A novel enzymatic tandem process: Utilization of biocatalytic promiscuity for high stereoselective synthesis of 5-hydroxyimino-4,5-dihydrofurans

Article abstract of DOI:10.1016/j.tet.2011.01.060

A lipase-catalyzed protocol for the synthesis of 5-hydroxyimino-4,5- dihydrofurans via tandem coupling between β-nitrostyrenes and 1,3-dicarbonyl compounds was developed in a 'one-pot' strategy. A series of β-nitrostyrenes were employed to expand the scope of this new biocatalytic promiscuity with high stereoselectivity (Z/E up to 99:1) and moderate to good yields. The reaction activity of 1,3-cyclohexanedione was found to be better than linear 2,4-pentanedione, while ethyl acetoacetate and diethylmalonate were not suitable for this reaction under the same conditions. Single-crystal X-ray diffraction analysis indicated that the reaction was stereoselective and Z-stereomer was found to be the major product. A reaction mechanism was supposed to elucidate the biocatalytic process.

Full text of DOI:10.1016/j.tet.2011.01.060

Tetrahedron 67 (2011) 2681e2688
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Tetrahedron
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A novel enzymatic tandem process: utilization of biocatalytic promiscuity for high
stereoselective synthesis of 5-hydroxyimino-4,5-dihydrofurans
,
a
a
a
b
a,
Ming-Yu Wu a, Kun Li a , Ting He , Xing-Wen Feng , Na Wang , Xiao-Yan Wang , Xiao-Qi Yu
*
*
a Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, PR China
b Analytical and Testing Center, Sichuan University, Chengdu 610064, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A lipase-catalyzed protocol for the synthesis of 5-hydroxyimino-4,5-dihydrofurans via tandem coupling
between -nitrostyrenes and 1,3-dicarbonyl compounds was developed in a ‘one-pot’ strategy. A series of
-nitrostyrenes were employed to expand the scope of this new biocatalytic promiscuity with high
stereoselectivity (Z/E up to 99:1) and moderate to good yields. The reaction activity of 1,3-cyclo-
hexanedione was found to be better than linear 2,4-pentanedione, while ethyl acetoacetate and dieth-
ylmalonate were not suitable for this reaction under the same conditions. Single-crystal X-ray diffraction
analysis indicated that the reaction was stereoselective and Z-stereomer was found to be the major
product. A reaction mechanism was supposed to elucidate the biocatalytic process.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 27 November 2010
Received in revised form 14 January 2011
Accepted 21 January 2011
b
b
Available online 3 February 2011
Keywords:
Biocatalytic promiscuity
Lipase
Dihydrofuran derivatives
Tandem reaction
Water-mediated reaction
1. Introduction
any other chemical catalysts, is extremely scarce. As one of the most
rapidly growing areas in enzymology, biocatalytic promiscuity not
Dihydrofuran derivatives have been considered as important
synthetic intermediates for their existence in a wide range of
biologically active synthetics and natural products.1 Explorations of
facile and green methods for the preparation of these functional-
ized heterocycles received considerable attentions in synthetic
organic chemistry.2 Among these methods, tandem catalysis pro-
vide the opportunities to improve such transformations because of
its atom economy and simple operation.3 Although several metal-
catalyzed tandem processes were developed,4 there is significant
interest in developing environmental friendly metal-free methods
for the preparation of dihydrofuran derivatives. Further more,
oxime compounds often show satisfactory insecticidal, fungicidal
or herbicidal activity,5 and the synthesis of dihydrofuran oxime
derivatives were seldom reported.6 Therefore, finding an efficient
process for the preparation of such bioactive oxime-functionalized
dihydrofuran derivatives is of great importance.
only highlights the existing catalysts, but provides novel and
practical synthetic pathways, which are not currently available.9
Nevertheless, the utilization of biocatalytic promiscuity of lipase
in the synthesis of heterocycles was seldom reported. Herein, we
wish to report a single lipase-catalyzed approach for the synthesis
of 5-hydroxyimino-4,5-dihydrofurans via a tandem process with
the utilization of biocatalytic promiscuity.
The lipase-catalyzed aldol, Mannich, and decarboxylative
Knoevenagel reactions were systematically studied in our group
previously.10 As the successive work, our initial efforts focused on
the biocatalytic promiscuity in lipase-catalyzed Michael addition
between nitrostyrene and acetylacetone. But to our surprise, under
the regular reaction conditions, except the routine Michael addition
product 3a, cyclic product 4a was obtained in comparable yield to
that of 3a (Scheme 1). For the potential as fungicidal or herbicidal
As an efficient and green tool for modern organic synthesis,
biocatalysis has attracted increased attention for its usually excel-
lent selectivity and mild conditions.7 Many enzymatic tandem
processes based on chemo-enzymatic reactions have been well
presented.8 However, to our knowledge, single enzymatic tandem
processes, which utilize only one type of enzyme in the absence of
* Corresponding authors. Tel.: þ86 28 85460576; fax: þ86 28 85415886; e-mail
Scheme 1. Lipase-catalyzed reaction of nitrostyrene and acetylacetone.
address: xqyu@tfol.com (X.-Q. Yu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.060

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M.-Y. Wu et al. / Tetrahedron 67 (2011) 2681e2688
agent of the oxime,5 product 4a was chosen to be the target product
in the novel lipase-catalyzed process.
obtained with higher yield than the desired product 4a. Therefore,
our subsequent studies were carried out for the improvement of the
reaction selectivity toward 4a in DMSO/H2O media.
Our previous studies suggested that the content of water in
reaction mixture could largely influence the results of biocatalytic
reactions.10 Experiments were performed to ascertain the catalytic
activity of PPL with different amounts of water in the reaction
system, and the results were listed in Table 2. The yield of 4a was
evidently improved to 50.3% when the content of water increased
to 40% (entry 4). Further increase of water led to the decrease of
yield, which could be attributed to the lower solubility of the
substrates.
2. Results and discussion
With the aim to get 4a in more efficient manner, the catalytic
activities of several lipases were firstly tested in mixed ethanol/
water solvents. As shown in Table 1, poor yields for 3a and 4a were
obtained in the absence of lipase (entry 12). Among the tested li-
pases, lipase from porcine pancreas (PPL) showed the best activity,
and the yield of 4a was 37.5%, which almost equaled that of 3a.
Meanwhile, other lipases, such as CCL, CRL, PCL, MJL, and PRL
exhibited slight lower catalytic activity than PPL. As a widespread
and inexpensive lipase, PPL was chosen as the biocatalyst in the
following experiments.
Table 2
The influence of different water content on the reactiona
Entry
Water content (%)
Yield of 4ab (%)
Table 1
The catalytic activities of different lipasesa
1
2
3
4
5
6
5
10
20
40
60
80
25.6
28.9
39.4
50.3
32.2
33.9
Entry
Enzyme
Yield 4ab (%)
Yield 3ab (%)
1
2
3
4
5
6
7
8
Lipase from porcine pancreas (PPL)
Lipase from C. cylindracea (CCL)
Lipase from C. rugosa (CRL)
Lipase from P. camemberti (PCL)
Lipase from M. javanicus (MJL)
Lipase from P. roqueforti (PRL)
Lipase from R. oryzae (ROL)
Lipase from M. miehei (MML)
Lipase from P. fluorescens (PFL)
Lipase from C. antarctica (CAL-B)
Denatured PPLc
37.5
31.6
34.5
33.2
32.9
32.1
28.3
28.2
24.7
23.3
5.4
38.9
36.4
38.5
38.3
40.2
32.3
34.6
37.3
25.3
33.6
2.8
a
Reactions were performed for 24 h in DMSO/H2O system.
Yields were determined by HPLC.
b
To obtain more information of this lipase-catalyzed tandem
reaction, we investigated the time course of the reaction. As shown
in Fig. 2, the yields of both 3a and 4a increased at first 12 h, in-
dicating that the formation of 3a and 4a might be two competing
reactions. Time extension of the reaction led to gradually decrease
of 3a along with the increase of 4a, suggesting that 3a could be
transformed to 4a under the reaction conditions. The result also
indicated that the Michael adduct might be the intermediate in this
tandem reaction. The yield of 4a reached to a relatively high plateau
of about 60% in 36 h. According to the results, subsequent reactions
were carried out for 48 h.
9
10
11
12c
No enzyme
4.3
3.6
a
Reaction performed on 0.1 mmol scale in 1 mL of EtOH/H2O (4: 1, v/v), 50 ꢀC,
24 h.
b
c
Yields were determined by HPLC.
Pre-treated with urea at 60 ꢀC for 12 h.
Solvents are auxiliary materials in biochemical synthesis and
productions, and they always play an important role in the bio-
catalytic process. Some commonly used solvents or mixed solvents
were screened subsequently for higher yield of 4a. Generally, as
shown in Fig.1, the reactions gave moderate yields in the mixture of
polar solvents and water (DMSO/H2O or EtOH/H2O), while poor
yields were obtained in the mixture of some aprotic solvents and
water (THF/H2O and acetone/H2O). Without the use ofwater, various
solvents could give different results. In the reactions using DMSO or
ethanol as solvents, poor yields of 4a but high yields of 3a were
observed. Meanwhile, no reaction was detected when using THF or
acetone as solvent. In the reactions studied above, 3a was always
Fig. 2. The content of 3a and 4a in the reaction system at different time (determined
by HPLC).
A range of b-nitrostyrenes and 1,3-diones were then surveyed to
expand the scope of this new biocatalytic promiscuity in the one-
pot tandem reaction. As shown in Tables 3 and 2, 4-pentanedione
(n¼0) and 1,3-cyclohexanedione (n¼1) were used as 1,3-dione
substrates. It was found that a wide range of b-nitrostyrenes could
effectively participate in this reaction and gave desired products 4
with moderate to good yields (50e86%). Electronic effect of sub-
Fig. 1. The influence of mixed solvents on the tandem reaction (24 h). The solvents
given in the figure indicate that the reaction was carried out in mixed solvents with the
given solvent/water volume ratio of 4:1.
stituents on phenyl ring of
b-nitrostyrenes did not seem to in-
fluence the yield, and o-chloro-
b
-nitrostyrene (entries 8 and 18)

Table 3
Synthesis of 5-hydroxyimino-4,5-dihydrofurans with different b
-nitrostyrene and 2,4-pentanedione or 1,3-cyclohexanedionea
Entry
1
R1
n
Product 4
Yieldb (%)
61.7
Z/Ec
Entry
11
R1
n
Product 4
Yieldb (%)
64.3
Z/Ec
C6H5
0
>99:1
C6H5
1
>99:1
2
3
4-CH3C6H4
0
0
51.4
63.6
>99:1
>99:1
12
13
4-CH3C6H4
1
1
54.6
73.8
71:29
4-CH3OC6H4
4-CH3OC6H4
>99:1
4
5
6
4-FC6H4
4-ClC6H4
4-BrC6H4
0
0
0
48.9
50.6
50.7
>99:1
>99:1
>99:1
14
15
16
4-FC6H4
4-ClC6H4
4-BrC6H4
1
1
1
63.5
70.8
61.2
91:9
65:35
64:36
7
4-CF3C6H4
0
0
52.3
80.6
96:4
17
4-CF3C6H4
1
65.4
46:54
8
9
2-ClC6H4
>99:1
18
19
2-ClC6H4
1
1
85.7
65.6
28:72
3-ClC6H4
0
0
54.5
51.4
97:3
3-ClC6H4
>99:1
10
C4H3O
>99:1
a
The reaction was conducted with 200 mg PPL, 2 mmol of nitrostyrene, 4 mmol of 2,4-pentanedione or 1,3-cyclohexanedione in 20 mL of DMSO/H2O mixture (3:2, v/v) at
50 ꢀC for 24 h (entries 11e19) or 48 h (entries 1e10).
b
Isolated yield.
c
Z/E Ratio was determined by 1H NMR.

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M.-Y. Wu et al. / Tetrahedron 67 (2011) 2681e2688
gave the highest yield of 85.7%. According to the single-crystal
X-ray diffraction analysis of products 4a and 4k (Fig. 3), we could
confirm that the reaction gave the product oximes with Z-stereo-
selectivity. 1H NMR showed that high Z/E selectivities (up to >99%)
were obtained in the reaction products. Further, the results also
indicated that the reaction activity of 1,3-cyclohexanedione (entries
11e19) was better than that of linear 2,4-pentanedione (entries
1e10). However, 2,4-pentanedione always gives better stereo-
selectivity. Other diones, such as 1,3-cyclopentanedione, ethyl
acetoacetate, and diethylmalonate could not give products 4 under
such conditions (data not shown). Detailed information revealed
that only Michael product was found for 1,3-cyclopentanedione,
while ethyl acetoacetate and diethylmalonate would hydrolyze by
lipase and therefore could not react smoothly. In the absence of
lipase, low yield of 4a (about 15%) was obtained. The rise of reaction
temperature to 80 ꢀC led to more unsatisfactory result, indicating
that lipase was indispensable for good yield of product 4. Compared
with the reaction catalyzed by NEt3 in methanol6c, much less by-
product of dihydrofuran with the nitro group leaving11 was pro-
duced, thus obtained good stereoselectivity (Z/E up to 99:1) and
extensive substrates.
3. Conclusion
In conclusion, we have developed a tandem process for pre-
paring 5-hydroxyimino-4,5-dihydrofurans and 2,3,6,7-tetrahy-
drobenzofurans via the reaction between
3-dicarbonyl compounds with the utilization of biocatalytic pro-
miscuity under mild conditions. The starting materials are com-
mercially available or can be easily prepared. We believe that these
results can not only highlight the biocatalytic promiscuity but also
afford a facile access to functionalized dihydrofurans and their
derivatives.
b-nitrostyrene and 1,
4. Experimental
4.1. Materials and general methods
Lipase from porcine pancreas (PPL), Lipase from Candida ant-
arctica (CAL-B), lipase from Candida cylindracea (CCL), lipase from
Mucor javanicus (MJL), lipase from Candida rugosa (CRL) and lipase
from Rhizopus oryzae (ROL) were purchased from Sigma. Lipase
from Mucor miehei (MML) and lipase from Penicillium camemberti
Fig. 3. Structures of 4a and 4k characterized by single-crystal X-ray diffraction.12
It is widely accepted that the hydrolysis site in hydrolase is still
responsible for its promiscuous catalysis.13 Combining such
viewpoint with the observations in this study, we proposed the
mechanism of this lipase-catalyzed tandem reaction, which was
(PCL) were purchased from Fluka. Lipase from Pseudomonas fluo-
rescens (PFL), and lipase from Penicillium roqueforti (PRL) are a gift
from the Amano Enzyme China Ltd. 1H NMR and 13C NMR spectra
were recorded on a Bruker 400 MHz instrument using CDCl3 and
DMSO-d6 as the solvent with tetramethylsilane (TMS) as an internal
described in Scheme 2. Firstly, b-nitrostyrene and 1,3-dicarbonyl
compounds were activated, respectively, by the serine residue and
standard at room temperature. Chemical shifts are given in d rela-
oxyanion hole of the lipases.14 Then intermediate II was generated
tive to TMS; the coupling constants J are given in hertz. HPLC was
carried out using a Shimadzu organizer consisting of an LC-2010A
HT Integrator, a UV/vIS Detector. C18 column was used in the HPLC
experiments with methanol/water¼50:50 (v/v), 0.8 mL/min and
UV¼254 nm. HRMS were performed on Bruker Daltonics Bio TOF
mass spectrometer. 1,3-Cyclohexanedione and 2,4-pentanedione
were purchased from Aladdin Reagent Company. Column chro-
matography was performed using EM Silica gel (300e400 mesh).
from enolate anion (I) and b-nitrostyrene with the assistance of
Asp-His dyad. II could be transformed to III (another form of 3) or
IV (which is the enolate of the III on the carbonyl group) easily.
Next, the intermediate IV could be activated by his and oxyanion
hole, and then formation of V via an intramolecular cyclization.
Further elimination of a water molecule gave the product 4. That is
to say, there are two reaction routes for intermediate II: (a) pro-
tonation to give compound 3 in a slow reversible reaction, and (b)
cyclization of the enolate of III on the dicarbonyl moiety to give 4.
Based on the mechanism from above and the experiment that
compound 3 could be gradually transformed to 4 when increasing
the reaction time, we can see that 4 was more stable than 3 under
the reaction condition. Further experiments are now in progress
to prove this hypothesis.
4.2. Typical experimental procedure for synthesis of
nitrostyrene
Aryl aldehyde (0.05 mol), nitromethane (0.05 mol), and MeOH
(10e20 mL) were added in round-bottom flask and then stirred
vigorously. 10 mL of 10.5 mol/L NaOH solution was added

M.-Y. Wu et al. / Tetrahedron 67 (2011) 2681e2688
2685
Scheme 2. Proposed mechanism of lipase-catalyzed tandem reaction.
dropwise in an ice bath, a larger number of white or yellow solid
would precipitated, stirring continued for 15 min. Distilled water
was added until the solution became clear, then the solution was
added dropwise to 30 mL concentrated HCl and yellow solid
would precipitated. The yellow solid were filtered and washed
with water, then evaporation under vacuum drying oven. After
recrystallization from ethanol, yellow needle-like crystalloid was
obtained.
added and the solution was extracted with ethyl acetate (50 mL) for
three times. The organic phase was combined and wished with
brine (25 mL), then dried (Na2SO4), filtered, and evaporated in
vacuum. The residue was purified by flash column chromatography
from 5:1 to 2:1 (petroleum ether: ethyl acetate), and compounds 3
as well as 4 were separated, respectively.
4.3.1. 3-(2-Nitro-1-phenylethyl)pentane-2,4-dione (3a). White solid;
1HNMR(400 MHz,TMS, CDCl3):
d7.35e7.29 (m, 3H, PheH), 7.20e7.17
4.3. Typical experimental procedure for synthesis of
5-hydroxyimino-4,5-dihydrofurans
(m, 2H, PheH), 4.63 (dd, 2H, J¼3.2, 5.2 Hz, eCH2), 4.37 (d, 1H,
J¼10.8 Hz, eCH), 4.27e4.21 (m, 1H, eCH), 2.30 (s, 3H, eCH3), 1.94 (s,
3H, eCH3); 13C NMR (100, MHz, CDCl3): 201.8, 201.0, 136.0, 129.4,
128.6, 127.9, 78.2, 70.8, 42.8, 30.4, 29.5. ESIMS: 272.1 [MþNa]þ.
Nitrostyrene (2 mmol), 1.3-dicarbonyl compounds (4 mmol),
200 mg PPL, 12 mL DMSO, and 8 mL water were added in a 50 mL
round-bottom flask. The mixture was stirred at 50 ꢀC for 24 h or
48 h, filtrated to get rid of the enzyme (PPL), then 25 mL brine was
4.3.2. 1-(5-(Hydroxyimino)-2-methyl-4-phenyl-4,5-dihydrofuran-3-
yl)ethanone (4a). White solid; mp 140e142 ꢀC; 1H NMR

2686
M.-Y. Wu et al. / Tetrahedron 67 (2011) 2681e2688
(400 MHz, CDCl3):
d
7.48 (s, 1H, eOH), 7.36e7.27 (m, 3H, PheH),
193.0, 164.5, 155.2, 137.5, 133.1, 130.3, 129.6, 128.1, 117.5, 47.5, 29.8,
14.7. HRMS (ESI) calcd for C13H13ClNO3 [MþH]þ: 266.0578; found:
266.0579.
7.19e7.17 (m, 2H, PheH), 4.90 (d, 1H, J¼2 Hz, eCH), 2.51 (d, 3H,
J¼1.6 Hz, eCH3), 1.97 (s, 3H, eCH3); 13C NMR (100 MHz, CDCl3):
193.9, 164.2, 157.9, 138.2, 129.3, 128.1, 127.5, 117.6, 49.3, 29.8, 14.3.
HRMS (ESI) calcd for C13H14NO3 [MþH]þ: 232.0968; found:
232.0974.
4.3.10. 1-(4-(3-Chlorophenyl)-5-(hydroxyimino)-2-methyl-4,5-dihy-
drofuran-3-yl)ethanone (4i). White solid; mp 147e150 ꢀC; 1H NMR
(400 MHz, DMSO-d6):
d 10.33 (10.12) (s, 1H, eOH), 7.39e7.33 (m,
4.3.3. 1-(5-(Hydroxyimino)-2-methyl-4-(p-tolyl)-4,5-dihydrofuran-
2H, PheH), 7.30e7.16 (m, 2H, PheH), 5.14 (5.27) (d, 1H, J¼1.6 Hz,
eCH), 2.46 (d, 3H, J¼2.0 Hz, eCH3), 2.06 (s, 3H, eCH3); 13C NMR
(100 MHz, DMSO-d6): 193.3, 164.6, 155.7, 142.8, 133.7, 131.1, 127.9,
127.8, 126.7, 117.7, 48.0, 30.1, 14.8. HRMS (ESI) calcd for C13H13ClNO3
[MþH]þ: 266.0578; found: 266.0579.
3-yl)ethanone (4b). White solid; mp 134e136 ꢀC; 1H NMR
(400 MHz, CDCl3):
d
7.64 (s, 1H, eOH), 7.13 (d, 2H, J¼8.0 Hz, PheH),
7.06 (d, 2H, J¼8.0 Hz, PheH), 4.86 (q, 1H, J¼1.6 Hz, eCH), 2.50 (d,
3H, J¼1.6 Hz, eCH3), 2.31 (s, 3H, PheCH3), 1.96 (s, 3H, eCH3); 13C
NMR (100 MHz, CDCl3): 194.1, 164.1, 158.1, 137.9, 135.1, 129.9, 127.3,
117.6, 49.0, 29.8, 21.1, 14.3. HRMS (ESI) calcd for C14H16NO3 [MþH]þ:
246.1125; found: 246.1131.
4.3.11. 1-(20-(Hydroxyimino)-50-methyl-20,30-dihydro-[2,30-bifuran]-
40-yl)ethanone (4j). White solid; mp 130e132 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 8.98 (s, 1H, eOH), 7.84(s, 1H, AreH), 7.17 (d,
4.3.4. 1-(5-(Hydroxyimino)-4-(4-methoxyphenyl)-2-methyl-4,5-di-
1H, J¼3.6 Hz, AreH), 6.63 (q, 1H, J¼1.6 Hz, AreH), 6.31 (s, 1H, eCH),
2.40 (s, 3H, eCH3), 1.51 (s, 3H, eCH3); 13C NMR (100 MHz, DMSO-
d6): 201.5, 166.9, 150.3, 145.6, 145.5, 120.6, 113.2, 112.5, 86.0, 32.2,
25.4. HRMS (ESI) calcd for C11H11NO4Na [MþNa]þ: 244.0580;
found: 244.0579.
hydrofuran-3-yl)ethanone (4c). White solid; mp 144e146 ꢀC; 1H
NMR (400 MHz, CDCl3):
d
. 7.15 (d, 2H, J¼8.8 Hz, PheH), 6.84 (d, 2H,
J¼8.8 Hz, PheH), 6.62 (s, 1H, eOH), 4. 88 (d, 1H, J¼2 Hz, eCH), 3.79
(s, 3H, eOCH3), 2.52 (d, 3H, J¼1.6 Hz, eCH3), 1.99 (s, 1H, eCH3); 13
C
NMR (100 MHz, CDCl3): 193.9, 163.8, 159.3, 158.3, 130.2, 128.6, 117.7,
114.7, 55.3, 48.6, 29.8, 14.3. HRMS (ESI) calcd for C14H16NO4
[MþH]þ: 262.1074; found: 262.1078.
4.3.12. 2-(Hydroxyimino)-3-phenyl-2,3,6,7-tetrahydrobenzofuran-4
(5H)-one (4k). White solid; mp 159e161 ꢀC; 1H NMR (400 MHz,
DMSO-d6):
d 10.21 (s, 1H, eOH), 7.30e7.18 (m, 5H, PheH), 4.99 (s,
4.3.5. 1-(4-(4-Fluorophenyl)-5-(hydroxyimino)-2-methyl-4,5-dihy-
1H, eCH), 2.81e2.63 (m, 2H, eCH2), 2.27e2.24 (m, 2H, eCH2),
2.06e1.99 (m, 2H, eCH2); 13C NMR (100 MHz, DMSO-d6): 192.9,
174.2, 165.4, 136.9, 128.6, 128.4, 127.3, 118.2, 44.9, 36.9, 22.9, 21.4.
ESIMS: 266.2 [MþNa]þ.
drofuran-3-yl)ethanone (4d). White solid; mp 138e140 ꢀC; 1H NMR
(400 MHz, CDCl3):
d 7.77 (s, 1H, eOH), 7.17e7.14 (m, 2H, PheH),
7.04e6.99 (m, 2H, PheH), 4.90 (d, 1H, J¼1.6 Hz, eCH), 2.50 (d, 3H,
J¼2.0 Hz, eCH3), 2.01 (s, 3H, eCH3); 13C NMR (100 MHz, CDCl3):
193.5, 163.9, 161.1, 157.6, 134.1, 129.2, 129.1, 117.8, 116.2, 116.0, 48.6,
29.7, 14.4. HRMS (ESI) calcd for C13H13FNO3 [MþH]þ: 250.0874;
found: 250.0879.
4.3.13. 2-(Hydroxyimino)-3-(p-tolyl)-2,3,6,7-tetrahydrobenzofuran-
4(5H)-one (4l). White solid; mp 150e152 ꢀC; 1H NMR (400 MHz,
CDCl3):
d 7.18 (7.20) (s, 1H, eOH), 7.14e7.09 (m, 4H, PheH), 4.85
(5.10, s) (t, 1H, J¼2.0 Hz, eCH), 2.83e2.66 (m, 2H, eCH2),
2.44e2.32 (m, 2H, eCH2), 2.30 (s, 3H, eCH3), 2.20e2.11 (m, 2H,
eCH2); 13C NMR (100 MHz, CDCl3): 193.6 (193.1), 172.7 (172.9),
158.4, 137.4 (137.1), 134.4 (132.3), 129.6 (129.3), 127.4 (127.7), 118.4
(119.2), 45.6 (45.0), 36.9 (36.8), 23.1, 21.3, 21.1 (21.1). ESIMS: 280.1
[MþNa]þ.
4.3.6. 1-(4-(4-Chlorophenyl)-5-(hydroxyimino)-2-methyl-4,5-dihy-
drofuran-3-yl)ethanone (4e). White solid; mp 139e141oC; 1H NMR
(400 MHz, DMSO-d6):
d
10.28 (s, 1H, eOH), 7.41 (d, 2H, J¼8.4 Hz,
PheH), 7.24 (d, 2H, J¼8.4 Hz, PheH), 5.12 (d, 1H, J¼1.6 Hz, eCH),
2.45 (d, 3H, J¼1.6 Hz, eCH3), 2.03 (s, 3H, eCH3); 13C NMR (100 MHz,
DMSO-d6): 192.8, 163.8, 155.4, 138.9, 131.9, 129.4, 128.7, 117.4, 47.3,
29.6, 14.2. HRMS (ESI) calcd for C13H13ClNO3 [MþH]þ: 266.0578;
found: 266.0579.
4.3.14. 2-(Hydroxyimino)-3-(4-methoxyphenyl)-2,3,6,7-tetrahy-
drobenzofuran-4(5H)-one (4m). White solid; mp 158e159 ꢀC; 1H
NMR (400 MHz, CDCl3):
d
7.77 (s, 1H, eOH), 7.15 (d, 2H, J¼8.8 Hz,
4.3.7. 1-(4-(4-Bromophenyl)-5-(hydroxyimino)-2-methyl-4,5-dihy-
PheH), 6.84 (d, 2H, J¼8.8 Hz, PheH), 4.85 (5.10) (s, 1H, eCH), 3.77
(s, 3H, eOCH3), 2.80e2.65 (m, 2H, eCH2), 2.46e2.35 (m, 2H, eCH2),
2.20e2.13 (m, 2H, eCH2); 13C NMR (100 MHz, CDCl3): 193.5, 172.6,
159.0, 158.2, 129.7, 128.9, 128.6, 118.4, 114.2, 114.0, 55.3, 45.2, 36.9,
23.1, 21.3. ESIMS: 296.1 [MþNa]þ.
drofuran-3-yl)ethanone (4f). White solid; mp 140e143 ꢀC; 1H NMR
(400 MHz, DMSO-d6):
d
10.28 (s, 1H, eOH), 7.54 (d, 2H, J¼8.4 Hz,
PheH), 7.18 (d, 2H, J¼8.4 Hz, PheH), 5.11 (d, 1H, J¼1.2 Hz, eCH),
2.45 (d, 3H, J¼1.2 Hz, eCH3), 2.03 (s, 3H, eCH3); 13C NMR (100 MHz,
DMSO-d6): 193.3, 164.3, 155.8, 139.9, 132.1, 130.2, 120.9, 117.9, 47.9,
30.1, 14.7. HRMS (ESI) calcd for C13H13BrNO3 [MþH]þ: 310.0073;
found 310.0077.
4.3.15. 3-(4-Fluorophenyl)-2-(hydroxyimino)-2,3,6,7-tetrahy-
drobenzofuran-4(5H)-one (4n). White solid; mp 146e148 ꢀC; 1H
NMR (400 MHz, DMSO-d6):
d 10.46 (10.24) (s, 1H, eOH), 7.29e7.20
4.3.8. 1-(5-(Hydroxyimino)-2-methyl-4-(4-(trifluoromethyl)phenyl)-
4,5-dihydrofuran-3-yl)ethanone (4g). White solid; mp 140e141 ꢀC;
(m, 2H, PheH), 7.17e7.07 (m, 2H, PheH), 4.93 (5.03) (s, 1H, eCH),
2.81e2.64 (m, 2H, eCH2), 2.55e2.24 (m, 2H, eCH2), 2.13e2.02 (m,
2H, eCH2); 13C NMR (100 MHz, DMSO-d6): 193.5, 174.1, 163.0, 156.5,
135.5 (JCF¼3 Hz), 130.0, 129.9, 117.1, 115.7, 115.5, 44.5, 36.9, 23.0,
21.4. HRMS (ESI) calcd for C14H13FNO3 [MþH]þ: 262.0874; found:
262.0883.
1H NMR (400 MHz, DMSO-d6):
d 10.32 (s, 1H, eOH), 7.71 (d, 2H,
J¼8.4 Hz, PheH), 7.45 (d, 2H, J¼8.4 Hz, PheH), 5.23 (d, 1H, J¼1.6 Hz,
eCH), 2.47 (d, 3H, J¼1.2 Hz, eCH3), 2.07 (s, 3H, eCH3); 13C NMR
(100 MHz, DMSO-d6): 193.1, 164.6, 155.6, 145.1, 128.9, 126.1, 126.0,
118.0, 48.2, 30.1, 14.8. HRMS (ESI) calcd for C14H13F3NO3 [MþH]þ:
300.0842; found: 300.0854.
4.3.16. 3-(4-Chlorophenyl)-2-(hydroxyimino)-2,3,6,7-tetrahy-
drobenzofuran-4(5H)-one (4o). White solid; mp 156e158 ꢀC; 1H
4.3.9. 1-(4-(2-Chlorophenyl)-5-(hydroxyimino)-2-methyl-4,5-dihy-
NMR (400 MHz, DMSO-d6): d 10.50 (10.28) (s, 1H, eOH), 7.37 (7.34)
drofuran-3-yl)ethanone (4h). White solid; mp 148e150 ꢀC; 1H NMR
(d, 2H, J¼8.4 Hz, PheH), 7.23 (7.27) (d, 2H, J¼8.4 Hz, PheH), 4.95
(5.04) (s, 1H, eCH), 2.81e2.63 (m, 2H, eCH2), 2.3e4-2.31 (m, 2H,
eCH2), 2.11e2.00 (m, 2H, eCH2); 13C NMR (100 MHz, DMSO-d6):
193.5 (192.9), 174.3 (174.4), 165.0 (156.3), 138.4 (135.9), 132.2
(400 MHz, DMSO-d6):
d 10.28 (s, 1H, eOH), 7.47e7.44 (m, 1H,
PheH), 7.32e7.25 (m, 3H, PheH), 5.45 (s, 1H, eCH), 2.45 (d, 3H,
J¼1.2 Hz, eCH3), 2.02 (s, 3H, eCH3); 13C NMR (100 MHz, DMSO-d6):

M.-Y. Wu et al. / Tetrahedron 67 (2011) 2681e2688
2687
ꢀ
ꢀ
Garzino, F.; Meou, A.; Brun, P. Eur. J. Org. Chem. 2003, 1410; (e) Garzino, F.; Meou,
A.; Brun, P. Synthesis 2003, 598; (f) Chuang, C.-P.; Chen, K.-P.; Hsu, Y.-L.; Tsai, A.-I.;
Liu, S.-T. Tetrahedron 2008, 64, 7511; (g) Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
2. (a) Nair, V.; Vinod, A. U. Chem. Commun. 2000, 1019; (b) Ma, S.; Zhang, J. Chem.
Commun. 2000, 117; (c) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1, 1.
3. (a) Pollard, D. J.; Woodley, J. M. Trends Biotechnol. 2007, 25, 66; (b) Aleu, J.;
Bustillo, A. J.; Hernandez-Galan, R.; Collado, I. G. Curr. Org. Chem. 2006, 10, 2037;
(c) Panke, S.; Held, M.; Wubbolts, M. Curr. Opin. Biotechnol. 2004, 15, 272; (d)
Gotor, V. Org. Process Res. Dev. 2002, 6, 420; (e) Koeller, K. M.; Wong, C.-H.
Nature 2001, 409, 232; (f) Witayakran, S.; Gelbaum, L.; Ragauskas, A. J. Tetra-
hedron 2007, 63, 10958.
(131.9), 130.0 (130.3), 128.6 (128.8), 117.8 (116.9), 44.7 (44.3), 36. 9
(36.8), 23.0 (22.9), 21.4 (21.3). ESIMS: 300.0 [MþNa]þ.
4.3.17. 3-(4-Bromophenyl)-2-(hydroxyimino)-2,3,6,7-tetrahy-
drobenzofuran-4(5H)-one (4p). White solid; mp 170e173 ꢀC; 1H
NMR (400 MHz, DMSO-d6):
d 10.32 (10.27) (s, 1H, eOH), 7.52e7.46
(m, 2H, PheH), 7.22e7.16 (m, 2H, PheH), 4.93 (5.02) (s, 1H, eCH),
2.81e2.63(m, 2H,eCH2), 2.32e2.23 (m, 2H,eCH2), 2.12e2.01(m, 2H,
eCH2); 13C NMR (100 MHz, DMSO-d6): 193.5 (192.9), 174.3 (172.4),
156.2 (165.0),138.8 (136.4),131.8 (131.5),130.3 (130.7),120.7 (120.4),
116.9 (117.8), 44.7 (44.4), 36.9 (36.8), 23.0 (23.0), 21.4 (21.3). HRMS
(ESI) calcd for C14H13BrNO3 [MþH]þ: 322.0073; found: 322.0070.
4. (a) Wang, Q.-F.; Hou, H.; Hui, L.; Yan, C.-G. J. Org. Chem. 2009, 74, 7403; (b) Shi,
Y.; Huang, J.; Yang, Y.-F.; Wu, L.-Y.; Niu, Y.-N.; Huo, P.-F.; Liu, X.-Y.; Liang, Y.-M.
Adv. Synth. Catal. 2009, 351, 141; (c) Asikainen, M.; Krause, N. Adv. Synth. Catal.
2009, 351, 2305.
5. (a) Abele, E.; Abele, R.; Lukevics, E. Chem. Heterocycl. Compd. 2008, 44, 637; (b)
Abele, E.; Abele, R.; Lukevics, E. Chem. Heterocycl. Compd. 2008, 44, 769; (c)
Singh, S.; Bharti, N.; Mohapatra, P. P. Chem. Rev. 2009, 109, 1900; (d) Wang, K.-
W.; Qian, X.-H.; Cui, J.-N. Tetrahedron 2009, 65, 10377.
6. (a) Hrnciar, P.; Culak, I. Collect. Czech. Chem. Commun. 1984, 49, 1421; (b) Bar-
ange, D. K.; Raju, B. R.; Kavala, V.; Kuo, C.-W.; Tu, Y.-C.; Yao, C.-F. Tetrahedron
2010, 66, 3754; (c) Wang, G.-H.; Yuan, C.-Y. Heteroat. Chem. 1992, 3, 521.
7. (a) Li, C.-J.; Trost, B. M. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 13197; (b) Wong, C. H.;
Whitesides, G. M. Enzymes in Synthetic Organic Chemistry; Elsevier Science:
New York, 1994; (c) Woodley, J. M. Trends Biotechnol. 2008, 26, 321; (d) Kopp, F.;
Marahiel, M. A. Curr. Opin. Biotechnol. 2007, 18, 513; (e) Hult, K.; Berglund, P. Curr.
Opin. Biotechnol. 2003, 14, 395; (f) Bennett, C. S.; Wong, C. H. Chem. Soc. Rev. 2007,
36, 1227; (g) Tao, J.-H.; Xu, J.-H. Curr. Opin. Chem. Biol. 2009, 13, 43; (h) Hudlicky, T.;
Reed, J. W. Chem. Soc. Rev. 2009, 38, 3117.
4.3.18. 2-(Hydroxyimino)-3-(4-(trifluoromethyl)phenyl)-2,3,6,7-tet-
rahydrobenzofuran-4(5H)-one (4q). White solid; mp 154e156 ꢀC;
ꢁ
ꢁ
1H NMR (400 MHz, DMSO-d6):
d 10.32 (10.54) (s, 1H, eOH), 7.65 (d,
2H, J¼8.0 Hz, PheH) (7.68, d, J¼8.4 Hz), 7.49 (d, 2H, J¼8.0 Hz, PheH)
(7.45, d, J¼8.4 Hz), 5.08 (5.16) (s, 1H, eCH), 2.83e2.66 (m, 2H,
eCH2), 2.34e2.24 (m, 2H, eCH2), 2.13e2.01(m, 2H, eCH2); 13C NMR
(100 MHz, DMSO-d6): 193.2 (192.9), 174.6 (174.5), 164.9 (156.0),
144.0 (141.7), 129.4, 129.0, 125.8, 125.7, 125.6, 125.5, 117.7 (116. 8),
45.1 (44.8), 36.9 (36.8), 23.0 (22.9), 21.4 (21.3). HRMS (ESI) calcd for
C15H13F3NO3 [MþH]þ: 312.0842; found: 312.0845.
€
8. (a) Burda, E.; Hummel, W.; Groger, H. Angew. Chem., Int. Ed. 2008, 47, 9551; (b)
~
ꢀ
Pena, C.; Gonzalez-Sabín, J.; Rebolledo, F.; Gotor, V. Tetrahedron: Asymmetry
2008, 19, 751; (c) Zhang, Z.-Q.; McCallum, S. A.; Xie, J.; Nieto, L.; Corzana, F.;
Jimenez-Barbero, J.; Chen, M.; Liu, J.; Linhardtt, R. J. J. Am. Chem. Soc. 2008, 130,
12998; (d) Simons, C.; Hanefeld, U.; Arends, I. W. C. E.; Maschmeyer, T.; Shel-
don, R. A. Top. Catal. 2006, 40, 35; (e) Akai, S.; Tanimoto, K.; Kita, Y. Angew.
Chem., Int. Ed. 2004, 43, 1407; (f) Akai, S.; Naka, T.; Omura, S.; Tanimoto, K.;
Imanishi, M.; Takebe, Y.; Matsugi, M.; Kita, Y. Chem.dEur. J. 2002, 8, 4255; (g)
Lu, W.-Y.; Chen, P.-R.; Lin, G.-Q. Tetrahedron 2008, 64, 7822; (h) Wu, Q.; Xia, A.-
H.; Lin, X.-F. J. Mol. Catal. B: Enzym. 2008, 54, 76; (i) Baba, A.; Yoshioka, T. J. Org.
Chem. 2007, 72, 9541; (j) Azerad, R.; Buisson, D. Curr. Opin. Biotechnol. 2000, 11,
565; (k) Karmee, S. K.; Roosen, C.; Kohlmann, C.; Lutz, S.; Greiner, L.; Leitner, W.
Green Chem. 2009, 11, 1052; (l) Simons, C.; Hanefeld, U.; Arends, I. W. C. E.;
Maschmeyer, T.; Sheldon, R. A. Adv. Synth. Catal. 2006, 348, 471; (m) Eyrisch, O.;
Fessner, W. D. Angew. Chem., Int. Ed. 2003, 24, 1639; (n) Baer, K.; Krausser, M.;
4.3.19. 3-(2-Chlorophenyl)-2-(hydroxyimino)-2,3,6,7-tetrahy-
drobenzofuran-4(5H)-one (4r). White solid; mp 146e148 ꢀC; 1H
NMR (400 MHz, DMSO-d6):
d 10.46 (10.16) (s, 1H, eOH), 7.44e7.21
(m, 4H, PheH), 5.24 (5.32) (s, 1H, eCH), 2.81e2.64 (m, 2H, eCH2),
2.31e2.21 (m, 2H, eCH2), 2.12e2.01 (m, 2H, eCH2); 13C NMR
(100 MHz, DMSO-d6): 193.2 (192.6), 174.5 (174.6), 155.7, 136.5
(133.1), 130.1 (129.7), 129.4, (129.0), 127.8 (127.7), 116.3, 44.5, 36.8,
23.1 (23.0), 21.4 (21.4). HRMS (ESI) calcd for C14H13ClNO3 [MþH]þ:
278.0578; found: 278.0583.
€
Burda, E.; Hummel, W.; Berkessel, A.; Groger, H. Angew. Chem., Int. Ed. 2009, 48,
4.3.20. 3-(3-Chlorophenyl)-2-(hydroxyimino)-2,3,6,7-tetrahy-
9355; (o) Cacchi, S.; Cirilli, R.; Fabrizi, G.; Sgalla, S.; Macone, A.; Bonamore, A.;
Boffi, A. J. Mol. Catal. B: Enzym. 2009, 61, 184; (p) Sharma, U. K.; Sharma, N.;
Kumar, R.; Kumar, R.; Sinha, A. K. Org. Lett. 2009, 11, 4846; (q) Bitencourt, T. B.;
Nascimento, M. G. Green Chem. 2009, 11, 209; (r) Rios, M. Y.; Salazar, E.; Olivo,
H. F. J. Mol. Catal. B: Enzym. 2008, 54, 61.
drobenzofuran-4(5H)-one (4s). White solid; mp 154e156 ꢀC; 1H
NMR (400 MHz, DMSO-d6): d 10.31 (s, 1H, eOH), 7.32e7.26 (m, 3H,
PheH), 7.23e7.19 (m, 1H, PheH), 5.07 (s, 1H, eCH), 2.81e2.62 (m,
2H, eCH2), 2.26 (t, 2H, J¼1.6 Hz, eCH2), 2.06e1.99 (m, 2H, CH2); 13
C
9. (a) Kazlauskas, R. J. Curr. Opin. Chem. Biol. 2005, 9, 195; (b) Berglund, P.; Park, S.
Curr. Org. Chem. 2005, 9, 325; (c) Schmidt, D. M. Z.; Mundorff, E. C.; Dojka, M.;
Bermudez, E.; Ness, J. E.; Govindarajan, S.; Babbitt, P. C.; Minshull, J.; Gerlt, J. A.
Biochemistry (Moscow) 2003, 42, 8387; (d) Khersonsky, O.; Roodveldt, C.;
Tawfik, D. S. Curr. Opin. Chem. Biol. 2006, 10, 498; (e) Dijoux, G. H.; Elenkov, M.
M.; Spelberg, J. H. L.; Hauer, B.; Janssen, D. B. ChemBioChem 2008, 9, 1048; (f)
Kourist, R.; Bartch, S.; Fransson, L.; Hult, K.; Bornscheuer, U. T. ChemBioChem
2008, 9, 67; (g) Li, C.; Hassler, M.; Bugg, T. D. H. ChemBioChem 2008, 9, 71; (h)
Wu, W.-B.; Xu, J.-M.; Wu, Q.; Lv, D.-S.; Lin, X.-F. Adv. Synth. Catal. 2006, 348, 487;
(i) Xu, J.-M.; Zhang, F.; Liu, B.-K.; Wu, Q.; Lin, X.-F. Chem. Commun. 2007, 2078;
(j) Wu, W.-B.; Wang, N.; Xu, J.-M.; Wu, Q.; Lin, X.-F. Chem. Commun. 2005, 2348;
(k) Torre, O.; Alfonso, I.; Gotor, V. Chem. Commun. 2004, 1724; (l) Svedendahl,
M.; Hult, K.; Berglund, P. J. Am. Chem. Soc. 2005, 127, 7988; (m) Xu, J.-M.; Zhang,
F.; Liu, B.-K.; Wu, Q.; Lin, X.-F. Chem. Commun. 2007, 2078; (n) Kitazume, T.;
Ikeya, T.; Murata, K. J. Chem. Soc., Chem. Commun. 1986, 1331; (o) Kitazume, T.;
Murata, K.; Kokusho, Y.; Iwasaki, S. J. Fluorine Chem. 1988, 39, 75.
NMR (100 MHz, DMSO-d6): 192.9, 174.6, 164.9, 139.3, 133.2, 130.5,
128.4, 127.4, 127.1, 117.6, 44.5, 36.8, 23.0, 21.4. HRMS (ESI) calcd for
C14H13ClNO3 [MþH]þ: 278.0578; found: 278.0583.
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (Nos. 20725206, 20732004, 21001077 and
21021001) and Program for Changjiang Scholars and Innovative
Research Team in University (IRT0846) for financial support; M.Y.W.
also thanks the sustentation of Student Innovation Fund of Sichuan
University (Nos. 091061005). We also thank the Sichuan University
Analytical & Testing Center for NMR analysis.
10. (a) Li, C.; Feng, X.-W.; Wang, N.; Zhou, Y.-J.; Yu, X.-Q. Green Chem. 2008, 10, 616;
(b) Li, K.; He, T.; Li, C.; Feng, X.-W.; Wang, N.; Yu, X.-Q. Green Chem. 2009, 11,
777; (c) Feng, X.-W.; Li, C.; Wang, N.; Li, K.; Zhang, W.-W.; Wang, Z.; Yu, X.-Q.
Green Chem. 2009, 11, 1933.
11. Wu, M.-Y.; Wang, M.-Q.; Li, K.; Feng, X.-W.; He, T.; Wang, N.; Yu, X.-Q. Tetra-
Supplementary data
hedron Lett. 2011, 52, 679.
ꢂ
ꢂ
12. Compound 4a: C13H13O3, M¼231.24, T¼292 (2) K, wavelength¼0.71073 A,
Supplementary data include 1H and 13C NMR spectra of the
target compounds described in this article. Supplementary data
associated with this article can be found in the online version at
doi:10.1016/j.tet.2011.01.060. These data include MOL file and
InChiKey of the most important compound described in this article.
monoclinic, space group P 21/n, a¼10.905 (3) A, b¼9.222 (3) A, c¼11.873 (4) A,
ꢂ
ꢂ
o
3
ꢂ
ꢁ3
, m
a
¼90o,
b
¼95.10(2)o,
g
¼90 , V¼1189.4 (6) A , Z¼4, Dc¼1.291 mg cm
¼0.
092 mmꢁ1, F(000)¼488, crystal size 0.40ꢂ0.38 ꢂ 0.18 mm3, theta range for data
collection 2.43e25.53ꢀ, independent reflections 2212 [R(int)¼0.0107], reflections
collected 2480, refinement method full-matrix least-squares on F2, goodness-of-
fit on F2 1.043, final R indices [I>2
s
(I)], R1¼0.0637, wR2¼0.1155, R indices (all data)
R1¼0.1528, wR2¼0.1324, extinction coefficient 0.0095 (18), largest diff. peak and
ꢂꢁ3
hole 0.184 and ꢁ0.174 e A . 4k: C14H13O3, M¼243.25, T¼113 (2) K, wavelength¼0.
ꢂ
ꢂ
ꢂ
71073 A, monoclinic, space group C2/c, a¼20.188 (15) A, b¼7.184 (5) A, c¼17.027
References and notes
o
3
ꢂ
ꢁ3
,
(12) A,
m
a
¼90o,
b
¼101.062 (2)o,
g
¼90 , V¼2424 (3) A , Z¼8, Dc¼1.333 mg cm
ꢂ
¼0.094 mmꢁ1, F(000)¼1024, crystal size 0.20ꢂ0.12ꢂ0.10 mm3, theta range for
1. (a) Fraga, B. M. Nat. Prod. Rep.1992, 9, 217; (b) Merrit, A. T.; Ley, S. V. Nat. Prod. Rep.
1992, 9, 243; (c) Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katze-
nellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 3838; (d)
data collection 2.06e25.02ꢀ, reflections collected/unique 7781/2136 [R(int)¼0.
0557], refinement method full-matrix least-squares on F2, goodness-of-fit on F2 1.

2688
043, final R indices [I>2
0693, wR2¼0.1493, largest diff. peak and hole 0.184 and ꢁ0.174 e A . CCDC
769655 (4a) and 769656 (4k) contain the supplementarycrystallographic data for
this paper. These data can be obtained free of charge from The Cambridge crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
13. Branneby, C.; Carlqvist, P.; Hult, K.; Brinck, T.; Berglund, P. J. Mol. Catal. B: Enzym.
2004, 31, 123.
M.-Y. Wu et al. / Tetrahedron 67 (2011) 2681e2688
(I)], R1¼0.0560, wR2¼0.1424, R indices (all data) R1¼0. 14. (a) Carlqvist, P.; Svedendahl, M.; Branneby, C.; Hult, K.; Brinck, T.; Berglung,
s
ꢂꢁ3
P. ChemBioChem 2005, 6, 331; (b) Sevedendahl, M.; Hult, K.; Berglung, P. J.
Am. Chem. Soc. 2005, 127, 17988; (c) Priego, J.; Ortíz-Nava, C.; Carrillo-
ꢀ
Morales, M.; Lopez-Munguía, A.; Escalante, J.; Castillo, E. Tetrahedron 2009,
ꢀ
65, 536; (d) Strohmeier, G. A.; Sovic, T.; Steinkellner, G.; Hartner, F. S.;
Andryushkova, A.; Purkarthofer, T.; Glieder, A.; Gruber, K.; Griengl, H. Tet-
rahedron 2009, 65, 5663.