Lipase-catalysed selective monoacylation of 1,n-diols with vinyl acetate

Article abstract of DOI:10.1016/j.tetlet.2004.05.001

A simple enzymatic methodology for the selective monoacetylation of 1,n-diols (n=5,8) using vinyl acetate is reported. Monoacetylation excesses of 81-87% at 74-90% 1,n-diol conversions were obtained in toluene and diisopropyl ether using Thermomyces lanuginosus lipase (TLL) immobilised on polypropylene powder as catalyst.

Full text of DOI:10.1016/j.tetlet.2004.05.001

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5031–5033
Lipase-catalysed selective monoacylation of 1,n-diols with
vinyl acetate
*
ꢀ
Victoria Framis, Francisco Camps and Pere Clapes
Institute for Chemical and Environmental Research of Barcelona-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain
Received 26 January 2004; revised 29 April 2004; accepted 3May 2004
Abstract—A simple enzymatic methodology for the selective monoacetylation of 1,n-diols (n ¼ 5,8) using vinyl acetate is reported.
Monoacetylation excesses of 81–87% at 74–90% 1,n-diol conversions were obtained in toluene and diisopropyl ether using Ther-
momyces lanuginosus lipase (TLL) immobilised on polypropylene powder as catalyst.
Ó 2004 Elsevier Ltd. All rights reserved.
In the course of an ongoing project for the application
of green methodology to the synthesis of insect sex
pheromones, we have sought for alternatives to the
selective monoesterification of polymethylene-1,n-diols,
an important step in the preparation of lepidopteran sex
pheromones.1–4 Chemical and enzymatic methods to
perform this reaction in an efficient way still remains a
current challenge.5–11 Selective chemical monoacylation
can be accomplished by metal sulfates supported on
silica gel12;13 or with acetyl chloride with the diol ad-
sorbed on silica gel.14 The latter methodology providing
both high yields and selectivity. Recently, a new chem-
ical method for monoesterification of diols with aro-
matic and aliphatic acids has been reported,2 in which
the selectivity was accomplished by using Al2O3/
MeSO3H. A simple process based on the selective
enzymatic hydrolysis of diacetates was reported by
Houille et al.15 This approach considers that the
hydrophobic diacetate is bounded to the enzyme tighter
than the monoacetate in aqueous media and, therefore,
the hydrolysis of the former is kinetically favoured.
Monoacetylation of diols in moderate to good yields
was reported using pronase E (i.e., a mixture of prote-
ases from Streptomyces griseus) in anhydrous pyridine
and p-nitrophenyl acetate as acyl donor.16 Ciuffreda
et al.17 have reported that Mucor miehei lipase (MML)
was, among five lipases tested, the most suitable enzyme
for the selective monobenzoylation of 1,4-diols using
vinyl benzoate as acyl transfer reagent in organic media.
Regioselective acetylation and hydrolysis of acyclic ter-
pene-1,n-diols and their diacetates was also accom-
plished using Pseudomonas cepacia lipase.7 However, in
most of the aforementioned methods the longer the
distance between the two alcohol groups the lower the
monoacylation yield obtained. Hence, none of these
methods, gave satisfactory yields for the monoacylation
of medium-long chain polymethylene-1,n-diols with
n > 5.
These previous publications prompted us to screen a
number of commercially available lipases for the selec-
tive monoacetylation of 1,n-diols with n ¼ 5, 6, 7 and 8
methylene groups (Fig. 1) using simple vinyl acetate
(VA) as acylating substrate. Eight lipases were investi-
gated to assess their suitability to carry out the mono-
acetylation reaction (Table 1). First, the screening was
conducted at analytical level with both pentane-1,5-diol
(1a) and octane-1,8-diol (1d). The reactions were carried
out in diisopropyl ether (DIPE) using the lipases
immobilised onto a polypropylene support (Accurel
EP100) as catalysts.18 The progress of mono and
Keywords: Symmetric diols; Lipases; Selective monoacetylation.
* Corresponding author. Tel.: +34-93-400-61-12; fax: +34-93-294-59-
04; e-mail: pcsqbp@iiqab.csic.es
Figure 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.001

5032
V. Framis et al. / Tetrahedron Letters 45 (2004) 5031–5033
Table 1. Lipase-catalysed acetylation of 1,n-diolsa
Entry
Enzymeb
Diol
Immobilised
enzyme (mg)
mec
Reaction
conversion
Reaction
time (min)
1
CAL-B
CAL-B
1a
1d
1a
1d
1a
1d
1a
1d
1a
1b
1c
1d
1a
1d
1a
1d
1a
1d
5
5
52
41
74
70
77
69
78
71
81
85
84
85
75
75
85
79
77
85
79
75
80
62
78
71
73120
70
86
77
77
74
74
72
52
47
32
27
40
40
2
3RML-IM
10
10
15
15
10
10
50
40
30
50
40
40
40
40
10
10
30
90
4
RML-IM
RAL
RAL
ROL
ROL
TLL
5
120
90
6
7
8
120
60
9
10
11
12
13CRL
14
15
16
17
18
TLL
TLL
240
198
120
1440
360
60
TLL
CRL
RNL
RNL
PPL
60
120
60
PPL
a Reactions were performed in 4 mL screw-capped flat bottom vials. To a mixture of the corresponding 1,n-aliphatic diol (0.032 mmol) and
immobilised lipase (5–50 mg) in diisopropyl ether (1 mL), was added vinyl acetate (19.4 lL, 0.032 mmol). The resulting mixture was shaken
reciprocally (125 rpm) at 25 °C. At different reaction times, samples were withdrawn from the reaction mixture, dissolved in hexane and subse-
quently analysed by GLC. The 1,n-diol consumption, mono and diacetate formation were quantified from the peak areas by the external standard
method.
b Candida antarctica (CAL-B) (i.e., Novozymeâ 435), Rhizomucor miehei (RML-IM), Rhizopus arrhizus (RAL), Rhizopus oryzae (ROL), Ther-
momyces lanuginosus (TLL) (i.e., Novozymeâ 871), Candida rugosa (CRL), Rhizopus niveus (RNL) and porcine pancreatic lipase (PPL).
c Monoacetylation excess (me) ¼ %monoacetylated ) %diacetylated/%monoacetylated + %diacetylated.
diacetylated products was monitored by GLC under the
conditions described below. An inspection of the time
evolution of the reactions indicated that the monoacet-
ylation excesses (me) decreased with the 1,n-diol con-
version. Hence, the results summarised in Table 1 were
the optimum considering a convenient balance between
me and substrate conversions. In most cases, the larger
the number of methylene units between the alcohol
groups the lower the me values obtained. CAL-B
showed high activity but low me values (Table 1, entries
1–2). Both, RNL and PPL gave good selectivity but 1,n-
diol conversions were too low for preparative scale
(Table 1, entries 15–18). Rather good results were
achieved with RAL, ROL and CRL (Table 1, entries 5–8
and 13–14) Remarkably, TLL gave both high me and
conversions suitable for the selective monoacetylation of
1,n-diols, with n ¼ 5, 6, 7 and 8, at preparative scale
(Table 1, entries 9–12). The influence of the organic
solvent on the TLL selectivity was also investigated. To
this end, the acetylation reaction was also conducted in
toluene, methyl tert-butyl ether (MTBE), tetrahydrofu-
ran (THF) and diethyleneglycol dimethyl ether (Dig-
lyme). The results, summarised in Table 2, show that the
best me and conversion were achieved in toluene and
DIPE. Interestingly, the lower the hydrophobicity of the
solvent (i.e., log P) the lower the me values. This may be
explained by the different solvation, akin to the partition
coefficient, of the diol and the corresponding mono-
acetate between the organic solvent and the predomi-
nantly aqueous microenvironment of the enzyme.19
To demonstrate the usefulness of the methodology
developed, the monoacetylation of pentane-1,5-diol and
octane-1,8-diol catalysed by TLL was performed at
preparative scale. A typical procedure was as follows: 1a
(2 g, 19.2 mmol) was dissolved in diisopropyl ether
Table 2. TLL-catalysed monoacetylation of pentane-1,5-diol and octane-1,8-diol in different organic solventsa
Solvent
LogPb
Diol 1a
Diol 1d
Immobilised
enzyme (mg)
mec
Conversion
(time, h)
mec
Conversion
(time, h)
d
Toluene
DIPE
2.7380
1.52
0.94
90 (24)
87
86 (1)
77 (2)
84 (4)
10
50
5
81
76
62
64
85
75
74 (2)
78 (2)
MTBE
THF
Diglyme
0.46
)0.36
83(48)
84 (48)
78
68
73(48)
81 (72)
150
50
a Reactions conditions are described in the footnote of Table 1.
b Logarithm of the octanol–water partition coefficient of the solvent; experimental data available from Syracuse Research Corporation
(http://www.syrres.com (main page) and http://esc.syrres.com/interkow/kowdemo.htm to find the specific LogP values).
c Monoacetylation excess.
d 5 mg of immobilised preparation was used.

V. Framis et al. / Tetrahedron Letters 45 (2004) 5031–5033
5033
(300 mL) and immobilised TLL (12 g) was added. To
this solution, was added vinyl acetate (1.79 mL,
19.2 mmol). The mixture was placed in a reciprocal
shaker at 25 °C and the progress of the reaction was
monitored by GLC: capillary column BPX5 (30 m,
0.25 mm internal diameter and 0.25 lm stationary phase
thickness), temperature programme from 50 to 200 °C
over 5 min and then from 200 to 300 °C over 7 min.
When the reaction reached the 80% conversion, the
enzyme was filtered off and washed with diisopropyl
ether. The solvent was evaporated under vacuum and
the residue purified by flash chromatography on silica
gel. Elution was performed with a hexane–ethyl acetate
stepwise gradient from 7:1 to 1:1 in volumes of 400 mL
each. Pure compound 2a was obtained as a colourless oil
(1.94 g 70% yield). 1H NMR spectrum is consistent with
that reported in the literature.313 C NMR (175 MHz,
zymes A/S Bagsvaerd, Denmark as well as Akzo
(Obernburg, Germany) for the polypropylene EP100
~
and Sociedad Espanola de Desarrollos Quımicos S.A.
(Barcelona, Spain) for diols and acetates samples.
ꢀ
References and notes
1. Henrick, C. A. Tetrahedron 1977, 33, 1845–1889.
2. Sharghi, H.; Sarvari, M. H. Tetrahedron 2003, 59, 3627–
3633.
3. Tortajada, A.; Mestres, R.; Iglesias-Arteaga, M. A. Synth.
Commun. 2003, 33, 1809–1814.
4. Babler, J. H.; Coghlan, M. J. Tetrahedron Lett. 1979,
1971–1974.
5. Takasu, M.; Naruse, Y.; Yamamoto, H. Tetrahedron Lett.
1988, 29, 1947–1950.
6. Nishiguchi, T.; Fujisaki, S.; Ishii, Y.; Yano, Y.; Nishida,
A. J. Org. Chem. 1994, 59, 1191–1195.
7. Takabe, K.; Mase, N.; Hisano, T.; Yoda, H. Tetrahedron
Lett. 2003, 44, 3267–3269.
8. Zhu, P. C.; Lin, J.; Pittman, C. U., Jr. J. Org. Chem. 1995,
60, 5729–5731.
9. Leznoff, C. C. Acc. Chem. Res. 1978, 11, 327–333.
10. Bouzide, A.; Sauve, G. Tetrahedron Lett. 1997, 38, 5945–
5948.
11. Bailey, W. F.; Zarcone, L. M. J.; Rivera, A. D. J. Org.
Chem. 1995, 60, 2532–2536.
CDCl3): d 171.3(CO), 64.3(
CH2OCOCH3), 62.2
(CH2OH), 32.0 (CH2CH2OH), 28.2 (CH2CH2OC-
OCH3), 22.1 (CH2CH2CH2CH2CH2), 20.8 (CH3). An
analogous procedure was used for the selective mono-
acetylation of 1d. The elution conditions for the purifi-
cation of 2d were: hexane–ethyl acetate stepwise
gradient from 7:1 to 2:1 in volumes of 400 mL. Pure
1
product was obtained as an oil (1.52 g, 60% yield). H
NMR spectrum is consistent with that reported in the
literature.4 13C NMR (175 MHz, CDCl3): d 171.22 (CO),
64.51 (CH2OCOCH3), 62.80 (CH2OH), 32.58, 29.16,
29.07, 28.45 (CH2CH2CH2OH and CH2CH2CH2OC-
OCH3), 25.70, 25.5 (CH2CH2CH2(CH2)2CH2CH2CH2),
20.90 (CH3).
12. Nishiguchi, T.; Kawamine, K.; Ohtsuka, T. J. Org. Chem.
1992, 57, 312–316.
13. Nishiguchi, T.; Taya, H. J. Am. Chem. Soc. 1989, 111,
9102–9103.
14. Ogawa, H.; Amano, M.; Chihara, T. Chem. Commun.
1998, 495–496.
15. Houille, O.; Schmittberger, T.; Uguen, D. Tetrahedron
Lett. 1996, 37, 625–628.
16. Bhattacharya, A.; Ali, E. Indian J. Chem. Sect. B 1992, 31,
898–899.
Acknowledgements
We gratefully acknowledge CICYT (AGL2001-0585)
and Generalitat de Catalunya (2001SGR 00342) for
financial support. The authors also acknowledge a
generous gift of lipases used in this work from Amano
Pharmaceuticals Co. Ltd (Nagoya, Japan) and Novo-
17. Ciuffreda, P.; Casati, S.; Santaniello, E. Tetrahedron Lett.
2003, 44, 3663–3665.
18. Abad, J. L.; Soldevila, C.; Camps, F.; Clapes, P. J. Org.
Chem. 2003, 68, 5351–5356.
19. Halling, P. J. Enzyme Microb. Technol. 1994, 16, 178–206.