Enzyme mediated kinetic resolution of δ-hydroxy-α,β-unsaturated esters as a route to optically active δ-lactones

Article abstract of DOI:10.1016/j.tetasy.2017.05.003

A novel synthetic route to optically active saturated and unsaturated δ-lactones based on enzymatic kinetic resolution and ring-closing metathesis reactions has been proposed. The influence of temperature, co-solvent, organic additives and the substrate s

Full text of DOI:10.1016/j.tetasy.2017.05.003

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enzyme mediated kinetic resolution of d-hydroxy-
a,b-unsaturated
esters as a route to optically active d-lactones
⇑
⇑
Dominik Koszelewski , Daniel Paprocki, Anna Brodzka, Ryszard Ostaszewski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthetic route to optically active saturated and unsaturated d-lactones based on enzymatic
kinetic resolution and ring-closing metathesis reactions has been proposed. The influence of temperature,
co-solvent, organic additives and the substrate structure on the catalytic behavior of selected hydrolases
was studied. The substantial impact of the organic co-solvent and surfactant type on the enzymatic activ-
Received 22 March 2017
Revised 28 April 2017
Accepted 4 May 2017
Available online xxxx
ity and enantioselectivity was observed providing enantiomerically pure d-hydroxy-a,b-unsaturated
esters. The established protocol combining enzymatic kinetic resolution with ring closing metathesis
was successfully applied in the synthesis of the enantiomerically pure (6R)-phenyl-5,6-dihydro-2H-
pyran-2-one which plays crucial role in the synthesis of the number of bioactive compounds.
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
are widely discussed in the literature (Fig. 1).13 In view of these
important applications, synthetic studies of d-lactones have
The unsaturated chiral d-lactone ring is an important structural
motif of many natural products such as massoia lactone, jasmine
lactone, mellein, altholactone or goniodiol. Various lactone deriva-
tives play an important role as sex attraction pheromones of differ-
ent insects and plant-growth regulators.1 Chiral d-lactones
comprise important parts of many immunosuppressants,2 and
inhibitors of different enzymes and antiproliferative agents,3
which display anti-tumor and anti-fungal properties, for example,
leptomycin B,4 kazusamycin A,5 fostriecin,6 callystatin A,7 gonio-
thalamin,8 asperlin.9 They serve as intermediates in the synthesis
of bioactive tetrahydrolipstatin, also known by the trade names
Orlistat, a drug designed to treat obesity.10 The beneficial or
adverse effects of these compounds depend on their absolute con-
figuration thus making the separation of the two enantiomers from
a racemic mixture an important issue, particularly in the pharma-
ceutical industry. Each enantiomer possesses different pharmaco-
attracted considerable interest. Although several chemical proce-
dures have been explored to provide the routes to them, only a
few are based on chemoenzymatic approaches. Those methods
comprise of enzymatic oxidation, promiscuous aldol reaction or
the lipase-catalyzed kinetic resolution of racemic 1,5-diols.14
Recently, some efforts have been made on the lipase-catalyzed
transesterification with unsaturated vinyl esters as the acyl donors,
as well as hydrolysis of secondary alcohols acrylic esters combined
with ring-closing metathesis to provide relevant unsaturated lac-
tones such as goniothalamin and (R)-5-butyl-2(5H)-furanone, the
penultimate precursor to (R)-(+)-trans-Whisky lactone.15 Most of
these methods suffer from poor enantioselectivity and often
require environmentally hazardous metal catalysts.16
Herein we propose a new approach for the synthesis of chiral
non-racemic d-lactones I; the retrosynthetic analysis is shown in
Figure 2.
logical
activities
and
pharmacokinetic
characteristics.11
Our proposed strategy involves disconnection of the target d-
Additionally, the lactone functionality exists in common flavor
components and hence is employed in the perfume and food
lactones I to give the key synthon chiral non-racemic
a,b-unsatu-
rated d-hydroxy- ,b-unsaturated esters II, which can be obtained
a
industry.12 Moreover, the presence of a double bond in
a,b-unsat-
in a catalytic asymmetric vinylogous Mukaiyama-aldol reaction.
urated d-lactones offers novel strategic functionalization in syn-
thetic planning. Several examples of the pharmaceutically
relevant compounds obtained via modification of the structure I
After derivatization of the same ester II, chiral non-racemic d-acry-
loyloxy-a,b-unsaturated ester IV can be obtained, which is a
synthon of
a,b-unsaturated d-lactones III. As shown in Figure 2,
d-lactones
I
can be also obtained from the corresponding
d-lactones III via double bond reduction. The major challenge for
the assembly of the desired chiral non-racemic ,b-unsaturated
d-lactones is the preparation of the optically active d-hydroxy-
⇑
Corresponding authors.
E-mail addresses: dominik.koszelewski@icho.edu.pl (D. Koszelewski), ryszard.
a
a,
ostaszewski@icho.edu.pl (R. Ostaszewski).
http://dx.doi.org/10.1016/j.tetasy.2017.05.003
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Koszelewski, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.003

2
D. Koszelewski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
O
purity.23 This prompted us to consider replacing the asymmetric
vinylogous Mukaiyama-aldol reaction with a more environmen-
tally friendly enzymatic reaction.
O
O
O
The development of environmentally benign methods for the
production of fine chemicals has attracted increasing attention in
recent years. Thus, it seems significant to find a method to fulfill
the requirements of green chemistry. An alternative way to synthe-
size target chiral molecules is via biotransformations, which have
attracted the interest of synthetic chemists because of the high-,
regio- and stereoselectivity.24 Recently, our group has exploited
whole-cell mediated enantioreduction for the preparation of enan-
tiomerically pure b-hydroxy esters, the b-lactam precursors.25 In
addition, we also used hydrolases to resolve racemic 3-hydroxy-
3-(aryl)propanoic acids via dynamic kinetic resolution.26 Herein,
we report our studies on lipase catalyzed enantioselective transes-
terification and hydrolysis for the preparation of chiral non-race-
R
Ar
Br
Br
O
G
O
O
E
R1
R
R
O
S
ref.[13g]
H
F
ref.[13f]
ref.[13h]
ref.[13a]
O
O
ref.[13e]
O
O
O
R
R
Me
R
I
A
ref.[13b]
ref.[13c]
ref.[13d]
mic d-hydroxy-a,b-unsaturated esters bearing aryl groups and
their application in the synthesis of saturated and unsaturated chi-
ral non-racemic six-membered d-lactones.
O
R
O
O
O
O
H
OH
OH
R
R1
O
2. Results and discussion
H
D
O
N
R
R2
In the model reactions, racemic (E)-methyl 5-hydroxy-5-aryl-
pent-2-enoates 1a-e were obtained in Tetrabutylammonium diflu-
orotriphenylsilicate (TBAT)-mediated vinylogous Mukaiyama
reaction from 1-(trimethylsiloxy)-1-methoxy-1,3-butadiene27 and
the corresponding aldehyde in good yields up to 81%. Further
derivatization of 1a-e with acetic acid anhydride provided corre-
sponding racemic (E)-methyl 5-(phenyl)-5-acetoxypent-2-enoates
2a-e with high yields (Scheme 1).
B
C
Figure 1. Synthetic applications of a,b-unsaturated d-lactones.
O
O
OH
O
Racemic (E)-methyl 5-hydroxy-5-phenylpent-2-enoate 1a is a
progenitor for diospongin B, which exhibits anti-osteoporotic
activity,28 and sedamine, which is useful for the treatment of res-
piratory illnesses such as asthma, bronchitis, and pneumonia.29
Compound 1a has been used as a model substrate for kinetic reso-
lutions. Two different enzyme mediated approaches were applied
for the synthesis of the optically active synthons II and IV; first
based on transesterification with various acrylates and acetates,
and second based on chemoselective hydrolysis of O-acyl and O-
acryl esters.
R
OMe
R
I
II
O
O
RCM
O
O
O
R
OMe
R
2.1. Enantioselective synthesis of (E)-methyl 5-hydroxy-5-
phenylpent-2-enoates via enzymatic transesterifications
III
IV
Figure 2. Retrosynthetic analysis of a,b-unsaturated d-lactones.
The initial studies on enzymatic kinetic resolution of 1a were
performed in methyl tert-butyl ether (TBME) with 2 equiv of vinyl
acetate at 40 °C for 7 days, employing several various commercially
available hydrolases and 5 domestic prepared liver acetone pow-
ders (Supplementary information) (Scheme 2).
b-unsaturated esters. There are several published protocols leading
to racemic d-hydroxy-a,b-unsaturated esters, as well recognized
vinylogous aldol reactions.17 Racemic esters are also available from
the zinc catalyzed Reformatsky reaction of 4-bromocrotonate or In
(OTf)3 catalyzed conversion of kinetically formed homoallylic alco-
hols.18 Some efforts have also been taken to develop the stereose-
lective vinylogous aldol reaction, to obtain enantiomerically
The screening results are summarized in Table 1. Out of the
tested enzymes, Pseudomonas fluorescens lipase (PfL), Pseudomonas
cepacia lipase (PcL), Mucor miehei lipase (MmL), Rhizopus niveus
lipase (RnL), Rhizopus arrhizus lipase (RaL) and polymer supported
Candida antarctica lipase (Novozym 435) showed various activities
toward transesterification of model compound 1a. In the control
experiment with the absence of the enzyme, the formation of the
desired product 2a was not observed (Table 1, entry 1). The highest
conversion 37% and 23% but low enantioselectivity (E), less than 5,
were observed in case of using Novozym 435 and MmL, respec-
tively (Table 1, entries 2 and 3). The application of PcL significantly
improved the enantioselectivity (98% ee) but the conversion
dropped below 10% (Table 1, entry 4). The lipases from Rhizopus
niveus and Rhizopus arrhizus provided enantiomerically pure pro-
duct 2a but with negligible conversion (<5%) (Table 1, entries 5
and 6). When PfL was used, a very high E value (>200) was
enriched d-hydroxy-a
,b-unsaturated esters.19 Bluet and Campagne
reported on an enantioselective vinylogous aldol reaction by
applying ethyl tiglate, silyl dienol ether and the titanium(IV)–binol
or cinchona alkaloids as catalysts to provide c-aldol adducts with
moderate enantiomeric ratio.20 Phosphoramide/SiCl4 and Sn
(OTf)2 species have also proven to be competent catalysts for the
vinylogous aldol reactions of silyl dienol ethers.21 This procedure
was further modified by applying Carreira’s catalyst to obtain a
mixture of the a,b-unsaturated d-lactone and the linear vinylogous
aldol product with 85 and 8% enantiomeric excesses, respec-
tively.22 The drawbacks of the above synthetic routes include harsh
reaction conditions, expensive reagents, and low enantiomeric
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D. Koszelewski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
OTMS
OMe
O
OH
O
OAc
O
Ac2O
TBAT
+
THF, rt
DCM, rt
R
H
R
OMe
R
OMe
2a-e
1a: R=Ph, 72%
1b: R=4-MeOC6H4, 81%
1c: R=4-FC6H4, 78%
1d: R=4-NO2C6H4, 63%
1e: R=2-naphthyl, 60%
Scheme 1. Synthesis of rac-(E)-methyl 5-hydroxy-5-arylpent-2-enoates 1a–e.
rac-1a providing enantiomerically pure product (R)-2a with 9%
conversion (Table 1, entry 12). For para-chlorophenyl acetate as
well as ethyl acrylate and 2,2,2-trifluoroethyl acrylate, only trace
amounts of the corresponding esters 2a and 3 were achieved,
which was ascribed to the steric hindrance due to the comparative
vinyl acetate
enzyme
O
O
OH
OAc
TMBE, 40 oC
Ph
OMe
Ph
OMe
rac-1a
(R)-2a
inflexibility of the a
,b-alkenic ester.32 All of the reactions followed
Scheme 2. Enzymatic transesterification of the racemic (E)-methyl 5-hydroxy-5-
phenylpent-2-enoates 1a.
the empirical rule proposed by Kazlauskas and in each case, the
(R)-enantiomer was transformed faster by the enzymes.33
The optimized reaction conditions were scaled up using Pseu-
domonas fluorescens lipase. Unfortunately, higher substrate con-
centration (100 mM) adversely affected the enantioselectivity
(E = 4) providing product (R)-2a with 52% enantiomeric excess
and 21% isolated yield only. Furthermore, many efforts have been
made toward development of dynamic kinetic resolution of the
model compound 1a. Unfortunately, under dynamic kinetic resolu-
tion conditions, the decomposition of 1a was observed exclusively.
obtained, providing enantiomerically pure product (R)-2a with
modest conversion 15%. (Table 1, entry 7).
Due to preliminary results, PfL was arbitrary selected for further
optimization studies. The choice of the proper organic solvent can
be critical, as it significantly affects the selectivity and activity of
the enzyme.31 Simultaneously, the influence of various co-solvents
(TBME, isopropyl ether, ethyl ether, c-hexane, n-hexane, toluene, p-
xylene, dichloromethane (DCM) and tetrahydrofuran (THF)) on the
reaction course was investigated. The results indicated that the
most suitable solvents for the enzymatic kinetic resolution of 1a
were TBME and c-hexane, which gave the highest conversions
(Table 1, entries 7 and 8). For other solvents the enantioselectivity
remained very high (E > 200) leading to enantiomerically pure (R)-
1a, but with low conversion, less than 8% (data not shown). The
application of higher excess of vinyl acetate (4 equiv) had no
impact on the reaction efficiency (Table 1, entry 9). In the next
step, the temperature effect on the reaction course was studied.
While the activity slightly increased at higher temperatures, a pro-
gressive decrease of the PfL enantioselectivity was also observed
(Table 1, entries 10 and 11). Taking both the selectivity and activity
into account, the optimal reaction temperature for the transester-
ification of rac-1a appeared to be 40 °C. Subsequently, we studied
the effect of the acyl donor on the reaction rate and the enantios-
electivity of the acyl transfer. Thus, it was observed that iso-
propenyl acetate was a poor donor for the transesterification of
2.2. Enantioselective synthesis of (E)-methyl 5-hydroxy-5-
phenylpent-2-enoates via enzymatic hydrolysis
Due to the inefficient up-scaling, the enzymatic transesterifica-
tion was no longer pursued. Since it was not possible to obtain
enantiomerically pure products by enzymatic transesterification
in good yield, we turned our attention to enzymatic kinetic resolu-
tion based on the hydrolysis reaction. Racemic (E)-methyl 5-(phe-
nyl)-5-acryloyloxypent-2-enoate 3, which was provided via
acylation of 1a with acryloyl chloride in 88% yield, was chosen as
a model compound (Scheme 3).
Despite numerous published examples of using acrylates as acyl
donors in lipase-catalyzed transesterifications of racemic sec-
ondary alcohols,34 only a few involve enzymatic hydrolysis of acry-
lates,35 unlike the enzymatic hydrolysis of the secondary alcohols
acetates.13k
Table 1
Enzymatic transesterification of the racemic (E)-methyl 5-hydroxy-5-phenylpent-2-enoates 1a in TBMEa
Entry
Enzyme
c (%)g
ee [(S)-1a](%)g
ee [(R)-2a] (%)g
Eh
1
2
3
4
5
6
7
8
None
Novozym 435
MmL
PcL
RnL
RaL
<1
37
23
8
<5
<5
15
13
14
18
16
9
Nd
<5
28
9
<5
<5
17
15
16
22
18
10
nd
5
96
nd
<5
64
108
nd
98
>99
>99
>99
>99
>99
98
nd
PfL
>200
>200
>200
123
29
PfLb
9
PfLc
10
11
12
PfLd
PfLe
92
>99
PfLf
>200
a
b
c
Reaction conditions: 0.04 mmol of 1a, vinyl acetate 2 equiv, TBME (1.0 mL), native enzyme (5 mg) or Novozym 435 (10 mg), 7 days, 40 °C.
c-Hexane.
4 equiv of vinyl acetate.
Temperature 50 °C.
Temperature 60 °C.
2 equiv of isopropenyl acetate.
d
e
f
g
h
Determined by HPLC on a Daicel Chiralcel OD-H column.
Calculated according to Chen et al.,30 using the equation: E = ln[(1 ꢀ ees)/(1 + ees/eep)]/ln[(1 + ees)/(1 + ees/eep)].
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4
D. Koszelewski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
According to literature data,36 10%v/v of acetone was used as a
(Table 3, entry 1). In order to determine the optimal reaction con-
ditions, various organic co-solvents were used as reaction media
for the PfL mediated selective hydrolysis of racemic 3a (Scheme 3).
co-solvent. Once again the same hydrolases were investigated for
hydrolysis in a phosphate buffer (PBS, pH 7.4) at 20 °C for 3 days
(Scheme 3). Six out of tested enzymes; Pseudomonas fluorescens
lipase (PfL), Pseudomonas cepacia lipase (PcL), Rhizopus niveus
lipase (RnL), Candida rugose lipase (CrL), Protease K (PK), Rhizopus
miehei lipase (RmL) and wheat germ lipase (WgL) were hydrolyzed
with the model substrate rac-3 (Table 2). The highest enantioselec-
tivity (up to 32) was observed for Pseudomonas fluorescens and
Pseudomonas cepacia lipases (Table 2, entries 1 and 2). In other
cases the model substrate 3 was pursued with higher conversion
but the enantiorecognition was disappointing (Table 2, entries 3–
5 and 7). Lipase from Rhizopus miehei preferentially hydrolyzed
the (S)-enantiomer of substrate rac-3, providing enantiomer
(S)-1a with low enantioselectivity (Table 2, entry 6). In studied
reactions, the hydrolases showed chemospecificity, and the
carboxymethyl function of the substrate 3 was not affected.
Based on the initial promising results with Pseudomonas fluo-
rescens lipase, this enzyme was further applied for the optimization
of the hydrolysis reaction conditions. The influence of the type of
water-immiscible co-solvent on the lipase-catalyzed reaction has
been widely reported in recent years, since it is one of the most
easily altered factors in enzymatic reactions.37 The results of the
optimization studies are shown in Table 3. Hydrolysis of racemic
3 was conducted in phosphate buffer (PBS, pH 7.4) with 10% v/v
co-solvent at 20 °C for 3 days Although, the acrylate was hardly
dissolve in water, enzymatic hydrolysis occurs without a co-sol-
vent to provide product 1a with moderate enantioselectivity
O
O
enzyme
OH
O
additive
Cl
O
O
1a
PBS, 20oC
Ph
OMe
88%
Ph
OMe
rac-3
(R)-1a
Scheme 3. Enzymatic hydrolysis of the racemic (E)-methyl 5-(phenyl)-5-acryl-
oyloxypent-2-enoate 3.
An enhancement in the enantioselectivity, compared to ace-
tone, was observed for water-miscible solvents, such as 1,4-diox-
ane and THF (Table 3, entries 4 and 5) as well as in non-polar
toluene (Table 3, entry 12). An adverse impact on the enantioselec-
tivity was noticed for acetonitrile and c-hexane (Table 3, entries 2
and 13). The application of ethyl ether and isopropyl ether (DIPE)
improved the enzyme activity but the enantioselectivity remained
comparable with acetone (Table 3, entries 6 and 11). A similar
effect was also detected for o-xylene and isooctane (Table 3, entries
14 and 15). The highest catalytic activity and enantioselectivity
were observed in TBME as a co-solvent (Table 3, entry 7). Substan-
tial improvement of the enantioselectivity (E > 300) leading to
enantiomerically pure product (R)-1a was established by increas-
ing the TBME concentration to a value of 20% v/v (Table 3, entry
8). Further increase of the solvent concentration or medium
Table 2
Enzymatic hydrolysis of the racemic (E)-methyl 5-(phenyl)-5-acryloyloxypent-2-enoate 3 in phosphate buffer (PBS)a
Entry
Enzyme
c (%)b
ee [(S)-3] (%)b
ee [(R)-1a] (%)b
Ec
1
2
3
4
5
6
7
PfL
37
21
19
56
60
28
37
52
24
8
73
15
90
89
35
57
10
32
22
<5
8
<5
<5
<5
PcL
RnL
CrL
PK
RmL
WgL
ꢀ19
ꢀ50
<3
<5
a
b
c
Conditions: 0.04 mmol of 3, acetone 10% v/v, PBS (50 mM, pH 7.4), native enzyme (5 mg), 72 h, 20 °C.
Determined by HPLC on a Daicel Chiralcel OD-H column.
Calculated according to Chen et al.,30 using the equation: E = ln[(1 ꢀ ees)/(1 + ees/eep)]/ln[(1 + ees)/(1 + ees/eep)].
Table 3
Optimization of enzymatic hydrolysis of racemic (E)-methyl 5-(phenyl)-5-acryloyloxypent-2-enoate 3 in phosphate buffer (PBS) with various additives catalyzed by PfLa
Entry
Additive/Co-solvent
c (%)c
ee [(S)-3] (%)c
ee [(R)-1a] (%)c
Ed
1
2
3
4
5
6
7
8
—
MeCN
12
21
37
10
42
45
47
36
24
7
37
43
32
28
24
22
33
20
<5
12
20
52
11
66
73
85
56
32
8
53
70
33
36
28
28
47
25
Nd
91
77
90
97
92
88
94
>99
>99
>99
90
92
70
91
90
98
97
98
Nd
24
9
Acetone
1,4-Dioxane
THF
Diethyl ether
TBME 10% v/v
TBME 20% v/v
TBMEb 20% v/v
TBME 30% v/v
DIPE
32
73
48
34
88
>300
>200
>200
32
50
8
30
25
9
10
11
12
13
14
15
16
17
18
19
Toluene
c-Hexane
o-Xylene
Isooctane
Tween80
DODAB
130
105
126
nd
AOT
SDS
a
b
c
Conditions: 0.04 mmol of 3, additive 10% v/v, PBS (50 mM, pH 7.4), PfL (5 mg), 72 h, 20 °C.
Temperature 30 °C.
Determined by HPLC on a Daicel Chiralcel OD-H column.
d
Calculated according to Chen et al.,30 using the equation: E = ln[(1 ꢀ ees)/(1 + ees/eep)]/ln[(1 + ees)/(1 + ees/eep)].
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D. Koszelewski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
temperature led to a decrease in enzyme activity, which may be
caused by the released acrylic acid, which exhibits a strong inhibi-
tory effect (Table 3, entries 9 and 10).38 Among the medium engi-
neering and temperature modulation employed to increase the
enantioselectivity of enzyme-mediated reactions, the additive
approach is very attractive due to its simplicity for practical appli-
cations.39 Furthermore, for the enzymatic hydrolysis of d-hydroxy-
both substrate (S)-2a and product (R)-1a with excellent enan-
tiomeric excess (ee >99%) (Table 4, entry 8).
Since the enzyme enantioselectivity for the conversion of rac-2a
was several-fold higher (E > 1000, Table 4, entry 8) in comparison
to the hydrolysis of rac-3 (E > 300, Table 3, entry 8), we decided
to screen other organic solvents in order to compare their impact
on the catalytic activity and enantioselectivity of PfL. The results
presented in Table 4 indicated the significant improvement of
enantioselectivities (Table 4, entries 2, 3, 5, 6, 10–12 and 14) in
comparison to (E)-methyl 5-(phenyl)-5-acryloyloxypent-2-enoate
3 for all of the applied co-solvents respectively (Table 3). When
using 1,4-dioxane and o-xylene, a large decrease in activity was
observed as in the case of kinetic resolution of the compound 3
(Table 4, entries 4 and 13). It is interesting o note that in the
absence of co-solvent, high conversion was achieved providing
a,b-unsaturated esters, an improvement in enantioselectivity by
an additive method is, to the best our knowledge, without prece-
dent in the literature.40 Our results are in accordance with the pre-
vious reports that the enhancement of lipase activity strongly
depends on the type of surfactants. Three of the four applied sur-
factants; non-ionic Tween 80 and ionic didodecyldimethylammo-
nium bromide (DODAB) and sodium bis(2-ethyl-1-hexyl)
sulfosuccinate (AOT) markedly enhanced the enantioselectivity of
studied reaction to E value up to 130 (Table 3, entries 16–18). It
is noteworthy that at the same time, another ionic surfactant,
sodium dodecyl sulfate (SDS) had a strong inhibitory effect on
the lipase activity (Table 3, entry 19). The inhibitory effect of SDS
may be attributed to the strong ionic interactions between the sur-
factant and the lipase, which induce an unfolding and denaturing
of the enzyme.41
enantiomerically pure d-hydroxy-a,b-unsaturated ester (R)-1a
(Table 4, entry 1).
Due to the highest catalytic activity and enantioselectivity of
the enzyme being obtained in 20% v/v TBME, this solvent was used
as the reaction medium in further experiments (Table 4, entries 7
and 8). Next, the effect of temperature on the enantioselectivity
and reaction rate was studied. However, when the temperature
rose to 40 °C, an adverse effect on enantioselectivity was noticed
(E = 100) (Table 4, entry 9). Finally, enzymatic kinetic resolution
was carried on a preparative scale. Thus, 250 mg (1 mmol) of race-
mic (E)-methyl 5-(phenyl)-5-acyloxypent-2-enoate 2a were
resolved into enantiomerically pure 1a within 20 h, and with
39% isolated yield (conv 40%). Optically active (E)-methyl
Due to the long reaction time (3 days) of the hydrolysis of the
racemic ester 3, additional efforts were taken to obtain enan-
tiomerically pure d-hydroxy-a,b-unsaturated ester 1a (R = Ph)
more efficiently. To reach this goal and to estimate the steric effect
of the acryloyloxy moiety on the enantioselectivity outcome, the
racemic
(E)-methyl
5-(phenyl)-5-acyloxypent-2-enoate
2a
(R = Ph) was evaluated as a potential substrate for Pseudomonas flu-
orescens lipase (Scheme 4). In order to determine the catalytic abil-
ity of PfL in the hydrolysis of rac-2a, the screening was carried out
analogous to the hydrolysis of ester 3 by applying the same set of
organic co-solvents. The reactions performed under the optimized
conditions (20% v/v of TBME, 20 °C) were monitored by HPLC and
stopped after 20 h when approximately 50% consumption of the
starting material rac-2a (Scheme 4, R = Ph) was recorded providing
(5R)-hydroxy-5-phenylpent-2-enoate (R)-1a is a precursor of
diospongins and cryptophycin analogues, anti-osteoporotic and
anti-cancer agents.28,42
At this point, in order to validate developed protocol a set of
experiments with different racemic (E)-methyl 5-(aryl)-5-acy-
loxypent-2-enoates 2b–e were conducted under optimized condi-
tions (Scheme 4), to obtain the corresponding enantiomerically
enriched d-hydroxy-a,b-unsaturated esters 1b–e (Table 5).
Pseudomonas fluorescens lipase was found as a versatile catalyst
providing, regardless of the electron-withdrawing or donating
group corresponding (E)-methyl 5-(aryl)-5-hydroxypent-2-enoates
1b–e with very high enantiomeric excess up to 98% (Table 5,
entries 1, 3 and 4). When the fluorine atom was located at the
para-position, the enantioselectivity increased to give an excellent
E value, more than 1000 (Table 5, entry 2).
O
PfL
OH
O
additive
O
O
PBS, 20 oC
R
OMe
R
OMe
rac-2a-e
1a-e
Compounds 2b–e were subjected to enzymatic kinetic resolu-
tion on a preparative scale with PfL to give the corresponding
Scheme 4. Enzymatic hydrolysis of racemic (E)-methyl 5-(aryl)-5-acyloxypent-2-
enoate (2a–e) in PBS/additive catalyzed by PfL.
Table 4
Enzymatic hydrolysis of racemic (E)-methyl 5-(phenyl)-5-acyloxypent-2-enoate 2a in phosphate buffer (PBS) catalyzed by PfLa
Entry
Co-solvent
c (%)d
ee [(S)-2a] (%)d
ee [(R)-1a] (%)d
Ee
>300
130
>300
>200
>400
150
>600
>1000
100
>200
120
1
2
3
4
5
6
7
8
—
MeCN
Acetone
1,4-Dioxane
THF
36
24
34
7
41
30
43
50
33
12
38
47
5
55
31
51
8
90
42
93
>99
48
13
60
92
5
>99
98
>99
>99
>99
98
>99
>99
97
>99
97
Ethyl ether
TBME
TBMEb
TBMEc
9
10
11
12
13
14
DIPE
Toluene
c-Hexane
o-Xylene
Isooctane
>99
>99
98
>500
>200
150
31
44
a
b
c
Conditions: 0.04 mmol of 2a, additive 10% v/v, PBS (50 mM, pH 7.4), PfL (5 mg), 20 h, 20 °C.
Temperature 20 °C, 20% v/v.
Temperature 40 °C, 20% v/v.
d
e
Determined by HPLC on a Daicel Chiralcel OD-H column.
Calculated according to Chen et al.,30 using the equation: E = ln[(1 ꢀ ees)/(1 + ees/eep)]/ln[(1 + ees)/(1 + ees/eep)].
Please cite this article in press as: Koszelewski, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.003

6
D. Koszelewski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 5
Enzymatic hydrolysis of racemic (E)-methyl 5-(aryl)-5-acyloxypent-2-enoates 2b–e in PBS/TBME catalyzed by PfLa
Entry
R
Product
c (%)b
ee [2] (%)b
ee [1] (%)b
Ec
1
2
3
4
4-MeOC6H4
4-FC6H4
4-NO2C6H4
2-Naphthyl
2b
2c
2d
2e
36
50
45
35
55
>99
79
98
>99
98
170
>1000
>200
170
53
98
a
b
c
Conditions: 0.04 mmol of 2, TBME 20% v/v, PBS (50 mM, pH 7.4), PfL (5 mg), 20 h, 20 °C.
Determined by HPLC on a Daicel Chiralcel OD-H column.
Calculated according to Chen et al.,30 using the equation: E = ln[(1 ꢀ ees)/(1 + ees/eep)]/ln[(1 + ees)/(1 + ees/eep)].
hydroxy esters (+)-1b–e with yields up to 41% and enantiomeric
excesses values similar to those shown in Table 5. Moreover, enan-
tiomerically pure (E)-methyl 5-(4-fluorophenyl)-5-acetoxypent-2-
enoate (ꢀ)-2c was gained with 43% isolated yield.
O
1. Pd/C, H2
2. TFA
OH
O
O
Ph
OMe
81%
Ph
The successful enzymatic preparation of enantiomerically pure
(E)-methyl (5R)-hydroxy-5-phenylpent-2-enoate (R)-1a allowed
for further attempts towards the synthesis of enantiomerically
pure d-lactones.
(R)-1a
(R)-7
Scheme 6. Synthesis of (6R)-phenyltetrahydropyran-2-one (R)-7.
The first trials performed on a model racemic compound 4
(R = 4-MeOC6H4, R1 = Et) under published conditions14c developed
for t-butyl esters and based on acidic hydrolysis followed by
intramolecular lactonization were unsuccessful and gave ethyl
(2E,4E)-5-(4-methoxyphenyl)penta-2,4-dienoate (R = 4-MeOC6H4,
R1 = Et) 5 in quantitative yield (Scheme 5). The obtained dienoate
5 is a precursor of pharmacologically relevant molecules as well
as color-tunable solid emitters (Scheme 5).43 An established proce-
dure toward compound 5 would be an attractive and efficient
alternative to already published protocols, which usually involve
either harsh reaction conditions or complex and expensive
reagents.44 The ring-closing metathesis (RCM) of dienes became a
general method for the construction of unsaturated carbocycles.45
Therefore, acylation of (R)-1a with acryloyl chloride and Et3N was
performed and gave enantiomerically pure acrylate (R)-3. Treat-
ment of RCM required substrate (R)-3 with 10 mol % of Grubbs
2nd gen. catalyst in dry DCM at 55 °C and gave the desired (6R)-
phenyl-5,6-dihydro-2H-pyran-2-one (R = Ph) (R)-6 in 72% yield
and with over 99% enantiomeric excess (Scheme 5). Analogous
reaction conducted in toluene at 80 °C resulted in enantiomerically
pure product (R)-6 with 52% yield. Additionally, Grubbs-Hoveyda
2nd gen. catalyst was used in DCM to provide enantiomerically
pure (R)-6 in 65% yield.
The absolute configurations of (R)-6 and (R)-7 were
determined by comparing the sign of their specific rotation
values with those in the literature.46 These compounds are versa-
tile building blocks for the chiral synthesis of several bioactive
compounds.47
3. Conclusions
In conclusion, two different enzymatic approaches were used
for the synthesis of d-lactones; transesterification and hydrolysis.
The choice of organic solvent and biocatalyst is crucial for efficient
kinetic resolution. A transesterification protocol was studied, but
was applicable only on an analytical scale. For the preparation of
the enantiomerically pure (E)-methyl (5R)-hydroxy-5-phenyl-
pent-2-enoates much attention was paid to enantioselective
hydrolysis. An intriguing influence of co-solvent on the enantiose-
lectivity of Pseudomonas fluorescens lipase catalyzed hydrolysis was
observed. The application of the (E)-methyl 5-(phenyl)-5-acryloy-
loxypent-2-enoate allowed us to obtain enantiomerically pure
(E)-methyl (5R)-hydroxy-5-phenylpent-2-enoate, however the
reaction time was long. Careful optimization of the reaction condi-
tions, including the type of the substrate used makes it possible to
control (with respect to the enantioselectivity) enzymatic kinetic
resolution, providing enantiomerically pure (E)-methyl (5R)-
hydroxy-5-phenylpent-2-enoate. The new protocol combining
enzymatic kinetic resolution with ring closing metathesis was
established and successfully applied to the synthesis of enan-
tiomerically pure (6R)-phenyl-5,6-dihydro-2H-pyran-2-one, which
plays crucial role in the synthesis of the number of bioactive com-
pounds. Additionally, performed studies under functionalization of
O
OH
O
Lit.[14c]
R
OR1
R
OR1
5
4
O
O
O
Grubbs (II) cat.
the d-hydroxy-a,b-unsaturated esters led to synthetically relevant
O
O
dienoate 5 using a straightforward synthesis. The protocol reported
herein is a useful alternative to known methods providing optically
active d-lactones.
R
R
OR1
(R)-6
(R)-3
Scheme 5. The synthesis of ethyl (2E,4E)-5-(4-methoxyphenyl)penta-2,4-dienoate
5 and (6R)-phenyl-5,6-dihydro-2H-pyran-2-one (R)-6.
4. Experimental
4.1. General
Finally, trifluoroacetic acid (TFA) catalyzed lactonization pre-
ceded by the reduction of the double bond in (R)-1 was performed
to give enantiomerically pure (6R)-phenyltetrahydropyran-2-one
(R)-7 in 88% yield (Scheme 6).
All reagents were purchased from either Aldrich, Acros, TCI or
Alfa Aesar and were used as received. The solvents were of ana-
lytical grade. Lipases from Pseudomonas cepacia, Pseudomonas flu-
orescens, Mucor miehei, Rhizopus niveus, Rhizopus arrhizus were
Please cite this article in press as: Koszelewski, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.003

D. Koszelewski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
purchased from Sigma–Aldrich. Immobilized lipase from Candida
4.2.2. rac-(E)-Methyl 5-hydroxy-5-(4-methoxyphenyl)pent-2-
enoate rac-1b
antarctica (Novozym 435) was purchased from Novo Nordisk.
Goose, horse, chicken, wild hog and deer livers were converted
to the acetone powder (GLAP) by the method of Connors et al.48
Column chromatography was performed on Merck silica gel
60/230–400 mesh. NMR spectra were recorded in CDCl3 with
TMS as an internal standard using 400 MHz spectrometer. The
chemical shifts are reported in ppm (d) and the coupling con-
stants (J) are given in Hz. The HPLC analyses were performed
on Chiralcel OD-H chiral column (£ 4.6 mm ꢁ 250 mm, from
Yield 81% (1.147 g, 4.86 mmol), colorless liquid. 1H NMR
(400 MHz, CDCl3) d 7.26 (d, J = 8 Hz, 2H), 6.98–6.89 (m, 1H), 6.87
(d, J = 8 Hz, 2H), 5.90 (dt, J = 16.0, 1.3 Hz, 1H), 4.76 (dd, J = 8.0,
4.0 Hz, 1H), 3.80 (s, 3H), 3.71 (s, 3H), 2.69–2.57 (m, 2H); 13C
NMR (100 MHz, CDCl3) 166.6, 159.3, 145.0, 135.5, 127.0, 123.4,
114.0, 72.7, 55.2, 51.4, 41.7. The 1H and 13C NMR data were in
accordance with those reported in the literature.15d HPLC:
Chiralcel OD-H; hexane/isopropanol (9:1), flow = 1.0 mL/min,
k = 256 nm, retention time of the racemic compound (in min):
tR = 17.1, tR = 19.7.
Diacel Chemical Ind., Ltd) equipped with
a pre-column (£
4 mm ꢁ 10 mm, 5 m) using an LC-6A Varian ProStar apparatus
l
with UV Varian ProStar 330 detector and Chromatopac C-R6A
analyser. The mobile phase was hexane/isopropanol. Melting
points are uncorrected. Optical rotations were measured in 1-
dm cell of 1 mL capacity using Jasco DIP-360 polarimeter operat-
ing at 589 nm. The elemental analyses were performed on CHN
Perkin-Elmer 240 apparatus. All the reactions were monitored
by TLC on Merck silica gel Plates 60 F254. To prove the ability
of the established protocol each reaction was repeated at least
three times. With racemic samples of both (E)-methyl 5-(phe-
nyl)-5-acetoxypent-2-enoate 2a and (E)-methyl 5-hydroxy-5-
phenylpent-2-enoates 1a in hand, chiral HPLC conditions were
developed in order to see separately both enantiomers of the
compounds 2a and 1a on the same chromatogram (Supplemen-
tary materials). With a single injection, ready monitoring of both
the efficiency and enantioselectivity of each of the enzyme medi-
ated transformations could be performed. The enantioselectivity
parameter E was calculated using the equation: E = ln[(1 ꢀ ees)/
(1 + ees/eep)]/ln[(1 + ees)/(1 + ees/eep)].30 Enzymatic reactions
were performed in a vortex (Heidolph Promax 1020) equipped
with incubator (Heidolph Inkubator 1000). To prove the ability
of the established protocol each reaction was repeated at least
three times. 1-(Trimethylsiloxy)-1-methoxy-1,3-butadiene and
4.2.3. rac-(E)-Methyl 5-(4-fluorophenyl)-5-hydroxypent-2-
enoate rac-1c
Yield 78% (1.049 g, 4.68 mmol), colorless liquid. 1H NMR
(400 MHz, CDCl3) d 7.31–7.27 (m, 2H), 7.03–6.99 (m, 2H), 6.92–
6.87 (m, 1H), 5.88 (dt, J = 16.0, 1.6 Hz, 1H), 4.77 (dd, J = 7.2,
5.2 Hz, 1H), 3.68 (s, 3H), 2.62–2.55 (m, 3H); 13C NMR (100 MHz,
CDCl3) 166.7, 163.5, 161.0, 144.7, 139.2, 139.2, 127.4, 127.3,
123.6, 115.4, 115.3, 72.3, 51.4, 41.8. The 1H and 13C NMR data were
in accordance with those reported in the literature.15d Chiralcel
OD-H; hexane/isopropanol (95:5), flow = 1.0 mL/min, k = 256 nm,
retention time of the racemic compound (in min): tR = 12.1,
tR = 13.8.
4.2.4. rac-(E)-Methyl 5-(4-nitrophenyl)-5-hydroxypent-2-
enoate rac-1d
Yield 63% (950 mg, 3.78 mmol), light yellowish liquid. 1H NMR
(400 MHz, CDCl3) d 8.20 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H),
6.96 (dt, J = 15.6, 7.2 Hz, 1H), 5.93 (dt, J = 15.6, 1.2 Hz, 1H), 5.00
(t, J = 6.0 Hz, 1H), 3.74 (s, 3H), 2.69–2.66 (m, 2H), 2.39 (s, 1H);
13C NMR (100 MHz, CDCl3) 166.4, 150.4, 143.4, 126.5, 124.5,
123.8, 72.0, 51.6, 51.4, 41.8; Element. Anal. calcd. for C12H13NO5:
C 57.37, H 5.22; found C 57.28, H 5.13. The 1H and 13C NMR data
were in accordance with those reported in the literature.17k
Chiralcel OD-H; hexane/isopropanol (9:1), flow = 1.0 mL/min,
k = 256 nm, retention time of the racemic compound (in min):
tR = 25.9, tR = 29.9.
1-(trimethylsiloxy)-1-ethoxy-1,3-butadiene
were
obtained
according to the literature procedure.27
4.2. General procedure for the synthesis of racemic alcohols rac-
1a–e and rac-4
4.2.1. Preparation of rac-(E)-methyl 5-hydroxy-5-phenylpent-2-
enoate rac-1a
4.2.5. rac-(E)-methyl 5-hydroxy-5-(naphthalen-2-yl)pent-2-
enoate rac-1e
Racemic (E)-methyl 5-hydroxy-5-phenylpent-2-enoate 1a was
obtained using a modified literature procedure.20b To a solution
of benzaldehyde (637 mg, 6 mmol) and tetrabutylammonium
difluorotriphenylsilicate (TBAT) (0.6 mmol, 324 mg, 10 mol %) in
dry THF (15 mL), 1-(trimethylsiloxy)-1-methoxy-1,3-butadiene
(1.034 g, 6 mmol) in dry THF (5 mL) was added dropwise to
provide a bright yellow solution, which was stirred for 6 h at
room temperature. After quenching (MeOH/HCl 9:1, 10 min), the
reaction mixture was diluted with a saturated aqueous solution
of NH4Cl and extracted with ether (3 ꢁ 20 mL). The organic
layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. The crude residue was then purified by
flash chromatography on silica gel (hexanes/EtOAc) providing
product 1a with 72% yield (891 mg, 4.30 mmol) as a colorless oil.
1H NMR (400 MHz, CDCl3) d 7.29–7.25 (m, 5H), 6.95 (dt, J = 15.5,
7.2 Hz, 1H), 5.88 (dt, J = 15.7, 1.3 Hz, 1H), 4.9 (dd, J = 7.2, 5.2 Hz,
1H), 3.69 (s, 3H), 2.65–2.61 (m, 2H), 2.34 (s, 1H); 13C NMR
(100 MHz, CDCl3) 166.7, 145.0, 143.4, 128.5, 127.8, 125.7, 123.5,
73.0, 51.4, 41.8. The 1H and 13C NMR data were in accordance
with those reported in the literature.15d HPLC: Chiralcel OD-H;
Yield 60% (923 mg, 3.60 mmol), colorless liquid. 1H NMR
(400 MHz, CDCl3) d 7.87–7.83 (m, 3H), 7.80 (s, 1H), 7.52–7.49
(m, 3H), 7.01 (dt, J = 15.6, 7.2 Hz, 1H), 5.93 (dt, J = 15.6, 1.2 Hz,
1H), 4.97 (dd, J = 7.6, 5.6 Hz, 1H), 3.72 (s, 3H), 2.78–2.70 (m, 2H),
2.52 (s, 1H); 13C NMR (100 MHz, CDCl3) d 166.7, 144.9, 140.8,
133.1, 133.0, 128.4, 127.9, 127.7, 126.2, 126.0, 124.5, 123.7,
123.6, 73.1, 51.4, 41.7; HRMS (ESI) calcd for C16H16O3Na (M+Na)
279.0997; found 279.0990. The 1H and 13C NMR data were in
accordance with those reported in the literature.49 Chiralcel
OD-H; hexane/isopropanol (9:1), flow = 1.0 mL/min, k = 256 nm,
retention time of the racemic compound (in min): tR = 28.1,
tR = 32.9.
4.2.6. rac-(E)-Ethyl 5-hydroxy-5-(4-methoxyphenyl)pent-2-
enoate rac-4
Compound
(trimethylsiloxy)-1-ethoxy-1,3-butadiene
4
was obtained analogously to 1a using 1-
with 76% yield
(1.141 mg, 4.56 mmol) as a colorless liquid. 1H NMR (400 MHz,
CDCl3) d 7.25 (d, J = 8 Hz, 2H), 6.98–6.89 (m, 1H), 6.86 (d, J = 8 Hz,
2H), 5.86 (dt, J = 16.0, 1.3 Hz, 1H), 4.76 (dd, J = 8.0, 4.0 Hz, 1H),
4.16 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 2.63–2.60 (m, 2H), 2.04 (s,
1H) 1.26 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) 166.2,
159.2, 144.7, 135.6, 126.9, 123.9, 113.9, 72.7, 60.2, 55.2, 41.7,
hexane/isopropanol
(9:1),
flow = 1.0 mL/min,
k = 256 nm,
retention time of the racemic compound (in min): tR (R) = 13.3, tR
(S) = 15.2.
Please cite this article in press as: Koszelewski, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.003

8
D. Koszelewski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
14.2; Element. Anal. calcd for C14H18O4: C, 67.18; H, 7.25; found C,
67.05; H, 7.28.
4.3.5. rac-(E)-methyl 5-acetoxy-5-(naphthalen-2-yl)pent-2-
enoate rac-2e
Yield 73% (435 mg, 1.46 mmol), colorless liquid. 1H NMR
(400 MHz, CDCl3) d 7.85–7.82 (m, 3H), 7.78 (s, 1H), 7.5–7.47 (m,
3H), 6.87 (dt, J = 15.6, 7.2 Hz, 1H), 6.02 (dd, J = 7.6, 5.6 Hz, 1H),
5.87 (dt, J = 15.6, 1.2 Hz, 1H), 3.70 (s, 3H), 2.90–2.80 (m, 2H), 2.10
(s, 3H); 13C NMR (100 MHz, CDCl3) d 170.0, 166.4, 143.2, 136.6,
133.2, 133.1, 128.5, 128.0, 127.6, 126.3, 126.2, 125.6, 124.0,
123.9, 74.4, 51.4, 38.9, 21.1; HRMS (ESI) calcd for C18H18O4Na (M
+Na) 321.1103; found 321.1103. Chiralcel OD-H; hexane/iso-
propanol (9:1), flow = 1.0 mL/min, k = 256 nm, retention time of
the racemic compound (in min): tR = 13.0, tR = 15.6.
4.3. General procedure for the synthesis of racemic acetates rac-
2a–e
4.3.1. Preparation of rac-(E)-methyl 5-(phenyl)-5-acetoxypent-
2-enoate rac-2a
To a solution of (E)-methyl 5-hydroxy-5-phenylpent-2-enoate
1a (412 mg, 2.00 mmol) in dry DCM (10 mL), Et3N (404 mg,
4.00 mmol) and 4-dimethylaminopyridine (12 mg, 0.10 mmol)
were subsequently added. The reaction was then cooled to 0 °C
and a solution of Ac2O (306 mg, 1.50 mmol) in dry DCM (3 mL)
was added dropwise through a syringe. After stirring for 20 min,
the reaction mixture was allowed to warm to room temperature
and stirred for 5 h. The reaction was quenched by saturated NH4Cl
solution (20 mL). The organic phase was extracted with ethyl acet-
ate (3 ꢁ 30 mL). The combined organic layers were washed with
brine and dried over dry Na2SO4. The solvent was removed in vacuo
and the residue was purified by silica gel column chromatography
(hexanes/EtOAc) to give the desire product 2a as a colorless liquid
(447 mg, 1.80 mmol) with 90%. 1H NMR (400 MHz, CDCl3) d 7.30–
7.27 (m, 5H), 6.84 (dt, J = 16.0, 7.2 Hz, 1H), 5.87 (t, J = 1.2 Hz, 1H),
5.85–5.82 (m, 2H), 3.70 (s, 3H), 2.81–2.70 (m, 2H), 2.07 (s, 1H);
13C NMR (100 MHz, CDCl3) 169.9, 166.4, 143.2, 139.3, 128.6,
128.2, 126.3, 123.9, 74.1, 51.4, 38.9, 21.0; Element. Anal. calcd for
4.4. Preparation of rac-(E)-methyl 5-(phenyl)-5-acrylo-
yloxypent-2-enoate rac-3
To a solution of (E)-methyl 5-hydroxy-5-phenylpent-2-enoate
1a (412 mg, 2.00 mmol) in dry DCM (20 mL), was added Et3N
(6.00 mmol, 840
lL). The solution was cooled to 0 °C, and a solu-
tion of acryloyl chloride (4.00 mmol, 325
lL) in dry DCM (5 mL)
slowly added. The mixture was warmed to ambient temperature,
poured into water, and the organic layer separated. The aqueous
layer was extracted with DCM, and the combined organic extracts
were dried over Na2SO4, filtered, and all of the volatiles were evap-
orated. The residue was purified by chromatography on silica (hex-
anes/EtOAc) to give product 3 (458 mg, 1.76 mmol) in 88% yield as
a colourless liquid. 1H NMR (400 MHz, CDCl3) d 7.29–7.25 (m, 5H),
6.88 (dt, J = 15.5, 7.2 Hz, 1H), 6.45 (dd, J = 16.0, 1.3 Hz, 1H), 6.17
(dd, J = 16.0, 8.0 Hz, 1H), 5.96 (dd, J = 16.0, 8.0 Hz, 1H), 5.91–5.85
(m, 2H), 3.69 (s, 3H), 2.86–2.72 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 166.4, 165.1, 143.1, 139.2, 131.2, 128.6, 128.2, 126.3, 124.0, 74.3,
51.4, 39.0. HRMS (ESI) calcd for C15H16O4Na (M+Na) 283.0946;
found 283.0937. HPLC: Chiralcel OD-H; hexane/isopropanol (9:1),
flow = 1.0 mL/min, k = 256 nm, retention time of the racemic com-
pound (in min): tR (R) = 8.4, tR (S) = 9.4.
C14H16O4: C, 67.73; H, 6.50; found C, 67.84; H, 6.42; HPLC: Chiralcel
OD-H; hexane/isopropanol (9:1), flow = 1.0 mL/min, k = 256 nm,
retention time of the racemic compound (in min): tR (R) = 7.5, tR
(S) = 8.6.
4.3.2. rac-(E)-Methyl 5-(4-methoxyphenyl)-5-acetoxypent-2-
enoate rac-2b
Yield 84% (467 mg, 1.68 mmol), colorless liquid. 1H NMR
(400 MHz, CDCl3) d 7.26 (d, J = 8 Hz, 2H), 6.87 (d, J = 8 Hz, 2H),
6.83–6.79 (m, 1H), 5.87 (t, J = 1.2 Hz, 1H), 5.83–5.79 (m, 2H), 3.78
(s, 3H), 3.70 (s, 3H), 2.82–2.66 (m, 2H), 2.04 (s, 1H); 13C NMR
(100 MHz, CDCl3) 170.0, 166.4, 159.5, 143.4, 131.4, 127.4, 123.8,
113.9, 73.8, 55.2, 51.4, 38.7, 21.1; HRMS (ESI) calcd for C15H18O5Na
(M+Na) 301.1052; found 301.1048. Chiralcel OD-H; hexane/iso-
propanol (9:1), flow = 1.0 mL/min, k = 256 nm, retention time of
the racemic compound (in min): tR = 8.6, tR = 10.5.
4.5. Preparation of ethyl (2E,4E)-5-(4-methoxyphenyl)penta-
2,4-dienoate 5
(E)-Ethyl 5-hydroxy-5-(4-methoxyphenyl)pent-2-enoate
4
(100 mg, 0.4 mmol) was dissolved in CH2Cl2 (10 mL), and trifluo-
roacetic acid (1 mL) was added. After 1 hour, toluene (5 mL) was
then added and the reaction mixture was concentrated in
vacuo. The resulting acid was dissolved in CH2Cl2 (10 mL) and N-
4.3.3. rac-(E)-Methyl 5-(4-fluorophenyl)-5-acetoxypent-2-
enoate rac-2c
(3-dimethylaminopropyl)-N0-ethylcarbodiimide
hydrochloride
Yield 89% (474 mg, 1.78 mmol), colorless liquid. 1H NMR
(400 MHz, CDCl3) d 7.28–7.26 (m, 2H), 7.05–7.00 (m, 2H), 6.84–
6.78 (m, 1H), 5.86 (t, J = 1.6 Hz, 1H), 5.82 (dd, J = 7.6, 6.0 Hz, 1H),
3.71 (s, 3H), 2.80–2.65 (m, 2H), 2.06 (s, 3H); 13C NMR (100 MHz,
CDCl3) 169.9, 166.3, 161.2, 142.9, 135.2, 128.2, 128.1, 124.1,
115.6, 115.4, 73.5, 51.5, 38.8, 21.0; HRMS (ESI) calcd for C14H15O4-
FNa (M+Na) 289.0852; found 289.0851. Chiralcel OD-H; hexane/
isopropanol (95:5), flow = 1.0 mL/min, k = 256 nm, retention time
of the racemic compound (in min): tR = 8.5, tR = 9.7.
(77 mg, 0.4 mmol) and 4-(dimethylamino)pyridine (49 mg,
0.4 mmol) were added. The reaction mixture was stirred at 70 °C
for 3 h. A saturated aqueous solution of NaHCO3 was added and
the aqueous phase was extracted with CH2Cl2. The organic layer
was dried over Na2SO4 and the residue was purified by column
chromatography to give 5 in 99% isolated yield (92 mg, 0.4 mmol)
as a colourless crystals; mp 53 °C [lit.50 52–54 °C]; 1H NMR (CDCl3,
400 MHz): d 7.39 (dd, J = 15.3, 10.9 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H),
6.83 (d, J = 8.7 Hz, 2H), 6.76 (d, J = 15.5 Hz, 1H), 6.74 (dd, J = 15.5,
10.9 Hz, 1H), 5.92 (d, J = 15.3 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.81
(s, 3H), 1.30 (t, J = 7.1 Hz 3H). 13C NMR (CDCl3, 100 MHz): d
167.2, 160.4, 144.9, 140.0, 128.6, 124.1, 120.0, 114.2, 60.1, 55.3,
14.3. The 1H and 13C NMR data were in accordance with those
reported in the literature.50
4.3.4. rac-(E)-methyl 5-(4-nitrophenyl)-5-acetoxypent-2-enoate
rac-2d
Yield 82% (481 mg, 1.64 mmol), light yellowish liquid. 1H NMR
(400 MHz, CDCl3) d 7.25 (d, J = 8H, 2H), 7.51 (d, J = 8H, 2H), 6.87–
6.80 (m, 1H), 5.95–5.92 (m, 1H), 5.82 (dt, J = 16.0, 1.2 Hz, 1H),
3.75 (s, 3H), 2.84–2.73 (m, 2H), 2.14 (s, 3H); 13C NMR (100 MHz,
CDCl3) 169.9, 166.1, 155.6, 141.8, 127.1, 124.7, 123.9, 73.1, 51.6,
38.7, 20.9; HRMS (ESI) calcd for C14H15NO6Na (M+Na) 316.0797;
found 316.0788. Chiralcel OD-H; hexane/isopropanol (9:1), flow =
1.0 mL/min, k = 256 nm, retention time of the racemic compound
(in min): tR = 18.5, tR = 20.2.
4.6. Enzymatic kinetic resolutions procedures
4.6.1. General procedure for analytical enzymatic kinetic
resolution via hydrolysis
To a solution of 2a (0.04 mmol) in PBS/co-solvent (50 mM, pH
7.4) (2 mL), an enzyme (5 mg) was added in a 10 mL screw-top vial.
Please cite this article in press as: Koszelewski, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.003

D. Koszelewski et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
9
The reaction mixture was stirred for 72 or 20 hours at 20 °C. The
aqueous phase was extracted with TBME. The organic phase was
dried over Na2SO4 and the solvent was removed under vacuum.
retention time of the racemic compound (in min): tR (S) = 50.8, tR
(R) = 58.4.
4.8.1. (R)-6-Phenyl-5,6-dihydro-2H-pyran-2-one (R)-6
4.7. Preparative synthesis of the (E)-methyl (5R)-hydroxy-5-
phenylpent-2-enoate (R)-1a
Yield 72%, colourless semi-solid (49 mg, 0.28 mmol); [a] =
D
+215.6 (c 0.5, CHCl3) >99% ee; lit.46b
[a]D = +198 (c 0.1, CHCl3)
90% ee for the (R)-enantiomer. The 1H and 13C NMR data were in
To a solution of 2a (250 mg, 1 mmol) in PBS (100 mM, pH 7.4)
with 20% v/v of TBME (20 mL), Pseudomonas fluorescence lipase
(50 mg) was added. The reaction mixture was stirred for 20 h at
20 °C. The aqueous phase was extracted with DCM (3 ꢁ 20 mL).
The combined organic phases were dried over Na2SO4 and the sol-
vent was evaporated under reduced pressure. Product was purified
using flash chromatography on silica gel (hexanes/EtOAc) provid-
ing (E)-methyl (5R)-hydroxy-5-phenylpent-2-enoate ((R)-1a) with
39% isolated yield (80.5 mg, 0.39 mmol) as colorless oil. The 1H
NMR data were in accordance with those recorded for racemate,
accordance with those reported in the literature.46b
4.9. Preparation of rac-6-phenyltetrahydropyran-2-one rac-7
After two vacuum/H2 cycles to remove air from the reaction
flask, a mixture of the (E)-methyl 5-hydroxy-5-phenylpent-2-eno-
ate 1a (100 mg, 0.48 mmol), and 10% Pd/C (10 wt % of the 1a) in dry
THF (5 mL) was vigorously stirred at ambient temperature (ca.
21 °C) under an ambient pressure of hydrogen (balloon). After
1.5 h, the quantitative conversion of the substrate was observed
(TLC analysis). The reaction mixture was filtered using a membrane
[
a]
D = +42.8 (c 1.0, CHCl3); lit.15d
the (S)-enantiomer ee = 95%.
[a
]D = ꢀ41.3 (c 0.48, CHCl3) for
filter (MilliporeMillex
x-LG, 0.20 mm). The solvent was evaporated
under vacuum and the obtained intermediate methyl 5-hydroxy-5-
phenylpentanoate (97 mg, ca. 97% yield) was subjected to further
transformation without purification. The hydroxy ester was dis-
solved in dry CH2Cl2 (10 mL), and the solution was cooled to 0 °C,
followed by the addition of 5 drops of trifluoroacetic acid. The reac-
tion mixture was stirred at room temperature for 8 hours, washed
with saturated NaHCO3 (2 ꢁ 20 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel using hexanes/ethyl acetate as the
eluent to provide product 7 as a colourless solid in 89% yield
(75 mg, 0.43 mmol); mp 69–71 °C [lit.52 69–70 °C methylcyclohex-
ane]; 1H NMR (400 MHz, CDCl3) d 7.40–7.28 (m, 5H), 5.35 (dd,
J = 10.5, 3.5 Hz, 1H), 2.70 (dddd, J = 17.8, 6.5, 6.5, 1.0 Hz, 1H), 2.58
(ddd, J = 17.7, 7.7, 7.7 Hz, 1H), 2.18 (dddd, J = 13.6, 4.4, 4.4,
4.4 Hz, 1H), 2.00–1.92 (m, 2H), 1.87 (ddd, J = 13.5, 10.3, 8.8,
6.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 171.2, 139.8, 128.5,
128.2, 125.6, 81.5, 30.5, 29.4, 18.5. The 1H and 13C NMR data were
in accordance with those reported in the literature.52 Chiralcel OJ;
hexane/isopropanol (9:1), flow = 0.8 mL/min, k = 256 nm, retention
time of the racemic compound (in min): tR (R) = 27.2, tR (S) = 30.0.
4.7.1. (+)-(E)-Methyl 5-hydroxy-5-(4-methoxyphenyl)pent-2-
enoate (+)-1b
Yield 35% (82.7 mg, 0.35 mmol), colorless liquid. The 1H NMR
data were in accordance with those recorded for racemate, [a] =
D
+9.2 (c 1.0, CHCl3) for 98% ee.
4.7.2. (+)-(E)-Methyl 5-(4-fluorophenyl)-5-hydroxypent-2-
enoate (+)-1c
Yield 41% (92 mg, 0.41 mmol), colorless liquid. The 1H NMR
data were in accordance with those recorded for racemate, [a] =
D
+38.2 (c 1.0, CHCl3) for >99% ee.
4.7.3. (+)-(E)-Methyl 5-(4-nitrophenyl)-5-hydroxypent-2-enoate
(+)-1d
Yield 32% (80 mg, 0.32 mmol), colorless liquid. The 1H NMR
data were in accordance with those recorded for racemate, [a] =
D
+15.3 (c 1.0, CHCl3) for 98% ee.
4.7.4. (+)-(E)-Methyl 5-hydroxy-5-(naphthalen-2-yl)pent-2-
enoate (+)-1e
Yield 20% (51 mg, 0.20 mmol), colorless liquid. The 1H NMR data
4.9.1. (R)-6-Phenyltetrahydropyran-2-one (R)-7
were in accordance with those recorded for racemate, [
(c 1.0, CHCl3) for 98% ee.
a
]
D = +22.7
Yield 88%, colourless semi-solid (62 mg, 0.35 mmol); [a] =
D
+37.2 (c 1.0, CHCl3) 99% ee; lit.46
[a]D = +34.4 (c 1, CHCl3) 97% ee
for the (R)-enantiomer. 1H and 13C NMR data were in accordance
4.8. Preparation of rac-6-phenyl-5,6-dihydro-2H-pyran-2-one
rac-6
with those reported in the literature.46
Acknowledgements
Substrate 3 (100 mg, 0.38 mmol) was dissolved in dry DCM
(30 mL) and stirred under an argon atmosphere. Grubbs 2nd gen-
eration catalyst (10 mol %) was added dropwise dissolved in dry
DCM (10 mL). The resulting solution was stirred at 55 °C under
an argon atmosphere for 18 hours. Reaction was quenched with
brine (10 mL). The organic layer was separated, dried over MgSO4,
and the volatiles were removed under reduced pressure. The crude
products was purified by column chromatography on silica gel
(n-hexanes/EtOAc) afforded the titled compound rac-6 as a colour-
less solid with 82% yield (55 mg, 0.31 mmol); mp 57 °C [lit.51 56–
58 °C]; 1H NMR (400 MHz, CDCl3) d 7.41–7.37 (m, 5H), 6.98 (ddd,
J = 8.4, 5.5, 2.9 Hz, 1H), 6.15 (dd, J = 9.9, 1.5 Hz, 1H), 6.14 (dd,
J = 9.9, 1.5 Hz, 1H), 5.46 (dd, J = 11.0, 4.7, Hz, 1H), 2.66 (ddt,
J = 18.3, 11.0, 2.6 Hz, 1H), 2.61 (dt, J = 18.7, 4.8 Hz, 1H); 13C NMR
This work was supported by Polish National Science Center pro-
ject No. 2013/11/B/ST5/02199 and COST CM1303 program. We
would like to dedicate this paper to Professor Vicente Gotor on
the occasion of his 70th birthday.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.05.
003.
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Please cite this article in press as: Koszelewski, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.003

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Please cite this article in press as: Koszelewski, D.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.05.003