Combining Photo-Organo Redox- and Enzyme Catalysis Facilitates Asymmetric C-H Bond Functionalization

Article abstract of DOI:10.1002/ejoc.201801692

In this study, we combined photo-organo redox catalysis and biocatalysis to achieve asymmetric C–H bond functionalization of simple alkane starting materials. The photo-organo catalyst anthraquinone sulfate (SAS) was employed to oxyfunctionalise alkanes to aldehydes and ketones. We coupled this light-driven reaction with asymmetric enzymatic functionalisations to yield chiral hydroxynitriles, amines, acyloins and α-chiral ketones with up to 99 % ee. In addition, we demonstrate functional group interconversion to alcohols, esters and carboxylic acids. The transformations can be performed as concurrent tandem reactions. We identified the degradation of substrates and inhibition of the biocatalysts as limiting factors affecting compatibility, due to reactive oxygen species generated in the photocatalytic step. These incompatibilities were addressed by reaction engineering, such as applying a two-phase system or temporal and spatial separation of the catalysts. Using a selection of eleven starting alkanes, one photo-organo catalyst and 8 diverse biocatalysts, we synthesized 26 products and report for the model compounds benzoin and mandelonitrile > 97 % ee at gram scale.

Full text of DOI:10.1002/ejoc.201801692

A Journal of
Accepted Article
Title: Combining Photo-Organo Redox- and Enzyme Catalysis
Facilitates Asymmetric C-H Bond Functionalization
Authors: Wuyuan Zhang, Elena Fernandez Fueyo, Frank Hollmann,
Laura Leemans Martin, Milja Pesic, Rainer Wardenga,
Matthias Höhne, and Sandy Schmidt
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801692
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801692
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10.1002/ejoc.201801692
European Journal of Organic Chemistry
COMMUNICATION
Combining Photo-Organo Redox- and Enzyme Catalysis
Facilitates Asymmetric C-H Bond Functionalization
Wuyuan Zhang[c], Elena Fernandez Fueyo[c], Frank Hollmann[c], Laura Leemans Martin[c], Milja Pesic[c],
Rainer Wardenga[d], Matthias Höhne*[b], and Sandy Schmidt*[a]
Dedication ((optional))
Abstract: In this study, we combined photo-organo redox catalysis
and biocatalysis to achieve asymmetric C–H bond functionalization
of simple alkane starting materials. The photocatalyst anthraquinone
sulfate (SAS) was employed to oxyfunctionalise alkanes to
aldehydes and ketones. We coupled this light-driven reaction with
asymmetric enzymatic functionalisations to yield chiral
hydroxynitriles, amines, acyloins and α-chiral ketones with up to
99% ee. In addition, we demonstrate functional group
interconversion to alcohols, esters and carboxylic acids. The
transformations can be performed as concurrent tandem reactions.
We identified the degradation of substrates and inhibition of the
biocatalysts as limiting factors affecting compatibility, due to reactive
oxygen species generated in the photocatalytic step. These
incompatibilities were addressed by reaction engineering such as,
applying a two-phase system or temporal and spatial separation of
the catalysts. Using a selection of eleven starting alkanes, one
photo-organo catalyst and 8 diverse biocatalysts, we synthesized 26
products and report for the model compounds benzoin and
mandelonitrile >97% ee at gram scale.
referred to as concurrent cascade or tandem reaction). As a further
advantage, tandem reactions facilitate steps that generate instable
or toxic intermediates, or that are thermodynamically challenging
and thus would not be beneficial if performed as a single reaction.[2]
Cascade reactions have been developed within the fields of
homogeneous-[3], heterogeneous-[1c,1d,4]
,
organo-[5], photo-, and
biocatalysis.[1a,6] On the contrary, combining catalysts from different
catalysis fields (“worlds”) is sometimes more challenging[1e,1f] for
compatibility reasons: Whereas there are many reactions in
homogeneous and organocatalysis operating in organic solvents,
enzyme catalysis, for example, requires aqueous conditions in most
cases, which is inconceivable for many transition metal-catalysed
reactions. Solving these compatibility challenges, in return, opens
the possibility to combine reaction steps relying on different
chemistries und thus to attain products that would not be accessible
in cascades including reactions from one catalysis domain alone.
A) Previous work
Enzyme
Substrate
Product
Introduction
NADH
NAD+
e–
e–
Combining several catalytic steps to conduct a precisely arranged
sequence of chemical transformations in a single reaction vessel
exhibits an enormous potential for more economically and
ecologically efficient synthesis routes, and thus, the development of
one-pot (cascade) reactions is a growing research field.[1] Cascades
are attractive from the perspective to reduce effort and waste, which
usually arises from intermittent work-up steps. Secondly, they also
allow minimizing production time, if all catalysts and reagents are
present from the beginning of the reaction (this type of reaction is
Photocatalyst
XH2
X + 2H+
B) Our work
Inter-
mediate
Substrate
Product
Organo
photocatalyst
Enzyme
[a]
[b]
[c]
[d]
Dr. S. Schmidt
Institute of Molecular Biotechnology
Graz University of Technology
Petersgasse 14/1, 8010 Graz, Austria
E-mail: s.schmidt@tugraz.at
Dr. M. Höhne
Figure 1. Cascade reactions combine catalysts from the same or different
fields of catalysts. B) Literature-reported photobiocatalytic approaches utilize
photocatalysts to provide redox co-substrates.[7] C) In this study, we combine
photocatalytic transformations with enzymatic reactions steps.
Institute of Biochemistry, Protein Biochemistry
University of Greifswald
Felix-Hausdorff-Str. 4, 17489 Greifswald, Germany
E-mail: Matthias.hoehne@uni-greifswald.de
Dr. W. Zhang, Prof. Dr. F, Hollmann, L. Leemans Martin, Dr. E.
Fernandez Fueyo, Dr. M. Pesic
Dept. of Biotechnology
Delft University of Technology
Van der Maasweg 9, 2629 HZ Delft, The Netherlands.
Dr. R. Wardenga
Fruitful interdomain combinations employ manifold solutions to
tackle compatibility issues,[1e,1f,4b] such as compartmentalization
by two-phase systems, nanoparticles or membrane systems.
Especially photocatalysts have been combined with various
types of other catalysts yielding synergistic dual catalytic
systems, where two types of catalysts participate in one catalytic
cycle.[8] The combination of photocatalytic and biocatalytic steps
for organic synthesis, however, are not systematically explored
until now. Most examples of combining photo- and biocatalysis
Enzymicals AG
Walther-Rathenau-Straße 49a, 17489 Greifswald, Germany
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801692
European Journal of Organic Chemistry
COMMUNICATION
focus on photocatalytic in situ regeneration of redox enzymes[7]
(Figure 1A). This approach, similar to Nature’s photosynthesis,
uses the light energy to feed electrons directly into the enzyme,
or to provide stoichiometric redox equivalents such as NADPH
or hydrogen peroxide for the enzymatic reaction step. Thus, light
is used indirectly to fuel chemical transformations.[7c,9] On the
contrary, in this study, we aim to couple photoorganocatalytic
reactions that use light energy directly to drive small molecule
conversions with further enzymatic functionalization steps to
develop photobiocatalytic one-pot (tandem) reactions (Figure
1B). Only two examples of photobiocatalytic cascades
combining metal photocatalysts with enzymes have been
reported very recently.[10] A very recent example couples an
organo-photocatalytic E/Z isomerization with an enzymatic
reduction of the double bond,[11] thereby increasing the
conversion of the enzymatic reaction from 50 to 95%. Beyond
E/Z isomerization, other photocatalytic reactions have been
developed also facilitating bond-cleaving and bond-forming
reactions, which are very useful for the functionalization of
simple starting materials.[12]
known to catalyse ketone oxidation. Indeed, when both catalysts
are present in the reaction mixture, phenyl formate 30 was
formed (Table 1, entry 1). Similarly, cyclohexanol could be
converted with cyclohexanone monooxygenase (CHMO) to ε-
caprolactone 41, although with lower conversion (Table 1, entry
5). When starting with the alkanes toluene 1 and cyclohexane 11
(20 mM dissolved in 10% (v/v) acetonitrile in reaction buffer), no
conversion could be detected. Interestingly, this changed if 1
was applied in excess, resulting in a two-phase system (Table 1,
entries 3 and 4). The improved conversion might be due to
protecting the BVMOs from inhibition, as these enzymes are
sensitive to product and substrate inhibitions. The non-activated
cyclohexane, however, could not be converted into 41.
A)
Step 1: Photoorgano catalysis
Step 2: Enzyme catalysis
O
O
H
X
SAS, hν
O
Enzyme
H
C
R1
R2
R1 R2
R1 R3
cosubstrate
SO3Na
2 H2O2
2 O2
In this study, we explored the potential of photocatalytic
oxidation/oxyfunctionalisation reactions generating aldehydes
and ketones from simple alkene starting materials followed by
biocatalytic asymmetric transformations yielding a range of chiral,
high-value added products. We demonstrate the general
feasibility of this approach and also identify limitations. This
asymmetric photo-chemo-enzymatic functionalization of a range
sodium anthraquinone
sulfonate (SAS)
B)
OH
OH
HNL
Ph
BAL
NaCN
Ph
Ar
CN
O
23-25
Toluenes
Ar CH3
1-4
26
O
of
hydrocarbons
substantially
extends
available
Ar
H
chemoenzymatic approaches.
O
O
HAPMO
O
Ph
AAO
O2
12-15
O2, NADPH
H
30
Ar
OH
27-29
Aryl alkanes
Results and Discussion
NH2
O
ATA
IPA
H
H
Ar
OH
Ar
KRED
NADH
Ar
We chose the photocatalytic oxyfunctionalisation of alkanes 1-11
(Scheme 1) catalysed by sodium anthraquinone sulfonate (SAS)
as a model reaction for the photocatalytic step. SAS is a quinoid
photocatalyst well-known for the light-driven oxidation of
alcohols. It also catalyses oxyfunctionalisation of alkanes in
benzylic and allylic positions with moderate efficiency, which are
the by far more attractive reactions.[13] Converting (non)activated
C-H-bonds by SAS into aldehydes 12-15 or ketones 16-22 does
not introduce chirality into the respective compounds. We thus
envisioned cascade reactions combining the SAS-catalysed
oxyfunctionalisation reactions with enzymatic reactions to
generate further functionalized products 23-41 and to introduce
the desired chirality. Due to the sulfonate substituent, SAS
dissolves well in an aqueous reaction media, allowing to easily
combine SAS-catalysed reactions with various enzymatic
reaction steps to explore the potential for different two-step
cascades.
Ar
31-33
5-6
16-17
34-36
Cycloalkenes
O
H
O
CH3
H
ERED
NADH
H
R
R
R
37-40
7-10
18-21
Cycloalkanes
O
H
O
BVMO
O2, NADH
H
O
41
11
22
Scheme 1. A) General principle of C–H functionalization by a photo-enzymatic
cascade B) Modular combinations of SAS-catalysed oxyfunctionalisation
reactions and enzymatic transformations explored in this study. HNL:
hydroxynitrile lyase; BAL: benzaldehyde lyase; AAO: aryl alcohol oxidase;
HAPMO:
4-hydroxyacetophenone
monooxygenase;
ATA:
amine
transaminase; KRED: keto reductase; ERED: ene-reductase; CHMO:
cyclohexanone monooxygenase.
Ideally, the reactions are taking place simultaneously in one
reaction vessel (concurrent cascade). To prove that
simultaneous catalysis by enzymes and SAS is possible, we first
investigated a simple reaction system to produce functionalized
but achiral products. We used benzyl alcohol as starting material,
which can be readily oxidised by SAS, and added 4-
hydroxyacetophenone monooxygenase (HAPMO) to the
reaction mixture, a Baeyer-Villiger monooxygenase (BVMO)
Next, we drew our attention on reactions directly starting
from toluene, phenylethane and cyclohexene derivatives 1-10
(Scheme 1, see SI for a complete list of substrates and
products) in the presence of biocatalysts chosen from three
enzyme
classes.
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10.1002/ejoc.201801692
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Concurrent cascades of photocatalytic oxidation and enzymatic functionalization. Standard reaction conditions: 20 mM substrate, 10% (v/v)
acetonitrile in aqueous reaction buffer, 1-2 mg/mL enzyme (lyophilisate), 30°C, 6-24 h. Details of buffer compositions, co-factors, co-substrates and
additives are given in the Supporting Information.
Cascade
mode
Substrate, Concentration
[mM]
Intermediate, Concentration[a]
(single step) [mM]
Product, Concentration, [mM][b] [% ee]
Enantiomeric excess
Entry
Enzyme
1
2
3
4
5
20
11.4
9.5
n.a.
n.a.
n.a.
n.a.
n.a.
OH
[c]
20
[c]
42.6
31.4
n.d.
23.5
2.0
O
H
O
HAPMO
O
10.9
86.6
OH
20
8.1
O
O
CHMO
HNL
O
6
7
20
25
7.5
9.4
n.d.
0.8
n.a.
92
OH
CN
concurrent
O
O
10
(6.5)
2.5
8
9
1.15
0.8
>99
>99
Ph
BAL
ATA
Ph
OH
NH2
25
1
O
KRED
KRED
10
11
12
20
[c]
20
8.5
20
1.9
16[c]
2.2
25
9
OH
O
O
O
n.d.
>99
ERED
OH
CN
O
13
14
[c]
[c]
20
40
5.8
>99
>99
HNL
stepwise
O
11.6
ERED
[a] Maximum formed concentration of the intermediate if the photocatalytic reaction is given only. Determined by GC; for details see Supporting Information. [b]
Concentration of product in the cascade reaction. [c] Substrate was used as solvent in a two-phase system, volume ratio 1:1 (v/v). n.a. – not applicable; n.d. – not
determined.
Benzaldehyde lyase (BAL), the nicotinamidedinucleotide-
dependent oxidoreductases ene-reductase (ERED) and
ketoreductase (KRED), as well the C-N-bond forming amine
transaminase (ATA) are well-known to convert carbonyl
substrates with high to excellent enantioselectivity to
functionalized products (Scheme 1). The photo-oxidation step
generated carbonyl intermediates in a concentration range of 2-
45 mM depending on the used alkane (Table 1, entries 7-12).
Pleasingly, in all cases the expected functionalized products 23-
40 were detected when theses enzymes were included in the
reaction mixtures (see Scheme 2 for structures of all products),
although the conversions of the carbonyl intermediates in the
enzymatic step were relatively low in most cases, ranging from
5-25%. The reaction involving BAL is a notable exception: an
equal amount of benzoin 26 formed corresponding to the
consumed two equivalents of benzaldehyde.
solvents often play a role, but also cross-reactivities leading to
side reactions of reaction participants might occur.[14]
Furthermore, the equilibrium constant of the biocatalytic step
might require actions to shift the equilibrium, especially in ATA
and HNL-catalysed reactions. In the modular reaction system,
we identified the following issues that have to be addressed: (i)
In the presence of SAS and light, substrates that are prone to
oxidation such as HCN and NADH decomposed over time (see
Figure S3), as observed in the HNL-catalysed reactions. (ii) As
reactive oxygen species and other radical intermediates are
formed in the photocatalytic reaction, it was not surprising to
note that also enzyme deactivation occurred over time: product
formation often declined after a few hours, but SAS-mediated
alkane oxidation still continued over time. (iii) Incompatibility of
catalysts with necessary co-solvents occurred in case of the
transaminase reactions. With our studied ATAs we had to
replace acetonitrile by DMSO due to rapid inactivation of the
transaminases.
For the optimization of cascade reactions, inhibition or
deactivation of the catalysts by reaction participants or (co)-
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10.1002/ejoc.201801692
European Journal of Organic Chemistry
COMMUNICATION
H
O
X
enzyme
OH
SAS, hυ
R1
R2
R1
R2
R1
R2
2-phase system
OH
OH
CN
OH
OH
OH
CN
CN
CN
CN
CN
MeO
MeO
Cl
Cl
(R)-23
(S)-23
(R)-24
(S)-24
(R)-25
(S)-25
99% conv.
>99% ee
81% conv.
88% ee
8% conv.
98% ee
21% conv.
87% ee
30% conv.
76% ee
27% conv.
>99% ee
NH2
NH2
NH2
NH2
O
O
NH2
OH
OH
Cl
31
(R)-32
(R)-33
(S)-32
(S)-33
27
(R)-26
92% conv.
33% conv.
>99% ee
96% conv.
>99% ee
4% conv.
>99% ee
16% conv.
>99% ee
85% conv.
>99% ee
9% conv.
OH
OH
OH
OH
O
O
O
OH
OH
Cl
F
(R)-35
34
(S)-35
(R)-36
(S)-36
28
30
73% conv.
23% conv.
24% conv.
9% conv.
<1% conv.
26% ee
25% ee
70% ee
49% ee
49% conv.
56% conv.
O
O
O
O
O
O
O
OH
Cl
O
29
41
37
(2R)-38
(2S)-39
(S)-40
67% conv.
29% conv.
8% conv.
87% ee
78% conv.
>99% ee
60% conv.
99% ee
20% conv.
>99% ee
Scheme 2. Scope of the photo-chemo-enzymatic approach for C-H bond transformation. The first step is performed as two phase reaction, where the substrate is
used as organic phase. Conversions refer to consumption of the intermediate (aldehyde/ketone) in the enzymatic step.
DMSO is often employed in transaminase reactions and
well-tolerated by many enzymes, but unfortunately it decreased
SAS activity by 25-fold: Only ~1 mM of benzaldehyde and
ketones formed when DMSO was present (compare entries 9
and 10, Table 1). (iv) Most enzymes maintained their excellent
stereoselectivities, only KRED-catalysed reactions yielded
alcohols with a low enantiomeric excess of 25% ee. This might
be attributed to a radical-mediated racemization of the alcohol
products.
in the KRED reaction is very likely due to the facile oxidation of
alcohols by SAS. In a two-phase system, the organic phase
provides a product sink, thereby protecting the alcohol product
34 from back oxidation. Therefore, the two-phase system
increased product concentrations by 10-fold for the KRED
reaction (entries 10 and 11), but had no impact on the ATA
reaction due to the higher solubility of the amine in the aqueous
phase. Spacial and temporal separation of catalysts is an often-
applied solution if incompatibility of reaction conditions cannot
be avoided.[1e,14] Therefore we turned our attention to
a
After having identified several incompatibility issues, we
aimed at improving the conversions especially of the enzymatic
step of the cascades. Reactive oxygen species such as H2O2,
which are produced also by other photocatalysts under an
oxidative reaction regime, are a general challenge for enzyme
stability. When we added catalase to the reaction mixture of the
ERED reaction to decompose H2O2, however, no beneficial
effect on conversion was detected. Inspired by the success of a
two-phase approach with BVMO, we therefore investigated this
approach for ATA and KRED. The low concentration of alcohol
sequential reaction mode: after the photocatalytic step, we
added the appropriate enzyme and protected the reactions from
light to decrease oxidative damage. This resulted in a 3-4-fold
increased formation of the final product: mandelonitrile 23
concentration in the HNL reaction increased 6-fold, and notably
also an excellent enantiomeric excess of >99% ee was obtained
(entry 13). Especially if the alcohols were employed as starting
material, HAPMO and ERED achieved 74% and >98%
conversions of the formed intermediates to yield 30 and 38
(Table 1, entry 14 and Table S6). Despite the increased product
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10.1002/ejoc.201801692
European Journal of Organic Chemistry
COMMUNICATION
formation in the enzymatic step, conversion was incomplete in
most cases and we observed that reactions stagnated after a
few hours. To exclude inhibitory effects of side-products from the
photocatalytic reactions, we modified the step-wise reaction as
follows: a two-phase SAS-catalysed oxidation resulted in the
accumulation of the intermediate in the organic phase. We then
discarded the SAS-containing aqueous phase and provided
reagents and enzymes dissolved in aqueous reaction buffer to
start the second reaction. In this way, we could further increase
conversions in the enzymatic step. To show the generality of this
approach, we explored different alkane substrates and also
employed ATA, HNL or KRED enzymes with opposite stereo-
preferences to produce both product enantiomers (Scheme 2,
(Figure S4-S17). In total, this approach generated 26 products
with varying conversion, but at least one example with good to
quantitative conversions of the formed intermediate was
obtained with most of the investigated enzymes. Finally, these
photo-chemo-enzymatic transformations were performed on
preparative scale for (R)-mandelonitrile and (R)-benzoin
acknowledge funding from the European Union’s Horizon 2020
MSCA ITN-EID program under grant agreement No. 634200
(Project BIOCASCADES). MH has received funding from the
European Research Council (ERC) under the European Union’s
Horizon 2020 research and innovation programme (grant
agreement No. 759262). SS has received funding from the
European Union’s Horizon 2020 MSCA ITN-EJD program under
the European Union’s Horizon 2020 research and innovation
programme (grant agreement No. 764920, Project PhotoBioCat).
Keywords: Photocatalysis • chemoenzymatic cascades • photo-
organo catalyst • asymmetric synthesis • enzymes
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photocatalytic water oxidation has been established as
a
generally applicable method for cofactor regeneration.
Furthermore, protein engineering can be used to improve
enzyme resistance to oxidative stress and photo-degradation to
further increase catalyst compatibility in photo-biocatalytic
cascades.
Experimental Section
All experimental details are given in the Supporting information.
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Acknowledgments
We gratefully acknowledge Prof. Wolfgang Kroutil for providing
us the vectors encoding the KREDs. FH thanks for the financial
support by the European Research Council (ERC Consolidator
Grant No. 648026) and the Netherlands Organisation for
Scientific Research (VICI grant, No. 724.014.003). RW and LLM
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Wuyuan Zhang, Elena Fernandez
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Combining Photo-Organo Redox- and
Enzyme Catalysis Facilitates
Asymmetric C-H Bond
Joint forces! The combination of a photo-organo redox catalyst with 8 diverse
biocatalysts achieves asymmetric C–H bond functionalization of simple alkane
starting materials to hydroxynitriles, amines, acyloins, α-chiral ketones, and
transformation into alcohols, esters and carboxylic acids.
Functionalization
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