Catalytic bio-chemo and bio-bio tandem oxidation reactions for amide and carboxylic acid synthesis

Article abstract of DOI:10.1039/c4gc01321b

A catalytic toolbox for three different water-based one-pot cascades to convert aryl alcohols to amides and acids and cyclic amines to lactams, involving combination of oxidative enzymes (monoamine oxidase, xanthine dehydrogenase, galactose oxidase and laccase) and chemical oxidants (TBHP or CuI(cat)/H₂O₂) at mild temperatures, is presented. Mutually compatible conditions were found to afford products in good to excellent yields. This journal is

Full text of DOI:10.1039/c4gc01321b

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Catalytic bio–chemo and bio–bio tandem
oxidation reactions for amide and
Cite this: DOI: 10.1039/c4gc01321b
carboxylic acid synthesis†
Received 13th July 2014,
Accepted 15th August 2014
Beatrice Bechi,‡a Susanne Herter,‡a Shane McKenna,b Christopher Riley,b
DOI: 10.1039/c4gc01321b
Silke Leimkühler,c Nicholas J. Turner*a and Andrew J. Carnell*b
www.rsc.org/greenchem
A
catalytic toolbox for three different water-based one-pot
cascades to convert aryl alcohols to amides and acids and cyclic
amines to lactams, involving combination of oxidative enzymes
(monoamine oxidase, xanthine dehydrogenase, galactose oxidase
and laccase) and chemical oxidants (TBHP or CuI(cat)/H2O2) at
mild temperatures, is presented. Mutually compatible conditions
were found to afford products in good to excellent yields.
Amides, lactams and carboxylic acids are ubiquitous functional
groups in organic chemistry found in natural products, pharma-
ceuticals and a wide range of synthetic polymers. Amide bond
formation can be achieved using activated carboxylic
acid derivatives or an increasingly elaborate range of coupling
reagents.1 However, these methods can be expensive and
involve the use of toxic and atom inefficient reagents, increas-
ing their environmental E factor.2 Due to their widespread
application in synthetic organic chemistry, there is a great deal
of interest in new sustainable and environmentally benign
alternatives for generating both carboxylic acids3 and amides.4
The approach described here exploits the increasing range
of oxidative enzymes that can work under ambient conditions
in aqueous buffer and use aerial oxygen as the electron accep-
tor, hence representing an ideal alternative to traditional oxi-
dants. The ability to tune enzyme activity and substrate
specificity using protein engineering and directed evolution
strategies4b,5 has resulted in the creation of biocatalysts that
can be used in vitro in catalytic cascade pathways on unnatural
substrates.6 This approach allows combination of enzymes
Scheme 1 Catalytic bio–chemo and bio–bio tandem oxidations.
(bio–bio)6a and of enzymes with chemocatalysts (bio–
chemo),6a,7 extending the range of sustainable chemistry poss-
ible. In this paper, we demonstrate three new one-pot tandem
cascade reactions using combinations of enzymes and chemo-
catalysts for: oxidative coupling of aryl alcohols with amines to
give amides (cascade 1), conversion of aryl alcohols to carb-
oxylic acids (cascade 2) and transformation of cyclic amines to
lactams (cascade 3) (Scheme 1).
Our objectives were realised by combination of enzymes and
chemocatalysts that can work cooperatively under mild aqueous
conditions, avoiding the use of organic solvents, hazardous
and toxic chemicals as well as heavy metal catalysts associated
with a minimisation of energy and waste production.
aSchool of Chemistry, Manchester Institute of Biotechnology, University of
Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
E-mail: nicholas.turner@manchester.ac.uk; Fax: +44 (0)161 2751311;
Tel: +44 (0)161 3065173
bDepartment of Chemistry, University of Liverpool, Crown Street, Liverpool, L69 7ZD,
UK. E-mail: acarnell@liv.ac.uk; Fax: +44 (0)151 7943500; Tel: +44 (0)151 7943534
cInstitute of Biochemistry and Biology, University of Potsdam, Maulbeerallee 2,
D-14476 Potsdam, Germany. E-mail: sleim@uni-potsdam.de; Fax: +44 331/977-5128;
(1) Alcohols to aldehydes to amides
(cascade 1)
Tel: +49 331/977-5603
†Electronic supplementary information (ESI) available: HPLC data and NMR
spectra. See DOI: 10.1039/c4gc01321b
Recently, there has been a great deal of interest in synthetic
organic chemistry in developing catalytic oxidative amidation
‡These authors contributed equally to the work.
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reactions to couple aldehydes with amines. The reactions are
thought to proceed by oxidation of the imine or hemi-aminal
intermediates and are catalysed by transition metals (Rh,
Ru, Pd, Fe),8 N-heterocyclic carbenes,9 Cu,10 Cu–Ag11 and
lanthanides.12 Stoichiometric terminal oxidants required are
tert-butyl hydroperoxide (TBHP) or aqueous 70% TBHP
(T-HYDRO), H2O2, or oxone. In some cases, it is possible to
start with the alcohol, which undergoes oxidation to the
aldehyde in situ.4c,13,14 Yields for oxidative amidation of benz-
aldehydes are generally good (46–96%), although aliphatic and
heteroaryl aldehydes give lower yields and require higher reac-
tion temperatures. Thus, mild catalytic conditions that can
run at ambient temperature without the need to use amine
HCl salts10 or a large excess of the aldehyde would be an attrac-
tive tool for future chemistry.
Table 1 Bio–chemo tandem conversion of alcohols 1 to amides 3 and 4
Conversion to amide 3/4 [%]
Alcohol 1
GOase M3–5-TBHPa
Laccase-TEMPO-TBHPb
1a
1b
1c
1d
1e
1f
1g
1h
1i
3a
3b
3c
3d
3e
3f
3g
3h
3i
100
87
63
26
21
14
4
91 (91)c
89 (57)
90 (60)
86 (73)
32
75 (53)
69
26 (22)
9
We have previously developed variants of F. graminearum
galactose oxidase (GOase), such as GOase M3–5, that show a
remarkable ability to oxidise secondary and primary benzylic
alcohols to their respective ketone and aldehyde products and
H2O2 as by-product.15 The combination of laccase from
T. versicolor with the redox mediator TEMPO16 can be
employed to achieve the same transformations. We now report
the application of both biocatalysts in a one-pot tandem reac-
tion with different amines (5 eq.) and TBHP (1.2 eq.) to
convert benzylic alcohols to aldehydes (1st step) and sub-
sequently to the tertiary amides (2nd step) (Table 1, Tables S1
and S2†). The reactions were run sequentially as one-pot-two-
step processes since the GOase M3–5 and laccase were found to
be sensitive or inhibited by the amines or TBHP required in
the second step. As GOase produces within its catalytic cycle
one mole H2O2 per mole of alcohol substrate being oxidised,
we attempted to use this natural in situ generated by-product
in the amide formation step in place of addition of TBHP. The
results, however, suggested the amount of enzymatically gener-
ated H2O2 to be insufficient for oxidation of the aminal inter-
mediate to yield the desired amide products 3a–k and 4b.
The temperature for the one-pot amide formation was
maintained at 20–37 °C. In the second step, in which the
assumed aminal intermediate is oxidised to the amide, the
tandem reactions worked optimally at higher initial substrate
concentrations (50–80 mM) which were found to be best toler-
0
0
1j
1k
1b
3j
36
38
—
87 (41)
45 (35)
(40)
3k
4bd
a Reaction conditions: GOase M3–5 (7.25 µM), 1a–k (10 mM) in sodium
phosphate buffer (50 mM pH 7.4), 25 °C , 16 h, then piperidine
(R2NH) (5 eq.), TBHP (1.2 eq., 6.6% v/v), 37 °C, 24 h. b Reaction
conditions: laccase (12 U), TEMPO (24 mM), 1a–k (80 mM) in sodium
citrate buffer (100 mM), 20 °C, 16 h, then piperidine (R2NH) (5 eq.),
TBHP (1.2 eq.), 37 °C, 24 h. c Isolated yields in parentheses. d R2NH =
N-methylpiperazine (5 eq.). Conversion to amides reported are based
on HPLC peak areas at λ = 254 nm (Tables S1 and S2).
for aldehyde formation from benzyl alcohols was quantitative
in both the GOase M3–5 and laccase–TEMPO systems
(Tables S1 and S2†), the amide forming second step was
clearly identified to determine yields of amide products due to
the concentration of aldehyde present. Most examples pre-
sented herein involved piperidine as a model amine, although
we were pleased to find that our method can be extended to
the formation of tertiary amide 4b, a feature frequently found
in drug molecules.
ated by the laccase–TEMPO system employed for the 1st step (2) Alcohols to carboxylic acids
(aldehyde formation). Thus, the highest conversions (9–91%)
(cascade 2)
and isolated yields (22–91%) of amides were obtained using
the laccase–TEMPO combination. Different benzyl alcohol The oxidation of alcohols to carboxylic acids very often requires
substrates exhibited a concentration-dependent effect on the a stepwise process via the aldehyde and typically employs
efficiency of conversion to the respective amide when compar- catalytic ruthenium or chromium and strong oxidants such as
ing the two biocatalytic systems. Substrates such as para-nitro- iodate or chlorite.17 Direct catalytic oxidation of alcohols to
benzyl alcohol 1a gave high conversion to amide 3a at lower carboxylic acids is relatively rare.3a,18 Biocatalytic processes
concentrations (10 mM) used in combination with GOase using whole cells and isolated enzymes are attractive tools for
M
3–5. In contrast, alcohols 1c–d and 1f–i showed distinct vari- synthesis of carboxylic acids due to the mild and green con-
ation in yields when comparing the GOase M3–5 (10 mM) and ditions employed.19 However, with whole cells, products often
laccase–TEMPO system (80 mM). In general, alcohols with need to be continuously removed from the reaction due to
electron-withdrawing substituents revealed a pronounced pro- toxicity of the intermediate aldehyde or acid. Therefore, in vitro
pensity for amide formation, whereas yields declined with elec- cascades employing isolated enzymes equally offer a very attrac-
tron-donating groups. Strictly speaking, although the first step tive alternative approach. Examples include the use of alcohol
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conversions. In order to facilitate increased substrate loading,
current work is focussed on finding improved enzymes for
both steps to increase rate and throughput.
(3) Cyclic amines to lactams
(cascade 3)
Scheme 2 Bio–bio cascade reaction for conversion of alcohols 1 to
acids 5. Reaction conditions: GOase M3–5 (1.3 mg mL−1), alcohols 1
(1 mM) in sodium phosphate buffer (50 mM, pH 7.6), catalase (0.25 mg
mL−1), E. coli XDH (0.18 mg mL−1), 37 °C, 16 h.
Catalytic methods for the direct α-oxidation of amines to
afford lactams are receiving a great deal of attention. However,
most methods require high temperatures or environmentally
undesirable stoichiometric reagents such as hypervalent
iodine25 or chlorite.26 Use of bulk gold27 and gold nanoparticle
catalysts28 have been reported but often require temperatures
up to 100 °C in organic solvents29 or the presence of 200 mol%
NaOH.28 Recently, use of a remarkable Ru-pincer complex
(150 °C, sealed tube) has been reported for the oxidation that
uses water as the oxygen source and produces hydrogen.30
Herein, we now present our initial results on the one-pot
oxidation of cyclic amines to lactams under mild (37 °C) and
aqueous conditions using two novel and related approaches
(Table 2). Both of these methodologies use a variant of A. niger
dehydrogenases and aldehyde dehydrogenases with recycling
of the oxidised NAD+ cofactor carried out by an oxygen-depen-
dent NADH oxidase.20 Whilst elegant, there is still the require-
ment for addition of cofactor and the auxiliary enzyme.
Aiming to expand the range of in vitro processes toward
carboxylic acid synthesis, we have developed a cascade reaction
using two oxidative enzymes, GOase M3–5 and xanthine dehy-
drogenase (XDH) from E. coli,21 to achieve direct and clean
conversion of aryl alcohols to acids via the in situ generated
aldehyde (Scheme 2). XDH belongs to a family of molyb-
denum-dependent enzymes22 and uses aerial O2 as an electron
acceptor in the absence of other mediators or cofactors. This
enzyme family is receiving increasing attention in the drug
metabolism field23 but has never before been exploited in syn-
thesis. Since the substrate specificity of E. coli XDH has not
previously been reported, we initially screened a panel of
ca. 65 aldehydes (Table S3†) using nitroblue tetrazolium
(NBT), a redox active dye previously used to examine micro-
organisms for xanthine oxidase activity.24 Substrate specificity
of E. coli XDH appeared to be dictated by enzyme–substrate
interactions since there were no obvious substrate electronic
effects dictating reactivity. We selected the best hits from the
NBT assay for more detailed analysis and were delighted to
observe 81–100% conversion in 1–5 h. While most of the alde-
hyde substrates were oxidised by E. coli XDH to >90% conver-
sion within 1 h, aldehydes 2d, 2i and 2m revealed slower turn-
over, taking 5 h to reach 80–90% conversion. There is no struc-
tural information on E. coli XDH although related aldehyde
oxidases are known to accept a wide range of substrates.23 The
aryl alcohols 1a, 1d–1f, 1h–j, 1l–t, corresponding to the best
aldehyde substrates 2 for E. coli XDH, were then selected for a
one-pot-one-step GOase M3–5-XDH cascade approach resulting
in quantitative conversion of 16 benzyl and heteroaryl alcohols
to the corresponding carboxylic acids over 16 h (Scheme 2,
Table S4†).
Table 2 Tandem bio–chemo and bio–bio catalysed conversion of
cyclic amines 6 to lactams 8
Conversion to
lactam 8a–c [%]
Substrate
Conditionsa
6a
6a
A (MAO-N D9/CuI/air)
B (MAO-N D9/XDH-E232V/Fe(III)/
DCPIP/air)
74
91
6a
C (MAO-N D9/XDH-E232V/laccase/
DCPIP/air)
54
6a
6b
6b
6b
6c
6c
D (MAO-N D9/E. coli XDH/catalase/air)
A
B
94
47b
—
D
A
—
42b
100b
Dc
a Conditions A: 6a–c (40 mM), MAO-N D9 (0.4 mg mL−1), MOPS buffer
(100 mM, pH 7.5), 10 eq. H2O2, CuI (1 mol%), 37 °C, 16 h. Conditions
B: 6a–c (1 mM), MAO-N D9 (1 mg mL−1), XDH E232V (1.7 mg mL−1),
potassium phosphate buffer (100 mM, 0.1% EDTA, pH 7.6), DCPIP
(10 mol%), K3Fe(CN)6 (1 eq.), 20 °C, 2 h. Conditions C: 6a (1 mM),
MAO-N D9 (1.1 mg mL−1), XDH E232V (1.7 mg mL−1) potassium
phosphate buffer (100 mM, 0.1% EDTA, pH 7.6), DCPIP (10 mol%),
T. versicolor laccase (0.6 mg mL−1), 20 °C, 2 h. Conditions D: 6a
(1 mM), 6c (10 mM), MAO-N D9 (1.1 mg mL−1), E. coli XDH (0.37 mg
mL−1), sodium phosphate buffer (50 mM, pH 7.4), 20 °C, 2 h.
b Addition of ammonia–borane prior to extraction and analysis.
c Includes addition of catalase (0.1 mg mL−1), reaction at pH = 8.0.
Conversion to lactams reported are based on response factors obtained
from NMR-HPLC correlations (ESI, chapter 5.4.1).
Following optimisation, the oxidation of 3-methoxybenzyl
alcohol 1s was run at 40 mM substrate concentration (Table S5
and Fig. S33†) showing complete conversion to the aldehyde
by GOase M3–5 after 30 min, followed by slower conversion by
E. coli XDH to reach 94% conversion to the acid 5s (81% iso-
lated yield) after 5 h. The addition of catalase to destroy the
H2O2 generated by GOase M3–5 and delivering additional
equivalents of O2 was found to be essential for achieving high
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monoamine oxidase (MAO-N D9) to catalyse the oxidation of provide additional equivalents for the Cu-catalysed lactam
the cyclic amine 6 to the imine/iminium 7 (1st step). The forming 2nd step, thus slightly increasing the yield and
second step uses either chemocatalysis (H2O2/cat. CuI) or bio- showing a mutual benefit of combining these two steps. In
catalysis (xanthine dehydrogenase (XDH)/electron acceptor) to addition, two related tetrahydroisoquinoline derivatives 6b
yield the desired lactam 8.
and 6c from the initial screen with MAO-N D9 also underwent
Our model substrate for initial studies on the tandem reac- the tandem reaction (Table 2). As previously described,6b
tion was tetrahydroisoquinoline 6a (THIQ) in view of the high MAO-N variant D9 has an active site which is sufficient for
activity displayed by the D9 variant of MAO-N (Table S6†). accommodation of bulky substrates. However, compound 6b
Thus, the corresponding imine dihydroisoquinoline 7a (DHIQ) produced a slightly lower activity (Table S6†), probably due to
generated by the MAO-N-catalysed 1st step became the sub- the position and nature of the NO2-substitutent. Both of these
strate for subsequent investigations on the chemo or biocata- substrates (6b, 6c) are N-methylated and thus the substrate for
lytic lactam forming 2nd step. Following the chemocatalytic the second step is an iminium. Although HPLC analysis of
approach for the 2nd step, we were able to achieve 69% conver- extracts indicated higher conversion, treatment of the reaction
sion of DHIQ 7a to lactam 8a using 10–20 equivalents of H2O2 mixture with ammonia–borane prior to extraction showed the
with 1 mol% CuI at 37 °C.
yields of 8b and 8c to be 47 and 42%, respectively.
We then searched for a biocatalytic approach making
use of an enzyme that is capable of oxidising THIQ-derived
imines/iminiums 7 to lactams 8. The drug metabolism litera-
ture contains reports of molybdenum-dependent aldehyde
oxidases that are capable of catalysing such oxygen-dependent
conversions. However, recombinant mammalian aldehyde
oxidases generally have quite low activity and have not been
exploited synthetically.31 A related bacterial enzyme, recombi-
nant xanthine dehydrogenase (XDH) from Rhodobacter capsula-
tus, can be expressed in reasonable yields and activity.
Moreover, variants of R. capsulatus XDH were examined and
showed a shift in substrate specificity from the natural sub-
strates xanthine and hypoxanthine towards aldehyde oxidase
type substrates.31 Hence, we investigated variant XDH-E232V
from R. capsulatus and found good activity towards DHIQ 7a.
Interestingly, the wild-type XDH from R. capsulatus revealed
no activity against this substrate. As R. capsulatus XDH has in
general only low reactivity with oxygen and preferentially uses
other electron acceptors, we screened a range of electron
acceptors (Table S8†) and found that either a combination of
the redox mediator DCPIP (10 mol%) and either 1 eq. K3Fe-
(CN)6 or T. versicolor laccase/aerial O2 could drive the reaction
yielding lactam 8a. In effect, the XDH-E232V/DCPIP/laccase
combination functions as an oxidase surrogate. In addition,
we examined E. coli XDH, in which case aerial O2 acts directly
as the terminal electron acceptor. Simply adding E. coli XDH
(0.04 mg mL−1) to a solution of imine 7a in NaPi buffer
(50 mM, pH 7.4) with periodic shaking gave complete conver-
sion to the corresponding lactam 8a at 20 °C in 2 h. Having
established chemocatalytic and biocatalytic methods for high
conversion of imine 7a to the lactam 8a we set about combin-
ing both reaction types with the MAO-N conversion to establish
the desired tandem reactions.
Bio–bio tandem catalysis
The conditions developed using the R. capsulatus XDH-E232V
variant and E. coli XDH for the conversion of DHIQ 7a to the
lactam 8a matched well with those required for the MAO-N D9
oxidation. A combination of MAO-N D9 and XDH-E232V with
the DCPIP (10 mol%)/Fe(III) (1 eq.) acceptor system gave an
excellent 91% conversion to the lactam in 2 h (conditions B,
Table 2). Moreover, laccase was also found to be applicable in
place of Fe(III) in the tandem reaction (condition C). Thus the
reaction uses 3 enzymes, buffer, catalytic DCPIP and aerial O2
at 22 °C. We were also pleased to find that the E. coli XDH,
which did not require any additional additives, could be
coupled with MAO-N D9 to afford the lactam 8a in 94% conver-
sion (conditions D, Table 2). Substrate 6b gave a complex
product mixture with R. capsulatus XDH-E232V, whereas E. coli
XDH was not able to catalyse the conversion of the iminium
7b to lactam 8b. In contrast, substrate 6c (10 mmol scale) was
converted quantitatively to the lactam 8c. The addition of cata-
lase was found to be necessary, presumably to destroy peroxide
produced by the E. coli XDH reaction. Interestingly, the
efficiency of the E. coli XDH reaction on 7c appeared to be pH
dependent as at pH 7.6 the overall conversion to lactam 8c
was 36%, whereas at pH 8.0 a quantitative conversion was
achieved. In this case, we hypothesise that a greater proportion
of the iminium 7c exists in the pseudobase (hemiaminal) form
at higher pH and that the latter may be the actual substrate for
the enzyme.23a
Conclusions
We have demonstrated
enzymes, which can be used in a simple and efficient fashion
a toolbox of oxygen-dependent
Bio–chemo tandem catalysis
Combination of the CuI/H2O2 reaction conditions with the together or in combination with chemocatalysts or chemical
MAO-N D9 biocatalyst resulted in a one-pot conversion of 6a to reagents in aqueous one-pot biocatalytic tandem cascades to
the lactam 8a in 74% yield, implying high conversion catalysed provide amides, carboxylic acids and lactams in good to excel-
by MAO-N D9 and at least as good performance by the copper lent yield under very mild conditions (20–37 °C). The enzymes
catalyst, if not better, in the tandem reaction (conditions A, MAO-N D9 and GOase M3–5 have previously been developed
Table 2). The MAO-N enzyme produces H2O2 which may for deracemisation of amines and resolution of secondary
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alcohols. In the present work, each of these enzymes has
been combined in a new way with xanthine dehydrogenases
(XDHs) to create novel synthetic cascade reactions. The
XDHs have been applied for the first time in preparative bio-
catalysis. They do not require addition of expensive cofactors
and were highlighted to be ideally suited for combination with
other oxidases. Evaluation of biocatalyst stability, immobilis-
ation and recycling will facilitate scale up of these cascade
5732; (f) J. W. W. Chang and P. W. H. Chan, Angew. Chem.,
Int. Ed., 2008, 47, 1138; (g) S. Muthaiah, S. C. Ghosh,
J.-E. Jee, C. Chen, J. Zhang and S. H. Hong, J. Org. Chem.,
2010, 75, 3002; (h) Y. Li, F. Jia and Z. Li, Chemistry, 2013,
19, 82.
9 (a) H. U. Vora and T. Rovis, J. Am. Chem. Soc., 2007, 129,
13796; (b) J. W. Bode and S. S. Sohn, J. Am. Chem. Soc.,
2007, 129, 13798.
processes. Work is currently ongoing to expand the range of 10 S. C. Ghosh, J. S. Y. Ngiam, A. M. Seayad, D. T. Tuan,
mutually compatible and greener oxidative functional group C. L. L. Chai and A. Chen, J. Org. Chem., 2012, 77, 8007.
transformations based on bio–bio and chemo–biocatalytic 11 W.-J. Yoo and C.-J. Li, J. Am. Chem. Soc., 2006, 128,
cascades.
13064.
12 (a) J. Li, F. Xu, Y. Zhang and Q. Shen, J. Org. Chem., 2009,
74, 2575; (b) C. Qian, X. Zhang, J. Li, F. Xu, Y. Zhang and
Q. Shen, Organometallics, 2009, 28, 3856; (c) S. Seo and
T. J. Marks, Org. Lett., 2008, 10, 317.
Acknowledgements
This paper is presented as part of CHEM21 under the 13 S. Gaspa, A. Porcheddu and L. De Luca, Org. Biomol. Chem.,
Innovative Medicines Initiative Joint Undertaking under 2013, 11, 3803.
the grant agreement no. 115360, resources of which are com- 14 X.-F. Wu, M. Sharif, A. Pews-Davtyan, P. Langer, K. Ayub
posed of financial contribution from the European Union’s and M. Beller, Eur. J. Org. Chem., 2013, 2783.
Seventh Framework Program (FP7/2007–2013) and EFPIA 15 (a) F. Escalettes and N. J. Turner, ChemBioChem, 2008, 9,
companies’ in-kind contributions. We also thank The
Engineering and Physical Sciences Research Council (EPSRC)
for funding.
857; (b) B. Yuan, A. Page, C. P. Worrall, F. Escalettes,
S. C. Willies, J. J. W. McDouall, N. J. Turner and J. Clayden,
Angew. Chem., Int. Ed., 2010, 49, 7010.
16 M. Fabbrini, C. Galli, P. Gentili and D. Macchitella, Tetra-
hedron Lett., 2001, 42, 7551.
17 M. Tojo and M. Fernandez, in Oxidation of Primary Alcohols
to Carboxylic Acids: a Guide to Current Common Practice,
Springer, 2007.
18 (a) B. N. Zope, D. D. Hibbitts, M. Neurock and R. J. Davis,
Science, 2010, 330, 74; (b) G. T. Brink, Science, 2000, 287,
1636.
Notes and references
1 V. R. Pattabiraman and J. W. Bode, Nature, 2011, 480, 471.
2 R. A. Sheldon, Chem. Soc. Rev., 2012, 41, 1437.
3 (a) E. Balaraman, E. Khaskin, G. Leitus and D. Milstein,
Nat. Chem., 2013, 5, 122; (b) S. Annen, T. Zweifel, F. Ricatto
and H. Grützmacher, ChemCatChem, 2010, 2, 1286; 19 (a) F. Hollmann, I. W. C. E. Arends, K. Buehler,
(c) T. Zweifel, J.-V. Naubron and H. Grützmacher, Angew.
Chem., Int. Ed., 2009, 48, 559.
4 (a) S. van Pelt, R. Teeuwen, M. Janssen, R. A. Sheldon,
A. Schallmey and B. Bühler, Green Chem., 2011, 13, 226;
(b) D. Romano, R. Villa and F. Molinari, ChemCatChem,
2012, 4, 739.
P. J. Dunn, R. M. Howard, R. Kumar, I. Martínez and 20 J.-I. Hirano, K. Miyamoto and H. Ohta, Tetrahedron Lett.,
J. W. Wong, Green Chem., 2011, 13, 1791; (b) M. T. Reetz, 2008, 49, 1217.
J. Am. Chem. Soc., 2013, 135, 12480; (c) C. Gunanathan, 21 Although this E. coli enzyme is named ‘xanthine oxidase,
Y. Ben-David and D. Milstein, Science, 2007, 317, 790;
(d) S. Lal and T. J. Snape, RSC Adv., 2013, 4, 1609.
5 N. J. Turner, Nat. Chem. Biol., 2009, 5, 567.
6 (a) V. Köhler, Y. M. Wilson, M. Dürrenberger, D. Ghislieri,
E. Churakova, T. Quinto, L. Knörr, D. Häussinger,
microbial’ by the supplier (Sigma-Aldrich) we have named
this enzyme E. coli xanthine dehydrogenase (XDH) since
one of us (S.L.) has unpublished results to show that
this enzyme will use NAD+ as an electron acceptor and is
therefore not formally an oxidase.
F. Hollmann, N. J. Turner, et al., Nat. Chem., 2013, 5, 93; 22 R. Hille, Arch. Biochem. Biophys., 2005, 433, 107.
(b) D. Ghislieri, A. P. Green, M. Pontini, S. C. Willies, 23 (a) C. Beedham, Drug Metab. Rev., 1985, 16, 119;
I. Rowles, A. Frank, G. Grogan and N. J. Turner, J. Am.
Chem. Soc., 2013, 135, 10863.
7 C. A. Denard, J. F. Hartwig and H. Zhao, ACS Catal., 2013,
3, 2856.
8 (a) Y. Tamaru, Y. Yamada and Z. Yoshida, Synthesis, 1983,
474; (b) T. Naota and S.-I. Murahashi, Synlett, 1991, 693;
(b) C. Beedham, Prog. Med. Chem., 1987, 24, 85;
(c) U. Dietzel, J. Kuper, J. A. Doebbler, A. Schulte,
J. J. Truglio, S. Leimkühler and C. Kisker, J. Biol. Chem.,
2009, 284, 8768; (d) D. C. Pryde, D. Dalvie, Q. Hu,
P. Jones, R. S. Obach and T.-D. Tran, J. Med. Chem.,
2010, 53, 8441.
(c) A. Tillack, I. Rudloff and M. Beller, Eur. J. Org. Chem., 24 A. Agarwal and U. C. Banerjee, Open Biotechnol. J., 2009, 3,
2001, 523; (d) W.-K. Chan, C.-M. Ho, M.-K. Wong and 46.
C.-M. Che, J. Am. Chem. Soc., 2006, 128, 14796; (e) Y. Suto, 25 T. Dohi, N. Takenaga, A. Goto, H. Fujioka and Y. Kita,
N. Yamagiwa and Y. Torisawa, Tetrahedron Lett., 2008, 49,
J. Org. Chem., 2008, 73, 7365.
This journal is © The Royal Society of Chemistry 2014
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26 M. A. Mohamed, K.-I. Yamada and K. Tomioka, Tetrahedron 29 M.-H. So, Y. Liu, C.-M. Ho and C.-M. Che, Chem. – Asian J.,
Lett., 2009, 50, 3436. 2009, 4, 1551.
27 E. R. Klobukowski, M. L. Mueller, R. J. Angelici and 30 J. R. Khusnutdinova, Y. Ben-David and D. Milstein, J. Am.
L. K. Woo, ACS Catal., 2011, 1, 703. Chem. Soc., 2014, 136, 2998.
28 P. Preedasuriyachai, W. Chavasiri and H. Sakurai, Synlett, 31 S. Schumann, M. Terao, E. Garattini, M. Saggu, F. Lendzian,
2011, 1121.
P. Hildebrandt and S. Leimkühler, PLoS One, 2009, 4, e5348.
Green Chem.
This journal is © The Royal Society of Chemistry 2014