Lipase-catalyzed selective benzoylation of 1,2-diols with vinyl benzoate in organic solvents

Article abstract of DOI:10.1016/j.tetasy.2003.07.003

Lipases from Mucor miehei (MML) and Candida antarctica (CAL) are able to catalyze the benzoylation of the primary hydroxy group of 1,2-diols with vinyl benzoate in organic solvents. We have studied the MML-catalyzed benzoylation that proceeds with high re

Full text of DOI:10.1016/j.tetasy.2003.07.003

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3197–3201
Lipase-catalyzed selective benzoylation of 1,2-diols with vinyl
benzoate in organic solvents
Pierangela Ciuffreda, Laura Alessandrini, Giancarlo Terraneo and Enzo Santaniello*
Dipartimento di Scienze Precliniche LITA Vialba-Universita` degli Studi di Milano, Via G. B. Grassi, 74-20157 Milano, Italy
Received 18 June 2003; accepted 24 July 2003
Abstract—Lipases from Mucor miehei (MML) and Candida antarctica (CAL) are able to catalyze the benzoylation of the primary
hydroxy group of 1,2-diols with vinyl benzoate in organic solvents. We have studied the MML-catalyzed benzoylation that
proceeds with high regioselectivity and moderate enantioselectivity, whereas in the dibenzoylation reaction activity of MML and
stereoselectivity of the enzymatic process is strongly influenced by steric factors.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
above premises, we have investigated the enzymatic
benzoylation of 1,2-diols that could be catalyzed by a
suitable lipase in an organic solvent using as acyl
transfer vinyl benzoate (VB), a commercially available
vinyl ester occasionally used for lipase-catalyzed
benzoylations.15–17
Ester synthesis via acyl transfer reactions can be
efficiently catalyzed by lipases in organic solvents and
the application of this biocatalytic approach to organic
synthesis has been extensively reviewed.1–4 One of the
most effective transesterification procedures relies upon
the irreversible reaction originally developed for vinyl
or propenyl esters as acylating reagents,5,6 a method
that has enjoyed widespread application in organic
synthesis.7–9 Vinyl acetate (VA) is by far the enol ester
most used in this reaction, although many reports have
pointed out the influence of the structure of the acyl
donor on the activity and selectivity of the enzyme.10–12
Considering an ester as an alcohol protecting group,
benzoate should be more resistant than acetate and,
therefore, more useful for applications in organic syn-
thesis, especially if applied to polyhydroxylated com-
pounds for which the regio- and enantioselective
control of protection procedures is highly desirable.
Furthermore, a benzoate should be less prone to migra-
tion towards a vicinal hydroxy group, a reaction that
frequently occurs for acetyl moieties,13 specially in the
case of 1,2-diols. It should finally be remembered that,
in general, the selective protection of diols by chemical
methods is often difficult to achieve or requires special
reagents and experimental conditions. For instance, the
selective benzoylation of the primary hydroxy group of
1,2-diols can be obtained only by a few methods,
including microwave heating.14 On the basis of the
2. Results and discussion
2.1. Lipase-catalyzed benzoylation of propane-1,2-diol
1a
We selected propane-1,2-diol 1a as a model substrate to
set up experimental conditions such as, choice of the
most suitable lipase, the proper organic solvent and the
lipase/substrate ratio. We focused on lipases that have
been most widely used for synthetic applications of the
transesterification with VA.18 Microbial lipases from
Pseudomonas cepacia (PCL), Muchor miehei (MML),
Candida antarctica (CAL), Candida cylindracea (or C.
rugosa, CCL) and the porcine pancreas lipase (pPL)
were selected as biocatalysts. It should be remembered
that some lipases are available as partially purified
native proteins (PCL, CCL, pPL) whereas CAL and
MML are also available in an immobilized form. There
are no rules to establish the amount of the enzyme to
be used in organic solvents and, therefore, we used 0.1
g of the enzymatic preparation per millimole of 1a,
independently from the hydrolytic activity of the lipase.
The time limit of the reaction was arbitrarily fixed in 72
h and tert-butyl methyl ether (tBuOMe) was selected as
* Corresponding author. Tel.: +390250319691; fax: +390250319631;
e-mail: enzo.santaniello@unimi.it
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.07.003

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P. Ciuffreda et al. / Tetrahedron: Asymmetry 14 (2003) 3197–3201
the solvent, on the basis of our recent report on the
enzymatic benzoylation to 1,4-diols.19 We have also
established that no benzoylation occurred in the
absence of lipase.
2.2. Lipase-catalyzed benzoylation of 2-hydroxypropyl
benzoate 2a
It should be mentioned that, in general, the lipase-cata-
lyzed monoacetylation of racemic 1,2-diols fails to
provide a stereoselective resolution,24 but this can be
successfully achieved only by converting the diol to the
corresponding diacetate. By this ‘sequential acetyla-
tion’, enantiomerically pure diacetate or unreacted diol
can be finally obtained.25 We considered that, by anal-
ogy with the enzymatic acetylation, the enantioselectiv-
ity of the lipase-catalyzed benzoylation could be
enhanced by converting the racemic monobenzoate 2a
to the dibenzoate 3a (Scheme 2). The dibenzoylation
was slow (62% in 40 h) and proceeded with an E value
of 9.2 that corresponds to an improvement of enan-
tioselectivity if compared to the monobenzoylation of
diol 1a (E 5.3). Application of modified Mosher’s
method and measurement of the optical rotation estab-
lished (S)-configuration for unreacted monobenzoate
2a. Therefore, the stereochemical outcome of the sec-
ond benzoylation was such that starting from (R,S)-
monobenzoate 2a the (R)-enantiomer was converted
into (R)-dibenzoate 3a. Finally, the above obtained E
value 9.2 can be considered just acceptable for asym-
metric synthesis and we decided to study in more detail
the dependence of the enantioselectivity on the nature
of the solvent26 (Table 2).
The results of the enzymatic benzoylation of 1a with all
previously selected lipases are shown in Table 1. CAL
and MML are able to catalyze the regioselective
acylation to the 1-benzoate 2a (Scheme 1) much faster
than other enzymes, MML being the most active bio-
catalyst. The monobenzoate 2a did not show any
propensity to migrate during the purification on silica
gel chromatography and could be stored at room tem-
1
perature with unlimited stability. H NMR analysis of
the ester obtained by reaction of 2a with (S)-a-
methoxy-a-(trifluoromethyl)-phenyl
chloride
[(S)-
MTPACl]20 indicated 61% enantiomeric excess (ee) at
30% conversion of 1a to the monobenzoate 2a that
corresponds to an enantiomeric ratio E of 5.3.21 The
(R)-configuration was assigned to the enzymatically
1
prepared monobenzoate 2a by analysis of the H NMR
data of the (R)- and (S)-MTPA esters of 2a, according
to the modified Mosher’s method.22 In fact, the chemi-
cal shifts of protons at position 1 of (R)-MTPA ester
appear significantly shielded with respect to those of the
(S)-MTPA diastereomer (+42 Hz for proton 1a, +24 Hz
for proton 1b). On the other hand, the chemical shifts
of methyl protons at position 3 appear deshielded in
(R)-MTPA ester relative to (S)-MTPA one (−18 Hz).
Finally, the assignment was confirmed by comparison
of the specific rotation of our sample with the value
reported in the literature.23
Scheme 2.
Table 2. MML-catalyzed benzoylation of monobenzoate
2a in different solvents
Scheme 1.
Solvent
Convn (%)
Time (h)
Eea (%)
E
Table 1. Lipase-catalyzed benzoylation of propane-1,2-diol
Hexane
Toluene
t-BuOMe
CHCl3
THF
61
63
62
17
26
4
29
40
168
168
85
82
88
–
8.7
6.9
9.2
–
1a
Lipasea
Convn (%)
Time (h)
Ee (%)
E
–
–
MML
MML
MML
CAL
CAL
CAL
PCL
100
30
60
100
37
63
52
21
33
1
–
–
61b
70c
–
5.3
5.5
–
4.5
4.6
–
a Determined by 1H NMR analysis of MTPA esters of unreacted
monobenzoate 2a.
0.10
0.25
4.5
1.5
2.1
72
54b
64c
–
–
–
The reaction was faster in apolar solvents such as
hexane or toluene, but no improvement of E could be
achieved. In polar solvents such as CHCl3 or THF the
reaction was considerably slower and the enantioselec-
tivity was not further examined.
CCL
pPL
72
72
–
–
a 100 mg enzyme/mmol substrate.
b Determined by 1H NMR analysis of MTPA esters of monobenzoate
2.3. Mono- and dibenzoylation of 1,2-diols 1b–f
2a.
c Determined by 1H NMR analysis of MTPA esters of unreacted 1a.
We extended the above preliminary observations to a
few additional diols (Scheme 3) that contained aliphatic
1b,c and aromatic residues 1d,e, as well as a double
bond near to the secondary hydroxy group 1f.
The reaction with CAL was also examined, but no
improvement of the enantioselectivity was observed.

P. Ciuffreda et al. / Tetrahedron: Asymmetry 14 (2003) 3197–3201
3199
Table 4. MML-catalyzed benzoylation of monobenzoates
2a–f in t-BuOMe
Substrate
Convn (%)
Time (days)
Eea (%)
E
2a
2b
2c
2d
2e
2f
65
66
60
64
62
64
2
5
5
7
20
2
88
52
38
26
40
50
9.2
2.7
2.3
1.7
2.3
2.8
Scheme 3.
a Determined by 1H NMR analysis of MTPA esters of unreacted
monobenzoate 2a.
For all substrates we examined only the MML-cata-
lyzed benzoylation in t-BuOMe that proceeded to
quantitative conversion in 1–5 h (Table 3).
3. Conclusions
Table 3. MML-catalyzed benzoylation of diols 1b–f in
t-BuOMe
We have shown that, among selected enzymes, CAL
and MML are suitable to carry on the benzoylation of
1,2-diols at a rate that can be compatible with prepara-
tive applications. The enantioselectivity of the
monobenzoylation is appreciable mainly for propane-
1,2-diol 1a and the stereoselection is enhanced by fur-
ther benzoylation only in the case of monobenzoate 2a.
Improved enantioselectivity was not observed for other
substrates 2b–2f. Presumably the steric constrictions
related to the presence of the benzoylated primary
group in the substrate of the enzymatic reaction deter-
mine also long time for conversion (2–20 days). These
limiting factors of the dibenzoylation reaction are
transformed into a clear advantage, if regioselectivity is
considered. In fact, under the selected conditions, the
efficient benzoylation of 1,2-diols catalyzed by CAL
and MML proceeds with an absolute regioselectivity to
the corresponding 1-benzoates. Further studies are
required to investigate in more detail these enzymatic
reactions and to answer to the questions raised by the
results so far obtained in the present research.
Substrate
Convn (%)
Time (h)
Ee (%)
E
1b
1b
1c
1c
1d
1d
1e
1e
1f
100
72
100
70
100
36
100
39
2
0.5
2
0.5
3
0.25
5
1.1
1
0.4
–
–
1.6
–
1.7
–
4.0
–
1.5
–
1.9
31a
–
30a
–
51b
–
15b
–
100
23
1f
27b
a Determined by 1H NMR analysis of MTPA esters of unreacted
diols.
b Determined by 1H NMR analysis of MTPA esters of monoben-
zoates.
Interestingly, the unsaturated diol 1f reacted as fast as
1a, whereas no significant differences could be observed
between diols of different structural frameworks such
as 1b–e. The enzymatic reaction proceeded with com-
plete regioselectivity, but the enantioselectivity was only
modest (E 1.6–4.0). For all monobenzoates 2b–f 1H
NMR analysis allowed the (R)-configuration to be
established. Enzymatic preparation of dibenzoates 3b–f
(Scheme 4) by VB-mediated benzoylation of monoben-
zoates 2b–f proceeded at a slow conversion rate (Table
4). Significantly, only monobenzoate 2f reacted as fast
as 2a suggesting that steric factors may play an impor-
tant role in the dibenzoylation reaction. The significant
enantioselectivity that had been obtained in the conver-
sion of monobenzoate 2a to 3a could not be observed
in all other cases, the E value not exceeding 2.8 and the
stereochemical outcome of the reaction was not
investigated.
4. Experimental
4.1. General
Optical rotations were measured on a Perkin–Elmer
241 polarimeter (sodium D line at 25°C). Melting
points were obtained using a Stuart Scientific SMP3
1
instrument and are uncorrected. H NMR spectra were
recorded on Bruker AM-500 spectrometer operating at
500.13 MHz and are referenced to residual CHCl3
proton of the solvent CDCl3 at 7.24 ppm; coupling
constants (J) are given in hertz. Thin-layer chromatog-
raphy (TLC) was performed using Merck silica gel 60
F254 precoated plates with a fluorescent indicator. Flash
chromatography27 was performed using Merck silica gel
60 (230–400 mesh) using appropriate mixtures of hex-
ane and ethyl acetate as eluants. GLC analyses were
carried out on a SPB-5 Supelco column (30 m×0.32
mm; 0.25 mm ID, film thickness 0.25 mm). (R)-MTPA
derivatives were prepared from the appropriate (S)-
MTPA chlorides. The progress of all reactions, column
chromatography and compound purity were monitored
by TLC, GLC and/or HPLC. All reagents were
obtained from commercial sources and used without
further purification.
Scheme 4.

3200
P. Ciuffreda et al. / Tetrahedron: Asymmetry 14 (2003) 3197–3201
Porcine pancreas lipase (24 U/mg solid) was purchased
from Fluka. Lipase from Pseudomonas sp. (Lipase PS
‘Amano’, 30 U/mg solid) and from Candida cylindracea
(Lipase AYS ‘Amano’, 31.6 U/mg solid) were pur-
chased from Amano Pharmaceutical. Candida antarc-
tica lipase (Novozym 435®, acrylic resin supported
lipase, 11.4 U/mg solid) was a generous gift of Novo
Nordisk Bioindustrial Group. Lipase from Mucor
miehei (Chirazyme® L-9, c.-f., C2, lyo, carrier-fixed
lipase, 8 U/mg solid) was purchased from Roche Diag-
nostics GmbH.
J=3.5, 7.0 and 7.0 Hz, H-2), 1.57–1.50 (2H, m, H-3a,
H-3b), 1.33–1.23 (12H, m, CH2 X 6) and 0.86 (3H, t,
J=7.0 Hz, CH3-6).
4.3.3. 2-Hydroxy-2-phenylethyl benzoate 2d.29 Mp 65–
1
67°C; H NMR l: 8.08 (2H, d, J=7.0 Hz, H-2% and
H-6%), 8.04 (2H, d, J=7.0 Hz, H-2%% and H-6%%), 7.60
(1H, t, J=7.0 Hz, H-4%%), 7.56 (1H, t, J=7.0 Hz, H-4%),
7.46 (2H, dd, J=7.0 and 7.0 Hz, H-3% and H-5%), 7.38
(2H, dd, J=7.0 and 7.0 Hz, H-3%% and H-5%%), 5.12 (1H,
dd, J=3.5 and 8.4 Hz, H-2), 4.52 (1H, dd, J=3.5 and
11.2 Hz, H-1a) and 4.42 (1H, dd, J=8.4 and 11.2 Hz,
H-1b).
Diols 1a–d and 1f were commercially available. Diol 1e
was prepared by lithium aluminum hydride reduction
of methyl phenyllactate.
4.3.4. 2-Hydroxy-2-phenylpropyl benzoate 2e. Colorless
oil, 1H NMR l 8.04 (2H, d, J=7.0 Hz, H-2%% and H-6%%),
7.55 (1H, t, J=7.0 Hz, H-4%%), 7.43 (2H, dd, J=7.0 and
7.0 Hz, H-3%% and H-5%%), 7.31 (2H, dd, J=7.0 and 7.0
Hz, H-3% and H-5%), 7.24 (2H, d, J=7.0 Hz, H-2% and
H-6%), 7.23 (2H, t, J=7.0 Hz, H-4%), 4.41 (1H, dd,
J=3.5 and 11.2 Hz, H-1a), 4.27 (1H, dd, J=7.0 and
11.2 Hz, H-1b), 4.22 (1H, dddd, J=3.5, 5.6, 7.0 and 7.0
Hz, H-2), 2.93 (1H, dd, J=5.6 and 13.3 Hz, H-3a), 2.87
(1H, dd, J=7.0 and 13.3 Hz, H-3b). Found: C, 73.30;
H, 9.44. Calcd for C17H26O3: C, 73.34; H, 9.41%.
4.2. Lipase-mediated benzoylation of propane-1,2-diol
1a
Propane-1,2-diol (76 mg, 1.0 mmol), VB (3.0 mmol)
and lipase (100 mg) were suspended in solvent (10 ml).
The mixture was allowed to react at rt and the progress
of the reaction monitored by TLC and GLC. When the
reaction was complete, the enzyme was filtered off and
washed with MeOH, the solvents were distilled under
vacuum and the product was purified by flash chro-
matography. Elution with hexane/AcOEt (8:2) afforded
pure compound 2a as a colorless oil (173 mg, 96% for
the MML catalyzed reaction at 100% conversion). At
30% conversion, purified (R)-2a was obtained in 28%
yield; [h]2D5 −12.9 (c 1, CHCl3); lit.:23 [h]2D5 +21.8 (c 1,
CHCl3) for enantiomerically pure (S)-2a; 1H NMR
(CDCl3) l 8.04 (2H, d, J=7.0 Hz, H-2% and H-6%), 7.54
(1H, t, J=7.0 Hz, H-4%), 7.41 (2H, dd, J=7.0 and 7.0
Hz, H-3% and H-5%), 4.30 (1H, ddq, J=4.2, 5.6 and 6.3
Hz, H-2), 4.21-4.16 (2H, m, part AB of system ABX,
H-1a and H-1b), 1.27 (3H, d, J=5.6 Hz, CH3).
4.3.5. 2-Hydroxybut-3-en benzoate 2f.30 1H NMR l 8.03
(2H, d, J=7.0 Hz, H-2% and H-6%), 7.56 (1H, t, J=7.0
Hz, H-4%), 7.43 (2H, dd, J=7.0 and 7.0 Hz, H-3% and
H-5%), 5.93 (1H, ddd, J=5.6, 10.5 and 16.8 Hz, H-3),
5.43 (1H, dd, J=1.4 and 16.8 Hz, H-4a), 5.27 (1H, dd,
J=1.4 and 10.5 Hz, H-4b), 4.52 (1H, ddd, J=3.5, 5.6
and 7.0 Hz, H-2), 4.41 (1H, dd, J=3.5 and 11.2 Hz,
H-1a), 4.28 (1H, dd, J=7.0 and 11.2 Hz, H-1b).
4.4. MML catalyzed benzoylation of monobenzoates
2b–f
The reaction was carried out following the same proto-
col of monobenzoylation. The dibenzoates 3a–f showed
spectroscopic data in accord with the structure.
4.3. Lipase-mediated benzoylation of diols 1b–f
The experimental protocol was as described for 1a
using a 100 mg/mmol enzyme/substrate ratio. At 100%
conversion, 96–98% yield of monobenzoates 2b–f were
isolated after flash chromatography using hexane/
Acknowledgements
1
AcOEt (90:10) as eluant. H NMR spectra of isolated
This work has been financially supported by Universita`
degli Studi di Milano (Fondi ex 60%) and the Italian
National Council for Research (CNR, Target Project in
Biotechnology). We thank former graduate students,
Drs. Deborah Bollini and Clara Bianchi, for participa-
tion to early stage of the work.
and purified monobenzoates 2b–f are described in
details.
4.3.1. 2-Hydroxyhexyl benzoate 2b.28 1H NMR l 8.04
(2H, d, J=7.0 Hz, H-2% and H-6%), 7.55 (1H, t, J=7.0
Hz, H-4%), 7.44 (2H, dd, J=7.0 and 7.0 Hz, H-3% and
H-5%), 4.39 (1H, dd, J=3.5 and 11.2 Hz, H-1a), 4.21
(1H, dd, J=7.0 and 11.2 Hz, H-1b), 3.97 (1H, ddt,
J=3.5, 7.0 and 7.0 Hz, H-2), 1.59–1.54 (2H, m, H-3a
and H-3b), 1.39–1.31 (4H, m, CH2-4, CH2-5) and 0.91
(3H, t, J=7.0 Hz, CH3-6).
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