1400
R. Sa´nchez et al. / Tetrahedron: Asymmetry 12 (2001) 1399–1401
O
O
O
OH
OH
OR
NH2
NH
NH
Ref. 9
Ref. 10
rac-1
rac-3
rac-2
enzymatic
hydrolysis
R
a: methyl
b: ethyl
c: butyl
O
O
OR
OH
NH
NH
(S)-2
(R)-3
Scheme 1.
Our result demonstrated that mouse and rat LAPs
showed no enantioselectivity, even at shorter reaction
times. On the other hand either commercial lipase or
animal LAPs were equally efficient to resolve the ester
3 with excellent enantioselectivity, toward the (S)-enan-
tiomer. The chicken LAP and commercial CLAP
showed the best enantioselectivity, after only 2 h of
reaction. It is worth mentioning that even after longer
reaction times the enantioselectivity remained
unchanged. Moreover, when purified (R)-3a was sub-
jected to biotransformation with fresh biocatalyst there
was no reaction, even after stirring the mixture for 144
h, clearly demonstrating that the enzymes in the crude
biocatalyst were unable to react with this enantiomer.
2. Lembeck, F.; Greisbacher, T.; Henke, S.; Breipohl, G.;
Knolle, J. Br J. Pharmacol. 1991, 102, 297–304 (Chem.
Abstr. 1991, 114, 157636).
3. Henke, S.; Anagnostopoulos, H.; Breipohl, G.; Gerhards,
H.; Knolle, J.; Scho¨lkens, B.; Lembeck, F. Ger. Offen.
DE 4,013,270 (1992) Heocht AG (Chem. Abstr. 1992,
116, 106824a).
4. Klutchko, S.; Blankey, C. J.; Fleming, R. W.; Hinkley, J.
M.; Werner, A. E.; Nordin, I.; Hoefle, M. L.; Cohen, D.
M. J. Med Chem. 1986, 29, 1953–1961.
5. Suh, J. T.; Williams, B. E.; Skiles, J. W. Eur. Patent-A
34804 (1981) USV Pharmaceuticals (Chem. Abstr. 1982,
96, 122647).
6. Arzeno, H. B.; Morgans, D. J. Eur. Patent-A 260118
(1988) Syntex, Inc. (Chem. Abstr. 1989, 110, 8697).
7. Remond, G.; Lambie, M.; Vincent, M. Eur. Patent-A
49658 (1982) Science Union et Cie.-Societe Francaise de
Reserche Medicale (Chem. Abstr. 1982, 97, 216716).
8. Nestor, J. J. Eur. Patent-A 196841 (1986) Syntex Inc.
(Chem. Abstr. 1987, 106, 214389)
9. Portlock, D. E. DOS 3018545 (1980) Morton-Norwich
Prod. Inc. (Chem. Abstr. 1981, 94, 208725).
10. Geiger, R.; Teetz, V.; Urbach, H.; Scho¨lkens, B.; Hen-
ning, R.; Eur. Patent-A 46956 (1982) Hoechst A.G.
(Chem. Abstr. 1982, 87, 92759)
We also observed no significant differences related to
the type of ester, methyl, ethyl or butyl and all three
were well resolved in excellent yield with chicken LAP.
In conclusion, the three esters of 1,2,3,4-tetra-
hydroisoquinoline-3-carboxylic acid tested were suc-
cessfully resolved via enzymatic hydrolysis using
chicken liver acetone powder. These bioresolutions
showed enantioselectivity towards the (S)-isomer.
Additionally, this procedure is remarkable in its sim-
plicity and low cost, because the biocatalyst is both
readily available and easy to prepare.
11. Huber, I. M. P.; Seebach, D. Helv. Chim. Acta 1987, 70,
1944–1954.
12. Yu, K.-L.; Harte, W. E.; Spinazze, P.; Martin, J. C.;
Mansuri, M. M. Bioorg. Med. Chem. Lett. 1996, 6,
535–538.
Acknowledgements
13. Houpis, I. N.; Molina, A.; Reamer, R. A.; Lynch, J. E.;
Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1993, 34,
2593–2596.
14. Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broad-
hurst, A. V.; Craig, J. C.; Duncan, I. B.; Gaplin, S. A.;
Handa, B. K.; Kay; Kroehn, A.; Lambert, R. W.; Merret,
J. H.; Mills, J. S.; Parkes, K. E. B.; Redshaw, S.; Ritchie,
A. J.; Taylor, D. L.; Thomas, G. J.; Manchin, P. J.
Science 1990, 248, 358–361.
The authors are grateful to the Consejo Nacional de
Ciencia y Tecnologia (CONACyT) for the financial
support (Grant No. 400200-5-0491PB).
References
1. Hock, F. J.; Wirth, K.; Albus, U.; Linz, W.; Gerhards, J.
M.; Wiemer, G.; Henke, St.; Breipohl, G.; Ko¨ning, W. J.
Pharmacol. 1991, 102, 769–773 (Chem. Abstr. 1991, 114,
200391).
15. Liu, L. T.; Lin, Y.-C.; Wang, C.-L.; Lin, M.-S.; Yen,
S.-C.; Chen, H.-J. Bioorg. Med. Chem. Lett. 1996, 6,
1335–1338.