Chemoenzymatic synthesis of trans-β-aryl-δ-hydroxy-γ-lactones and enzymatic kinetic resolution of their racemic mixtures

Article abstract of DOI:10.3390/molecules21111552

Two novel and convenient routes to obtain enantiomerically enriched trans-β-aryl-δ-hydroxy-γ-lactones 5a-d with potential antifeedant and anticancer activity were developed. In the first method starting from corresponding enantiomers of γ,δ-unsaturated es

Full text of DOI:10.3390/molecules21111552

molecules
Article
Chemoenzymatic Synthesis of
trans-β-Aryl-δ-hydroxy-γ-lactones and Enzymatic
Kinetic Resolution of Their Racemic Mixtures
Andrzej Skrobiszewski 1,*, Witold Gładkowski 1, Gabriela Maciejewska 2 and
Czesław Wawrzen´czyk 1
1
Department of Chemistry, Wrocław University of Environmental and Life Sciences, Norwida 25,
Wrocław 50-375, Poland; glado@poczta.fm (W.G.); czeslaw.wawrzenczyk@up.wroc.pl (C.W.)
Central Laboratory of the Instrumental Analysis, Wrocław University of Technology,
2
˙
Wybrzeze Wyspian´skiego 27, Wrocław 50-370, Poland; gabriela.maciejewska@pwr.edu.pl
*
Correspondence: andrzej.skrobiszewski@gmail.com; Tel.: +48-661-464-355
Academic Editor: Roman Dembinski
Received: 11 October 2016; Accepted: 11 November 2016; Published: 23 November 2016
Abstract: Two novel and convenient routes to obtain enantiomerically enriched trans-β-aryl-δ-
hydroxy-
first method starting from corresponding enantiomers of
from enzymatically resolved allyl alcohols 1a , both enantiomers of hydroxylactones 5a–d
γ
-lactones 5a
–d
with potential antifeedant and anticancer activity were developed. In the
-unsaturated esters 4a derived
were
γ
,δ
–d
–
d
synthesized with high enantiomeric excesses (73%–97%). Configurations of the stereogenic centers
of the synthesized compounds were assigned based on the mechanism of acidic lactonization
of esters 4a
the production of optically active trans-
–
d
in the presence of m-chloroperbenzoic acid (m-CPBA). An alternative method for
-aryl- -hydroxy- -lactones 5a was lipase-catalyzed
β
δ
γ
–d
kinetic resolution of their racemic mixtures by transesterification with vinyl propionate as the acyl
donor. The most efficient enzyme in the screening procedure was lipase B from Candida antarctica.
Its application on a preparative scale after 6 h afforded unreacted (+)-(4S,5R,6S)-hydroxylactones
5a–d and (+)-(4R,5S,6R)-propionates 6a–d, most of them with high enantiomeric excesses (92%–98%).
Resolution of lactone 5d with bulky 1,3-benzodioxol ring provided products with significantly
lower optical purity (ee = 89% and 84% for hydroxylactone 5d and propionate 6d, respectively).
The elaborated methods give access to both enantiomers of trans-β-aryl-δ-hydroxy-γ-lactones 5a–d
with the defined absolute configurations of stereogenic centers, which is crucial requirement for the
investigations of relationship: spatial structure–biological activity.
Keywords: hydroxylactones; kinetic resolution; lipases
1. Introduction
Lactones with an aromatic substituent are widely present in the plant kingdom. They are isolated
from roots, tubers, knots, stalks, seeds and fruits [
and cyanobacteria [ ]. They are reported to display a wide variety of biological activities such
as anticancer [ ], antioxidant [ ], antifungal [10 11], antiviral [12 13], anti-inflammatory [14],
antifeedant [15], anticonvulsant [16] and phytoestrogenic [17,18].
Optically active lactones are of high importance due to their application as building blocks in
natural therapeutic compounds [19 20] and the well-known relationship between the configuration of
stereogenic centers and their biological activity [21 22]. Therefore, there is a growing need to develop
new methods for the synthesis of enantiomerically enriched lactones. These strategies involve i.a.
alkylation of chiral precursors [23 24], catalytic asymmetric hydrogenation of butenolides [25], kinetic
1–3] and have also been found in mushrooms
4,5
6,
7
8,
9
,
,
,
,
,
resolution of lactone precursors by hydrolysis of ester bond [26
,27] and different whole-cell mediated
Molecules 2016, 21, 1552; doi:10.3390/molecules21111552
www.mdpi.com/journal/molecules

Molecules 2016, 21, 1552
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reactions including reduction of unsaturated formyl esters [28], stereoselective reduction of a carbonyl
group in γ-acetyl-γ-lactones [29] and enantioselective hydrolysis of nitriles [30].
With regard to these reports, we have taken up research on the synthesis of a series of
racemic γ-lactones with various β-phenyl substituents at the lactone ring [31–35]. We have also
developed convenient chemoenzymatic methods for the synthesis of optically active iodolactones with
antiproliferative activity starting from enantiomerically enriched allyl alcohols with 4-arylbut-3-en-2-ol
system as chiral precursors [36
methods for the production of optically active trans-
–
38]. In this paper, we would like to present two novel, alternative
-aryl- -hydroxy- -lactones. One of these methods
β
δ
γ
involves the application of chiral precursors, and an alternative method is based on lipase-catalyzed
kinetic resolution of racemic mixtures in the transesterification process.
2. Results and Discussion
In our previous paper [33] using methodology reported earlier by Gowri-Shankar [39],
we reported the synthesis of racemic trans-
δ-hydroxy-
γ
-lactones 5a–d as the main products of
lactonization of corresponding of -unsaturated esters 4a–d
γ
,
δ
. Because of their proven biological
activities, i.e., antifeedant and antiproliferative, we decided to evaluate methods for the production of
these compounds in an optically active form.
The first elaborated method was based on the lactonization of chiral precursors, enantiomerically
enriched
γ
,
δ
-unsaturated esters 4a
–
d
in the presence of m-CPBA. These precursors are products of the
. During
stereoselective Claisen–Johnson rearrangement of enzymatically resolved allyl alcohols 1a
–d
this reaction, a complete transfer of chirality from atom C-2 of alcohols to the benzylic position C-3 of
ester is observed. The details of this two-step synthesis involving lipase-catalyzed enzymatic resolution
of allyl alcohols 4a
enantiomeric pairs of esters with unsubstituted phenyl ring (4a), p-methylphenyl substituent (4b) and
1,3-benzodioxol ring (4d) [36 38]. In order to obtain both enantiomers of ester 4c with p-methoxyphenyl
,b,d and their orthoester Claisen rearrangement were reported earlier for synthesis of
,
substituent, a kinetic resolution of racemic alcohol 1c via transesterification process catalyzed by lipase
B from C. antarctica (CAL-B) was applied (Scheme 1). Reaction was monitored by chiral GC after
derivatization of unreacted alcohol into acetate. Standards used in this analysis—racemic acetate
2
and propionate —were synthesized by the esterification of rac-1c with acetyl and propionyl chloride,
3
respectively (Section 3.3).
O
O
R
O
2: R = Me
3: R = Et
rac-2,3
a
O
OH
OH
O
R
b
+
O
O
O
c
(+)-(3E,2R)-3
(−)-(3E,2S)-1c
rac-1c
OH
O
(+)-(3E,2R)-1c
Scheme 1. Enzymatic resolution of racemic 4-(4’-methoxyphenyl)but-3-en-2-ol and synthesis of racemic
◦
esters
2,
3
. Reagents and conditions: (a) MeC(O)Cl or EtC(O)Cl, Et2O, pyridine, 0 C to r.t., 24 h; (b) CAL-B,
vinyl propionate, DIPE, r.t., 4 h; and (c) 5% NaOH, reflux, 3 h.

Molecules 2016, 21, 1552
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Vinyl propionate was used as the acyl donor because it was successfully used in the resolution of
analogs of 1c with 4-phenylbut-3-en-2-ol system [36 38]. After 4 h (
)-(3E,2S)-4-(40-methoxyphenyl)
but-3-en-2-ol (1c) and its propionate (+)-(3E,2R)- were obtained in 45% and 43% yield and 78%
–
−
3
and 82% ee, respectively. Products were separated by column chromatography. The configuration
S of slowly reacting enantiomer of alcohol 1c was confirmed by the negative specific rotation sign
corresponding with that reported in the literature for the known (S)-alcohol [40]. Consequently, the
configuration of propionate (+)-
Propionate (+)-(3E,2R)- , which was not previously obtained in optically active form, was subsequently
hydrolyzed under basic conditions to (+)-(3E,2R)-alcohol 1c (yield 98%, ee = 82%). Enantiomerically
enriched alcohols ( )-(3E,2S)-1c and (+)-(3E,2R)-1c were subjected to Johnson–Claisen rearrangement.
As expected, the reactions proceeded with complete retention of configuration of both stereogenic
center and double bond. In the result, respective enantiomers of ester 4c: (+)-(4E,3S) and ( )-(4E,3R)
3, product of faster reacting enantiomer of alcohol 1c, was assigned as R.
3
−
−
with exactly the same enantiomeric excesses as starting alcohols were obtained as the only products
(Scheme 2).
Both enantiomeric forms of four
γ,δ-unsaturated esters 4a–d were subjected to lactonization with
m-CPBA and catalytic amount of trifluoroacetic acid (Scheme 2).
Scheme 2. Synthesis of optically active hydroxylactones 5a−d from enantiomerically enriched alcohols
Reagents and conditions: (a) CH3C(OEt)3, propionic acid, 138 ◦C, 24 h; and (b) m-CPBA,
1a−d
.
CF3COOH, CHCl3, 24 h.
During the reaction two epoxyesters, threo and erythro are formed and four possible lactones could
be the final products: two
reaction carried out earlier for racemic compounds [33],
mixture of stereoisomers. cis -Lactones formed from erythro epoxyesters were not isolated and the only
isomers isolated in pure form were trans -lactones 5a d, which are the products of lactonization of
threo epoxyesters. Advantageous formation of trans isomers 5a over the cis isomers can be explained
γ
-lactones and two
δ-lactones (Figure S1). Unfortunately, similarly to the
δ
-lactones were isolated as the unseparable
γ
γ
–
–
d
by the fact that in threo epoxyesters oxygen of the epoxide ring is less hindered by large aromatic
substituent compared with erythro epoxyesters (Scheme 3).

Molecules 2016, 21, 1552
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Scheme 3. Formation of two epoxyesters from esters (4E,3S)-4a–d and mechanism of acidic
lactonization of favoured threo isomer showing the configurations of stereogenic centers of isolated
trans-δ-hydroxy-γ-lactones 5a–d.
Chiral GC analysis indicated that enantiomeric excesses of lactones 5a
determined earlier for starting esters 4a and ranged from 73% to 90% in the case of hydroxylactones
obtained from (S)-esters 4a and 82%–97% for their antipodes synthesized from (R)-esters 4a–d.
–d corresponded with those
–d
–d
The important challenge was the assignment of the configurations of stereogenic centers at C-4, C-5
and C-6 for newly synthesized enantiomers, which was made based on the mechanism of acidic
lactonization (Scheme 3). Monitoring the composition of the reaction mixture did not show the
presence of possible intermediate diolester, which excluded the opening of epoxide ring by water
and confirmed the mechanism of lactonization proposed by Olejniczak et al. [41]. This mechanism
involves the protonation of an oxirane ring followed by its nucleophilic opening by the attack of an
oxygen from carboethoxy group with the simultaneous formation of hydroxy group. In the next step
of reaction, nucleophilic addition of water to carboethoxy group takes place with subsequent release
of the ethanol. Considering lactonization of (S)-esters 4a–d (Scheme 3), the configuration R at C-4 of
forming trans-( )- -hydroxy- -lactones 5a is the result of the configuration of starting ester, and its
−
δ
γ
–d
apparent change is only the result of different priority of substituents after formation of oxirane ring.
The configurations S at C-5 and R at C-6 are the consequence of stereochemical course of reaction in
which the carboethoxy group approaches the C-5 atom from the opposite side of the oxirane ring.
Thus, the C-O bond of the
reasoning let us assign the configuration of (+)-
4a as 4S,5R and 6S. The presented stereochemical course of reaction was earlier confirmed for
γ
-lactone ring and hydroxy group are oriented antiperiplanary. Similar
δ
-hydroxy- -lactones 5a formed from (R)-esters
γ
–d
–
d

Molecules 2016, 21, 1552
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the products of lactonization of ethyl esters of 3,7-dimethyl-4,5-epoxyoctanoic acid and its 7-methyl
homolog, in which the configurations of stereocenters were determined by CD (Circular Dichroism)
measurements [42].
The alternative method for the production of trans-β-aryl-δ-hydroxy-γ-lactones 5a–d in
enantiomerically enriched form was kinetic resolution of their racemic forms synthesized
previously [33]. Due to the large difference in sizes of two substituents at the stereogenic center C-6
joined with a secondary hydroxy group, the hydroxylactones 5a
for the lipase-catalyzed transesterification [43 44], and high enantiomeric excesses of the products
were expected. In the screening procedure, racemic trans- -phenyl- -hydroxy- -lactone 5a as a model
–d seemed to be excellent substrates
,
β
δ
γ
substrate was subjected to the action of four commercially available lipases in the presence of vinyl
propionate as the acyl donor (Scheme 4). The reaction was conducted in diisopropyl ether (DIPE) and
monitored by chiral gas chromatography with racemic lactones 5a
–
d
[
33] and racemic propionates
6a–d (Section 3.3) as the standards. The results are shown in Table 1.
Scheme 4. Enzymatic resolution of racemic hydroxylactones 5a−d
.
Reagents and conditions:
◦
(a) EtC(O)Cl, Et2O, pyridine, 0 C to r.t., 24 h; and (b) CAL-B, vinyl propionate, DIPE, r.t., 2 h.
Table 1. Results of enzymatic transesterification of rac-δ-hydroxy-γ-lactone 5a with vinyl propionate.
Time
(h)
Conversion a
(mol %)
ee of (+)-Hydroxylactone
ee of (+)-Propionyloxylactone
E b
Enzyme
5a (%)
6a (%)
1
2
4
6
49
51
51
51
96
99
99
99
99
96
96
96
>200
>200
>200
>200
CAL-B
2
4
6
17
34
44
20
42
55
97
80
71
80
13
10
CCL
2
4
6
11
43
53
12
68
91
99
90
80
>200
38
28
Lipozyme TL IM
2
4
6
11
25
40
12
34
65
99
99
99
>200
>200
>200
Amano Lipase PS
a
Conversion calculated according to equation: c = (ees/ees + eep)
×
100; b The enantiomeric ratio calculated
according to equation: E = ln[(1
unreacted hydroxylactone 5a, eep = enantiomeric excess of propionate 6a.
−
ees)/(1 + (ees/eep)]/ln[(1 + ees)/(1 + (ees/eep)]; ees = enantiomeric excess of
The most effective biocatalyst was CAL-B. At 49% conversion after 1 h of the reaction catalyzed by
this enzyme, the enantiomeric excesses of the slower reacting (+)-enantiomer of δ-hydroxy-γ-lactone
5a and its propionate (+)-6a were 96% and 99% respectively. Continuing the process, a slight decrease
of ee for (+)-propionate 6a was observed, reaching 96% after 6 h, whereas ee of hydroxylactone 5a raised
to 99%. Good results were achieved for Lipozyme TL IM (Thermomyces lanuginosus lipase) as well,

Molecules 2016, 21, 1552
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but the transesterification proceeded at a lower rate. After 6 h, the 53% conversion was observed.
During this period, the enantiomeric excess of unreacted (+)-hydroxylactone 5a gradually increased
from 12% to 91%, whereas the optical purity of (+)-propionate 6a decreased from 99% to 80%. High
enantioselectivity (E > 200) was found for Amano PS (lipase from Burkholderia cepacia). In this case,
high enantiomeric enrichment of (+)-propionate 6a was found (ee = 99%), but the ee of unreacted
(+)-hydroxylactone 5a even after 6 h was unsatisfactory (65%). After 6 h of the process catalyzed
by CCL low (ee = 55%) and moderate (ee = 71%), enantiomeric purity of substrate 5a and ester 6a
,
respectively, was observed at the 44% conversion. For all enzymes, prolonging reaction time affected
neither conversion nor enantiomeric composition of the products.
Taking into consideration the highest enantiomeric excesses obtained after 6 h for both
hydroxylactone 5a and propionate 6a, CAL-B was selected as the biocatalyst for the kinetic resolution
of hydroxylactones 5a
the substrates in all cases was 50%–52%. The unreacted substrates 5a
were separated by column chromatography in yields ranging from 34% to 45%, respectively, which
is a very satisfactory result for kinetic resolution. (+)- -Hydroxy- -lactone 5a with unsubstituted
phenyl ring and its (+)-propionate 6a were obtained with a very high enantiomeric excesses, 99% and
92%, respectively. Taking into consideration the increasing size of an aryl substituent at -position
in substrates 5b , comparably high enantioselectivity of the kinetic resolution was expected. It was
–
d
on a preparative scale (Table 2). After 6 h of reaction, the conversion of
–
d
and their propionates 6a
–d
δ
γ
β
–d
confirmed in the case of (+)-hydroxylactones with p-methylphenyl- and p-methoxyphenyl ring
(5b and 5c) (ee = 99% and 98%, respectively) and their corresponding (+)-propionates 6b and 6c
(ee = 91% and 98%, respectively). The presence of additional 1,3-benzodioxol ring condensed with
benzene resulted in the lowest effectiveness of kinetic resolution for hydroxylactone 5d, of which
(+)-enantiomer was obtained with ee = 89%. Optical purity of its (+)-propionate 6d was comparably
low (ee = 84%). A similar effect of the 1,3-benzodioxol ring on the enantioselectivity of lipase-catalyzed
transesterification with vinyl propionate was also reported for allyl alcohol 1d [37]. It is likely that
the steric hindrance in the molecules alcohol 1d and hydroxylactone 5d impedes the binding of these
substrates to the active site of the lipase.
Table 2. Results of CAL-B-catalyzed preparative transesterification of rac-δ-hydroxy-γ-lactones 5b–d
with vinyl propionate after 6 h of process.
Conversion a
(mol %)
ee of (+)-Hydroxylactone
ee of (+)-Propionyloxylactone
E b
Substrate
(%)
(%)
5b
5c
5d
a
52
50
51
99 (5b)
98 (5c)
89 (5d)
91 (6b)
98 (6c)
84 (6d)
111
>200
34
Conversion calculated according to equation: c = (ees/ees + eep)
×
100; b The enantiomeric ratio calculated
ees)/(1 + (ees/eep)]/ln[(1 + ees)/(1 + (ees/eep)]; ees = enantiomeric excess of
according to equation: E = ln[(1
unreacted hydroxylactones 5b–d, eep = enantiomeric excess of propionates 6b–d.
−
Comparison of the specific rotation signs of slowly transesterified δ-hydroxy-γ-lactones 5a–d
and those found for isomers with defined absolute configurations synthesized earlier from (R)- and
(S)-esters 4a let us establish undoubtedly the absolute configurations of both products of
enzymatic transesterification. Slowly reacting (+)- -hydroxy- -lactones 5a possessed configurations
4S,5R,6S, and opposite configurations 4R,5S,6R were consequently ascribed to (+)-propionates 6a–d.
–
d
δ
γ
–d
The configuration of these products at C-6 is consistent with that predicted based on the Kazlauskas’
rule. In this case, taking into consideration that the order of substituents at stereogenic center C-6
follows the rule: OH > large substituent (β-aryl substituted γ-lactone ring) > medium substituent
(methyl group), lipases preferentially catalyze the esterification of isomers with configuration 6R,
leaving those with 6S configuration untouched.

Molecules 2016, 21, 1552
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3. Experimental Section
3.1. General
Analytical thin layer chromatography (TLC) was performed on silica gel-coated aluminum plates
(DC-Alufolien Kieselgel 60 F254, Merck, Darmstadt, Germany), and the chromatograms were developed
using hexane/acetone mixture (4:1, v/v) as the developing system. Compounds were detected by
submersing the plates in a solution of 2 g H3[P(Mo3O10)4] and 1 g Ce(SO4)2 in 100 mL 10% H2SO4.
The course of reactions was monitored by gas chromatography (GC) on Agilent Technologies
(Palo Alto, CA, USA) 6890N with hydrogen as the gas carrier and autosampler instrument using
DB-5HT column (polyimide-coated fused silica tubing, 30 m
×
0.25 mm
×
0.10 µm). The temperature
programme was as follows: injector 220 ◦C, detector (FID) 330 ◦C, initial column temperature column
90 ◦C, 90–330 ◦C (rate 20 ◦C·min−1), final column temperature 330 ◦C (hold 2 min).
Enantiomeric compositions of synthesized compounds were determined by chiral gas
chromatography (CGC, Agilent Technologies) using CP (Chrompack)-Chiral-Dex CB (Cyclodextrin
Beta) column (25 m
was as follows: injector 260 ◦C, detector (FID) 280 ◦C; for acetate
temperature 80 ◦C, 80–200 ◦C (5 ◦C min−1), final column temperature 200 ◦C (1 min); for esters 4a
initial column temperature 50 ◦C, 80–200 ◦C (0.5 ◦C min−1), final column temperature 200 ◦C (1 min);
: initial column temperature: 80 ◦C, 80–200 ◦C
, final column temperature 200 ◦C (1 min). Racemic acetate
and racemic propionates
×
0.25 mm
×
0.25
µ
m, Varian, Palo Alto, CA, USA). The temperature programme
2
and propionate : initial column
2
·
–d:
·
for hydroxylactones 5a–d and the propionates 6a–d
(3 ◦C·min−1
)
2
3
and 6a–d were used as standards.
Products of synthesis and enzymatic reactions were separated by preparative column
chromatography on silica gel (Kieselgel 60, 230–400 mesh, Merck) using mixtures of various organic
solvents as a mobile phase.
The NMR spectra (1H-NMR, 13C-NMR, HMBC and HMQC) were recorded in a CDCl3 solution
on a Bruker Avance II 600 MHz spectrometer (Bruker, Rheinstetten, Germany). The IR spectra were
determined using a Mattson IR 300 Thermo Nicolet spectrophotometer (Mattson, Waltham, MA, USA)
using KBr pellets or as neats. High resolution mass spectra (HRMS) were recorded using electron spray
ionization (ESI) technique on spectrometer Waters ESI-QTOF Premier XE (Waters Corp., Millford, MA,
USA). The optical rotations were measured on a Jasco P-2000-Na digital polarimeter (Easton, PA, USA)
with an intelligent Remote Module (iRM) controller. The indexes of refraction were measured on an
Abbe refractometer (Carl Zeiss, Jena, Germany). Melting points were determined on Boetius apparatus
(Nagema, Germany).
3.2. Chemicals and Enzymes
Diisopropyl ether (purity
(purity ≥ 99%), vinyl propionate (purity 98%), triethyl orthoacetate (purity 97%), 3-chloroperbenzoic
acid (purity 77%), trifluoroacetic acid (purity 99%) and diatomaceous earth (Celite 560) were
≥
98.5%), propionyl chloride (purity 99%), acetyl chloride
≤
purchased from Sigma-Aldrich (St. Louis, MO, USA). Analytical grade chemicals: propionic acid,
sodium hydrogen carbonate, sodium hydroxide, anhydrous magnesium sulphate, sodium chloride
and hydrochloric acid (35%–37%) and organic solvents of analytical grade were purchased from
POCH (Gliwice, Poland). Racemic trans-
β
-aryl- -lactones (5a
δ
-hydroxy-
γ
–d) were synthesized from
corresponding racemic
γ
,
δ
-unsaturated ethyl esters 4a–d as described previously [33]. Racemic
0
(E)-4-(4 -methoxyphenyl)but-3-en-2-ol (1c) was obtained from anisaldehyde according to the procedure
described by Mazur et al. [31]. Enantiomerically enriched esters: (S)-4a (ee = 90%) and (R)-4a
(ee = 97%), (S)-4b (ee = 83%) and (R)-4b (ee = 87%), (S)-4d (ee = 73%) and (R)-4d (ee = 82%) were
obtained according to the procedures described by Gładkowski et al. [36
Burkholderia cepacia ( 30,000 U/g), lipase B from Candida antarctica immobilized in a macroporous
acrylic resin (CAL-B > 5000 U/g), lipase from Candida cylindracea (CCL, 5.18 U/mg) were purchased
,38]. Amano Lipase PS from
≥

Molecules 2016, 21, 1552
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from Sigma-Aldrich and immobilized granulate Thermomyces lanuginosus lipase (Lipozyme TL IM,
250 U/g) from Novozymes (Bagsvaerd, Denmark).
3.3. General Procedure for the Synthesis of Racemic Esters 2, 3 and 6a–d
Racemic allyl alcohol 1c and racemic
β-aryl-δ-hydroxy-γ-lactones (5a–d) (0.003 mol) were
esterified according to the standard procedure [37] using propionyl chloride or acetyl chloride in
dry diethyl ether and dry pyridine (Scheme 1).
(E)-4-(40-Methoxyphenyl)but-3-en-2-yl acetate . Yield 83% (0.55 g); n2D0 = 1.5439; spectroscopic data in
2
accordance with those reported earlier [40].
(E)-4-(40-Methoxyphenyl)but-3-en-2-yl propionate
1732 (s), 1608 (s), 1512 (s) 1249 (s), 1187 (s), 1036 (s), 968 (m), 808 (m); H-NMR (300 MHz, CDCl3)
3
. Yield 85% (0.6 g); n2D0 = 1.5263; IR (film, cm−1):
1
δ
: 1.15 (t, J = 7.8 Hz, 3H, CH3CH2C(O)), 1.39 (d, J = 6.3 Hz, 3H, CH3-1), 2.34 (quartet, J = 7.8 Hz, 2H,
CH3CH2C(O)), 3.80 (s, 3H, –OCH3), 5.52 (m, 1H, H-2), 6.05 (dd, J = 15.9, 6.9 Hz, 1H, H-3), 6.55 (d,
J = 15.9 Hz, 1H, H-4), 6.84, 7.30 (two m, 4H, –C6H4); 13C-NMR (75 MHz, CDCl3)
: 9.08 ( H3CH2C(O)),
δ
C
20.42 (C-1), 27.88 (CH3C
H2C(O)), 55.23 (–OCH3), 70.99 (C-2), 113.91, 127.73 (C-20, C-30, C-50, C-60),
126.66 (C-3), 129.05 (C-10), 131.06 (C-4), 159.38 (C-40), 173.76 (CH3CH2
for C14H18O3 [M + H]+: 235.1334, found 235.1339.
C(O)); HRMS (ESI): m/z calcd.
4-Phenyl-5-(1-propionyloxyethyl)dihydrofuran-2-one 6a. Yield 87% (0.68 g); n2D0 = 1.3834; IR (KBr, cm−1):
1786 (s), 1738 (s), 1456 (m), 1184 (s), 701 (m) cm−1; 1H-NMR (300 MHz, CDCl3)
: 1.07 (t, J = 7.5 Hz, 3H,
H3CH2C(O)), 1.28 (d, J = 6.6 Hz, 3H, CH3-7), 2.17, 2.25 (two dq, J = 16.8, 7.5, 2H, CH3CH2C(O)), 2.65
δ
C
(dd, J = 18.0, 8.1 Hz, 1H, one of CH2-3), 3.05 (dd, J = 18.0, 9.6 Hz, 1H, one of CH2-3), 3.58 (ddd, J = 9.6,
8.1, 6.6 Hz, 1H, H-4), 4.54 (dd, J = 6.6, 4.5 Hz, 1H, H-5), 5.15 (qd, J = 6.6, 4.5 Hz, 1H, H-6), 7.21–7.40 (m,
5H, H-20, H-30, H-40, H-50, H-60); 13C-NMR (75 MHz, CDCl3)
δ
: 8.92 (
C
H3CH2C0(O)), 15.80 (C-7), 27.62
0
0
(CH3CH2C(O)), 37.69 (C-3), 42.70 (C-4), 70.36 (C-6), 86.98 (C-5), 126.89 (C-2 , C-6 ), 127.78 (C-4 ), 129.33
(C-30, C-50), 140.65 (C-10), 173.47 (CH3CH2
[M + H]+: 263.1283, found 263.1280.
C(O)), 175.31 (C-2); HRMS (ESI): m/z calcd. for C15H18O4
4-(40-Methylphenyl)-5-(1-propionyloxyethyl)dihydrofuran-2-one 6b. Yield 82% (0.68 g), n2D0 = 1.5542, IR
(KBr, cm−1): 1786 (s), 1736 (s), 1457 (m), 1182 (s), 814 (m) cm−1; 1H-NMR (300 MHz, CDCl3)
: 1.07
(t, J = 7.5 Hz, 3H, CH3CH2C(O)), 1.26 (d, J = 6.6 Hz, 3H, CH3-7), 2.18, 2.25 (two dq, J = 15.9, 7.5, 2H,
CH3CH2C(O)), 2.33 (s, 3H, CH3-11), 2.63 (dd, J = 18.0, 7.8 Hz, 1H, one of CH2-3), 3.02 (dd, J = 18.0
δ
,
9.3 Hz, 1H, one of CH2-3), 3.54 (ddd, J = 9.3, 7.8, 6.6 Hz, 1H, H-4), 4.51 (dd, J = 6.6, 4.2 Hz, 1H,
H-5), 5.13 (qd, J = 6.6, 4.2 Hz, 1H, H-6), 7.09–7.12 (m, 2H, H-20, H-60), 7.16–7.18 (m, 2H, H-30, H-50);
13C-NMR (75 MHz, CDCl3)
δ: 8.93 (CH3CH2C(O)), 15.66 (C-7), 20.05 (C-11), 27.63 (CH3CH2C(O)),
37.71 (C-3), 42.33 (C-4), 70.30 (C-6), 87.12 (C-5), 126.77 (C-20, C-60), 129.94 (C-30, C-50), 137.52 (C-10),
137.59 (C-40), 173.47 (CH3CH2
277.1440, found 277.1447.
C
(O)), 175.45 (C-2); HRMS (ESI): m/z calcd. for C16H20O4 [M + H]+:
4-(40-Methoxyphenyl)-5-(1-propionyloxyethyl)dihydrofuran-2-one 6c. Yield 86% (0.75 g), n2D0 = 1.5925, IR
(KBr, cm−1): 1784 (s), 1736 (s), 1516 (s), 1253 (m), 1181 (s), 832 (m) cm−1; 1H-NMR (300 MHz, CDCl3)
δ
: 1.08 (t, J = 7.5 Hz, 3H, CH3CH2C(O)), 1.26 (d, J = 6.6 Hz, 3H, CH3-7), 2.19, 2.26 (two dq, J = 16.5, 7.5,
2H, CH3C 2C(O)), (2.61 (dd, J = 18.0, 8.1 Hz, 1H, one of CH2-3), 3.01 (dd, J = 18.0, 9.3 Hz, 1H, one of
H
CH2-3), 3.53 (ddd, J = 9.3, 8.1, 6.6 Hz, 1H, H-4), 4.04 (s,03H, CH3-11), 4.49 (dd, J = 6.60, 4.2 Hz, 1H, H-5),
0
0
5.13 (qd, J = 6.6, 4.2 Hz, 1H, H-6), 6.86–6.91 (m, 2H, H-3 , H-5 ), 7.11–7.17 (m, 2H, H-2 , H-6 ); 13C-NMR
(75 MHz, CDCl3) δ: 8.94 (CH3CH2C(O)), 15.66 (C-7), 27.64 (CH3CH2C(O)), 3.78 (C-3), 41.9 (C-4), 55.38
(C-11), 70.25 (C-6), 87.16 (C-5), 114.64 (C-30 and C-50), 127.95 (C-20 and C-60), 132.45 (C-10), 159.06
(C-40), 173.49 (CH3CH2C(O)), 175.39 (C-2); HRMS (ESI): m/z calcd. for C16H20O5 [M + H]+: 293.1389,
found 293.1386.

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4-(Benzo[d][10,30]dioxol-50-yl)-5-(1-propionyloxyethyl)dihydrofuran-2-one 6d
.
Yield 88% (0.81 g),
n2D0 = 1.4941, IR (KBr, cm−1): 1782 (s), 1735 (s), 1490 (m), 1251 (s), 1188 (s), 1037 (s), 932 (m),
736 (m) cm−1; 1H-NMR (300 MHz, CDCl3)
δ: 1,09 (t, J = 7.5 Hz, 3H, CH3CH2C(O)), 1.26 (d, J = 6.3 Hz,
3H, CH3-7), 2.21, 2.28 (two dq, J = 18.0, 7.8 Hz, 2H, CH3CH2C(O)), 2.59 (dd, J = 18.0, 7.8 Hz, 1H,
one of CH2-3), 3.00 (dd, J = 18.0, 9.6 Hz, 1H, one of CH2-3), 3.50 (ddd, J = 9.6, 7.8, 6.6 Hz, 1H, H-4),
4.47 (dd, J = 6.6, 4.2 Hz, 1H, H-5), 5.13 (qd, J = 6.3, 4.2 Hz, H-6), 5.97 (s, 2H, CH2-20) 6.67 (dd, J = 7.8,
1.5 Hz, 1H, H-60), 6.70 (d, J = 1.5 Hz, 1H, H-40), 6.78 (d, J = 7.8 Hz, 1H, H-70); 13C-NMR (75 MHz,
CDCl3) δ: 8.95 (CH3CH2C(O)), 15.65 (C-7), 27.66 (CH3CH2C(O)), 37.70 (C-3), 42.39 (C-4), 70.22 (C-6),
87.07 (C-5), 101.37 (C-20), 106.96 (C-40), 108.79 (C-70), 120.22 (C-60), 134.32 (C-50), 147.13 (C-30a), 148.46
0
(C-7 a), 173.48 (CH3CH2
C
(O)), 175.20 (C-2); HRMS (ESI): m/z calcd. for C16H18O6 [M + H]+: 307.1182,
found 307.1188.
3.4. Enzymatic Resolution of Racemic Allyl Alcohol 1c
To the solution of racemic alcohol 1c (5 g, 28 mmol) in DIPE (50 mL), 1 mL of vinyl propionate and
lipase B from C. antartica (2 g) were added. The reaction was carried out in the 250 mL round-bottom
flask on a magnetic stirrer at room temperature. The reaction was monitored by chiral GC after treating
the samples with acetyl chloride to derivatize the unreacted alcohol into corresponding acetate
2.
Racemic acetate and propionate were used as the standards. After 4 h of reaction, the enzyme was
2
3
filtered off and the organic solvent was evaporated in vacuo. Products of enzymatic tranesterification
were separated by column chromatography (hexane/acetone, 15:1) and analyzed by chiral GC.
(
−
)-(2S,3E)-4-(40-Methoxyphenyl)but-3-en◦-2-ol (
−
)-1c. Yield (45%, 2.25 g); colourless crystals, Rf = 0.25
(hexane/acetone 4:1, v/v), m.p. 76–80 C; ee = 78% (determined after derivatization into acetate);
[α]2D0 = −28.5 (c 1.8, CH2Cl2) (lit. [40] [
α
]
=
−
37.4 (c 0.84, CHCl3), ee = 99%), spectroscopic data
25
D
identical to those reported for rac-1c [31].
(+)-(2R,3E)-4-(40-Methoxyphenyl)but-3-en-2-yl propionate (+)-
Rf = 0.66 (hexane/acetone 4:1, v/v), n2D0 = 1.5263; ee = 82%, [
3
. Yield 43% (2.82 g); pale-brown liquid,
20
α
]
= +113.5 (c 1.6, CH2Cl2); physical and
D
spectroscopic data identical to those reported herein for rac-3.
Hydrolysis of (+)-(2R,3E)-4-(40-methoxyphenyl)but-3-en-2-yl propionate. Ester (+)-
3
(11 mmol) was
hydrolyzed under reflux in 5% ethanolic solution of NaOH (40 mL). When the reaction was finished
(3 h, TLC), ethanol was evaporated in vacuo and the residue was diluted with water. Alcohol (+)-1c
was extracted with CH2Cl2 (3
until neutral and dried over anhydrous MgSO4. After evaporation of solvent in vacuo, pure alcohol
×
30 mL) and the organic fractions were pooled, washed with brine
(+)-1c was obtained.
(+)-(2R,3E)-4-(40-Methoxyphenyl)but-3-en-2-ol (+)-1c. Yield 98% (1.61 g); colourless crystals, ee = 82%;
[α] α]
20 = +25.0 (c 1.6, CH2Cl2), (lit. [45] [ 23 = +30.68 (c 1.6, CHCl3), spectroscopic data identical to those
D D
reported for rac-1c [31].
3.5. Johnson–Claisen Rearrangement of Enantiomerically Enriched Allyl Alcohols (−)-1c and (+)-1c
Mixture of enantiomerically enriched alcohol (
−
)-1c or (+)-1c (0.012 mol), triethyl orthoacetate
◦
(25 mL) and a drop of propionic acid was heated at 138–140 C under reflux for 24 h with simultaneous
removal of ethanol by distillation. The crude product was purified by column chromatography
(hexane/acetone, 10:1, v/v).
(+)-(3S,4E)-3-(40-Methoxyphenyl)hex-4-enoic acid ethyl ester (+)-3c. Obtained from alcohol (
−
)-(S)-1c
.
20
Yield 2.5 g (83%), ee = 78%, [
with those of rac-3c [31].
α
]
= +8.8 (c 3.6, CH2Cl2), Physical and spectroscopic data are consistent
D

Molecules 2016, 21, 1552
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(
−
)-(3R,4E)-3-(40-Methoxyphenyl)hex-4-enoic acid ethyl ester (
−
)-3c. Obtained from alcohol (+)-(R)-1c
.
20
Yield 2.6 g (82%), ee = 82%, [
with those of rac-3c [31].
α
]
=
−
9.4 (c 1.8, CH2Cl2); Physical and spectroscopic data are consistent
D
3.6. Lactonization of Enantiomerically Enriched γ,δ-Unsaturated Esters (S)-4a–d and (R)-4a–d
Enantiomerically enriched -unsaturated ester (S)-4a or (R)-4a (0.007 mol) was dissolved in
γ
,
δ
–
d
–d
50 mL of CHCl3 and m-CPBA (0.008 mol) and a drop of trifluoroacetic acid were added. The reaction
mixture was stirred on a magnetic stirrer for 24 h. Then, the crude mixture was diluted with
CHCl3 (100 mL), and successively washed with NaHSO3, NaHCO3 and brine. The combined
organic layers were dried over anhydrous MgSO4 and filtered. The organic solvent was evaporated
under vacuo and after column chromatography (silica gel, hexane/isopropanol/acetone/ethyl
acetate/methylene chloride/diethyl ether (100:10:0.1:0.1:0.1:0.1, v/v/v/v/v/v) unseparable mixture
of
γ-hydroxy-δ-lactones and pure δ-hydroxy-γ-lactones 5a–d were isolated. Their spectroscopic data
were consistent those reported for their racemic form [33].
(–)-trans-(4R,5S,6R)-5-(1-Hydroxyethyl)-4-phenyldihydrofuran-2-one (
−
)-5a
.
Obtained from ester
Obtained from ester
(+)-(4E,3S)-4a. Yield 0.12 g (8%), [α]2D0 = −19.0 (c = 3.25, CH2Cl2), ee = 90%.
(+)-trans-(4S,5R,6S)-5-(1-Hydroxyethyl)-4-phenyldihydrofuran-2-one (+)-5a
.
(−)-(4E,3R)-4a. Yield 0.12 g (8%), [α]2D0 = +20.6 (c = 2.45, CH2Cl2), ee = 97%.
(–)-trans-(4R,5S,6R)-5-(1-Hydroxyethyl)-4-(40-methylphenyl)dihydrofuran-2-one (
−
)-5b. Obtained from
ester (+)-(4E,3S)-4b. Yield 0.12 g (8%), [α]2D0 = −16.5 (c = 5.0, CH2Cl2), ee = 83%.
0
(+)-trans-(4S,5R,6S)-5-(1-Hydroxyethyl)-4-(4 -methylphenyl)dihydrofuran-2-one (+)-5b. Obtained from ester
(−)-(4E,3R)-4b. Yield 0.11 g (7%), [α]2D0 = + 17.5 (c = 2.14, CH2Cl2), ee = 87%.
(–)-trans-(4R,5S,6R)-5-(1-Hydroxyethyl)-4-(40-methoxyphenyl)dihydrofuran-2-one (
ester (+)-(4E,3S)-4c. Yield 0.12 g (7%), [α]2D0 = −8.3 (c = 3.53, CH2Cl2), ee = 78%.
−
)-5c. Obtained from
(+)-trans-(4S,5R,6S)-5-(1-Hydroxyethyl)-4-(40-methoxyphenyl)dihydrofuran-2-one (+)-5c. Obtained from
ester (−)-(4E,3R)-4c. Yield 0.12 g (8%), [α]2D0 = +8.9 (c = 2.0, CH2Cl2), ee = 82%.
0
0
0
(–)-trans-(4R,5S,6R)-4-(Benzo[d][1 ,3 ]dioxol-5 -yl)-5-(1-hydroxyethyl)-dihydrofuran-2-one ( )-5d. Obtained
−
from ester (−)-(4E,3R)-4d. Yield 0.13 g (7.5%), [α]2D0 = −6.3 (c = 4.40, CH2Cl2), ee = 73%.
0
0
0
(+)-trans-(4S,5R,6S)-4-(Benzo[d][1 ,3 ]dioxol-5 -yl)-5-(1-hydroxyethyl)-dihydrofuran-2-one (+)-5d. Obtained
from ester (+)-(4E,3S)-4d. Yield 0.14 g (8%), [α]2D0 = +6.7 (c = 2.58, CH2Cl2), ee = 82%.
3.7. Enzymatic Resolution of Hydroxylactones 5a–d
3.7.1. Screening Procedure
To a solution of hydroxylactone 5a in 10 mL of DIPE 5 mg of lipase and 0.1 mL of vinyl propionate
was added. The reaction mixture was stirred in a magnetic stirrer in 20 mL-vial at room temperature.
At several time intervals, the samples (0.5 mL) were withdrawn from reaction mixture and filtered
through Celite 560. The organic solvent was evaporated under vacuo, and the residue was dissolved
in acetone (0.2 mL) and analyzed by CGC. The results are shown in Table 2.
3.7.2. Preparative Transesterification
To a solution of
from Candida antarctica (CAL-B) and 1 mL of vinyl propionate were added and the mixture was stirred
at room temperature. The reaction was monitored by chiral GC and racemic hydroxylactones 5a
and propionates 6a were used as the standards. After 6 h the enzyme was filtered off and organic
solvent was evaporated in vacuo. Slowly reacting hydroxylactones 5a and propionates 6a were
β-aryl-δ-hydroxy-γ-lactone 5a–d (0.97 mmol) in 50 mL of DIPE, 100 mg of lipase B
–
d
–
d
–d
–d

Molecules 2016, 21, 1552
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separated by column chromatography (hexane/acetone, 20:1, v/v). Their physical and spectroscopic
data were in accordance with those of racemic forms of lactones [33] and propionates reported herein
(Section 3.3).
(+)-trans-(4S,5R,6S)-5-(1-Hydroxyethyl)-4-phenyldihydrofuran-2-one (+)-5a. Yield 0.08 g (38%), Rf = 0.21
(hexane/acetone 4:1, v/v), [α]2D0 = +21.0 (c = 0.55, CH2Cl2), ee = 99%.
(+)-trans-(4R,5S,6R)-4-Phenyl-5-(1-propionyloxyethyl)-dihydrofuran-2-one (+)-6a
Rf = 0.71 (hexane/acetone 4:1, v/v), [α]2D0 = + 33.7 (c = 0.60, CH2Cl2), ee = 92%.
. Yield 0.11 g (44%),
(+)-trans-(4S,5R,6S)-5-(1-Hydroxyethyl)-4-(40-methylphenyl)dihydrofuran-2-one (+)-5b. Yield 0.09 g (41%),
Rf = 0.22 (hexane/acetone 4:1, v/v), [α]2D0 = +16.9 (c = 0.40, CH2Cl2), ee = 99%.
(+)-trans-(4R,5S,6R)-4-(40-Methylphenyl)-5-(1-propionyloxyethyl)-dihydrofuran-2-one (+)-6b. Yield 0.12 g
(44%), Rf = 0.68 (hexane/acetone 4:1, v/v), [α]2D0 = +30.1 (c = 0.65, CH2Cl2), ee = 91%.
0
(+)-trans-(4S,5R,6S)-5-(1-Hydroxyethyl)-4-(4 -methoxyphenyl)dihydrofuran-2-one (+)-5c. Yield 0.103 g (45%),
Rf = 0.27 (hexane/acetone 4:1, v/v), [α]2D0 = +9.5 (c = 0.40, CH2Cl2), ee = 98%.
(+)-trans-(4R,5S,6R)-4-(40-Methoxyphenyl)-5-(1-propionyloxyethyl)-dihydrofuran-2-one (+)-6c. Yield 0.10 g
(36%), Rf = 0.67 (hexane/acetone 4:1, v/v), [α]2D0 = +14.4 (c = 2.8, CH2Cl2), ee = 98%.
(+)-trans-(4S,5R,6S)-4-(Benzo[d][10,30]dioxol-50-yl)-5-(1-hydroxyethyl)-dihydrofuran-2-one (+)-5d. Yield
0.08 g (34%), Rf = 0.23 (hexane/acetone 4:1, v/v), [α]2D0 = +6.8 (c = 0.40, CH2Cl2), ee = 89%.
0
0
0
(+)-trans-(4R,5S,6R)-4-(Benzo[d][1 ,3 ]dioxol-5 -yl)-5-(1-propionyloxyethyl)-dihydrofuran-2-one (+)-6d. Yield
0.10 g (35%), Rf = 0.70 (hexane/acetone 4:1, v/v), [α]2D0 = +15.6 (c = 0.80, CH2Cl2), ee = 84%.
4. Conclusions
In conclusion, we have presented two alternative methods for the production of enantiomerically
enriched trans-β-aryl-δ-hydroxy-γ-lactones 5a–d with the defined absolute configurations of their
stereogenic centers, which were not reported previously in optically active forms. Chemoenzymatic
synthesis gives direct access to both enantiomers of desired lactones (ee = 73%–97%), and kinetic
resolution of their racemic mixtures by CAL-B delivers (+)-enantiomers 5a
6a d, which can be further hydrolyzed to ( )-enantiomers of desired hydroxylactones. Most of the
products of enzymatic reaction were obtained with excellent enantiomeric excesses (ee = 91%–99%).
1,3-Benzodioxol ring as the steric hindrance lowered enantioselectivity of resolution of lactone 5d
The methods presented above are convenient routes to obtain both enantiomers of optically active
trans- -aryl- -hydroxy- -lactones 5a d, which will let us study the dependence between their spatial
structure and biological activity.
–d and (+)-propionates
–
−
.
β
δ
γ
–
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
11/1552/s1.
Acknowledgments: This research was supported financially by the European Union as a part of the
European Social Fund, Human Capital Operational Programme. This publication was supported by Wroclaw
Centre of Biotechnology, programme The Leading National Research Centre (KNOW) for years 2014–2018
(http://know.wroc.pl).
Author Contributions: Andrzej Skrobiszewski and Czesław Wawrzen´czyk conceived and designed the
experiments; Andrzej Skrobiszewski performed the experiments; Witold Gładkowski and Czesław Wawrzen´czyk
analyzed the data; Andrzej Skrobiszewski and Gabriela Maciejewska contributed analysis tools;
Andrzej Skrobiszewski and Witold Gładkowski wrote the paper.
Conflicts of Interest: The authors declare no conflicts of interest.

Molecules 2016, 21, 1552
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Sample Availability: Samples of the compounds 5a−d are available from the authors.
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