Lactonization reactions through hydrolase-catalyzed peracid formation. Use of lipases for chemoenzymatic Baeyer-Villiger oxidations of cyclobutanones

Article abstract of DOI:10.1016/j.molcatb.2014.09.002

A one-pot chemoenzymatic method has been described for the synthesis of γ-butyrolactones starting from the corresponding ketones through a Baeyer-Villiger reaction. The approach is based on a lipase-catalyzed perhydrolysis for the formation of peracetic acid, which is the responsible for the ketone oxidation. Optimization studies have been performed in the oxidation of cyclobutanone, finding Candida antarctica lipase type B, ethyl acetate and urea-hydrogen peroxide complex as the best system. The relative ratio of these reagents has also been analyzed in depth. This synthetic approach has been successfully extended to a family of 3-substituted cyclobutanones in high substrate concentration, yielding the corresponding lactones with excellent isolated yields and purities, under mild reaction conditions and after a simple extraction protocol.

Full text of DOI:10.1016/j.molcatb.2014.09.002

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Contents lists available at ScienceDirect
Journal of Molecular Catalysis B: Enzymatic
journal homepage: www.elsevier.com/locate/molcatb
Lactonization reactions through hydrolase-catalyzed peracid
formation. Use of lipases for chemoenzymatic Baeyer–Villiger
oxidations of cyclobutanones
Daniel González-Martínez, María Rodríguez-Mata, Daniel Méndez-Sánchez,
Vicente Gotor∗, Vicente Gotor-Fernández∗
Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, Avenida Julián Clavería 8,
33006 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online xxx
A one-pot chemoenzymatic method has been described for the synthesis of ␥-butyrolactones starting from
the corresponding ketones through a Baeyer–Villiger reaction. The approach is based on a lipase-catalyzed
perhydrolysis for the formation of peracetic acid, which is the responsible for the ketone oxidation.
Optimization studies have been performed in the oxidation of cyclobutanone, finding Candida antarctica
lipase type B, ethyl acetate and urea-hydrogen peroxide complex as the best system. The relative ratio of
these reagents has also been analyzed in depth. This synthetic approach has been successfully extended
to a family of 3-substituted cyclobutanones in high substrate concentration, yielding the corresponding
lactones with excellent isolated yields and purities, under mild reaction conditions and after a simple
extraction protocol.
Keywords:
Baeyer–Villiger reaction
Candida antarctica lipase type B
Cascade reactions
Cyclobutanones
Lactones
© 2014 Elsevier B.V. All rights reserved.
1. Introduction
In this context, the synthesis of lactones is highly appealing
because of their interesting properties as subunits for polymer
Hydrolases are enzymes capable to naturally catalyze hydrolytic
reactions for a vast number of organic compounds such as pep-
tides, esters or amides [1,2]. Alternatively, and depending on the
reaction conditions, they can also accelerate the reverse transfor-
mations leading to the corresponding esterification, aminolysis,
ammonolysis, perhydrolysis, hydrazynolysis or thiolysis products,
specially when working in non-aqueous media [3,4]. Within this
class of enzymes, perhydrolases are able to efficiently catalyze
perhydrolysis reactions for the formation of peracids [5,6], but
the unusual participation of lipases for global oxidative process
has attracted the attention of different research groups in the
last decade [5,7,8]. Thus, examples of lipase-mediated epoxidation
[9–14], Baeyer–Villiger reactions [15–19], perhydrolysis of car-
boxylic acid and esters [20], sequential Baeyer–Villiger reaction and
ring-opening polymerization [21], and also consecutive esterifica-
tion and Baeyer–Villiger cascade reactions [22] have appeared in
the literature, giving access to synthetically useful oxygenated het-
erocycles through clean and selective transformations under mild
reaction conditions.
industry, and their applications in medicinal chemistry, fragrance
and food industry. Lipases provide useful possibilities for the syn-
thesis of lactones by the proper combination of a peracid precursor,
solvent and an oxidizing agent in mild reaction conditions [7],
avoiding the use and storage of peracids that are usually associated
with explosion risks. This in situ formation of a peracid, commonly
large aliphatic linear peracids or peracetic acid, provides an envi-
ronmentally friendly alternative route to the desired oxygenated
heterocyles [23].
Examples described in the literature have been mainly
focused on the oxidation of cyclopentanones and cyclohexanones
[15–19,24,25]. Herein we have explored the possibility of using
a cascade chemoenzymatic strategy for the production of ␥-
butyrolactones from cyclobutanones. With that purpose, different
enzymes have been tested in order to find adequate oxidizing
conditions, paying special attention to the oxygen source and the
substrate concentration.
2. Experimental
2.1. Materials and methods
∗
Candida antarctica lipase type
7300 PLU/g) and Rhizomucor miehei lipase (RML, 150 IUN/g)
B (CAL-B, Novozym-435,
Corresponding authors. Tel.: +34 985103454; fax: +34 985103456.
E-mail address: vicgotfer@uniovi.es (V. Gotor-Fernández).
http://dx.doi.org/10.1016/j.molcatb.2014.09.002
1381-1177/© 2014 Elsevier B.V. All rights reserved.
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Scheme 1. Chemical synthesis of 3-methyl-3-phenylcyclobutanone (1b).
were kindly gifted by Novo-Nordisk. Pseudomonas cepacia lipase
supported on diatomite (PSL-SD, 23,000 U/g), AK lipase from Pseu-
domonas fluorescens (AK, 23,700 U/g) and Candida rugosa lipase
(CRL, 1410 U/g) were acquired from Sigma–Aldrich. Other chem-
ical reagents were used as purchased from Sigma–Aldrich, Acros or
Fluka, without further additional purification. The only exceptions
were phosphoryl chloride (POCl3) that was used freshly distilled,
and distilled Et2O and THF, which were dried over sodium under
inert atmosphere using benzophenone as indicator.
NMR spectra were recorded on Bruker AV-300 and Bruker DPX-
300 spectrometers (300.13 MHz for 1H and 75.5 MHz for 13C).
All chemical shifts (ı) are given in parts per million (ppm) and
referenced to the residual solvent signal as internal standard. All
coupling constants (J) are reported in Hz. Mass spectra (MS) were
recorded using a MAT-95 Finnigan spectrometer by positive elec-
trospray ionization (ESI+). High resolution mass spectra (HRMS)
were obtained using a Bruker MicroQtof spectrometer by positive
electrospray ionization (ESI+). Gas chromatography (GC) analyses
were performed on a Hewlett Packard 6890 Series chromatograph
equipped with FID. All the data have been included in the suppor-
ting information file. IR spectra were recorded as thin films on NaCl
plates on a Perkin-Elmer Spectrum 100 FT-IR and are reported in
frequency of absorption (cm−1). Thin-layer chromatography (TLC)
was conducted with Merck Silica Gel 60 F254 precoated plates and
visualized using a UV lamp and/or potassium permanganate stain.
Column chromatography was performed using Merck Silica Gel 60
(230–400 mesh).
Scheme 2. General synthesis of 3-arylcyclobutanones 1c–f, i.
(20% EtOAc/hexane): 0.68; IR (NaCl): ꢀ 3059, 3026, 2958, 2921,
1785, 1602, 1496, 1445, 1381, 1080, 764 cm−1 1H RMN (CDCl3,
;
300.13 MHz): ı 1.62 (s, 3H, CH3), ı 3.07–3.17 (m, 2H, CHH), ı
3.42–3.53 (m, 2H, CHH), ı 7.23–7.42 (m, 5H) ppm; 13C RMN (CDCl3,
75.5 MHz): ı 31.1 (CH3), ı 34.0 (C), ı 59.3 (2CH2), ı 125.7 (2CH),
ı 126.3 (CH), ı 128.6 (2CH), ı 148.3 (C), ı 206.6 (CO) ppm; HRMS
(ESI+, m/z): calculated for (C11H12NaO) (M+Na)+: 183.0780, found:
183.0776.
2.3. Typical procedure for the synthesis of 3-arylcyclobutanones
1c–f, i [27,28] (Scheme 2)
a) Preparation of the Cu–Zn complex. To a suspension of Zn (6.5 g,
99.4 mmol) in water (10 mL), a solution of CuSO4·5H2O (760 mg,
4.76 mmol) in water (5 mL) was added in two times. After 1 min,
the solid was filtered and washed with water (2× 5 mL), acetone
(2× 5 mL) and Et2O (2× 5 mL). The resulting grey-black solid was
dried in a Kugelrohr apparatus at 100 ◦C for 6 h, and stored under
inert atmosphere.
b) [2 + 2] Cycloaddition reaction. A suspension of the corre-
sponding styrene 3c–f, i (5.0 mmol) and Cu–Zn complex (1.31 g,
0.26 g/mmol styrene) in dry Et2O (20 mL) was prepared under
inert atmosphere. A mixture composed by trichloroacetyl chloride
(3, 1.116 mL, 10.0 mmol) and freshly distilled phosphoryl chloride
(POCl3, 512 ␮L, 5.5 mmol) in dry Et2O (11 mL) was slowly added
under inert atmosphere at room temperature, and once the addi-
tion was finished, the mixture was refluxed for 24 h. After this
time, the mixture was left to cool down until room temperature,
and filtered over celite. A major part of the Et2O was evaporated
in the rotary evaporator, adding then hexane (100 mL). The mix-
ture was vigorously stirred and then left unaltered, observing the
formation of a precipitate. The supernatant was washed with an
aqueous NaHCO3 saturated solution (2× 40 mL) and brine (40 mL).
The organic phase was dried over Na2SO4, filtered and the solvent
evaporated under reduced pressure, yielding the corresponding
2,2-dichloroketone 5c–f, i.
c) Reduction with Zn. The previous reaction crude containing the
dichlorinated cyclobutanone 5c–f, i (5.0 mmol) was dissolved in
glacial acetic acid (20 mL) and Zn (1.34 g, 20.0 mmol) was added.
The reaction was refluxed for 12 h, and after this time water (25 mL)
was added. The solution was extracted with Et2O (2× 15 mL),
the organic phases were combined and washed with an aqueous
NaHCO3 saturated solution (4× 15 mL) and brine (2× 15 mL). The
resulting organic phase was dried over Na2SO4, filtered and the sol-
vent was evaporated under reduced pressure. The reaction crude
was purified by column chromatography on silica gel (10–20%
EtOAc/hexane), yielding the cyclobutanones 1c–f, i (12–50% iso-
lated yield).
2.2. Typical procedure for the synthesis of
3-methyl-3-phenylcyclobutanone (1b) (Scheme 1)
a) [2 + 2] Cycloaddition reaction [26]. To
a solution of ␣-
methylstyrene (4b, 650 ␮L, 5.0 mmol) in dry Et2O (50 mL), Zn
(654 mg, 10.0 mmol) was added under inert atmosphere. The sys-
tem was sonicated, while a solution of trichloroacetyl chloride (3,
837 ␮L, 7.5 mmol) in dry Et2O (25 mL) was carefully added under
inert atmosphere, maintaining the bath temperature between 15
and 20 ◦C. Sonication was extended for an additional hour after
the addition was completed, and after this time the reaction was
stopped by filtration over celite. The reaction crude was washed
with water (2× 25 mL), an aqueous NaHCO3 saturated solution (5×
25 mL) and brine (25 mL). The organic phase was dried over Na2SO4,
filtered and the solvent was evaporated under reduced pressure.
The resulting crude was purified by column chromatography on
silica gel (5% EtOAc/hexane), yielding the 2,2-dichloro-3-methyl-
3-phenylcyclobutanone 5b (92% yield).
b) Reduction with Zn. The 2,2-dichloro-3-methyl-3-
phenylcyclobutanone (5b, 1.160 g, 5.06 mmol) was dissolved
in MeOH (20 mL), and NH4Cl was added until saturation. Then, Zn
(1.987 g, 30.38 mmol) was added and the mixture stirred at 40 ◦C
for 6 h. After this time, the reaction was filtered over celite and
the solvent was evaporated under reduced pressure. The reaction
crude was redissolved in Et2O (100 mL) and washed with water
(2× 50 mL), an aqueous NaHCO3 saturated solution (2× 50 mL)
and brine (50 mL). The organic phase was dried over Na2SO4,
filtered and the solvent was evaporated under reduced pressure.
The resulting crude was purified by column chromatography
on silica gel (10% EtOAc/hexane), yielding the cyclobutanone 1b
(71% yield; 65% global yield for the two steps). Colourless oil; Rf
3-Phenylcyclobutanone (1c). 34% yield. Colourless oil; Rf (20%
EtOAc/hexane): 0.45; IR (NaCl): ꢀ 3062, 3029, 2975, 2923, 1785,
1603, 1496, 1380, 1104, 780 cm−1 1H NMR (CDCl3, 300.13 MHz):
;
ı 3.10–3.22 (m, 2H, CHH), 3.35–3.47 (m, 2H, CHH), 3.51–3.65 (m,
1H, CH), 7.13–7.31 (m, 5H) ppm; 13C NMR (CDCl3, 75.5 MHz): ı
28.5 (CH), 54.8 (2CH2), 126.6 (2CH), 126.7 (CH), 128.8 (2CH), 143.7
(C), 206.8 (CO) ppm; HRMS (ESI+, m/z): calculated for (C10H10NaO)
(M+Na)+: 169.0624, found: 169.0632.
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3-(2-Bromophenyl)cyclobutanone (1d). 31% yield. Yellow oil; Rf
(20% EtOAc/hexane): 0.72; IR (NaCl): ꢀ 3062, 2983, 2927, 1788,
Then the solvent was evaporated in the rotary evaporator and the
reaction crude purified by column chromatography on silica gel
(20% EtOAc/hexane), yielding the cyclobutanone 1k as a pale yel-
low oil (76% isolated yield). Rf (30% EtOAc/hexane): 0.56; IR (NaCl):
ꢀ 3034, 2926, 2854, 1792, 1732, 1498, 1456, 1380, 1347, 1186,
1590, 1567, 1472, 1380, 1102, 1027, 755 cm−1 1H NMR (CDCl3,
;
300.13 MHz): ı 3.16–3.29 (m, 2H, CHH), 3.46–3.59 (m, 2H, CHH),
3.87–4.02 (m, 1H, CH), 7.10–7.19 (m, 1H), 7.30–7.39 (m, 2H),
7.57–7.64 (m, 1H) ppm; 13C NMR (CDCl3, 75.5 MHz): ı 29.1 (CH),
53.2 (2CH2), 124.9 (CBr), 126.6 (CH), 127.8 (CH), 128.4 (CH), 133.3
(CH), 141.7 (C), 206.0 (CO) ppm; HRMS (ESI+, m/z): calculated for
(C10H9BrNaO) (M79Br+Na)+: 246.9729, found: 246.9703.
1100, 1051, 752 cm−1 1H NMR (CDCl3, 300.13 MHz): ı 3.20–3.50
;
(m, 5H, 2CH2 + CH), 5.19 (s, 2H, CH2Ph), 7.33–7.39 (m, 5H) ppm;
13C NMR (CDCl3, 75.5 MHz): ı 27.5 (CH), 51.7 (2CH2), 67.2 (OCH2),
128.4 (2CH), 128.6 (CH), 128.7 (2CH), 135.5 (C), 173.9 (COO), 203.6
(CO) ppm; HRMS (ESI+, m/z): calculated for (C12H12NaO3) (M+Na)+:
227.0679, found: 227.0660.
3-(3-Bromophenyl)cyclobutanone (1e). 32% yield. Pale yellow oil;
Rf (30% EtOAc/hexane): 0.77; IR (NaCl): ꢀ 3062, 2975, 2923, 1785,
1636, 1596, 1566, 1477, 1378, 1102, 1074, 780 cm−1 1H NMR
;
(CDCl3, 300.13 MHz): ı 3.18–3.30 (m, 2H, CHH), 3.45–3.58 (m, 2H,
CHH), 3.61–3.74 (m, 1H, CH), 7.22–7.27 (m, 2H), 7.36–7.43 (m, 1H),
7.45–7.48 (m, 1H) ppm; 13C NMR (CDCl3, 75.5 MHz): ı 28.3 (CH),
54.7 (2CH2), 122.9 (CBr), 125.3 (CH), 129.9 (2CH), 130.4 (CH), 146.0
(C), 205.7 (CO) ppm; HRMS (ESI+, m/z): calculated for (C10H10BrO)
(M79Br+H)+: 224.9910, found: 224.9889.
2.6. General procedure for the synthesis of lactones 2b–l with
m-chloroperbenzoic acid (MCPBA)
To a solution of the corresponding 3-arylcyclobutanone 1b–l
(0.25 mmol) in CH2Cl2 (1.0 mL), MCPBA (88 mg, 0.50 mmol) was
added and the mixture was stirred for 20 h. The mixture was
washed with an aqueous NaHCO3 saturated solution (6× 5 mL), the
organic phase dried over Na2SO4, filtered and the solvent evap-
orated under reduced pressure. The reaction crude was purified
by column chromatography on silica gel (10–30% EtOAc/hexane),
yielding the lactones 2b–l (44–99% isolated yield: 93% for 2b; 83%
for 2c; 72% for 2d; 99% for 2e; 85% for 2f; 86% for 2g; 88% for 2h; 44%
for 2i; 77% for 2j; 75% for 2k; and 96% for 2l). These standards were
used for the development of GC analysis methods prior to carry out
the chemoenzymatic reactions.
3-(4-Bromophenyl)cyclobutanone (1f). 50% yield. Yellowish-
orangish solid. Mp: 49–51 ◦C; Rf (30% EtOAc/hexane): 0.59; IR
(nujol): ꢀ 3055, 2987, 1786, 1489, 1422, 1395, 1101, 1075, 1009,
821 cm−1 1H NMR (CDCl3, 300.13 MHz): 3.13–3.25 (m, 2H, CHH),
;
3.42–3.55 (m, 2H, CHH), 3.57–3.69 (m, 1H, CH), 7.13–7.19 (m, 2H),
7.42–7.48 (m, 2H) ppm; 13C NMR (CDCl3, 75.5 MHz): ı 28.2 (CH),
54.8 (2CH2), 120.6 (CBr), 128.4 (2CH), 131.9 (2CH), 142.7 (C), 206.0
(CO) ppm; MS (ESI+, m/z): 225 (M79Br+H)+; 227 (M81Br+H)+.
3-(4-Methylphenyl)cyclobutanone (1i). 12% yield. Yellowish oil;
Rf (30% EtOAc/hexane): 0.79; IR (NaCl): ꢀ 3023, 2974, 2922, 1785,
1608, 1516, 1450, 1417, 1379, 1167, 1109, 1020, 813 cm−1
;
1H
2.7. General procedure for the chemoenzymatic synthesis of
NMR (CDCl3, 300.13 MHz): ı 2.36 (s, 3H, CH3), 3.17–3.29 (m, 2H,
CHH), 3.42–3.55 (m, 2H, CHH), 3.59–3.71 (m, 1H, CH), 7.15–7.23
(m, 4H); 13C NMR (CDCl3, 75.5 MHz): ı 21.0 (CH3), 28.1 (CH), 54.8
(2CH2), 126.4 (2CH), 129.4 (2CH), 136.2 (CMe), 140.6 (C), 206.9 (CO)
ppm; HRMS (ESI+, m/z): calculated for (C22H24NaO2) (2M+Na)+:
343.1669, found: 343.1654.
lactones 2a–l using CAL-B, UHP and EtOAc
Over a solution of the corresponding cyclobutanone 1a–l
(0.25 mmol) in EtOAc (379 ␮L, 30.0 mmol), complex urea-hydrogen
peroxide (UHP, 35 mg, 0.38 mmol) and CAL-B (12.5 mg) were added.
The suspension was shaken for 20 h at 30 ◦C and 250 rpm, then an
aliquot was analyzed by GC. The reaction was left shaken until com-
plete conversion was reached, then water was added (2 mL) and
the enzyme filtered off. The solution was extracted with EtOAc (3×
5 mL) and the organic phases combined and washed with water (2×
5 mL) and brine (5 mL). The resulting organic phase was dried over
Na2SO4, filtered and the solvent was evaporated under reduced
pressure to obtain the corresponding lactones 2a–l (51–99% iso-
lated yield). For fluorinated lactone 2k a column chromatography
on silica gel (30% EtOAc/hexane) was necessary, as the reaction did
not lead to complete conversion.
2.4. Synthesis of ethyl 3-oxocyclobutanecarboxylate (1j)
3-Oxocyclobutanecarboxylic acid (6, 200 mg, 1.75 mmol) was
dissolved in dry THF (7 mL) and a drop of DMF was added under
inert atmosphere. The solution was cooled down in an ice-bath,
and oxalyl chloride (276 ␮L, 3.51 mmol) was added, stirring the
mixture for 30 min. After this time, the reaction was left to warm
to room temperature, the solvent evaporated under reduced pres-
sure and the residue redissolved in ethanol (7 mL). The solution was
stirred for 1 h at room temperature. Then the solvent was evap-
orated in the rotary evaporator and the reaction crude purified
by column chromatography on silica gel (20–30% EtOAc/hexane),
yielding the cyclobutanone 1j as a pale yellow oil (82% isolated
yield). Rf (20% EtOAc/hexane): 0.30; IR (NaCl): ꢀ 2985, 2937, 1797,
4-Methyl-4-phenyldihydrofuran-2(3H)-one (2b). 93% yield;
White solid; Mp: 49–51 ◦C; Rf (30% EtOAc/hexane): 0.43; IR
(nujol): ꢀ 3024, 2969, 2930, 2904, 1773, 1601, 1497, 1305, 1173,
1094, 1020, 767 cm−1 1H NMR (CDCl3, 300.13 MHz): ı 1.54 (s, 3H,
;
CH3), 2.68 (dd, 2JHH = 16.8, 4JHH = 0.4, 1H, CHH), 2.93 (dd, 2JHH = 16.8,
4JHH = 0.6, 1H, CHH), 4.39–4.47 (m, 2H, OCH2), 7.18–7.23 (m, 2H),
7.27–7.33 (m, 1H), 7.36–7.42 (m, 2H) ppm; 13C NMR (CDCl3,
75.5 MHz): ı 28.1 (CH3), 42.1 (CH2), 44.2 (C), 78.5 (OCH2), 125.2
(2CH), 127.3 (CH), 129.1 (2CH), 144.4 (C), 176.2 (CO) ppm; HRMS
(ESI+, m/z): calculated for (C11H12NaO2) (M+Na)+: 199.0730, found:
199.0781.
1733, 1467, 1375, 1346, 1215, 1193, 1099, 1052, 858 cm−1 1H
;
NMR (CDCl3, 300.13 MHz): ı 1.25 (t, 3JHH = 7.1, 3H, CH3), 3.12–3.43
3
(m, 5H, 2CH2 + CH), 4.17 (q, JHH = 7.1, 2H, OCH2) ppm; 13C NMR
(CDCl3, 75.5 MHz): ı 14.2 (CH3), 27.4 (CH), 51.6 (2CH2), 61.3 (OCH2),
174.1 (COO), 203.9 (CO) ppm; HRMS (ESI+, m/z): calculated for
(C7H10NaO3) (M+Na)+: 165.0522, found: 165.0531.
4-Phenyldihydrofuran-2(3H)-one (2c). 83% yield; White solid;
2.5. Synthesis of benzyl 3-oxocyclobutanecarboxylate (1k)
Mp: 46–47 ◦C; Rf (20% EtOAc/hexane): 0.20; IR (nujol): ꢀ 3064,
3032, 2973, 2904, 1763, 1601, 1456, 1355, 1163, 1010, 761 cm−1
;
3-Oxocyclobutanecarboxylic acid (6, 200 mg, 1.75 mmol) was
dissolved in dry THF (7 mL), and a drop of DMF was added under
inert atmosphere. The solution was cooled down in an ice-bath,
and oxalyl chloride (276 ␮L, 3.51 mmol) was added, stirring the
mixture for 30 min. After this time, the reaction was left to warm
to room temperature and benzyl alcohol (544 ␮L, 5.26 mmol) was
added. The solution was stirred overnight at room temperature.
1H NMR (CDCl3, 300.13 MHz): ı 2.67 (dd, 2JHH = 17.5, 3JHH = 9.1, 1H,
CHH), 2.92 (dd, 2JHH = 17.5, 3JHH = 8.3, 1H, CHH), 3.73–3.85 (m, 1H,
CH), 4.26 (dd, 2JHH = 9.0, 3JHH = 8.1, 1H, OCHH), 4.66 (dd, 2JHH = 9.0,
3JHH = 8.3, 1H, OCHH), 7.21–7.40 (m, 5H) ppm; 13C NMR (CDCl3,
75.5 MHz): ı 35.8 (CH2), 41.2 (CH), 74.1 (OCH2), 126.8 (2CH), 127.8
(CH), 129.2 (2CH), 139.5 (C), 176.5 (COO) ppm; HRMS (ESI+, m/z):
calculated for (C10H10NaO2) (M+Na)+: 185.0573, found: 185.0592.
Please cite this article in press as: D. González-Martínez, et al., J. Mol. Catal. B: Enzym. (2014),
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Table 1
4
4-(2-Bromophenyl)dihydrofuran-2(3H)-one (2d). 72% yield;
White solid; Mp: 56–57 ◦C; Rf (20% EtOAc/hexane): 0.41; IR
(nujol): ꢀ 3064, 2990, 2914, 1779, 1568, 1473, 1440, 1372,
Baeyer–Villiger reaction of cyclobutanone (1a) using 1 equivalent of UHP, different
lipases (50 mg enzyme/mmol 1a) in EtOAc (0.66 M of 1a) after 24 h at 30 ◦C and
250 rpm.
1168, 1023, 753 cm−1
;
1H NMR (CDCl3, 300.13 MHz): 2.67 (dd,
2JHH = 17.6, JHH = 6.7, 1H, CHH), 2.97 (dd, JHH = 17.6, JHH = 8.6,
3
2
3
2
1H, CHH), 4.17–4.24 (m, 2H, CH + OCHH), 4.71 (dd, JHH = 9.0,
3JHH = 7.2, 1H, OCHH), 7.17 (ddd, JHH = 8.0, JHH = 7.1, JHH = 1.9,
3
3
4
1H), 7.26–7.35 (m, 2H), 7.61 (dd, 3JHH = 8.0, 4JHH = 1.3, 1H) ppm; 13
C
NMR (CDCl3, 75.5 MHz): ı 34.9 (CH2), 40.3 (CH), 73.0 (OCH2), 124.5
(CBr), 126.8 (CH), 128.4 (CH), 129.3 (CH), 133.6 (CH), 140.0 (C),
176.2 (COO) ppm; HRMS (ESI+, m/z): calculated for (C10H9BrNaO2)
(M79Br+Na)+: 262.9678, found: 262.9670.
4-(3-Bromophenyl)dihydrofuran-2(3H)-one (2e). 99% yield; Yel-
lowish oil; Rf (30% EtOAc/hexane): 0.50; IR (NaCl): ꢀ 3058, 2971,
2913, 1781, 1597, 1568, 1479, 1266, 1169, 1024, 737 cm−1; 1H NMR
(CDCl3, 300.13 MHz): 2.64 (dd, 2JHH = 17.5, 3JHH = 8.8, 1H, CHH), 2.93
(dd, 2JHH = 17.5, 3JHH = 8.7, 1H, CHH), 3.70–3.82 (m, 1H, CH), 4.25 (dd,
2JHH = 9.1, 3JHH = 7.6, 1H, OCHH), 4.66 (dd, 2JHH = 9.1, 3JHH = 7.8, 1H,
.
Entry
Lipase
Conversion (%)a
1
2
3
4
5
6
–
3
77
32
34
46
42
CAL-B
RML
AK
PSL-SD
CRL
a
Calculated by GC analyses of the reaction crudes.
3
4
3
OCHH), 7.16 (dt, JHH = 7.7, JHH = 1.2, 1H), 7.25 (t, JHH = 7.8, 1H),
21.1 (CH3), 35.9 (CH2), 40.9 (CH), 74.3 (OCH2), 126.7 (2CH), 129.9
(2CH), 136.4 (CMe), 137.6 (C), 176.6 (COO) ppm; HRMS (ESI+, m/z):
calculated for (C11H12NaO2) (M+Na)+: 199.0730, found: 199.0728.
Ethyl 5-oxotetrahydrofuran-3-carboxylate (2j). 77% yield; Yel-
lowish liquid; Rf (40% EtOAc/hexane): 0.30; IR (NaCl): ꢀ 2986, 2941,
4
3
4
4
7.38 (t, JHH = 1.8, 1H), 7.42 (ddd, JHH = 7.8, JHH = 1.8, JHH = 1.2,
1H) ppm; 13C NMR (CDCl3, 75.5 MHz): ı 35.6 (CH2), 40.8 (CH),
73.7 (OCH2), 123.3 (CBr), 125.4 (CH), 130.1 (CH), 130.9 (CH), 131.0
(CH), 141.9 (C), 175.9 (COO) ppm; HRMS (ESI+, m/z): calculated for
(C10H9BrNaO2) (M79Br+Na)+: 262.9678, found: 262.9657.
1783, 1733, 1477, 1375, 1348, 1198, 1176, 1024, 845 cm−1 1H
;
4-(4-Bromophenyl)dihydrofuran-2(3H)-one (2f). 85% yield;
White solid; Mp: 72–74 ◦C; Rf (30% EtOAc/hexane): 0.31; IR
(nujol): ꢀ 3016, 2930, 2901, 1767, 1589, 1487, 1424, 1221,
NMR (CDCl3, 300.13 MHz): ı 1.25 (t, 3JHH = 7.1, 3H, CH3), 2.70 (dd,
2JHH = 17.9, 3JHH = 9.6, 1H, CHH), 2.83 (dd, 2JHH = 17.9, 3JHH = 7.2, 1H,
3
CHH), 3.36–3.47 (m, 1H, CH), 4.17 (q, JHH = 7.1, 2H, OCH2CH3),
1158, 1016, 826 cm−1
;
1H NMR (CDCl3, 300.13 MHz): ı 2.62 (dd,
4.37–4.52 (m, 2H, OCH2) ppm; 13C NMR (CDCl3, 75.5 MHz): ı
14.1 (CH3), 30.9 (CH2), 40.0 (CH), 61.9 (OCH2CH3), 69.1 (OCH2),
171.2 (CO2Et), 175.3 (COO) ppm; HRMS (ESI+, m/z): calculated for
(C7H10NaO4) (M+Na)+: 181.0471, found: 181.0477.
3
2
3
2JHH = 17.5, JHH = 8.8, 1H, CHH), 2.93 (dd, JHH = 17.5, JHH = 8.7,
2
3
1H, CHH), 3.68–3.83 (m, 1H, CH), 4.23 (dd, JHH = 9.1, JHH = 7.6,
2
3
1H, OCHH), 4.65 (dd, JHH = 9.1, JHH = 7.8, 1H, OCHH), 7.08–7.14
(m, 2H), 7.46–7.52 (m, 2H) ppm; 13C NMR (CDCl3, 75.5 MHz): ı
35.7 (CH2), 40.7 (CH), 73.8 (OCH2), 121.7 (CBr), 128.5 (2CH), 132.4
(2CH), 138.6 (C), 176.0 (COO) ppm; HRMS (ESI+, m/z): calculated
for (C10H9BrNaO2) (M79Br+Na)+: 262.9678, found: 262.9673.
4-(4-Chlorophenyl)dihydrofuran-2(3H)-one (2g). 86% yield; Pale
yellow solid; Mp: 54–56 ◦C; Rf (30% EtOAc/hexane): 0.41; IR (nujol):
Benzyl 5-oxotetrahydrofuran-3-carboxylate (2k). 75% yield;
White gummy solid; Rf (30% EtOAc/hexane): 0.33; IR (NaCl): ꢀ 3066,
3034, 2959, 1779, 1736, 1636, 1498, 1456, 1383, 1350, 1175, 1013,
754 cm−1
;
1H NMR (CDCl3, 300.13 MHz): ı 2.74 (dd, JHH = 17.9,
2
3JHH = 9.6, 1H, CHH), 2.88 (dd, JHH = 17.9, JHH = 7.3, 1H, CHH),
3.44–3.56 (m, 1H, CH), 4.42–4.56 (m, 2H, OCH2), 5.20 (s, 2H, CH2Ph),
7.33–7.44 (m, 5H) ppm; 13C NMR (CDCl3, 75.5 MHz): ı 30.9 (CH2),
40.1 (CH), 67.7 (CH2Ph), 69.0 (OCH2), 128.5 (2CH), 128.8 (3CH),
135.0 (C), 171.0 (CO2Bn), 175.1 (COO) ppm; HRMS (ESI+, m/z): cal-
culated for (C12H12NaO4) (M+Na)+: 243.0628, found: 243.0671.
4-(Benzyloxy)dihydrofuran-2(3H)-one (2l). 96% yield; White
gummy solid; Rf (40% EtOAc/hexane): 0.30; IR (NaCl): ꢀ 3066,
3034, 2923, 1779, 1603, 1455, 1401, 1374, 1333, 1166, 1086, 1050,
2
3
ꢀ 3055, 2987, 2914, 1782, 1496, 1423, 1170, 1094, 1025, 828 cm−1
;
1H NMR (CDCl3, 300.13 MHz): ı 2.61 (dd, 2JHH = 17.5, 3JHH = 8.9, 1H,
CHH), 2.92 (dd, 2JHH = 17.5, 3JHH = 8.7, 1H, CHH), 3.70–3.82 (m, 1H,
CH), 4.23 (dd, 2JHH = 9.1, 3JHH = 7.7, 1H, OCHH), 4.65 (dd, 2JHH = 9.1,
3JHH = 7.8, 1H, OCHH), 7.13–7.19 (m, 2H), 7.30–7.36 (m, 2H) ppm;
13C NMR (CDCl3, 75.5 MHz): ı 35.7 (CH2), 40.6 (CH), 73.9 (OCH2),
128.2 (2CH), 129.4 (2CH), 133.6 (CCl), 138.1 (C), 176.1 (COO)
ppm; HRMS (ESI+, m/z): calculated for (C10H9ClNaO2) (M+Na)+:
219.0183, found: 219.0156.
993, 886, 747 cm−1 1H NMR (CDCl3, 300.13 MHz): ı 2.58–2.73 (m,
;
2H), 4.34–4.41 (m, 3H, CH + OCH2), 4.49–4.57 (m, 2H, OCH2Ph),
7.27–7.40 (m, 5H) ppm; 13C NMR (CDCl3, 75.5 MHz): ı 35.0 (CH2),
71.2 (OCH2Ph), 73.2 (OCH2), 73.9 (CH), 127.8 (2CH), 128.2 (CH),
128.7 (2CH), 137.0 (C), 175.6 (COO) ppm; HRMS (ESI+, m/z): calcu-
lated for (C11H12NaO3) (M+Na)+: 215.0679, found: 215.0726.
4-(4-Fluorophenyl)dihydrofuran-2(3H)-one (2h). 88% yield;
White solid; Mp: 65–67 ◦C; Rf (30% EtOAc/hexane): 0.38; IR
(nujol): ꢀ 3068, 2914, 1777, 1602, 1514, 1433, 1219, 1165, 1013,
2
843 cm−1
;
1H NMR (CDCl3, 300.13 MHz): ı 2.62 (dd, JHH = 17.5,
2
3
3JHH = 8.9, 1H, CHH), 2.92 (dd, JHH = 17.5, JHH = 8.7, 1H, CHH),
3.71–3.84 (m, 1H, CH), 4.23 (dd, JHH = 9.1, JHH = 7.7, 1H, OCHH),
2
3
2
3
4.65 (dd, JHH = 9.1, JHH = 7.8, 1H, OCHH), 7.00–7.09 (m, 2H),
3. Results and discussion
7.16–7.24 (m, 2H) ppm; 13C NMR (CDCl3, 75.5 MHz): ı 35.9
2
(CH2), 40.6 (CH), 74.1 (OCH2), 116.2 (d, JCF = 21.5, 2CH), 128.4 (d,
To start with, a screening of biocatalysts for the oxidation of
cyclobutanone (1a) was performed, considering a representative
set of lipases such as CAL-B, RML, AK, PSL-SD and CRL. Searching
for a simple catalytic cascade system, ethyl acetate (EtOAc) was
selected as both solvent and peracetic acid precursor, using the
stable and safe urea-hydrogen peroxide (UHP) complex as oxidizing
agent. Initially, the reactions were carried out with 1 equivalent of
UHP complex and a 0.66 M concentration of 1a in EtOAc at 30 ◦C
(Table 1).
3JCF = 8.0, 2CH), 135.3 (d, JCF = 2.9, C), 162.2 (d, JCF = 246.6, CF),
176.2 (COO) ppm; HRMS (ESI+, m/z): calculated for (C10H9FNaO2)
(M+Na)+: 203.0479, found: 203.0474.
4
1
4-(4-Methylphenyl)dihydrofuran-2(3H)-one (2i). 44% yield;
White solid; Mp: 40–42 ◦C; IR (nujol): ꢀ 2978, 2948, 2916, 1761,
1608, 1519, 1484, 1455, 1427, 1350, 1214, 1158, 1008, 827 cm−1
;
Rf (30% EtOAc/hexane): 0.54; 1H NMR (CDCl3, 300.13 MHz): ı 2.34
2
3
(s, 3H, CH3), 2.65 (dd, JHH = 17.5, JHH = 9.2, 1H, CHH), 2.90 (dd,
2JHH = 17.5, JHH = 8.6, 1H, CHH), 3.69–3.82 (m, 1H, CH), 4.24 (dd,
In all cases conversions into the lactone 2a were much higher
(>30%, entries 2–6) compared to that in the absence of enzyme,
which just proceeded in 3% conversion (entry 1). Moreover, 2a
3
2JHH = 9.1, 3JHH = 8.0, 1H, OCHH), 4.65 (dd, 2JHH = 9.1, 3JHH = 7.9, 1H,
OCHH), 7.10–7.20 (m, 4H) ppm; 13C NMR (CDCl3, 75.5 MHz): ı
Please cite this article in press as: D. González-Martínez, et al., J. Mol. Catal. B: Enzym. (2014),
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Table 3
5
Table 2
Baeyer–Villiger reaction of cyclobutanone (1a) using UHP complex and CAL-B
Baeyer–Villiger reaction of 3-substituted cyclobutanones 1b–l using 1.5 equiva-
(50 mg/mmol 1a) in EtOAc at 30 ◦C and 250 rpm.
lents of UHP and CAL-B (50 mg/mmol 1b–l) in EtOAc (0.66 M) at 30 ◦C and 250 rpm.
.
Entry
Time (h)
UHP (eq)
[1a] (M)
Conversion (%)a
.
1
2
3
4
5
6
7
8
9
24
24
20
20
20
20
20
20
20
20
20
1.0
2.0
2.0
1.5
1.0
1.0
1.0
1.0
1.2
1.5
2.0
0.66
0.66
0.66
0.66
0.5
0.66
0.8
1.0
77
>99
91
>99
64
71
74
75
79
Entry
Substrate
R1
R2
t (h)
Conversion (%)a
Yield (%)c
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
1g
1h
1i
Me
H
H
H
H
H
H
H
H
H
H
Ph
Ph
30
30
20
20
20
20
20
20
20
20
40
>99 (94)b
>99 (94)b
>99
>99
>99
>99
78
>99
>99
93
99
98
97
99
87
51
97
84
96
94
2-Br-C6H4
3-Br-C6H4
4-Br-C6H4
4-Cl-C6H4
4-F-C6H4
4-Me-C6H4
COOEt
1.0
1.0
1.0
10
11
83
96
1j
1k
1l
10
11
COOBn
OBn
>99
a
>99 (90)b
Calculated by GC analyses of the reaction crudes. Lactone 2a was the only prod-
uct detected.
a
Calculated by GC analyses of the reaction crudes.
Conversion values after 20 h appear in parentheses.
Isolated yields after purification by extraction of the final products, once com-
b
c
plete conversions were detected by GC. For 1h none significant improvements in
the conversion value were observed over the time, so 2h was purified by column
chromatography on silica gel.
was found to be the unique final product, not detecting any other
side reactions. Remarkably, the use of an aqueous 30% H2O2 solu-
tion [29,30] led to the formation of various by-products and poor
reproducibility. CAL-B came out as the most efficient catalyst [31],
reaching a 77% conversion after 24 h (entry 2), while RML, AK, PSL-
SD and CRL did not overcome a 46% yield (entries 3–6).
and EtOAc. Control experiments in the absence of the enzyme led
in all cases to poor conversions (lower than 22%), the highest value
being obtained with the brominated derivative 1d. This observa-
tion demonstrates the efficiency of the chemoenzymatic system
here employed. Lower conversion values (<5%) were reached with
ketoesters 1j and 1k, and in the presence of unsubstituted phenyl
derivatives 1b and 1c.
Remarkably, after 20 h conversions were equal or higher than
90% in all cases except for the fluorinated derivative in the para-
position of the phenyl ring 1h (entry 7). A periodic time course
analysis was performed in order to reach complete conversions,
which facilitates the purification of the final products, avoiding
column chromatography separations. Thus, high to excellent iso-
lated yields were achieved for the final ␥-butyrolactones after a
simple and effective extraction protocol following the enzyme fil-
tration, which is in contrast with traditional oxidative processes
using metal complexes or inorganic salts. It is also worthy to men-
tion that ketoesters 1j and 1k (entries 9 and 10) led to the lactones
without formation of any undesired hydrolytic products in spite of
using a hydrolase in the transformation.
Complete conversions were found for seven out of the
eleven tested substrates after 20 h, requiring 30 h for the
3-phenyl-cyclobutanones 1b and 1c and 40 h for the 3-
(benzyloxy)cyclobutanone (1l). Nevertheless, the oxidation of the
3-(4-fluorophenyl)cyclobutanone (1h) did not proceed to complete
conversion after prolonged time periods. The chemoenzymatic
global oxidative approach was extremely effective for ketones pre-
senting substitutions in the phenyl ring such as alkyl rests (methyl,
1i) or halogen atoms (bromine or chlorine, 1d–g) in different pos-
itions (orto, meta or para), but also when alkyl carboxylates (1j
and 1k) and the benzyloxy rest (1l) were considered. All the final
products were racemic, probing that the enzyme is only responsi-
ble for the perhydrolysis reaction leading to the formation of non
chiral peracetic acid, which is in turn the responsible for the non
enantioselective oxidation [8]. The scalability of the process was
probed at a 250 mg-scale using 3-(4-methylphenyl)cyclobutanone
In order to obtain complete conversions, different reaction
parameters were studied such as the amount of UHP or the sub-
strate concentration, maintaining CAL-B as biocatalyst (Table 2)
[28]. Thus, the amount of UHP was varied between 1.0 and 2.0
equivalents, 1a being used in a really high concentration if com-
pared to other classes of enzymes (0.5–1.0 M). Regarding previous
results (entry 1), doubling the amount of UHP led to a complete con-
version in the same reaction time (entry 2). It must be noticed that
24 h were necessary to reach complete conversion, as a 91% conver-
sion was achieved after 20 h (entry 3). Satisfactorily, 1.5 equivalents
of the oxidizing agent allowed the formation of 2a quantitatively
after 20 h (entry 4), which suggests a deactivation of the enzyme
during the timeframe at higher UHP concentration. This reaction
was performed with both 0.25 mmol and 0.5 mmol of 1a observ-
ing identical results. Unfortunately a decrease of UHP to only 1
equivalent at both lower (0.5 M, entry 5) or very high substrate con-
centration (0.8 and 1.0 M, entries 7 and 8), led to modest 64–75%
conversion values after 20 h (entries 5–8). Finally, a 1.0 M substrate
concentration was studied. Hence, after examining the influence of
UHP ratio (1–2 equivalents, entries 8–11), it was observed that an
almost complete conversion could only be achieved using 2 equiv-
alents of the oxidizing agent (entry 11).
With these results in hand, the strategy was extended to a broad
panel of 3-substituted cyclobutanones, some of them commercially
available and other synthesized through conventional chemical
protocols (see Section 2). For this study, prochiral cyclobutanones,
such as the 3,3-disubstituted 1b, 3-aryl-substituted 1c–i, ketoesters
1j and 1k and the alkoxy substituted 1l, were considered. Prior
to the performance of the chemoenzymatic studies, lactones 2b–l
were synthesized by reaction of the corresponding cyclobutanone
1b–l with m-chloroperbenzoic acid in dichloromethane, develop-
ing adequate GC methods for the analysis of the lipase-mediated
oxidations of 1b–l (see Section 2 and supporting information).
Table 3 shows the results achieved for the Baeyer–Villiger reaction
of 3-substituted cyclobutanones 1b–l using CAL-B, UHP complex
Please cite this article in press as: D. González-Martínez, et al., J. Mol. Catal. B: Enzym. (2014),
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6
(1i) as substrate. Gratifyingly, it was quantitatively transformed
References
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The development of cascade reactions is a challenging task for
organic chemists since they simplify the overall process, allow-
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yields of the final products. Herein, we have described a chemoen-
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the corresponding cyclobutanones. This Baeyer–Villiger reaction
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lipase-catalyzed perhydrolysis of ethyl acetate allows the forma-
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the ketones into the lactones in a non-enzymatic fashion. Cyclobu-
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(MICINN-12-CTQ2011-24237 and CTQ-2013-44153-P), Principado
de Asturias (SV-PA-13-ECOEMP-42) and the University of Oviedo
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2014.09.002.
Please cite this article in press as: D. González-Martínez, et al., J. Mol. Catal. B: Enzym. (2014),
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