Stereochemical studies on the synthesis of 1,2,3,4- tetrahydroisoquinolin-4-ols

Article abstract of DOI:10.1016/S0957-4166(98)00164-5

The stereoselectivity of the acid catalyzed promoted cyclization of adequately substituted α-aminoaldehydes to afford a series of tetrahydroisoquinolin-4-ols is studied. The results illustrate the effect of the substituents at C-1 and/or C-3 in the target

Full text of DOI:10.1016/S0957-4166(98)00164-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1809–1816
Stereochemical studies on the synthesis of
1,2,3,4-tetrahydroisoquinolin-4-ols
Luisa Carrillo, Dolores Badía,∗ Esther Domínguez,∗ Imanol Tellitu and José Luis Vicario
Departamento de Química Orgánica, Facultad de Ciencias, Universidad del País Vasco, PO Box 644-48080 Bilbao, Spain
Received 6 April 1998; accepted 21 April 1998
Abstract
The stereoselectivity of the acid catalyzed promoted cyclization of adequately substituted α-aminoaldehydes to
afford a series of tetrahydroisoquinolin-4-ols is studied. The results illustrate the effect of the substituents at C-1
and/or C-3 in the target heterocycle. The required precursors 5 and 10 were synthesized from the enantiomerically
pure (−)-imines 1 by two different routes, and reacted with conc. HCl. © 1998 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Despite the extensive results gathered over recent years on the synthesis of different isoquinolin-4-
ols,1 some aspects of the stereocontrolled access to their polysubstituted derivatives remain unexplored.
In this context, pioneering work by Bates2 on the Pictet–Spengler cyclization of (−)-norepinephrine
and (−)-epinephrine revealed some deficiencies from regioselective and stereoselective points of view.
Attracted also by their substantial biological and pharmacological activities,3 we recently have been
involved in a major effort to design and optimize different strategies conducive to the stereoselective
preparation of the title compounds, and preliminary results have already been published. Thus, different
sequences to obtain either (1R,3S,4R)- or (1S,3S,4R)-3-aryl-1-methyltetrahydroisoquinolin-4-ols from
cyanohydrins4 and, more recently, the transformation of enantiopure imines 1 into (3S,4S)-3-phenyl-
tetrahydroisoquinolin-4-ol 2 have been delineated.5
∗
Corresponding authors. Fax: +34-94-4648500; e-mail: qopdopee@lg.ehu.es
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00164-5

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Trying to improve our knowledge about the factors that govern the stereochemical outcome of our
last strategy, and complementary to the observed 1,2-asymmetric induction due to the presence of an
adjacent stereogenic center in imines 1, the cyclization reaction of structurally related precursors was
tested. Thus, the presence of a second stereogenic center (as in 5), the steric and electronic nature of the
α-substituent to the carbonyl function (5a vs 5b), and the effect of a sole stereogenic center at a remote
site (as in 10) were investigated. The already mentioned precursors 5 and 10 were prepared starting from
(−)-imines 1, and then transformed into the corresponding tetrahydroisoquinolin-4-ols by electrophilic
aromatic substitution with the results shown in this paper.
2. Results and discussion
First, imines 1 were alkylated with the appropriate Grignard reagent6 to afford (1S,10S)-aminoalcohols
3a and 3b which, in turn, were N-methylated and oxidized to α-aminoaldehydes 5a and 5b (Scheme 1).
Due to their lability, aldehydes 5 were immediately reacted with an acetone solution of conc. HCl7
yielding the corresponding (1S,3S,4S)-tetrahydroisoquinolin-4-ols 6a and 7a as the major (d.e.=80%)
diastereoisomers. Alternatively, the hydrogenolytic removal of the chiral auxiliary in aminoalcohol 3a
afforded amine 8 which, after treatment with bromoacetaldehydediethylacetal (BADA) followed by
formaldehyde, was transformed into aminoacetal 10.†
Scheme 1.
The thus-formed derivative 10 was submitted to an acid-catalyzed heterocyclization process leading
to (1S,4S)-6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-ol 11a, al-
though with poor diastereoselectivity (d.e.=33%). It has to be pointed out that the use of non-protic
solvents, such as acetone, in the heterocyclization step enables the target heterocycle to be obtained
avoiding formation of undesired isopavine derivatives.6
†
The alternative N-alkylation sequence of 8 with formaldehyde followed by BADA was also evaluated and ruled out since it
resulted in significant racemization of 10.6

L. Carrillo et al. / Tetrahedron: Asymmetry 9 (1998) 1809–1816
1811
After separation of the pair of C-4 epimers, the enantiomeric excess was determined by chiral
HPLC for all the stereoisomers prepared, and no racemization was detected in any of the described
transformations (e.e.=95%).
On the other hand, the stereochemical relationships of the stereogenic centers of heterocycles 6, 7
and 11 were determined either by extensive NMR experiments or by comparison with spectroscopic
data of structurally related compounds with well defined stereochemistry. In order to gain additional
data, we have also studied the stereochemical behavior of isoquinoline (3S,4S)-2 previously synthesized
by our group.5 Thus, the observation of an intense nuclear Overhauser effect between H-3 and H-4 in
compound 2, as well as the small value of their coupling constant (2.6 Hz), revealed a 3,4-cis relationship
of the substituents at both stereogenic carbons. This stereochemical proposal could also be confirmed
by comparison with spectroscopic data of the known stereoisomer (3S,4R)-2.4 Thus, presumably, the
isoquinoline (3S,4S)-2 must be stabilized in a chair-like conformation with the phenyl substituent in an
equatorial position, and the hydroxy group in a pseudoaxial orientation that enables the formation of a
H-bond with the lone electron pair on the nitrogen.
Analogously, for both tetrahydroisoquinoline derivatives, 6 and 7, the relative configuration of the
major stereoisomers were assigned on the basis of NOE experiments. Thus, a 3,4-cis relationship between
the substituents at C-3 and C-4 accounts for the observation of that effect between H-3 and H-4, as well
as H-3 and the NMe group in compounds 6a and 7a, which is in good agreement with the absence of
NOE in the corresponding minor epimers (1S,3S,4R)-6b and (1S,3S,4R)-7b.
1
However, because of the presence of several revealing masked signals in the H-NMR spectra of
isoquinolines 11, their stereochemical relationships had to be assigned by comparison with similar
compounds (roemecarine and epiroemecarine), whose stereostructures were established by Hoshino
1
by X-ray crystallographic analysis of a roemecarine derivative.8 The H-NMR spectrum of the latter
compound revealed a significant upfield-shifted absorption (1 ppm) for H-8 with respect to the same
proton in its epimer epiroemecarine. A similar behavior was observed in the major stereoisomer of
compound 11 which strongly suggests the same 1,4-trans relationship for the involved substituents. Other
significant chemical shifts of compound 11, which are also in good accordance with those reported for
the natural alkaloid and its epimer, are shown in Scheme 2.
Scheme 2.
The observed stereoselectivity of the cyclization step could be rationalized in terms of the diastereo-
selective formation of the ammonium salt intermediate (epimer I vs II in Scheme 3) and thus, when
R1=Ph or i-Pr, the most stable epimer I (S configuration on the nitrogen) is the only stereoisomer formed.
In this case, the electrophilic attack took place through an intramolecular H-bonded cyclic conformation
(IA), and under these circumstances derivatives 2, 6a and 7a were obtained diastereoselectively. On the
other hand, an equilibrium between cyclic conformation IA and the open conformation IB, stabilized by a
σ*–π* interaction,9 could be proposed to explain the loss of stereoselectivity found in the cyclization of

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L. Carrillo et al. / Tetrahedron: Asymmetry 9 (1998) 1809–1816
aldehydes 5a and 5b to yield tetrahydroisoquinolines 6 and 7 respectively. Finally, such control was not
observed for precursor 10 where the lack of substitution (R1=H) in the adjacent position to the acetalic
carbon led to epimers I and II with similar energetic contents. In this case, the poor stereoselectivity
found in isoquinoline 11a could be explained as a result of the slightly energetically preferred epimer
I vs II, both stabilized by an intramolecular H-bond, where the steric interaction between the bulky
substituent (R2=CH2Ar) and the carbonyl group is minimized.
Scheme 3.
To sum up, from our studies we can propose that, in order to get high diastereoselection in the
cyclization reaction of α-aminoaldehydes to substituted tetrahydroisoquinolin-4-ols, a substituent (either
aromatic or aliphatic) adjacent to the new stereogenic center is required. On the contrary, the presence of
a bulky substituent at C-1 in the target heterocycle leads to losses of diastereoselectivity.
3. Experimental section
3.1. General procedures
Melting points were determined on a Gallenkamp apparatus and are uncorrected. The IR spectra were
measured on a Perkin–Elmer 1430 spectrophotometer as KBr plates or as neat liquid and peaks are
1
reported in cm−1. H-NMR spectra were recorded on a Bruker ACE-250 apparatus at 250 MHz with
CHCl3 (7.26 ppm) as an internal reference in CDCl3 solutions. 13C-NMR spectra were recorded on the
same spectrometer at 62.8 MHz with CHCl3 (77.0 ppm) as an internal reference in CDCl3 solutions.
Chemical shifts are given in ppm (δ); multiplicities are indicated by s (singlet), br s (broad singlet),
br t (broad triplet), d (doublet), t (triplet), q (quadruplet), m (multiplet) or dd (doublet of doublets).
Coupling constants, J, are reported in hertz. All solvents used were technical grade and purified according
to standard procedures.10 Thin layer chromatography was performed on silica gel 60 F254 plates and
visualized by UV light or Dragendorf’s reagent.11 Flash column chromatography12 was performed on
Merck kieselgel 60 (70–230 mesh ASTM). All transfers of liquid solution and solvents were performed
by syringe techniques or via cannula.13 Combustion analyses were performed with a Perkin–Elmer
2400 CHN apparatus. Mass spectra were recorded under electron impact at 70 eV. GC–MS analyses
were performed using a HP-5 column (5% phenylmethylpolysiloxane, 30 m×0.25 mm×0.25 µm). The
HPLC separations were performed on a Hibar Lichrosorb Si 60 column (7 µm). Enantiomeric excess
determinations were made by HPLC with a Chiralcel OD column, using a UV detector, and employing
n-hexane:isopropanol 75:25 as eluent; flow rate 0.5 mL/min.

L. Carrillo et al. / Tetrahedron: Asymmetry 9 (1998) 1809–1816
1813
3.2. General procedure for the N-methylation of compounds 3
Over a solution of the corresponding amino derivative 3 (1 mmol) and aqueous HCHO (35%, 5
mmol) in 8 mL of MeCN, NaBH3CN (5 mmol) was added in three portions at room temperature. When
the starting material was completely consumed (TLC), water was added (5 mL) and the mixture was
extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried over Na2SO4 and the
solvent was distilled at reduced pressure. The crude product obtained was purified as specified for each
compound.
3.2.1. (+)-(2S,10S)-2-[N-1,2-Bis(3,4-dimethoxyphenyl)ethyl-N-methyl]amino-2-phenylethanol 4a
Following the general procedure, the reaction of (+)-aminoalcohol 3a (0.52 g, 1.2 mmol), HCHO (0.5
mL, 6.0 mmol) and NaBH3CN (0.39, 6.0 mmol) yielded, after 20 h, the N-methylated aminoalcohol 4a
which was purified by flash column chromatography (CH2Cl2:EtOAc, 6:4) as a colorless oil (0.43 g,
0.96 mmol), yield 80%. [α]D20 +31.5 (c=1.0, CH2Cl2); 1H-NMR (δ, ppm): 2.20 (s, 3H, CH3), 2.60–2.80
(br s, 1H, OH), 2.85 (dd, J=13.5, 9.0, 1H, ArCHaHb), 3.27 (dd, J=13.5, 5.6, 1H, ArCHaHb), 3.64–3.89
(m, 3H, ArCH, CH2OH), 3.69 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.82 (s, 3H,
OCH3), 4.10 (dd, J=8.0, 5.2, 1H, PhCH), 6.34 (d, J=1.9, 1H, Harom), 6.53 (dd, J=8.2, 1.9, 1H, Harom),
6.66–6.71 (m, 4H, Harom), 7.24–7.33 (m, 5H, Harom); 13C-NMR (δ, ppm): 32.6 (CH3), 36.9 (ArCH2),
55.3, 55.4 (OCH3), 61.5 (CH2OH), 65.6, 65.7 (ArCH, PhCH), 110.1, 110.5, 111.6, 112.0, 120.4, 120.9,
127.4, 127.8, 128.5 (tCarom), 133.5, 138.0, 146.8, 147.6, 147.8, 148.2 (qCarom); IR (neat): 3600–3400;
EI-MS m/z: 300 (100), 286 (8), 180 (71), 151 (15), 120 (13), 103 (13).
3.2.2. (+)-(2S,10S)-2-[N-1,2-Bis(3,4-dimethoxyphenyl)ethyl-N-methyl]amino-2-isopropylethanol 4b
Following the general procedure, the reaction of (+)-aminoalcohol 3b (0.60 g, 1.5 mmol), HCHO
(0.6 mL, 7.5 mmol) and NaBH3CN (0.47 g, 7.5 mmol) yielded after 15 h a crude product that
was flash column chromatographed (hexanes:EtOAc, 8:2), and the resulting oil was crystallized from
20
EtOH:hexanes to afford aminoethanol 4b as a white solid (0.46 g, 1.1 mmol), yield 80%. [α]D +73.0
(c=1.0, CH2Cl2); m.p.: 95–96°C; 1H-NMR (δ, ppm): 0.80 (d, J=6.8, 3H, CH3CH), 0.95 (d, J=6.8, 3H,
CH3CH), 1.66–1.77 (m, 1H, CH(CH3)2), 2.22 (s, 3H, NCH3), 2.71 (dd, J=13.5, 9.0, 1H, ArCHaHb),
2.82–2.90 (m, 1H, CHCH(CH3)2), 3.27–3.35 (m, 2H, ArCHaHb, CHaHbOH), 3.52 (dd, J=10.4, 4.8, 1H,
CHaHbOH), 3.69 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.88 (dd,
J=8.9, 2.5, 1H, ArCH), 6.35 (d, J=2.0, 1H, Harom), 6.52 (dd, J=8.2, 2.0 Hz, 1H, Harom), 6.62–6.74 (m,
4H, Harom); 13C-NMR (δ, ppm): 19.3 (CH3CH), 22.0 (CH(CH3)2), 27.4 (CHCH(CH3)2), 30.7 (NCH3),
39.9 (ArCH2), 55.5, 55.6, 55.7 (OCH3), 58.6 (CH2OH), 66.1, 70.7 (ArCH, PhCH), 110.5, 110.7, 111.1,
112.5, 120.4, 121.0 (tCarom), 131.5, 134.4, 147.1, 147.9, 148.2, 148.5 (qCarom); IR (KBr): 3450; EI-MS
m/z: 300 (100), 285 (49), 225 (9), 181 (5), 151 (14); anal. calcd for C24H35NO5: C, 69.04; H, 8.45; N,
3.35. Found: C, 68.96; H, 8.45; N, 3.31.
3.3. One-pot general procedure for the transformation of aminoalcohols 4 into tetrahydroisoquinolines
6 and 7
Over a cooled (−60°C) solution of oxalyl chloride (1.1 mmol) in 3 mL of CH2Cl2, a solution of
DMSO (0.16 mL, 2.30 mmol) in 3 mL of the same solvent was added dropwise under argon, and the
mixture was stirred for 15 min. Then, a solution of aminoalcohol 4 (1.1 mmol) in 10 mL of CH2Cl2
was added dropwise and the stirring was continued for 30 min. Working at the same low temperature,
diisopropylethylamine (5.0 mmol) was added slowly and, after stirring for 15 min, the solution was

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L. Carrillo et al. / Tetrahedron: Asymmetry 9 (1998) 1809–1816
allowed to reach ambient temperature. The reaction was quenched with water (10 mL) and extracted
with CH2Cl2 (3×25 mL). The combined organic extracts were dried over Na2SO4 and the solvent was
distilled under reduced pressure to afford aldehydes 5 that were immediately submitted to acid catalyzed
cyclization. Crude aldehydes 5 were dissolved in acetone (15 mL) and, after cooling with an ice bath,
conc HCl (2 mL) was added and the mixture was stirred for 15 min at room temperature. Then, the
crude product was basified with 1 M NaOH and extracted with CH2Cl2 (3×25 mL). The combined
organic extracts were dried over Na2SO4, the solvent was distilled under vacuum and the resulting oil
was purified as specified for each compound.
3.3.1. (+)-(1S,3S,4S)-6,7-Dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-3-phenyl-1,2,3,4-tetrahydro-
isoquinolin-4-ol 6a and (−)-(1S,3S,4R)-6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-3-phenyl-
1,2,3,4-tetrahydroisoquinolin-4-ol 6b
Following the general procedure, (+)-aminoalcohol 4a (0.43 g, 0.95 mmol) was transformed into a
diastereomeric mixture (9:1) of tetrahydroisoquinolines (1S,3S,4S)-6a and (1S,3S,4R)-6b which were
separated by flash column chromatography (CH2Cl2:EtOAc, 6:4), yield 75% (combined yield for the
two steps).
6a: [α]D20 +25.3 (c=1.0, CH2Cl2); 1H-NMR (δ, ppm): 2.49 (s, 3H, NCH3), 2.86 (dd, J=13.5, 7.0, 1H,
ArCHaHb), 3.14 (dd, J=13.5, 3.9, 1H, ArCHaHb), 3.68 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3), 3.83 (s, 3H, OCH3), 4.05 (dd, J=7.0, 3.9, 1H, H-1), 4.25 (d, J=4.6, 1H, H-3), 4.65 (d, J=4.6,
1H, H-4), 6.25 (s, 1H, H-8), 6.55 (d, J=1.8, 1H, Harom-20), 6.56 (dd, J=8.1, 1.8, 1H, Harom-60), 6.74 (d,
J=8.1, 1H, Harom-50), 6.88 (s, 1H, H-5), 7.12–7.30 (m, 5H, Harom); 13C-NMR (δ, ppm): 39.6 (ArCH2),
40.1 (NCH3), 55.7, 55.8 (OCH3), 64.4, 66.1, 68.6 (C-1, C-3, C-4), 109.1, 109.6, 110.7, 113.1, 122.2,
127.5, 128.2, 129.7 (tCarom), 129.1, 129.6, 131.5, 137.6, 147.3, 147.6, 147.9, 148.3 (qCarom); IR (neat):
3600–3300; EI-MS m/z: 447 (M+−2, 2), 298 (100), 207 (27), 151 (52), 105 (26), 91 (25), 77 (20); anal.
calcd for C27H31NO5: C, 72.14; H, 6.95; N, 3.12. Found: C, 72.35; H, 6.78; N, 3.34.
20
1
6b: [α]D −62.3 (c=0.5, CH2Cl2); H-NMR (δ, ppm): 2.54 (s, 3H, NCH3), 3.15 (d, J=4.5, 2H,
ArCH2), 3.65 (s, 3H, OCH3), 3.81 (s, 9H, OCH3), 4.07–4.10 (m, 2H, H-1, H-3), 4.40 (br s, 1H, H-
4), 6.32 (d, J=1.8, 1H, Harom-20), 6.52 (dd, J=8.0, 1.9, 1H, Harom-60), 6.53 (s, 1H, H-8), 6.72 (d, J=8.0,
1H, Harom-50), 6.73 (s, 1H, H-5), 7.01–7.04 (m, 2H, Harom), 7.20–7.24 (m, 3H, Harom); 13C-NMR (δ,
ppm): 38.9 (ArCH2), 39.7 (NCH3), 55.6, 55.7, 55.8 (OCH3), 62.6, 69.1, 70.9 (C-1, C-3, C-4), 109.1,
110.5, 111.3, 113.3, 122.1, 127.2, 128.2, 128.5 (tCarom), 127.7, 129.7, 130.2, 138.8, 147.5, 147.8, 148.2,
148.3 (qCarom); IR (neat): 3500–3300; EI-MS m/z: 447 (M+−2, 1), 298 (100), 207 (21), 192 (11), 151
(27), 83 (24), 77 (16).
3.3.2. (+)-(1S,3S,4S)-6,7-Dimethoxy-1-(3,4-dimethoxybenzyl)-3-isopropyl-2-methyl-1,2,3,4-tetra-
hydroisoquinolin-4-ol 7a and (−)-(1S,3S,4R)-6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-3-isopropyl-2-
methyl-1,2,3,4-tetrahydroisoquinolin-4-ol 7b
Following the general procedure, (+)-aminoalcohol 4b (0.67 g, 1.60 mmol) was transformed into a
diastereomeric mixture (9:1) of tetrahydroisoquinolines (1S,3S,4S)-7a and (1S,3S,4R)-7b which were
separated by HPLC (hexanes:EtOAc, 4:6), yield 70% (combined yield for the two steps).
20
1
7a: [α]D +32.1 (c=1.0, CH2Cl2); H-NMR (δ, ppm): 1.06 (d, J=6.5, 3H, CH3CH), 1.12 (d, J=6.5,
3H, CH3CH), 2.20–2.30 (m, 1H, CH(CH3)2), 2.44 (s, 3H, NCH3), 2.59–2.71 (m, 2H, H-3, ArCHaHb),
3.00 (dd, J=13.5, 7.0, 1H, ArCHaHb), 3.64 (s, 3H, OCH3), 3.78–3.85 (m, 1H, H-1), 3.81 (s, 3H, OCH3),
3.83 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.56 (d, J=2.8, 1H, H-4), 6.14 (s, 1H, H-8), 6.67 (dd, J=8.1, 1.5,
1H, Harom-60), 6.75 (d, J=8.2, 1H, Harom-50), 6.80 (d, J=1.5, 1H, Harom-20), 6.89 (s, 1H, H-5); 13C-NMR
(δ, ppm): 20.2 (CH3CH), 20.4 (CH3CH), 25.5 (CH(CH3)2), 38.4 (NCH3), 41.6 (ArCH2), 55.5, 55.7,

L. Carrillo et al. / Tetrahedron: Asymmetry 9 (1998) 1809–1816
1815
55.8 (OCH3), 60.8 (C-3), 65.0 (C-1), 66.7 (C-4), 110.5, 110.8, 111.8, 112.7, 121.5 (tCarom), 128.4, 129.0,
133.0, 147.2, 147.8, 148.2, 148.5 (qCarom); IR (neat): 3600–3400; EI-MS m/z: 414 (M+−1, 1), 264 (100),
151 (19).
7b: [α]D −20.2 (c=0.5, CH2Cl2); 1H-NMR (δ, ppm): 0.68 (d, J=6.7, 3H, CH3CH), 1.03 (d, J=6.7,
20
3H, CH3CH), 1.51–1.72 (m, 1H, CH(CH3)2), 2.61 (dd, J=8.6, 3.1, 1H, H-3), 2.84 (s, 3H, NCH3), 3.06
(dd, J=14.1, 2.7, 1H, ArCHaHb), 3.17 (dd, J=14.1, 4.9, 1H, ArCHaHb), 3.58 (s, 3H, OCH3), 3.78 (s, 3H,
OCH3), 3.85 (s, 6H, 2×OCH3), 4.08 (br t, 1H, H-1), 4.22 (d, J=3.1, 1H, H-4), 6.17 (d, J=1.4, 1H, Harom
-
20), 6.45 (dd, J=8.2, 1.4, 1H, Harom-60), 6.60–6.70 (m, 3H, H-5, H-8, Harom-50); 13C-NMR (δ, ppm):
20.2 (CH3CH), 20.5 (CH3CH), 25.6 (CH(CH3)2), 38.4 (NCH3), 40.6 (ArCH2), 55.5, 55.7, 55.9 (OCH3),
60.8 (C-3), 65.1 (C-1), 66.8 (C-4), 110.6, 110.7, 111.8, 112.7, 121.4 (tCarom), 128.3, 129.0, 133.0, 147.2,
147.8, 148.2, 148.4 (qCarom); IR (neat): 3600–3400 (OH).
3.4. Synthesis of tetrahydroisoquinolin-4-ol 11
A solution of 1 mmol of aminoacetal 106 in conc. HCl (15 ml) was stirred overnight at room
temperature. The mixture was cooled in an ice bath, basified with 1 M NaOH and extracted with CH2Cl2
(3×25 mL). The combined organic extracts were dried over Na2SO4 and the solvent was distilled under
vacuum to afford tetrahydroisoquinoline 11 as a mixture (66:34) of two diastereoisomers in a combined
85% yield. Both diastereoisomers were separated by flash column chromatography (CH2Cl2/MeOH
0–2%) to afford pure oily samples of tetrahydroisoquinolines (+)-(1S,4S)-11a and (−)-(1S,4R)-11b.
3.4.1. (+)-(1S,4S)-6,7-Dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-ol
11a
[α]D20 +25.0 (c=1.0, CH2Cl2); 1H-NMR (δ, ppm): 1.70–1.90 (br s, 1H, OH), 2.55 (dd, J=13.1, 9.1, 1H,
ArCHaHb), 2.66 (s, 3H, NCH3), 2.77 (dd, J=12.5, 2.8, 1H, H-3a), 3.13–3.22 (m, 2H, H-3b, ArCHaHb),
3.48 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.77–3.81 (m, 1H, H-1), 3.84 (s, 3H, OCH3), 3.87 (s, 3H,
OCH3), 4.47 (br s, 1H, H-4), 5.80 (s, 1H, H-8), 6.48 (d, J=1.7, 1H, Harom-20), 6.54 (dd, J=8.2, 1.7, 1H,
H
arom-60), 6.76 (d, J=8.2, 1H, Harom-50), 6.89 (s, 1H, H-5); 13C-NMR (δ, ppm): 34.7 (C-3), 42.8 (NCH3),
54.3 (ArCH2), 55.2, 55.7, 55.8, 55.9 (OCH3), 64.0, 65.9 (C-1, C-4), 110.1, 111.0, 111.2, 113.0, 122.0
(tCarom), 127.5, 129.5, 131.1, 147.2, 147.5, 147.9, 148.6 (qCarom); IR (neat): 3500–3300; EI-MS m/z: 371
(12), 222 (100), 208 (36), 190 (25), 151(61).
3.4.2. (−)-(1S,4R)-6,7-Dimethoxy-1-(3,4-dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-
4-ol 11b
20
1
[α]D −70.4 (c=1.0, CH2Cl2); H-NMR (δ, ppm): 2.66 (s, 3H, NCH3), 2.84–2.98 (m, 1H, H-3a),
3.02 (dd, J=11.6, 4.0, 1H, H-3b), 3.13–3.15 (m, 2H, H-3b, ArCH2), 3.63 (s, 3H, OCH3), 3.77 (s, 3H,
OCH3), 3.79 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 3.77–3.82 (m, 1H, H-3), 4.39 (br s, 1H, H-4), 6.32
(d, J=1.8, 1H, Harom-20), 6.50 (s, 1H, H-8), 6.49–6.54 (m, 1H, Harom-60), 6.68 (d, J=8.2, 1H, Harom-50),
6.77 (s, 1H, H-5); 13C-NMR (δ, ppm): 39.3 (C-3), 43.1 (NCH3), 55.6, 55.7, 55.8, 55.9 (OCH3), 57.4
(ArCH2), 64.6, 65.9 (C-1, C-4), 109.5, 110.5, 110.9, 113.1, 122.1 (tCarom), 128.3, 129.5, 129.9, 147.5,
147.7, 148.2, 148.4 (qCarom); IR (neat): 3450–3200.

1816
L. Carrillo et al. / Tetrahedron: Asymmetry 9 (1998) 1809–1816
Acknowledgements
Financial support from the University of Basque Country (Project UPV 170.310-EA 154/96) and
Basque Government (PI 96/53) is gratefully acknowledged. One of us (J.L.V.) thanks the Basque
Government for a grant. The authors gratefully acknowledge PETRONOR, S. A. (Muskiz, Bizkaia) for
the generous gift of hexane during the last few years.
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