A facile asymmetric synthesis of 1-substituted tetrahydroisoquinoline based on a chiral ligand-mediated addition of organolithium to imine

Article abstract of DOI:10.1016/S0957-4166(98)00509-6

A two-step methodology involving an asymmetric addition of organolithium to an imine and subsequent Moffat oxidation as the key steps provided a new synthetic way to the optically and biologically active 1-substituted tetrahydroisoquinolines.

Full text of DOI:10.1016/S0957-4166(98)00509-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 221–223
A facile asymmetric synthesis of 1-substituted
tetrahydroisoquinoline based on a chiral ligand-mediated addition
of organolithium to imine
Daisuke Taniyama, Masayoshi Hasegawa and Kiyoshi Tomioka∗
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 27 November 1998; accepted 17 December 1998
Abstract
A two-step methodology involving an asymmetric addition of organolithium to an imine and subsequent Moffat
oxidation as the key steps provided a new synthetic way to the optically and biologically active 1-substituted
tetrahydroisoquinolines. © 1999 Elsevier Science Ltd. All rights reserved.
Tetrahydroisoquinolines are a class of biologically potent compounds. The existence of 1,2,3,4-
tetrahydroisoquinoline (TIQ) and 1-methyl-TIQ (1MeTIQ, 1a) in the human brain is now in no doubt.1
The complete prevention of MPTP induced parkinsonism by pretreatment with 1a2 and the inhibition
of monoamine oxidase3 have renewed interest related to the pathogenesis of Parkinson’s disease. 1-
Phenyl-TIQ 1b, originally developed as a general anesthetic agent, shows phencyclidine-like stereotyped
behavior and ataxia.4 Since the enantiomers were observed to vary in affinity,4b the synthesis of chiral
1-substituted TIQ is the current focus in medicinal organic chemistry.5
The diastereoselective Pictet–Spengler reaction is well established, but requires tedious methodology
for the construction of the chiral TIQ.6 The asymmetric alkylation of TIQ has also been developed.7
The asymmetric reduction8 and alkylation9 of the dihydroisoquinoline derivatives are the most recently
explored technology. Although the two-step process of construction of the chirality and subsequent
cyclization to the target TIQ has been developed,10 enantioselective construction of the secondary amine
by the electrophilic alkylation of the imine and followed by cyclization to the chiral TIQ have not yet
been explored. We describe herein that the chiral ligand-mediated asymmetric addition of organolithiums
to the acyclic imine 311,12 and subsequent cyclization of the secondary amine 5 under Moffat oxidation
conditions provide the new route to the chiral 1-substituted TIQ 1 (Fig. 1).
The reaction of 2 equiv. of methyllithium with 3a,b, prepared by the condensation of 213 with anisidine
or 2-methylanisidine, in the presence of 2.6 equiv. of the chiral ligand 6 in toluene at −95°C afforded
4a,b (R=Me, Ar=PMP, MePMP) in 71 and 84% ee, respectively (Table 1, entries 1, 3).14 The catalytic
∗
Corresponding author. E-mail: tomioka@pharm.kyoto-u.ac.jp
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00509-6

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D. Taniyama et al. / Tetrahedron: Asymmetry 10 (1999) 221–223
Figure 1. The synthesis of 1 by asymmetric addition and cyclization
asymmetric reaction was possible by using 0.3 equiv. of 6 at −42°C to afford 4b in 62% ee (entries 5, 6).
The reaction of phenyllithium with 3a under the control of 6 gave, however, 4c in only 9% ee (entry 7).
After examination of the ligands 7–9 (Fig. 2), the ligand 915 was found to give 4c in 50% ee (entry 10).16
The enantioenrichment of 4c-hydrochloride was possible by recrystallization from hexane–chloroform
to give 4c of 71% ee in 62% yield.
Table 1
The ligand-mediated asymmetric reaction of methyl- and phenyllithium with the imine 3a
Figure 2. The chiral ligands 6–9
Hydroboration with disiamylborane and oxidative work-up of 4a of 71% ee afforded 5a quantitatively.
Treatment of 5a with DMSO-DCC under Moffat oxidation conditions directly afforded 10a in 71% yield.
Removal of the PMP group of 10a with ammonium cerium(IV) nitrate (CAN) completed the synthesis
of R-1a17 without racemization in 50% overall yield from 4a (Fig. 3). The MePMP-amine 4b of 84% ee
was also successfully converted by the same method, to R-1a in 20% overall yield.
Figure 3. The asymmetric synthesis of 1a

D. Taniyama et al. / Tetrahedron: Asymmetry 10 (1999) 221–223
223
The same reaction sequence for 1a was applicable to the synthesis of R-1b18 of 52% ee in 57% overall
yield from 4c of 50% ee (Fig. 4).
Figure 4. The asymmetric synthesis of 1b
The presented two-step procedure for the asymmetric synthesis of 1-substituted TIQ is facile and will
be applicable to other biologically potent TIQ. Further studies directed toward more efficient asymmetric
alkylation of the imine are in progress in our laboratories.
Acknowledgements
We gratefully acknowledge financial support from Japan Society for Promotion of Science and the
Science and Technology Agency, Japan.
References
1. Kohno, M.; Ohta, S.; Hirobe, M. Biochem. Biophys. Res. Commun. 1986, 140, 448–454.
2. Yamakawa, T.; Ohta, S. Biochem. Biophys. Res. Commun. 1997, 236, 676–681.
3. Thull, U.; Kneubühler, S.; Gaillar, D. P.; Carrupt, P.-A.; Testa, B.; Altomare, C.; Carotti, A.; Jenner, P.; McNaught, K. St.
P. Biochem. Pharmacology 1995, 50, 869–877.
4. (a) Gray, N. M.; Cheng, B. K.; Mick, S. J.; Lair, C. M.; Contreras, P. C. J. Med. Chem. 1989, 32, 1242–1248. (b) Minor,
D. L.; Wyrick, S. D.; Charifson, P. S.; Watts, V. J.; Nichols, D. E.; Mailman, R. B. J. Med. Chem. 1988, 31, 1941–1946.
5. Rozwadowska, M. D. Heterocycles 1994, 39, 903–931.
6. For example, see: Tomioka, K.; Koga, K.; Yamada, S. Chem. Pharm. Bull. 1977, 25, 2689–2691. Enantioselective
Pictet–Spengler reaction of β-carboline has been reported. Kawate, T.; Yamada, H.; Soe, T.; Nakagawa, M. Tetrahedron:
Asymmetry 1996, 7, 1249–1252.
7. Meyers, A. I. Tetrahedron 1992, 48, 2589–2612.
8. (a) Morimoto, T.; Ohta, M.; Suzuki, N.; Achiwa, K. Tetrahedron: Asymmetry 1998, 9, 183–187. (b) Kitamura, M.; Hsiao,
Y.; Tsukamoto, M.; Ohta, T.; Takaya, H.; Noyori, R. J. Org. Chem. 1994, 59, 297–310. (c) Murahashi, S.-I.; Watanabe, S.;
Shiota, T. J. Chem. Soc., Chem. Commun. 1994, 725–726. (d) Willoghby, C. A.; Buchwald, S. L. J. Org. Chem. 1993, 58,
7627–7629. (e) Yamada, K.; Takeda, M.; Iwakuma, T. J. Chem. Soc., Perkin Trans. 1 1983, 265–270.
9. (a) Wünsch, B.; Nerdinger, S. Chem. Lett. 1998, 799–800. (b) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahmed, A.; Inomata,
K. Chem. Lett. 1997, 59–60. (c) Warrener, R. N.; Liu, L.; Russell, R. A. Chem. Commun. 1997, 2173–2174. (d) Nakamura,
M.; Hirai, A., Nakamura, E. J. Am. Chem. Soc. 1996, 118, 8489–8490.
10. Ponzo, V. L.; Kaufman, T. S. Tetrahedron Lett. 1995, 36, 9105–9108.
11. Taniyama, D.; Kanai, M.; Iida, A.; Tomioka, K. Chem. Pharm. Bull. 1997, 45, 1705–1707.
12. (a) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895–1946. (b) Denmark, S. E.; Nicaise, O. J.-C. Chem.
Commun. 1996, 999–1004.
13. Dale, W. J.; Starr, L.; Strobel, C. W. J. Org. Chem. 1961, 26, 2225–2227.
14. The new compounds described herein gave the satisfactory analytical and spectroscopic data. The ee was determined by
the chiral stationary phase HPLC (Daicel Chiralcel OD-H, i-PrOH:hexane, 1:100).
15. Corey, E. J.; Imai, N.; Zhang, H.-U. J. Am. Chem. Soc. 1991, 113, 728–729.
16. The ee was determined by NMR of the 1-methoxyphenylacetamide derivative.
17. (a) Craig, J. C.; Lee, S.-Y. C.; Chan, R. P. K.; Wang, I. Y.-F. J. Am. Chem. Soc. 1977, 99, 7996–8002. (b) Leith, W.
Monatsch Chem. 1929, 53, 956–962.
18. Ludwig, M.; Beer, H.; Lotter, H.; Wanner, K. Th. Tetrahedron: Asymmetry 1997, 8, 2693–2695.