A biocatalytic approach for regioselective monoacetylation of 3-aryloxy-1,2-propanediols by porcine pancreatic lipase

Article abstract of DOI:10.1007/s00706-011-0688-y

Among the various lipases screened for the regioselective monoacetylation of 3-aryloxy-1,2-propanediols, porcine pancreatic lipase was found to afford a higher yield. The selectivity for the monoacetylation process was maximized by using different organic solvents and diisopropyl ether gave the highest conversion to monoacetylated product (ca. 98%). The optimized reaction afforded excellent yields of the monoacetylated product with regioselectivity at the terminal hydroxyl group in the presence of various aryl substituents in the starting material. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0688-y

Monatsh Chem (2012) 143:951–953
DOI 10.1007/s00706-011-0688-y
ORIGINAL PAPER
A biocatalytic approach for regioselective monoacetylation
of 3-aryloxy-1,2-propanediols by porcine pancreatic lipase
•
Vachan Singh Meena U. C. Banerjee
Received: 11 September 2011 / Accepted: 6 November 2011 / Published online: 29 November 2011
Ó Springer-Verlag 2011
Abstract Among the various lipases screened for the
regioselective monoacetylation of 3-aryloxy-1,2-propane-
diols, porcine pancreatic lipase was found to afford a
higher yield. The selectivity for the monoacetylation pro-
cess was maximized by using different organic solvents
and diisopropyl ether gave the highest conversion to
monoacetylated product (ca. 98%). The optimized reaction
afforded excellent yields of the monoacetylated product
with regioselectivity at the terminal hydroxyl group in
the presence of various aryl substituents in the starting
material.
ethers and many other synthetic sequences [13, 14]. It is
necessary to synthesize these molecules in optically pure
form as chirality governs the major biological interactions.
One of the existing methods employed for obtaining the
optically pure diols is the kinetic resolution of their
monoacetylated derivatives; therefore regioselective mono-
acetylation of diols becomes crucial [15, 16]. The chemical
methods for monoacetylation using active acyl donors and
amine base or complex catalysts suffer from the disad-
vantages of poor regioselectivity, longer reaction time, low
yield, harsh reaction conditions, and formation of side
products [17–20]. Biocatalysis provides an alternative for
the regioselective monoacetylation by lipases which have
additional advantages of their easy availability, simple
workup and handling, low cost, mild reaction conditions,
avoidance of side reactions, and ability to work without
requiring cofactors [21–30]. Regioselective monoacetyla-
tion of 3-aryloxy-1,2-propanediols by porcine pancreatic
lipase has not been reported so far. We tried to develop a
new enzymatic method by screening various lipases for the
regioselective monoacetylation of 3-aryloxy-1,2-propane-
diols that can allow the product formation in a short period
of time with high regioselectivity and yield.
Keywords Lipases Á Monoacetylation Á Regioselectivity Á
3-Aryloxy-1,2-propanediol Á Biocatalysis
Introduction
Optically pure 3-aryloxy-1,2-propanediols are valuable
precursors for the synthesis of important pharmaceuticals
such as centrally acting muscle relaxants [1], antifungal
agents [2], b-blockers [3], drugs for treating arthritis and
osteoporosis [4], and antibacterial agents [5]. Other exten-
sive applications include preservatives in cosmetics and
foods [5], gene therapy [6], optics [7], pigmented ink [8],
polyesters [9], resins [10], dyes [11], and nonspreading
lubricants [12]. 3-Aryloxy-1,2-propanediols are also often
used as intermediates in the synthesis of chiral ligands for
transition metal complexes or building blocks for crown
Results and discussion
Herein we report a regioselective monoacetylation of
3-aryloxy-1,2-propanediol derivatives using porcine pan-
creatic lipase (PPL) that afforded the product in excellent
yield by transesterification from vinyl acetate over a short
period of time. As a model reaction, 3-phenoxy-1,2-pro-
panediol was treated with vinyl acetate in the presence of
Amano ‘‘AY’’ lipase using toluene as the solvent. The
reaction was continued for 8 h and the conversion of the
V. S. Meena Á U. C. Banerjee (&)
Department of Pharmaceutical Technology (Biotechnology),
National Institute of Pharmaceutical Education and Research,
Sector 67, S.A.S. Nagar, Mohali 160062, Punjab, India
e-mail: ucbanerjee@niper.ac.in
123

952
V. S. Meena, U. C. Banerjee
Table 1 Screening of lipase for regioselective monoacetylation
Table 2 Screening of solvents for regioselective monoacetylation
Entry
Lipase
Conversion/%
Entry
Solvent
log P value
Conversion/%
MA
DA
Diol
MA
DA
Diol
1
2
3
4
5
6
7
8
9
Amano ‘‘AY’’
69
59
93
51
92
39
8
31
41
7
0
0
0
0
3
4
0
4
0
1
Dichloromethane
Hexane
0.60
3.50
-0.23
-1.10
-0.33
2.50
4.1
34
90
22
47
28
93
89
98
42
93
33
26
91
31
93
8
9
58
1
Candida rugosa
2
Pancreatic porcine
3
Acetone
23
0
55
53
64
0
Candida cylindracea
Aspergillus niger
49
5
4
1,4-Dioxane
Acetonitrile
Toluene
5
8
Candida antarctica (acrylic resin)
Candida antarctica (CLEA)
Mucor miehei
57
92
13
13
6
7
7
Heptane
10
2
1
83
87
8
Diisopropyl ether
Tetrahydrofuran
Diethyl ether
Pyridine
2.3
0
Pseudomonas cepaceia (sol gel)
9
0.49
–
2
55
6
10
11
12
13
14
15
1
MA monoacetate, DA diacetate
0.65
–
10
0
57
74
1
Isobutyl alcohol
Isooctane
diol to the acetylated products was monitored by HPLC at
different time intervals. The reaction formed both the
mono- and diacetylated products in quantitative yield.
Comparison of the 1H NMR spectra of the monoacetylated
product with those of standard compounds revealed that the
monoacetylation had taken place at the terminal position.
Although the reaction afforded good product yield, lipases
from various sources were also screened for the transe-
sterification as shown in Table 1.
4.5
8
Xylene
3.10
3.20
39
4
30
3
Cyclohexane
MA monoacetate, DA diacetate
As expected, most of the lipases afforded the monoesters
but the best results were obtained with porcine pancreatic
and Aspergillus niger lipase. PPL showed the best activity as
compared with lipases from other sources. Previous findings
are in accordance with this observation. The higher stability
of PPL is attributed to its tight binding of water molecules
that cannot be stripped out even by hydrophilic organic
solvents. These inherent water molecules are essential for
enzyme activity [31]. Recent findings support similar
observations whereby higher conversions have been
achieved in lipase-mediated monoacetylation in organic
solvents [32]. Both the enzymes directed the acetylation to
the terminal hydroxyl group with the formation of the di-
acetylated product in trace amounts. As the solvent plays an
important role in the course of the reaction, various solvents
were screened for the transesterification of the diols with
vinyl acetate using PPL and the results are shown in Table 2.
It is evident from Table 2 that maximum conversion was
obtained with the nonpolar solvents such as toluene,
cyclohexane, isooctane, diethyl ether, but diisopropyl ether
showed the best results with 98% conversion. An increase
in the polarity of the solvent led to a sluggish reaction with
poor yields. Therefore, diisopropyl ether was used as the
solvent for further optimization. Further, we tried to study
the reaction kinetics by taking aliquots from the reaction
mixture over a period of 3 h and the relative ratio of the
diol and the monoacetylated product formed was deter-
mined by HPLC with a C18 column. The time course of
Fig. 1 Course of reaction of regioselective monoacetylation of
3-aryloxy-1,2-propanediols
reaction in Fig. 1 shows that the concentration of mono-
acetate increased gradually and the complete conversion of
the diol to the monoacetylated product was achieved within
3 h.
After optimizing the reaction conditions, we tried to
generalize the reaction with 3-aryloxy-1,2-propanediols
(Scheme 1). It has been observed that the reaction is
compatible with a range of substrates leading to the
monoacetylation at the primary hydroxyl group and the
products were obtained in excellent yield in a short
period of time as shown in Table 3. When the reaction
was continued for a prolonged time, diacetylated prod-
ucts were formed in trace amount as observed in the
HPLC chromatogram.
123

A biocatalytic approach for regioselective monoacetylation
953
Acknowledgments VSM gratefully acknowledges the Department
of Biotechnology, Government of India, New Delhi for providing the
Senior Research Fellowship during the entire period of study.
OH
OH
R
R
O
OH
PPL, vinyl acetate
Diisopropyl ether
O
OAc
1a-1h
2a-2h
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To a round-bottom flask containing 3-aryloxy-1,2-propane-
diols (1 mmol) was added 5 cm3 diisopropyl ether fol-
lowed by the addition of lipase (100 mg) and 200 mm3
vinyl acetate. The reaction mixture was stirred for 3 h at
room temperature. The product was extracted with ethyl
acetate, which was evaporated under reduced pressure to
afford the crude product. The reaction progress was mon-
itored using reversed-phase HPLC.
Quantification of product by HPLC analysis
The amount of product formed and the remaining substrate
was quantified by HPLC (Shimadzu 10AD VP, Kyoto,
Japan) using a Phenomenex C18 column (250 9 4.6 mm,
5 lm, Madrid Ave, USA) at a flow rate of 1 cm3/min with
a solvent system of water/acetonitrile (35:65, v/v). The
absorbance was monitored at 254 nm.
´
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123