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fragmentor voltage of 20 V. Starting materials: alcohols
and aldehydes used as starting materials in Tables 1, 2,
and 4 were commercially available or known com-
pounds. Primary alcohols 1c, 1d, 1 f, 1j, 1k, 1l, and 1p
were obtained by reduction of the corresponding com-
Table 4. Bio-oxidation of secondary alcohols with laccase from TvL.
[
a]
[b]
mercial aldehyde with NaBH in MeOH; compound 1g
Entry RR’CHOH
Conditions
t
Yield of RCOR’
4
[
d] [%]
was obtained by reduction of the corresponding alde-
hyde with BH ·THF (5 equiv) in THF; 1h and 1p were ob-
tained from the corresponding carboxylic acids by reduc-
3
1
2
3
4
5
6
7
8
9
1
cyclohexanol (7a)
1-phenylethanol (7b)
7b
1-phenylpropanol (7c)
mandelic acid methyl ester (7d)
mandelic acid (7e)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
2
2
2
2
2
2
O, RT
O, RT
O, pH 4.5, 0.1m, RT
O, RT
O, RT
O, pH 4.5, 0.1m, RT
O, RT
O, acetone 10%
O, RT
O, RT
O, RT
6
6
7
7
80
>99
77
tion with borane–dimethylsulfide (BH · Me S) in Et O; 1s
3
2
2
>99
was obtained by reduction from 1b with H2 on Pd/C.
Racemic 2-arylpropanols 4a–f in Table 3 were obtained
by BH ·Me S reduction of racemic commercial acids,
0.1 >99
8
8
7
8
7
7
7
7
7
66
60
61
50
12
0
42
0
0
3
2
7e
enantiomerically pure (S)-4a–f were obtained by enan-
diphenylmethanol (7 f)
lactic acid ethyl ester (7g)
cis-2-methoxycyclohexanol (7h)
trans-2-methoxycyclohexanol (7h)
cis-2-methylcyclohexanol (7i)
trans-2-methylcyclohexanol (7i)
(À)-menthol (7j)
tioselective biocatalysis starting from the corresponding
[19]
racemic aldehydes. Secondary alcohols 7a, 7b, 7 f, 7i,
0
and 7j were obtained by LiAlH reduction from the cor-
4
1
1
responding ketone in Et O; 7d was obtained by acid-cat-
1
1
1
2
3
4
O, RT
O, RT
O, RT
2
alyzed esterification of 7e and MeOH.
Procedure A: Experimental oxidation procedure for com-
pounds reported in Tables 1 and 2. TEMPO (0.1 mmol)
and the enzyme (5 mg) were added to a stirred solution
of the alcohol or aldehyde (0.5 mmol) in the appropriate
[a] Procedure C. Substrate (0.5 mmol), enzyme (5 mg), mediator TEMPO (20 mol%),
solvent (6 mL), oxygen bubbled in a closed vial. [b] Yield calculated from NMR spec-
troscopic analysis of the crude reaction mixture.
greener catalysts; thus avoiding the use of harsh organic and
inorganic oxidants, even in catalytic amounts. From this point
of view, the combination of two green and efficient catalysts,
such as the commercially available enzyme laccase TvL and the
stable free radical TEMPO, offers great opportunities. We wid-
ened the range of applicability by exploring the oxidation, in
water, of some primary alcohols to the corresponding carbox-
ylic acids or aldehydes and of selected secondary alcohols to
ketones.
Moreover, we succeeded in an important application: the
development of the laccase-mediator system (LMS) oxidation
of 2-arylpropanols (profenols) to the corresponding 2-arylpro-
Figure 2. Chemoenzymatic route to enantiomerically pure arylpropanoic
acids. HLADH=horse liver alcohol dehydrogenase, NADH/
NAD =nicotinamide adenine dinucleotide redox couple.
pionic acids (profens), in high yields and with complete reten-
tion of configuration.
+
Thus, the chemoenzymatic reduction of arylpropanals we al-
[19a,b]
ready successfully developed through the DKR process,
solvent (6 mL) in a 10 mL vial with a screw cap, and then O was
bubbled for 30 s. The solution was stirred on an orbital shaker at
2
coupled with the chemoenzymatic oxidation reported herein,
depict a more environmentally friendly alternative route to the
synthesis of enantiomerically pure profens and contributes to
improved sustainability in the synthesis of this important class
of drugs (Figure 2).
1
50 rpm, retained, and the reaction was monitored by TLC. When
the reaction was complete, the aqueous solution was kept at 08C
and adjusted to pH 2 by slow addition of aqueous HCl (1n). The
acid aqueous phase was then extracted with CH
Cl (3ꢁ5 mL). The
2
2
collected organic phases were dried over Na SO , filtered, concen-
2
1
4
19
trated in vacuo, and analyzed by HPLC and H and F NMR for al-
1
9
cohols 1h and 1i; F NMR for 1q. In the case of compounds 1j,
k, 1l, 2j, and 2k, the crude aqueous phase was directly lyophi-
Experimental Section
1
General: Commercial reagents were used as received without addi-
1
lized and analyzed by H NMR spectroscopy. Spectroscopic data
were consistent with those reported in the literature and in the
NMR spectroscopy database (Reaxys and AIST SDBS).
1
19
tional purification. H and F NMR spectra were recorded with an
INOVA 400 instrument with a 5 mm probe. TLC: Merck 60 F254
plates. HPLC-MS: Agilent Technologies HP1100 instrument,
equipped with a ZOBRAX-Eclipse XDB-C8 Agilent Technologies
Procedure B: Experimental procedure for the synthesis of 2-arylpro-
pionic acids (profens; Table 3): TEMPO (0.2 mmol) and the enzyme
20 mg) were added to a stirred solution of the alcohol 4a–f
À1
column; mobile phase: H O/CH CN, 0.4 mLmin , gradient from 30
2
3
(
(
to 80% of CH CN in 8 min, 80% of CH CN until 25 min, coupled
3
3
1 mmol) in the appropriate solvent (20 mL) in a 50 mL balloon. O2
with an Agilent Technologies MSD1100 single-quadrupole mass
was bubbled for 30 s and then the balloon was closed with a cap.
The solution was stirred on an orbital shaker at 150 rpm and kept
at room temperature. The reaction course was monitored by TLC.
spectrometer, full-scan mode from m/z 50 to 2600, scan time of
0
.1 s in positive ion mode, ESI spray voltage of 4500 V, nitrogen
À1
gas of 35 psi (1 psi=6894.7 Pa), drying gas flow of 11.5 mLmin ,
ꢀ
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2014, 7, 2684 – 2689 2688