Biocatalytic promiscuity of lipase in chemoselective oxidation of aryl alcohols/acetates: a unique synergism of cal-b and [hmim]br for the metal-free h2o2 activation

Article abstract of DOI:10.1021/ol901917e

A unique synergistic combination of lipase and Ionic liquid [hmlm]Br Is reported for metal-free H₂O₂ activation, which is the first example of blocatalytlc promiscuity of CAL-B for chemoselectlve oxidation of aryl alcohols/acetates. The catalytic system exhibits excellent functional group compatibility under neutral conditions besides reusability up to ten cycles thereby making the process economically and environmentally viable.

Full text of DOI:10.1021/ol901917e

ORGANIC
LETTERS
2
009
Vol. 11, No. 21
846-4848
Biocatalytic Promiscuity of Lipase in
Chemoselective Oxidation of Aryl
Alcohols/Acetates: A Unique Synergism
of CAL-B and [hmim]Br for the
4
†
Metal-Free H O Activation
2
2
Upendra K. Sharma, Nandini Sharma, Rakesh Kumar, Rajesh Kumar, and
Arun K. Sinha*
Natural Plant Products DiVision, Institute of Himalayan Bioresource Technology,
CSIR, Palampur-176061 (H.P.), India
aksinha08@rediffmail.com
Received August 18, 2009
ABSTRACT
2 2
A unique synergistic combination of lipase and ionic liquid [hmim]Br is reported for metal-free H O activation, which is the first example of
biocatalytic promiscuity of CAL-B for chemoselective oxidation of aryl alcohols/acetates. The catalytic system exhibits excellent functional
group compatibility under neutral conditions besides reusability up to ten cycles thereby making the process economically and environmentally
viable.
1
3
The recent development in the biocatalytic promiscuity of
at laboratory and industrial scales. Conventionally, oxidation
enzymes has greatly extended their application in organic
is brought up by utilizing stoichiometric/superstoichiometric
amounts of inorganic oxidants which are incongruous to
the principles of Green Chemistry.
4
syntheses such as various lipase catalyzed C-C, C-N, and
2
C-S bond formations. In this Letter, we have assessed the
catalytic activity of lipase for oxidation.
2 2
Currently, the use of H O as a terminal oxidant has
Oxidation of alcohols to corresponding carbonyl com-
pounds is an important and challenging transformation both
received great attention from both economic and environ-
mental viewpoints. This reagent has, however, high activation
energy, making catalysis necessary, and thus many systems
5
†
IHBT Communication No. 1020.
(
1) (a) Bornscheuer, U. T.; Kazlauskas, R. J. Angew. Chem., Int. Ed.
2 2
have been developed for H O activation using either
2
2
2
004, 43, 6032–6040. (b) Li, C.; Hassler, M.; Bugg, T. D. H. ChemBioChem
008, 9, 71–76. (c) Hult, K.; Berglund, P. Trends Biotechnol. 2007, 25,
31–238.
(3) (a) Jones, C. W. Application of Hydrogen Peroxide and DeriVatiVes;
RSC: Cambridge, UK, 1999. (b) Sheldon, R. A.; Kochi, J. K. Metal
Catalyzed Oxidations of Organic Compounds; Academic Press: London,
UK, 1981.
(
2) (a) Svedendahl, M.; Hult, K.; Berglund, P. J. Am. Chem. Soc. 2005,
1
27, 17988–17989. (b) Branneby, C.; Carlqvist, P.; Magnusson, A.; Hult,
K.; Brinck, T.; Berglund, P. J. Am. Chem. Soc. 2003, 125, 874–875. (c)
Torre, O.; Alfonso, I.; Gotor, V. Chem. Commun. 2004, 1724–1725. (d)
Li, C.; Feng, X. W.; Wang, N.; Zhou, Y. J.; Yu, X. Q. Green Chem. 2008,
(4) (a) Hudlicky, M. Oxidations in Organic Chemistry; ACS Monograph
no. 186; American Chemical Society: Washington, DC, 1990. (b) Cainelli,
G.; Cardillo, G. Chromium Oxidants in Organic Chemistry; Springer: Berlin,
Germany, 1984.
1
0, 616–618. (e) Lou, F. W.; Liu, B. K.; Wu, Q.; Lv, D. S.; Lin, X. F. AdV.
Synth. Catal. 2008, 350, 1959–1962. (f) Li, K.; He, T.; Li, C.; Feng, X. W.;
Wang, N.; Yu, X. Q. Green Chem. 2009, 11, 777–779.
(5) Marinescu, L.; Molbach, M.; Rousseau, C.; Bols, M. J. Am. Chem.
Soc. 2005, 127, 17578–17579.
10.1021/ol901917e CCC: $40.75
Published on Web 09/29/2009
 2009 American Chemical Society

6
transition metals or organocatalysts. However, most of these
Mechanistically, it is presumed that the hydroxy group of
alcohol interacts with the imidazolium cation of IL (Scheme
1) resulting in polarization of the C-O bond followed by
methods suffer from limitations such as use of strong acidic/
basic conditions, lower yields, and laborious workup pro-
cedures besides poor recovery of expensive metal catalysts.
Consequently, in an endeavor to develop more efficient
processes, much attention has been paid by chemists to
design new metal based ligands while the inherent advan-
tages of enzymes as catalysts has remained largely over-
looked except for a few reports. For the past few years, the
9
c
6b
Scheme 1
.
A Plausible Mechanism for Lipase-IL Catalyzed
Oxidation of Aryl Alcohols with H
2 2
O
7
use of room temperature ionic liquids (ILs) for transforma-
tions with enzymes is gaining attraction due to their
versatility, stability, and environmental credentials compared
8
to conventional solvents.
Recently, our group has reported the use of neutral ILs
9
for expediting various organic reactions. Encouraged by the
results we were particularly interested in exploring the
potential of IL and a biocatalyst for alcohol oxidations with
H
O
2 2
. Herein, we report a highly efficient and recyclable
combination of Candida antarctica lipase B (CAL-B) and
neutral ionic liquid [hmim]Br for metal-free H activation
2 2
O
in the chemoselective oxidation of aryl alcohols/acetates into
carbonyls.
Initial investigation of CAL-B and [hmim]Br catalyzed
oxidation was carried out with 4-methoxyphenylpropanol
(
2 2
1a) as substrate with 30% H O at 40 °C for 16 h thereby
attack of H
oxyanion hole of lipase
product along with the release of water.
Under the following conditionss0.25 mmol of alcohol,
2 2
O . Subsequent charge stabilization by an
providing 4-methoxyphenylpropanone (1b) in 90% yield.
Increasing the temperature from 40 to 60 °C significantly
brought down the reaction time from 16 to 8 h. After
systematic optimization of reaction temperature, the amount
of oxidant, and effect of different solvents, lipases, ILs, and
oxidants were established for the oxidation of 1a (see the
Supporting Information, Tables S1 and S2). The different
lipases (immobilized or lyophilized powder) furnished almost
a similar effect on yield, but with respect to stability and
reusability; CAL-B is markedly preferred. Interestingly,
replacement of [hmim]Br with acidic, basic, or even other
neutral ILs provided 1b in low yield wherein the type of
anion (Br vs. Cl ) in the IL plays a decisive role. A very
trace conversion was observed in the presence of lipase or
IL alone even if the reaction mixture was stirred for 5 days
at 60 °C. Also, control experiments with inactivated
enzymes, solid support, and bovine serum albumin did not
show appriciable yields (see the Supporting Information,
Table S1), clearly indicating the role of a lipase-IL
2
a-c,7a,10
results in the formation of
50 mg of CAL-B, 1 mL of [hmim]Br, 4 equiv of 30% H
2 2
O ,
6
0 °Csvarious 1° and 2° benzylic alcohols, without deac-
tivation by halogen- and nitrogen- substituents, were con-
verted into their corresponding carbonyls in high to moderate
yields within 8 to 12 h (Tables 1 and 2). In the case of 2°
alcohols the oxidation proceeded without discrimination
between R and S forms (Supporting Information, Figure S3).
Compared to benzylic and allylic alcohols, aliphatic
alcohols showed no conversionswherein oxidation of an
equimolar mixture of 1a and octanol provided only 1b, with
octanol being unreactedsdemonstrating the remarkable
chemoselectivity for the oxidation of benzyl alcohols over
aliphatic analogues (see the Supporting Information, Table
S3).
-
-
2c
Subjecting acetylated derivatives of 1° and 2° alcohols to
oxidation resulted in simultaneous hydrolysis and oxidation
which is an additional benefit of the developed protocol
2 2
combination as an H O activator.
(
6) (a) Kon, Y.; Usui, Y.; Sato, K. Chem. Commun. 2007, 4399–4400.
(Table 1, entries 12-15; Table 2, entry 7).
(
b) Zhang, S.; Zhao, G.; Gao, S.; Xi, Z.; Xu, J. J. Mol. Catal. A: Chem.
2
008, 289, 22–27. (c) Jiang, N.; Ragauskas, A. J. Tetrahedron Lett. 2005,
6, 3323–3326. (d) Hida, T.; Nogusa, H. Tetrahedron 2009, 65, 270–274.
In the case of 1° benzylic alcohols, formation of acid
5-10%) was also observed in some cases. To address this,
4
(
(
e) Ming-Lin, G.; Hui-Zhen, L. Green Chem. 2007, 9, 421–423. (f) Shi, F.;
we conveniently replaced H
O
2 2
2 2
with a urea-H O adduct
Tse, M. K.; Beller, M. AdV. Synth. Catal. 2007, 349, 303–308. (g) Muzart,
J. Tetrahedron 2003, 59, 5789–5816.
(UHP) without affecting the efficiency of the process,
although urea was generated as an additional byproduct.
As a demonstration of the utility of this catalytic protocol
for the complex organic compounds and natural products,
we investigated the oxidation of podophyllotoxin, a well-
known natural anticancer drug, and achieved podophyllo-
(
7) (a) Svedendahl, M.; Carlqvist, P.; Branneby, C.; Allner, O.; Frise,
A.; Hult, K.; Berglund, P.; Brinck, T. ChemBioChem 2008, 9, 2443–2451.
(
b) R ´ı os, M. Y.; Salazar, E.; Olivo, H. F. Green Chem. 2007, 9, 459–462.
(
8) (a) van Rantwijk, F.; Sheldon, R. A. Chem. ReV. 2007, 107, 2757–
2
4
785. (b) Park, S.; Kazlauskas, R. J. Curr. Opin. Biotechnol. 2003, 14,
32–437.
(
9) (a) Sharma, A.; Kumar, R.; Sharma, N.; Kumar, V.; Sinha, A. K.
AdV. Synth. Catal. 2008, 350, 2910–2920. (b) Sharma, A.; Sharma, N.;
Kumar, R.; Sharma, U. K.; Sinha, A. K. Chem. Commun. 2009, 5299–
5
301. (c) Kumar, R.; Sharma, A.; Kumar, V.; Sinha, A. K. Eur. J. Org.
(10) Khersonsky, O.; Roodveldt, C.; Tawfik, D. S. Curr. Opin. Chem.
Chem. 2008, 5577–5582.
Biol. 2006, 10, 498–508.
Org. Lett., Vol. 11, No. 21, 2009
4847

Table 1. CAL-B/[hmim]Br Catalyzed Oxidation of 2° Alcohols
Scheme 2. Oxidation of Podophyllotoxin to Podophyllotoxon
a
2 2
and Their Derivatives with H O
catalytic system (CAL-B and [hmim]Br). While the recov-
ered catalysts retained high activity for ten cycles, yield
decreased below 85% afterward with certain minor side
products, which was compensated by adding a few mil-
ligrams of fresh lipase and 2-3 drops of IL (Scheme 3).
Scheme 3. Recyclability Study of Catalytic System
a
Reaction conditions: 0.25 mmol of substrate, 50 mg of CAL-B, 1 mL
b
of IL, 4 equiv of H
to standard and product identification by GC-MS. Isolated yield in
parentheses. 6 equiv of H O .
2 2
2 2
O , at 60 °C. Yield based on HPLC with comparison
c
d
In conclusion, we have successfully developed a highly
efficient process for the chemoselective oxidation of a wide
range of aryl alcohols/acetates using CAL-B and cheaper
IL [hmim]Br whose significant features are the following:
a
Table 2. Lipase-IL Catalyzed Oxidation of 1° Alcohols by
or by UHP
2 2
H O
(
(
(
2 2
i) metal-free activation of H O , (ii) catalyst recyclability,
iii) waste-free process, (iii) easy isolation of the product,
iv) high efficiency under relatively mild conditions, (v) and
b
yield (%)
compatibility with base- and acid-sensitive substrates. To the
best of our knowledge, this is the first report on lipase-IL
entry
R
1
R
2
time (h)
H
O
2 2
UHP
2 2
catalyzed oxidation with H O .
c
c
1
2
3
4
5
6
7
8
9
a
3,4-(MeO)
2
C
6
H
3
H
H
H
H
H
H
8
8
8
8
24
8
8
8
24
80(10) 84(t)
c
c
c
4-MeOC
2-ClC
2-MeC
4-MeOC
6
H
4
75(8)
78(5)
68(5)
nd
77(t)
81(t)
70
c
c
Acknowledgment. U.K.S., N.S., and R.K. are indebted
to CSIR, New Delhi, for the award of research fellowships.
The authors gratefully acknowledge the Director, IHBT
Palampur, for his kind cooperation and encouragement as
well as project MLP 0025 for financial assistance.
6
H
4
6
H
4
6
H
4
CH
2
nd
d
3,4-OCH
3,4-OCH
2
OC
OC
6
H
3
76
65
78 [71]
65
2
6
H
3
COCH
H
3
C H
6 5
CHdCH
2
55
50
n-octanol
nd
nd
Supporting Information Available: Complete experi-
mental details and HPLC and spectroscopic data of com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Reaction conditions: 0.25 mmol of substrate, 50 mg of CAL-B, 1 mL
b
of IL, 4 equiv of H O or UHP, at 60 °C. Yield on the basis of HPLC
conversion. Yield of acid (1b′-3b′) in parentheses. isolated yield in
sqaure brackets; t ) traces.
2 2
c
d
OL901917E
1
1
toxon in 60% yield with high product selectivity (more
than 90%; Scheme 2).
(
11) (a) Kamal, A.; Damayanthi, Y. Bioorg. Med. Chem. Lett. 1997, 7,
57–662. (b) Li, Q. R.; Zhangi, T. H.; Ward, R. S. Chin. Chem. Lett. 2001,
12, 1057–1060.
Having established the optimum conditions and scope for
the reaction, we proceeded to assess the recyclability of the
6
4848
Org. Lett., Vol. 11, No. 21, 2009