The studies on the chemoenzymatic synthesis of 2-benzyl-3-butenoic acid

Article abstract of DOI:10.1016/j.catcom.2018.05.020

The studies on the chemoenzymatic synthesis of 2-benzyl-3-butenoic acid 3 were performed. The alkylation of dienolates derived from the crotonic and vinylacetic acids with different types of alkylating agents was examined. In all cases the inseparable mixture of isomeric acids 3 and 4 were obtained. Chemoselective enzymatic esterification of those mixtures provides ester 6 in 86% yield as a single product without double bond isomerization. None common method can be used for its hydrolysis since under basic conditions only isomeric acid 5 is formed. To overcome this limitation enzyme catalysed hydrolysis process was design. This protocol afforded isomerically pure acid 3 in 98% yield.

Full text of DOI:10.1016/j.catcom.2018.05.020

Catalysis Communications 114 (2018) 6–9
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short communication
The studies on the chemoenzymatic synthesis of 2-benzyl-3-butenoic acid
⁎
Filip Borys, Daniel Paprocki, Dominik Koszelewski, 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
Keywords:
Alkylation
Enzyme catalysis
Dienolates
The studies on the chemoenzymatic synthesis of 2-benzyl-3-butenoic acid 3 were performed. The alkylation of
dienolates derived from the crotonic and vinylacetic acids with different types of alkylating agents was ex-
amined. In all cases the inseparable mixture of isomeric acids 3 and 4 were obtained. Chemoselective enzymatic
esterification of those mixtures provides ester 6 in 86% yield as a single product without double bond iso-
merization. None common method can be used for its hydrolysis since under basic conditions only isomeric acid
5
is formed. To overcome this limitation enzyme catalysed hydrolysis process was design. This protocol afforded
isomerically pure acid 3 in 98% yield.
1. Introduction
their derivatives are very prone to the double bond isomerization (eg.
under basic or acidic conditions, elevated temperatures) [17,18]. It is
well recognized that an addition of copper (I) salts to lithium un-
saturated carboxylic acid dienediolates results mainly in alkylation on
γ‑carbon position [19]. The introduction of regiodirective groups, e.g.
silyl, sulfonyl group improves γ-regioselectivity of aldol additions of
esters, but not for alkylation [20]. Despite of numerous studies devoted
to this synthetic matter [21–23] including enantioselective alkylation
with chiral auxiliaries [24], condensation of dienolates with aldehydes
and ketones [25] as well as Michael addition of dienolates to un-
saturated ketones [26], the development of simple and efficient syn-
thetic pathways towards this class of compounds still remain challen-
ging. Several attempts have been made to develop biocatalitic routes
towards β,γ-unsaturated carboxylic acids. Recently, Okrasa et al. ob-
tained a new crystal structure of arylmalonate decarboxylase isolated
from the B. bronchiseptica and designed mutants which showed in-
creased activity with α-aryl and α-alkenyl malonates [27]. Gao, et al.
used microbial whole-cell catalyst Rhodococcus erythropolis AJ270
containing a nitrile hydratase/amidase for biotransformation of various
functionalized racemic nitriles. This protocol provide a synthetic route
to highly enantiopure carboxylic acids and amides functionalized with
an allyl, propargyl, allenyl, or vinyl group [28]. Herein, we describe the
studies on preparative, isomerically pure, chemoenzymatic synthesis of
2-benzyl-3-butenoi acid 3.
The β,γ-unsaturated carboxylic acids are valuable building blocks
for the synthesis of numerous relevant biologically active compounds,
e.g. factor Xia inhibitors [1], dl-bisnorvernolepin [2], vineomycinone
B [3], and many other. Among other species, rac-2-benzyl-3-butenoic
2
acid 3 is an important starting material for the synthesis of various
medicaments such as carboxypeptidase A inhibitors [4], functionalized
piperidinones
– HIV protease inhibitors [5], lignin-related tetra-
hydrofurans [6], γ-resorcylates [7], (Z)-ethylenic pseudopeptides [8].
So high functionality of unsaturated carboxylic acids is among others a
result of possibility of transforming double bond in to the oxirane,
thiirane, aziridine or cyclopropane ring [4], moreover double bond can
contribute in olefin metathesis reaction [8,9] (Fig. 1). Various available
methods towards β,γ-unsaturated carboxylic derivatives including re-
duction of triple bond [10], nickel-catalysed coupling reactions [11],
indium-mediated addition [12], palladium-catalysed alkylation of ke-
tone enolates [13], Cu-catalysed allylic alkylations [14] and many
others are detailed described in literature. However, all the previously
mentioned methods suffer from some serious disadvantages such as
necessity of use environmentally polluting metal complexes or many
chemical transformations resulting in low overall yield. In this context
alkylation of dienolates still remains useful method for preparation of
this class of compounds due to its wide generality and versatility.
[
15,16]. However the major drawback of mentioned method is asso-
ciated with low regioselectivity and difficult separation procedure of
obtained complex reaction mixture, using common purification
methods such as vacuum distillation or column chromatography.
Moreover, it is well known that β,γ-unsaturated carboxylic acids and
2. Results and discussion
The common substrates for synthesis of 2-benzyl-3-butenoic acid 3
are usually crotonic 1a or vinylacetic 1b acids. The treatment of those
⁎
Corresponding author.
E-mail address: ryszard.ostaszewski@icho.edu.pl (R. Ostaszewski).
https://doi.org/10.1016/j.catcom.2018.05.020
Received 16 April 2018; Received in revised form 25 May 2018; Accepted 26 May 2018
Available online 29 May 2018
1566-7367/ © 2018 Published by Elsevier B.V.

F. Borys et al.
Catalysis Communications 114 (2018) 6–9
Table 1
Alkylation of 1a and 1b with different alkylation agents.
Entry
Substrate
X
3:4 ratioa
Yielda [%]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
Cl
Br
I
OTs
OMs
Cl
Br
I
27: 1
5: 1
3: 1
49: 1
21: 1
12: 1
4: 1
1: 1
140: 1
9: 1
49
54
33
63
46
8
18
16
10
14
OTs
OMs
1
0
a
Determined by RP-HPLC after derivatization of crude reaction mixture by
diazomethane.
acids mixture to their methyl ester using diazomethane followed by
reversed-phase high-performance liquid chromatography (RP-HPLC)
chromatogram analysis (for more details see supplementary materials).
Diazomethane is a particularly convenient methylating agent because it
reacts with carboxylic acids quantitatively at room temperature. Also,
the unreacted diazomethane is easy to remove from reaction medium
[
29]. Having analytical method for determination yield and the α/γ
Fig. 1. Synthetic applications of rac-2-benzyl-3-butenoic acid.
products ratio in hand, we performed experiments to clarify the influ-
ence of leaving group present in electrophile structure as well as ad-
dition of cooper (I) salts on alkylation reaction of 1a and 1b. As a al-
kylating agents benzyl halides (X = Cl, Br, I) as well as benzyl tosylates
and mesylates (X = OTs, OMs) were used. To validate our results each
experiment was repeated at least three times. Obtained results are
summarised in Table 1. Benzyl halides, tosylates and mesylates used as
alkylating agents tend to react mainly at α‑carbon atom of dienolate 2
(
Table 1, Entry 1–10). The higher amounts of γ-alkylated products can
be obtained by changing leaving group. With increasing of atomic ra-
dius of halide present in an alkylating agent the surge of γ-product
formation has been observed what is in agreement with literature data
for alkylation reaction of dienolates [19,21] (Table 1, Entry 1–3). To-
sylates and mesylates are good leaving groups and provided the higher
α:γ ratios when compare it to an benzyl halides (Table 1, Entry 4–5 and
9–10).
The analysis of products proportion has been repeated after seven
Scheme 1. Alkylation of dienolate 2 with different types of alkylating agents.
days, and no change in it was observed. The yields varied in a range
from 8% to 63%. This results may be explained by high chemical re-
activity of enolates witch can easily undergoes site reactions (e.g.
polymerisation, multiple alkylation). Reactions carried out with viny-
lacetic acid 1b (Table 1, Entries 6–10) resulted in much lower yield,
than reactions with crotonic acid 1a (Entries 1–5). Presumably it is
caused by different rate constant of deprotonation resulting in not equal
formation of dienolate 2.
compounds with strong base (e.g. LDE – lithium diethylamide), lead to
respective lithium dienolates 2 which can subsequently react at the α-
or γ‑carbon atom, resulting in the mixture of isomeric acids 3 and 4.
The ratio between products dependent on both: type of alkylating
agents used and reaction conditions. Furthermore, β,γ-unsaturated
carboxylic acid 3 undergoes double bond isomerization to thermo-
dynamically more stable α,β-unsaturated acid 5 (Scheme 1). This syn-
thetic problem is well recognized in literature, unfortunately most
It is well recognized that the exchange of counterion from lithium to
the cuprous (I) influences the regioselectivity in alkylation of dienolates
1
available data are based mostly on the analysis of H NMR [21–23]
[
19,30]. This characteristic and still unclear effect has been studied.
spectra of crude reaction products. Results obtained using this method
are often ambiguous, due to complex composition of reaction mixture
and low accuracy of NMR measurement. Initially we employed meth-
odology proposed by Aurell et al. for the synthesis of model compounds
using 2-benzylbut-3-enoic acid 3 and 5-phenylpent-2-enoic acid 4 as
analytical standards for further research [22]. Unfortunately, the
method reported was difficult to reproduce, and provided, after tedious
and time consuming purification, the acid 3 with low, 40% yield. De-
spite of many efforts, we were not be able to directly isolate pure acid 4
by this method. Thus, this compound was synthesized by Knoevenagel
condensation of 3-phenylpropanal with malonic acid, which provided
pure acid 4 in 90% yield.
The distribution of product has been analyzed by RP-HPLC after deri-
vatization with diazomethane. The results showed limited efficiency
addition of cuprous (I) additives which do not influenced regioselec-
tivity significantly (Table S1 in SI). The alkylation of dicopper dienolate
gives higher amount of γ-alkylated product in comparison with corre-
sponding lithium dienolate, but still approximately 1:1 mixtures of
products is obtained.
The results of our studies on alkylation reaction of dienolate 2
showed that this method suffers from a low regioselectivity and re-
quires time-consuming, cumbersome purification steps and cannot be
consider as a preparative method for synthesis of 2-benzyl-3-butenoic
acid 3. Thus, we turned our attention to an enzymatic process that
could lead to overcome this limitations. Biocatalysts exhibit high sub-
strate specificity and require mild operational condition, hence they
were promising candidates for selective purification protocol. Taking
The next goal of our research was to develop the analytical method
for determination of reaction mixture composition (α and γ-substituted
acids 3 and 4). Our protocol is based on esterification of carboxylic
7

F. Borys et al.
Catalysis Communications 114 (2018) 6–9
Table 3
The solvent influence on Novozym 435 catalysed esterification of mixture of 3
a
and 4 .
Entry
Solvent
Yield of 6b,d [%]
Yield of 7c,d [%]
1
2
3
4
5
6
7
8
Toluene
Hexane
TBME
Acetone
Acetonitrile
Dichloromethane
Diethyl ether
Chloroform
83
36
27
8
1
0
0
0
0
0
0
0
0
12
0
80
Scheme 2. Selective enzyme-catalysed esterification of mixture of 3 and 4 and
subsequent Novozyme 435 catalysed hydrolysis of 6.
a
Reaction conditions: 10 mg of mixture of 3 and 4 (ratio 5:1), Novozym 435
5 mg), trimethyl orthoacetate (3 equiv.), solvent (1 mL), 48 h, room tempera-
(
Table 2
ture.
The influence of different methoxy group donors on Novozym 435 catalysed
b
Yield according to amount of 3 in starting mixture.
Yield according to amount of 4 in starting mixture.
Determined by RP-HPLC after derivatization of crude reaction mixture by
a
esterification of mixture of 2a and 3a .
c
Entry
Methoxy group donor
Yield of 6b,d [%]
Yield of 7c,d [%]
d
diazomethane.
1
2
3
4
5
6
7
8
9
Trimethyl orthoacetate
Trimethyl orthobenzoate
Benzaldehyde dimethyl acetal
Trimethyl orthoformate
Methanol
Tetramethoxymethane
Trimethyl orthobutyrate
Trimethyl orthovalerate
Trimethyl orthopropionate
83
35
24
11
10
7
6
6
5
0
0
0
0
0
0
0
0
0
1% yield. Enzymatic reaction was completely inhibited when di-
chloromethane or ethyl ether were used. The reaction carried out in
toluene result in the highest yield of 6, 83% (Table 3, Entry 1). This
solvent turned out to be the most suitable for examined enzymatic re-
action what correlates with previous literature data [33–35].
In the next step of our studies, we applied developed protocol on a
preparative scale. Thus, 500 mg of mixture of acids 3 and 4 (ratio 5:1),
Novozym 435, trimethyl orthoacetate, and toluene were stirred for
2 days at room temperature. This procedure afforded pure ester 6
(463 mg, 2.44 mmol) in 83% yield, according to amount of 3 in starting
mixture. Similar reaction conducted for 3 days result in pure 6 in almost
quantitative yield Finally, ester 6 was subjected to hydrolysis reaction
in methanol with sodium hydroxide for 12 h. Unfortunately, under
basic conditions double bond isomerization occurred and α,β-un-
saturated acid 5 was the only isolated product with 92% yield (Scheme
a
Reaction conditions: 10 mg of mixture of 3 and 4 (ratio 5:1), Novozym 435
5 mg), methoxygorup donor (3 equiv.), toluene (1 mL), 48 h, room tempera-
(
ture.
b
Yield according to amount of 3 in starting mixture.
Yield according to amount of 4 in starting mixture.
Determined by RP-HPLC after derivatization of crude reaction mixture by
c
d
diazomethane.
into account collected experience from our previous research [31] en-
zyme catalysed esterification of crude acids mixture with orthoesters
was applied (Scheme 2). In preliminary study, several commercially
available enzymes have been tested as biocatalysts for selective ester-
ification of 3 from reaction mixture. All tested lipases catalysed speci-
fically esterification providing ester 6 with yields varied from 22% to
2
). Any change in reaction conditions by other solvents or bases pro-
vides complex product mixtures. To overcome this inconvenience we
employed enzyme catalysed hydrolysis under near to neutral pH con-
ditions to supress isomerization. Substrate 6 was dissolved in acetone:
phosphate buffer pH 7.4 (2:8 v/v) mixture and Novozym 435 was used
as a biocatalyst. The reaction was conducted at 20 °C for 24 h in sealed
glass vials. This protocol allows to isolate 2-benzyl-3-butenoic acid 3 in
83% (Table S2). Unfortunately, no enantiomeric enrichment was ob-
served and in all cases product was obtained in its racemic form. For
confirming the substrate selectivity similar experiment has been per-
formed, using only γ–substituted acid 4 as a substrate. Significantly, no
reaction occurred, indicating that compound 4 is not accepted as a
substrate by the selected enzymes. Among the tested enzymes Novozym
9
8% yield. The formation of isomeric acid 5 was not observed. The
biocatalyst can be reused up to five times without significant loss of
activity. There was gradually decrease in yield of product 3 during
consecutive runs, the yield dropped to 74% after completion of the fifth
run. The decreased activity of Novozym 435 over five reaction cycles is
largely due to mechanical loss of catalyst (Fig. S1 in supplementary
materials). These experiments showed, that newly developed che-
moenzymatic synthesis of acid 3 can be also applied in preparative
scale.
435 exhibited the highest catalytic activity under studied conditions
(
Table S2, Entry 1). Therefore, Novozym 435 was consequently used
throughout the further studies. To optimize the reaction conditions the
influence of the different methoxy group donors were examined. Tri-
methyl orthoacetate gave the highest yield of ester 6, 83% (Table 2,
Entry 1). The others methoxy group donors gave 6 with yield 5–35%. In
all cases Novozym 435 selectively catalysed only esterification of acid
3
. Conclusions
2.
Many literature reports have shown that the organic medium is one
of the most significant factor influencing the enzyme catalytic activity
32]. On the basis of this fact, eight commonly used organic solvents
were investigated. The results are presented in Table 3. Reaction carried
out in chloroform resulted in high yield of products (92%), but un-
fortunately it was not selective and provided also acid 7 in 12% yield.
The studies on the chemoenzymatic synthesis of 2-benzyl-3-bute-
noic acid 3 were performed. The proposed methodology is based on
esterification and subsequent RP-HPLC analysis of α and γ-substituted
acids 3 and 4 mixtures. We have studied the influence of different types
of alkylating agents on the alkylation of lithium dienolates provided
from the crotonic acid 1a and vinylacetic acid 1b. A new chemoenzy-
matic method for the synthesis of 2-benzyl-3-butenoic 3 based on
combination of the alkylation reaction of dienolate 2 with enzyme
catalysed esterification and subsequent hydrolysis has been proposed.
Both enzymatic transformations are catalysed by the same enzyme –
Novozym 435. Under optimized conditions the isomerically pure 2-
[
(
Table 3, Entry 8). Therefore chloroform should not be used as a solvent
for this reaction. Use of methyl tert-butyl ether and n-hexane caused
drop in reaction yield to 27% and 36%, respectively (Entry 3 and 2).
Acetone and acetonitrile turned out to be unsuitable solvents for ex-
amined esterification reaction, product 6 was formed with only 8% and
8

F. Borys et al.
Catalysis Communications 114 (2018) 6–9
benzyl-3-butenoic acid 3 was obtained in almost quantitative yield. This
approach provides a new methodology for synthesis of acid 3 under
mild conditions that do not promote double bond isomerization and
allow to avoid tedious and time consuming purification steps.
Acknowledgments
This work was supported by the Polish National Science Centre
project No. 2014/14/M/ST5/00030.
4. Experimental
Appendix A. Supplementary data
4
.1. General methods
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.catcom.2018.05.020.
1H NMR and 13C NMR spectra were recorded with Varian 200 MHz
and Bruker 400 MHz spectrometers, with TMS used as an internal
standard or the residual chloroform signal. HPLC analysis were per-
formed with a ProStar HPLC instrument (Varian/Agilent Technologies)
equipped with a Kromasil C18 column (5 μm; 250 × 4 mm; flow rate
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4
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8
9