5650
of glutaric acid monoesters to d-hydroxy esters with opposite stereocon®guration to that obtained
from borane reduction has been developed. This one-pot reaction sequence should be applicable
to other monoester dicarboxylates where unwanted lactonization needs to be minimized or for
the formation of esters which would otherwise be inappropriate substrates for PLE. With this
new method, the desymmetrization may be optimized for enzyme and substrate without regard to
stereochemical outcome, since either d-hydroxy ester can be realized without the involvement of
other chemical intermediates. Future activities in these areas are planned and will be disclosed in
due course.
Acknowledgements
The authors would like to thank R. Lee Webb for conducting the CD experiments, which
determined that (+)-paroxetine had been synthesized.
References
1. For other routes to paroxetine, see: (a) Gledhill, L.; Martin, C. PCT Int. Appl., WO 9802556 A2 980122. (b)
Kreidl, J. et al. PCT INT. Appl., WO9801424 A1 980115. (c) Sugi, K. Eur. Patent Appl., EP 182827 A1 971217.
(d) Keverline-Frantz, K. I.; Boja, J. W.; Kuhar, M. J.; Abraham, P.; Burgess, J. P.; Lewin, A. H.; Carroll, F. I.
J. Med. Chem. 1988, 41, 247. (e) Wang, S.; Okazee, T.; Matsumura, Y. Eur. Pat. Appl., EP 819224 A1 971203. (f)
Adger, B. M.; Potter, G. A.; Fox, M. E. PCT Int. Appl., WO 9724323 A1 970710. (g) Engelstoft, M.; Hansen, J. B.
Acta Chem. Scand. 1996, 50, 164. (h) Zepp, C. M.; Gao, Y.; Heefner, D. L. US 25258517 A 931102. (i) Lundbeck,
J. M.; Everland, P.; Treppendahl, S.; Jakobsen, P. Eur. Pat. Appl., EP 374674 A2 900627. (g) Amat, M.; Hidalgo,
J.; Bosch, J. Tetrahedron: Asymmetry 1996, 7, 1591.
2. (a) Toone, E. J.; Werth, M. J.; Jones, J. B. J. Am. Chem. Soc. 1990, 112, 4969. (b) Lam, L. K.-P.; Jones, J. B. Can.
J. Chem. 1988, 66, 1422. (c) Francis, C. J.; Jones, J. B. J.C.S. Chem. Comm. 1984, 579. (d) Ohno, M.; Otsuka, M.
Org. React. 1989, 37, 1-55.
3. Perregaard, J.; Moltzen, E. K.; Meier, E.; Sanchez, C. J. Med. Chem. 1995, 38, 1998.
4. Enantiomeric purity of 3 determined by HPLC. Column: Chiracel OB-H, 25 cmÂ4.6 mm. Mobile phase: 95:5
hexane:ethanol with 0.1% TFA. Detection: UV absorbance at 210 nm. Flow rate: 1 mL/min.
5. (a) Huang, F.-C.; Lee, L. F. H.; Mittal, R. S. D.; Ravikumar, P. R.; Chan, J. A.; Sih, C. J.; Caspi, E.; Eck, C. R.
J. Am. Chem. Soc. 1975, 97, 4144. (b) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc.
1982, 104, 7294. (c) Francis, C. J.; Jones, J. B. J. Chem. Soc., Chem. Commun. 1984, 579.
6. Enantiomeric purity of 6 determined by HPLC. Column: Regis (S,S) Whelk O-1, 25 cmÂ4.6 mm. Mobile phase:
95:5 hexane:ethanol. Detection: UV Absorbance at 210 nm. Flow rate: 1 mL/min.
7. Procedure for synthesis of 12: Acid ester 3 (5.0 g, 20.8 mmol) was dissolved in 50 mL THF in a 250 mL round-
bottomed ¯ask equipped with spinbar and condenser. LiH (200 mg, 25 mmol, 1.2 equiv.) was added and the
mixture heated at re¯ux and stirred for 1 h. LiBH4 (300 mg, 13.5 mmol, 0.65 equiv.) was added and stirring at
re¯ux continued for 10 h. The mixture was cooled to ambient temperature and 25 mL DMF added followed by
dimethylsulfate (3.30 mL, 34.5 mmol, 1.6 equiv.). After 4 h at ambient temperature the mixture had turned into a
clear pale yellow and reaction was complete as monitored by HPLC. MeOH (5 mL) and SiO2 (5 g) were added.
After 45 min the mixture was ®ltered and ®ltrate taken up in 100 mL t-butyl methyl ether and washed twice with
10% aq. NH4Cl. The organic layer was rotary evaporated and dried in vacuo to give 4.65 g of 12 as a pale yellow
oil, which was used without further puri®cation. Crude yield=99%. HPLC assay of this material showed it to be
1
86% by weight. H NMR (300 MHz, CDCl3, TMS/ppm) ꢀ 7.15 (dd, 2H, J=2.8, 3.3 Hz), 7.02 (apparent t, 2H,
J=2.8, 6.3 Hz), 3.56 (s, 3H), 3.50 (m, 2H), 3.31 (m, 1H), 2.61 (m, 2H), 1.86 (m, 2H), 1.62 (br s, 1H).
8. Examples of NaBH4 reduction of esters include: (a)Yang, C.; Pittmanm Jr., C. U. Synth. Commun. 1998, 28, 2027.
(b) Prasad, A. S. Bhanu; Kanth, J. V. Bhaskar; Periasamy, M. Tetrahedron 1992, 48, 4623. (c) Yamakawa, T.;