Pseudomonas Cepacia Lipase catalysed synthesis of the chiral methacrylate monomers by kinetic resolution of the secondary alcohols: Effect of the substrate structure on enantioselectivity

Article abstract of DOI:10.1055/s-2000-6493

Optically active methacrylate monomers of secondary alcohols have been synthesised using oxime methacrylate as an acylating agent. The type of solvent used for the reaction had a profound effect on the reaction time and enantioselectivity. Various aryl, cyclic and linear secondary alcohols were screened for their structural effect on enantioselectivity. The nature and position of the substituents in the case of aryl carbinols, had a remarkable effect on the conversion and enantioselectivity, whereas, in the case of linear alcohols, the enantioselectivity was influenced by the increase in the chain length.

Full text of DOI:10.1055/s-2000-6493

LETTER
225
Pseudomonas Cepacia Lipase Catalysed Synthesis of the Chiral Methacrylate
Monomers by Kinetic Resolution of the Secondary Alcohols: Effect of the
Substrate Structure on Enantioselectivity
*
Vilas Athawale, Narendra Manjrekar
Department of Chemistry, University of Mumbai, Vidyanagari, Mumbai- 400 098, India
Fax +91 22 6528547; E-mail: polymerchemistry@yahoo.com
Received 9 December 1999
Abstract: Optically active methacrylate monomers of secondary al-
cohols have been synthesised using oxime methacrylate as an acy-
lating agent. The type of solvent used for the reaction had a
profound effect on the reaction time and enantioselectivity. Various
aryl, cyclic and linear secondary alcohols were screened for their
structural effect on enantioselectivity. The nature and position of
the substituents in the case of aryl carbinols, had a remarkable effect
on the conversion and enantioselectivity, whereas, in the case of lin-
ear alcohols, the enantioselectivity was influenced by the increase
in the chain length.
Key words: chiral methacrylate, enzymatic resolution, oxime
methacrylate, secondary alcohols
Enantiomerically pure secondary alcohols are useful
chiral auxiliaries in the organic synthesis and they are
preferably synthesised by the enzymatic kinetic resolu-
tion. In the presence of a suitable acyl donor, one enanti-
omer of the racemic alcohol is selectively converted into
corresponding ester. The enzymatic process being revers-
ible requires a long reaction time and a large excess of the
esters as acyl donors in order to achieve a reasonable de-
1
gree of conversion. In order to make the process irrevers-
ible, use of various activated esters like trifluoroethyl
2
3
esters, chloroethyl esters, cyanomethyl esters, and acid
4
anhydrides has been reported. However, these methods
have some drawbacks, like the generation of the toxic side
products thereby inhibiting the formation of the required
Scheme
5
product. On the contrary, oxime esters have been shown
6
to act as irreversible acylating agents, wherein the leav-
ing group, an oxime, owing to its low nucleophilicity sup- In order to find out the effect of solvent on the reaction ki-
presses the reversible reaction.
netics and enantioselectivity, the acylation of (±)-1a was
performed in various polar solvents (Table, entries 1-4),
such as diisopropylether (DIPE), chloroform (CHCl ), di-
ethyl ether (Ether) and hexane. It is reported that the sol-
vents with log P values more than two are good solvents,
whereas solvents with log P values less than 2 show detri-
Optically active synthetic polymers are of current interest
because of their chiral recognition properties and their po-
tential applications for asymmetric synthesis and as chiral
stationary phases in HPLC for separation of mixtures of
3
7
enantiomers.
8
mental effects on the enzymes. It can be easily seen that
We report in the present study, the synthesis of the chiral
methacrylate monomers by the enzymatic resolution of
the secondary alcohols with Pseudomonas Cepacia Li-
pase (Amano PS) as a catalyst and 2,3-butanedione mo-
nooxime methacrylate (9) as an acyl donor (Scheme).
the choice of solvent has a profound effect on the reaction
kinetics and to a lesser extent on the enantioselectivity.
The reactions in CHCl and ether with log P values 2.0
3
and 0.85 respectively took a longer time whereas in hex-
ane with log P value 3.5 the reaction was over in a shorter
time. Surprisingly DIPE with log P value 2.0 proved to be
the best solvent of all and was chosen for the other sub-
strates.
To begin with, we examined the resolution of (±) phenyl
ethyl alcohol (1a) with Amano PS lipase and 9 as an acy-
lating donor in diisopropyl ether (DIPE) and correspond-
ing ester was obtained in 89% enantiomeric excess.
Encouraged by these results we extended this approach to
other secondary alcohols (2a-8a). Initially, the aryl
Synlett 2000, No. 2, 225–226 ISSN 0936-5214 © Thieme Stuttgart · New York

2
26
V. Athawale, N. Manjrekar
LETTER
carbinols (2a-5a) were studied to find out the effect of
electron donating as well as electron withdrawing substit-
uents on the ease of esterification and enantiomeric ex-
cess. In all the substrates examined the (R)-enantiomers of
the starting alcohols (±)1a-5a reacted faster giving the
Table 1 Results of the transesterification of (±) 1a-8a and oxime
methacrylate catalysed by Pseudomonas Cepacia Lipase.a
(
R)-methacrylates 1b-5b and the (S)-alcohols, (-)-1a-5a.9
It was observed that 1-(4 - chlorophenyl) ethanol (2a) and
-(4 - bromophenyl) ethanol (3a) reacted faster than 1-
1
phenyl ethanol (1a) whereas 1-(4 - methoxy phenyl) etha-
nol (4a) reacted slower than 1a. 1-(2 - methoxy phenyl)
ethanol (5a) reacted very slowly as compared to 4a. These
results indicated that when the electron withdrawing
groups such as Cl and Br were substituted at the para po-
sition, the activity of the substrate with the enzyme was
more compared to the electron donating group such as -
MeO at the same position. This may be mainly due to the
electronic factor rather than steric factor since the substit-
uents are far away from the chiral centre. However, in
case of 5a, the additional steric effect due to the ortho sub-
stituted - MeO group further lowers the rate of reaction
compared to 4a, as expected.
Enantioselectivity for the cyclic alcohol was tested for
(
±)-1,2,3,4-tetrahydro-1-naphthol (6a) which showed
good E value. Among the linear 2-alkanols, (±)-2-butanol
7a) and (±)-2-octanol (8a), the latter was fast reacting
(
a
Pseudomonas Cepacia (Amano PS) was from Amano, Japan, ha-
and showed a higher E value than the former.
ving activity of ca. 30U/mg. All the reactions were carried out using
0
.5 mol. equivalent of oxime methacrylate and 1.0 mol. equivalent of
In summary, the results obtained from the present study
elucidate the compatibility of various substrates and
oxime methacrylate, an acylating agent, with the enzyme,
Amano PS. The results could be utilised in conceptualis-
ing a model to predict the enantioselection of Amano PS
and redesign the substrate or acylating agent to achieve
optimal enantioselection and reaction rate.
(
±)-1a-5a in 20 mL solvent using 300 mg of lipase Amano PS in a 50
mL screw-cap vial and the suspension was shaken at 30°C and 200
rpm. All the solvents were of analytical grade (Fluka or Merck) and
kept over molecular sieves. (±)-1a-5a prepared by sodium borohydri-
de reduction of the corresponding commercially available ketones by
the standard procedure. (±)-6a & (±)-7a were purchased from Aldrich
and (±)-8a from Fluka.
b
Monitored by GC.
c
The enantiomeric excesses (ee) were determined by chiral HPLC
References and Notes
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5
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(
(
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25
9) (9) IR (film): ν = 1762 cm , 1625 cm ,
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D
1
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3
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2
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5
3
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Article Identifier:
D
5.9 to 6.4 (m, 2H), 5.83 (m, 1H), 2.2 (s, 3H), 1.52 (d, 3H),
1437-2096,E;2000,0,02,0225,0226,ftx,en;L16599ST.pdf
Synlett 2000, No. 2, 225–226 ISSN 0936-5214 © Thieme Stuttgart · New York