A facile and efficient asymmetric synthesis of (+)-salsolidine

Article abstract of DOI:10.1016/S0040-4039(00)00830-3

A three-key step methodology involving a highly selective asymmetric addition of an organolithium reagent to an N-naphthalenylimine, cyclization and oxidative removal of the N-naphthalenyl group provided a facile and efficient synthetic way to (+)-salsolidine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00830-3

Tetrahedron Letters 41 (2000) 5533±5536
A facile and ecient asymmetric synthesis of (+)-salsolidine
Daisuke Taniyama, Masayoshi Hasegawa and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 21 April 2000; accepted 19 May 2000
Abstract
A three-key step methodology involving a highly selective asymmetric addition of an organolithium
reagent to an N-naphthalenylimine, cyclization and oxidative removal of the N-naphthalenyl group pro-
vided a facile and ecient synthetic way to (+)-salsolidine. # 2000 Elsevier Science Ltd. All rights reserved.
Biological activity, especially that related to the pathogenesis of Parkinson's disease, has
recently renewed interest in tetrahydroisoquinolines (TIQs) and related natural isoquinoline
alkaloids.1,2 Since the enantiomers were observed to vary in activity,3 the synthesis of chiral
1-substituted TIQ is the current focus in medicinal organic chemistry.4 We have previously
reported an approach to asymmetric synthesis of chiral 1-methyl and 1-phenyl TIQs based on a
chiral external ligand-mediated asymmetric 1,2-addition reaction of organolithium reagents with
the corresponding N-p-methoxyphenyl (PMP) imines.5 Extension of the method to an alkaloid
natural product, salsolidine 1, incurred several crucial problems such as moderate enantio-
selectivity and poor eciency in oxidative removal of the N-PMP group.6 We describe herein a
facile asymmetric synthesis of (+)-salsolidine 1 by employing highly ecient asymmetric addition
of an organolithium reagent to N-1-naphthalenylimine and a new procedure for oxidative
removal of the N-aryl group.7,8
At ®rst, we examined asymmetric addition reaction of methyllithium with imines 2 bearing
substituted phenyl and naphthalenyl groups as an N-substituent, Ar (Fig. 1). The reaction was
conducted in the presence of a stoichiometric amount of 3 in toluene at ^95ꢀC for 0.5 h to give the
corresponding amines 4 in reasonably high chemical yields (Table 1). The enantioselectivity was
not very high for 2a,b bearing substituted phenyl groups as Ar (entries 1 and 2). We were very
pleased to ®nd that 2d±f bearing substituted 1-naphthalenyl groups were converted to the amines
4d±f (R=Me) in quite high ees, 97±94% (entries 4±6). It is interesting to note that enantio-
selectivity rises from 73 to 97% in the reverse order of electronegativity of the 4-substituent on
the naphthalene, Cl, H, NMe2 and OMe. This indicates that loss of electrophilicity of the imine
gives rise to higher enantioselectivity, probably due to formation of a tight, three-component
* Corresponding author. E-mail: tomioka@pharm.kyoto-u.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00830-3

5534
complex between imine 2, MeLi, and the chiral ligand 3 (entries 3±6). Enantioenrichment was
possible by recrystallizing 4 to a€ord optically pure amines in high overall yield (entries 4 and 5).
The imine 2f bearing a 4-methoxynaphthalenyl group is also a suitable substrate for addition of
butyl- and phenyllithiums to a€ord the corresponding amines 4f (R=Bu, Ph) in 86 and 92% ees,
respectively (entries 7±8).
Figure 1. Asymmetric addition of organolithium reagents to 2 in the presence of 3
Table 1
Asymmetric addition of RLi to 2 in the presence of 3 producing 4
The next problem to be solved was oxidative removal of the N-aryl group. Treatment of 4f
(Ar=4-MeONaph, R=Me)) with ammonium cerium(IV) nitrate (CAN) in aqueous acetonitrile
under standard conditions5 failed to provide the corresponding primary amine 5 in a detectable
yield (Fig. 2). To avoid further Michael-type addition reaction of the primary amine 5 with
naphtho-1,4-quinone 6 produced, sodium borohydride was added to the mixture to reduce 6 to
naphthalene-1,4-diol 7. To our delight, under these conditions the primary amine 5 was isolated
in 47% yield. Substantial improvement in yield was realized by further treatment with acetic
anhydride to a€ord a mixture of the primary amine 5 and its acetoamide 8 in 75% combined yield.
This new procedure for CAN oxidation is applicable to 4a (Ar=PMP, R=Me) to a€ord a
mixture of the amine 5 and amide 8 in 89% combined yield. Isolation of diacetate of benzene-1,4-
diol 9 in 67% yield indicates that treatment with sodium borohydride reduces benzoquinone to

5535
Figure 2. Successful treatment of 4 with CAN±NaBH4±Ac2O for oxidative removal of N-aryl group
benzene-1,4-diol, and further treatment with acetic anhydride acetylates diol to diacetate 9, which
process avoids back-oxidation to benzoquinone (Fig. 2).
Having established a new procedure for asymmetric alkylation and oxidative removal of the
N-aryl group, we then focused on asymmetric synthesis of (+)-salsolidine 1. Condensation of 10
and 119 gave an imine 12, which was subjected asymmetric alkylation with MeLi in the presence
of a stoichiometric amount of 3 to give an amine 13 in 93% ee and quantitative yield (Fig. 3).
Figure 3. Asymmetric synthesis of (+)-salsolidine 1 from 10

5536
Hydroboration and subsequent oxidation gave an alcohol 14, which was then subjected to cyclization
to a€ord 15 in 75% overall yield from 13. New CAN procedure gave 16 in 94% yield. Hydrolysis
25
D
of 16 a€orded the target (+)-1 in 69% yield. Speci®c rotation of synthetic (+)-R-1 (‰ꢀŠ +54.0
(c 0.63, EtOH)) is indistinguishable from that of the reported (^)-S-1 ([ꢀ]D ^59.5 (c 4.39, EtOH)).10
The presented three-step procedure for the highly selective asymmetric synthesis of salsolidine
is applicable to other biologically potent TIQ and related natural alkaloids. Further studies
directed toward more ecient asymmetric alkylation of imines are in progress in our laboratories.
Acknowledgements
We acknowledge ®nancial support from the Japan Society for Promotion of Science (RFTF-
96P00302) and the Ministry of Education, Science, Sports and Culture, Japan.
References
1. (a) Nagatsu, T. Neurosci. Res. 1997, 29, 99±111. (b) Sano, T. J. Synth. Org. Chem. Jpn. 1999, 57, 136±140.
2. Tetrahydroisoquinoline (TIQ) and 1-methyl TIQ: (a) Yamakawa, T.; Ohta, S. Biochem. Biophys. Res. Commun.
1997, 236, 676±681. (b) Thull, U.; Kneubuhler, S.; Gaillard, P.; Carrupt, P.-A.; Testa, B.; Altomare, C.; Carotti,
A.; Jenner, P.; McNaught, K. St. P. Biochem. Pharmacol. 1995, 50, 869±877. (c) Kohno, M.; Ohta, S.; Hirobe, M.
Biochem. Biophys. Res. Commun. 1986, 140, 448±454. 1-Phenyl TIQ: (d) Gray, N. M.; Cheng, B. K.; Mick, S. J.;
Lair, C. M.; Contreras, P. C. J. Med. Chem. 1989, 32, 1242±1248. (e) Charifson, P. S.; Wyrick, S. D.; Ho€man,
A. J.; Simmons, R. M. A.; Bowen, J. P.; McDougald, D. L.; Mailman, R. B. J. Med. Chem. 1988, 31, 1941±1946.
3. (a) Maruyama, W.; Naoi, M.; Kasamatsu, T.; Hashizume, Y.; Takahashi, T.; Kohda, K.; Dostert, P.
J. Neurochem. 1997, 69, 322±329. (b) Tatton, W. G.; Ju, W. Y. L.; Holland, D. P.; Tai, C.; Kwan, M.
J. Neurochem. 1994, 63, 1572±1575.
4. (a) Rozwadowska, M. D. Heterocycles 1994, 39, 903±931. b) Shinohara, T.; Takeda, A.; Toda, J.; Sano, T. Chem.
Pharm. Bull. 1998, 46, 430±433.
5. Taniyama, D.; Hasegawa, M.; Tomioka, K. Tetrahedron: Asymmetry 1999, 10, 221±223.
6. Gittins (nee Jones), C. A.; North, M. Tetrahedron: Asymmetry 1997, 8, 3789±3799.
7. Enantioselective Pictet±Spengler reaction of b-carboline has been reported. (a) Kawate, T.; Yamada, H.; Soe, T.;
Nakagawa, M. Tetrahedron: Asymmetry 1996, 7, 1249±1252. Asymmetric alkylation of an amine: (b) Meyers, A. I.
Tetrahedron 1992, 48, 2589±2612. Asymmetric reduction: (c) Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron:
Asymmetry 1998, 9, 183±187. (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. Asymmetric alkylation of
an imine: (f) Wunsch, B.; Nerdinger, S. Chem. Lett. 1998, 799±800. (g) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.;
Ahmed, A.; Inomata, K. Chem. Lett. 1997, 59±60. (h) Warrener, R. N.; Liu, L.; Russell, R. A. Chem. Commun.
1997, 2173±2174. (i) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 1996, 118, 8489±8490.
8. For recent asymmetric synthesis of 1, see: (a) Hajipour, A. R.; Hantehzadeh, M. J. Org. Chem. 1999, 64, 8475±
8478. (b) Ukaji, Y.; Kenmoku, Y.; Inomata, K. Tetrahedron: Asymmetry 1996, 7, 53±56. (c) Munchhof, M. J.;
Meyers, A. I. J. Org. Chem. 1995, 60, 7086±7087. (d) Ponzo, V. L.; Kaufman, T. S. Tetrahedron Lett. 1995, 36,
9105±9108. (e) Suzuki, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1995, 36, 6709±6712. (f) Kitamura, M.;
Hsiao, Y.; Ohta, M.; Tsukamoto, M.; Ohta, T.; Takaya, H.; Noyori, R. J. Org. Chem. 1994, 59, 297±310. (g)
Murahashi, S.; Watanabe, S.; Shiota, T. J. Chem. Soc., Chem. Commun. 1994, 725±726. (h) Willoughby, C. A.;
Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11703±11714. (i) Yamato, M.; Hashigaki, K.; Qais, N.; Ishikawa, S.
Tetrahedron 1990, 46, 5909±5920.
9. Karuso, P.; Taylor, W. C. Aust. J. Chem. 1984, 37, 1271±1282.
10. Battersby, A. R.; Edwards, T. P. J. Chem. Soc. 1960, 1214±1221.