Enzymatic kinetic resolution of pantolactone: Relevance to chiral auxiliary chemistry

Article abstract of DOI:10.1016/S0957-4166(00)00130-0

Racemic pantolactone was converted into either enantiomerically enriched pantolactone acetate or pantolactone acrylate by an enzyme-catalysed kinetic resolution process. Pantolactone is known to be a good auxiliary for acrylate in the Diels-Alder reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00130-0

Tetrahedron: Asymmetry 11 (2000) 1697±1701
Enzymatic kinetic resolution of pantolactone:
relevance to chiral auxiliary chemistry
Louise Haughton, Jonathan M. J. Williams* and Jochen A. Zimmermann
Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
Received 20 March 2000; accepted 31 March 2000
Abstract
Racemic pantolactone was converted into either enantiomerically enriched pantolactone acetate or
pantolactone acrylate by an enzyme-catalysed kinetic resolution process. Pantolactone is known to be a
good auxiliary for acrylate in the Diels±Alder reaction. # 2000 Elsevier Science Ltd. All rights reserved.
The enzyme-catalysed kinetic resolution of substrates by esteri®cation or hydrolysis has found
widespread application in the preparation of enantiomerically enriched building blocks.1 Indeed,
the preparation of chiral auxiliaries using such procedures has been reported. For example,
Whitesell et al. have prepared their auxiliary using enzyme-catalysed kinetic resolution methodology.2
Enantiomerically pure pantolactone has been employed as a chiral auxiliary for acrylate in the
highly diastereoselective Diels±Alder reaction with cyclopentadiene.3 A brief report of the enzymatic
resolution of pantolactone has been published.4 Herein, we report our results on the resolution of
pantolactone by enzyme-catalysed acylation, and the application of this methodology to the
direct preparation of the acrylate derivative.
Treatment of racemic pantolactone 1 with vinyl acetate a€ords the corresponding pantolactone
ester (S)-2 with high enantioselectivity (Scheme 1). The CLEC (cross-linked enzyme crystal)5
version of Candida cylindracea lipase (Altus 20) was found to be the most suitable of the enzymes
screened.6,7
Since the acrylate derivative (S)-3 can be used in subsequent chiral auxiliary-based chemistry,
we wished to prepare this compound directly from the enzyme-catalysed reaction. In order to
achieve this goal, we chose to employ vinyl acrylate as the acyl donor (Scheme 2). This acyl donor
has not been widely employed in kinetic resolutions, although a few reports are available.8 Of the
enzymes screened, only the lipase from Candida cylindracea was e€ective,7 and the reaction was
optimised by variation of the solvent and the acyl donor concentration (Table 1). We again found
that the CLEC enzyme Altus 20 was the most e€ective.
* Corresponding author.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00130-0

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Scheme 1. Conversion of pantolactone into pantolactone acetate
Scheme 2. Enzyme-catalysed pantolactone acrylate formation
Table 1
Variation of solvent and acyl donor concentration
Variations in the temperature between 25ꢀC and 45ꢀC did not show a large e€ect on either the
reaction rate or enantiomeric excess of the product (S)-3, but revealed that above 40ꢀC
polymerisation of the acyl donor was problematic. Nevertheless, an increase in the concentration
of enzyme resulted in an acceleration of the reaction with the consequence that at high enzyme
concentrations and long reaction times the enantiomeric excess of pantolactone acrylate
decreased again (Table 2).

L. Haughton et al. / Tetrahedron: Asymmetry 11 (2000) 1697±1701
1699
Table 2
In¯uence of enzyme concentration on reaction time and enantiomeric excess
The enantiomeric excess of the recovered starting material 1 and pantolactone acrylate 3 were
monitored during the course of a reaction (20% w/w, enzyme to pantolactone) and the data
are plotted in Fig. 1. It can be seen that at 50% conversion (after 8 h) the enantiomeric excess
of both pantolactone 1 and the acrylate 3 were approximately 90% (somewhat lower than for the
corresponding reaction to form the acetate).
Figure 1. Kinetic study of enantiomeric excess versus conversion
Scheme 3. Enzyme-catalysed acyl oxazolidinone formation

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L. Haughton et al. / Tetrahedron: Asymmetry 11 (2000) 1697±1701
The enzyme-catalysed acylation of a racemic Evans auxiliary 4 has also been performed using
Candida antarctica lipase.10 To the best of our knowledge, this is the ®rst example of an enzyme-
catalysed reaction involving an oxazolidinone, although we saw no kinetic resolution during the
reaction (Scheme 3, Table 3). Hydrolysis of the acyl oxazolidinone 5 was also possible using
Candida antarctica lipase in phosphate bu€er:tBuOMe (80:20).
Table 3
Variations in acyl oxazolidinone formation
In summary, pantolactone has been converted into the corresponding acetate in high enantiomeric
excess by an enzyme-catalysed kinetic resolution strategy. Formation of the acrylate, which is
useful in auxiliary controlled reactions, has been achieved using a similar strategy but with
somewhat lower enantioselectivity.
Acknowledgements
We wish to thank the University of Bath and the ERASMUS exchange programme for funding
(to L.H. and J.A.Z., respectively), and Boehringer Mannheim for donating the enzyme (CAL).
References
1. (a) Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1999, 1±21.
2. (a) Whitesell, J. K.; Lawrence, R. M. Chimia 1986, 9, 318±321. (b) Schwartz, A.; Madan, P.; Whitesell, J. K.;
Lawrence, R. M. Org. Synth. 1990, 69, 1±9.
3. Poll, T.; Sobczak, A.; Hartmann, H.; Helmchen, G. Tetrahedron Lett. 1985, 26, 3095±3098.
4. (a) Gamalevich, G. D.; Serebryakov, E. P. Russian Chemical Bulletin 1997, 46, 171±183. (b) Shimizu, S.; Kataoka,
M. Ann. NY Acad. Sci. 1996, 799, 650±658. (c) Bevinakatti, H. S.; Banerji, A. A.; Newadkar, R. V. J. Org. Chem.
1989, 54, 2453±2455.
5. (a) Vilenchik, L. Z.; Grith, J. P.; St. Clair, N. L.; Navia, M. A.; Margolin, A. L. J. Am. Chem. Soc. 1998, 120,
4290±4294. (b) St. Clair, N. L.; Navia, M. A. J. Am. Chem. Soc. 1992, 114, 7314±7316.
6. Altus 20 from Altus Biologics Inc., 40 Allston Street, Cambridge, MA 02139-4211, USA.
7. Using a gammadex column from Supelco, the pantolactone acetate enantiomers were separated at 110ꢀC with
retention times of 16.48 min (R) and 17.57 min (S). Other enzymes examined for the conversion of pantolactone
into pantolactone acrylate include Altus 17 (CRL), lipases from Candida antarctica, Pseudomonas cepecia, and
Pseudomonas ¯uorescens, and hog liver esterase and a-chymotrypsin, but none of these a€orded any signi®cant
conversion.
8. Margolin, A. L.; Fitzpatrick, P. A.; Dubin, P. L.; Klibanov, A. M. J. Am. Chem. Soc. 1991, 113, 4693±4694.
Acrylate esters of oximes have been used in enzyme-catalysed acylation reactions: Athawale, V.; Manjrekar, N.
Synlett 2000, 225±226.

L. Haughton et al. / Tetrahedron: Asymmetry 11 (2000) 1697±1701
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9. (a) (S)-Pantolactone acrylate (S)-3 was separated from pantolactone by column chromatography (MeOH:toluene,
1:9); IR: 996 ꢀmax/cm^1 (CˆC), 1634 (CˆC), 1737 (O±CO±R), 1792 (R±O±CO±R, lactone), 2970/2935/2911/2879
(C±H); 1H NMR: ꢁH (400 MHz, CDCl3) 1.14/1.23 (s, 3H, CH3), 4.06 (d, 1H, J=9.0 Hz, CH2), 4.09 (d, 1H, J=9.0
Hz, CH2), 5.45 (s, 1H, CH), 5.98 (dd, 1H, J=1.2 and 10.5 Hz, CH2ˆ), 6.23 (dd, 1H, J=10.5 and 17.2 Hz, CHˆ),
6.53 (dd, 1H, J=1.2 and 17.2 Hz, CH2ˆ); 13C NMR: ꢁC (100 MHz, CDCl3) 20.2/23.4 (CH3), 40.7 (C), 75.4 (*CH),
76.5 (CH2), 127.2 (CHˆ), 133.0 (CH2ˆ), 164.9 (CO), 172.4 (CˆO); m/z (EI): 55 (100); m/z (isobutane CI): 185
(100), 85 (25), 100 (20). C9H12O4 requires: C, 58.69%; H, 6.57%. Found: C, 58.70%; H, 6.63%. ‰ꢂŠ2D3=+9.5 (c=2,
CHCl3). (b) (R)-Pantolactone acrylate (R)-3 was prepared for comparison purposes: Under nitrogen, acryloyl
chloride (62.5 mmol, 5.65 g, 1.25 equiv.) was added over 1 h to a stirred cold (^24ꢀC) solution of (R)-pantolactone
(50.0 mmol, 6.50 g, 1 equiv.) and triethylamine (75.0 mmol, 7.60 g, 1.5 equiv.) in dry DCM (75 ml) and stirred at
that temperature for 5 h. The organic layer was washed with 1 M HCl, sat. aq. NaHCO3 and H2O, followed by
drying (over MgSO4), evaporation and distillation, bp 88±90ꢀC (0.85±0.90 mmHg), which a€orded a colourless
liquid (37.1 mmol, 6.79 g, 74%). ‰ꢂŠ2D3=^10 (c=2, CHCl3).
10. Candida antarctica lipase (500kU, Chirazyme L-2 c.-f. C2, lyo) from Boehringer Mannheim.