Diastereoselective and enantioselective lipase-catalyzed hydrolysis of stereoisomeric 2-methylene, 5-t-butylcyclohexyl acetates

Article abstract of DOI:10.1016/S0040-4039(02)00425-2

cis- and trans-2-Methylene-5-t-butylcyclohexanols are obtained in high (>90%) e.e. through Rabbit Gastric Lipase (RGL)-catalyzed acylation or hydrolysis of the stereoisomeric racemic alcohols or their corresponding acetates. Since these reactions were diastereomer-selective, enantiomerically enriched cis- and trans-5-t-butyl-2-methylenecyclohexanols could also be prepared from cis/trans isomeric mixtures.

Full text of DOI:10.1016/S0040-4039(02)00425-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3025–3027
Diastereoselective and enantioselective lipase-catalyzed hydrolysis
of stereoisomeric 2-methylene, 5-t-butylcyclohexyl acetates
Chahra Bidjou,a Louisa Aribi-Zouiouechea,* and Jean-Claude Fiaudb,*
aDepartment of Organic Chemistry, University of Annaba, B.P. 12, 23000 Annaba, Algeria
bInstitut de Chimie Mole´culaire d’Orsay, Universite´ Paris-Sud, F-91405 Orsay cedex, France
Received 7 January 2002; accepted 25 February 2002
Abstract—cis- and trans-2-Methylene-5-t-butylcyclohexanols are obtained in high (>90%) e.e. through Rabbit Gastric Lipase
(RGL)-catalyzed acylation or hydrolysis of the stereoisomeric racemic alcohols or their corresponding acetates. Since these
reactions were diastereomer-selective, enantiomerically enriched cis- and trans-5-t-butyl-2-methylenecyclohexanols could also be
prepared from cis/trans isomeric mixtures. © 2002 Elsevier Science Ltd. All rights reserved.
The stereoisomeric cis- and trans-2-methylene, 5-t-
butylcyclohexanols 1 and their corresponding acetates 2
are useful models to investigate the stereochemistry of
transition metal-catalyzed transformations operating
with allylic compounds.
We looked for ways of preparing 1 or 2 in enantioen-
riched forms by kinetic resolution through lipase-cata-
lyzed acylation of racemic 1 or hydrolysis of the
corresponding acetates 2. Lipase-catalyzed acylation6 of
( )-trans-17 with isopropenyl acetate in diethyl ether at
room temperature was performed with pig pancreatic
lipase (PPL),8a rabbit gastric lipase (RGL),8b Candida
cylindracea lipase (CCL),8c immobilized Candida
antarctica (SP 435).8d Only RGL showed a low-rate
conversion of ( )-trans-1 with 11% conversion into a
single enantiomer of (+)-trans-2 (non-isolated and of
unknown configuration) over 8 days, corresponding to
a high enantioselectivity (E>200) (Scheme 1). Under the
same conditions, ( )-cis-17 underwent
a
faster
We have demonstrated with these models the strong
stereoelectronic control exerted in palladium-catalyzed
alkylations of allylic acetates and molybdenum-cata-
lyzed isomerization of allylic alcohols.1 These com-
pounds have also been used in stereochemical
investigations of hydroformylation,2 epoxidation3,4 and
osmylation4 reactions. Enantiomerically enriched (−)-
cis-1 has been prepared in 70% e.e., and (+)-trans-1 in
25% e.e. (1H NMR spectroscopy in the presence of a
chiral shift reagent).5 However, to the best of our
knowledge, these compounds are unknown in enan-
tiomerically pure form. It would thus be desirable to get
them in high e.e., as references for evaluating kinetic
resolution processes in the above-described reactions.
acylation, albeit less enantioselective. After 2 days, at
41% extent of conversion of the starting alcohol, (−)-
cis-2 was produced in 45% e.e. (E=4). SP 435 was less
efficient as a catalyst (27% conversion after 5 days of
reaction) but more enantioselective (E>200), since the
(+)-cis-2 acetate was produced enantiomerically pure,
as determined by chiral GLC.9 RGL and SP 435 thus
showed opposite enantiopreference.
These results indicate that with RGL, the acylation
should be diastereoselective. Since the mixture of cis-1
and trans-1 (25:75) is more readily prepared than each
separate stereoisomer, we looked whether (−)-cis-1 and
(+)-trans-2 could be produced in high enantiomeric
purity. Indeed, an 8 day RGL-catalyzed acylation of a
stereomeric mixture of ( )-cis-1 and ( )-trans-1 gave
7.5% of enantioenriched (>99% e.e., by chiral GLC)
(+)-trans-2, readily separated from the unreacted alco-
hols and cis-2 (Scheme 2).
Keywords: kinetic resolution; enzyme; catalysis; enantioselective;
acylation; hydrolysis.
* Corresponding authors. Fax: 331 69 15 46 80; e-mail: fiaud@
icmo.u-psud.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00425-2

3026
C. Bidjou et al. / Tetrahedron Letters 43 (2002) 3025–3027
Scheme 1. RGL-catalyzed acylation of ( )-trans-1 and ( )-cis-1.
Scheme 2. RGL-catalyzed acylation of a diastereomeric mixture of ( )-trans-1 and ( )-cis-1.
Scheme 3. RGL-catalyzed hydrolysis of ( )-trans-2 and ( )-cis-2.

C. Bidjou et al. / Tetrahedron Letters 43 (2002) 3025–3027
3027
References
Enzymatic hydrolysis by the same lipases in phosphate
buffer10 showed the same trends. PFL PPL, SP 435
were inefficient as catalysts for hydrolysis of both ( )-
cis-2 and ( )-trans-2. Once again RGL was the most
performing (Scheme 3). At 16% conversion, hydrolysis
of ( )-trans-2 produced 10% of (+)-trans-1 (correspond-
ing to an enantioselectivity factor over 200). RGL
performed well on kinetic resolution of ( )-cis-2, pro-
ducing (+)-cis-1 of 90% e.e. at 27% conversion and 99%
e.e. at 44% conversion. This corresponds to a satisfac-
tory E>100. Interestingly, a 60:40 mixture of racemic
cis-2 and trans-2 afforded through RGL-catalyzed
hydrolysis 26% of (+)-cis-1 (94% e.e.). Only traces of
trans-1 were formed, facilitating the isolation of the
cis-alcohol.
1. Fiaud, J.-C.; Aribi-Zouioueche, L. J. Chem. Soc., Chem.
Commun. 1986, 390–392.
2. Doi, T.; Komatsu, H.; Yamamoto, K. Tetrahedron Lett.
1996, 37, 6877–6880.
3. Chautemps, P.; Pierre, J. L. Tetrahedron 1976, 32, 549–
557.
4. (a) Vedejs, E.; Dent, W. H.; Kendall, J.; Oliver, P. A. J.
Am. Chem. Soc. 1996, 118, 3556–3567; (b) Vedejs, E.;
Dent, W. H. J. Am. Chem. Soc. 1989, 111, 6861–6862.
5. Hoffmann, R. W.; Gerlach, R.; Goldmann, S. Chem. Ber.
1980, 113, 856–863.
6. To a solution of alcohol-1 (2 mmol) and isopropenyl
acetate (6 mmol) in diethyl ether (12 mL) was added the
enzyme (100 mg RGL, or 300 mg CCL, or 300 mg
SP435) and the reaction mixture was stirred at room
(18–22°C) temperature for the required time. After filtra-
tion (Celite), yields and e.e.s were measured by chiral
GLC (Chiraldex b-PM, 50 m.). The relative retention
times were, at 120°C (in min): (−)-cis-1: 73.5; (+)-cis-1:
77.5; (−)-cis-2: 69.0; (+)-cis-2: 66.0; trans-1: 47.3 and
48.8; trans-2: 52.5. The compounds were isolated through
silicagel column chromatography (heptane/ethyle acetate:
80/20).
It is worth noting that hydrolysis of ( )-cis-2 with CCL
as catalyst afforded 12% (c=0.13) of enantiomerically
pure (>99% e.e., GLC) (+)-cis-1 (corresponding to E>
200).11
In summary, both the RGL-catalyzed acylation and
hydrolysis of 2-methylene 5-t-butylcyclohexanols 1 and
their acetates 2, respectively, were diastereoselective.
The cis-compounds were more reactive than the trans
stereoisomers. This allowed us to carry out the reac-
tions onto the more readily available cis–trans mixtures
of racemic 1 or 2 and to isolate either cis or trans
material (alcohol or acetate) in high (>95%) enan-
tiomeric purities.
7. Cross, B.; Whitham, G. H. J. Chem. Soc. 1961, 1650–
1654.
8. (a) Porcine Pancreas lipase, type II, purchased from
Sigma; (b) Prepared according to: Moreau, H.; Gargouri,
Y.; Lecat, D.; Junien, J.-L.; Verger, R. Biochim. Biophys.
Acta 1988, 960, 286–293; (c) Purchased from Sigma; (d)
Novozym SP 435 (immobilized C. antarctica-B lipase)
purchased from Novo Nordisk.
9. (+)-cis-(1S,5S)-2: [h]2D0=+15.4 (c=1, ethanol).
10. To 12 mL of a phosphate buffer (pH 7) was added the
racemic acetate (2 mmol) dissolved in 2 mL diethyl ether,
followed by the enzyme. After being stirred at room
temperature for the required time, the mixture was
extracted with diethyl ether. The extracts were treated
and analyzed as above.
Acknowledgements
This work was financially supported by CMEP (AP-95
MDU 327). The Algerian Ministry of Education and
Scientific Research is gratefully acknowledged. We
thank the Sipsy company for a generous gift of rabbit
gastric lipase.
11. (+)-cis-(1R,5R)-1: [h]2D0=+8.0 (c=1, ethanol).