Enantioselective syntheses of dopaminergic (R)- and (S)-benzyltetrahydroisoquinolines

Article abstract of DOI:10.1021/jm001128u

Optically pure (1S,R)- and (1R,S)-benzyltetrahydroisoquinolines (BTHIQs), 12a,b as the major diastereomers, were prepared by stereoselective reduction of the isoquinolinium salt possessing (R)- and (S)-phenylglycinol as the chiral auxiliary, respectively. The absolute configurations of (1S,R)-13a hydrochloride (O-debenzoylated derivative from 12a) and (1R,S)-12b diastereomers were unambiguously determined by single-crystal X-ray analysis. Reductive removal of the chiral auxiliary group, subsequent N-propylation, and cleavage of the methylenedioxy group furnished the optically active catecholamines (1S)-16a and (1R)-16b in good overall yield. We have separately prepared for the first time pairs of dopaminergic 1-BTHIQs enantiomers through a classical methodology in asymmetric synthesis. The (1S)-enantiomers (14a-16a) bind to D₁ and D₂ dopamine receptors with affinities 5-15 times higher than those of the corresponding (IR)-enantiomers (14b-16b). Moreover, (1S)-14a inhibits [³H]dopamine uptake with high affinity. It appears that synthesis and testing of (S)-enantiomers of BTHIQ are very important for the search for new active drugs at dopamine receptors.

Full text of DOI:10.1021/jm001128u

1794
J . Med. Chem. 2001, 44, 1794-1801
En a n tioselective Syn th eses of Dop a m in er gic (R)- a n d
(S)-Ben zyltetr a h yd r oisoqu in olin es
Nuria Cabedo,† Inmaculada Andreu,† M. Carmen Ram´ırez de Arellano,‡ Abdeslam Chagraoui,§ Angel Serrano,†
Almudena Bermejo,† Philippe Protais,§ and Diego Cortes*,†
Departamento de Farmacologı´a, Laboratorio de Farmacognosia, and Departamento de Qu´ımica Orga´nica,
Universidad de Valencia, 46100 Burjassot, Valencia, Spain, and Laboratoire de Physiologie,
UFR de Me´decine-Pharmacie, 76183 Rouen Cedex, France
Received December 5, 2000
Optically pure (1S,R)- and (1R,S)-benzyltetrahydroisoquinolines (BTHIQs), 12a ,b as the major
diastereomers, were prepared by stereoselective reduction of the isoquinolinium salt possessing
(R)- and (S)-phenylglycinol as the chiral auxiliary, respectively. The absolute configurations
of (1S,R)-13a hydrochloride (O-debenzoylated derivative from 12a ) and (1R,S)-12b diastereo-
mers were unambiguously determined by single-crystal X-ray analysis. Reductive removal of
the chiral auxiliary group, subsequent N-propylation, and cleavage of the methylenedioxy group
furnished the optically active catecholamines (1S)-16a and (1R)-16b in good overall yield. We
have separately prepared for the first time pairs of dopaminergic 1-BTHIQs enantiomers
through a classical methodology in asymmetric synthesis. The (1S)-enantiomers (14a -16a )
bind to D1 and D2 dopamine receptors with affinities 5-15 times higher than those of the
corresponding (1R)-enantiomers (14b-16b). Moreover, (1S)-14a inhibits [3H]dopamine uptake
with high affinity. It appears that synthesis and testing of (S)-enantiomers of BTHIQ are very
important for the search for new active drugs at dopamine receptors.
In tr od u ction
of isoquinoline enantiomers was scarcely reported in the
literature. The D1 and D2 dopaminergic affinities of a
pair of enantiomers with a structure related to the
BTHIQs, the (R)- and (S)-tertiary N-methyl-1-phenyl-
1,2,3,4-tetrahydroisoquinolines, have been compared.14
The (S)-enantiomer showed the best affinity and selec-
tivity for D1 receptors.
Recently we have described the synthesis of (R)-nor-
roefractine,8 a monophenolic unmethylated BTHIQ, and
have also accomplished the synthesis of racemic mono-
phenolic N-alkyl-BTHIQs by a new method incorporat-
ing a ‘one-pot’ cyclization-reduction-alkylation se-
quence.15 All those compounds were reported to bind to
D1 and/or D2 dopamine receptors.8,15
Several important asymmetric approaches have been
reported for the stereoselective synthesis of tetrahydro-
isoquinoline and benzyltetrahydroisoquinoline skele-
tons.1-3 Many of the synthetic methods are based on
the procedures employing chiral building blocks, aux-
iliaries, or reagents, via, for example, Pictet-Spengler
condensation,4 asymmetric alkylation5,6 into the 1-posi-
tion, or asymmetric reduction of dihydroisoquinolines.7
Some natural and synthetic 1-benzyl-1,2,3,4-tetrahy-
droisoquinoline (BTHIQ) alkaloids bind to dopamine
receptors from striatal membranes8 and in some cases
inhibit dopamine uptake by striatal synaptosomes.9 The
application of gene cloning techniques has allowed the
identification of five dopamine receptors subtypes which
can be classified into two classes: D1-like dopamine
receptors (D1 and D5) and D2-like dopamine receptors
(D2, D3, and D4).10,11 The D2-like dopamine receptors
show high affinities for drugs (antagonists) used for the
treatment of schizophrenia (antipsychotics) and those
(agonists) used in the treatment of Parkinson’s dis-
ease.10 A natural catecholic BTHIQ (the 4′-glycoside of
1-benzyl-6,7,4′-trihydroxy-1,2,3,4-tetrahydroisoquino-
line) exhibits a better selectivity for D2 and D4 dopamine
receptors than standard dopaminergic antagonists in-
cluding the clinically useful compound clozapine.12
Other racemic catecholic BTHIQs show significant in
vivo or in vitro dopaminergic activities. It is proposed
that 6,7-dihydroxy-BTHIQs can act as dopaminergic
antagonists.13 The study of the dopaminergic efficiency
To further explore the comparative affinity of BTHIQs
for dopamine receptors, we decided to prepare BTHIQs
which included two important structural factors:
a
catecholic moiety (6,7-diphenolic) and a well-defined
configuration at C-1 (pair of (S)- and (R)-enantiomers).
Thus, we describe here the enantioselective syntheses
of (S)- and (R)-1-benzyl-6,7-dioxygenated-1,2,3,4-tet-
rahydroisoquinolines 14a-16a and 14b-16b. Our strat-
egy was based on the enantioselective construction of
these pairs of enantiomers by Polniaszek’s method16,17
using as chiral source (R)- and (S)-phenylglycinol,18,19
respectively, in two different routes. These compounds
were tested for their ability to displace [3H]raclopride
(a D2 dopamine receptor-selective ligand) and [3H]SCH
23390 (a D1 dopamine receptor-selective ligand) from
their specific binding sites in rat striatum and to inhibit
[3H]dopamine uptake by rat striatal synaptosomes.9
* Corresponding author. Tel: (34) 96 386 49 75. Fax: (34) 96 386
49 43. E-mail: dcortes@uv.es.
Resu lts a n d Discu ssion
† Departamento de Farmacolog´ıa.
Our synthetic route involves N-acylation of an opti-
cally pure â-amino-O-protected alcohol 7a (obtained
‡ Departamento de Qu´ımica Orga´nica (X-ray diffraction studies).
§ Laboratoire de Physiologie.
10.1021/jm001128u CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/27/2001

(R)- and (S)-Benzyltetrahydroisoquinolines
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1795
Sch em e 2. Preparation of BTHIQs 16a
Sch em e 1. Preparation of Iminiums 11a
a
Reagents: (j) NaBH4/MeOH; (k) 5% HCl concd-MeOH; (l)
H2/10% C-Pd/5% HCl-EtOH; (m) PrBr/K2CO3/DMF; (n)
BBr3/CH2Cl2.
diastereomer (1S)-1-benzyl-(R)-N-(1-phenyl-2-phenyl-
acetylethoxy)-6,7-methylenedioxy-1,2,3,4-tetrahydroiso-
quinoline (12a ) was converted into its O-deprotected 13a
hydrochloride salt, whose absolute stereochemistry was
confirmed by single-crystal X-ray analysis [13a base,
[R]D +29° (c 0.8, EtOH)].
a
Reagents: (a) H2SO4/MeOH; (b) CH2Cl2/CsF/DMF; (c) 20% aq
KOH/MeOH; (d) SOCl2/CH2Cl2; (e) t-BDMS chloride/DMF/imida-
zole; (f) 4-DMAP/Et3N/CH2Cl2; (g) BF3-etherate/BH3-THF/THF;
(h) PhCH2COCl/4-DMAP/Et3N/CH2Cl2; (i) POCl3/CH2Cl2.
Removal of the chiral auxiliary of (1S,R)-12a (or
(1S,R)-13a ) was accomplished by catalytic hydrogena-
tion over Pd/C to give the optically active secondary
amine (1S)-14a [base, [R]D -33° (c 0.7, EtOH)]. When
the chiral inductor of the epimer of 12a , (1R,R), was
removed, the corresponding (1R)-enantiomer was ob-
tained. This compound is identical to that prepared from
the major diastereoisomer of the series “b”, (1R)-14b
(see later).
from (R)-(-)-phenylglycinol, 6a ) with the acid chloride
5, which was prepared from 3,4-dihydroxyphenylacetic
acid (1), as starting material. To avoid side reaction due
to the presence of the catechol group on the phenylacetic
acid 1 and the free hydroxyl on the chiral appendage
6a , we decided to protect both groups with O,O-acetal
and O-TBDMS to give 3 and 7a , respectively. Then
esterification of 5 with 7a allows us to afford (R)-N-(1-
phenyl-2-tert-butyldimethylsilylethoxy)-2-(3,4-methyl-
enedioxyphenyl)-acetamide (8a ) (Scheme 1).
The amide 8a was reduced by borane affording a 90%
yield of desilylated (R)-N-[2-(3,4-methylenedioxyphen-
yl)ethyl]-1-phenylethanol amine (9a ). A second N-acy-
lation17 with 2 equiv of phenylacetyl chloride attained
the N,O-diacylated amide 10a as an inseparable mix-
ture of cis,trans rotamers. A Bischler-Napieralski cy-
clization, refluxing with excess of POCl3 in dry CH2Cl2,
allowed us to obtain the iminium ion 11a possessing
the corresponding chiral auxiliary.16-19 The unpurified
iminium ion was reduced with sodium borohydride
under controlled conditions, furnished the 1-BTHIQ
(1S,R)-12a as a major diastereomer (Scheme 2), in
addition to the (1R,R)-epimer obtained in small amounts.
The optical purity was determined by 1H NMR,
affording an 89:11 ratio (1S,R)/(1R,R) corresponding to
78% ed. These two compounds were readily purified by
silica gel column chromatography. The slower eluting
To prepare the amine (R)-14b, we carried out a
synthetic strategy as above using the optically pure
â-amino alcohol, (S)-phenylglycinol (6b). In this case,
the stereoselective reduction of (S)-11b led us to obtain
(1R,S)-12b and the corresponding (1S,S)-epimer as a
1
mixture (87:13 ratio, 74% ed, determined by H NMR),
which was also purified by silica gel chromatography.
The absolute configuration of (1R,S)-12b was confirmed
by single-crystal X-ray analysis. Reductive removal of
the chiral auxiliary group of the major diastereomer
(1R,S)-12b (or (1R,S)-13b) gave the optically active (1R)-
14b [base, [R]D +29° (c 0.3, EtOH)].
X-ray crystal structures of the compounds (1S,R)-13a ‚
HCl and (1R,S)-12b are shown in Figures 1 and 2. Both
molecular structures show the N and C(3) atoms out of
the isoquinoline main plane on a half-chair conforma-
tion. For both compounds the C(1) atom in the benzyl
group is in a pseudoaxial position trans to the pseudo-

1796 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Cabedo et al.
F igu r e 1. Thermal ellipsoid plot of compound 13a hydrochlo-
ride with the molecular labeling. Phenyl hydrogen atoms have
been omitted for clarity.
F igu r e 3. Packing diagram of compound 12b.
Ta ble 1. IC50 Valuesa of BTHIQ Enantiomers on [3H]SCH
23390 and [3H]Raclopride Binding to Rat Striatal Membranes
and on [3H]Dopamine Uptake by Rat Striatal Synaptosomes
IC50 (µM) on
[3H]SCH 23390
binding
[3H]raclopride
binding
[3H]dopamine
uptake
compd
14a
14b
15a
15b
16a
16b
23.9 ( 2.5
>100
4.0 ( 0.5
53.1 ( 4.2
21.9 ( 3.1
>100
3.6 ( 0.6
6.8 ( 0.5
20.3 ( 9.1
43.6 ( 8.4
64.8 ( 3.6
91.5 ( 13.2
F igu r e 2. Thermal ellipsoid plot of compound 12b with the
molecular labeling. Phenyl hydrogen atoms have been omitted
for clarity.
51.9 ( 4.7
>100
16.6 ( 0.4
>100
14.7 ( 0.6
61.2 ( 1.5
axial N-substituent. In the crystal structure of 13a ‚HCl
an anti conformation of the phenyl ring C(21)-C(26) and
the N atom respect the C(1)-C(12) bond has been
observed. However, for compound 12b the crystal
structure shows the phenyl ring C(21)-C(26) anti to
C(9) with respect to the C(1)-C(12) bond, due to
sterically unfavorable conformation. However, in solu-
tion an anti conformation of the phenyl ring and the
a
IC50 values were calculated from concentration-effect curves
with 4-11 concentrations and 4-6 determinations for each
concentration.
all the (1S)-BTHIQs 14a -16a were able to displace [3H]-
SCH 23390 and [3H]raclopride from their respective
binding sites. Therefore, it appears clearly that in this
series of BTHIQs, the (1S)-enantiomers are 5-15 time
more effective at D1-like and D2-like dopamine receptors
than the (1R)-enantiomers. In addition to this difference
between enantiomers, it appears that the 6,7-methyl-
enedioxy derivative (1S)-14a is slightly more effective
at dopamine receptors and more selective for D2-like
dopamine receptors than the corresponding N-propyl
derivative (1S)-15a . This result seems to indicate that
introduction of a propyl chain on the N atom is not
favorable for activity of BTHIQs. This could account for
the low increase of affinity of the catecholic compound
(1S)-16a , as compared to its methylenedioxy homologue
(1S)-15a .
Contrary to what occurred at dopamine receptors, the
efficiency of the enantiomers of each compound ap-
peared relatively similar on [3H]dopamine uptake (the
ratios of the IC50 of (1R)/(1S)-enantiomers were less than
2), even if differences were observed between the IC50
measured for the different compounds: 14a ,b were more
effective than 15a ,b which were more effective than
16a,b (Table 1). As was previously described for anonaine
in the case of aporphine derivatives,9 the BTHIQs with
a methylenedioxy group were more effective on [3H]-
1
N-substituted atom has been observed by H NMR for
13a ‚HCl and 12b and similar described compounds.8,15
In 12b crystal, weak C-H‚‚‚O intermolecular interac-
tions form infinite linear chains (C(16)-H(16)‚‚‚O(2#))
perpendicular to zigzag chains (C(23)-H(23)‚‚‚O(4*))
thus producing molecular layers (see Figure 3). The
shortest contacts between layers correspond to weak
C-H‚‚‚π and C-H‚‚‚O interactions. In 13a ‚HCl crystal
an N-H‚‚‚Cl hydrogen bond has been observed.
N-Propyl derivatives, (1S)-15a and (1R)-15b, were
prepared with corresponding halide under reflux in
alkaline conditions,20 from both enantiomers (1S)-14a
and (1R)-14b, respectively. Finally, the expected cat-
echolamines (1S)-16a and (1R)-16b were prepared in
good yield from (1S)-15a and (1R)-15b by cleavage of
the methylenedioxy group with boron tribromide.21
The (1R)-BTHIQs 14b-16b were poorly effective at
dopamine receptors. None of them were able to displace
[3H]SCH 23390 from its D1 binding sites in striatum at
concentrations up to 0.1 µM. However, 14b and 16b,
but not 15b, were able to displace [3H]raclopride from
its D2 binding sites at high concentrations. In contrast,

(R)- and (S)-Benzyltetrahydroisoquinolines
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1797
supernatant was centrifuged at 15000g for 30 min (4 °C). The
resultant pellet was resuspended in 20 volumes of ice-cold
Krebs-Ringer medium previously oxygenated (95% O2-5%
CO2). The medium contained (mM): NaCl ) 109, KCl ) 3.6,
KH2PO4 ) 1.1, CaCl2 ) 2.4, MgSO4 ) 0.6, NaHCO3 ) 25,
glucose ) 5.5, pH ) 7.6. [3H]Dopamine uptake was evaluated
on aliquots of the synaptosomal preparation. After a 5 min
preincubation in Krebs-Ringer buffer containg 10 µM par-
gyline, [3H]dopamine (47 Ci/mmol; Amersham, France) was
added to a final 2 nM concentration. Five-minute incubations
were stopped by dilution into ice-cold Krebs-Ringer medium
followed by filtration in vacuo on Whatman GF/B filters.
Filters were washed twice with 3 mL cold Krebs-Ringer
medium and dried. Tissue radioactivity retained by synapto-
somes was determined by liquid scintillation spectrometry.
Blank values, obtained by incubating parallel samples at 0
°C, were subtracted.
dopamine uptake than the catecholic one. Again, an
N-propyl chain appears to not be favorable.
In conclusion, this is the first report on the compara-
tive efficiency of pairs of enantiomers (1S)- and (1R)-
BTHIQs at dopamine receptors and on [3H]dopamine
uptake. It appears that synthesis and testing of (S)-
enantiomers of BTHIQs are very important in the
search for new active drugs at dopamine receptors, but
not at the dopamine uptake site.
Exp er im en ta l Section
Gen er a l In str u m en ta tion . Optical rotations were deter-
mined with a Perkin-Elmer 241 polarimeter. IR spectra (film)
were run on a Perkin-Elmer 1750 FTIR spectrometer. EIMS,
LSIMS, and HREIMS were determined on a VG Auto Spec
Fisons instrument, and electrospray ionization (LC-MSD,
API-electrospray positive) was determined on a Hewlett-
Packard (HP-1100). NMR spectra were recorded on a Bruker
AC-250, Varian Unity-300, or Varian Unity-400 spectrometer
at 250, 300, or 400 MHz for 1H and 75 or 100 MHz for 13C.
Multiplicities of 13C NMR signals were assigned by DEPT
experiments. NOEDIFF irradiations, COSY 45, and HMQC
correlations were recorded at 400 MHz. All reactions were
monitored by analytical TLC with silica gel 60 F254 (Merck
5554). The residues were purified through 60 H silica gel
column (5-40 µm, Merck 7736) and by flash chromatography
(230-400 µm, Merck 9385).
Bioa ssa ys. Binding experiments were performed on striatal
membranes. Each striatum was homogenized in 2 mL 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 experiments) or four times ([3H]raclopride binding
experiments) at 20000g 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 incu-
bated for 1 h at 25 °C with 100 µL Tris buffer containing [3H]-
SCH 23390 (0.25 nM final concentration) and 800 µL of Tris-
Mg buffer containing the required drugs. Non-specific 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 suspension (200 µg of striatal
protein) was incubated for 1 h at 25 °C with 200 µL of Tris
buffer containing [3H]raclopride (0.5 nM final concentration)
and 400 µL of Tris-ions buffer containing the drug being
investigated. Non specific binding was determined in the
presence of 50 µM apomorphine and represented around 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-ions
buffer, as appropriate) followed by rapid filtration through
Whatman GF/B filters. Tubes were rinsed with 3 mL ice-cold
buffer, and filters were washed with 3 × 3 mL 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.
3,4-Meth ylen ed ioxyp h en yla cetyl Meth yl Ester , 3. 3,4-
Dihydroxyphenylacetic acid (1; 2.0 g, 11.9 mmol) was treated
by MeOH (40 mL) in acid medium with concentrated H2SO4
(0.5 mL), stirred and refluxed for 3 h. Then, the MeOH was
evaporated off under reduced pressure to afford a residue of
3,4-dihydroxyphenylacetyl methyl ester (2; 2.1 g): 97% yield;
IR (film) νmax 3370, 1714 (CO), 1608, 1523, 1445, 1350, 1285,
1197, 1150, 1115, 1012, 964, 797, 726 cm-1
.
Dichloromethane (3 mL, 46.7 mmol) and CsF (8.4 g, 55.3
mmol) were added to a solution of this compound 2 (2.1 g, 11.5
mmol) in anhydrous DMF (40 mL), and the mixture was
refluxed for 3 h with stirring. After cooling, the reaction
mixture was extracted with CH2Cl2 and the organic layer was
washed with 5% aq NaHCO3 and water, dried over Na2SO4
and concentrated in vacuo to dryness. The residue was purified
by flash chromatography (CH2Cl2/hexane 6:4) furnishing 1.23
g (55%) of 3,4-methylenedioxyphenylacetyl methyl ester (3) as
a pale yellow oil; IR (film) νmax 1737 (CO), 1504, 1492, 1445,
1
1248, 1161, 1039, 929, 810 cm-1; H NMR (250 MHz, CDCl3)
δ 6.72 (d, J ) 1.4 Hz, 1H), 6.69 (d, J ) 7.5 Hz, 1H), 6.64 (dd,
J ) 7.5, 1.4 Hz, 1H), 5.83 (s, 2H), 3.61 (s, 3H), 3.46 (s, 2H);
13C NMR (75 MHz, CDCl3) δ 171.7 (CO), 147.7, 146.6, 127.7,
122.2, 109.6, 108.0, 101.0, 51.5, 40.3; EIMS m/z (%) 194 [M]+
(100), 136 (91), 135 [M - COOCH3]+ (91), 105 (78), 77 (87).
3,4-Meth ylen ed ioxyp h en yla cetyl Ch lor id e, 5. Hydroly-
sis of ester was carried out dissolving 3,4-methylenedioxyphe-
nylacetyl methyl ester (3; 1.0 g, 5.15 mmol) in MeOH (2 mL)
and 20% aq KOH solution (10 mL), stirred and refluxed for 3
h. Methanol was evaporated and the aqueous solution was
made acid with 5% aq HCl and extracted with AcOEt. The
organic layer was washed with brine and water, dried over
Na2SO4 and concentrated to dryness to yield a white solid
which was recrystallized from AcOEt/CH2Cl2, to give 4: 0.9 g
(97%) as colorless needles; mp 129-131 °C; IR (film) νmax 3200,
2911, 1698 (CO), 1504, 1448, 1408, 1339, 1254, 1184, 1038,
925, 785, 692 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.78 (d, J )
1.1 Hz, 1H), 6.76 (d, J ) 7.9 Hz, 1H), 6.71 (dd, J ) 7.9, 1.1 Hz,
1H), 5.93 (s, 2H), 3.55 (s, 2H); 13C NMR (75 MHz, CDCl3) δ
178 (CO), 147.8, 146.9, 126.7, 122.5, 109.7, 108.3, 101.0, 40.6;
LSIMS m/z 180 [M]+, 135 [M - COOH]+.22
A mixture of 3,4-methylenedioxyphenylacetic acid (4; 0.5 g,
2.78 mmol) and SOCl2 (1.5 mL, 20.6 mmol) in anhydrous
CH2Cl2 was refluxed for 3 h. Then, the solvent was removed
to obtain compound 5 as a pale yellow oil which was used in
the next step without further purification.
Syn th esis of (S)-BTHIQs Usin g (R)-(-)-P h en ylglycin ol
(6a ). (R)-N-(1-P h en yl-2-ter t-bu tyld im eth ylsilyleth oxy)-2-
(3,4-m eth ylen ed ioxyp h en yl)a ceta m id e, 8a . The hydroxyl
group of the chiral auxiliary was protected treating a solution
of (R)-1-phenylethanolamine (6a ; 1.0 g, 7.3 mmol) in anhydrous
DMF (4 mL) with tert-butyldimethylsilane chloride (1.3 g, 8.62
mmol), imidazol (1.3 g, 19.1 mmol) under N2 atmosphere, at
room temperature and stirring for 7 h. The reaction mixture
was extracted with CH2Cl2, washed with 5% aq NaHCO3 and
water, dried, and concentrated. This residue was purified
through flash chromatography (CH2Cl2/MeOH/DEA 9.9:0.1:0.1)
to afford a colorless oil of (R)-N-(1-phenyl-2-tert-butyldimeth-
[3H]Dopamine uptake was studied using a preparation of
rat striatal synaptosomes. For the preparation of synapto-
somes, rats (male Wistar rats, 150-250 g; Charles River,
France) were killed by decapitation and the striatum was
dissected (temperature ) 0-4 °C) and homogenized in 10
volumes (w/v) of 0.32 M sucrose using 10 up-and-down strokes
of a Teflon glass homogenizer (800 rpm). Nuclear material was
removed by centrifugation at 1000g for 10 min (4 °C). The

1798 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Cabedo et al.
ylsilylethoxy)amine (7a ; 1.3 g, 71%): [R]D -16.6° (c 0.6, EtOH);
IR (film) νmax 3385, 2954, 2929, 2856, 1690, 1471, 1256, 1089,
compound 10a (60%): LSIMS m/z 522 [MH]+, 386 [MH -
OCOCH2Ph]+; EIMS m/z (%) 521 [M]+ (5), 385 (62), 268 (20),
238 (54), 148 (100), 136 (49), 91 (79).
1
837, 777, 700 cm-1; H NMR* (300 MHz, CDCl3) δ 7.40-7.23
(m, 5H), 4.07 (dd, J ) 8.4, 3.9 Hz, 1H, CHPh), 3.72 (dd, J )
9.6, 3.9 Hz, 1H, CH2O), 3.52 (dd, J ) 9.6, 8.4 Hz, 1H, CH2O),
1.85 (br s, exchange with D2O), 0.90 (s, 9H), 0.04 (s, 6H); 13C
NMR* (75 MHz, CDCl3) δ 142.6, 128.2, 127.2, 126.9, 69.5
(CH2O), 57.6 (CHPh), 25.9, 18.2, -5.5; LSIMS m/z 252 [MH]+,
235 [M - NH2]+, 194 [M - t-BDMS]+. *The assignments were
made by COSY 45, DEPT, and HMQC.
(1S)-1-Ben zyl-(R)-N-(1-p h en yl-2-p h en yla cetyleth oxy)-
6,7-m eth ylen ed ioxy-1,2,3,4-tetr a h yd r oisoqu in olin e, 12a ,
a n d (1R,R)-Ep im er . A mixture of amide 10a (200 mg, 0.38
mmol) as inseparable cis and trans rotamers, and POCl3 (1.5
mL, 16.1 mmol) in dry CH2Cl2 (4.0 mL) was refluxed overnight
with stirring. Excess reagent and solvent were removed in
vacuo to give yellow residue of iminium 11a (LC-MSD, API-
electrospray positive: m/z 386 [M - COCH2Ph]+; LISMS m/z
504 [M]+). This compound was used for the following reaction
without purification.
A solution of this chiral isoquinolinium salt (11a ) in dry
MeOH (15 mL) was reduced by means of NaBH4 (420 mg, 11.1
mmol) at -78 °C and in stirring for 2 h. Excess NaBH4 was
decomposed with 5% aq HCl solution. The mixture was
concentrated, made basic with 5% aq NH4OH solution, ex-
tracted with CH2Cl2, washed with brine, water, dried and the
solvent was evaporated off to dryness. The crude was purified
by silica gel 60H column chromatography (hexane/AcOEt 9.2:
0.8) to attain 159 mg of (1S,R)-12a (83%) and 8 mg of (1R,R)-
epimer (4.2%).
The crude of 3,4-methylenedioxyphenylacetyl chloride (5)
obtained as described above from 0.5 g of 4 (2.78 mmol) in dry
CH2Cl2 (10 mL) was added dropwise to a solution of (R)-N-(1-
phenyl-2-tert-butyldimethylsilylethoxy)amine (7a ; 680 mg, 2.71
mmol), 4-DMAP (50 mg, 0.41 mmol) and Et3N (0.4 mL, 2.88
mmol) in dry CH2Cl2 (10 mL) under N2 atmosphere and in a
cooling ice bath. After stirring at room temperature for 1 h,
5% aq HCl (15 mL) solution was added and extracted with
CH2Cl2. The organic layer was washed with 5% aq NaHCO3
solution, brine, water, dried and the solvent was removed
under reduced pressure to give 1.03 g of compound 8a (92%):
[R]D - 8.2° (c 0.6, EtOH); IR (film) νmax 3289, 2953, 2857, 1645
(CO), 1546, 1503, 1444, 1247, 1119, 1041, 837, 779, 700 cm-1
;
1H NMR* (300 MHz, CDCl3) δ 7.30-7.13 (m, 5H), 6.79 (d, J )
7.8 Hz, 1H), 6.75 (d, J ) 1.7 Hz, 1H), 6.71 (dd, J ) 7.8, 1.7
Hz, 1H), 6.33 (d, J ) 7.5 Hz, 1H, NHCO), 5.95 (s, 2H), 4.97
(m, 1H, CHPh), 3.78 (dd, J ) 10.0, 4.0 Hz, 1H, CH2O), 3.65
(dd, J ) 10.0, 3.8 Hz, 1H, CH2O), 3.51 (s, 2H), 0.74 (s,
9H), -0.15 (s, 3H), -0.26 (s, 3H); 13C NMR* (75 MHz, CDCl3)
(1S,R)-12a : [R]D +32° (c 0.4, EtOH); IR (film) νmax 2920,
1729 (CO), 1496, 1378, 1261, 1226, 1149, 1043, 925, 850 cm-1
;
1H NMR* (300 MHz, CDCl3) δ 7.25-6.94 (m, 13H), 6.79 (d, J
) 8.4 Hz, 2H), 6.52 (s, 1H, H-5), 6.11 (s, 1H, H-8), 5.81 (s, 2H,
OCH2O), 4.39 (dd, J ) 11.2, 5.6 Hz, 1H, CH2O), 4.21 (dd, J )
11.2, 5.6 Hz, 1H, CH2O), 3.84 (t, J ) 5.6 Hz, 1H, CHPh), 3.59
(dd, J ) 8.7, 5.4 Hz, 1H, H-1), 3.44 (m, 2H, OCOCH2Ph), 3.38
(m, 1H, H-3a), 3.11 (dd, J ) 14.4, 5.4 Hz, 1H, H-3b), 2.98 (dd,
J ) 13.6, 8.7 Hz, 1H, H-R1), 2.86 (m, 1H, H-4a), 2.68 (dd, J )
13.6, 5.4 Hz, 1H, H-R2), 2.32 (dd, J ) 17.1, 3.3 Hz, 1H, H-4b);
13C NMR* (100 MHz, CDCl3) δ 171.2 (CO), 145.8 and 145.3
(C-6 and C-7), 140.3-125.8 (CH, C), 108.5 (C-5), 107.9 (C-8),
100.4 (OCH2O), 67.1 (CH2O), 62.3 (CHPh), 61.1 (C-1), 43.2
(C-R), 41.3 (OCOCH2Ph), 39.6 (C-3), 23.6 (C-4); LSIMS m/z 506
[MH]+, 414 [M - CH2Ph]+. *The assignments were made by
COSY 45, DEPT, NOESY and HMQC.
δ
170.4 (CO), 148.2, 147.0, 140.2, 128.4, 128.2, 127.2,
126.6, 122.7, 109.8, 108.8, 101.1, 66.0 (CH2O), 54.2 (CHPh),
43.5, 25.6, 17.9, -5.9; EIMS m/z (%) 413 [M]+ (1.2), 398 (14),
356 [M - tBu]+ (100), 268 (62), 236 (90), 177 (71), 135 (88),
106 (94). *The assignments were made by COSY 45, DEPT
and HMQC.
(R)-N-[2-(3,4-Met h ylen ed ioxyp h en yl)et h yl]-1-p h en yl-
eth a n ola m in e, 9a . (R)-N-(1-Phenyl-2-tert-butyldimethylsi-
lylethoxy)-2-(3,4-methylenedioxyphenyl)acetamide (8a ; 0.5 g,
1.21 mmol) in anhydrous THF (25 mL) was reduced by BF3-
etherate (ca. 47%, 0.3 mL, 1.14 mmol) and 1 M BH3-THF
solution (4.0 mL, 4.0 mmol) carefully added dropwise, at room
temperature and then, the mixture was refluxed for 2.5 h,
under N2 atmosphere. Excess reagent was destroyed with 5
N aq HCl solution. The organic solvent was evaporated off and
the aqueous solution was made basic with 15% aq NH4OH,
then extracted with AcOEt. The combined organic phases were
washed with brine, water, dried over Na2SO4 and concentrated
to dryness. Compound 9a , (310 mg, 90%) was obtained as a
white solid: [R]D -55.9° (c 0.8, EtOH); IR (film) νmax 3300,
2923, 1608, 1502, 1443, 1366, 1246, 1191, 1039, 938, 891, 809,
(1R,R)-Ep im er : [R]D -46° (c 0.3, EtOH); IR (film) νmax
2921, 1735 (CO), 1482, 1379, 1228, 1152, 1049 cm-1; 1H NMR*
(400 MHz, CDCl3) δ 7.31-7.05 (m, 15H), 6.53 (s, 1H, H-5), 6.29
(s, 1H, H-8), 5.88 and 5.86 (2d, J ) 1.4 Hz, 2H, OCH2O), 4.12-
4.02 (m, 3H, H-1 and CH2O), 3.90 (t, J ) 5.4 Hz, 1H, CHPh),
3.38 (s, 2H, OCOCH2Ph), 3.16 (m, 1H, H-3a), 3.05 (dd, J )
13.6, 8.4 Hz, 1H, H-R1), 2.86 (dd, J ) 13.6, 5.2 Hz, 1H, H-R2),
2.70 (m, 2H, H-4a and H-3b), 2.25 (m, 1H, H-4b); 13C NMR*
(75 MHz, CDCl3) δ 171.1 (CO), 146.0 and 145.4 (C-6 and
C-7), 140.1-126.0 (CH, C), 108.5 (C-5), 107.8 (C-8), 100.5
(OCH2O), 67.5 (CH2O), 62.6 (CHPh), 60.6 (C-1), 42.7 (C-R), 41.2
(OCOCH2Ph), 40.1 (C-3), 24.3 (C-4); LSIMS m/z 506 [MH]+,
414 [M-CH2Ph]+. *The assignments were made by COSY 45,
DEPT and HMQC.
(1S )-1-Be n zyl-(R )-N -(1-p h e n yl-2-h yd r oxye t h yl)-6,7-
m eth ylen edioxy-1,2,3,4-tetr ah ydr oisoqu in olin e, 13a. Com-
pound (1S,R)-12a (10 mg, 0.02 mmol) was dissolved in 5%
methanol/HCl concentrated (2 mL) and then this solution was
evaporated under reduced pressure. The residue was crystal-
lized from a mixture of CH2Cl2/MeOH affording 7 mg (91%) of
13a ‚HCl: colorless needles; mp 164-166 °C; [R]D +29° (c 0.8,
EtOH); IR (film) νmax 3435, 2918, 1481, 1379, 1227, 1038, 937
cm-1; 1H NMR* (400 MHz, CDCl3) δ 7.35-7.09 (m, 13H), 6.90
(d, J ) 7.2 Hz, 2H), 6.53 (s, 1H, H-5), 6.20 (s, 1H, H-8), 5.86
(s, 2H, OCH2O), 3.78 (m, 2H, CH2OH), 3.72 (dd, J ) 9.4, 5.3
Hz, 1H, H-1), 3.65 (dd, J ) 9.8, 3.0 Hz, 1H, CHPh), 3.55 (td,
J ) 14.0, 4.9 Hz, 1H, H-3a), 3.26 (dd, J ) 14.0, 6 Hz, 1H, H-3b),
3.05 (dd, J ) 13.7, 9.4 Hz, 1H, H-R1), 2.96 (m, 1H, H-4a), 2.80
(dd, J ) 13.7, 5.3 Hz, 1H, H-R2), 2.48 (dd, J ) 16.8, 4.9 Hz,
1H, H-4b); 13C NMR* (100 MHz, CDCl3) δ 145.8 and 145.3 (C-6
and C-7), 140.2-126.2 (CH, C), 108.4 (C-5), 107.5 (C-8), 100.4
(OCH2O), 65.4 (CHPh), 63.5 (CH2OH), 60.1 (C-1), 43.0 (C-R),
40.3 (C-3), 23.9 (C-4); LSIMS m/z 388 [MH]+; EIMS m/z (%)
386 [M - 1]+, 296 [M - CH2Ph]+, 280, 176. *The assignments
were made by COSY 45 and DEPT.
1
760, 702 cm-1; H NMR* (400 MHz, CDCl3) δ 7.35-7.20 (m,
5H), 6.71 (d, J ) 8.0 Hz, 1H), 6.62 (d, J ) 1.2 Hz, 1H), 6.59
(dd, J ) 8.0, 1.2 Hz, 1H), 5.91 (s, 2H), 3.78 (dd, J ) 8.4, 4.4
Hz, 1H, CHPh), 3.69 (dd, J ) 10.5, 4.4 Hz, 1H, CH2O), 3.53
(dd, J ) 10.5, 8.4 Hz, 1H, CH2O), 2.80-2.66 (m, 4H), 2.21 (br
s, exchange with D2O); 13C NMR* (100 MHz, CDCl3) δ 147.6,
145.8, 140.3, 133.4, 128.6, 127.6, 127.1, 121.4, 109.0, 108.1,
100.7, 66.5 (CH2O), 64.5 (CHPh), 48.5, 36.0; LSIMS m/z 286
[MH]+; EIMS m/z (%) 254 [M - CH2OH]+ (93), 150 (100), 135
(72), 121 (95). *The assignments were made by COSY 45,
DEPT and HMQC.
(R)-N-(1-P h en yl-2-p h en yla cetyleth oxy)-N-[2-(3,4-m eth -
ylen ed ioxyp h en yl)eth yl]-2-p h en yla ceta m id e, 10a . Com-
mercially available phenylacetyl chloride (0.53 mL, 4.0 mmol)
in dry CH2Cl2 (20 mL) was added dropwise to a solution of
(R)-N-[2-(3,4-methylenedioxyphenyl)ethyl]-1-phenylethanol-
amine (9a ; 560 mg, 1.96 mmol), 4-DMAP (60 mg, 0.49 mmol)
and Et3N (0.6 mL, 4.31 mmol) in dry CH2Cl2 (20 mL) under
N2 atmosphere, in an ice bath, then stirred at room temper-
ature for 2.5 h. The mixture reaction was washed with 5% aq
HCl and 5% aq NaHCO3 solutions, brine, water, dried over
Na2SO4 and concentrated under reduced pressure. The residue
was purified by silica gel 60H column chromatography (toluene/
CH2Cl2/AcOEt 7.2:2.2:0.6) to afford 613 mg of a colorless oily

(R)- and (S)-Benzyltetrahydroisoquinolines
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1799
(1S)-1-Ben zyl-6,7-m eth ylen edioxy-1,2,3,4-tetr ah ydr oiso-
qu in olin e, 14a . A solution of (1S,R)-12a (21 mg, 0.04 mmol)
in ethanol (2.5 mL) and 5% HCl (0.34 mL) was shaken under
hydrogen atmosphere (1 atm) in the presence of 10% palladium
on charcoal (8 mg) for 29 h at rt. To remove the catalyst, the
mixture was filtered through Celite and then, the solution was
evaporated off in vacuo. The residue was basified with 5% aq
NH4OH and extracted with CH2Cl2. The organic layer was
washed with brine, water and dried over anhydrous Na2SO4.
The filtrate was concentrated and the residue purified by silica
gel 60H column chromatography (toluene/AcOEt/methanol/
DEA 3:6.8:0.2:0.1) to give 9 mg of (1S)-1-benzyl-6,7-methyl-
enedioxy-1,2,3,4-tetrahydroisoquinoline (14a ; 84%): [R]D -33°
(c 0.7, EtOH); IR (film) νmax 3391, 2923, 2853, 1618, 1484, 1381,
Syn th esis of (R)-BTHIQs Usin g (S)-(+)-P h en ylglycin ol
(6b). Our purpose to approach the major (R)-enantiomer
should be feasible following this same route, by means of (S)-
(+)-phenylglycinol and subjected to the above conditions.
(S)-N-(1-P h en yl-2-ter t-bu tyldim eth ylsilyleth oxy)-2-(3,4-
m eth ylen ed ioxyp h en yl)a ceta m id e, 8b. (S)-1-Phenyletha-
nolamine (6b; 1.0 g, 7.3 mmol) was also protected by tert-
butyldimethylsilyl group as noted above, giving a colorless oil
of (S)-N-(1-phenyl-2-tert-butyldimethylsilylethoxy)amine (7b;
1.15 g, 63%): [R]D +16.9° (c 2.6, EtOH); IR (film) νmax 3387,
2954, 2929, 2857, 1696, 1462, 1256, 1088, 837, 777, 700 cm-1
;
1H NMR* (300 MHz, CDCl3) δ 7.40-7.22 (m, 5H), 4.08 (dd, J
) 8.2, 3.9 Hz, 1H, CHPh), 3.73 (dd, J ) 9.8, 3.9 Hz, 1H, CH2O),
3.52 (dd, J ) 9.8, 8.2 Hz, 1H, CH2O), 1.79 (br s, exchange with
D2O), 0.91 (s, 9H), 0.03 (s, 6H); 13C NMR (100 MHz, CDCl3)*
identical chemical shifts to 7a ; LSIMS m/z 252 [MH]+, 235 [M
- NH2]+, 194 [M - t-BDMS]+. *The assignments were made
by COSY 45, DEPT and HMQC.
1247, 1038, 934 cm-1 1H NMR* (400 MHz, CDCl3) δ 7.35-
;
7.25 (m, 5H), 6.72 (s, 1H, H-8), 6.57 (s, 1H, H-5), 5.91 (s, 2H,
OCH2O), 4.11 (dd, J ) 10.0, 3.6 Hz, 1H, H-1), 3.18 (m, 2H,
H-3a and H-R1), 2.87 (m, 2H, H-3b and H-R2), 2.72 (m, 2H,
H-4), 1.73 (br s, exchange with D2O); 13C NMR (100 MHz,
CDCl3) δ 145.8 and 145.7 (C-6 and C-7), 138.8-126.5 (CH, C),
108.8 (C-5), 106.2 (C-8), 100.6 (OCH2O), 57.2 (C-1), 42.5
(C-3), 40.4 (C-R), 29.9 (C-4); LSIMS m/z 268 [MH]+, 176 [M -
CH2Ph]+; HRLISMS m/z 268.13267 [MH]+ (268.13375 calcd
for C17H18NO2); HREIMS m/z 176.07121 (176.07115 calcd for
C10H10NO2). *The assignments were made by COSY 45 and
NOEDIFF.
The crude of 3,4-methylenedioxyphenylacetyl chloride (5)
obtained as described above from 0.5 g of 4 (2.78 mmol) in dry
CH2Cl2 (10 mL) was added dropwise to a solution of (S)-N-(1-
phenyl-2-tert-butyldimethylsilylethoxy)amine (7b; 680 mg,
2.71 mmol), in the presence of 4-DMAP (50 mg, 0.41 mmol)
and Et3N (0.4 mL, 2.88 mmol) in dry CH2Cl2 (10 mL), under
N2 atmosphere, and in an ice bath. After stirring at room
temperature for 1 h, classical workup gave 1.0 g (89%) of 8b:
[R]D + 10.0° (c 2.4, EtOH); IR (film) νmax 3289, 2929, 2857, 1646
(CO), 1543, 1490, 1444, 1361, 1248, 1118, 1041, 932, 837, 779,
(1S)-N-P r op yl-1-ben zyl-6,7-m eth ylen ed ioxy-1,2,3,4-tet-
r a h yd r oisoqu in olin e, 15a . A suspension of secondary amine
14a (6 mg, 0.023 mmol) in dry DMF (2 mL) and anhydrous
K2CO3 (6 mg) was treated with 1-bromopropane (9 µL, 0.1
mmol) in stirring overnight at 70 °C, under N2 atmosphere.
The mixture reaction was diluted with water (5 mL) and
extracted with CH2Cl2. The combined organic layers were
washed with brine, water, dried over Na2SO4 and evaporated
off under reduced pressure. The residue was purified through
flash chromatography (CH2Cl2/AcOEt 6:4) to obtain 5 mg of
15a (70%): [R]D +24° (c 1, EtOH); IR (film) νmax 2964,
1
700 cm-1; H NMR* (400 MHz, CDCl3) δ 7.28-7.13 (m, 5H),
6.79 (d, J ) 7.4 Hz, 1H), 6.75 (d, J ) 1.6 Hz, 1H), 6.73 (dd, J
) 7.4, 1.7 Hz, 1H), 6.32 (d, J ) 7.6 Hz, 1H, NHCO), 5.95 (s,
2H), 4.97 (m, 1H, CHPh), 3.78 (dd, J ) 10.0, 4.0 Hz, 1H,
CH2O), 3.65 (dd, J ) 10.0, 3.6 Hz, 1H, CH2O), 3.52 (s, 2H),
0.72 (s, 9H), -0.16 (s, 3H), -0.27 (s, 3H); 13C NMR* (100 MHz,
CDCl3) δ identical chemical shifts to 8a ; EIMS m/z (%) 413
[M]+ (11), 398 (50), 357 (92), 268 (82), 236 (82), 177 (83), 135
(100), 106 (96). *The assignments were made by COSY 45,
DEPT and HMQC.
1
2928, 1619, 1486, 1390, 1342, 1254, 1036, 937, 863 cm-1; H
NMR* (400 MHz, CDCl3) δ 7.28-7.14 (m, 5H), 6.54 (s, 1H,
H-5), 6.19 (s, 1H, H-8), 5.87 and 5.84 (2d, J ) 1.2 Hz, 2H,
OCH2O), 3.78 (t, J ) 6.8 Hz, 1H, H-1), 3.26 (m, 1H, H-3a),
3.09 (m, 1H, H-R1), 2.83 (m, 3H, H-3b, H-4a and H-R2), 2.48
(m, 3H, H-4b and NCH2-), 1.41 (m, 2H, CH2-), 0.78 (t, J ) 7.4
Hz, 3H, CH3); 13C NMR* (75 MHz, CDCl3) δ 148.1 and 146.4
(C-6 and C-7), 135.6-122.5 (CH, C), 108.6 (C-5), 108.3 (C-8),
101.4 (OCH2O), 64.6 (C-1), 54.5 (NCH2-), 42.1 (C-3), 41.6
(C-R), 22.0 (CH2-), 18.0 (C-4), 11.2 (CH3); LSIMS m/z 310
[MH]+, 218 [M - CH2Ph]+; HREIMS m/z 308.16614 [M - 1]+
(308.16505 calcd for C20H22NO2), 218.11900 (218.11810 calcd
for C13H16NO2). *The assignments were made by COSY 45,
DEPT and HMQC.
(S)-N-[2-(3,4-Meth ylen ed ioxyp h en yl)eth yl](1-p h en yl)-
eth a n ola m in e, 9b. A mixture of 8b (0.67 g, 1.62 mmol) in
anhydrous THF (25 mL), BF3-etherate (ca. 47%, 0.3 mL, 1.14
mmol) and 1 M BH3-THF solution (4.0 mL, 4.0 mmol) were
carefully added dropwise, at room temperature. Afterward, it
was refluxed for 2.5 h, under N2 atmosphere to yield a solid
9b (430 mg, 93%) in white crystals from CH2Cl2/EtOH: mp
96-98 °C; [R]D +52° (c 0.7, EtOH); IR (film) νmax 3321, 2924,
1606, 1489, 1443, 1363, 1246, 1189, 1099, 1039, 934, 809, 759,
1
702 cm-1; H NMR* (300 MHz, CDCl3) δ 7.34-7.19 (m, 5H),
6.70 (d, J ) 7.8 Hz, 1H), 6.61 (d, J ) 1.5 Hz, 1H), 6.58 (dd, J
) 7.8, 1.5 Hz, 1H), 5.89 (s, 2H), 3.75 (dd, J ) 8.7, 4.4 Hz, 1H,
CHPh), 3.67 (dd, J ) 10.7, 4.4 Hz, 1H, CH2O), 3.49 (dd, J )
10.7, 8.7 Hz, 1H, CH2O), 2.78-2.62 (m, 4H), 2.36 (br s,
exchange with D2O); 13C NMR* (75 MHz, CDCl3) δ identical
chemical shifts to 9a ; LSIMS m/z 286 [MH]+.*The assignments
were made by COSY 45, DEPT and HMQC.
(S)-N-(1-P h en yl-2-p h en yla cetyleth oxy)-N-[2-(3,4-m eth -
ylen ed ioxyp h en yl)eth yl]-2-p h en yla ceta m id e, 10b. Phen-
ylacetyl chloride (0.50 mL, 3.78 mmol) in dry CH2Cl2 (15 mL)
was added dropwise to a solution of (S)-N-[2-(3,4-methylene-
dioxyphenyl)ethyl]-1-phenylethanolamine (9b; 440 mg, 1.54
mmol), 4-DMAP (40 mg, 0.33 mmol) and Et3N (0.5 mL, 3.60
mmol) in dry CH2Cl2 (15 mL) in a cooling ice bath, then stirred
at room temperature for 2.5 h. After classical workup and 60H
column chromatography purification, 530 mg of compound 10b
were afforded as a colorless oil (66%): EIMS m/z (%) 521 [M]+
(9), 385 (57), 374 (58), 268 (66), 239 (59), 148 (100), 136 (49),
118 (56), 91 (90).
(1S)-N-P r op yl-1-ben zyl-6,7-d ih yd r oxy-1,2,3,4-tetr a h y-
d r oisoqu in olin e, 16a . Boron tribromide (5 µL, 0.053 mmol)
was added to a solution of (1S)-N-propyl-BTHIQ (15a ; 5.6 mg,
0.018 mmol) in anhydrous CH2Cl2 (1.4 mL) at -78 °C under
N2 atmosphere, and then the mixture was stirred for 4h at
room temperature. Water was added dropwise to decompose
the excess of BBr3. The mixture was made basic with 5% aq
NH4OH and extracted with CH2Cl2. The organic layer was
washed with brine, water and dried over Na2SO4. The organic
solvent was partially removed and diluted with 5% methanolic
HCl solution to obtain a residue which was purified through
Sephadex column chromatography affording 3.5 mg of (1S)-
N-propyl-1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquino-
line (16a ‚HCl; 58%): [R]D +50° (c 0.5, EtOH); IR (film) νmax
3370, 2925, 2854, 1602, 1453, 1370, 1267, 1109, 1030 cm-1
;
1H NMR* (300 MHz, D2O) δ 7.28-7.08 (m, 5H), 6.65 (s, 1H,
H-5), 6.09 (s, 1H, H-8), 4.54 (t, J ) 7.6 Hz, 1H, H-1), 3.65 and
3.46 (2m, 2H, H-3a and H-R1), 3.27 and 3.14 (2m, 3H, H-3b,
H-4a and H-R2), 2.92 (m, 3H, H-4b and NCH2-), 1.60 (m, 2H,
CH2-), 0.70 (t, J ) 7.4 Hz, 3H, CH3); LSIMS m/z 298 [MH]+,
206 [M-CH2Ph]+; HREIMS m/z 296.16317 [M - 1]+ (296.16505
(1R)-1-Ben zyl-(S)-N-(1-p h en yl-2-p h en yla cetyleth oxy)-
6,7-m eth ylen ed ioxy-1,2,3,4-tetr a h yd r oisoqu in olin e, 12b,
a n d (1S,S)-Ep im er . Compound 10b (312 mg, 0.6 mmol) was
refluxed overnight with POCl3 (1.5 mL, 16.1 mmol) in dry
CH2Cl2 (2.5 mL) to obtain 11b in the same conditions as above
for 11a . Then, 11b was reduced with NaBH4 (240 mg, 6.34
mmol) in dry MeOH (10 mL) at -78 °C with stirring for 2 h.
calcd for C19H22NO2), 206.11801 (206.11810 calcd for C12H16
NO2). *The assignments were made by COSY 45.
-

1800 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Cabedo et al.
2923, 2854,1602, 1464, 1375, 1350, 1267, 1114, 941, 868 cm-1
Workup attained 175 mg of (1R,S)-12b (58%) and 12 mg of
(1S,S)-epimer (4%).
;
1H NMR* (400 MHz, D2O) δ 7.28-7.11 (m, 5H), 6.67 (s, 1H,
H-5), 6.11 (s, 1H, H-8), 4.56 (t, J ) 7.6 Hz, 1H, H-1), 3.55-
3.15 (m, 5H, H-3, H-R and H-4a), 2.90 (m, 3H, H-4b and NCH2-
), 1.45 (m, 2H, CH2-), 0.75 (t, J ) 7.4 Hz, 3H, CH3); LSIMS
m/z 298 [MH]+, 206 [M - CH2Ph]+.
(1R,S)-12b: mp 106-108 °C; [R]D -34° (c 0.3, EtOH); IR
(film) νmax 2912, 1953, 1734 (CO), 1602, 1482, 1454, 1380, 1229,
1147, 1038, 938, 860, 753, 700 cm-1 1H NMR* (300 MHz,
;
CDCl3) δ 7.25-6.94 (m, 13H), 6.79 (d, J ) 6.9 Hz, 2H), 6.52
(s, 1H, H-5), 6.11 (s, 1H, H-8), 5.81 (s, 2H, OCH2O), 4.39 (dd,
J ) 11.0, 5.6 Hz, 1H, CH2O), 4.21 (dd, J ) 11.0, 5.6 Hz, 1H,
CH2O), 3.84 (t, J ) 5.6 Hz, 1H, CHPh), 3.59 (dd, J ) 8.7, 5.4
Hz, 1H, H-1), 3.44 (m, 2H, OCOCH2Ph), 3.38 (m, 1H, H-3a),
3.11 (dd, J ) 14.4, 5.7 Hz, 1H, H-3b), 2.98 (dd, J ) 13.7, 8.7
Hz, 1H, H-R1), 2.86 (m, 1H, H-4a), 2.68 (dd, J ) 13.7, 5.4 Hz,
1H, H-R2), 2.32 (dd, J ) 17.1, 3.6 Hz, 1H, H-4b); 13C NMR*
(75 MHz, CDCl3) δ identical chemical shifts to (1S,R)-12a ;
LSIMS m/z 506 [MH]+, 414 [M - CH2Ph]+. *The assignments
were made by COSY 45, DEPT and HMQC.
(1S,S)-Ep im er : [R]D +41° (c 0.5, EtOH); IR (film) νmax 2920,
1735 (CO), 1601, 1482, 1380, 1229, 1145, 1038, 937, 863, 754,
700 cm-1; 1H NMR* (400 MHz, CDCl3) δ 7.31-7.05 (m, 15H),
6.53 (s, 1H, H-5), 6.29 (s, 1H, H-8), 5.88 and 5.86 (2d, J ) 1.4
Hz, 2H, OCH2O), 4.11-4.02 (m, 3H, H-1 and CH2O), 3.90 (t,
J ) 5.6 Hz, 1H, CHPh), 3.38 (s, 2H, OCOCH2Ph), 3.16 (m,
1H, H-3a), 3.05 (dd, J ) 13.6, 8.4 Hz, 1H, H-R1), 2.86 (dd, J )
13.6, 5.6 Hz, 1H, H-R2), 2.70 (m, 2H, H-4a and H-3b), 2.25
(m, 1H, H-4b); 13C NMR* (100 MHz, CDCl3) δ identical
chemical shifts to (1R,R)-epimer; LSIMS m/z 506 [MH]+, 414
[M - CH2Ph]+, 370 [M - OCOCH2Ph]+. *The assignments
were made by COSY 45, DEPT and HMQC.
Ack n ow led gm en t. This research was supported by
the Spanish DGICYT under Grant SAF 97-0013.
M.C.R.A. acknowledges the Generalitat Valenciana for
financial support (Project GVDOC99-22).
Su p p or tin g In for m a tion Ava ila ble: X-ray data of com-
pounds (1S,R)-13a ‚HCl and (1R,S)-12b; crystal data, final
atomic positional parameters, atomic thermal parameters, full
bond lengths and angles, torsion angles, and hydrogen bond
tables for both compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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(1R )-1-Be n zyl-(S )-N -(1-p h e n yl-2-h yd r oxye t h yl)-6,7-
m eth ylen edioxy-1,2,3,4-tetr ah ydr oisoqu in olin e, 13b. Com-
pound 13b was prepared from (1R,S)-12b as above for 13a :
[R]D -24° (c 1.2, EtOH); all its spectroscopic data were identical
to those reported for 13a .
(1R)-1-Ben zyl-6,7-m eth ylen edioxy-1,2,3,4-tetr ah ydr oiso-
qu in olin e, 14b. A solution of (1R,S)-12b (19 mg, 0.038 mmol)
in ethanol (2.5 mL), 5% HCl (0.34 mL) and 10% palladium on
charcoal (7 mg) was shaken under hydrogen atmosphere (1
atm) for 29 h at room temperature. The mixture was filtered
through Celite and then, the solution was evaporated off in
vacuo. After classical workup we obtained the secondary amine
14b (8.3 mg, 82%): [R]D +29° (c 0.3, EtOH); IR (film) νmax 3365,
1
2922, 2852, 1484, 1380, 1265, 1241, 1038, 936, 862 cm-1; H
NMR* (400 MHz, CDCl3) δ 7.35-7.25 (m, 5H), 6.71 (s, 1H,
H-8), 6.57 (s, 1H, H-5), 5.91 (s, 2H, OCH2O), 4.12 (dd, J ) 9.8,
3.8 Hz, 1H, H-1), 3.18 (m, 2H, H-3a and H-R1), 2.88 (m, 2H,
H-3b and H-R2), 2.72 (m, 2H, H-4), 1.80 (br s, exchange with
D2O); LSIMS m/z 268 [MH]+, 176 [M - CH2Ph]+; HREIMS
m/z 266.11558 [M - 1]+ (266.11810 calcd for C17H16NO2),
176.07109 (176.07115 calcd for C10H10NO2). *The assignments
were made by COSY 45 and NOEDIFF.
(1R)-N-P r op yl-1-ben zyl-6,7-m eth ylen ed ioxy-1,2,3,4-tet-
r a h yd r oisoqu in olin e, 15b. 1-Bromopropane (8 µL, 0.09
mmol) was added to the amine 14b (5.1 mg, 0.019 mmol) in
dry DMF (2 mL) and K2CO3 (5 mg) under N2 atmosphere and
in stirring overnight at 70 °C. The mixture reaction was
treated as described above for preparing 15a and purified
through flash chromatography (CH2Cl2/AcOEt 6:4) to obtain
4.5 mg of 15b (77%): [R]D -21° (c 0.8, EtOH); IR (film) νmax
2964, 2928, 1605, 1460, 1390, 1312 cm-1; 1H NMR* (300 MHz,
CDCl3) δ 7.27-7.16 (m, 5H), 6.55 (s, 1H, H-5), 6.17 (s, 1H,
H-8), 5.88 and 5.85 (2d, J ) 1.3 Hz, 2H, OCH2O), 3.80 (t, J )
6.6 Hz, 1H, H-1), 3.25 (m, 1H, H-3a), 3.12 (m, 1H, H-R1), 2.85
(m, 3H, H-3b, H-4a and H-R2), 2.54 (m, 3H, H-4b and NCH2-
), 1.44 (m, 2H, CH2-), 0.78 (t, J ) 7.4 Hz, 3H, CH3); LSIMS
m/z 310 [MH]+, 218 [M - CH2Ph]+.*The assignments were
made by COSY 45.
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propyl-1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline
(16b‚HCl; 69%): [R]D -55° (c 0.6, EtOH); IR (film) νmax 3391,
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J M001128U