10.1002/cctc.201801760
ChemCatChem
COMMUNICATION
Hemoglobin: a new biocatalyst for the synthesis of 2-substituted
benzoxazoles via oxidative cyclization
Fengxi Li [a], Zhengqiang Li [a], Xuyong Tang [a], Xinyu Cao [a], Chunyu Wang [b], Jialin Li [a], Lei Wang *[a]
Abstract: Efficient and mild synthesis of a series of 2-substituted
benzoxazoles via oxidative cyclization catalyzed by hemoglobins
reported here for the first time. Satisfactory yields (84%-97%) and
mild reaction conditions make this method highly viable for practical
applications.
Scheme 1. Synthesis of 2-substituted benzoxazoles catalyzed by hemoglobin
Initially, synthesis of 2-phenylbenzoxazole (2a) via oxidative
cyclization of phenolic imine 1a (X: phenyl) was adopted as the
model reaction. Our investigations began by testing the catalytic
2-Substituted benzoxazoles are important scaffolds due to their
occurrence within a wide range of biologically active natural
[1-3]
products and pharmaceutical agents
.
Consequently,
ability of several hemoproteins in the presence of tert-butyl
hydroperoxide (TBHP) as an inexpensive and mild oxidant agent.
As shown in Table 1, all tested hemoproteins exhibited oxidative
cyclization catalytic abilities that generated product yields within
a broad range (Entries 1-5). Notably, hemoglobins exhibited
higher catalytic performance than other hemoproteins, reaching
the highest yield observed of 90% (Entry 5) when hemoglobin
from Vitreoscilla (VHb) was used as catalyst (heme
concentration: 0.05 mol%, 8 mg). Conversely, free hemin
significant efforts have been focused on the development of new
synthetic procedures for generation of these heterocyclic
compounds. 2-Substituted benzoxazoles are generally
synthesized by the oxidative cyclization of phenolic imines
mediated by strong oxidants working in concert with transition
[4-10]
metal catalysts, such as Pd, Cu, Fe, Ni, Ag, and Ru
.
However, toxic metal catalysts, strong and expensive oxidants,
high catalyst loading, and high reaction temperatures are
required for the preparation of 2-substituted benzoxazoles in
most cases. Therefore, a milder and more efficient method to
prepare these compounds would be highly desirable.
Biocatalysis is an important tool used in environmentally friendly
and sustainable processes for the synthesis of organic
molecules [11]. Mining for new types of organic reactions that can
be catalyzed by proteins has drawn much attention in recent
years and has dramatically expanded the application of proteins
within the field of organic chemistry [12-18]. Hemoproteins are
promising biocatalysts for synthetic applications that incorporate
generated
a poor yield (29%) under the same reaction
conditions even when the hemin dosage was increased to 5
mol% (Entry 6). Apo-VHb (VHb without a heme cofactor) could
not catalyze the reaction in the presence of TBHP (Entry 7),
while no product was observed in the absence of either VHb or
TBHP (Entries 8 and 9, respectively). These results indicate that
the reaction occurred at the heme center of hemoglobin and that
ferric hemoglobin is the catalytically active form of the protein.
Moreover, no product could be obtained using denatured VHb
indicated that the specific active conformation of hemoglobin is
important for catalytic activity (Entry 10). Furthermore, the yield
increased with the use of increasing amount of oxidant (0.1-1
equiv.), although excessive oxidant did not obviously enhance
yield above a maximal level. It is noteworthy that the dosage of
oxidant (1 equiv.) in this process was distinctly lower than those
reported previously. FeCl3, a general transition metal-catalyst,
was also used to catalyze this reaction (Entry 14), and its
catalytic performance was much worse than that of VHb. Taken
together, the aforementioned results demonstrate that this
hemoglobin-catalyzed method has great potential for industrial
oxidative
reactions
(hydroxylation,
epoxidation,
and
sulfoxidation) and carbene-mediated transformations (olefin
cyclopropanation, carbene insertion, and aldehyde olefination)
[19-25]. Hemoglobin, a necessary vehicle for oxygen transport in
the body, has been also used in several organic reactions as a
stable and abundant biocatalyst, such as lipid peroxidation,
aniline hydroxylation, oxidation of hydrogen sulfide and pyrene
[26-30]. Considering the above-mentioned points and our previous
hemoglobin studies [31-32], herein we report an efficient and mild
hemoglobin-catalyzed oxidative cyclization for the synthesis of
2-substituted benzoxazoles (Scheme 1). To the best of our
knowledge, synthesis of 2-substituted benzoxazoles catalyzed
by protein has not yet been reported. Furthermore, this
hemoglobin-catalyzed reaction within the oxidative cyclization
process extends the toolbox of currently available biocatalytic
strategies.
applications.
Table 1. Synthesis of 2- phenylbenzoxazole 2a catalyzed by hemoprotein a
TBHP
(mmol)
Isolated yield
Entry
Catalyst
(%)
42
71
1
2
Horseradish peroxidase
Myoglobin from equine heart
1
1
3
Hemoglobin from porcine blood
1
81
4
5
6
7
8
9
10
11
12
13
14
Hemoglobin from bovine blood
1
1
1
1
0
1
1
0.1
0.5
1.5
1
85
93
29
[a]Dr. F. Li, Prof. Z. Li, Dr. X. Tang, Dr. X. Cao, Bs. J. Li, Prof. L. Wang
Key Laboratory of Molecular Enzymology and Engineering of Ministry of Education
School of Life Sciences
Jilin University
Changchun 130023 (P. R. China)
E-mail: w_lei@jlu.edu.cn
[b]Dr. C. Wang
State Key Laboratory of Supramolecular Structure and Materials
Jilin University
Changchun 130023 (P. R. China)
Hemoglobin from Vitreoscilla (VHb)
Hemin b
Apo VHb
VHb
ND c
ND
ND
ND
7
None
denatured VHb d
VHb
VHb
47
95
27
VHb
FeCl3
b
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