Laccase-catalysed α-arylation of cyclic β-dicarbonyl compounds

Article abstract of DOI:10.1039/c2gc35662g

In this protocol we described an environmentally friendly synthesis of α-arylated cyclic β-dicarbonyl compounds employing various catechols as precursors through an oxidation/Michael addition sequence. The process proceeded under the catalysis of a commercially available laccase at room temperature with the use of aerial oxygen as the oxidant affording the products in moderate to excellent yields (36-96%). Furthermore, a highly functionalized cyclopentane bearing an all-carbon quaternary stereogenic centre was synthesized through the arylation in excellent diastereoselectivity (dr > 99 : 1, 95% ee).

Full text of DOI:10.1039/c2gc35662g

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PAPER
Laccase-catalysed α-arylation of cyclic β-dicarbonyl compounds†
Jörg Pietruszka* and Chuan Wang
Received 1st May 2012, Accepted 13th June 2012
DOI: 10.1039/c2gc35662g
In this protocol we described an environmentally friendly synthesis of α-arylated cyclic β-dicarbonyl
compounds employing various catechols as precursors through an oxidation/Michael addition sequence.
The process proceeded under the catalysis of a commercially available laccase at room temperature with
the use of aerial oxygen as the oxidant affording the products in moderate to excellent yields (36–96%).
Furthermore, a highly functionalized cyclopentane bearing an all-carbon quaternary stereogenic centre
was synthesized through the arylation in excellent diastereoselectivity (dr > 99 : 1, 95% ee).
cause fires) as the reducing agent for the rearomatisation of the
Introduction
products. Moreover, the spectrum of the catechols is restricted to
the 3-substituted derivatives. No example using 4-substituted
catechols as precursors has been reported in their protocol, while
the use of non-substituted catechol results in a very low yield
(18%). Therefore, development of a more environmentally
benign method for the arylation of β-dicarbonyl compounds with
broader reaction scope is of great interest.
Applications of enzymes as catalysts in organic synthesis have
been investigated intensively, since high stereo- and regioselec-
tivities are often obtained in many types of reactions under mild
conditions employing non-toxic enzymes as promoters.7
Laccases (EC 1.10.3.3), blue oxidoreductases of the multi-
copper oxidase family, find many applications not only in
organic synthesis, but also in industry.8,9 Especially interesting is
the use of a laccase as a catalyst in oxidation reactions, because
readily available aerial oxygen can be used as a stoichiometric
oxidant for a wide spectrum of substrates, such as phenols,
aminophenols, polyphenols and related compounds.10
Recently, we developed a laccase-catalysed arylation reaction
between 3-substituted N-Boc-oxindoles and catechols affording
the products in moderate to high yields and complete regioselec-
tivities.11 In continuation of our investigations in this field we
envisaged a laccase-catalysed α-arylation of cyclic β-dicarbonyl
compounds by catechols. The process is assumed to start with a
laccase-catalysed oxidation of the catechol A to the correspond-
ing o-quinone C, which subsequently gets involved in a Michael
addition with the cyclic β-dicarbonyl compound B as a nucleo-
phile (general base catalysis), forming the α-arylated compound
D as a product with para/meta selectivity (Scheme 1).12
All-carbon quaternary stereogenic centres containing a 1,2-di-
hydroxylated aryl are present in a large number of biologically
active compounds, such as verapamil,1 mastigophorenes2 and
amaryllidaceae alkaloids.3 Classically, this type of structural
motif is constructed through Friedel–Crafts alkylation using cate-
chol derivatives as nucleophiles.4 Recently, a conceptionally
distinct strategy, in which quinones are employed as Michael
acceptors in 1,4-conjugated additions, has been applied to
approach the compounds bearing arylated all-carbon quaternary
stereogenic centres. Excellent results have been achieved in both
metal- and organo-catalysed Michael addition reactions of
carbonyl nucleophiles to p-quinones.5 However, the scope of all
these processes is limited to the use of p-quinonones as sub-
strates, which are notoriously toxic. A breakthrough in this field
was achieved by Dixon et al., who successfully utilized less
toxic catechols as o-quinone precursors in an oxidation/Michael
addition/rearomatisation sequence for the arylation of β-dicarbo-
nyl compounds affording the products generally in high
yields.6a,b Furthermore, this method was successfully applied by
the same group for the total synthesis of ( )-poweline and
( )-buphanidrine.6b,c However, this well-developed organo-
catalytic oxidative coupling reaction still has several dis-
advantages from synthetic and environmental perspectives. For
instance, the catalyst, polymer-supported BEMP (2-tert-butyl-
imino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphospho-
rine; R-phrase: 34), is a corrosive base, while highly oxidizing
and irritant polymer-supported periodate (R: 8-36/37/38) was
employed as the oxidant. Furthermore, all the reactions were
conducted at low temperature (−20 °C) and necessitate the use
of irritant sodium hyposulphite (R: 7-22-31) (that also may
Results and discussion
Institut für Bioorganische Chemie der Heinrich-Heine-Universität
Düsseldorf im Forschungszentrum Jülich, Stetternicher Forst,
Geb. 15.8, 52426 Jülich, Germany. E-mail: j.pietruszka@fz-juelich.de;
Fax: +49-2461-616196; Tel: +49-2461-614158
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2gc35662g
The aromatic β-ketoester 1a and the catechol (2a) were
employed as standard substrates for optimization of the reaction
conditions (Table 1).
In the first instance the reaction was performed in a mixture of
acetonitrile and phosphate buffer under the catalysis of the
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laccase from Agaricus bisphorus giving the product 3a in
moderately good yield (62%) (entry 1). Next, three additional
laccases with the same catalyst load were tested for this arylation
reaction. In the cases of the enzymes from Trametes versicolor
and Rhus vernicifera only traces of the product 3a were formed
(entries 2–3). To our delight, when the laccase from Pleurotus
ostreatus was utilized as the catalyst the reaction was completed
within 21 h at room temperature affording the product 3a in
excellent yield (96%) (entry 4). Subsequently, a brief solvent
screening was undertaken at room temperature using the laccase
from Pleurotus ostreatus as the catalyst. When the reaction was
carried out in the phosphate buffer without organic solvent, the
reaction provided the product 3a only in moderate yield (46%)
(entry 5). In the cases of other mixtures of organic solvent and
buffer, no better result concerning the yield was achieved
(entries 6–8). Then we started to study the influence of the cata-
lyst load on the outcome of this reaction. Lowering the catalyst
load to 10 U, the reaction proceeded still smoothly and afforded
the product 3a after 21 h without decrease of yield (entry 9).
When the catalyst amount was further lowered to 3 U, the yield
of this reaction diminished also to 52% (entry 10).
After optimizing the reaction conditions we started to evaluate
the scope of the reaction by varying the structure of both cyclic
β-dicarbonyl compounds 1 and catechols 2. At first the aromatic
β-ketoester 1a was reacted with various catechols 2a–d
(Table 2). In the case of 3-methyl catechol (2b) the reaction
afforded the product 3b in a moderately good yield (68%) and
with complete regioselectivity (>99 : 1) (entry 2). In contrast,
when 3-methoxy catechol (2c) was employed as the precursor
the reaction gave only a complex mixture (entry 3). Using
3-bromo catechol (2d) as the starting material resulted in the
formation of two regioisomers 3d and 4d as products with a
ratio of 71 : 29 (entry 4).
Then various cyclic β-dicarbonyl compounds 1b–e bearing a
cyclopentane or – as a singular example – a cycloheptane
scaffold were reacted with different catechols 2a–c (Table 3).
Generally, these compounds 1b–e were less reactive in compari-
son to indanone derivative 1a. Notably, 3-methoxy catechol (2c)
turned out to be more reactive than the other two catechols 2a
and 2b (entry 3). In the case of non-substituted catechol 2a and
3-methoxy catechol (2c) as substrates the corresponding products
3e, 3g, 3h and 3k were obtained in moderate to good yields
(44–73%) and with complete regioselectivities (entries 1, 3,
4, 7). In contrast, using 3-methyl catechol (2b) as the precursor
led to formation of a mixture of two regioisomers in all cases
with moderate to excellent yields (36–92%) and high regio-
isomeric ratios (entries 2, 5, 6).
Furthermore, 4-substituted catechols 2e and 2f were also
explored as precursors for the title reaction. In the case of
Scheme 1 Laccase-catalysed arylation of cyclic β-dicarbonyl com-
pounds via an oxidation/Michael addition sequence.
Table 1 Searches for laccase-catalysed arylation of cyclic β-dicarbonyl compoundsa
Entry
Laccase
Ub (unit)
Solvent
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
Agaricus bisphorus
Rhus vernicifera
15
15
15
15
15
15
15
15
10
3
MeCN–phosphate bufferd (1 : 2)
MeCN–phosphate bufferd (1 : 2)
MeCN–phosphate bufferd (1 : 2)
MeCN–phosphate bufferd (1 : 2)
Phosphate bufferd
62
Traces
Traces
96
46
88
86
78
96
52
Trametes versicolor
Pleurotus ostreatus
Pleurotus ostreatus
Pleurotus ostreatus
Pleurotus ostreatus
Pleurotus ostreatus
Pleurotus ostreatus
Pleurotus ostreatus
EtOH–phosphate bufferd (1 : 2)
THF–phosphate bufferd (1 : 2)
MeCN–acetate buffere (1 : 2)
MeCN–phosphate bufferd (1 : 2)
MeCN–phosphate bufferd (1 : 2)
a Reactions were performed on a scale of 0.25 mmol β-ketoester 1a, 1.2 equiv. catechol (2a) in 3 mL solvent. b Activities of the laccases as given by
the supplier. c Yields of the isolated product. d pH = 6.0, c = 0.2 M. e pH = 4.4, c = 0.2 M.
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Table 2 Laccase-catalysed arylation of β-ketoester 1a and catechols
2a–da
Table 3 Laccase-catalysed arylation of β-dicarbonyl compounds 1b–e
with catechols 2a–ca
Entry
3
N
R1
R2
t (h) Yieldb (%)
3/4c
1
2
3
4
5
6
7
e
f
g
h
i
j
k
1
1
1
1
1
3
1
OMe (1b)
OMe (1b)
OMe (1b) OMe (2c)
OEt (1c)
OEt (1c)
OMe (1d)
Me (1e)
H (2a)
Me (2b)
72
72
18
72
72
72
72
66
92
73
70
86
36
44
—
93 : 7
>99 : 1
—
96 : 4
97 : 3
—
Entry
3
R
t (h)
Yieldb (%)
96
3/4c
H (2a)
Me (2b)
Me (2b)
H (2a)
1
2
3
4
a
b
c
H (2a)
Me (2b)
OMe (2c)
Br (2d)
21
21
18
18
—
>99 : 1
68
d
n.d.e
a Reaction conditions: a mixture of 0.25 mmol β-dicarbonyl compounds
1b–e, 1.2 equiv. catechol 2a–c and 10 U of a laccase from Pleurotus
ostreatus in 3 mL solvent was stirred at room temperature (pH = 6.0).
d
52
71 : 29
a Reaction conditions: a mixture of 0.25 mmol β-ketoester 1a, 1.2 equiv.
catechol 2a–d and 10 U of a laccase from Pleurotus ostreatus in 3 mL
solvent was stirred at room temperature (pH = 6.0). b Combined yields
of the isolated two regioisomers 3 and 4. c Determined by 1H-NMR-
spectroscopy. d A complex mixture was obtained. e Not determined.
b Combined yields of the isolated two regioisomers
c Determined by 1H-NMR-spectroscopy.
3 and 4.
4-methyl catechol (2e) the arylation reaction proceeded at
position 5 of the phenyl ring selectively furnishing the product
after 18 h in a high yield (83%) and complete regioselectivity
(Scheme 2). In contrast, when 4-carboxylated catechol 2f was
used as an educt, the arylation reaction occurred at position 3 of
the phenyl ring indicating that the electronic property of the sub-
stituent shows significant influence on the regioselectivity of this
arylation reaction. Subsequently, the arylated product underwent
an intramolecular ketalization forming the tricyclic compound
3m as the final product in a moderately good yield (55%)
(Scheme 2).
Moreover, the cyclic lactam 1f was also investigated as a
nucleophile for this laccase-catalysed arylation reaction by react-
ing with different catechols 2a–c (Table 4). In all cases the reac-
tions were completed within 21 h providing the products 3n–p
in high to excellent yields (83–91%) (entries 1–3). In the cases
of catechol (2a) and 3-methoxy catechol (2c) only one regioi-
somer was obtained as a product (entries 1, 3), while the use of
3-methyl catechol (2b) as a substrate resulted in two regio-
isomers with a ratio of 90 : 10 (entry 2).
As shown in Scheme 3 the arylated product 3p was success-
fully converted into its piperonylated derivative 5 by treatment
with dibromomethane in the presence of caesium carbonate. In
this process the crude 3p could be used for the piperonylation
directly furnishing the product 5 in a good yield (68%) over two
steps, which can act as the precursor for the synthesis of
Scheme 2 Laccase-catalysed arylation of β-ketoester 1b and 4-substi-
tuted catechols 2e and 2f.
( )-poweline and ( )-buphanidrine according to the known
literature.6c
Furthermore, the enantioenriched β-ketoester 1g (Scheme 4),
which was synthesized through a quinine-catalysed asymmetric
Michael addition,13 was successfully employed as a nucleophile
in the laccase-catalysed arylation reaction. Although the com-
pound 1g bears two nucleophilic centres, the α-position of the
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Table 4 Laccase-catalysed arylation of β-ketoester 1f and catechols
2a–ca
Scheme 4 Diastereoselective arylation of the enantioenriched β-ketoe-
ster 1g.
was efficiently promoted by a commercially available enzyme
under mild reaction conditions employing aerial oxygen as the
oxidizing agent without an additional reducing agent for the
rearomatisation. Various catechols bearing substituents in differ-
ent positions have been successfully employed as precursors for
this arylation reaction furnishing the products in moderate to
excellent yields (36–96%) and in most cases high regioselec-
tivities. Furthermore, a highly functionalized cyclopentane
bearing an all-carbon quaternary stereogenic centre has been syn-
thesized through this arylation reaction in excellent diastereo-
and enantioselectivity.
Entry
3
R2
Yieldb (%)
3/4c
1
2
3
n
o
p
H (2a)
Me (2b)
OMe (2c)
83
91
88
—
90 : 10
>99 : 1
a Reaction conditions: a mixture of 0.25 mmol β-ketoester 1f, 1.2 equiv.
catechol 2a–c and 10 U of a laccase from Pleurotus ostreatus in 3 mL
solvent was stirred at room temperature (pH = 6.0). b Combined yields
of the isolated two regioisomers 3 and 4. c Determined by 1H-NMR-
spectroscopy.
Experimental section
General methods
Preparative column chromatography was performed using silica
gel 60, particle size 0.040–0.063 mm (230–240 mesh). Analyti-
cal TLC was carried out on pre-coated plastic sheets (Polygram®
SIL G/UV254, Macherey-Nagel) with detection by ultraviolet
1
irradiation (254 nm). H- and 13C-NMR spectra were recorded
on a Bruker Advance/DRX 600 at ambient temperature in
CDCl3 at 600 and 151 MHz. The chemical shifts are given in
ppm relative to tetramethylsilane [1H: δ(SiMe4) = 0.00 ppm] as
an internal standard or relative to the resonance of the solvent
[13C: δ(CDCl3) = 77.0 ppm]. In spectra of higher order the δ and
J values were not corrected. Coupling constants J were given in
Hz. NMR signals were assigned by means of H-COSY, DEPT
and HSQC.
Scheme 3 Synthesis of piperonylated β-ketoester 5 over two steps.
ester group and the α-position of the nitro moiety, this process
proceeded highly chemo-, regio- and diastereoselectively afford-
ing the highly functionalized cyclopentane 3q containing an all-
carbon quaternary stereogenic centre as the only product in a
moderately good yield (54%) and an excellent enantiomeric
excess (95% ee). The relative configuration of the compound 3q
was deduced by NOE measurements, also confirming the
expected addition anti to the β-nitromethylene substituent. Based
on this result and the reported fact that the stereogenic centres at
C-2 of 1g are R-configured, the newly formed stereogenic centre
at C-1 of 3q was assigned to be S.
Materials
All laccases used were purchased from Sigma Aldrich.
Petroleum ether (40–60 °C) and ethyl acetate for column
chromatography were distilled prior to use. All other chemicals
and solvents were used as purchased from commercial suppliers
without further purification.
General procedure for the α-arylation of the cyclic β-dicarbonyl
compounds 3
To a mixture of β-dicarbonyl compounds 1 (0.25 mmol) and
catechols 2 (0.30 mmol) in acetonitrile (1.0 mL) were added
phosphate buffer (pH = 6.0, c = 0.2 M, 1.0 mL) and the solution
of Pleurotus ostreatus (10 U) in phosphate buffer (pH = 6.0,
Conclusions
In conclusion we have developed a laccase-catalysed α-arylation
of cyclic β-dicarbonyl compounds by catechols. This process
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Characterisation of 3b. tert-Butyl 2-(3,4-dihydroxy-5-methyl-
phenyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3b) was
isolated through flash column chromatography (petroleum
ether–ethyl acetate = 4 : 1) as a pale yellow solid (60 mg, 68%).
Mp. 169–170 °C; Rf = 0.19 (petroleum ether–ethyl acetate =
4 : 1); IR (film): 3501, 3312, 3001, 2971, 2945, 1742, 1688,
1608, 1591, 1528, 1422, 1366, 1287, 1229, 1217, 1205, 1151,
1093, 1077, 1054, 1008, 967, 929, 908, 870, 859, 842, 804,
778, 749, 732, 706 cm−1; 1H NMR (600 MHz, CDCl3): δ = 7.79
(d, J = 7.8 Hz, 1 H, H-7), 7.62 (t, J = 7.2 Hz, 1 H, H-5), 7.47 (d,
J = 7.2 Hz, 1 H, H-4), 7.38 (t, J = 7.8 Hz, 1 H, H-6), 6.90 (d,
J = 1.8 Hz, 1 H, H-2′), 6.71 (brs, 1 H, OH), 6.65 (d, J = 1.8 Hz,
H-6′), 5.54 (brs, 1 H, OH), 4.03 (d, J = 17.4 Hz, 1 H, H-3), 3.57
(d, J = 17.4 Hz, 1 H, H-3), 2.19 (s, 3 H, CH3), 1.37 (s, 9 H,
OC(CH3)3) ppm; 13C NMR (151 MHz, CDCl3): δ = 202.2
c = 0.2 M, 1.0 mL) successively. After stirring for 18 h (for 3d,
3g and 3l), 21 h (for 3a, 3b and 3n–p) or 72 h (for 3e, 3f, 3h–k,
3m and 3q) at room temperature, the reaction mixture was
treated with water and then extracted with ethyl acetate. The com-
bined organic phase was washed with saturated aqueous NaCl
solution, dried over MgSO4, filtered, and then the volatiles were
removed under reduced pressure. The crude products were purified
by flash column chromatography on silica gel affording the corre-
sponding arylated cyclic β-dicarbonyl compounds 3 as products.
Procedure for the piperonylated β-ketoester 5 over two steps
To a mixture of the lactam 1f (0.50 mmol) and catechol 2c
(0.60 mmol) in acetonitrile (2.0 mL) were added phosphate
buffer (pH = 6.0, c = 0.2 M, 2.0 mL) and the solution of Pleuro-
tus ostreatus (20 U) in phosphate buffer (pH = 6.0, c = 0.2 M,
2.0 mL) successively. After stirring for 21 h at room temperature,
the reaction mixture was treated with water and then extracted
with ethyl acetate. The combined organic phase was washed
with saturated aqueous NaCl solution, dried over MgSO4,
filtered, and then the volatiles were removed under reduced
pressure. The crude product was dissolved in dry DMF (2.5 mL)
and Cs2CO3 (0.75 mmol, 1.5 equiv.) as well as dibromomethane
(0.75 mmol, 1.5 equiv.) were added successively at room temp-
erature. After stirring for 3 h at 85 °C, the reaction was cooled to
ambient temperature and then quenched with water. The mixture
was extracted with ethyl acetate. The combined organic layer
was washed with saturated aqueous NaCl solution, dried over
MgSO4, filtered and then the volatiles were removed under
reduced pressure. The crude product was purified by flash
column chromatography on silica gel (petroleum ether–ethyl
acetate = 3 : 1) affording the corresponding lactam 5 as a yellow
syrup (134 mg, 68%).
t
(CvO), 170.2 (CO2 Bu), 152.5 (CCH2), 143.2 (COH), 142.1
(COH), 135.6 (C-5), 135.1 (CCO), 129.4 (C-1′), 127.9 (C-6),
126.2 (C-4), 125.1 (C-7), 124.4 (C-5′), 121.4 (C-2′), 112.4
(C-6′), 82.8 (CO2C(CH3)3), 65.6 (C-2), 40.8 (C-3), 27.8 (3 C,
CO2C(CH3)3), 15.8 (ArCH3) ppm; MS (ESI, positive ion): m/z
(%): 377 [M + Na]+ (45), 321 (100); anal. calcd for C21H22O5:
C, 71.17; H, 6.26; found: C, 71.07; H, 6.27.
Characterisation of 3d and 4d. tert-Butyl 2-(3-bromo-4,5-
dihydroxyphenyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate
(3d) and tert-butyl 2-(2-bromo-3,4-dihydroxyphenyl)-1-oxo-2,3-
dihydro-1H-indene-2-carboxylate (4d) were isolated through
flash column chromatography (petroleum ether–ethyl acetate =
4 : 1) as a colourless solid (54 mg, 52%). Rf = 0.30 (petroleum
ether–ethyl acetate = 7 : 3); IR (film): 3487, 3285, 1742, 1686,
1607, 1590, 1523, 1466, 1418, 1368, 1328, 1283, 1250, 1210,
1128, 1151, 1075, 1052, 1018, 966, 943, 911, 882, 868, 855,
1
841, 801, 782, 756, 741, 725, 705, 684 cm−1; H NMR for 3c
(600 MHz, CDCl3): δ = 7.81 (d, J = 7.8 Hz, 1 H, H-7), 7.64 (t,
J = 7.8 Hz, 1 H, H-5), 7.48 (d, J = 7.2 Hz, 1 H, H-4), 7.45–7.40
(m, 1 H, H-6), 7.11 (d, J = 2.4 Hz, 1 H, H-6′), 6.99 (d, J =
1.8 Hz, H-2′), 5.90 (brs, 1 H, OH), 5.60 (brs, 1 H, OH), 4.04 (d,
J = 17.4 Hz, 1 H, H-3), 3.53 (d, J = 17.4 Hz, 1 H, H-3), 1.39 (s,
9 H, OC(CH3)3) ppm; 13C NMR for 3c (151 MHz, CDCl3): δ =
Spectroscopic and analytical data
Characterisation of 3a. tert-Butyl 2-(3,4-dihydroxyphenyl)-1-
oxo-2,3-dihydro-1H-indene-2-carboxylate (3a) was isolated
through flash column chromatography (petroleum ether–ethyl
t
200.5 (CvO), 169.4 (CO2 Bu), 152.0 (CCH2), 144.4 (COH),
140.1 (COH), 135.6 (C-5), 135.0 (CCO), 132.1 (C-1′), 128.0
(C-6), 126.1 (C-4), 125.1 (C-7), 122.5 (C-2′), 114.6 (C-6′),
109.3 (C-3′), 83.0 (CO2C(CH3)3), 65.0 (C-2), 40.5 (C-3), 27.8
acetate
= 7 : 3) as a colourless solid (82 mg, 96%).
Mp. 139–141 °C; Rf = 0.13 (petroleum ether–ethyl acetate =
4 : 1); IR (film): 3398, 3003, 2971, 2946, 1742, 1688, 1606,
1591, 1530, 1435, 1366, 1290, 1262, 1229, 1217, 1151, 1122,
1080, 1034, 913, 880, 856, 834, 804, 784, 769, 743, 722, 703,
687 cm−1; 1H NMR (600 MHz, CDCl3): δ = 7.79 (d, J = 7.2 Hz,
1 H, H-7), 7.62 (dt, J = 7.8, 1.2 Hz, 1 H, H-5), 7.47 (d, J =
7.8 Hz, 1 H, H-4), 7.39 (t, J = 7.8 Hz, 1 H, H-6), 7.02 (d, J =
1.8 Hz, 1 H, H-2′), 6.73 (dd, J = 8.4, 2.4 Hz, H-6′), 6.71
(d, J = 8.4 Hz, 1 H, H-5′), 6.52 (brs, 1 H, OH), 5.54 (brs, 1 H,
OH), 4.03 (d, J = 16.8 Hz, 1 H, H-3), 3.57 (d, J = 16.8 Hz, 1 H,
H-3), 1.38 (s, 9 H, OC(CH3)3) ppm; 13C NMR (151 MHz,
1
(3 C, CO2C(CH3)3) ppm; H NMR for 4d (600 MHz, CDCl3):
δ = 7.87 (d, J = 7.8 Hz, 1 H, H-7), 7.64 (t, J = 7.8 Hz, 1 H,
H-5), 7.45–7.40 (m, 2 H, H-4, 6), 6.65 (d, J = 8.4 Hz, 1 H,
H-5′), 6.63 (d, J = 8.4 Hz, H-6′), 6.00 (brs, 1 H, OH), 5.80 (brs,
1 H, OH), 4.45 (d, J = 17.4 Hz, 1 H, H-3), 3.31 (d, J = 17.4 Hz,
1 H, H-3), 1.41 (s, 9 H, OC(CH3)3) ppm; 13C NMR for 4d
t
(151 MHz, CDCl3): δ = 200.9 (CvO), 168.6 (CO2 Bu), 153.2
(CCH2), 143.6 (COH), 141.7 (COH), 135.9 (C-5), 135.0 (CCO),
131.9 (C-1′), 127.8 (C-6), 126.4 (C-4), 125.0 (C-7), 120.8
(C-6′), 113.8 (C-5′), 111.7 (C-2′), 83.0 (CO2C(CH3)3), 65.0
(C-2), 40.5 (C-3), 27.8 (3 C, CO2C(CH3)3) ppm; MS (ESI, posi-
tive ion): m/z (%): 441 [M + Na]+ (29), 385 (100); HRMS (ESI):
calcd for C20H19O5BrNa+: 441.0308; found: 441.0309.
t
CDCl3): δ = 202.2 (CvO), 170.3 (CO2 Bu), 152.6 (CCH2),
143.9 (COH), 143.6 (COH), 135.7 (C-5), 135.0 (CCO), 130.5
(C-1′), 128.0 (C-6), 126.2 (C-4), 125.1 (C-7), 119.7 (C-6′),
115.2 (C-5′), 114.7 (C-2′), 83.0 (CO2C(CH3)3), 65.6 (C-2), 40.7
(C-3), 27.8 (3 C, CO2C(CH3)3) ppm; MS (ESI, positive ion):
m/z (%): 363 [M + Na]+ (62), 307 (100); anal. calcd for
C20H20O: C, 70.58; H, 5.92; found: C, 70.33; H, 5.93.
Characterisation of 3e. Methyl 1-(3,4-dihydroxyphenyl)-2-
oxocyclopentane-carboxylate (3e) was isolated through flash
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column chromatography (petroleum ether–ethyl acetate = 2 : 1)
as a colourless syrup (41 mg, 66%). Rf = 0.17 (petroleum ether–
ethyl acetate = 7 : 3); IR (film): 3016, 2971, 1735, 1436, 1366,
1.8 Hz, 1 H, H-2′), 6.77 (d, J = 7.8 Hz, 1 H, H-5′), 6.74 (dd,
J = 7.8, 1.8 Hz, 1 H, H-6′), 6.30 (brs, 2 H, OH), 4.18 (q, 2 H,
J = 6.6 Hz, CO2CH2CH3), 2.80–2.76 (m, 1 H, H-5), 2.54–2.50
(m, 1 H, H-5), 2.49–2.44 (m, 1 H, H-3), 2.39–2.34 (m, 1 H,
H-3), 2.01–1.80 (m, 2 H, H-4), 1.22 (t, 3 H, J = 6.6 Hz,
CO2CH2CH3) ppm; 13C NMR (151 MHz, CDCl3): δ = 213.6
(CvO), 171.6 (CO2Et), 143.8 (2 C, C-3′ + C-4′), 127.7 (C-1′),
119.6 (C-6′), 115.3 (C-5′), 114.9 (C-2′), 64.5 (C-1), 62.2
(CO2CH2CH3), 37.7 (C-3), 34.8 (C-5), 19.3 (C-4), 14.0
(CO2CH2CH3) ppm; MS (ESI, positive ion): m/z (%): 287
[M + Na]+ (52), 259 (25), 242 (100), 214 (19); HRMS (ESI):
calcd for C14H16O5Na+: 287.0890; found: 287.0888.
1
1229, 1217, 750 cm−1; H NMR (600 MHz, CDCl3): δ = 6.93
(d, J = 2.4 Hz, 1 H, H-2′), 6.78 (d, J = 8.4 Hz, 1 H, H-5′), 6.74
(dd, J = 8.4, 2.4 Hz, 1 H, H-6′), 6.32 (brs, 2 H, OH), 3.71 (s,
3 H, CO2CH3), 2.80–2.75 (m, 1 H, H-5), 2.55–2.51 (m, 1 H, H-5),
2.48–2.43 (m, 1 H, H-3), 2.40–2.34 (m, 1 H, H-3), 2.00–1.87
(m, 2 H, H-4) ppm; 13C NMR (151 MHz, CDCl3): δ = 213.7
(CvO), 172.1 (CO2Me), 143.9 (2 C, C-3′ + C-4′), 127.5 (C-1′),
119.6 (C-6′), 115.4 (C-5′), 114.9 (C-2′), 64.5 (C-1), 53.2
(CO2CH3), 37.8 (C-3), 34.8 (C-5), 19.3 (C-4) ppm; MS (ESI,
positive ion): m/z (%): 273 [M + Na]+ (54), 255 (14), 245 (22),
228 (45), 195 (100); HRMS (ESI): calcd for C13H14O5Na+:
273.0733; found: 273.0732.
Characterisation of 3i. Ethyl 1-(3,4-dihydroxy-5-methyl-
phenyl)-2-oxocyclopentanecarboxylate (3i) and its regiomer 4i
were isolated through flash column chromatography (petroleum
ether–ethyl acetate = 3 : 1) as a colourless solid (60 mg, 86%). Rf
= 0.18 (petroleum ether–ethyl acetate = 4 : 1); IR (film): 3539,
3237, 2971, 2953, 1737, 1600, 1527, 1448, 1420, 1366, 1354,
1304, 1290, 1257, 1228, 1217, 1667, 1116, 1057, 1018, 994,
Characterisation of 3f. Methyl 1-(3,4-dihydroxy-5-methyl-
phenyl)-2-oxocyclopentane-carboxylate (3f) and its regiomer 4f
were isolated through flash column chromatography (petroleum
ether–ethyl acetate = 2 : 1) as a colourless solid (61 mg, 92%).
Mp. 116–118 °C; Rf = 0.14 (petroleum ether–ethyl acetate =
7 : 3); IR (film): 3450, 3016, 2971, 2949, 1745, 1436, 1366,
1
967, 880, 857, 840, 830, 758, 736, 696, 678 cm−1; H NMR
(600 MHz, CDCl3): δ = 6.78 (d, J = 1.8 Hz, 1 H, H-2′), 6.64 (s,
1 H, H-6′), 6.58 (brs, 1 H, OH), 5.60 (brs, 1 H, OH), 4.18 (q,
2 H, J = 7.2 Hz, CO2CH2CH3), 2.79–2.74 (m, 1 H, H-5),
2.54–2.43 (m, 2 H, H-5, 3), 2.40–2.34 (m, 1 H, H-3), 2.20 (s,
3 H, CH3), 1.99–1.89 (m, 2 H, H-4), 1.22 (t, 3 H, J = 7.2 Hz,
CO2CH2CH3) ppm; 13C NMR (151 MHz, CDCl3): δ = 213.9
(CvO), 171.6 (CO2Et), 143.2 (COH), 142.4 (COH), 126.6,
124.5, 121.2 (C-6′), 112.5 (C-2′), 64.6 (C-1), 62.2
(CO2CH2CH3), 37.8 (C-3), 34.9 (C-5), 19.3 (C-4), 15.8
(ArCH3), 14.0 (CO2CH2CH3) ppm; MS (ESI, positive ion): m/z
(%): 301 [M + Na]+ (45), 273 (100), 265 (28), 229 (94); anal.
calcd for C15H18O5: C, 64.74; H, 6.52; found: C, 64.47; H, 6.55.
1229, 1217, 1120, 982, 916, 848, 692 cm−1
;
1H NMR
(600 MHz, CDCl3): δ = 6.79 (s, 1 H, H-2′), 6.63 (s, 1 H, H-6′),
6.70 (brs, 1 H, OH), 5.67 (brs, 1 H, OH), 3.70 (s, 3 H,
CO2CH3), 2.79–2.74 (m, 1 H, H-5), 2.55–2.51 (m, 1 H, H-5),
2.48–2.35 (m, 2 H, H-3), 2.20 (s, 3 H, CH3), 1.99–1.87 (m, 2 H,
H-4) ppm; 13C NMR (151 MHz, CDCl3): δ = 214.0 (CvO),
172.1 (CO2Me), 143.3 (COH), 142.5 (COH), 126.4, 124.7,
121.1 (C-6′), 112.4 (C-2′), 64.5 (C-1), 53.2 (CO2CH3), 37.8
(C-3), 34.9 (C-5), 19.2 (C-4), 15.8 (ArCH3) ppm; MS (ESI,
positive ion): m/z (%): 287 [M + Na]+ (70), 242 (100); anal.
calcd for C14H16O5: C, 63.63; H, 6.10; found: C, 63.63; H, 6.10.
Characterisation of 3g. Methyl 1-(3,4-dihydroxy-5-methoxy-
phenyl)-2-oxocyclopentane-carboxylate (3g) was isolated
through flash column chromatography (petroleum ether–ethyl
Characterisation of 3j. Methyl 1-(3,4-dihydroxy-5-methyl-
phenyl)-2-oxocycloheptane-carboxylate (3j) and its regiomer 4j
were isolated through flash column chromatography (petroleum
ether–ethyl acetate = 3 : 1) as a pale yellow solid (27 mg, 36%).
Rf = 0.38 (petroleum ether–ethyl acetate = 3 : 2); IR (film):
3430, 3309, 3016, 2970, 2947, 2864, 1727, 1684, 1621, 1605,
1530, 1449, 1429, 1366, 1309, 1310, 1263, 1229, 1217, 1149,
1140, 1102, 1092, 1069, 1047, 1002, 973, 960, 941, 912, 881,
acetate
= 7 : 3) as a colourless solid (51 mg, 73%).
Mp. 132–134 °C; Rf = 0.24 (petroleum ether–ethyl acetate =
7 : 3); IR (film): 3443, 2971, 1740, 1724, 1608, 1519, 1433,
1365, 1310, 1229, 1217, 1204, 1168, 1091, 1038, 1003, 946,
842, 808, 787, 734, 702 cm−1; 1H NMR (600 MHz, CDCl3): δ =
6.62 (d, J = 1.8 Hz, 1 H, H-2′), 6.57 (d, J = 1.8 Hz, 1 H, H-6′),
5.63 (brs, 2 H, OH), 3.85 (s, 3 H, OCH3), 3.70 (s, 3 H,
CO2CH3), 2.82–2.78 (m, 1 H, H-5), 2.53–2.48 (m, 1 H, H-5),
2.48–2.43 (m, 1 H, H-3), 2.39–2.33 (m, 1 H, H-3), 2.01–1.87
(m, 2 H, H-4) ppm; 13C NMR (151 MHz, CDCl3): δ = 212.3
(CvO), 171.4 (CO2Me), 147.0 (C-5′), 143.8 (C-3′), 132.3
(C-4′), 127.3 (C-1′), 108.1 (C-2′), 103.1 (C-6′), 64.4 (C-1), 56.3
(ArOCH3), 53.0 (CO2CH3), 37.8 (C-3), 35.0 (C-5), 19.3 (C-4)
ppm; MS (ESI, positive ion): m/z (%): 303 [M + Na]+ (55), 287
(34), 273 (100), 252 (41); anal. calcd for C14H16O6: C, 60.00;
H, 5.75; found: C, 59.88; H, 5.76.
1
868, 858, 842, 833, 804, 757, 738, 716, 658 cm−1; H NMR
(600 MHz, CDCl3): δ = 6.56 (brs, 1 H, OH), 6.53 (d, J =
1.8 Hz, 1 H, H-2′), 6.51 (d, J = 1.8 Hz, 1 H, H-6′), 5.51 (brs,
1 H, OH), 3.68 (s, 3 H, CO2CH3), 3.73–3.69 (m, 1 H, H-7),
2.62–2.57 (m, 1 H, H-3), 2.53–2.49 (m, 1 H, H-3), 2.21 (s, 3 H,
CH3), 2.17–2.13 (m, 1 H, H-7), 1.98–1.92 (m, 1 H), 1.84–1.76
(m, 2 H), 1.70–1.56 (m, 2 H), 1.48–1.40 (m, 1 H) ppm; 13C
NMR (151 MHz, CDCl3): δ = 210.9 (CvO), 173.3 (CO2Me),
143.1 (COH), 142.3 (COH), 129.5, 124.5, 121.1 (C-2′), 112.6
(C-6′), 67.7 (C-1), 52.8 (CO2CH3), 41.8 (C-3), 33.6 (C-7), 30.5,
26.7, 25.6, 15.8 (ArCH3) ppm; MS (ESI, positive ion): m/z (%):
291 [M − H]+ (15), 263 (30), 259 (100), 231 (30), 203 (10),
194 (11), 149 (36); anal. calcd for C16H20O5: C, 65.74; H, 6.90;
found: C, 65.98; H, 6.93.
Characterisation of 3h. Ethyl 1-(3,4-dihydroxyphenyl)-2-oxo-
cyclopentane-carboxylate (3h) was isolated through flash
column chromatography (petroleum ether–ethyl acetate = 2 : 1)
as a colourless syrup (46 mg, 70%). Rf = 0.31 (petroleum ether–
ethyl acetate = 3 : 2); IR (film): 2971, 1740, 1436, 1366, 1229,
Characterisation of 3k. 2-Acetyl-2-(3,4-dihydroxyphenyl)-
cyclopentanone (3k) was isolated through flash column chrom-
atography (petroleum ether–ethyl acetate = 3 : 1) as a colourless
1
1217, 750 cm−1; H NMR (600 MHz, CDCl3): δ = 6.94 (d, J =
Green Chem.
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syrup (25 mg, 42%). Rf = 0.18 (petroleum ether–ethyl acetate =
4 : 1); IR (film): 3385, 2971, 1735, 1697, 1605, 1520, 1435,
1355, 1262, 1228, 1217, 1204, 1122, 1006, 966, 865, 812, 786,
ether–ethyl acetate = 3 : 2) as a colourless solid (73 mg, 83%).
Mp. 153–151 °C; Rf = 0.11 (petroleum ether–ethyl acetate =
7 : 3); IR (film): 3456, 3016, 2971, 2946, 1737, 1522, 1438,
1366, 1318, 1279, 1266, 1230, 1217, 1205, 1153, 1124, 1093,
1060, 1045, 976, 915, 892, 882, 849, 789, 775, 753, 693,
682 cm−1; 1H NMR (600 MHz, CDCl3): δ = 7.11 (d, J = 2.4 Hz,
1 H, H-2′), 6.82 (d, J = 7.8 Hz, 1 H, H-5′), 6.79 (dd, J = 8.4,
2.4 Hz, 1 H, H-6′), 5.60 (brs, 2 H, OH), 3.79–3.74 (m, 1 H,
H-5), 3.73 (s, 3 H, CO2CH3), 3.68–3.64 (m, 1 H, H-5),
2.92–2.89 (m, 1 H, H-4), 2.49–2.45 (m, 1 H, H-4), 1.53 (s, 9 H,
OC(CH3)3) ppm; 13C NMR (151 MHz, CDCl3): δ = 170.5,
765, 735, 701 cm−1 1H NMR (600 MHz, CDCl3): δ = 6.90
;
(d, J = 2.4 Hz, 1 H, H-2′), 6.87 (d, J = 8.4 Hz, 1 H, H-5′), 6.71
(dd, J = 8.4, 2.4 Hz, 1 H, H-6′), 2.84–2.70 (m, 1 H, H-3),
2.48–2.36 (m, 2 H, H-5), 2.34–2.29 (m, 1 H, H-3), 2.09 (s, 3 H,
COCH3), 191–1.86 (m, 2 H, H-4) ppm; 13C NMR (151 MHz,
CDCl3): δ = 215.4 (CvOMe), 205.9 (C-1), 144.1 (COH), 144.0
(COH), 129.4 (C-1′), 119.2 (C-6′), 115.7 (C-5′), 114.1 (C-2′),
71.8 (C-2), 39.1 (C-5), 34.0 (C-3), 26.8 (C-4), 19.0 (CvOCH3)
ppm; MS (ESI, positive ion): m/z (%): 257 [M + Na]+ (39),
179 (100); HRMS (ESI): calcd for C13H14O4Na+: 257.0784;
found: 257.0783.
t
170.4, 150.1 (NCO2 Bu), 144.1 (COH), 143.7 (COH), 127.9
(C-1′), 119.4 (C-6′), 115.3 (C-5′), 114.8 (C-2′), 83.8 (CO2C-
(CH3)3), 61.2 (C-3), 53.5 (CO2CH3), 43.5 (C-5), 30.1 (C-4),
28.0 (3 C, CO2C(CH3)3) ppm; MS (ESI, positive ion): m/z (%):
374 [M + Na]+ (15), 274 (100); anal. calcd for C17H21NO7: C,
58.11; H, 6.02; N, 3.99; found: C, 58.09; H, 6.02; N, 3.91.
Characterisation of 3l. Methyl 1-(4,5-dihydroxy-2-methyl-
phenyl)-2-oxocyclopentane-carboxylate (3l) was isolated
through flash column chromatography (petroleum ether–ethyl
acetate
= 7 : 3) as a colourless solid (56 mg, 83%).
Characterisation of 3o. 1-tert-Butyl 3-methyl 3-(3,4-di-
hydroxy-5-methylphenyl)-2-oxo-pyrrolidine-1,3-dicarboxylate (3o)
and its regiomer 4o were isolated through flash column
chromatography (petroleum ether–ethyl acetate = 3 : 2) as a pale
yellow solid (83 mg, 91%). Rf = 0.12 (petroleum ether–ethyl
acetate = 7 : 3); IR (film): 3430, 3336, 2955, 1780, 1714, 1618,
1605, 1523, 1425, 1370, 1310, 1295, 1249, 1212, 1144, 1111,
1089, 1065, 1023, 1001, 969, 948, 861, 848, 803, 776, 754,
740, 734, 706, 689 cm−1; 1H NMR (600 MHz, CDCl3): δ = 6.96
(d, J = 2.4 Hz, 1 H, H-2′), 6.66 (d, J = 2.4 Hz, 1 H, H-6′), 6.60
(brs, 1 H, OH), 5.65 (brs, 1 H, OH), 3.76–3.73 (m, 1 H, H-5),
3.72 (s, 3 H, CO2CH3), 3.67–3.63 (m, 1 H, H-5), 2.87–2.85
(m, 1 H, H-4), 2.50–2.46 (m, 1 H, H-4), 1.52 (s, 9 H, OC-
(CH3)3) ppm; 13C NMR (151 MHz, CDCl3): δ = 170.7 (2 C,
Mp. 153–155 °C; Rf = 0.38 (petroleum ether–ethyl acetate =
7 : 3); IR (film): 3473, 3004, 2971, 2954, 1742, 1723, 1602,
1519, 1437, 1397, 1366, 1322, 1296, 1278, 1226, 1218, 1164,
1140, 1094, 1061, 1011, 983, 937, 924, 914, 900, 859, 837, 828,
810, 760, 725, 705, 675 cm−1; 1H NMR (600 MHz, CDCl3): δ =
6.68 (s, 1 H, H-5′), 6.43 (s, 1 H, H-2′), 5.59 (brs, 2 H, OH), 3.75
(s, 3 H, CO2CH3), 3.01–2.96 (m, 1 H, H-5), 2.53–2.48 (m, 2 H,
H-3), 2.30–2.26 (m, 1 H, H-5), 2.08–2.02 (m, 1 H, H-4), 2.06 (s,
3 H, CH3), 1.87–1.79 (m, 1 H, H-4) ppm; 13C NMR (151 MHz,
CDCl3): δ = 215.3 (CvO), 171.8 (CO2Me), 142.9 (COH), 140.9
(COH), 129.3, 129.0, 119.2 (C-5′), 114.7 (C-2′), 66.1 (C-1),
53.3 (CO2CH3), 39.1 (C-2), 35.8 (C-5), 19.6 (C-4), 19.3
(ArCH3) ppm; MS (ESI, positive ion): m/z (%): 287 [M + Na]+
(35), 242 (100); anal. calcd for C14H16O5: C, 63.63; H, 6.10;
found: C, 63.33; H, 6.10.
t
CO2Me, BocNCvO), 150.1 (NCO2 Bu), 143.4 (COH), 142.8
(COH), 126.4 (C-1′), 124.5 (C-5′), 120.8 (C-6′), 112.4 (C-2′),
83.8 (CO2C(CH3)3), 61.3 (C-3), 53.4 (CO2CH3), 43.6 (C-5),
30.2 (C-4), 28.0 (3 C, CO2C(CH3)3), 15.8 (ArCH3) ppm; MS
(ESI, positive ion): m/z (%): 388 [M + Na]+ (21), 288 (100);
anal. calcd for C18H23NO7: C, 59.17; H, 6.34; N, 3.84; found:
C, 59.10; H, 6.52; N, 3.84.
Characterisation of 3m. 8-Ethyl 8b-methyl 3a,5-di-hydroxy-
2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-8,8b-di-
carboxylate (3m) was isolated through flash column chromato-
graphy (petroleum ether–ethyl acetate = 7 : 3) as a colourless
solid (45 mg, 55%). Mp. 154–155 °C; Rf = 0.19 (petroleum
ether–ethyl acetate = 3 : 2); IR (film): 3416, 3134, 2982, 2951,
1698, 1633, 1596, 1508, 1480, 1437, 1381, 1328, 1305, 1290,
1264, 1233, 1212, 1192, 1172, 1108, 1088, 1039, 1003, 989,
Characterisation of 3p. 1-tert-Butyl 3-methyl 3-(3,4-di-
hydroxy-5-methoxyphenyl)-2-oxopyrrolidine-1,3-dicarboxylate
(3p) was isolated through flash column chromatography
(petroleum ether–ethyl acetate = 3 : 2) as a colourless solid
(84 mg, 88%). Mp. 167–169 °C; Rf = 0.17 (petroleum ether–
ethyl acetate = 3 : 2); IR (film): 3455, 3017, 2971, 2947, 1735,
1680, 1609, 1520, 1448, 1369, 1314, 1259, 1229, 1217, 1204,
962, 934, 897, 882, 832, 815, 774, 732, 676 cm−1; H NMR
1
(600 MHz, CDCl3): δ = 7.57 (d, J = 8.4 Hz, 1 H, H-6), 6.82 (d,
J = 8.4 Hz, H-7), 6.40 (brs, 1 H, OH), 4.34–4.21 (m, 2 H,
CO2CH2CH3), 3.68 (s, 3 H, CO2CH3), 3.09–3.01 (m, 1 H, H-1),
2.29–2.25 (m, 1 H, H-3), 2.12–2.05 (m, 1 H, H-3), 1.85–1.81
(m, 1 H, H-1), 1.55–1.46 (m, 2 H, H-2), 1.33 (t, J = 7.2 Hz, 3 H,
CO2CH2CH3) ppm; 13C NMR (151 MHz, CDCl3): δ = 172.1
(CO2Me), 165.4 (CO2Et), 146.3 (C-4a), 143.9 (C-5), 131.7, 125.5
(C-6), 121.9, 118.5, 115.6 (C-7), 67.1 (C-8b), 60.9
(CO2CH2CH3), 52.7 (CO2CH3), 39.1 (C-3), 37.2 (C-1), 22.8
(C-2), 14.3 (CO2CH2CH3) ppm; MS (ESI, positive ion): m/z (%):
345 [M + Na]+ (23), 317 (23), 313 (62), 203 (10), 163 (100); anal.
calcd for C16H18O7: C, 59.44; H, 5.92; found: C, 59.40; H, 5.92.
1
1180, 1151, 1101, 1087, 972, 917, 844, 832, 776, 699 cm−1; H
NMR (600 MHz, CDCl3): δ = 6.73 (d, J = 2.4 Hz, 1 H, H-2′),
6.63 (d, J = 2.4 Hz, 1 H, H-6′), 5.55 (brs, 2 H, OH), 3.82 (s,
3 H, OCH3), 3.77–3.73 (m, 1 H, H-5), 3.75 (s, 3 H, CO2CH3),
3.68–3.64 (m, 1 H, H-5), 2.92–2.88 (m, 1 H, H-4), 2.46–2.42
(m, 1 H, H-4), 1.53 (s, 9 H, OC(CH3)3) ppm; 13C NMR (151 MHz,
t
CDCl3): δ = 170.3, 169.8, 150.1 (NCO2 Bu), 147.0 (C-5′), 143.8
(C-3′), 132.5 (C-4′), 127.3 (C-1′), 107.6 (C-6′), 102.9 (C-2′), 83.6
(CO2C(CH3)3), 61.2 (C-3), 56.3 (ArOCH3), 53.4 (CO2CH3), 43.4
(C-5), 30.2 (C-4), 28.0 (3 C, CO2C(CH3)3) ppm; MS (ESI, positive
ion): m/z (%): 404 [M + Na]+ (17), 304 (100); HRMS (ESI): calcd
for C18H23NO8Na+: 404.1316; found: 404.1314.
Characterisation of 3n. 1-tert-Butyl 3-methyl 3-(3,4-di-
hydroxyphenyl)-2-oxopyrrolidine-1,3-dicarboxylate (3n) was
isolated through flash column chromatography (petroleum
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2 Y. Fukuyama and Y. Asakawa, J. Chem. Soc., Perkin Trans. 1, 1991,
2737–2741.
Characterisation of 3q. (1S,2R)-Ethyl 1-(3,4-dihydroxyphe-
nyl)-2-(nitromethyl)-5-oxo-cyclopentane-carboxylate (3q) was
isolated through flash column chromatography (petroleum
ether–ethyl acetate = 4 : 1) as a yellow syrup (44 mg, 54%). Rf =
0.38 (petroleum ether–ethyl acetate = 3 : 2); the ee (95%) was
determined by HPLC on a chiral stationary phase [Chiralpak IC,
n-heptane–isopropanol = 8 : 2, 0.5 mL min−1), tR = 91 min
(major), 152 min (minor)]; [α]2D0 = −28.4 (c = 0.50, CHCl3); IR
(film): 3443, 2971, 1724, 1607, 1551, 1523, 1434, 1366, 1226,
1214, 1204, 1154, 1121, 1085, 1017, 871, 846, 809, 784, 737,
3 (a) J. R. Lewis, Nat. Prod. Rep., 2002, 19, 223–258; (b) Z. Jin, Z. Li and
R. Huang, Nat. Prod. Rep., 2002, 19, 454–476; (c) Z. Jin, Nat. Prod.
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1
672, 662 cm−1; H NMR (600 MHz, CDCl3): δ = 6.84 (d, J =
8.4 Hz, 1 H, H-5′), 6.77 (d, J = 2.4 Hz, 1 H, H-2′), 6.67 (dd, J =
8.4, 2.4 Hz, 1 H, H-6′), 5.50 (brs, 2 H, OH), 4.80 (dd, J = 13.2,
3.0 Hz, 1 H, CHHNO2), 4.66 (dd, J = 13.2, 10.2 Hz, 1 H,
CHHNO2), 4.28–4.23 (m, 2 H, CO2CH2CH3), 3.37–3.34 (m,
1 H, CHCH2NO2), 2.76–2.71 (m, 1 H, H-4), 2.45–2.39 (m, 2 H,
H-3, 4), 1.96–1.93 (m, 1 H, H-3), 1.28 (t, 3 H, J = 7.2 Hz,
CO2CH2CH3) ppm; 13C NMR (151 MHz, CDCl3): δ = 209.5
(CvO), 168.9 (CO2Et), 143.9 (COH), 143.8 (COH), 127.2
(C-1′), 119.9 (C-6′), 115.7 (C-5′), 115.0 (C-2′), 76.6 (NO2CH2),
67.0 (C-1), 62.6 (CO2CH2CH3), 44.5 (C-2), 36.7 (C-4), 24.4
(C-3), 14.1 (CO2CH2CH3) ppm; MS (ESI, positive ion): m/z
(%): 346 [M + Na]+ (12), 299 (59), 277 (100), 249 (31); HRMS
(ESI): calcd for C15H17NO7Na+: 346.0897; found: 346.0896.
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8 For reviews on the applications of laccases in organic synthesis, see:
(a) S. J. Burton, Curr. Org. Chem., 2003, 7, 1317–1331; (b) S. Riva,
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Characterisation of 5. 1-tert-Butyl 3-methyl 3-(7-methoxy-
benzo[d][1,3]dioxol-5-yl)-2-oxopyrrolidine-1,3-dicarboxylate (4)
Rf = 0.15 (petroleum ether–ethyl acetate = 4 : 1); IR (film):
3003, 2971, 2950, 1782, 1737, 1722, 1634, 1511, 1549, 1429,
1366, 1297, 1229, 1217, 1147, 1097, 1039, 969, 948, 926, 844,
803, 776, 732, 702 cm−1; 1H NMR (600 MHz, CDCl3): δ = 6.72
(s, 1 H, H-2′), 6.65 (s, 1 H, H-6′), 5.96 (s, 2 H, OCH2O), 3.90
(s, 3 H, OCH3), 3.77–3.73 (m, 1 H, H-5), 3.76 (s, 3 H,
CO2CH3), 3.68–3.65 (m, 1 H, H-5), 2.95–2.91 (m, 1 H, H-4),
2.43–2.38 (m, 1 H, H-4), 1.54 (s, 9 H, OC(CH3)3) ppm;
13C NMR (151 MHz, CDCl3): δ = 170.1, 169.4, 150.0
9 For reviews on the applications of laccases in industry, see:
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t
(NCO2 Bu), 149.1 (C-5′), 143.4 (C-3′), 135.2 (C-4′), 130.2
(C-1′), 107.5 (C-2′), 101.7 (2 C, C-6′ +OCH2O), 83.6 (CO2C-
(CH3)3), 61.4 (C-3), 56.9 (ArOCH3), 53.5 (CO2CH3), 43.3
(C-5), 30.6 (C-4), 28.0 (3 C, CO2C(CH3)3) ppm; MS (ESI, posi-
tive ion): m/z (%): 416 [M + Na]+ (100), 316 (100); anal. calcd
for C19H23NO8: C, 58.01; H, 5.89; N, 3.56; found: C, 57.80;
H, 5.92; N, 3.47.
Acknowledgements
11 J. Pietruszka and C. Wang, ChemCatChem, 2012, 4, 782–785.
12 For examples of laccase-catalysed reactions with an oxidation/Michael
addition sequence, see ref. 10c–10e, and: (a) H. Leutbecher, J. Conrad,
I. Klaiber and U. Beifuss, Synlett, 2005, 3126–3130; (b) S. Hajdok,
H. Leutbecher, G. Greiner, J. Conrad and U. Beifuss, Tetrahedron Lett.,
2007, 48, 5073–5076; (c) S. Witayakran, L. Gelbaum and
A. J. Raugaskas, Tetrahedron, 2007, 63, 10958–10962; (d) S. Hajdok,
J. Conrad, H. Leutbecher, S. Strobel, T. Schleid and U. Beifuss, J. Org.
Chem., 2009, 74, 7230–7237; (e) F. Bruyneel, O. Payen, A. Rescigno,
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We gratefully acknowledge the Ministry of Innovation, Science
and Research of the German federal state of North Rhine-West-
phalia (technology platform ‘ExpressO’ within the ‘Ziel 2-Pro-
gramm 2007-2013, NRW – EFRE’), and the Heinrich-Heine-
Universität Düsseldorf, the Deutsche Forschungsgemeinschaft,
and the Forschungszentrum Jülich GmbH for the generous
support of our projects.
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