Enantioselective synthesis of (S)-calycotomine employing catalytic asymmetric hydrogenation with an iridium(I)-(R)-BINAP-phthalimide complex

Article abstract of DOI:10.1016/S0957-4166(97)00635-6

An optically active 1-hydroxymethyl-substituted tetrahydroisoquinoline alkaloid, (S)-calycotomine 1, was conveniently synthesized by using catalytic asymmetric hydrogenation of 1-benzyloxymethyl-3,4-dihydro-6,7-dimethoxyisoquinoline 6 with 0.5 mol % of an

Full text of DOI:10.1016/S0957-4166(97)00635-6

Pergamon
Tetrahedron: Asymmetry 9 (1998) 183–187
Enantioselective synthesis of (S)-calycotomine employing
catalytic asymmetric hydrogenation with an
iridium(I)–(R)-BINAP–phthalimide complex1
Toshiaki Morimoto,∗ Naoaki Suzuki and Kazuo Achiwa
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka-shi 422, Japan
Received 17 November 1997; accepted 15 December 1997
Abstract
An optically active 1-hydroxymethyl-substituted tetrahydroisoquinoline alkaloid, (S)-calycotomine 1, was
conveniently synthesized by using catalytic asymmetric hydrogenation of 1-benzyloxymethyl-3,4-dihydro-6,7-
dimethoxyisoquinoline 6 with 0.5 mol % of an iridium(I) complex of (R)-BINAP in the presence of 3,4,5,6-
tetrafluorophthalimide. © 1998 Elsevier Science Ltd. All rights reserved.
Development of the methods for enantioselective or diastereoselective synthesis of optically active 1-
substituted 1,2,3,4-tetrahydroisoquinolines has been an important subject in synthetic organic chemistry,2
since most naturally occurring tetrahydroisoquinolines and their derivatives are optically active and have
marked physiological activities3 which are commonly different from those of their antipodes. Most of the
traditional synthetic methods are based on the procedures employing a stoichiometric amount of chiral
building blocks, auxiliaries, or reagents; for example, the Pictet–Spengler condensation,4 nucleophilic
or electrophilic introduction of carbon units into 1-position of dihydro- or tetrahydroisoquinolines,5
and asymmetric (or diastereoselective) reduction of dihydroisoquinolines with chiral (or achiral) hy-
dride reagents (Scheme 1).6 Although catalytic asymmetric syntheses are much more efficient than
stoichiometric ones for the preparation of optically active isoquinolines, very few methods using chiral
catalysts have been developed. After the pioneering works by Kagan7 and Achiwa,8 Noyori and co-
workers developed an efficient catalytic procedure for their preparation by reduction of cyclic enamides
with Ru–BINAP complexes.9 A more direct and efficient method for the preparation is the catalytic
asymmetric hydrogenation of 1-substituted dihydroisoquinolines, and several new methods have recently
been developed by ourselves, Buchwald, Noyori, and Kang employing BCPM or BINAP–Ir–phthalimide
complexes,10 a chiral titanocene complex,11 chiral N-sulfonated diamine–Ru complexes (hydrogen
source: formic acid),12 and thiazazincolidine complexes (hydrogen source: BH3),13 respectively.
∗
Corresponding author. E-mail: morimtt@ys2.u-shizuoka-ken.ac.jp
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00635-6

184
T. Morimoto et al. / Tetrahedron: Asymmetry 9 (1998) 183–187
Scheme 1.
(S)-(+)-Calycotomine 1, a 1,2,3,4-tetrahydroisoquinoline bearing a 1-hydroxymethyl group, whose
absolute configuration is different from that of many other 1-substituted tetrahydroisoquinoline alkaloids,
is a base constituent of Calycotome spinosa Link. and some other plants.14 The absolute configuration
of the naturally occurring calycotomine 1 was determined by its conversion to an (R)-salsolidine N-tosyl
derivative which was correlated with the antipode (S-form) derived from the known (S)-salsolidine.15
Enantioselective syntheses of (R)- or (S)-calycotomine 1 and its derivatives have been investigated by
employing the Pictet–Spengler condensation of (R)-glyceraldehyde,4d,16 or (2R)-N-glyoxyloylbornane-
10,2-sultam17 with dopamine hydrochloride and catalytic reduction of a chiral dihydroisoquinoline
derived from D-ribonolactone.18 However, to our knowledge, catalytic asymmetric synthesis of 1 has
not been reported. We report herein an efficient enantioselective synthesis of (S)-calycotomine 1 using
catalytic asymmetric hydrogenation with a catalyst system of a BINAP–Ir–phthalimide complex as a key
step.
As mentioned above, we reported a convenient method for the enantioselective synthesis of several
naturally occurring tetrahydroisoquinolines by catalytic asymmetric hydrogenation with Ir complexes of
(2S,4S)-BCPM and (S)-BINAP in the presence of phthalimides.10 Since (2S,4S)-BCPM and (S)-BINAP
were found to show (1S)-enantioselectivity in the hydrogenation of 1-alkyl (or aralkyl)-substituted
dihydroisoquinolines, we employed the antipode, (R)-BINAP to gain (S)-calycotomine 1 whose absolute
configuration corresponds to that of the other (1R)-alkyl (or aralkyl) derivatives. Initially, asymmetric
hydrogenation of ethyl 3,4-dihydro-6,7-dimethoxyisoquinoline-1-carboxylate 2 was carried out with a
BINAP (or BCPM)–Ir–phthalimide complex catalyst under 100 atm of hydrogen, but unfortunately,
the reaction proceeded only slowly to give an almost racemic hydrogenation product 3 (Scheme 2).
Asymmetric hydrosilylation of 2 with diphenylsilane and several chiral Rh-complex catalysts gave
unsatisfactory results also.
Scheme 2.
Therefore, we employed a 1-benzyloxymethyl-substituted dihydroisoquinoline 6 as a substrate. The
synthetic route of 1 via 6 is described in Scheme 3. 3,4-Dimethoxyphenethylamine 4 was acylated
with benzyloxyacetyl chloride in the presence of K2CO3 in a two phase system of ether and water,
affording the corresponding amide 5 (95%). The Bischer–Napieralski reaction of the amide 5 by
heating with POCl3 in toluene gave 1-benzyloxymethyl-3,4-dihydro-6,7-dimethoxyisoquinoline 6 in
77% isolated yield. Asymmetric hydrogenation of the dihydroisoquinoline 6 was carried out in a
mixed solvent of MeOH–toluene with 0.5 mol% of an (R)-BINAP–Ir(I) complex in the presence of
a phthalimide (1 mol%) under 100 atm of hydrogen.19 A better enantioselectivity was obtained with
3,4,5,6-tetrafluorophthalimide (86% ee) in comparison with phthalimide (75% ee). The hydrogenation

T. Morimoto et al. / Tetrahedron: Asymmetry 9 (1998) 183–187
185
product, (S)-1-benzyloxymethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline 7 was isolated in 85%
yield by silica gel chromatography. Hydrogenolysis of the O-benzyl group was difficult with Pd on
carbon (1 atm H2) in EtOH, but could be accomplished with a Pd(OH)2 catalyst in a mixed solvent
system of EtOH:AcOH (10:1), yielding natural (S)-calycotomine 1 (86% ee) in high yield;20,21 without
AcOH, partial racemization occurred. Recrystallization from toluene increased the enantiomeric purity
to 96% ee. Palladium black using HCOOH as a hydrogen source was less active, affording a lower yield
of the product than the Pd(OH)2 catalyst (H2).
Scheme 3.
Asymmetric hydrogenation of 1-[3-(benzyloxy)propyl]-3,4-dihydro-6,7-dimethoxyisoquinoline 8 was
also performed under similar conditions using (S)-BINAP and parabanic acid (as an additive), leading
to the corresponding tetrahydroisoquinoline 9 with 89% ee (estimated to be S) in a quantitative yield
(Scheme 4).
Scheme 4.
Thus we developed a convenient method for the enantioselective synthesis of (S)-calycotomine em-
ploying asymmetric hydrogenation with an (R)-BINAP–Ir–tetrafluorophthalimide complex as a key reac-
tion. Since optically active calycotomine or its derivative is known to be a useful synthetic intermediate
of other isoquinoline alkaloids,4d,16 further application of this procedure to asymmetric synthesis of
naturally occurring compounds is in progress.

186
T. Morimoto et al. / Tetrahedron: Asymmetry 9 (1998) 183–187
Acknowledgements
The present work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, and Culture of Japan.
References
1. Asymmetric Reactions Catalyzed by Chiral Metal Complexes. LXXXII.
2. For a review, see: Rozwadowska, M. D. Heterocycles 1994, 39, 903.
3. For reviews, see: (a) Herbert, R. B. in The Chemistry and Biology of Isoquinoline Alkaloids, ed. by Philipson, J. D.;
Roberts, M. F.; Zenk, M. H., Springer Verlag, Berlin, Heidelberg, New York, Tokyo, 1985, p. 213. (b) Shamma, M.
Isoquinoline Alkaloids, Chemistry and Pharmacology, Academic Press, New York, 1972. (c) Kametani, T. The Chemistry
of the Isoquinoline Alkaloids, Elsevier, Amsterdam, 1969.
4. (a) Brossi, A.; Focella, A.; Teitel, S. Helv. Chim. Acta 1972, 55, 15. (b) Konda, M.; Shioiri, T.; Yamada, S. Chem. Pharm.
Bull. 1975, 23, 1025. (c) Piper, I. M.; MacLean, D. B.; Kvarnstrom, I.; Szarek, W. Can. J. Chem. 1983, 61, 2721. (d)
Czarnocki, Z.; MacLean, D. B.; Szarek, W. Can. J. Chem. 1986, 64, 2205. (e) Comins, D. L.; Badawi, M. Tetrahedron Lett.
1991, 32, 2995. (f) Kawate, T.; Yamada, H.; Matsumizu, M.; Nishida, A.; Nakagawa, M. Synlett. 1997, 761, and references
cited therein.
5. (a) For a review, see: Meyer, A. I. Tetrahedron 1992, 48, 2589. (b) Hashigaki, K.; Kan, K.; Qais, N.; Takeuchi, Y.; Yamato,
M. Chem. Pharm. Bull. 1991, 39, 1126. (d) Pyne, S. G.; Dikic, S. J. Org. Chem. 1990, 55, 1932. (e) Catalytic asymmetric
addition of dialkylzinc to cyclic nitrone has recently been reported [Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahmed, A.;
Inomata, K. Chem. Lett. 1997, 59].
6. (a) Yamada, K.; Takeda, M.; Iwakuma, T. J. Chem. Soc., Perkin Trans. 1 1983, 265. (b) Polniaszek, R. P.; Kaufman, C. R.
J. Am. Chem. Soc. 1989, 111, 4859.
7. Kagan, H. B.; Langlois, N.; Dang, T. P. J. Organomet. Chem. 1975, 90, 353.
8. Achiwa, K. Heterocycles 1977, 8, 247.
9. Kitamura, M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.; Ohta, T.; Takaya, H.; Noyori, R. J. Org. Chem. 1994, 59, 297.
10. (a) Morimoto T.; Achiwa, K. Tetrahedron: Asymmetry 1995, 6, 2661. (b) Morimoto, T.; Suzuki, N.; Achiwa, K. Heterocycles
1996, 43, 2557.
11. (a) Willoughby, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8952; Willoughby, C. A.; Buchwald, S. L. J. Am.
Chem. Soc. 1994, 116, 11703.
12. Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916.
13. Kang, J.; Kim, J. B.; Cho, K. H.; Cho, B. T. Tetrahedron: Asymmetry 1997, 8, 657.
14. (a) White, E. P. New Zealand J. Sci. Tech. 1944, 25B, 137. (b) Tosun, F.; Tanker, M.; Ozden, T.; Tosun, A. Planta Med.
1987, 53, 499.
15. Battersby, A. R.; Edwards, T. P. J. Chem. Soc. 1960, 1214.
16. Czarnocki, Z.; MacLean, D. B.; Szarek, W. A. Bull. Soc. Chim. Belg. 1986, 95, 749.
17. Czarnocki, Z.; Mieczkowski, J. B.; Kiegiel, J.; Arazny, Z. Tetrahedron: Asymmetry 1995, 6, 2899.
18. Czarnocki, Z. J. Chem. Research (S) 1992, 334; J. Chem. Research (M) 1992, 2801.
19. Catalytic asymmetric hydrogenation of 6: A solution of (R)-BINAP (1.8×10−2 mmol, 11.2 mg) and chloro(1,5-
cyclooctadiene)iridium(I) dimer, [Ir(COD)Cl]2 (7.5×10−3 mmol, 5.0 mg) in a mixed solvent (18 ml) of toluene and MeOH
(1:1) was stirred at rt for 15 min under argon. The catalyst solution was added to a mixture of dihydroisoquinoline
6 (3 mmol, 934 mg) and tetrafluorophthalimide (3×10−2 mmol, 6.6 mg) in a glass tube. The glass tube was placed
in an autoclave, pressurized with hydrogen to 100 atm after several exchange with hydrogen, and the mixture was
stirred at 2–5°C for 3 days. The reaction solution was concentrated in vacuo, and the residue was purified by silica gel
column chromatography using a mixed solvent of EtOH, AcOEt, and Et2NH (1:1:0.001). (S)-1-Benzyloxymethyl-1,2,3,4-
tetrahydro-6,7-dimethoxyisoquinoline 7 was isolated as a syrup in 85% yield; [α]D25 +19.3 (c 1.23, EtOH). After conversion
of a small portion of the product to its N-acetyl derivative, the enantiomeric excess was determined to be 86% ee (S) by
HPLC with a chiral column (Chiralpak AS); solvent: 2-propanol:hexane=5:1, 0.7 ml/min; detection: 235 nm light; tR=45.8
min, tS=84.1 min.
20. (S)-Calycotomine 1: A mixture of (S)-1-benzyloxymethyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline 7 (0.7 mmol, 220
mg) and 20% Pd(OH)2 on carbon (70 mg) in a mixed solvent of EtOH (5 ml) and AcOH (0.5 ml) was stirred at rt for 15
h under an atmospheric pressure of hydrogen. After filtration of the catalyst through Celite, the filtrate was concentrated

T. Morimoto et al. / Tetrahedron: Asymmetry 9 (1998) 183–187
187
in vacuo. The residue was treated with 20% KOH (4 ml) and extracted with CHCl3 (4×10 ml). The combined extracts
25
were dried over K2CO3 and concentrated in vacuo to give (S)-calycotomine 1 (145 mg, 93%) as a solid; [α]D +30.1 (c
1.06, H2O) [lit.21 [α]D +36 (c 1, H2O)]. The enantiomeric excess of the product was determined to be 86% ee by HPLC
(Chiralpak AS) analysis of its N-BOC derivative. Recrystallization from toluene gave pure 1 as prisms (66%, 96% ee),
29
[α]D +33.7 (c 1.05, H2O).
21. Brossi, A.; Burkhardt, F. Helv. Chim. Acta 1961, 44, 1588.