Enzymatic synthesis of both enantiomeric forms of 3-allyloxy-propane-1,2- diol

Article abstract of DOI:10.1016/j.tetasy.2012.03.008

The stereoselective synthesis of (S)- and (R)-3-allyloxy-propane-1,2-diol has been accomplished in four steps from (RS)-3-allyloxy-propane-1,2-diol. Only one intermediate, namely 1-benzoyloxy-3-allyloxy-2-propanone has been prepared by a chemical reaction, that is, pyridinium chlorochromate oxidation of 1-benzoyloxy-3-allyloxypropan-2-ol. All of the remaining reactions (regioselective acylations, asymmetric bioreduction of prochiral ketones, and enzymatic alcoholysis) have been carried out in the presence of biocatalysts.

Full text of DOI:10.1016/j.tetasy.2012.03.008

Tetrahedron: Asymmetry 23 (2012) 395–400
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Tetrahedron: Asymmetry
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Enzymatic synthesis of both enantiomeric forms of 3-allyloxy-propane-1,2-diol
Silvana Casati a, Enzo Santaniello b, Pierangela Ciuffreda a,
⇑
a Università degli Studi di Milano, Dipartimento di Scienze Cliniche ‘L. Sacco’, via G.B. Grassi 74, 20157 Milano, Italy
b Università degli Studi di Milano, Dipartimento di Medicina, Chirurgia e Odontoiatria, via A. di Rudinì 8, 20142 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of (S)- and (R)-3-allyloxy-propane-1,2-diol has been accomplished in four
steps from (RS)-3-allyloxy-propane-1,2-diol. Only one intermediate, namely 1-benzoyloxy-3-allyloxy-
2-propanone has been prepared by a chemical reaction, that is, pyridinium chlorochromate oxidation
of 1-benzoyloxy-3-allyloxypropan-2-ol. All of the remaining reactions (regioselective acylations, asym-
metric bioreduction of prochiral ketones, and enzymatic alcoholysis) have been carried out in the pres-
ence of biocatalysts.
Received 15 February 2012
Accepted 13 March 2012
Available online 5 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
transfer reagents. We have applied both reagents to the biocata-
lytic asymmetric synthesis of chiral glycerol intermediates10 as
Glycerol derivatives are common building blocks for a number
of chiral natural and synthetic products.1 A general chemical ap-
proach to these requires selective blocking of a primary hydroxyl
group in the 1,2-diol system and further manipulation, including
protection–deprotection steps. This process is not always totally
selective and proceeds in variable yield.2,3 Recently, the use of en-
zymes has been reported for the preparation of chiral glycerol
derivatives.4
Herein we report a novel and simple chemo-enzymatic ap-
proach for the preparation of both (S)- and (R)-3-allyloxy-pro-
pane-1,2-diol [(S)-1 and (R)-1], a glycerol derivative that has
been used as an intermediate for further elaboration to more com-
plex chiral molecules such as an analogue of the platelet-activating
factor (PAF)5 or plasmenylcholine.6
The usefulness of allyl ethers in asymmetric organic synthesis is
well established; therefore the 3-allyl ether moiety in compound 1
makes this glycerol derivative particularly attractive, due to the
stability of the allyl group during further synthetic manipulations
and to the increasing number of methods available for the removal
of this protecting group.7
well as to enzymatic benzoylation and debenzoylation.11,12
Specifically, microbial lipases from Pseudomonas cepacia (PCL),
Muchor miehei (MML), and Candida antarctica (CAL-B) were se-
lected as biocatalysts. tert-Butyl methyl ether (tBuOMe) was se-
lected as a sole solvent, due to its frequent use in several
synthetic applications involving lipases.
The transesterifications were carried out using a millimole of
commercially available diol 1, and stopped at <50% conversion to
monoacetate 2 or monobenzoate 3. In all cases products with mod-
erate enantiomeric excess (ee, maximum 57% and 60% respectively
for acetate 2 and benzoate 3) were formed (Scheme 1 and Table 1).
As a general comment, with VA a fast esterification (0.15–1.5 h
for 32–37% conversion to the monoacetate 2) was observed. The
rate of the enzymatic benzoylation with VB depends on the lipase
and MML catalyzed the fastest reaction (0.5 h for 40% conversion to
the monobenzoate 3).
The (S)-configuration was assigned to the products of the enzy-
matic acylation, by preparing the corresponding Mosher esters
with (R) or (S)-a-methoxy-a-trifluoromethylphenylacetic acid
according to a well established protocol.13
For (S)-monoacetates 2 the ee (38–57%) of the enzymatic proce-
dure was established by recording and analyzing the 1H NMR spec-
tra of the MTPA esters of each enzymatic preparation. In the case of
the (S)-monobenzoates 3 the ee (54–60%) was established by GC
using a chiral column.
2. Results and discussion
2.1. Lipase-catalyzed acylation of 3-allyloxy-propane-1,2-diol 1
The ee of the above procedure could be eventually improved
using different experimental conditions, testing other lipases or
applying other resolution conditions reported for the enzymatic
transesterification of 1,2-diol systems.14 However, this approach
is time consuming and so we preferred to investigate another
chemo-enzymatic approach for the preparation of both enantio-
meric forms of 3-allyloxy-propane-1,2-diol, (S)-1 and (R)-1.
In order to obtain both the enantiomeric forms of 3-allyloxy-
propane-1,2-diol, (S)-1 and (R)-1, we tested a few lipases with well
recognized stereoselective transesterification activity in organic
solvents using vinyl acetate (VA)8 or vinyl benzoate (VB)9 as acyl
⇑
Corresponding author.
E-mail address: pierangela.ciuffreda@unimi.it (P. Ciuffreda).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.008

396
S. Casati et al. / Tetrahedron: Asymmetry 23 (2012) 395–400
OH
O
O
CH3
VA, tBuOMe
max ee 57%
(S)-2
O
lipase
OH
O
OH
(RS)-1
OH
O
O
VB, tBuOMe
max ee 60%
(S)-3
O
lipase
Scheme 1. Enzymatic resolution of (RS)-3-allyl-propane-1,2-diol 1 to (S)-acetate 2 or (S)-benzoate 3.
Table 1
OH
OH
Lipase-catalyzed acetylation and benzoylation of 3-allyloxy-propane-1,2-diol 1 in
tBuOMe
O
OH
O
O
VB, tBuOMe
Acylating agenta
Conversion (%)
Time (h)
Productb
eec
3
(RS)-1
Enzyme
MML
O
PCL
VA
VA
VA
VB
VB
VB
37
36
32
39
40
36
1.5
0.15
0.15
24
0.5
2.3
S-2
S-2
S-2
S-3
S-3
S-3
40d
57d
38d
56e
60e
54e
MML
CAL
PCL
MML
CAL
PCC
CH2Cl2
O
O
octan-1-ol
DIPE
O
O
O
OH
a
b
c
3 equiv.
Configuration determined from 1H NMR spectrum of the MTPA ester.
Determined for the product.
4
5
MML
O
d
e
% ee were determined from 1H NMR spectrum of the MTPA ester.
% ee were calculated using GC chiral column.
Scheme 3. Chemo-enzymatic synthesis of 3-allyloxy-1-hydroxypropan-2-one 4.
2.2. Fermenting baker’s yeast bioreduction of hydroxyketone 4
and its esters
The ketone 5 was obtained from its hydroxy precursor 3 by oxida-
tion with PCC (64% yield).
A smooth debenzoylation of ketone 5 to the required hydroxyk-
etone 4 was achieved enzymatically with MML in diisopropyl ether
(DIPE), using octan-1-ol as the acceptor of the benzoyl group.12
The bioreduction of 3-allyloxy-1-hydroxypropan-2-one 4 gave
the corresponding alcohol (R)-1 in 2.0 h in high yields (68%). How-
ever, the enantioselectivity of the bioreduction was not satisfactory
(75% ee), and this could be tentatively explained by considering
that baker’s yeast has a plurality of reducing enzymes.18 Thus,
we cannot exclude that an oxidoreductase with opposite stereose-
lectivity is present in the reducing medium. Another possible
explanation for the observed, non-complete enantioselectivity
could rely on a partial tautomerization of the hydroxyketone 4 to
the corresponding (RS)-hydroxyaldehyde and reduction of this
compound to (RS)-1.19
We considered the asymmetric bioreduction of a suitable
hydroxyketone (or that of the corresponding esters) since the bio-
reduction of carbonyl compounds has been investigated exten-
sively due to its high stereoselectivity, mild reaction conditions
and environmental compatibility.15 The most commonly used bio-
catalyst in asymmetric reduction is baker’s yeast. This microorgan-
ism is commercially available, easy to handle, and able to be used
in the asymmetric reduction of a wide range of carbonyl function-
alities.16 The bioreduction of hydroxyketones and related esters
has also been applied in the preparation of optically active 1,2-
diols or to chiral mono-protected glycerol.17
For the preparation of one enantiomer of 3-allyloxy-propane-
1,2-diol 1 by baker’s yeast bioreduction, the hydroxyketone 4
was required (Scheme 2).
In order to investigate the preparation of (S)-1, we relied on the
observation that, by altering the size of the substituents on the
keto group, a reverse enantioselectivity of baker’s yeast reduction
can be observed. This has also been broadened to ketoesters18 or
hydroxyketones.20
OH
O
fermenting
O
OH
O
OH
baker's yeast
1
We therefore decided to submit the previously prepared 1-ben-
zoyloxyderivative 5 to the baker’s yeast bioreduction. The corre-
sponding alcohol (R)-321 was obtained in 3.5 h in good yields
(78%), but the reduction proceeded with only moderate selectivity
(44%).
4
Scheme 2. Baker’s yeast-mediated bioreduction of 3-allyloxy-1-hydroxypropan-2-
one 4.
The acetate of the hydroxyketone 4 was quantitatively prepared
by a lipase mediated acetylation of 5 using MML and VA in
tBuOMe. The acetoxy derivative 6 proved to be a better substrate
for the asymmetric reduction with baker’s yeast than the
benzoyloxy derivative 5 or the hydroxyketone 4. In fact, when 1-
acetoxy-3-allyloxypropan-2-one 6 was submitted to an asymmet-
ric reduction with baker’s yeast, the corresponding alcohol (R)-2
was obtained in 3.5 h in high yields (76%) and high ee (>98%)
(Scheme 4).
The hydroxyketone 4 was prepared by a chemo-enzymatic ap-
proach as shown in Scheme 3. Thus, the starting diol (RS)-3-allyl-
oxy-propane-1,2-diol (RS)-1 was converted into the stable
monobenzoate 3 by an enzymatic regioselective monobenzoyla-
tion in the presence of lipase from Muchor miehei (MML) in
tBuOMe using VB as an acyl transfer agent.9 The reaction
proceeded smoothly at room temperature to provide exclusively
1-benzoyloxy-3-allyloxypropan-2-ol 3 with greater than 95% yield.

S. Casati et al. / Tetrahedron: Asymmetry 23 (2012) 395–400
397
OH
O
O
O
O
O
BY, H2O
EtOH
(R)-3
O
O
5
O
OH
O
O
OH
BY, H2O
EtOH
O
O
CH3
VA, tBuOMe
O
O
CH3
4
MML
6
(R)-2
O
O
Scheme 4. Baker’s yeast mediated reduction of 1-benzoyloxy-3-allyloxypropan-2-one 5 and 1-acetoxy-3-allyloxypropan-2-one 6.
In conclusion, the reduction of the hydroxyketone 4 affords di-
rectly the (R)-diol 1 (75% ee). The enantiomeric (S)-3-allyloxy-pro-
pane-1,2-diol 1 can be prepared by MML-catalyzed deacylation of
on the hydroxyketone 4 (75% ee). Moreover, (R)-3-allyloxy-
propane-1,2-diol (R)-1 (maximum 60%) has been obtained by the
alcoholysis of the (S)-acetate 2 and (S)-benzoate 3 by the MML-
catalyzed acylation of (RS)-1.
(R)-1-benzoyloxy-3-allyloxypropan-2-ol
3 and (R)-1-acetoxy-3-
allyloxy-propan-2-ol
Scheme 5).
2
(44 and >99% ee, respectively; see
Finally, it is noteworthy that the only chemical step in the
whole synthetic approach corresponds to the PCC oxidation of 1-
benzoyloxy-3-allyloxypropan-2-ol 3 to 1-benzoyloxy-3-allyloxy-
propan-2-one 5. A few attempts to carry out the oxidation step
enzymatically using commercial NAD(P)+-dependent oxidoreduc-
tases22 have been, at present, unsuccessful.
O
OH
O
OH
O
OH
(R)-1 (75% ee)
OH
BY, H2O/EtOH
4
4. Experimental
OH
MML, DIPE
O
O
O
O
O
OH
4.1. General
1-octanol
O
O
(R)-3
(S)-1 (44% ee)
1H and 13C NMR spectra were recorded at 298 K in the indicated
OH
deuterated solvents on
a Bruker AVANCE 500 spectrometer
OH
O
CH3
equipped with a 5 mm broadband reverse probe with field z-gradi-
ent operating at 500.13 MHz for 1H and 125.76 MHz for 13C. Chem-
ical shifts (d) are given as parts per million relative to the residual
solvent peak and coupling constants (J) are in Hertz. The splitting
pattern abbreviations are as follows: s, singlet; d, doublet; t, trip-
let; q, quartet; m, multiplet, and bs, broad peak. Column chroma-
tography was performed on Silica Gel 60 (70–230 mesh) using
the specified eluents. Optical rotations were measured on a Per-
kin-Elmer 241 polarimeter (sodium D line at 25 °C). Melting points
were determined with a Stuart Scientific SMP3 melting point appa-
ratus and are uncorrected.
The progress of the reactions was monitored by analytical thin-
layer chromatography (TLC) on pre-coated glass plates (silica gel
60 F254-plate-Merck, Darmstadt, Germany) and the products were
visualized by UV light.
Purity of all compounds (P99%) was verified by thin layer chro-
matography and NMR measurements. The enantiomeric purity of
alcohols (S)-1 and (R)-1 was determined by 1H NMR analysis of
their Mosher’s ester prepared as previously described.10
The enantiomeric excess (ee) of the enantiomerically enriched
monobenzoate 3 was determined by a HP 6890 series split/less
GC, equipped with chiral column, HP chiral 20% permethylated
MML, DIPE
1-octanol
OH
(R)-2
(S)-1 (> 99% ee)
Scheme 5. Enzymatic synthesis of enantiomerically enriched (R)-1 and (S)-1.
In order to assign unequivocally the configuration of the C(2)-
secondary alcohol of glycerol derivatives (compounds 1–3) ob-
tained by the asymmetric bioreduction of prochiral ketones 4, 5,
and 6, we applied the modified Mosher’s method13 to the products
of the baker’s yeast reduction. Treatment of compounds 1, 2, and 3
with (R)- and (S)-a-methoxy-a-trifluoromethylphenyl acetic acid
(MTPA) in the presence of N,N0-dicyclohexylcarbodiimide (DCC),
4-dimethylaminopyridine in dichloromethane afforded the corre-
sponding (R)- and (S)-MTPA esters.10
The
NMR spectra at 500 MHz, are shown in Table 2. All protons of
the allyl moiety have d >0 values while the C(1)-methylene pro-
tons and acyl group (in Table 2 depicted with R) have a d <0 val-
D
d (dS–dR) values, expressed in Hertz, obtained from 1H
D
D
ues. According to the model adopted to determine the absolute
configuration of secondary alcohols,13 we conclude that the config-
uration of the alcohol in all cases is (R). This result confirmed the
original configurational assignment that was based on chemical
correlations by alcoholysis to the corresponding alcohol 1 and
the measurement of its specific rotation.
B-cyclodextrin (30 m ꢀ 0.32 mm ꢀ 0.25
lm), and FID detector.
The following conditions were used for the chiral separation: injec-
tor 200 °C, detector 200 °C, carrier gas nitrogen, column flow:
1.00 ml/min, maximum temperature 220 °C, and temperature pro-
gram: start 180 °C, hold time 3 min, rate 50 °C/min to 200 °C hold
time 15.00 min. Retention times of (R)- and (S)-3 were found to be
16.8 and 16.3 min.
3. Conclusion
In conclusion, a selective and facile strategy to prepare both (S)-
and (R)- 3-allyloxy-propane-1,2-diol has been developed. The most
satisfactory result, in terms of enantioselectivity, was obtained by
the baker’s yeast bioreduction of 1-acetoxy-3-allyloxypropan-2-
one 6 from which enantiomerically pure (S)-1 could be prepared.
Compound (R)-1 can be prepared by two different biocatalytical
approaches, that is, enzymatic transesterification of the racemic
diol 1 (maximum 60% ee) or the fermentation route carried out
Elemental analyses were obtained for all intermediates and are
within 0.4% of theoretical values.
The chemicals and solvents, including diol 1, were obtained
from Sigma–Aldrich and used without further purification.
Lipase from Pseudomonas sp. (Lipase PS ‘Amano’, 30 U/mg solid)
was purchased from Amano Pharmaceutical. Candida antarctica
lipase (Novozym 435Ò, acrylic resin supported lipase, 11.4 U/mg

398
S. Casati et al. / Tetrahedron: Asymmetry 23 (2012) 395–400
Table 2
D
d = dS–dR values, expressed in Hertza of the (S)-MTPA and (R)-MTPA esters
Substrate
H-1a
H-1b
R
H-3
CH2CH@CH2
CH@CHH
CH@CHH
CH@CHH
(R)-1
(R)-2
(R)-3
ꢂ60
ꢂ10
ꢂ45
ꢂ30
ꢂ50
ꢂ35
—
+45
+45
+35
+40
+45
+40
+25
+35
+30
+15
+30
+30
+10
+25
+20
ꢂ10
ꢂ5;ꢂ10;ꢂ20
a
Obtained from 1H NMR spectrum at 500 MHz.
solid) was purchased from Novo Nordisk Bioindustrial Group. Li-
pase from Muchor miehei (ChirazymeÒ L-9,c.-f., C2, lyo, carrier-
fixed lipase, 8 U/mg solid) was purchased from Roche Diagnostics
GmbH. Baker’s yeast by Saccharomyces cerevisiae was purchased
from a local store. There are no rules to define the amount of the
enzyme to be used in organic solvents and, therefore, we decided
to rely upon the hydrolytic activity of the lipases expressed as
units.
pad. Evaporation of the solvent and purification on column chro-
matography (petroleum ether/ethyl acetate 8:2) gave 5. Yield:
840 mg, 64% of viscous liquid. Rf (20% ethyl acetate/petroleum
ether) 0.58; 1H NMR (CDCl3)
d
4.11 (2H, d, J = 5.6 Hz,
OCH2CH@CH2), 4.22 (2H, s, 3-CH2), 5.14 (2H, s, 1-CH2), 5.27 (1H,
dd, J = 1.4, 10.0 Hz, (Z)-CH@CHH), 5.34 (1H, dd, J = 1.4, 17.3 Hz,
(E)-CH@CHH), 5.99 (1H, ddt J = 5.6, 10.0, 17.3 Hz, CH@CH2), 7.47
(2H, dd, J = 7.0, 7.0 Hz, m-Ph H), 7.60 (1H, t, J = 7.0, p-Ph H), 8.10
(2H, d, J = 7.0, o-Ph H); 13C NMR d, 67.3 (1-C), 72.6 (OCH2CH@CH2),
73.8 (3-C), 118.3 (CH@CH2), 128.4 (m-PhCH), 129.2 (PhC), 129.9 (o-
PhCH), 133.4 (p-PhCH), 133.5 (CH@CH2), 165.9 (OCOPh), 202.0
(CO). Anal. Calcd for C13H14O4 (234.09): C, 66.66; H, 6.02. Found:
C, 66.79; H, 6.14.
4.2. General procedure for lipase-mediated benzoylation and
acetylation of 3-allyloxy-propane-1,2-diol 1
Substrates (1.0 mmol), VA or VB, (3.0 mmol) and lipase (PCL
80 mg; MML 100 mg; CAL 200 mg) were suspended in 10.0 ml of
tBuOMe. The mixture was stirred at rt and the formation of the
acetylated or benzoylated compounds was monitored by GC
analysis. The reaction was stopped at the reported conversion
(see Table 1) by filtration of the enzyme and evaporation of the sol-
vent at reduced pressure. The residue was then purified by chro-
matography. For time, see Table 1.
4.4. 1-Acetoxy-3-allyloxypropan-2-one 6
Compound 4 (130 mg, 1.0 mmol), vinyl acetate (3.0 mmol), and
MML (100 mg) were suspended in 10.0 ml of tBuOMe. The mixture
was stirred at rt for 4 h until GC analysis showed up to 100% con-
version. The mixture was filtered and evaporated at reduced pres-
sure. Yield 169 mg (98%) of viscous liquid. Rf (20% ethyl acetate/
petroleum ether) 0.42; 1H NMR (CDCl3) d 2.16 (3H, s, COCH3),
4.06 (2H, d, J = 5.6 Hz, OCH2CH@CH2), 4.13 (2H, s, 3-CH2), 4.89
(2H, s, 1-CH2), 5.25 (1H, dd, J = 1.4, 10.0 Hz, (Z)-CH@CHH), 5.35
(1H, dd, J = 1.4, 17.3 Hz, (E)-CH@CHH), 5.89 (1H, ddt J = 5.6, 10.0,
4.2.1. (S)-1-Acetoxy-3-allyloxy-propan-2-ol 223
According to the general procedure, compound 2 was prepared
from (RS)-3-allyloxy-propane-1,2-diol 1 and purified by column
chromatography (petroleum ether/ethyl acetate 7:3). Viscous li-
quid; Rf (40% ethyl acetate/petroleum ether) 0.40; 1H NMR (CDCl3)
d 2.10 (3H, s, COCH3), 3.46 (1H, dd, J = 6.2, 9.7 Hz, 3-CHHO), 3.53
(1H, dd, J = 4.2, 9.7 Hz, 3-CHHO), 4.00–4.05 (3H, m, 2-CHOH and
OCH2CH@CH2), 4.12 (1H, dd, J = 6.2, 11.8 Hz, 3-CHHO), 4.18 (1H,
dd, J = 4.9, 11.8 Hz, 3-CHHO), 5.20 (1H, dd, J = 2.0, 10.4 Hz, (Z)-
CH@CHH), 5.28 (1H, dd, J = 2.0, 17.3 Hz, (E)-CH@CHH), 5.91 (1H,
ddt J = 7.2, 10.4, 17.3 Hz, CH@CH2); 13C NMR d 20.4 (CH3), 65.6
(1-C), 68.8 (2-C), 70.9 (3-C), 72.4 (OCH2CH@CH2), 117.5 (CH@CH2),
134.3 (CH@CH2), 171.2 (CO).
17.3 Hz, CH@CH2); 13C NMR
d 20.5 (CH3), 67.0 (1-C), 72.5
(OCH2CH@CH2), 73.7 (3-C), 118.4 (CH@CH2), 133.4 (CH@CH2),
170.5 (OCOCH3), 202.2 (CO). Anal. Calcd for C8H12O4 (172.18): C,
55.81; H, 7.02. Found: C, 55.89; H, 7.14.
4.5. General procedure for the microbial reduction
A suspension of baker’s yeast (20 g) and sucrose (20 g) in water
(100 ml) was preincubated at 38 °C for 20 min. Thereafter, a solu-
tion of the ketone (1.5 mmol) in EtOH (2 ml) was added and the
resulting mixture was stirred magnetically at 38 °C for 2 h, until
GC analysis showed up 95% conversion. The mixture was filtered
on a Celite pad and extracted with ethyl acetate (3 ꢀ 30 ml). The
solvent was removed under reduced pressure and the residue
was purified by column chromatography to afford the desired alco-
hol which was recovered as an oil.
4.2.2. 1-Benzoyloxy-3-allyloxypropan-2-ol 324
According to the general procedure, compound 3 was prepared
from (RS)-3-allyloxy-propane-1,2-diol 1 and purified by column
chromatography (petroleum ether/ethyl acetate 8:2). Viscous li-
quid; Rf (20% ethyl acetate/petroleum ether) 0.31; 1H NMR (CDCl3)
d 3.56 (1H, dd, J = 5.5, 9.7 Hz, 3-CHHO), 3.62 (1H, dd, J = 6.2, 9.7 Hz,
3-CHHO), 4.05 (2H, d, J = 5.6 Hz, OCH2CH@CH2), 4.18 (1H, dddd,
J = 4.8, 5.5, 6.2, 7.6 Hz, 2-CHOH), 4.38–4.45 (2H, m, part AB of
ABX system, 1-CH2O), 5.20 (1H, dd, J = 2.0, 10.4 Hz, (Z)-CH@CHH),
5.29 (1H, dd, J = 2.0, 17.3 Hz, (E)-CH@CHH), 5.90 (1H, ddt J = 7.2,
10.4, 17.3 Hz, CH@CH2), 7.43 (2H, dd, J = 7.0, 7.0 Hz, m-Ph H),
7.55 (1H, t, J = 7.0, p-Ph H), 8.05 (2H, d, J = 7.0, o-Ph H); 13C NMR
d, 66.0 (1-C), 68.9 (2-C), 71.0 (3-C), 72.4 (OCH2CH@CH2), 117.5
(CH@CH2), 128.4 (m-PhCH), 129.7 (o-PhCH), 129.9 (PhC), 133.1
(p-PhCH), 134.3 (CH@CH2), 166.6 (CO).
4.5.1. (R)-1-Benzoyloxy-3-allyloxypropan-2-ol (R)-35
(R)-3 was prepared from 1-benzoyloxy-3-allyloxypropan-2-one
5 (350 mg, 1.5 mmol), purified by column chromatography (petro-
leum ether/ethyl acetate 8:2) to yield 276 mg (78%); ½a D20
¼ ꢂ1:3 (c
ꢁ
1, CHCl3), 44% ee. Rf (20% ethyl acetate/ petroleum ether) 0.31.
4.5.2. (R)-3-Allyloxypropane-1,2-diol (R)-125
Compound (R)-1 was prepared from 3-allyloxy-1-hydroxypro-
pan-2-one 4 (195 mg, 1.5 mmol), purified by column chromatogra-
phy (petroleum ether/ethyl acetate 7:3) to yield 135 mg (68%);
4.3. 1-Benzoyloxy-3-allyloxypropan-2-one 5
viscous liquid. ½a D20
ꢁ
¼ þ5:5 (c 1, CHCl3), 75% ee {lit.25
½
a 2D5
ꢁ
¼ þ7:5
PCC (5.0 g; 24 mmol) was added to a solution of 3 (1.32 g,
5.6 mmol) in dichloromethane (20 ml). The mixture was
stirred at room temperature for 24 h, then filtered on a Celite
(c 0.11)}. Rf (40% ethyl acetate/petroleum ether) 0.12; 1H NMR
(CDCl3) d 3.43 (1H, dd, J = 5.5, 9.7 Hz, 3-CHHO), 3.47 (1H, dd,
J = 4.2, 9.7 Hz, 3-CHHO), 3.54 (1H, dd, J = 6.2, 11.8 Hz, 1-CHHO),

S. Casati et al. / Tetrahedron: Asymmetry 23 (2012) 395–400
399
3.62 (1H, dd, J = 3.5, 11.8 Hz, 3-CHHO), 3.81 (1H, dddd, J = 3.5, 4.2,
5.5, 6.2, Hz, 2-CHOH), 3.98 (2H, d, J = 6.2 Hz, OCH2CH@CH2), 5.16
(1H, dd, J = 2.0, 10.4 Hz, (Z)-CH@CHH), 5.24 (1H, dd, J = 2.0,
17.3 Hz, (E)-CH@CHH), 5.86 (1H, ddt J = 6.2, 10.4, 17.3 Hz,
CH@CH2); 13C NMR d, 63.7 (1-C), 70.9 (2-C), 71.5 (3-C), 72.3
(OCH2CH@CH2), 117.4 (CH@CH2), 134.2 (CH@CH2).
4.6.5. (R)-MTPA ester of 1-acetoxy-3-allyloxypropan-2-ol 2
Colorless oil; 1H NMR (CDCl3) representative signals d 2.07 (3H,
s, CH3), 3.57–3.60 (2H, m, part AB of ABX system, 3-CH2O),
3.90–3.97 (2H, m, part AB of ABX system, OCH2CH@CH2), 4.22
(1H, dd, J = 6.9, 12.4 Hz, 1-CHHO), 4.47 (1H, dd, J = 3.5, 12.4 Hz, 1-
CHHO), 5.18 (1H, dd, J = 1.4, 10.4 Hz, (Z)-CH@CHH), 5.23 (1H, dd,
J = 1.4, 17.4 Hz, (E)-CH@CHH), 5.50–5.54 (1H, m, 2-CH), 5.81 (1H,
ddt J = 5.6, 10.4, 17.4 Hz, CH@CH2).
4.5.3. (R)-1-Acetoxy-3-allyloxy-propan-2-ol (R)-223
(R)-2 was prepared from 1-acetoxy-3-allyloxypropan-2-one 6
(258 mg, 1.5 mmol), purified by column chromatography (petro-
leum ether/ethyl acetate 7:3) yield 198 mg (76%); viscous liquid.
4.6.6. (S)-MTPA ester of 1-acetoxy-3-allyloxypropan-2-ol 2
Colorless oil; 1H NMR (CDCl3) representative signals d 2.01 (3H,
s, CH3), 3.65–3.70 (2H, m, part AB of ABX system, 3-CH2O),
3.99–4.07 (2H, m, part AB of ABX system, OCH2CH@CH2), 4.16
(1H, dd, J = 6.9, 12.4 Hz, 1-CHHO), 4.37 (1H, dd, J = 3.5, 12.4 Hz, 1-
CHHO), 5.23 (1H, dd, J = 1.4, 10.4 Hz, (Z)-CH@CHH), 5.29 (1H, dd,
J = 1.4, 17.4 Hz, (E)-CH@CHH), 5.50–5.54 (1H, m, 2-CH), 5.88 (1H,
ddt J = 5.6, 10.4, 17.4 Hz, CH@CH2).
½
a 2D0
ꢁ
¼ þ1:4 (c 1, CHCl3), >98% ee.
4.6. General procedure for lipase-mediated alcoholysis
To a solution of benzoate or acetate (1.0 mmol) in DIPE
(10.0 ml) containing octan-1-ol (2.5 mmol) MML (200 mg) was
added. The suspension was stirred vigorously at room temperature
and the progress of the reaction monitored until a TLC analysis
(petroleum ether/ethyl acetate 80:20) showed up 100% conversion.
After 20 h the reaction mixture was filtered to remove lipase. The
filtrate was diluted with AcOEt and washed with saturated aq NaH-
CO3, the organic layer washed with saturated aq NaCl and dried
over Na2SO4. The solvent was removed under reduced pressure,
and the crude product was purified by column chromatography
4.6.7. (R)-MTPA ester of 1-benzoyloxy-3-allyloxypropan-2-ol 3
Colorless oil; 1H NMR (CDCl3) representative signals d 3.69 (2H,
d, J = 5.6 Hz, 3-CH2), 3.98 (2H, d, J = 5.6 Hz, OCH2CH@CH2), 4.54
(1H, dd, J = 7.6, 12.5 Hz, 1-CHHO), 4.66 (1H, dd, J = 3.5, 12.5 Hz,
1-CHHO), 5.19 (1H, dd, J = 1.4, 10.4 Hz, (Z)-CH@CHH), 5.26 (1H,
dd, J = 1.4, 17.4 Hz, (E)-CH@CHH), 5.66–5.71 (1H, m, 2-CH), 5.83
(1H, ddt J = 5.6, 10.4, 17.4 Hz, CH@CH2), 7.46 (2H, dd, J = 7.0,
7.0 Hz, m-Ph H), 7.60 (1H, t, J = 7.0, p-Ph H), 8.02 (2H, d, J = 7.0, o-
Ph H).
4.6.1. 3-Allyloxy-1-hydroxypropan-2-one 4
Compound 4 was prepared from 1-benzoyloxy-3-allyloxypro-
pan-2-one 5 (350 mg, 1.5 mmol), purified by column chromatogra-
phy (petroleum ether/ethyl acetate 8:2) yield 126 mg (65%);
viscous liquid. Rf (40% ethyl acetate/petroleum ether) 0.44; 1H
NMR (CDCl3) d 4.07 (2H, d, J = 5.6 Hz, OCH2CH@CH2), 4.18 (2H, s,
3-CH2), 4.48 (2H, s, 1-CH2), 5.27 (1H, dd, J = 1.4, 10.0 Hz,
(Z)-CH@CHH), 5.33 (1H, dd, J = 1.4, 17.3 Hz, (E)-CH@CHH), 5.90
(1H, ddt J = 5.6, 10.0, 17.3 Hz, CH@CH2); 13C NMR d, 66.7 (1-C),
72.7 (OCH2CH@CH2), 73.3 (3-C), 118.4 (CH@CH2), 133.6 (CH@CH2)
208.8 (CO). Anal. Calcd for C6H10O3 (130.06): C, 55.37; H, 7.74.
Found: C, 55.49; H, 7.84.
4.6.8. (S)-MTPA ester of 1-benzoyloxy-3-allyloxypropan-2-ol 3
Colorless oil; 1H NMR (CDCl3) representative signals d 3.73–3.79
(2H, m, part AB of ABX system, 3-CH2O), 4.06 (2H, d, J = 5.6 Hz,
OCH2CH@CH2), 4.47 (1H, dd, J = 7.6, 12.5 Hz, 1-CHHO), 4.58 (1H,
dd, J = 3.5, 12.5 Hz, 1-CHHO), 5.23 (1H, dd, J = 1.4, 10.4 Hz,
(Z)-CH@CHH), 5.31 (1H, dd, J = 1.4, 17.4 Hz, (E)-CH@CHH), 5.66–
5.71 (1H, m, 2-CH), 5.90 (1H, ddt J = 5.6, 10.4, 17.4 Hz, CH@CH2),
7.45 (2H, dd, J = 7.0, 7.0 Hz, m-Ph H), 7.58 (1H, t, J = 7.0, p-Ph H),
7.98 (2H, d, J = 7.0, o-Ph H).
Acknowledgment
4.6.2. (S)-3-Allyloxy-propane-1,2-diol (S)-125
This work has been financially supported by the Università de-
gli Studi di Milano (Fondi PUR).
According to the general procedure, compound (S)-1 was ob-
tained
from
(R)-1-benzoyloxy-3-allyloxypropan-2-ol
(R)-3
(1.5 mmol) or from (R)-1-acetoxy-3-allyloxypropan-2-ol (R)-2
(1.5 mmol), purified by column chromatography (petroleum
ether/ethyl acetate 7:3) to yield 130 mg (66%) From (R)-3
References
1. (a) Behr, A.; Eilting, J.; Irawadi, K.; Leschinski, J.; Lindner, F. Green Chem. 2008,
10, 13–30; (b) Beatriz, A.; Araújo, Y. J. K.; de Lima, D. P. Quim. Nova 2011, 34,
306–319; (c) Sakakura, A.; Umemura, S.; Ishihara, K. Adv. Synth. Catal. 2011,
353, 1938–1942; (d) Acosta, A.; Filice, M.; Fernandez-Lorente, G.; Palomo, J. M.;
Guisan, J. M. Bioresource Technol. 2011, 102, 507–512.
½
a 2D0
ꢁ
¼ ꢂ3:1 (c 1, CHCl3), 44% ee. From (R)-2 ½a D20
¼ ꢂ7:2 (c 1,
ꢁ
CHCl3), >98% ee.
2. Ashton, W. T.; Canning, L. F.; Reynolds, G. F.; Tolman, R. L.; Karkas, J. D.; Liou, R.;
Davies, M. M.; DeWitt, C. M.; Perry, H. C.; Field, A. K. J. Med. Chem. 1985, 28,
926–933.
3. (a) Hirth, G.; Saroka, H.; Bannwarth, W.; Barner, R. Helv. Chim. Acta 1983, 66,
1210–1240; (b) VanBoeckel, C. A. A.; van der Marel, G. A.; Westerduin, P.;
VanBoom, J. H. Synthesis 1982, 399–402.
4. (a) Duclos, R. I., Jr.; Johnston, M.; Vadivel, S. K.; Makriyannis, A.; Glaser, S. T.;
Gatley, S. J. J. Org. Chem. 2011, 76, 2049–2055; (b) Sun, S.; Yang, G.; Bi, Y.; Xiao,
F. Biotechnol. Lett. 2009, 1885–1889; (c) Kristinsson, B.; Haraldsson, G. G. Synlett
2008, 2178–2182; (d) Cateni, F.; Bonivento, P.; Procida, G.; Zacchigna, M.;
Gabrielli Favretto, L.; Scialino, G.; Banfi, E. Bioorg. Med. Chem. 2007, 15, 815–
826.
4.6.3. (R)-MTPA ester of 3-allyloxy-propane-1,2-diol 1
Colorless oil; 1H NMR (CDCl3) representative signals d 3.54 (2H,
d, J = 5.6, 3-CH2O), 3.90 (2H, d, J = 5.6, OCH2CH@CH2), 4.46 (1H, dd,
J = 6.9, 12.4 Hz, 1-CHHO), 4.77 (1H, dd, J = 3.5, 12.4 Hz, 1-CHHO),
5.18 (1H, dd, J = 1.4, 10.4 Hz, (Z)-CH@CHH), 5.23 (1H, dd, J = 1.4,
17.4 Hz, (E)-CH@CHH), 5.50–5.54 (1H, m, 2-CH), 5.79 (1H, ddt
J = 5.6, 10.4, 17.4 Hz, CH@CH2).
4.6.4. (S)-MTPA ester of 3-allyloxy-propane-1,2-diol 1
Colorless oil; 1H NMR (CDCl3) representative signals d 3.58–3.65
(2H, m, part AB of ABX system, 3-CH2O), 3.93–4.00 (2H, m, part AB
of ABX system, OCH2CH@CH2), 4.40 (1H, dd, J = 6.9, 12.4 Hz, 1-
CHHO), 4.65 (1H, dd, J = 3.5, 12.4 Hz, 1-CHHO), 5.20 (1H, dd,
J = 1.4, 10.4 Hz, (Z)-CH@CHH), 5.26 (1H, dd, J = 1.4, 17.4 Hz, (E)-
CH@CHH), 5.50–5.54 (1H, m, 2-CH), 5.84 (1H, ddt J = 5.6, 10.4,
17.4 Hz, CH@CH2).
5. Mickeleit, M.; Wieder, T.; Arnold, M.; Geilen, C. C.; Mulzer, J.; Reutter, W.
Angew. Chem., Int. Ed. 1998, 37, 351–353.
6. Shin, J.; Thompson, D. H. J. Org. Chem. 2003, 68, 6760–6766.
7. (a) Yuan, C.; Hollingsworth, R. I. Tetrahedron Lett. 2011, 52, 5421–5423; (b)
Enugala, R.; Carvalho, L. C. R.; Marques, M. M. B. Synlett 2010, 2711–2716; (c)
Tsukamoto, H.; Suzuki, T.; Sato, M.; Kondo, Y. Tetrahedron Lett. 2007, 48, 8438–
8441.
8. Sontakke, J. B.; Yadav, G. D. Ind. Eng. Chem. Res. 2011, 50, 12975–12983.
9. Santaniello, E.; Ciuffreda, P.; Casati, S.; Alessandrini, L.; Repetto, A. J. Mol. Catal.
B-Enzym. 2006, 40, 81–85.

400
S. Casati et al. / Tetrahedron: Asymmetry 23 (2012) 395–400
10. Casati, S.; Ciuffreda, P.; Santaniello, E. Tetrahedron: Asymmetry 2011, 22, 658–
661.
11. Santaniello, E.; Casati, S.; Ciuffreda, P.; Gamberoni, L. Tetrahedron: Asymmetry
2004, 15, 3177–3179.
12. Santaniello, E.; Casati, S.; Ciuffreda, P.; Gamberoni, L. Tetrahedron: Asymmetry
2005, 16, 1705–1708.
13. (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543–2549; (b)
Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092–4096.
14. For representative reviews, see: (a) Theil, F. Chem. Rev. 1995, 95, 2203–2227;
(b) Theil, F. Catal. Today 1994, 22, 517–536.
15. (a) Khor, G. K.; Uzir, M. H. Yeast 2011, 28, 93–107; (b) Moore, J. C.; Pollard, D. J.;
Kosjek, B.; Devine, P. N. Accounts Chem. Res. 2007, 40, 1412–1419; (c) Johanson,
T.; Katz, M.; Gorwa-Grauslund, M. F. FEMS Yeast Res. 2005, 5, 513–525; (d)
Patel, R. N. Adv. Synth. Catal. 2001, 343, 527–546.
18. (a) Zhou, B.; Gopalan, A. G.; VanMiddlesworth, F.; Shieh, W.-R.; Sih, C.-J. J. Am.
Chem. Soc. 1983, 105, 5925–5926; (b) Shieh, W.-R.; Gopalan, A. G.; Sih, C.-J. J.
Am. Chem. Soc. 1985, 107, 2993–2994.
19. The NMR spectrum of the hydroxyketone 4 in CDCl3 shows no trace of an
aldehyde signal, but a partial tautomerization of the hydroxyketone 4 to the
corresponding (RS)-hydroxyaldehyde in the fermentation medium cannot be
excluded.
20. Manzocchi, A.; Fiecchi, A.; Santaniello, E. J. Org. Chem. 1988, 53, 4405–4407.
21. Note that for derivative 3 there is a change in the CIP preference with regards
to diol 1.
22. (a) Yan, Z.; Nie, Y.; Xu, Y.; Liu, X.; Xiao, R. Tetrahedron Lett. 2011, 52, 999–1002;
(b) Musa, M. M.; Ziegelmann-Fjeld, K. I.; Vieille, C.; Zeikus, J. G.; Phillips, R. S. J.
Org. Chem. 2007, 72, 30–34; (c) Kroutil, W.; Mang, H.; Edegger, K.; Faber, K.
Curr. Opin. Chem. Biol. 2004, 8, 120–126; (d) van Deursen, R.; Stampfer, W.;
Edegger, K.; Faber, K.; Kroutil, W. J. Mol. Catal. B-Enzym. 2004, 31, 159–163.
23. Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Shaibani, R. Tetrahedron
2004, 60, 6105–6111.
16. Csuk, R.; Glanzer, B. I. In Stereoselective Biocatalysis; Patel, R. N., Ed.; Marcel
Dekker: New York, 2000; pp 527–578.
17. (a) Nakamura, K.; Yamanaka, R.; Matsudab, T.; Haradab, T. Tetrahedron:
Asymmetry 2003, 14, 2659–2681; (b) Wei, Z.-L.; Lin, G.-Q.; Li, Z.-Y. Bioorg.
Med. Chem. 2000, 8, 1129–1137; (c) Lee, L. G.; Whitesides, G. M. J. Org. Chem.
1986, 51, 25–36.
24. Khalafi-Nezhad, A.; Soltani Rad, M. N.; Khoshnood, A. Synthesis 2003, 2552–
2558.
25. Sugawara, F.; Nakayama, H.; Strobel, G. A.; Ogawa, T. Agric. Biol. Chem. 1986, 50,
2261–2271.