Dynamic Kinetic Resolution of 3-Aryl-4-pentenoic Acids

Article abstract of DOI:10.1021/acscatal.6b00271

The first example of dynamic kinetic resolution (DKR) of chiral unsaturated carboxylic acids is described. The application of tandem metal-enzyme DKR is a powerful tool for the manufacture of high-value chemical commodities. This new protocol of kinetic r

Full text of DOI:10.1021/acscatal.6b00271

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Article
Dynamic Kinetic Resolution of 3-aryl-4-Pentenoic Acids
Dominik Koszelewski, Anna Brodzka, Anna ##d#o, Daniel Paprocki,
Damian Trzepizur, Malgorzata Zysk, and Ryszard Ostaszewski
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00271 • Publication Date (Web): 14 Apr 2016
Downloaded from http://pubs.acs.org on April 15, 2016
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ACS Catalysis
Dynamic Kinetic Resolution of 3ꢀarylꢀ4ꢀpentenoic Acids
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Dominik Koszelewski, Anna Brodzka, Anna Żądło, Daniel Paprocki, Damian Trzepizur,
Małgorzata Zysk and Ryszard Ostaszewski*
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Institute of Organic Chemistry Polish Academy of Sciences, Kasprzaka 44/52, 01ꢀ224 Warsaw (Poland)
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KEYWORDS dynamic kinetic resolution, unsaturated carboxylic acids, racemization, biotransformations, rhodium catalyst
ABSTRACT: : The first example of dynamic kinetic resolution (DKR) of the chiral unsaturated carboxylic acids is described. The
application of tandem metalꢀenzyme DKR is a powerful tool for the manufacture of highꢀvalue chemical commodities. This new
protocol of kinetic resolution based on irreversible enzymatic esterification of 3ꢀarylꢀ4ꢀpentenoic acids with orthoesters was introꢀ
duced to obtain optically active unsaturated carboxylic acids. This procedure was combined with metal catalyzed racemization of
the target substrate providing optically pure (S)ꢀenantiomer of ethyl 3ꢀ(phenyl)pentꢀ4ꢀenoate with very high isolated yield (98%). A
substantial influence of organic coꢀsolvent, and metal catalyst on conversion and enantioselectivity of the enzymatic dynamic kinetꢀ
ic resolution was noted.
INTRODUCTION
crobial agents, and also antitumor antibiotic methylenolactocin
14
(Figure 1).
The synthesis of enantiomerically pure compounds is of
great importance for pharmaceutical industry. Large amount
1
of medicines are chiral, nonꢀracemic compounds which bioꢀ
logical activity is highly dependent on their absolute configuꢀ
ration of the stereogenic centers. The application of a racemic
mixture as a medicine is undesirable because it generally
requires a higher dose to cause the wanted biological response.
Additionally, the presence of the other enantiomer may have
adverse side effects. Thus, the demand for methods for the
synthesis of chiral nonꢀracemic substances has increased rapꢀ
idly in response to these commercial considerations.
One of the most convenient way to obtain enantiomerically
2
pure compounds is still based on kinetic resolution (KR).
Kinetic resolution requires a nonꢀracemic catalyst or reagent to
promote a selective reaction with one of the enantiomers,
providing enantioenriched unreacted substrate and enantioenꢀ
riched product. In this methodology the major limitation is that
3
the maximum theoretical yield is 50%. If the racemization
Figure 1. Pharmaceutical relevant compounds derived from 3ꢀ
arylꢀ4ꢀpentenoic acids.
can occur concurrently with the kinetic resolution, known as
dynamic kinetic resolution (DKR), then theoretically 100% of
racemic mixture can be converted to one enantiomer. During
the last decade DKR has significantly evolved and become an
important area in organic synthesis. Several examples of effiꢀ
cient dynamic enzymatic resolution have been reported and
recently the use of transition metals for substrate racemization
In all cases, the beneficial or adverse effects of these comꢀ
pounds depend on their absolute configuration. In the view of
the medicinal importance, synthetic studies of these comꢀ
pounds have attracted considerable interest. Several chemical
procedures have been explored to provide the routes to them.
Two common approaches include lengthy asymmetric syntheꢀ
4
has attracted some interest. However, this methodology has
15
successfully been applied to resolution the racemic mixture of
ses using chiral auxiliaries as well as microwave assisted
5
,6
16
alcohol and amine derivatives.
molybdenumꢀcatalyzed allylic alkylations. The enzymatic
method is available as well and comprises the nitrile hydraꢀ
tase/amidaseꢀcontaining microbialꢀ catalyzed kinetic resoluꢀ
Among others optically active 3ꢀarylꢀ4ꢀpentenoic acid is an
important substrate for the synthesis of numerous medicaꢀ
®
7
17
ments like Rolipram , an antiꢀinflammatory drug and one of
the family of γꢀaminobutyric acid (GABA) derivatives as well
®10
tion of racemic nitriles. All of these chemical and enzymatic
methods have several disadvantages. The wholeꢀcell preparaꢀ
tion catalyzed the hydration of a nitrile followed by the amide
hydrolysis catalyzed by the amidase, have become effective
methods for the production of carboxylic acids in aqueous
environment. However, starting from a racemic mixture, kinetꢀ
ic resolution is always limited to a maximum yield of 50% of
the enantiopure material, additionally isolation of products
from aqueous solution is usually tedious and time consuming.
®
8
® 9
® 10
as Citrocard , Lioresal , Femoxetine , or Paroxetine
1
1
another drugs belonging to the GABA family. Optically
active 3ꢀphenylꢀ4ꢀpentenoic acid is the key intermediate in the
synthesis of LG 121071 a modulator of androgen receptors
1
2
and Neurokinin NK1/NK2 antagonists. The (S)ꢀ3ꢀarylꢀ4ꢀ
pentenoic acid derivatives were also used for the synthesis of
10e,13
antiproliferation lactones (HLꢀ60 cells inhibitors),
antimiꢀ
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Thus, it seems significant to find a method to overcome these (Table 1, entries 2 and 3). Taking into the consideration variꢀ
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limitations. New methods providing enantiomerically pure
compounds based on tandem metalꢀenzyme dynamic kinetic
resolution are still of high interest due to the concepts of
asymmetric synthesis.
ous factors which may impact the racemization efficiency two
different organic solvents were tested. In case of applying
cyclohexane adverse effect on racemization rate has been
observed (Table 1, entry 4). The use of toluene as the solvent
led to substantial racemization rate at 40 °C (Table 1, entry 5).
Table 1. Racemization of (S)-3-phenylpent-4-enoic acid
((S)-1a)
RESULTS AND DISSCUSION
a
In continuation with our current studies on dynamic kinetic
resolution of chiral carboxylic acids, we recently reported on
the dynamic kinetic resolution of 3ꢀhydroxyꢀ3ꢀ(aryl)propanoic
acids. In this reaction a rhodium catalyst racemizes βꢀhydroxy
acid during enzymatic esterification with orthoesters.
Previously, we have successfully developed the kinetic resoluꢀ
c
entry
metal
solvent
T (°C)
ee (%)
catalyst
0
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9
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0
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0
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9
0
1
8a,18b
1
2
3
4
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6
7
8
A: Rh(II)
A: Rh(II)
A: Rh(II)
A: Rh(II)
A: Rh(II)
A: Rh(II)
A: Rh(II)
TBME
40
50
50
50
40
50
60
60
60
35
21
24
37
26
12
rac
24
50
TBME
8
a,10a
tion of 3ꢀphenylꢀ4ꢀpentenoic acid.
Unfortunately, estabꢀ
b
TBME
lished methodology is limited to the maximum yield of 50%.
To overcome this inconvenience, we have envisioned to introꢀ
duce the racemization of the unreacted enantiomer to set up a
dynamic kinetic resolution (DKR). The classical and commonꢀ
ly applied tandem metalꢀenzyme DKR is based on secꢀalcohol
racemization and enzymatic acylation of preferred enantioꢀ
cyclohexane
toluene
toluene
toluene
toluene
toluene
19
b
mer. In the case of alcohols the racemization predominantly
B: Ru(II)
C: Pd(0)
2
0
occurs through hydrogen transfer process. To the best of our
knowledge there is not any literature report of tandem metalꢀ
enzyme DKR of carboxylic acids possessing double bond at γ
position. Drueckhammer and coꢀworkers have extensively
studied racemization of thioesters of αꢀphenylpropionate
which after enzymatic hydrolysis provided enantiomerically
9
a
Reaction conditions: All the reactions were run for 24 h, 0.1
b
mmol of (S)ꢀ1a, solvent (3.0 mL), metal catalyst (10 mol%). tꢀ
BuOK (4 mol%). Determined by HPLC on a Chiralcel ODꢀH
c
column.
21
enriched αꢀsubstituted carboxylic acids.
Detailed temperature studies show that full racemization of
(
(
S)ꢀ1a can be achieved within 24 hours in toluene at 60 °C
Table 1, entries 6 and 7). Also two other metal complexes
Due to well recognized fact that transition metal catalysts
interact reversible with activated and nonꢀactivated carbonꢀ
4
catalyze racemization but with relevantly lower rates (Table 1,
entries 8 and 9). Putative mechanism of studied racemization
can be analogous to already known mechanism reported for
palladium catalysts. Palladium complexes such as C catalyze
racemization of allylic esters under conditions compatible with
carbon double bounds we investigated the racemization of
ꢁꢂ
8a,10a
(
S)ꢀ3ꢀphenylꢀ4ꢀpentenoic acid ((S)ꢀ1a) ([α] = −19.3)
ꢀ
with different transition metal catalysts (Table 1). We applied
several commercially available catalysts which are commonly
2
2
used in DKR ꢀ rhodium(II) acetate dimer (A), dichloro(pꢀ
5
a, 25
2
3
use of lipases via πꢀallyl complex formation.
Several addiꢀ
cymene)ꢀruthenium(II)
dimer
(B),
a4 nd
2
tional experiments were performed to obtain more information
about the mechanism of the racemization process. It is well
recognized that the rhodium(II) acetate readily exchange the
bridging acetate groups what may explain high efficiency of
Rh(II) catalyst in racemization of the acid 1a exclusively what
tetrakis(triphenylphosphine) palladium(0) (C) (Scheme 1).
Scheme 1. Racemization catalysts
18c
can be followed by UvꢀVis spectroscopy. The absorption
spectra of acid 1a and ester 2b were recorded using the same
concentration after 2 hours of agitation at ambient temperature
in DCM. In case of formed rhodium complex with 3ꢀphenylꢀ4ꢀ
pentenoic acid (1a) decreasing in intensity together with new
band at 308 nm was observed (Figure 2). The same exchange
with rhodium acetate ligands does not occur for ester 2a what
manifests in overlapping of UvꢀVis spectras. Previous study
1
using H NMR spectroscopy have showed that chiral dirhodiꢀ
um Mosher’s acid complex Rh (MTPA) obtained upon exꢀ
2
4
change the acetate groups with Mosher’s acid interacts with
carbon ꢀ carbon double bonds (C=C). Detailed investigation of
several compounds possessing two C=C reveals that such
In all cases catalyst racemization of (S)ꢀ1a occurred. The
best results were obtained with rhodium acetate (A) (Table 1).
This metal complex has been successfully used previously for
2
6
interaction is much stronger with terminal C=C bonds.
This very efficient ligand exchange between dirhodium
tetraacetate and carboxylic acid (1a) manifests also by forming
the racemization of βꢀhydroxy acids in tertꢀbutyl methyl ether
18a
(
TBME) at 40 °C. This procedure was initially used for the
immediately a greenish solution in CDCl during NMR probe
3
racemization of ((S)ꢀ1a). Whereas, racemization occurred, the
conversion was low which made it necessary to modify our
protocol (Table 1, entry 1). Elevated temperature to 50 °C as
well as addition of base enhanced only a bit racemization rates
preparation (photographs are given in supplementary data).
Analogous behavior of rhodium (II) was observed by Cotton
27
and Falvello. Authors reported the strong binding of caryoꢀ
phyllene molecules with tetrakis(trifluoroacetato)dirothium
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ACS Catalysis
(
II) through the endo double bonds. Similar phenomena has
OEt
OEt
OEt
OEt
OEt
EtO OEt Ph
OEt
OEt
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not been observed for ester 2a where both spectra with and
without rhodium catalyst overlap each other. Ester (S)ꢀ2a does
not racemize in the presence of rhodium(II) complex. Addiꢀ
tional useful data were elicited from the racemization of 3ꢀ
phenylꢀ4ꢀpentenoic acid (1a) performed under isotopic exꢀ
change conditions in the presence of deuterium oxide. The
detailed analysis of isotope patterns for acid 1a shown on
Figure S1 (supplementary data) and corresponding ester 2a
Ph
OEt
OEt
I
II
III
IV
OEt
OEt
O
OEt
OEt
EtO
OEt EtO
OEt
VII
V
VI
(not shown) indicate only slight incorporation of deuterium
Figure 3. Alkoxy donors used in EKR of racꢀ1a catalyzed by
Novozym 435.
into acid 1a. This observation may suggests that the racemizaꢀ
tion of acid 1a is not assisted by πꢀallyl complex.
0
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Application of 1,1ꢀdiethoxyethane (V) and diethyl carbonate
(VI) led to racemic product 2a with very low yield (Table 2,
entries 5, 6). Slightly better results regarding productivity, up
to 57% isolated yield, were obtained with triethyl orthoacetate
II), triethyl orthoformate (III) and tetraethyl orthocarbonate
VII) (Table 2, entries 2,3 and 7). Finally, the highest enantiꢀ
omeric excess was observed in case of donors possessing
aromatic moieties, triethyl orthobenzoate (I) and benzyl diethꢀ
yl acetate (IV) providing enantiomerically pure ester (>99%
ee) (S)ꢀ2a with 47% isolated yield (Table 2, entries 1 and 4).
(
(
Table 2. Kinetic resolution of rac-3-phenylpent-4-enoic
acid (1a) with different alkoxy group
a
b
c
entry
donor
I
yield (%)
ee (%)
1
2
3
4
5
6
7
47
57
13
32
3
>99 (S)
69 (S)
68 (S)
81 (S)
nd
II
Figure 2. Absorption spectra of free and rhodium complex with
acid 1a and ester 2a recorded in DCM.
III
IV
V
Collected data enriched by the literature reports on olefin
isomerization and hydrogenation catalyzed by rhodium cataꢀ
28
VI
VII
9
nd
lysts may indicate that the racemization process of studied
acid 1a consists of two individuals; first activation of catalyst
by ligand exchanges followed by double bond isomerization.
This conclusion was supported by the fact that the racemizaꢀ
tion has not been observed in case of optically active ester (S)ꢀ
23
29 (S)
a
Reaction conditions: 0.2 mmol of 1a, triethyl orthobenzoate 2
b
equiv., toluene (5.0 mL), Novozym 435 (10 mg), 72 h. Isolated
c
yield. Determined by HPLC on a Chiralcel ODꢀH column.
2
a.
The immobilized lipase B from Candida antarctica (Novoꢀ
zym 435) was employed for the kinetic resolution of racemic
ꢀphenylꢀ4ꢀpentenoic acid (1a) (Scheme 2).
Next, the series of experiments with different racꢀ3ꢀarylꢀ4ꢀ
pentenoic acid derivatives 1bꢀg were performed providing
corresponding enantiomerically enriched esters 2bꢀc and 2eꢀg
3
(
Scheme 3).
Scheme 2. Enzymatic kinetic resolution of rac-1a
Scheme 3. Enzymatic kinetic resolution of acid rac-1a-g
triethyl orthobenzoate
CO H
Novozym 435
2
CO Et
2
toluene, 60 o
C
R
R
rac-1a-g
(S)-2a-g
The substrates 1bꢀg were synthetized according to the literaꢀ
ture procedure in JohnsonꢀClaisen rearrangement of correꢀ
sponding allylic alcohols and followed by basic hydrolysis.
Obtained results applying Novozym 435 as biocatalyst indiꢀ
cate that there are specific substrate requirements (Table 3).
Reactions were performed for 72 hours in toluene in 0.2
mmol scale at 60 °C using seven different alkoxy donors IꢀVII
(Figure 3).
2
9
Table 3. Kinetic resolution of rac-3-aryl-4-pentenoic acids
a
(1a-g)
b
c
entry
R
product yield (%)
ee (%)
1
2
3
H
2a
2b
2c
47
21
0
>99 (S)
48 (S)
nd
MeO
Me
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Page 4 of 7
4
5
6
7
3,4ꢀOCH O
2d
2e
2f
0
nd
As it can be noticed, appropriate combination of enzyme,
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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3
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4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
transition metal catalyst and organic solvent is required for
successful enzymatic DKR procedure. Further studies under
optimization and amplification of herein proposed protocol are
still underway. In spite of described limitations proposed
approach diversifies already knew methods and lead to optiꢀ
cally pure products with very high yield.
Cl
41
45
48
92 (S)
97 (S)
16
F
NO2
2g
a
Reaction conditions: 0.2 mmol of 1, triethyl orthobenzoate 2
equiv., toluene (5.0 mL), Novozym 435 (10 mg). Isolated yield.
Determined by the chiral HPLC.
b
c
CONCLUSIONS
In summary, we have featured the generality of the previꢀ
The results indicated that the most suitable substrates for the
enzymatic reactions are these with small attached groups at
para position 1a, 1e and 1f, which offer the best compromise
between conversion and selectivity (Table 3, entries 1, 5 and
18a
ously established protocol and shown high potential in the
synthesis of enantiomerically enriched pharmacologically
relevant unsaturated carboxylic acids. Nowadays, enzymatic
dynamic kinetic resolution was limited to compound possess
hydroxy or amino functional groups. Here we have shown that
our protocol works efficiently for compounds possessing
carbonꢀcarbon double bond and phenyl group in allylic posiꢀ
tion without mentioned functional groups. Under optimized
conditions in situ racemization of the substrate carboxylic acid
by rhodium catalyst and enzymatic esterification with a specifꢀ
ically selected alkoxy donor resulted in full transformation of
the racemic carboxylic acid in to enantiomerically pure ester
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
). In case of derivative 1g with strong electron withdrawing
nitro group corresponding ester 2g was obtained with 48%
yield but with very low enantiomeric excess (Table 3, entry 7).
Moreover, the size of substituent attached to the para position
of the phenyl ring cannot exceed the size of the active pocket
in the enzyme and only in case of substrate 1b corresponding
ester 2b was obtained with moderate yield and low enantioꢀ
meric excess (Table 3, entries 2ꢀ4).
The next step of our studies was to combine the racemizaꢀ
tion with the enzymatic transformation in oneꢀpot procedure
(Scheme 4).
2
a with very high isolated yield. It was demonstrated that the
high enantioselectivity of the enzyme is compatible with the
rhodium catalyzed racemization of various paraꢀsubstituted 3ꢀ
arylꢀ4ꢀpentenoic acid derivatives. The protocol reported here
should be a useful complement to known methods. Moreover,
the easy recovery of both catalyst makes this process suitable
for up scaling.
Scheme 3. Dynamic kinetic resolution of acid rac-3-aryl-4-
pentenoic acid derivatives catalyzed by Novozym 435
EXPERIMENTAL SECTION
General Considerations. All the chemicals were obtained
from commercial sources and the solvents were of analytical
grade. Immobilized lipase B from Candida antarctica (Novoꢀ
zym 435) was purchased from Novo Nordisk. Column chroꢀ
matography was performed on Merck silica gel 60/230ꢀ400
mesh. Enzymatic reactions were performed in a vortex (Heiꢀ
dolph Promax 1020) equipped with incubator (Heidolph Inkuꢀ
bator 1000). To prove the ability of the established protocol
each reaction was repeated at least three times.
Further experiments were assigned with Novozym 435 and
rhodium(II) acetate in toluene at 60 °C for 120 hours (Table
).
4
Table 4. Dynamic kinetic resolution of racemic rac-3-aryl-
-pentenoic acid derivatives catalyzed by Novozym 435
a
4
General procedure for enzymatic kinetic resolution. To
the solution of acid 1aꢀg (0.2 mmol) in toluene (5 mL), triethyl
orthobenzoate or other alkoxy group donor (3 equiv.) and
enzyme (10 mg) were added in 10 mL screwed vial. The reacꢀ
tion mixture was stirred for 72 hours at 60 °C. After cooling,
crude product was purified by column chromatography (ethyl
b
c
entry
R
product
2a
yield (%)
ee (%)
1
2
3
4
5
H
98
37
78
92
98
>99 (S)
43 (S)
90 (S)
95 (S)
10
MeO
Cl
2b
2e
1
F
2f
acetate/hexanes). The H NMR data were in accordance with
those recorded for racemates.
NO2
2g
General procedure for dynamic enzymatic kinetic reso-
lution. To the solution of acid 1aꢀg (0.2 mmol) in toluene (5
mL), triethyl orthobenzoate (3 equiv.), enzyme (10 mg) and
metal catalyst (10 mol%) were added in 10 mL vial. The reacꢀ
tion mixture was stirring for 120 hours at 60 °C. After cooling,
crude product was purified by column chromatography (ethyl
acetate/hexanes).
a
Reaction conditions: 0.2 mmol of 1, triethyl orthobenzoate 3
equiv., toluene (5.0 mL), Novozym 435 (10 mg) and metal cataꢀ
lyst (10 mol%). Isolated yield. Determined by the chiral HPLC.
b
c
Finally, we applied this protocol on a preparative scale.
Thus, 176 mg (1 mmol) of racemic 3ꢀphenylꢀ4ꢀpentenoic acid
1a) was transformed into optically pure ester (S)ꢀ2a within
six days, and with 97% yield of isolated product. To show the
applicability of this concept, other unsaturated acids 1e and 1f
were subjected to DKR with Novozym 435 leading to correꢀ
sponding esters (S)ꢀ2e and (S)ꢀ2f with 76% and 90% yield and
enantiomeric excess values identical with those obtained for
the initial DKR (Table 4, entries 3 and 4). Optically active
ethyl 3ꢀ(phenyl)pentꢀ4ꢀenoate (2a) is a precursor of two mediꢀ
(
ASSOCIATED CONTENT
Supporting Information. Supporting Information Available:
1
13
Experimental details, H, C NMR spectra, and HPLC traces.
This material is available free of charge via the Internet at
http://pubs.acs.org.
®
® 8,10
cines, Femoxetine and Citrocard .
AUTHOR INFORMATION
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Corresponding Author
ryszard.ostaszewski@icho.edu.pl
(7) (a) Tsubogo, T. Oyamada, H. Kobayashi, S. Nature 2015, 520,
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ACKNOWLEDGMENT
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62, 4907ꢀ4916.
8) (a) Brodzka, A. Koszelewski, D. Cwiklak, M. Ostaszewski, R.
This work was supported by the Polish National Science Centre
project No. 2013/11/B/ST5/02199. We gratefully acknowledge
Przemysław Sendys for his assistance in mass spectroscopy
measurements.
(
Tetrahedron: Asymmetry 2013, 24, 427ꢀ433. (b) Goodman & Gilꢀ
man’s The Pharmacological Basis of Therapeutics; Hardman, J. G.
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This work was dedicated to prof.Janusz Jurczak on the occasion in
his 75th birthday
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