (1 H, d, J = 1.4 Hz, H-2'),
6.79 (1 H, d, J = 8.5 Hz, H-5'), 6.78 (1 H, dd,
J = 8.5, 1.4 Hz, H-6'), 6.52 (1 H, s, H-5), 4.04 (1
H, s, H-1), 3.86, 3.81 (3 H each, two s, 2 ÂOMe),
3.79 (1 H, d, J = 13.3 Hz, H-a), 3.36 (1 H, d,
J = 13.3 Hz, H-a'), 3.03 (1 H, ddd, J3eq,3ax=11.0,
J3eq,4ax=4.3, J3eq,4eq=3.5 Hz, H-3eq), 2.79 (1 H,
ddd, J4ax,4eq=16.0, J4ax,3ax=11.0, J4ax,3eq=4.3 Hz,
1
108±1108. IR nmax cm (KBr): 3440 (OH), 1732
(CO); 1H NMR (CDCl3):
d 6.93 (1 H, d,
J = 1.4 Hz, H-2'), 6.82 (1 H, dd, J = 8.1, 1.4 Hz,
H-6'), 6.76 (1 H, d, J = 8.1 Hz, H-5'), 6.76 (1 H, s,
H-8), 6.57 (1 H, s, H-5), 4.39 (1 H, s, H-1), 3.70±
3.60 (2 H, m, CH2Ph), 3.86, 3.83 (3 H each, two s,
2 ÂOMe), 3.70 (3 H, s, CO2Me), 3.40±2.10 (4 H, m,
H-3, H-4); 13C NMR (CDCl3): d 173.0 (CO), 145.9,
145.7, 145.5, 143.7 (C-6, C-7, C-3', C-4'), 131.5,
126.7, 124.5, (C-1', C-4a, C-8a), 120.4 (C-6'), 115.1,
112.6, 110.9, 110.3 (C-5, C-8, C-2', C-5'), 63.9 (C-1),
58.7 (CH2Ph), 55.9, 55.8 (2ÂOMe), 51.7 (CO2Me),
44.7 (C-3), 28.1 (C-4); EIMS m/z (rel. int.): 314 [M-
59]+ (70), 178 (6), 137 (100).
To a stirred soln of 6a (90 mg, 0.24 mmol) in dry
THF (10 ml) a soln of LiAlH4 (40 mg, 1 mmol) in
THF (8 ml) was added under a N2 atmosphere.
After stirring for 1 hr, excess hydride was destroyed
with H2O (0.15 ml) and 1% H2SO4 was added to
make the pH slightly acidic. The ppt. was removed
by ®ltration, the residue washed with CHCl3 and
MeOH, and the combined ®ltrate concentrated to
dryness. The residues was taken up in CHCl3,
washed with diluted aq. NaHCO3 and dried
(MgSO4). After solvent removal, the crude product
was puri®ed by prep. TLC to a€ord heterocarpine
(1) as a yellowish foam that was identical in all
respects with the alkaloid isolated from the plant.
H-4ax),
2.57
(1
H,
dt,
J4eq,4ax=16.0,
J4eq,3ax=J4eq,3eq=3.5 Hz, H-4eq), 2.39 (1 H, dt,
J3ax,3eq=J3ax,4ax=11.0, J3ax,4eq=3.5 Hz, H-3ax); 13C
NMR (CDCl3): d 176.6 (CO), 146.3, 146.0, 145.7,
144.2 (C-6, C-7, C-3', C-4'), 130.7, 125.5, 124.2, (C-
1', C-4a, C-8a), 120.4 (C-6'), 115.0, 113.2, 110.7,
110.5 (C-5, C-8, C-2', C-5'), 67.5 (C-1), 59.5
(CH2Ph), 55.9, 55.8 (2 ÂOMe), 46.4 (C-3), 28.1 (C-
4); EIMS m/z (rel. int.): 314 [M-44]+ (67), 178 (11),
137 (100); CIMS (CH4, probe) m/z: 358 [M + H]+.
Found:
C,
60.49;
H,
6.57;
N,
7.41.
C19H22N2O5.H2O requires: C, 60.63; H, 6.43; N,
7.44%.
1-Carbamoyl-2-(3,4-dimethoxybenzyl)-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline (5b). Yield
65%, white solid, mp 156±98 (Me2CO) (Lit.: 189±
1
1928 [19]). IR n max cm (KBr): 3437, 3319 (NH),
1659 (Amide I); 1H NMR (CDCl3): d 7.0 (2 H, s,
H-2', H-8), 6.84 (1 H, d, J = 8.0 Hz, H-6'), 6.82 (1
H, d, J = 8.0 Hz, H-5'), 6.54 (1 H, s, H-5), 5.50 (2
H, br s, NH2), 4.09 (1 H, s, H-1), 3.85 (6 H, s,
2 ÂOMe), 3.84 (1 H, d, J = 13.5 Hz, H-a), 3.81 (6
H, s, 2 ÂOMe), 3.44 (1 H, d, J = 13.5 Hz, H-a'),
Synthesis of O,O-dimethyl-heterocarpine (2)
The reaction of the carboxyamide 5b with amber-
3.07 (1 H, ddd, J3eq,3ax=11.0, J3eq,4ax=4.5, lite in MeOH was carried out as above. The ester
J3eq,4eq=3.6 Hz, H-3eq), 2.82 (1 H, ddd, 6b was extracted from the resin with MeOH±pyri-
J4ax,4eq=16.0, J4ax,3ax=11.0, J4ax,3eq=4.5 Hz, H- dine (3:1). 6b (96% yield) was characterized and
4ax),
2.61
(1
H,
dt,
J4eq,4ax=16.0, used without further puri®cation in the reduction

(
)-Heterocarpine, a hydroxymethylated isoquinoline alkaloid
2555
1
step. IR nmax cm
(®lm): 1732 (CO); 1H NMR
F. and Cabezudo, B., Phytochemistry, 1995, 38,
113.
(CDCl3): d 6.92 (1 H, d, J = 1.4 Hz, H-2'), 6.83 (1
H, dd, J = 8.2, 1.4 Hz, H-6'), 6.77 (1 H, d,
J = 8.2 Hz, H-5'), 6.68 (1 H, s, H-8), 6.58 (1 H, s,
H-5), 4.40 (1 H, s, H-1), 3.95±3.75 (2 H, m,
CH2Ph), 3.83 (6 H, s, 2Â OMe), 3.80, 3.77 (3 H
each, two, s, 2 ÂOMe), 3.69 (3 H, s, CO2Me), 3.50±
2.60 (4 H, m, H-3, H-4); 13C NMR (CDCl3): d
172.7 (CO), 148.8, 148.3, 148.2, 147.2 (C-6, C-7, C-
3', C-4'), 130.0, 127.0, 123.0, (C-1', C-4a, C-8a),
121.0 (C-6'), 111.9, 111.4, 110.6, 109.8 (C-5, C-8, C-
2', C-5'), 63.5 (C-1), 58.7 (CH2Ph), 55.8, 55.7, 55.6
(4 ÂOMe), 51.6 (CO2Me), 44.6 (C-3), 27.6 (C-4);
EIMS m/z (rel. int.): 342 [M-59]+ (45), 151 (100).
The reduction of 6b with LiAlH4 was carried out
as above. Although the work up of the reaction was
conducted a alkaline pH. The 1-hydroxymethyl de-
rivative 2 was puri®ed by prep. TLC (CHCl3±
MeOH, 20:1). The product was identical to the
above described O,O-dimethyl heterocarpine.
10. Suau, R., Garcõa-Segura, R., Silva, M. V.,
Valpuesta, M., Domõnguez, D. and Castedo,
L., Heterocycles, 1995, 41, 2575.
11. Suau, R., Garcõa-Segura, R., Silva, M. V. and
Valpuesta, M., Phytochemistry, 1996, 43, 1389.
12. Silva, M. V., PhD thesis, University of Malaga,
1991.
13. Ohashi, M., Wilson, J. M., Budzikiewicz, H.,
Shamma, M., Slusarchyk, W. A. and Djerassi,
C., Journal of the American Chemical Society,
1963, 85, 2807.
14. Suau, R., Ruiz, I., Posadas, N. and Valpuesta,
M., Heterocycles, 1996, 43, 545.
15. Suau, R., Najera, F. and Rico, R., Tetrahedron
Letters, 1996, 37, 3575.
16. Mariano, P. S., The Photochemistry of
Substances Containing the C-C1N moiety
with Emphasis on Electron Transfer Processes,
In Organic Photochemistry, Vol. 9, Chap. 1, ed.
A. Padwa. Marcel Dekker, Inc., New York, pp.
1-128.
AcknowledgementsÐThe authors wish to acknowl-
edge ®nancial support from the Spanish DGES
(Project PB97-1077).
17. Kobor, J. and Kozcka, C., Szegedi Tanarkepzo
Foiskola Tudomanyos. Kozlemenyeibol, 1969,
179.
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