A contribution to the asymmetric synthesis of isoquinolines: Concise stereoselective approach to (3S,4S)-6,7-dimethoxy-4-hydroxy-3-phenyl-1,2,3,4- tetrahydroisoquinoline

Article abstract of DOI:10.1016/S0957-4166(97)00607-1

A highly efficient stereoselective synthesis of (3S,4S)-6,7-dimethoxy- 4-hydroxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline 8 (e.e.=96%) starting from enantiomerically pure imine 3 is reported.

Full text of DOI:10.1016/S0957-4166(97)00607-1

Pergamon
Tetrahedron: Asymmetry 9 (1998) 151–155
A contribution to the asymmetric synthesis of isoquinolines:
Concise stereoselective approach to (3S,4S)-6,7-dimethoxy-
4-hydroxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline
Luisa Carrillo, Dolores Badía«,∗ Esther Domínguez«, Fátima Ortega and Imanol Tellitu
Departamento de Química Orgánica, Facultad de Ciencias, Universidad del País Vasco, PO Box 644, 48080 Bilbao, Spain
Received 4 November 1997; accepted 20 November 1997
Abstract
A
highly efficient stereoselective synthesis of (3S,4S)-6,7-dimethoxy-4-hydroxy-3-phenyl-1,2,3,4-
tetrahydroisoquinoline 8 (e.e.=96%) starting from enantiomerically pure imine 3 is reported. © 1998 Elsevier
Science Ltd. All rights reserved.
The potent physiological activity of simple 4-hydroxytetrahydroisoquinolines has attracted the at-
tention of the research community because of, for example, (1) their involvement in the development
of alcohol dependence and withdrawal symptoms and other pharmacological actions of ethanol1; (2)
racemic 4-hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (PI-OH) has been shown to have
a potentiating effect on the response of rat anococcygeus muscle to noradrenaline without any side
effects, such as postsynaptic inhibition, at higher concentrations2; (3) 4-hydroxytetrahydroisoquinolines
act as substrates or inhibitors of phenylethanolamine N-methyltransferase (PNMT)3; (4) the derivatives
under study are metabolized to tetrahydroisoquinolines, possible parkinsonism-inducing substances4; (5)
this type of compound shows anti-proliferative activity against human mammary and nasopharyngeal
carcinomas.5
Despite their interest, very few reports on the stereoselective synthesis of chiral 4-hydroxy-
tetrahydroisoquinolines have been published and, as far as we know, in all of them kinetic resolution
of racemic mixtures was the method of choice.6 On the other hand, in a previous paper we reported
the preparation of enantiopure (3S,4R)-4-hydroxy-3-phenyl-1,2,3,4-tetrahydroisoquinolines starting
from enantiomerically pure (R)-cyanohydrins via erythro-1,2-diarylethanolamine formation.7 In
the present paper we would like to report a concise stereoselective approach to the corresponding
(3S,4S)-diastereoisomer 8.
This synthetic proposal involves a route that includes the C4–C4a bond formation in the final step, as
depicted in Scheme 1 and, to that end, the chiral imine 3 was selected as the starting material. This
∗
Corresponding author. E-mail: qopdopee@lg.ehu.es
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00607-1

152
L. Carrillo et al. / Tetrahedron: Asymmetry 9 (1998) 151–155
building block, (−)-(10S)-(E)-N-(1-phenyl-2-hydroxyethyl)-3,4-dimethoxybenzylideneimine 3, easily
accessible by condensation of (S)-phenylglycinol with veratraldehyde,8 was stable and consisted of the
typical imine–oxazolidine tautomeric mixture.9 An E configuration has been proposed for this compound
based upon the report by Hine and 13C-NMR studies, which showed only a single resonance for the amino
carbon (163 ppm).10 Imine 3 was first reduced with NaBH4 to aminoalcohol 4 which, in turn, was N-
methylated in a one-pot two-step reaction, via formation of the isolable oxazolidine intermediate 5 by
reaction with HCHO, followed by a ring opening process, which takes place employing NaBH3CN.
Scheme 1. Reagents and conditions: (i) NaBH4, MeOH, r.t., 3 h, 98%; (ii) HCHO, CH2Cl2, r.t., 15 min, 100%; (iii) NaBH3CN,
MeCN, r.t., 28 h, 80%; (iv) (COCl)2, DMSO, iPr2EtN, CH2Cl2, −60°C, 15 min; (v) HCl (conc), acetone, r.t., 10 min, 70% (two
steps).
In order to complete the projected synthesis, we had to perform the transformation of the benzylic
β-aminoalcohol 6 into the α-aminoaldehyde 7. After several experiments, based on the classical Swern
oxidation reaction,11 we found that when diisopropylethylamine was employed instead of the typical, less
bulky, triethylamine,11c the starting alcohol 6 was completely consumed and aldehyde 7 was obtained in
very good yield and then isolated as a colourless oil prone to decomposition.
Finally, with freshly prepared aldehyde 7 in hand, the classical acid catalyzed aromatic electrophilic
substitution reaction12 was performed, affording the expected (3S,4S)-3-phenyl-4-hydroxy-1,2,3,4-
tetrahydroisoquinoline 8 as a single diastereoisomer, as deduced from extensive NMR studies. Thus,
the observation of a nuclear Overhauser effect between protons H3 and H4, as well as the value of
their coupling constant (JH3/H4=2.6 Hz) revealed a cis relationship of the substituents at both stereogenic
carbons C3 and C4. Moreover, the enantiomeric excess of the target isoquinoline 8, was determined
by chiral HPLC (Chiralcel OD, hexanes:iPrOH=75:25, 0.5 mL/min) and calculated to be 96% by
comparison with a racemic sample of the derivative under study 8 (retention time for (R,R)-8=18.84
min; retention time for (S,S)-8=24.54 min).
In summary, a new and highly efficient route for the stereoselective preparation of (3S,4S)-3-phenyl-
4-hydroxy-1,2,3,4-tetrahydroisoquinoline 8 from chiral imine 3 has been performed. It is noteworthy to
point out some of the advantageous features of the reported synthesis, as follows: (1) the relatively few
steps involved; (2) the high overall yield; (3) the complete stereocontrol achieved in the generation of the
second stereogenic center at carbon C4; (4) the lack of racemization under the described reactions; and
(5) the versatility of the synthetic procedures to be extended to a series of isoquinolines of type 8.

L. Carrillo et al. / Tetrahedron: Asymmetry 9 (1998) 151–155
153
1. Experimental section
1.1. 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 films; bands are
reported in cm−1 and only noteworthy absorptions are given. 1H-NMR spectra were recorded at ambient
temperature on a Bruker ACE-250 apparatus at 250 MHz with CHCl3 (7.26 ppm) as an internal reference
1
in CDCl3 solutions. H–1H NOE experiments were carried out in the difference mode by irradiation of
all the lines of a multiplet.13 13C-NMR spectra were recorded in the same spectrometer at 62.8 MHz
with CHCl3 (77.0 ppm) as an internal reference in CDCl3 solutions and were completely decoupled.
Chemical shifts are given in ppm (δ); multiplicities are indicated by s (singlet), br s (broad singlet), d
(doublet), t (triplet), m (multiplet) or dd (doublet of doublets). Coupling constants, J, are reported in hertz.
Optical purity was determined by HPLC using a Chiracel OD column and mixtures of hexanes:iPrOH
(75:25) as eluent (0.5 mL/min). Flash column chromatography14 was performed with Merck Kieselgel
60 (230–400 mesh). Analytical thin-layer chromatography (TLC) was performed with 0.2 mm thick
silica gel plates (Merck Kieselgel GF254). Specific optical rotations were recorded on a Perkin–Elmer
241 polarimeter at 20°C, using a 1 dm cell and a sodium lamp. The reactions were carried out under an
atmosphere of dry, deoxygenated argon unless otherwise indicated. All transfers of liquid solutions and
solvents were performed by syringe techniques or via cannula.15 Tetrahydrofuran was freshly distilled
from benzophenone–sodium ketyl. All other solvents used were technical grade and purified according to
standard procedures.16 Combustion analyses were performed on a Perkin–Elmer 2400 CHN apparatus.
Mass spectra were recorded under electron impact at 70 eV. GC–MS analyses were performed using an
HP-5 column (5% phenyl methyl polysiloxane, 30 m×0.25 mm×0.25 µm).
1.2. (+)-(2S)-2-[N-(3,4-Dimethoxybenzyl)]amine-2-phenylethanol 4
Over a cooled (ice bath) solution of imine 3 (0.28 g, 1 mmol) in MeOH (25 mL), NaBH4 (0.76
g, 2 mmol) was added in three portions. The ice bath was removed and the mixture was stirred at
room temperature for 3 h. Then, water (15 mL) was added and the mixture was extracted with CH2Cl2
(3×25 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed under
reduced pressure to afford the aminoalcohol 4 as an essentially pure orange oil (0.28 g, 98%), which
was crystallized from EtOH as the HCl salt. [α]D20: +63.0 (c=1.0, CH2Cl2); m.p. (HCl salt, EtOH):
1
164–166°C; IR (HCl salt, KBr) υ: 3500–3200, 3000–2700; H-NMR δ: 3.46–3.68 (m, 4H, ArCH2,
CH2OH), 3.78 (dd, J=8.8, 4.2, 1H, PhCH), 3.82 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.77–6.79 (m, 3H,
H
arom), 7.27–7.35 (m, 5H, Harom); 13C-NMR δ: 50.7 (ArCH2), 55.5, 55.6, (OCH3), 63.5 (PhCH), 66.5
(CH2OH), 110.8, 111.2, 120.1, 127.2, 127.4, 128.4 (t Carom), 132.3, 140.2, 147.8, 147.9 (q Carom); EI-
MS m/z: 256 (M+−31, 21), 152 (11), 151 (100). Anal. Calcd for C17H21NO3: C, 71.04; H, 7.37; N, 4.88.
Found: C, 71.28; H, 7.43; N, 4.75.
1.3. (+)-(4S)-N-(3,4-Dimethoxybenzyl)-4-phenyloxazolidine 5
A mixture of aminoalcohol 4 (0.28 g, 1 mmol) and 35% aq HCHO (0.4 ml, 5 mmol) in 10 mL
of CH2Cl2 was stirred at room temperature over 15 min in the presence of molecular sieves (4 Å).
The molecular sieves were filtered and the solvent was distilled under reduced pressure. The resulting
syrup was purified by flash column chromatography (hexanes:EtOAc=6:4) to afford analytically pure

154
L. Carrillo et al. / Tetrahedron: Asymmetry 9 (1998) 151–155
oxazolidine 5 as a colorless oil (yield=100%). [α]D20: +52.6 (c=3.5, CH2Cl2); H-NMR δ: 3.48 (d,
J=13.2, 1H, ArCH), 3.74 (t, J=7.7, 1H, PhCH), 3.84 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.88–3.94
(m, 2H, ArCH, H-5), 4.26–4.33 (m, 2H, H-5, H-2), 4.60 (d, J=3.7, 1H, H-2), 6.77–6.90 (m, 3H, Harom),
7.24–7.46 (m, 5H, Harom); 13C-NMR δ: 55.7, 55.8 (OCH3), 56.3 (C-5), 66.9 (C-4), 73.2 (ArCH2), 86.9
(C-2), 110.8, 111.5, 120.3, 127.3, 127.5, 128.5 (t Carom), 131.1, 139.9, 148.0, 148.8 (q Carom); EI-MS
m/z: 152 (82), 151 (100), 148 (24), 137 (11), 121 (15), 118 (15), 197 (10), 91 (22). Anal. Calcd for
C18H21NO3: C, 72.20; H, 7.08; N, 4.68. Found: C, 71.95; H, 7.15; N, 4.46.
1
1.4. (+)-(2S)-2-[N-(3,4-Dimethoxybenzyl)-N-methyl]amino-2-phenylethanol 6
To a cooled (0°C) solution of oxazolidine 5 (0.30 g, 1 mmol) in 25 mL of MeCN, NaBH3CN (0.31, 5
mmol) was added in three portions. The ice bath was removed and the mixture was stirred under argon
over 28 h. After total consumption of the starting material (TLC, hexanes:EtOAc=7:3), water (5 mL)
was added and the mixture was extracted with CH2Cl2 (3×25 ml). The combined extracts were dried
over Na2SO4, the solvent was distilled under reduced pressure and the resulting oil was flash column
chromatographed to afford the aminoalcohol 6 as a colourless oil, which was crystallized from MeOH
(yield: 80%). [α]D20: +44.0 (c=1.0, CH2Cl2); m.p. (MeOH): 117–118°C; IR (KBr) υ: 3400–3300; H-
1
NMR δ: 2.14 (s, 3H, CH3), 3.20 (br s, 1H, OH), 3.31 (d, J=13.0, 1H, ArCH), 3.56 (d, J=13.0, 1H,
ArCH), 3.67 (dd, J=10.2, 4.9, 1H, PhCH), 3.84–3.89 (m, 1H, CHOH), 3.88 (s, 6H, OCH3), 4.06 (t,
J=10.2, 1H, CHOH), 6.82–6.84 (m, 3H, Harom), 7.22–7.39 (m, 5H, Harom); 13C-NMR δ: 36.6 (CH3),
55.8 (OCH3), 58.2, 60.6 (ArCH2, CH2OH), 67.7 (PhCH), 110.9, 111.8, 120.9, 127.9, 128.2, 129.0 (t
C
arom), 131.3, 135.2, 148.1, 148.9 (q Carom); EI-MS m/z: 270 (M+−31, 27), 152 (10), 151 (100). Anal.
Calcd for C18H23NO3: C, 71.72; H, 7.70; N, 4.65. Found: C, 71.90; H, 7.58; N, 4.90.
1.5. (+)-(3S,4S)-6,7-Dimethoxy-4-hydroxy-2-methyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline 8
To a cooled (−60°C) solution of oxalyl chloride (0.10 mL, 1.16 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, and the mixture
was stirred for 15 min. Then, a solution of aminoalcohol 6 (0.32 g, 1.06 mmol) in 15 mL of CH2Cl2
was added dropwise and the stirring was continued for 30 min. Working at the same low temperature,
diisopropylethylamine (0.92 mL, 5.30 mmol) was added slowly and, after stirring for 15 min, the
solution was 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 (S)-2-[N-(3,4-dimethoxybenzyl)-N-methyl]amine-
2-phenylacetaldehyde 7. A small portion of aldehyde 7 was purified by flash column chromatography
(hexanes:EtOAc=3:7). IR (neat) υ: 1730; 1H-NMR δ: 2.18 (s, 3H, NCH3), 3.32 (d, J=13.3, 1H, ArCH),
3.60 (d, J=13.3, 1H, ArCH), 3.87 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.96 (d, J=3.6, 1H, PhCH),
6.83–6.88 (m, 3H, Harom), 7.39–7.42 (m, 5H, Harom), 9.65 (d, J=3.6, 1H, CHO). Crude aldehyde 7 was
dissolved in acetone (8 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 (3×15 mL). The combined organic extracts were dried over Na2SO4,
the solvent was distilled under vacuum and the resulting oil was purified by flash column chromatography
(hexanes:EtOAc=2:8) to afford tetrahydroisoquinoline 8 (yield=70%, two steps) which was obtained as a
white solid after crystallization from Et2O. [α]D20: +135.0 (c=1.0, CH2Cl2); m.p. 165–167°C; IR (KBr)
1
υ: 3650–3300; H-NMR δ: 2.19 (s, 3H, NCH3), 3.29 (br s, 1H, OH), 3.39 (d, J=15.2, 1H, H-1), 3.52
(d, J=2.6, 1H, H-3), 3.63 (d, J=15.2, 1H, H-1), 3.87 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 4.49 (br s, 1H,

L. Carrillo et al. / Tetrahedron: Asymmetry 9 (1998) 151–155
155
H-4), 6.51 (s, 1H, H-8), 6.88 (s, 1H, H-5), 7.30–7.43 (m, 5H, Ph); 13C-NMR δ: 43.4 (NCH3), 55.8, 56.1
(OCH3), 57.8 (C-1), 70.2, 71.9 (C-3, C-4), 108.9, 111.3 (t Carom), 126.3 (q Carom), 127.4, 127.9, 129.3 (t
C
arom), 129.8, 138.0, 148.0, 148.6 (q Carom); EI-MS m/z: 180 (34), 179 (18), 121 (10), 120 (100). Anal.
Calcd for C18H21NO3: C, 72.21; H, 7.07; N, 4.68. Found: C, 72.61; H, 7.06; N, 4.48.
Acknowledgements
The authors gratefully acknowledge PETRONOR, S. A. (Muskiz, Bizkaia) for the generous gift of
solvents. Financial support from the Basque Government (Project GV PI 96/53) and from the University
of the Basque Country (Project UPV 170.310-EA154/96) is gratefully acknowledged.
References
1. (a) Haber, H.; Roske, I.; Rottmann, M.; Georgi, M.; Melzig, M. F. Life Sci. 1997, 60, 79. (b) Bates, H. A.; Garelick, J. S. J.
Org. Chem. 1984, 49, 4552. (c) Cohen, G.; Collins, M. Science 1970, 167, 1749.
2. (a) Kihara, M.; Ikeuchi, M.; Kobayashi, Y.; Nagao, Y.; Hashizume, M.; Moritoki, H. Drug Des. Discov. 1994, 11, 175. (b)
Kihara, M.; Kashimoto, M.; Kobayashi, Y.; Nagao, Y.; Moritoki, H. Chem. Pharm. Bull. 1994, 42, 67.
3. Grunewald, G. L.; Ye, Q.; Kieffer, L.; Monn, J. A. J. Med. Chem. 1988, 31, 169.
4. Ohta, S.; Tachikawa, O.; Makino, Y.; Tasaki, Y.; Hirobe, M. Life Sci. 1990, 46, 599.
5. (a) Kihara, M.; Ikeuchi, M.; Yamauchi, A.; Nukatsuka, M.; Matsumoto, H.; Toko, T. Chem. Pharm. Bull. 1997, 45, 939. (b)
Kihara, M.; Ikeuchi, M.; Nagao, Y. Drug Des. Discov. 1995, 12, 259.
6. (a) Bates, H. A. J. Org. Chem. 1981, 46, 4931. (b) Bates, H. A. J. Org. Chem. 1982, 48, 1932. (c) Hoshino, O.; Itoh, K.;
Tanahashi, R.; Umezawa, B.; Akita, H.; Oishi, T. Chem. Pharm. Bull. 1990, 38, 3277.
7. (a) Badía, D.; Domínguez, E.; Tellitu, I. Tetrahedron 1992, 48, 4419 and references cited therein. (b) Tellitu, I.; Badía, D.;
Domínguez, E.; García, F. J. Tetrahedron: Asymmetry 1994, 5, 1567.
8. (a) Carrillo, L.; Badía, D.; Domínguez, E.; Vicario, J. L.; Tellitu, I. J. Org. Chem. 1997, 62, 6716. (b) (S)-(+)-Phenylglycinol
was prepared by reduction of L-phenylglycine at r.t. for 24 h using LiBH4–Me3SiCl in THF. Nicolás, E.; Russell, K. C.;
Hruby, V. J. J. Org. Chem. 1993, 58, 766.
9. (a) Valters, R. E.; Fülöp, F.; Korbonits, D. Adv. Heterocyclic. Chem. 1996, 66, 1. (b) Fülöp, F. Acta. Chim. Hung. 1994, 131,
697 and references therein. (c) Lambert, J. B.; Majchrzak, M. W. J. Am. Chem. Soc. 1980, 102, 3588. (d) Lázár, L.; Lakatos,
A. G.; Fülöp, F.; Bernáth, G.; Riddell, F. G. Tetrahedron 1997, 53, 1081 and references therein.
10. Hine, J.; Yeh, C. H. J. Am. Chem. Soc. 1967, 89, 2669.
11. (a) When aminoalcohol 6 was made to react in the presence of oxalyl chloride, dimethyl sulfoxide and triethylamine,
aldehyde 7 was detected in the crude mixture (1H-NMR, δ=9.65 ppm; IR, υ=1730 cm−1) together with unreacted starting
material (65% conversion). See for example, Chrisman, W.; Singaram, B. Tetrahedron Lett. 1997, 38, 2053. (b) Similar
results were achieved when triphosgene was employed instead of oxalyl chloride. See for example, Eckert, H.; Forster, B.
Angew. Chem., Int. Ed. Engl. 1987, 26, 894, and also Palomo, C.; Cossio, F. P.; Ontoria, J. M.; Odriozola, J. M. J. Org.
Chem. 1991, 56, 5948. (c) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
12. Hirsenkorn, R. Tetrahedron Lett. 1990, 31, 7591.
13. (a) Hall, L. D.; Sanders, J. K. M. J. Am. Chem. Soc. 1980, 102, 5703; (b) Kinns, M.; Sanders, J. K. M. J. Magn. Res. 1984,
56, 518.
14. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
15. Kramer, G. W.; Levy, A. B.; Midland, M. M. Organic Synthesis via Boranes, John Wiley & Sons, New York, 1975.
16. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd Edition, Pergamon Press, Oxford, 1988.