Chemo-enzymatic Baeyer-Villiger oxidation of 4-methylcyclohexanone via kinetic resolution of racemic carboxylic acids: Direct access to enantioenriched lactone

Article abstract of DOI:10.1039/c5cc08519e

A new method for the asymmetric chemo-enzymatic Baeyer-Villiger oxidation of prochiral 4-methylcyclohexanone to (R)-4-methylcaprolactone in the presence of (±)-4-methyloctanoic acid, Candida Antarctica lipase B and 30% aq. H₂O₂ has been developed. A mechanism for the asymmetric induction based on kinetic resolution of racemic carboxylic acids is proposed.

Full text of DOI:10.1039/c5cc08519e

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Chemo-enzymatic Baeyer-Villiger oxidation of 4-
methylcyclohexanone via kinetic resolution of racemic
carboxylic acids: direct access to enantioenriched lactone
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Agnieszka Drożdż,a Anna Chrobok*a
chemoꢀenzymatic approach involving relatively stable and
A new method for the asymmetric chemo-enzymatic Baeyer-
Villiger oxidation of prochiral 4-methylcyclohexanone to (R)-4-
methylcaprolactone in the presence of (±)-4-methyloctanoic acid,
Candida Antarctica lipase B and 30% aq. H2O2 has been
developed. A mechanism for the asymmetric induction based on
kinetic resolution of racemic carboxylic acids is proposed.
inexpensive lipase. Several early examples for lipaseꢀmediated
14ꢀ22
BaeyerꢀVilliger oxidation were reported.
In the chemoꢀ
enzymatic method the enzyme is used in only one step of the
reaction, and therefore, the reaction is called chemoꢀenzymatic. This
reaction involves the oxidation of longꢀ or mediumꢀchain carboxylic
acids with hydrogen peroxide in the presence of lipase to generate in
situ peracid, which is used to oxidise ketones to lactones in the
second step. The chemoꢀenzymatic approach is an attractive
alternative, avoiding handling of often unstable, hazardous and fairly
expensive organic percarboxylic acids, which are typical oxidants
used in the BaeyerꢀVilliger reaction.
Lipases are used in the pharmaceutical industry for the
preparation of singleꢀisomer chiral drugs, either by kinetic resolution
of racemic molecules, or by the desymmetrisation of prochiral
compounds.23
The BaeyerꢀVilliger (BV) oxidation of ketones to lactones with
peroxide derivatives is a powerful methodology for oxygen insertion
into the carbonꢀcarbon bond breaking process.1 Of particular
importance are new protocols for the asymmetric version of this
reaction which allows rapid access to chiral lactones. Natural
products containing the lactone skeleton attract considerable
attention from scientists. Lactones are valuable building blocks for
the natural synthesis of biologically important substances such as
alkaloids, steroids, pheromones, macrocyclic antibiotics, lignan
lactones and antileukaemics.2 In recent years, strategies to perform
BaeyerꢀVilliger reactions in an enantioselective manner have been
continuously improved. Organometallic approaches and biocatalytic
methods have been described.3
The first data concerning asymmetric BV reactions catalysed by
metal complexes date back to 1994.4 Since then, synthetic methods
for chiral lactones using both chiral catalysts and chiral
hydroperoxides have been described. Chiral complexes of metals
such as Al, Cu, Zr, Hf, Pt, Sn, Zn with different chiral ligands, e.g.,
based on BINOL (1,1′ꢀbiꢀ2ꢀnaphthol) or VANOL (3,3′ꢀdiphenylꢀ
2,2′ꢀbiꢀ1ꢀnaphthol) are known to catalyse the synthesis of lactones
with high enantiomeric excess ee up to 87%.3, 5ꢀ7
However, to date, there is only one example of chiral lactones
synthesis in a chemoꢀenzymatic BV reaction utilising ethyl acetate
as a peracetic acid precursor and chiral ketone levoglucosenone as a
starting material that is converted to (S)ꢀγꢀhydroxymethylꢀα,βꢀ
butenolide.24
Another study describes autocatalytic Baeyer–Villiger oxidation
of cyclic ketones to lactones mediated by lipases using urea–
hydrogen peroxide as the primary oxidant without the addition of
carboxylic acid.15 A different mechanism for this reaction was
proposed. In this method the lactone that is created can undergo
lipaseꢀmediated perhydrolysis to peroxy acids that can oxidise
ketones, thereby achieving an autocatalytic process. Lipaseꢀcatalysed
perhydrolysis is enantiospecific and gives 6ꢀsubstituted
caprolactones or the corresponding hydroxy acids in
enantiomerically enriched form. The best results were obtained for
the oxidation of 2ꢀmethylcyclohexanone where the S isomer of the
lactone was obtained with 44% yield and 60% enantioselectivity.15
To date, no examples of an asymmetric version of the Baeyerꢀ
Villiger reaction can be found in the literature with the application of
chiral acid as the precursor of a chiral peracid or racemic carboxylic
acids which after kinetic resolution serve as an effective chiral
oxidant.
Biocatalysis offers a “green chemistry” alternative for BV
transformation.8,9 The enzymes that are used for the transformations
described are known as BaeyerꢀVilliger monooxygenases.10ꢀ12 These
enzymes utilise molecular oxygen to generate a peroxoꢀflavin
species, which attacks the carbonyl group in a nucleophilic reaction
similar to
the classical chemical BaeyerꢀVilliger reaction mechanism.13 In this
method lactones are obtained with enantioselectivities up to 100%.
However, BaeyerꢀVilliger monooxygenases are relatively expensive
and poorly stable enzymes for practical synthetic use.
For other known chemoꢀenzymatic approaches, only one report of
Another interesting method for the synthesis of lactones is the
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a chiral epoxide synthesis uses chiral acid ((2R,3S,4R,5S)ꢀ(–)ꢀ enantioselectivity had grown. The rate of reaction for the application
2,3:4,6ꢀdiꢀOꢀisopropylidieneꢀ2ꢀketoꢀLꢀgulonic acid monohydrate) in of 2, 4 and 8 equivalents of acid to the ketone was similar, while 1
oxidation step has been found.25
equivalent was not enough (Fig. S1, ESI). The yield of lactone for
Building on this, we propose herein for the first time the the application of 4 and 8 equivalents of acid after 8 days are slightly
asymmetric chemoꢀenzymatic BaeyerꢀVilliger reaction for the lower. That can be the result of saturation of active centres of lipase.
synthesis of chiral lactones with the application of simple and The enantiomeric excess was growing during the reaction time to
inexpensive racemic carboxylic acids.
reach 90ꢀ96% in the presence of 2 and 4 equivalents of acid after 8
In order to develop a clean asymmetric BaeyerꢀVilliger process days (Fig. 1). In this case the 1 eq was also
the racemic mixture of enantiomers of carboxylic acids as chiral sufficient. A large excess of acid (8 eq) caused lowering of the ee.
peracid precursors was applied. As shown in Scheme 1, the chemoꢀ As a result, 2 equivalents of acid was sufficient to obtained high
enzymatic method for chiral lactone synthesis involves lipase as the yields and enantioselectivity.
biocatalyst for chiral peracid formation and 30% aq. H2O2 as the
Table 1 The influence of the structure of peracid precursor on the yield and
ee of (R)ꢀ4ꢀmethylcaprolactonea
primary oxidant. In contrast to published works concerning the
chemoꢀenzymatic BV reaction, the lipase was not attached to a solid
support (commercial name Novozymeꢀ435) but was used in the free
form as commercially available water solution of Candida Antarctica
lipase B (CALB).
25oC
18oC
No. Carboxylic acid
1
Yield
[%]
ee (R)
[%]
Yield
[%]
ee (R)
[%]
99 (4 days)
99 (5 days)
94 (7 days)
62
61
40
99 (8 days)
95 (8 days)
95 (8 days)
80
83
82
2
3
4
89 (3 days)
89 (4 days)
95 (5 days)
51
55
67
87 (8 days)
77 (8 days)
97 (8 days)
89
81
96
Scheme 1 Chemoꢀenzymatic Baeyer–Villiger oxidation of 4ꢀ
5
6
methylcyclohexanone
First, the influence of the structure of racemic acids on the
asymmetric induction in this process was studied (Table 1). The
experiments were carried out at 25oC as well as at 18oC which are
the optimum rage of temperatures for CALB. Toluene was used as
the best organic solvent for this process.22 The oxidation of 4ꢀ
methylcyclohexanone was chosen as a model reaction using 0.10 g
native lipase (CALB) for 0.5 mmol of ketone. The molar ratio of the
ketone to the carboxylic acid to H2O2 was fixed as 1:2:2. The
progress of the reaction was checked by GC.26
7
8
9
rac. 92 (8 days)
43
ꢀ
82 (8 days)
86 (8 days)
57
66
(R)ꢀ
(S)ꢀ
ꢀ
ꢀ
ꢀ
4
(8 days)
ꢀ
rac.
52 (8 days)
ꢀ
44
ꢀ
30 (8 days)
39 (8 days)
49
(R)ꢀ
(S)ꢀ
72
ꢀ
14
50
ꢀ
(8 days)
85 (2 days)
99 (8 days)
ꢀ
ꢀ
Several acids were chosen for the model oxidation reaction of 4ꢀ
methylcyclohexanone. In the literature only nonꢀchiral medium
chain and unbranched long chain acids were studied in chemoꢀ
enzymatic processes. In this work, the chiral carbon was located as
first, second or third in the alkyl chain of the acid. The longer alkyl
chain and the later location of the chiral carbon from the carboxylic
group in the acid caused the better performance of the peracid
precursor. Acids with phenyl or branched substituent as well as
esters were much less reactive (Table S1, S2, ESI). Higher
enantiomeric excess of (R)ꢀ4ꢀmethylcaprolactone was observed at a
lower temperature 18oC. Then, the reaction was slower, allowing
higher ee. The best results were obtained for the application of (±)ꢀ4ꢀ
methyloctanoic acid at 18oC which allows full conversion of 4ꢀ
methylcyclohexanone and the formation of 4ꢀmethylcaprolactone
with 97% yield and an enantiomeric excess of 96% (R isomer) in 8
days (Table 1, entry 6). The faster the reaction is with completion
after 3, 4 or 5 days, the lower the enantiomeric excess that is
observed.
a
Reaction conditions: 4ꢀmethylcyclohexanone (0.5mmol), 30% aq. H2O2
(1mmol), acid (1mmol), 0.10 g of CALB, 18 oC, toluene (1ml), yields and ee
determined by GC.
For further studies, (±)ꢀ4ꢀmethyloctanoic acid was chosen as the
peracid precursor. The influence of the amount of (±)ꢀ4ꢀ
methyloctanoic acid on the yield and ee of (R)ꢀ4ꢀ
methylcaprolactone was determined (Fig. 1). In each case during the
reaction time chiral induction was observed and the
Fig. 1 The influence of the amount of (±)ꢀ4ꢀmethyloctanoic acid on the ee of
(R)ꢀ4ꢀmethylcaprolactone obtained during the chemoꢀenzymatic oxidation of
4ꢀmethylcyclohexanone (0.5mmol) with 30% aq. H2O2 (1mmol) in the
presence of 0.10g of CALB at 18 oC in toluene (1ml).
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In order to study the influence of the primary oxidant 30%, 50% system and stopped at the level ee of 40% and 20%, respectively.
and 60% aq. H2O2 as well as anhydrous urea–hydrogen peroxide Referring to the initial assumption that a further increase of the
(UHP) were used in the model oxidation of 4ꢀmethylcyclohexanone amount of enzyme over 0.1 g did not influence the yield of the
at 18oC. The molar ratio of ketone to (±)ꢀ4ꢀmethyloctanoic acid to lactone formed, a study of the influence of the amount of CALB on
oxidant was 1:2:2. The type of oxidant only slightly influenced the the reaction course was performed (Fig. 4 and Fig. 4S, ESI). Below
reaction rate (Fig. S2, ESI) but in each case the high conversion of 0.1 g of CALB per 0.5 mmol of ketone, the full conversion of ketone
was reached but the ee was poor (37%). With higher amounts of
CALB, above 0.1 g, the reactions were slower and for 0.2 g of
CALB only 44% of lactone was obtained after 8 days. In all cases
high ee were obtained. Lower yields of lactone obtained for the
application of higher amounts of CALB can be caused by
detrimental effect of high amounts of water which is introduced to
the system with the native CALB.
The 0.10 g of CALB per 0.5 mmol of ketone was appropriate to
carry out the reaction in the region where the reaction kinetic is
controlled by the formation of lactone, not by the formation of
peracid in the enzymeꢀcatalysed reaction.
ketone was achieved. The type of oxidant had a tremendous impact
on the enantiomeric excess (Fig. 2). Asymmetric synthesis can be
achieved only by using 30% aq. H2O2.
Fig. 2 The influence of the structure of primary oxidant on the ee of (R)ꢀ4ꢀ
methylcaprolactone obtained during the chemoꢀenzymatic oxidation of 4ꢀ
methylcyclohexanone (0.5mmol) in the presence of oxidant (1mmol), (±)ꢀ4ꢀ
methyloctanoic acid (1mmol) and 0.10 g of CALB at 18 oC in toluene (1ml).
The optimum molar ratio of ketone to oxidant was proven to be
1:2. The molar excess of oxidant was varied from 1 to 6 (Fig. S3,
ESI). The reaction rate increases rapidly with the higher molar ratio
of oxidant (3ꢀ6 equivalents) but in all cases except equimolar
amounts the full conversion of the ketone was achieved.
Fig. 4 The influence of the amount of CALB on the ee of (R)ꢀ4ꢀ
methylcaprolactone obtained during the chemoꢀenzymatic oxidation of
4ꢀmethylcyclohexanone (0.5mmol) with 30% aq. H2O2 (1mmol) in the
presence of (±)ꢀ4ꢀmethyloctanoic acid (1mmol) at 18 oC in toluene (1ml).
In this work, the native lipase was used because the rate of the
model reaction under the conditions used in this work were much
higher with the application of Novozymeꢀ435, e. g., with 0.03 g of
Novozymeꢀ435 per 0.5 mmol of ketone just after 4 days, the full
conversion of ketone was obtained with only 15% of ee.
We also noticed that the solvent has an immense impact on the
enantiomeric excess (Table 2). The best solvent for this reaction was
found to be toluene, and the concentration of the reagents also has an
influence on enantiomeric purity. The application of diethyl ether
and hexane resulted in lower yields and ee in the same reaction time.
Table 2 The influence of the solvent on the reactiona
No.
1
Solvent
toluene
toluene
diethyl ether
diethyl ether
diethyl ether
hexane
V [ml] Time [days]
Yield [%]
ee (R) [%]
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
8
8
6
7
8
6
7
8
95
97
79
79
79
86
88
89
87
96
37
48
56
40
45
55
Fig. 3 The influence of the amount of 30% aq. H2O2 on the ee of (R)ꢀ4ꢀ
methylcaprolactone obtained during the chemoꢀenzymatic oxidation of
4ꢀmethylcyclohexanone (0.5mmol) in the presence of (±)ꢀ4ꢀmethylꢀ
octanoic acid (1mmol) and 0.10g of CALB at 18 oC in toluene (1ml).
2
3
hexane
hexane
Interestingly, the ee reached 96% after 8 days only with the
application of a 2ꢀfold molar excess of oxidant to ketone (Fig. 3).
When using a triple excess of oxidant ee, was still growing after 8
days; fourfold and sixfold excess of oxidant deactivated the reaction
a Reaction conditions: 4ꢀmethylcyclohexanone (0.5mmol), 30% aq. H2O2 (1
mmol), (±)ꢀ4ꢀmethyloctanoic acid (1mmol), 0.10g of CALB, 18 oC,
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To learn more about the mechanism, the reactions with the
application of optically pure R and S as well as a racemic mixtures of
the acids: 2ꢀmethylꢀ3ꢀhydroxybutyric and 2ꢀphenylbutyric were
performed (Table 1, entry 7, 8). These acids are not the most reactive
in the chemoꢀenzymatic reaction but both pure isomers were
commercially available, and we could learn about the influence of
the R and S isomers on the reaction course. Additionally, the test
reaction with octanoic acid without any substituents was performed
(Table 1, entry 9).
Acknowledgements
This work was financed by the Polish National Science Centre
(Grant no. UMOꢀ2013/09/N/ST8/02059). The authors would like to
thank Professor Ryszard Ostaszewski from Institute of Organic
Chemistry, Polish Academy of Science for fruitful discussion.
As shown in Table 1, the pure S isomers of the acids do not work
in this reaction. Thus, the lipase does not catalyse the conversion of
acid to peracid. However, the pure R isomers of the acids work
almost as well as the racemic mixture. Based on these experiments,
the proposed mechanism of the asymmetric BaeyerꢀVilliger reaction
via kinetic resolution of racemic carboxylic acids is depicted in
Scheme 2. Lipase converts only the R isomer from the racemic
mixture of acid to peracid (R isomer). Next, the optically pure
peracid oxidises prochiral 4ꢀmethylcyclohexanone to (R)ꢀ4ꢀ
methylcaprolactone with high ee. After one cycle of the reaction,
the waste R isomer of acid is again converted with the aid of lipase
to R isomer of peracid enable to form the lactone with high yield and
enantiomeric excess. To enriched the created mixture of isomers in
the isomer R the additional kinetic resolution takes place catalysed
by CALB. Finally, high ee of lactone is obtained (96%).
Notes and references
1
2
3
4
(a) G. Krow, Org. React., 1993, 43, 251; (b) M. Renz, B. Meunier,
Eur. J. Org. Chem., 1999, 737.
(a) T. Fischer and J. Pietruszka, Top Curr.
R. S. Ward, Tetrahedron, 1990, 46, 5029.
M. D. Mihovilovic, F. Rudroff and B. Groetzl, Curr. Org. Chem.
, Chem., 2010, 297, 1; (b)
,
2004, 1057.
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C. Bolm, G. Schlingloff and K. Weickhardt, Angew. Chem., 1994,
106, 1944.
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7
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M. M. Kayser, Tetrahedron, 2009, 65, 947.
C. Bolm, J. C. Frison and C. Palazzi, Tetrahedron, 2006, 62, 6700.
A. Drożdż, A. Foreiter and A. Chrobok, Synlett, 2014, 25, 559.
D. E. T. Pazmino, H.M. Dudek and M. W. Fraaije, Curr. Opin.
Chem. Biol., 2010, 14, 138.
9
V. Alphand and R. Wohlgemuth, Curr. Org. Chem., 2010, 14, 1928.
10 M. J. Taschner and D. J. J. Black, J. Am. Chem. Soc., 1988, 110
,
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11 V. Alphand, A. Archelas and R. Furstoss, Tetrahedron Lett., 1989,
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12 A. Drożdż and A. Chrobok, Curr. Top. Catal., 2014, 11, 25.
13 D. Sheng, D. P. Ballou and V. Massey, Biochem., 2001, 40, 11156.
14 S. C. Lemoult, P. F. Richardson and S. M. Roberts, J. Chem. Soc.
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16 M. Y. Rios, E. Salazar and H. F. Olivo, J. Mol. Catal. B, 2008, 54
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17 A. J. Kotlewska, F. van Rantwijk, R. A. Sheldon, I. W. C. E. Arends,
Green Chem., 2011, 13, 2154.
18 G. Chavez, R. HattiꢀKaul, R. A. Sheldon, G. Mamo, J. Mol. Catal. B
2013, 89, 67.
Scheme 2 The proposition of the mechanism of asymmetric chemoꢀ
enzymatic Baeyer–Villiger oxidation of 4ꢀmethylcyclohexanone
,
19 A. Drożdż, A. Chrobok, S. Baj, K. Szymańska, J. MrowiecꢀBiałoń,
A. B. Jarzębski, Appl. Catal. A, 2013, 467, 163.
20 D. GonzálezꢀMartínez, M. RodríguezꢀMata, D. MéndezꢀSánchez, V.
Gotor and V. GotorꢀFernández, J. Mol. Catal. B, 2014, 114, 31.
21 G. Chavez, J.ꢀA. Rasmussen, M. Janssen, G. Mamo, R. HattiꢀKaul
and R. A. Sheldon, Top. Catal., 2014, 57, 349.
22 A. Drozdz, K. Erfurt, R. Bielas and A. Chrobok, New J. Chem., 2015,
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To confirmed the possibility of kinetic resolution of isomers of
lactone the additional experiment was performed. (±)ꢀ4ꢀ
methylcaprolactone was mixed with CALB in toluene for 8 days.
After this time ee of R isomer reached 45%.
Two other cyclic ketones were also oxidised using this method
and optimised conditions (ESI, Table S3). The oxidation of 4ꢀ
ethylcyclohexanone during 6 days gave 4ꢀethylcaprolactone with
99% yield and 69% ee of R isomer. In the same reaction time the 4ꢀ
phenylbutyrolactone was obtained with 99% yield and 76% ee of R
isomer.
24 A. L. Flourat, A. A. M. Peru, A. R. S. Teixeira, F. Brunissen and F.
Allais, Green Chem., 2015, 17, 404.
In summary, lipaseꢀmediated Baeyer–Villiger oxidation procedure
offers mild reaction conditions, low toxicity and a green oxidant that
25 K. Sarma, A. Goswami and B. C. Goswami, Tetrahedron Asymm.
,
2009, 20, 1295.
make this method costꢀeffective, and a greener alternative to the 26 General method for BaeyerꢀVilliger oxidation: the ketone (0.5
mmol), carboxylic acid (1 mmol) and
1 ml of toluene were
metallorganic conventional asymmetric BaeyerꢀVilliger reaction.
The ability for the chiral induction in lactones has not yet been
explored with the application of racemic mixtures of carboxylic
acids. This enzymatic oxygen insertion represents a promising
approach for the synthesis of chiral lactones. The additional studies
under the development of lipaseꢀmediated asymmetric Baeyerꢀ
Villiger oxidation using different ketones are being undertaken in
our laboratory.
introduced into a 25 ml roundꢀbottom flask and the contents of the
flask was shaken. Next, 0.1 g of native CALB was introduced, and
30% H2O2 (1 mmol) was added dropwise. The flask was sealed with
a septum and mixed in a thermostatted shaker (±0.5ºC) with orbital
stirring at 250 rpm at 18 and 25°C for 3ꢀ8 days, depending on the
reaction rate. Periodically, 15 ꢁl of the sample diluted with 1 ml of
dichloromethane was collected during the reaction to monitor the
progress of the reaction (yield and ee
)
utilising GC
(SUPELCOWAXTM 10 column (30 m×0.2 mm×0.2 ꢁm) with
nꢀ
decane as an external standard or Astec CHIRALDEXTM GꢀTA
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capillary column (30 m×0.25 mm×0.12 ꢁm)). When the reaction was
completed, the postꢀreaction mixture was washed with 5 ml of a 10%
NaHCO3 solution in water, dried over anhydrous MgSO4 and
concentrated under vacuum. The yield of 4ꢀmethylcaprolactone after
purification by column chromatography with a hexane:ethyl acetate
ratio of 4:1 as an eluent was 93%.
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