L. F. Solares et al. / Tetrahedron: Asymmetry 13 (2002) 2577–2582
2581
dried over Na2SO4, filtered and evaporated under
reduced pressure. The residue was washed with diethyl
ether to afford compound ( )-2h as a white solid (>95%
yield). No further purification was necessary. Mp 177–
well resolved peaks were obtained for the racemic com-
pound (1 mg in 4 ml mobile phase; 20 ml sample) at
20°C in hexane:i-propanol (60:40), 0.8 cm3 min−1, Rs
2.8. (S)-(+)-2h, tR 26.0.4 min; (R)-(−)-2h, tR 32.89 min.
1
178°C; H NMR (CDCl3) l 8.86 (dd, 2H, 2 CH), 8.52
3
4
(d, 1H, CH, JHH=8.98 Hz), 8.39 (d, 1H, CH, JHH
=
4.3.2. (S) - (+) - 7 - Chloromethyloxycarbonyloxy - 6 - (5-
chloropyridin - 2 - yl) - 6,7 - dihydro - 5H - pyrrolo[3,4 - b]-
pyrazin-5-one, (S)-(+)-2i. [h]2D0 +94 (c 1.1, CHCl3), e.e.
>99%. Determination of the e.e. by HPLC analysis: two
well resolved peaks were obtained for the racemic com-
pound (1 mg in 4 ml mobile phase; 20 ml sample) at
20°C in hexane:ethanol:i-propanol (60:35;5), 1 cm3
min−1, Rs 4.1. (S)-(+)-2i, tR 10.34 min; (R)-(−)-2i, tR
15.28 min.
3
2.58 Hz), 7.99 (s, 1H, CH), 7.82 (dd, 1H, CH, JHH
=
4
8.98 Hz, JHH=2.58), 4.53 (m, 2H, CH2), 3.74 (t, 2H,
CH2); 13C NMR (CDCl3) l (ppm): 162.8 (CꢀO), 154.6
(CꢀO), 153.6 (C), 148.6 (CH), 148.6 (CH), 147.8 (C),
147.1 (CH), 144.3 (C), 138.6 (CH), 128.9 (C), 116.3
(CH), 80.8 (CH), 68.5 (CH2), 41.3 (CH2). MS (ESI+)
m/z (%): 391 [(M+Na)+, 100%].
4.2. Synthesis of ( )-7-chloromethyloxycarbonyloxy-6-
(5-chloropyridin-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]-
pyrazin-5-one, ( )-2i
4.4. Synthesis of (S)-(+)-6-(5-chloropyridin-2-yl)-7-[(4-
methyl - 1 - piperazinyl)carbonyloxy] - 6,7 - dihydro - 5H-
pyrrolo[3,4-b]pyrazin-5-one, (S)-(+)-Zopiclone, (S)-(+)-3
Chloromethyl chloroformate (1.02 ml, 11.42 mmol) was
slowly added to a solution of the alcohol ( )-1 (1 g, 3.8
mmol) and anhydrous pyridine (1.2 ml) in anhydrous
CH2Cl2 (8 ml) under nitrogen at 0°C. The resulting
mixture was allowed to warm to rt, stirred for 17 h and
then extracted with CH2Cl2. The organic fraction was
dried over Na2SO4, filtered and evaporated under
reduced pressure to afford compound ( )-2i as a white
solid (86% yield). No further purification was necessary.
Mp 55–58°C; 1H NMR (CDCl3) l 8.89 (dd, 2H, 2 CH),
8.50 (d, 1H, CH, 3JHH=8.85 Hz), 8.37 (d, 1H, CH,
4JHH=2.52 Hz), 7.97 (s, 1H, CH), 7.80 (dd, 1H, CH,
N-Methylpiperazine (0.48 ml, 4.2 mmol) was slowly
added to a solution of the carbonate (S)-(+)-2i (0.5 g,
1.4 mmol) in anhydrous acetone (6 ml) under nitrogen
at 0°C. The resulting mixture was allowed to warm to
rt, stirred for 2 h and then the solvent was evaporated
under reduced pressure and the crude residue was
purified by flash chromatography on silica gel to afford
the corresponding (S)-(+)-3 (acetone) as a white solid
(90% yield). No further purification was necessary. Mp
1
176–178°C; H NMR (CDCl3) l 8.85 (dd, 2H, 2 CH),
8.48 (d, 1H, CH, 3JHH=8.85 Hz), 8.36 (d, 1H, CH,
4JHH=2.49 Hz), 7.99 (s, 1H, CH), 7.77 (dd, 1H, CH,
3
4JHH=2.52 Hz, JHH=8.85 Hz), 5.81 (dd, 2H, CH2);
3
4JHH=2.49 Hz, JHH=8.85 Hz), 3.56 (bd, 2H, CH2),
13C NMR (CDCl3) l (ppm): 163.0 (CꢀO), 154.5 (CꢀO),
152.8 (C), 149.1 (CH), 148.0 (C), 147.4 (CH), 144.5 (C),
139.0 (CH), 129.2 (C), 116.3 (CH), 81.6 (CH), 73.2
(CH2). MS (ESI+) m/z (%): 377 [(M+Na)+, 100%], 355
[(M+H)+, 68%].
3.22 (bs, 2H, CH2), 2.33 (bs, 2H, CH2), 2.22 (s, 3H,
CH3), 2.08 (sa, 2H, CH2); 13C NMR (CDCl3) l (ppm):
162.7 (CꢀO), 155.2 (CꢀO), 153.2 (C), 148.2 (CH), 147.6
(CH), 146.5 (CH), 143.6 (C), 137.9 (CH), 128.0 (C),
115.8 (CH), 78.8 (CH), 54.2 (2 CH2), 45.9 (CH3), 43.8
(2 CH2). MS (ESI+) m/z (%): 411 [(M+Na)+, 100%], 389
[(M+H)+, 72%]. [h]D20 +176 (c 1.1, CHCl3), e.e. >99%.
Determination of the e.e. by HPLC analysis: two well
resolved peaks were obtained for the racemic com-
pound (1 mg in 4 ml mobile phase; 20 ml sample) at
20°C in hexane:ethanol:i-propanol (60:35:5), 1 cm3
min−1, Rs 3.9. (S)-(+)-3, tR 8.08 min; (R)-(−)-3, tR 12.83
min.
4.3. General procedure for lipase-catalyzed hydrolysis
of carbonates
The reaction mixture contained the carbonate ( )-2h or
( )-2i (0.2 g), the immobilized lipase (0.2 g) and phos-
phate buffer pH 7 (amount indicated in Tables 1 and 2)
in the corresponding organic solvent (40 ml). In the
enzymatic hydrolysis carried out in the presence of an
additive, the amount indicated in Table 2 was also
added to the reaction mixture. The resulting mixture
was shaken at 250 rpm in a rotatory shaker. The
progress of the reaction was monitored by TLC using
the solvent system hexane:ethyl acetate 1:1. The enzyme
was removed by filtration and washed with ethyl ace-
tate. The solvent was evaporated under reduced pres-
sure and the crude residue was purified by flash
chromatography on silica gel to afford the correspond-
ing remaining substrate (S)-(+)-2h (hexane:ethyl acetate
6:4) or (S)-(+)-2i (hexane:ethyl acetate 1:1), and the
racemic product ( )-1.
Acknowledgements
This work was supported by the Ministerio de Ciencia
y Tecnolog´ıa (FEDER project 1FD97-1255-C02-01).
We express our appreciation to Novo Nordisk Co. for
the generous gift of the lipase Novozym 435. We thank
Luc´ıa Rodr´ıguez for her technical assistance.
References
1. Schmid, A.; Dordick, J. S.; Hauer, B.; Kiener, A.; Wub-
bolts, M.; Witholt, B. Nature 2001, 409, 258–268.
2. Blaschke, G.; Hempel, G.; Mu¨ller, W. E. Chirality 1993,
5, 419–421.
3. Cotrel, C.; Roussel, G., Eur. Pat. Appl. 495,717 (Chem.
Abstr., 1992, 117, 191870a).
4.3.1. (S)-(+)-7-(2-Chloroethyloxycarbonyloxy)-6-(5-
chloropyridin - 2 - yl) - 6,7 - dihydro - 5H - pyrrolo[3,4 - b]-
pyrazin-5-one, (S)-(+)-2h. [h]2D0 +87 (c 1.1, CHCl3), e.e.
>99%. Determination of the e.e. by HPLC analysis: two