Synthesis and dopamine receptor selectivity of the benzyltetrahydroisoquinoline, (R)-(+)-nor-roefractine

Article abstract of DOI:10.1021/np980008a

(R)-(+)-nor-Roefractine (1) was synthesized by the Bischler-Napieralski route, using asymmetric reduction of the 1,2-didehydro precursor imine with sodium (S)-N-CBZ-prolinyloxyborohydride. Compound 1 was able to displace [³H]-raclopride (a D₂ dopamine receptor-selective ligand) from its specific binding sites in rat striatum with selectivity vs [³H]-SCH23390 (D₁ dopamine receptor-selective ligand).

Full text of DOI:10.1021/np980008a

© Copyright 1998 by the American Chemical Society and the American Society of Pharmacognosy
Volume 61, Number 6
J une 1998
Rapid Communications
a fluorine atom at C-2 (meta to a “folded” aminoethyl
chain) only enhances this behavior (Figure 1). Never-
theless, recent work from our laboratories has shown
that four tetrahydroprotoberberine (THPB) alkaloids
that possess two O-methylated dopamine moieties locked
in “folded” conformations displace [3H]raclopride (a D2
dopamine receptor-selective ligand) from its specific
binding sites in rat striatum with IC50 0.028-0.075 µM
and [3H]-SCH 23390 (a D1 dopamine receptor-selective
ligand) with IC50 1.14-7.13 µM. These results indicate
that such alkaloids, and particularly coreximine, have
rather high affinity and selectivity for the striatal D2
receptor despite the lack of an “extended” dopamine
moiety. Although the two hydroxyl groups of coreximine
occupy positions corresponding to the para hydroxyl of
dopamine, no clear structure-activity relationships can
be delineated from the measured affinities of these few
compounds. It is noteworthy, however, that even (S)-
tetrahydropalmatine, which is completely O-methylated,
retains quite strong affinity for the D2 site.2
Syn th esis a n d Dop a m in e Recep tor
Selectivity of th e
Ben zyltetr a h yd r oisoqu in olin e,
(R)-(+)-n or -Roefr a ctin e
Nuria Cabedo,† Philippe Protais,‡
Bruce K. Cassels,§ and Diego Cortes*,†
Departamento de Farmacologı´a, Farmacognosia y
Farmacodinamia, Facultad de Farmacia, Universidad de
Valencia, 46100 Burjassot, Valencia, Spain, Laboratoire de
Physiologie, Faculte´ de Me´decine et de Pharmacie,
Universite´ de Rouen, 76800 Saint Etienne du Rouvray,
France, and Departamento de Quı´mica, Facultad de
Ciencias, Universidad de Chile, Casilla 653, Santiago, Chile
Received J anuary 15, 1998
Abstr a ct: (R)-(+)-nor-Roefractine (1) was synthesized
by the Bischler-Napieralski route, using asymmetric
reduction of the 1,2-didehydro precursor imine with
sodium (S)-N-CBZ-prolinyloxyborohydride. Compound
1 was able to displace [3H]-raclopride (a D2 dopamine
receptor-selective ligand) from its specific binding sites
in rat striatum with selectivity vs [3H]-SCH23390 (D1
dopamine receptor-selective ligand).
The conformationally labile 1-benzyl-1,2,3,4-tetrahy-
droisoquinolines (BTHIQ) are able to exist as either syn
or anti rotamers (named on the basis of the spatial
relationship of the benzene rings) approximating the
geometries of aporphines or protoberberines, respec-
tively. 1H NMR studies have suggested that the “pro-
toberberine-like” conformation is preferred in solution
when the nitrogen atom is unsubstituted, while for
N-methylated or more highly substituted compounds the
“aporphinoid-like” conformation predominates.3 Race-
mic tetrahydropapaveroline and some of its O-methy-
lated derivatives, including reticuline and norreticuline,
were tested 15 years ago as dopamine receptor ligands.
In general, they were found to displace [3H]spiroperidol
from dopamine binding sites with IC50 values in the
4-20 µM range, with only 4′-O-methyltetrahydropa-
paveroline showing much lower affinity.4 More recently,
we have found that (S)-reticuline and (R)-coclaurine
bind with low micromolar or submicromolar affinities
to both D1 and D2 rat striatal receptors, possibly with
some marginal selectivity for the latter.5 In these
Among the isoquinoline alkaloids and related syn-
thetic compounds, the conformationally restricted apor-
phines have been the subject of extensive structure-
activity studies with regard to their interactions with
dopamine receptors.1 As a consequence, it is commonly
accepted that the D ring of the aporphine skeleton,
together with atoms C-7, C-6a, and N-6, mimic an
“extended” pharmacophoric conformation of dopamine
and that a hydroxyl group at C-11 (corresponding to the
meta hydroxyl of dopamine) is necessary for high
dopamine receptor affinity, while a hydroxyl group or
* To whom correspondence should be addressed. Tel: (34)
963.86.49.75. Fax: (34) 963.86.49.43. E-mail: dcortes@uv.es.
† Universidad de Valencia.
‡ Universite´ de Rouen.
§ Universidad de Chile.
S0163-3864(98)00008-1 CCC: $15.00
© 1998 American Chemical Society and American Society of Pharmacognosy
Published on Web 05/19/1998

710 J ournal of Natural Products, 1998, Vol. 61, No. 6
Rapid Communications
methyl ether linkage remained intact. This final de-
blocking stage afforded 1 (92%) as its hydrochloride salt,
whose structure was confirmed by spectroscopic meth-
ods and assigned as (R)-(+)-1-(4′-methoxybenzyl)-6-
hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (1).
HPLC analysis with UV detection at 282.5 nm estab-
lished the purity of 1 (Scheme 1).
The 1R configuration of our (+)-nor-roefractine (1) is
indicated by the positive optical rotation of the free base
and the negative optical rotation of the salt. This result
is in line with those for analogous N-unsubstituted
compounds in the BTHIQ series.3,12-15
(R)-(+)-nor-Roefractine (1) was able to displace both
[3H]-SCH 23390 (a D1 dopamine receptor-selective
ligand) and [3H]raclopride (a D2 dopamine receptor-
selective ligand) from their specific binding sites in rat
striatum (Figure 2).16,17
F igu r e 1. Aporphine, dopamine, THPB, and BTHIQs.
alkaloids, one (O-methylated) dopamine moiety is held
in a “folded” conformation, and the free hydroxyl group
of this substructure is para to the amine side chain, as
is the case for both dopamine moieties of coreximine.
The pendant 1-benzyl substituent affords a second
dopamine-like fragment in reticuline, but this does not
seem to enhance dopamine receptor affinity, as the
simple p-hydroxybenzyl group of coclaurine is associated
with several times greater potency: the IC50 values for
the displacement of tritiated raclopride or SCH23390
by (R)-(+)-coclaurine are 0.13 and 0.24 µM, respectively.
In coclaurine, but not reticuline, the lack of an N-methyl
group suggests that a “protoberberine-like” conforma-
tion should be preferred in the absence of specific
ligand-receptor interactions. Contrary to what may be
the rule in aporphines, N-demethylation appears to be
associated with greater rather than lesser potency in
these BTHIQ’s, although obviously more extensive
series must be studied in this regard.
As an initial target, we considered (R)-nor-roefractine
[1, 1-(4′-methoxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-
tetrahydroisoquinoline], a hitherto unknown (R)-coclau-
rine analogue with the apparently unimportant 4′-
hydroxy group O-methylated to enhance lipophilicity
and the C-6 and C-7 substituents exchanged to leave a
hydroxyl meta to the amine side chain. We accom-
plished the synthesis of this analogue of natural roe-
fractine6 in a seven-step stereoselective sequence.
Compound 17 was prepared starting from isovanillin
(2) via O-benzylisovanillin (3, yield 90%), (4-methoxy-
3-benzyloxy)-â-nitrostyrene (4, 77%), and â-(3-benzyl-
oxy-4-methoxyphenyl)ethylamine (5, 68%) by standard
methods.8,9 This amine and 4-methoxyphenylacetyl
chloride (6) were condensed under Schotten-Baumann
conditions,10,11 and the resulting N-(4-methoxy-3-ben-
zyloxy)phenylethyl-4′-methoxyphenacetamide (7, 44%)
was cyclized by a Bischler-Napieralski approach to
afford 1-(4′-methoxybenzyl)-6-benzyloxy-7-methoxy-3,4-
dihydroisoquinoline (8, 89%).9,11 This product was
reduced without purification using sodium (S)-N-CBZ-
prolinyloxyborohydride prepared in situ from NaBH4 (1
equiv) and (S)-N-CBZ-proline (3 equiv).13,14 The reac-
tion gave (+)-1-(4′-methoxybenzyl)-6-(benzyloxy)-7-meth-
oxy-1,2,3,4-tetrahydroisoquinoline (10, 49%). The re-
ducing agent provided an effective asymmetric reduction
of the prochiral cyclic imine. Selective hydrolysis of the
benzyloxy protective group in this compound was
achieved in 72% yield by refluxing (3 h) with equal
volumes of ethanol and concentrated HCl, while the
Compared to the other BTHIQs previously tested by
us, coclaurine and reticuline,5 1 appears to be less potent
at both the D1 and D2 dopamine receptors. Neverthe-
less, although our results are not strictly comparable
with those of Nimit et al.,4 the dopamine receptor
affinity of 1 seems to be in the same range as that of
most of the assayed tetrahydropapaveroline analogues.
More interestingly, 1 exhibits 6-fold selectivity for D2
receptors, while the other similar ligands for which
affinity measurements have been made with both major
dopamine receptor subtypes are practically unselective.
The decreased affinity of 1 with regard to coclaurine and
reticuline could be attributed to the fact that in the
“folded” O-methylated dopamine moiety in coclaurine
and reticuline the free hydroxyl group lies para to the
amine side chain, whereas it is meta to the amine side
chain in 1. However, we have observed that the THPBs
coreximine, containing two meta O-methylated dop-
amine moieties in “folded” conformations, and 10-
demethyldiscretine, containing two para O-methylated
dopamine moieties in “folded” conformations, display
similar micromolar affinities for D1 dopamine receptors
and nanomolar affinities for D2 dopamine receptors.2
Comparison of data obtained for THPB and aporphine
alkaloids18 leads to another suggestion: since the nor-
roefractine structure is present both in 10-demethyl-
discretine (THPB) and in laurolitsine (aporphine), and
the affinities of 1 for D1 and D2 dopamine receptors
resemble those of laurolitsine much more closely than
those of 10-demethyldiscretine, it would seem possible
that the “aporphine-like” conformation of 1 is preferred
when this BTHIQ is bound to the active site of dopamine
receptors. NMR studies consistently suggest that in
N-unsubstituted BTHIQs the “protoberberine-like” con-
formation predominates in solution. Experimental and
theoretical studies on the rotational behavior of BTHIQ’s
are lacking, however, and it seems possible that any one
conformer may undergo rotation through a large angle
around the C-1/C-R bond upon binding to a receptor
macromolecule.
Molecular biology studies on seven transmembrane
segment G-protein-coupled receptors19 indicate that the
binding of catecholamines involves specific interactions
between certain critical amino acid residues and comple-
mentary groups on the neurotransmitter molecule: the
positively charged, protonated amino group with an
aspartate residue and the phenolic hydroxyl groups with

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J ournal of Natural Products, 1998, Vol. 61, No. 6 711
Sch em e 1. Synthesis of 1a
a
Reagents and conditions: (a) benzyl chloride, K2CO3/EtOH, reflux, 5 h; (b) H3CNO2, NH4OAc/AcOH, reflux, 3 h; (c) LiH4Al, ether/
THF (1:1), reflux, 2 h; (d) CH2Cl2/NaOH 5%, rt, 2 h; (e) POCl3, CH2Cl2, reflux, 3 h; (f) CH2Cl2, -30 °C, 7 h; (g) HCl-EtOH (1:1), reflux,
3 h.
chain, as opposed to a para hydroxyl, only increases
selectivity for D2 receptors by selective reduction of D1
receptor affinity. If hydrogen bonding to only one of the
active-site serine residues were important for high
affinity binding, this interaction with a para (C-7)
hydroxyl might allow the BTHIQ molecule to adopt a
less energetic conformation and thus obtain a lower IC50
value. These hypotheses will be tested using data
obtained from a rational series of BTHIQs that are now
being synthesized.
Ack n ow led gm en ts. This research was supported by
the Spanish DGICYT under Grant No. SAF 97-0013,
by an ECOS (France)/CONICYT (Chile) exchange pro-
gram, and by the Presidential Chair in Science (Chile,
1996).
F igu r e 2. Displacement curves of [3H]-SCH 23390 and
[3H]raclopride binding by (R)-(+)-nor-roefractine. Displace-
ment curves correspond to four determinations at each con-
centration. IC50 (µM) values are 32.9 (11.9-80.4) and 5.0 (2.0-
12.6) for [3H]-SCH 23390 and [3H]raclopride binding, respec-
tively.
Refer en ces a n d Notes
(1) Neumeyer, J . L. In The Chemistry and Biology of Isoquinoline
Alkaloids; Phillipson, J . D., Roberts, M. F., Zenk, M. H., Eds.;
Springer-Verlag: Berlin, 1985; pp 146-170.
(2) Cortes, D.; Arbaoui, J .; Protais, P. Nat. Prod. Lett. 1993, 3, 233-
238.
two serine residues are apparently similar but with
different global environments in different receptors. In
addition, some amino acid residues (especially pheny-
lalanine and tryptophan) appear to be involved in
conformational changes of the receptors and, for con-
formationally labile ligands, in conformational changes
of dopamine or of nonphysiological ligands. It seems
reasonable to assume that a protonated BTHIQ, even
if lacking an N-substituent, may tend to assume an
“aporphine-like” conformation when interacting with the
key aspartate residue of the receptor. Comparison of
our data obtained with coclaurine and 1 seems to
indicate that a hydroxyl group meta to the amine side
(3) Tomita, M.; Shingu, T.; Fujitani, K.; Furukawa, H. Chem.
Pharm. Bull. 1965, 921-926.
(4) Nimit, Y.; Schulze, J . L.; Ruchirawat, C. S.; Davis, V. E. J .
Neurosci. Res. 1983, 10, 175-189.
(5) Bermejo, A.; Protais, P.; Bla´zquez, M. A.; Rao, K. S.; Zafra-Polo,
M. C.; Cortes, D. Nat. Prod. Lett. 1995, 6, 57-62.
(6) Go¨zler, B.; Kivc¸ak, B.; Go¨zler, T.; Shamma, M. J . Nat. Prod.
1990, 53, 666-668.
(7) All compounds were purified by chromatography on SiO2 (60 H,
Merck) and characterized by full spectroscopic (1H and 13C NMR,
IR, and low-resolution MS) data. Yields refer to spectroscopically
and chromatographically homogeneous (HPLC, TLC) materials.
Selected data for key intermediates and products are sum-
marized below. Compound 4: 3-(benzyloxy)-4-methoxy-â-ni-
trostyrene, C16H15NO4; mp 126-128 °C; IR (film) νmax 1621
(NO2), 1334 (NO2) cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.92 (3H,
s, OCH3-4), 5.17 (2H, s, OCH2-3), 6.91 (1H, d, J ) 8.4 Hz, H-5),

712 J ournal of Natural Products, 1998, Vol. 61, No. 6
Rapid Communications
7.04 (1H, d, J ) 2.0 Hz, H-2), 7.15 (1H, dd, J ) 8.4 Hz, J ′ ) 2.0
Hz, H-6), 7.33-7.44 (5H, m, Ph), 7.44 (1H, d, J ) 13.5 Hz,
R-CHAr), 7.89 (1H, d, J ) 13.5 Hz, â-CHNO2); EIMS m/z 285
[M]+ (62), 91 (100). Compound 5: â-(3-(benzyloxy)-4-methoxy-
(10) Ammar, H. A.; Schiff, P. L., J r.; Slatkin, D. J . Heterocycles 1983,
20, 451-454.
(11) Oger, J . M.; Duval, O.; Richomme, P.; Bruneton, J .; Guinaudeau,
H. Heterocycles 1992, 34, 17-20.
phenyl)ethylamine, C16H19NO2; IR (film) νmax 3326 (NH2) cm-1
;
(12) Corrodi, H.; Hardegger, E. Helv. Chim. Acta 1956, 39, 889-897.
(13) Yamada, K.; Takeda, M.; Iwakuma, T. Tetrahedron Lett. 1981,
22, 3869-3872.
1H NMR (CDCl3, 400 MHz) δ 2.60 (2H, t, J ) 6.8 Hz, R-CH2-
NH2), 2.83 (2H, t, J ) 6.8 Hz, â-CH2Ar), 3.85 (3H, s, OCH3-4),
5.13 (2H, s, OCH2-3), 6.73 (1H, d, J ) 1.8 Hz, H-2), 6.74 (1H,
dd, J ) 8.8 Hz, J ′ ) 1.8 Hz, H-6), 6.83 (1H, d, J ) 8.8 Hz, H-5),
7.30 (1H, d, J ) 7.4 Hz, H-4′), 7.35 (2H, t, J ) 7.4 Hz, H-3′, 5′),
7.43 (2H, d, J ) 7.4 Hz, H-2′, 6′); EIMS m/z 257 [M]+ (45), 228
(76), 137 (34), 91 (100). Compound 7: N-(3-(benzyloxy)-4-
methoxyphenylethyl)-4′-methoxyphenacetamide, C25H27NO4; IR
(14) Yamada, K.; Takeda, M.; Iwakuma, T. J . Chem. Soc., Perkin
Trans. 1 1983, 265-270.
(15) Shamma, M. The Isoquinoline Alkaloids; Academic Press: New
York, 1972; pp 44-89.
(16) Protais, P.; Cortes, D.; Pons, J . L.; Lo´pez, S.; Villaverde, M. C.;
Castedo, L. Experientia 1992, 48, 27-30.
(film) νmax 3250 (NH), 2950, 1700 (amide I), 1600, 1510 cm-1
;
(17) Binding experiments were performed on striatal membranes.
Each striatum was homogenized in 2 mL of ice-cold Tris-HCl
buffer (50 mM, pH ) 7.4 at 22 °C) with a Polytron (4 s, maximal
scale) and immediately diluted with Tris buffer. The homogenate
was centrifuged either twice ([3H]-SCH 23390 binding experi-
ments) or four times ([3H]raclopride binding experiments) at 20
000g for 10 min at 4 °C with resuspension in the same volume
of Tris buffer between centrifugations. For [3H]-SCH 23390
binding experiments, the final pellet was resuspended in Tris
buffer containing 5 mM MgSO4, 0.5 mM EDTA, and 0.02%
ascorbic acid (Tris-Mg buffer), and the suspension was briefly
sonicated and diluted to a protein concentration of 1 mg/mL. A
100 µL aliquot of freshly prepared membrane suspension (100
µg of striatal protein) was incubated for 1 h at 25 °C with 100
µL of Tris buffer containing [3H]-SCH 23390 (0.25 nM final
concentration) and 800 µL of Tris-Mg buffer containing the
required drugs. Nonspecific binding was determined in the
presence of 30 µM SK&F 38393 and represented around 2-3%
of total binding. For [3H]raclopride binding experiments, the final
pellet was resuspended in Tris buffer containing 120 mM NaCl,
5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, and 0.1% ascorbic acid
(Tris-ions buffer), and the suspension was treated as described
above. A 200 µL aliquot of freshly prepared membrane suspen-
sion (200 µg of striatal protein) was incubated for 1 h at 25 °C
with 200 µL of Tris-ion buffer containing [3H]raclopride (0.5
nM final concentration) and 400 µL of Tris-ion buffer containing
the drug being investigated. Nonspecific binding was determined
in the presence of 50 µM apomorphine and represented ∼5-7%
of total binding. In both cases, incubations were stopped by
addition of 3 mL of ice-cold buffer (Tris-Mg buffer or Tris-ion
buffer, as appropriate) followed by rapid filtration through
Whatman GF/B filters. Tubes were rinsed with 3 mL of ice-cold
buffer, and filters were washed with 3 × 3 mL of ice-cold buffer.
After the filters had been dried, radioactivity was counted in 4
mL BCS scintillation liquid at an efficiency of 45%. Filter blanks
corresponded to approximately 0.5% of total binding and were
not modified by drugs.
1H NMR (CDCl3, 250 MHz) δ 2.61 (2H, t, J ) 6.6 Hz, â-CH2Ar),
3.38 (2H, t, J ) 6.6 Hz, R-CH2NHCO), 3.42 (2H, s, CH2CO), 3.78
(3H, s, OCH3-4′), 3.86 (3H, s, OCH3-4), 5.08 (2H, s, OCH2-3),
6.56 (1H, dd, J ) 8.1 Hz, J ′ ) 1.9 Hz, H-6), 6.64 (1H, d, J ) 1.9
Hz, H-2), 6.75 (1H, d, J ) 8.1 Hz, H-5), 6.82 (2H, d, J ) 6.7 Hz,
H-3′, 5′), 7.05 (2H, d, J ) 6.7 Hz, H-2′, 6′), 7.27-7.45 (5H, m,
Ph); 13C NMR (CDCl3, 62.5 MHz) δ 171.4 (CO), 158.6 (C-4′), 148.0
(C-3), 147.8 (C-4), 137.3, 128.4, 127.8 and 127.3 (Ph), 131.0 (C-
1), 130.4 (C-2′, 6′), 126.8 (C-1′), 121.3 (C-6), 114.7 (C-2), 114.3
(C-3′, 5′), 112.0 (C-5), 71.0 (OCH2Ph), 56.0 (OCH3-4), 55.2 (OCH3-
4′), 42.8 (â-CH2Ar), 40.5 (CH2CO), 34.8 (R-CH2NH2); EIMS m/z
405 [M]+ (30), 240 (100), 91 (98). Compound 8: 1-(4′-methoxy-
benzyl)-6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinoline, C25H25
-
NO3; IR (film) νmax 1657 (CdN) cm-1; 1H NMR (CDCl3, 250 MHz)
δ 2.79 (2H, t, J ) 7.6 Hz, CH2-4), 3.71 (3H, s, OCH3-4′), 3.78
(3H, s, OCH3-7), 3.83 (2H, t, J ) 7.6 Hz, CH2-3), 4.36 (2H, s,
CH2-R), 5.16 (2H, s, OCH2-6), 6.72 (1H, s, H-8), 6.83 (2H, d, J )
8.5 Hz, H-3′, 5′), 7.17 (1H, s, H-5), 7.27 (2H, d, J ) 8.5 Hz, H-2′,
6′), 7.30-7.42 (5H, m, Ph); 13C NMR (CDCl3, 62.5 MHz) δ 165.6
(C-1), 158.1 (C-4′), 149.9 (C-6), 147.7 (C-7), 136.5, 128.4, 127.8,
and 127.3 (Ph), 131.6 (C-4a), 130.0 (C-2′, 6′), 129.5 (C-8a), 126.6
(C-1′), 114.0 (C-3′, 5′), 112.3 (C-5), 110.2 (C-8), 70.7 (OCH2-6),
56.1 (OCH3-7), 55.1 (OCH3-4′), 47.0 (CH2-R), 42.4 (CH2-3), 25.6
(CH2-4); EIMS m/z 387 [M]+ (89), 296 (71), 267 (5), 121 (30), 91
(100). (R)-(+)-n or -Roefr a ctin e (1): (1-(4′-methoxybenzyl)-6-
hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline), C18H21NO3;
[R]25 +5° (c 1.2, EtOH) base form; [R]25 -12° (c 1.0, H2O) salt
D
D
form; IR (film) νmax 3363, 2922, 1594, 1509, 1458, 1246, 1175,
1109, 1031 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.71 (2H, m, H-4),
2.90 (2H, m, H-3), 2.90 (1H, m, R1), 3.16 (1H, m, R2), 3.80 (3H,
s, OCH3-4′), 3.81 (3H, s, OCH3-7), 4.13 (1H, m, H-1), 6.57 (1H,
s, H-8), 6.65 (1H, s, H-5), 6.87 (2H, d, J ) 8.4 Hz, H-3′, 5′), 7.16
(2H, d, J ) 8.4 Hz, H-2′, 6′);13C NMR (CDCl3, 100 MHz) δ 158.3
(C-4′), 144.7 (C-6), 144.0 (C-7), 130.8 (C-8a), 130.4 (C-2′, 5′), 129.5
(C-1′), 127.8 (C-4a), 114.7 (C-5), 114.0 (C-3′, 5′), 108.7 (C-8), 56.9
(C-1), 56.0 (OCH3-7), 55.3 (OCH3-4′), 41.7 (C-3), 40.5 (CH2-R),
29.0 (C-4); EIMS m/z 178 (100), 163 (31), 121 (16), 91 (22); CIMS
m/z 300 [M]+. Inspection of the 2D homonuclear correlation (1H-
1H COSY 45) and carbon-multiplicity spectra (DEPT) allowed
resonance assignments and complete characterization of com-
pound 1.
(18) Protais, P.; Arbaoui, J .; Bakkali, E. H.; Bermejo, A.; Cortes, D.
J . Nat. Prod. 1995, 58, 1475-1484.
(19) Hibert, M. F.; Trumpp-Kallmeyer, S.; Bruinvels, A.; Hoflack, J .
Mol. Pharmacol. 1991, 40, 8-15.
(8) Meyers, A. I.; Guiles, J . Heterocycles 1989, 28, 295-301.
(9) Chen, C. M.; Fu, Y. F.; Yang, T. H. J . Nat. Prod. 1995, 58, 1767-
1771.
NP980008A