F. Ferna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 365–368
367
Table 1.
Entry Vinyl acetate (equiv.) Time (h) T (°C) Conversion c (%)a
Acetate (+)-5
Alcohol (−)-6
Eb
e.e. (%) Yield (%) [h]D
e.e. (%) Yield (%) [h]D
1
2
3
4
5
0.6
0.6
0.55
0.7
0.6
21
24
50
50
50
35
50
T.a.
T.a.
50
40
43
44
46
50
\99
\99
\99
\99
\99
49
40
36
47
45
+110.05
+110.58
+110.33
+110.16
66
76
78
84
44
28
44
42
46
−53.53
−62.68
−65.25
−68.91
397
483
521
617
+109.96 \99
−82.80 1059
a Conversion of the substrate, c=e.e.s/(e.e.s+e.e.p) (%).
b Enantioselectivities of the reactions (E) were determined from the equation E=ln[1−c(1+e.e.p)]/ln[1−c(1−e.e.p)], where e.e.p=product enan-
tiomeric excess.
vinyl acetate (0.55–0.70 equiv.) in benzene (35 mL), and
the mixture was stirred for 20–50 hours (optimisation
of time and temperature is discussed below). The lipase
was then removed by filtration, the solvent was
removed in a rotary evaporator, and the resulting
residue was purified by chromatography on silica gel
with 3:1 (v/v) hexane:AcOEt as eluent. The early frac-
tions afforded (+)-endo-2-benzonorbornenyl acetate
(+)-511 as an orange oil, and the later fractions (−)-
endo-2-benzonorbornenol (−)-612 as a yellowish liquid
that crystallised to a white solid. Treatment of the
acetate (+)-5 with KOH/EtOH 50% over 50 hours at
room temperature afforded (+)-endo-2-benzonorbor-
nenol (+)-6,13 the absolute configuration of which was
confirmed as (1R) by X-ray diffractometry of its 3,5-
dinitrobenzoate (+)-714 (see Fig. 1).
References
1. (a) Ferna´ndez, F.; Garc´ıa-Mera, X.; Lo´pez, C.;
Rodr´ıguez, G.; Rodr´ıguez-Borges, J. E. Tetrahedron:
Asymmetry 2000, 11, 4805; (b) Caaman˜o, O.; Ferna´ndez,
F.; Garc´ıa-Mera, X.; Rodr´ıguez-Borges, J. E. Tetra-
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2. Blanco, J. M.; Caaman˜o, O.; Ferna´ndez, F.; Garc´ıa-
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3. Sandman, D.; Mislow, K.; Giddings, W.; Dirlam, J.;
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82, 1240.
6. Mravik, A.; Bo¨cskei, Z.; Katona, Z.; Markovits, I.;
Pokol, G.; Menyha´rd, D.; Fogassy, E. Chem. Commun.
1996, 1983.
A series of experiments was completed with reaction
times of between 21 and 50 hours and temperatures
ranging from room temperature to 50°C, acetate 5 was
produced in yields of 36–49% with an e.e. that was
always greater than 99%, while the yield of alcohol
(−)-6 ranged from 28 to 46% and its e.e. varied from 66
to >99% (see Table 1, which also lists [h]D values,
substrate conversion rates and enantioselectivities).
7. Latypov, S.; Seco, J. M.; Quin˜oa´, E.; Riguera, R. J. Am.
Chem. Soc. 1998, 120, 877.
8. Enders, D.; Hundertmark, T.; Lazny, R. Synlett 1998,
721.
9. Adam, W.; D´ıaz, M. T.; Fell, R. T.; Saha-Mo¨ller, C. R.
Tetrahedron: Asymmetry 1996, 7, 2207.
10. Master, H. E.; Newadkar, R. V.; Rane, R. A.; Kumar, A.
The best results were achieved with 0.6 equiv. of vinyl
acetate, a reaction time of 50 hours and a temperature
of 50°C: under these conditions (+)-5 and (−)-6 were
obtained in yields of 45–46% and with e.e. of >99%,
giving an enantiomer ratio (E) of greater than 1000.
Tetrahedron Lett. 1996, 37, 9253.
11. (+)-(1R)-endo-2-Benzonorbornenyl acetate (+)-5
[h]D +110.0 (c 1, CHCl3). IR (NaCl): 2972, 2870, 1738,
1469, 1441, 1374, 1243, 1191, 1038, 755 cm−1
.
1H
NMR (CDCl3): 1.04–1.10 (d×t, 1H, J3endo–3exo=12.81
Hz, J3endo–2exo=3.30 Hz, 3endo-H), 1.70–1.73 (d×t, 1H,
In summary, we have developed a simple, efficient
method for the resolution of ( )-endo-2-benzonorbor-
nenol by transesterification with C. antarctica lipase.
The transesterification proceeded with very high E val-
ues and workable yields.
Jd=9.50 Hz, Jt=1.23 Hz, 9-H), 1.83 (s, 3H, CH6 3CO),
1.83–1.89 (m, 1H, 9-H), 2.34–2.43 (d×d×d, 1H,
J3exo–3endo=12.81 Hz, J3exo–2exo=9.06 Hz, J3exo–4=4.10
Hz, 3exo-H), 3.32–3.33 (d, 1H, J=3.34 Hz, 1-H), 3.63–
3.66 (d×d, 1H, J4–3exo=3.66 Hz, J=0.81 Hz, 4-H), 5.34–
5.40 (d×d×d, 1H, J2exo–3exo=9.06 Hz, J=4.01 Hz,
J=3.16 Hz, 2exo-H), 7.10–7.23 (m, 4H, ArH). 13C NMR
(CDCl3): 21.41 (C6 H3C(O)), 36.02 (C-3), 43.78 (C-4),
Acknowledgements
48.17 (C-1), 48.62 (C-9), 74.73 (C-2), 120.79 (C-5), 123.81
(C-8), 126.06 (C-7), 126.67 (C-6), 142.99 (C-8a), 148.65
(C-4a), 171.64 (C(O)). Anal. calcd for C13H14O2: C,
77.20; H, 6.98. Found: C, 77.47; H, 6.69%.
We thank Amano Pharmaceutical Co. Ltd., Japan, and
Novo Nordisk, Denmark, for the generous gifts of
lipases and Christian F. Massaguer for helpful conver-
sations. This work was supported by the Xunta de
Galicia (Spain) under project XUGA 203079B978.
12. (−)-(1S)-endo-2-Benzonorbornenol (−)-6
[h]D −82.80 (c 1, CHCl3). Mp 92–94°C (hex.). IR (NaCl):
3260, 3015, 2952, 1458, 1293, 1117, 1048, 952, 754 cm−1
.