Enantioselective synthesis of amines by combining photoredox and enzymatic catalysis in a cyclic reaction network

Article abstract of DOI:10.1039/c8sc01561a

Visible light-driven reduction of imines to enantioenriched amines in aqueous solution is demonstrated for the first time. Excitation of a new water-soluble variant of the widely used [Ir(ppy)₃] (ppy = 2-phenylpyridine) photosensitizer in the p

Full text of DOI:10.1039/c8sc01561a

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Enantioselective synthesis of amines by combining
photoredox and enzymatic catalysis in a cyclic
reaction network†
Cite this: DOI: 10.1039/c8sc01561a
b
a
b
Xingwei Guo,a Yasunori Okamoto,
Mirjam R. Schreier, Thomas R. Ward
*
a
*
and Oliver S. Wenger
Visible light-driven reduction of imines to enantioenriched amines in aqueous solution is demonstrated for
the first time. Excitation of a new water-soluble variant of the widely used [Ir(ppy)3] (ppy ¼ 2-phenylpyridine)
photosensitizer in the presence of a cyclic imine affords a highly reactive a-amino alkyl radical that is
intercepted by hydrogen atom transfer (HAT) from ascorbate or thiol donors to afford the corresponding
amine. The enzyme monoamine oxidase (MAO-N-9) selectively catalyzes the oxidation of one of the
enantiomers to the corresponding imine. Upon combining the photoredox and biocatalytic processes
under continuous photo-irradiation, enantioenriched amines are obtained in excellent yields. To the best
of our knowledge, this is the first demonstration of a concurrent photoredox- and enzymatic catalysis
leading to a light-driven asymmetric synthesis of amines.
Received 5th April 2018
Accepted 5th May 2018
DOI: 10.1039/c8sc01561a
rsc.li/chemical-science
chemical reduction step was performed inside tailored articial
metalloenzymes, and combination with biocatalysts for the
Introduction
recycling step led to multi-enzymatic cascades.10 We were
curious whether the enzymatic recycling would be compatible
with a light-driven catalytic step, such as typically the case in
photoredox catalysis. Compared to small molecular catalysts,
biocatalysts frequently offer the advantage of superior selec-
tivity and efficiency, hence the idea of incorporating a photo-
redox step into a cyclic reaction network together with an
enzyme for overall asymmetric catalysis seemed very appealing.
Light-driven biocatalysis has gained increasing attention in
recent years,11 however, mostly in the context of co-factor
regeneration.12 To complement these efforts, Hyster and co-
workers reported on an elegant strategy to access highly selec-
tive radical-mediated reactions by irradiating nicotinamide-
dependent enzymes.13 To the best of our knowledge, there are
no prior photoredox studies that have made use of cyclic reac-
tion networks to achieve overall enantioselective catalysis.
Direct photoredox-driven reduction of imines to amines
does not appear to have been reported previously.14 This may be
traced back to the fact that, aer initial imine reduction by
photoinduced (single) electron transfer, the resulting a-amino
alkyl radicals must be intercepted rapidly by (thermal) hydrogen
atom transfer (HAT) to achieve the overall two-electron reduc-
tion. This may be somewhat challenging as photochemical
multi-electron reductions are usually non-trivial to perform.15 In
the present case, the identication of suitable HAT donors was
of key importance. Thiols and disuldes have recently been
identied as suitable co-catalysts to intercept carbon radicals in
a variety of different photoredox processes.16 We and others
found that thiols react very rapidly with photo-generated a-
Photoredox catalysis has become a very popular research eld,1
and while most prior studies reported on the formation of
racemic product mixtures, increasing attention is now being
devoted to enantioselective photoredox chemistry.2 Dual catal-
ysis methods have oen been employed to gain control over
stereoselectivity using for example chiral amines,3 N-heterocy-
clic carbenes,4 chiral Brønsted acids,5 chiral Lewis acids,6 or
chiral counter-ions as co-catalysts.7 Independently of these
photoredox catalysis endeavors, cyclic reaction networks have
emerged as an attractive strategy for asymmetric synthesis
(Fig. 1a).8 In a typical network of this type, an initial endergonic
process converts the substrate into a racemic product, and
a subsequent exergonic process selectively converts one of the
enantiomers back to the starting material, while the other
enantiomer accumulates. Over time, such selective recycling
leads to the enrichment of the unreactive enantiomer.8 This
strategy, also termed cyclic deracemization, was used for the
chemo-enzymatic de-racemization of amines, using an amine
oxidase or reductive aminase (in reverse mode) as recycling
catalyst combined with
a non-enantioselective chemical
reduction or an imine reductase.9 More recently, the initial
aDepartment of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel,
Switzerland. E-mail: oliver.wenger@unibas.ch
bDepartment of Chemistry, University of Basel, Mattenstrasse 24a, BPR 1096, 4002 Basel,
Switzerland. E-mail: thomas.ward@unibas.ch
† Electronic supplementary information (ESI) available: Complete experimental
details, additional reference experiments, spectroscopic and electrochemical
results. See DOI: 10.1039/c8sc01561a
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molecule photoredox catalyst and the enzyme, which is oen
observed for similar systems.10,19
Results and discussion
We started our investigations with 2-cyclohexyl-1-pyrroline (1a)
as a model substrate using [Ru(bpy)3]Cl2 as a photocatalyst
(1 mol%) and ascorbic acid (2 eq.) as a reductant in aqueous
phosphate buffer solution at pH 8.0 (Scheme 1). Over the course
of 20 h of irradiation with a blue LED (455 nm, 3 W) at room
temperature, only trace amounts of the desired product rac-2a
were formed. We attribute this to insufficient reducing power of
[Ru(bpy)3]Cl2,20 as the peak reduction potential of 1a in aqueous
solution at pH 8 was determined to be ꢀ1.84 V vs. SCE (ESI page
S30†). Compared with [Ru(bpy)3]Cl2 ðEo*x ¼ ꢀ0:81 V vs: SCEÞ,
fac-[Ir(ppy)3] ðEo*x ¼ ꢀ1:73 V vs: SCEÞ is a much stronger pho-
toreductant.21 To our delight, when using this complex, the
reduction of 1a to rac-2a did indeed proceed with 59% yield
aer 6 h of irradiation (405 nm, 3 W). However, due to the very
low solubility of fac-[Ir(ppy)3] in water, the reaction had to be
carried out in acetonitrile, and this would be incompatible with
enzyme catalysis. We therefore prepared a new tri-sulfonated
variant of fac-[Ir(ppy)3] (Scheme 1, right), which turns out to
have very similar electrochemical and optical spectroscopic
properties as the parent complex (ESI page S5†), despite the
electron withdrawing substituents and negative charges at the
ligand periphery. Specically, the excited state oxidation
potential of the Na3[Ir(sppy)3] complex is ꢀ1.89 V vs. SCE,
slightly stronger than its parent complex, and it exhibits 3MLCT
luminescence centered at 508 nm with a lifetime of 700 ns in
aerated aqueous solution. With Na3[Ir(sppy)3] as a photocatalyst
the conversion of 1a to rac-2a in water proceeded in 95% yield
aer irradiation for 10 hours (Scheme 1). Thus, efficient
photoredox-driven reduction of imines to amines in aqueous
solution becomes possible, owing to the high reducing power of
the water-soluble Na3[Ir(sppy)3] complex and the use of ascorbic
acid as a HAT donor that intercepts highly reactive a-amino
alkyl radical intermediates formed in the initial light-induced
Fig. 1 (a) Principle of an enantiomer-recycling reaction network. (b)
Photoredox-catalyzed reduction of cyclic imines using an Ir sensitizer,
and subsequent re-oxidation of the (S)-amine back to the imine
starting material by monoamine oxidase (MAO-N-9) expressed in E.
coli cells. The overall two-electron reduction process is driven by
visible light and relies on ascorbic acid (AscH2) as a reductant and HAT
donor. (c) Energy profile for the light-driven cyclic deracemization.
amino alkyl radicals,17 owing to the principle of polarity-
matching.18 We hypothesized that the light-driven reduction of
imines to amines with ascorbic acid might be possible using
a similar strategy, and we anticipated that this methodology
may be coupled with an enzymatic reaction if the photoredox
process could be performed in aqueous solution.
reaction step (Fig. 1b).17 Expectedly,
mixture was obtained.
a racemic product
With these optimized conditions at hand, we attempted to
integrate this photoredox step into a cyclic reaction network by
Thus, we designed a cyclic reaction network for the enantio-
selective synthesis of amines from cyclic imines as illustrated in
Fig. 1b. A water-soluble photosensitizer serves to reduce iminium
ions to a-amino alkyl radicals, which are further converted to the
respective amines by HAT from ascorbic acid (AscH2/AscHꢀ). This
photoredox-driven formation of amines can only lead to racemic
amines. Gratifyingly, monoamine oxidase (MAO-N-9) catalyzes the
oxidation of cyclic amines with excellent selectivity for the (S)-
enantiomer (Fig. 1c).10 Accordingly, under continuous photo-
irradiation, this concurrent enzymatic recycling process should
ultimately lead to the accumulation of the (R)-amine. If successful,
photoredox catalysis may allow the enantioselective imine-to-
amine reduction in a cyclic reaction network. A potential chal-
lenge may however be mutual deactivation between the small
Scheme 1 Identification of a suitable photocatalyst for the reduction
of 1a.
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combining the light-driven imine reduction with enantiose-
lective amine oxidation catalyzed by MAO-N-9.
Toward this end, imine 1a (10 mmol) was added to a 1 mL
phosphate-buffered aqueous suspension at pH 8 containing E.
coli cells with recombinantly expressed monoamine oxidase
(180 mg, wet weight), Na3[Ir(sppy)3] (1 mol%), and ascorbic acid
(0.2 M). Gratifyingly, photo-irradiation by a blue LED (405 nm)
for 20 h under air led to 92% conversion of 1a and 91% e.e. (R)
(Table 1, entry 1). Aer a prolonged reaction time (30 h),
enantiomerically pure product (R)-2a was obtained (Table 1,
entry 2). Control experiments without any biocatalyst (Table 1,
entry 3) or using E. coli cells with an empty vector (pET-16b)
(Table 1, entry 4) afforded rac-2a in quantitative yield. When
using the lysate of E. coli cells containing MAO-N-9, decreased
conversion (83%) and lower enantioselectivity (77% e.e.) were
observed (Table 1, entry 5). This nding suggests that photo-
redox and enzymatic catalysis mutually perturb each other in
Fig. 2 The conversion of 1a (10 mmol) to (R)-2a with 2 mol% photo-
catalyst and MAO-N-9 (180 mg wet cells) monitored by chiral GC over
time. The data at each time point were determined from the relative
peak integrals of starting material and products in a single measure-
ment on chiral phase GC.
To gain mechanistic insight of this system, we monitored the
the cell lysate. Independent kinetic resolution experiments of conversion of imine substrate 1a to the amine product (R)-2a
rac-2a using E. coli (MAO-N-9) cell lysate support our hypothesis and the enantiomeric excess as a function of time (Fig. 2). It
that the lowered enantioselectivity of the imine to amine appears that the enzyme-catalyzed amine oxidation is the rate
reduction in the cell lysate (Table 1, entry 5) is due to partial determining step in the overall enantioselective conversion of
inactivation of MAO-N-9 by the photocatalyst. Conversely, the 1a to (R)-2a. The photoredox-driven reduction of imine to amine
lower yield for the overall reaction (83%) is likely caused by is almost complete within 2 hours (black trace), whilst the
a detrimental effect of the biocatalyst (or cellular debris) on the enantiomeric excess lags much behind (red trace). The slight
photoredox process (see ESI page S10†). As noted above, such decrease in the conversion beyond 2 h is likely due to slow
mutual inhibition of chemo- and biocatalysts is a widely- deactivation of the photoredox catalyst.
observed phenomenon.19 To circumvent this challenge, the
The cyclohexyl residue of 1a is known to t well into the
MAO-N-9 was compartmentalized in the cytoplasm of E. coli active site of MAO-N-9,10 and thus it seemed worthwhile to
cells. We hypothesize that the negatively charged [Ir(sppy)3]3ꢀ explore the possibility of using imine substrates with other
photocatalyst cannot diffuse through the cell membrane due to hydrophobic substituents. We found that an imine substrate
its anionic nature and high molecular weight, thus warranting bearing an n-butyl side chain (substrate 1b) was converted to the
the spatial separation of photoredox-related processes and the respective amine with >95% yield without biocatalyst (Table 2,
biocatalyzed reaction steps when using whole cells instead of entry 1), whilst in presence of MAO-N-9 (S)-2b was formed in
lysates.
95% yield and 98% e.e. (Table 2, entry 2). When installing
a benzyl substituent on the 3,4-dihydro-2H-pyrrole core unit
(substrate 1c), the photoredox step affords rac-2c quantitatively
in the absence of MAO-N-9 (Table 2, entry 3), but only 8% e.e. of
(R)-2c was obtained in presence of biocatalyst (entry 4). This low
enantioselectivity suggests that substrate 1c cannot be effi-
ciently converted by MAO-N-9.
Table 1 Reaction conditions for the photoredox/enzyme catalysis
cascadea
To extend the applicability of our concept beyond imine to
secondary amine reduction, we investigated whether iminium
ion 1d can be converted to tertiary amine product rac-2d (Table
2, entries 5 and 6). With standard conditions, enantiomerically
pure tertiary amine (R)-2d was readily obtained.
Entry
Biocatalyst
t/h
Yield [e.e.] (%)b
To further extend the substrate scope from aliphatic to
aromatic imines, we examined 1-methyl-3,4-dihydroisoquinoline
(1e) as a substrate.10 Due to signicant stabilization of the
respective carbon-centered radical intermediate resulting from
initial reduction of the aromatic substrate, HAT is considerably
less exergonic than in the case of aliphatic substrates and no
product formation is observed as long as only ascorbate is
present (ESI, page S15†). Therefore, we attempted to lower the
1
2
3
4
5
E. coli (MAO-N-9) whole cell/180 mg
E. coli (MAO-N-9) whole cell/180 mg
—
E. coli (empty) whole cell/120 mg
E. coli (MAO-N-9) lysate/180 mg
20
30
10
20
20
92 [91]
92 [>99]
95 [0]
>95 [0]
83 [77]
a
Reaction conditions: 1a (10 mM), Na3[Ir(sppy)3] (0.1 mM), AscH2 (200
mM), biocatalyst (180 or 120 mg, wet weight of cell pellets) in 1.0 mL
phosphate buffer solution (pH 8.0) at ambient temperature with
405 nm LED (3 W) irradiation on a shaking agitator (at 200 rpm) activation barrier for HAT by adding 4-mercaptophenylacetic acid
b
under air.
Yields were determined by 1H NMR analysis,
and 3-mercaptopropionic acid derivatives (MPAA-PEG and MPA-
PEG, respectively, ESI page S16†), hypothesizing that polarity-
matched HAT between these thiol donors and the a-amino
enantiomeric excess was determined by GC on a chiral stationary
phase (see ESI for details).
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Table 2 Substrate scope of the combined photoredox/enzyme catalysisa
Entry
Substrate
Photocat. & reducing agent
Biocat.
Product
Yield [e.e.] (%)b
>95c
1
2
Na3Ir(sppy)3(1 mol%) + AscH2 (0.2 M)
Na3Ir(sppy)3 (1 mol %) + AscH2 (0.2 M)
—
1b
MAO-N-9 (180 mg)
>95 [98]
3
4
5
Na3Ir(sppy)3 (1 mol %) + AscH2 (0.2 M)
Na3Ir(sppy)3 (1 mol %) + AscH2 (0.2 M)
Na3Ir(sppy)3 (1 mol %) + AscH2 (0.2 M)
Na3Ir(sppy)3 (1 mol %) + AscH2 (0.2 M)
—
>95c
1c
MAO-N-9 (180 mg)
>95 [8]
>95c
—
6
7
1d
1e
MAO-N-9 (180 mg)
—
>95 [>99]
>95d
Ru(bpy)3Cl2(1 mol %) + AscH2 (20 mM) +
MPAA-PEG (10 eq.) + MPA-PEG (100 eq.)
Ru(bpy)3Cl2(1 mol %) + AscH2 (20 mM) +
MPAA-PEG (10 eq.) + MPA-PEG (100 eq.)
8
MAO-N-9 (180 mg)
>95 [35]e
a
Reaction conditions: 1 (10 mM), E. coli whole cells (MAO-N-9) (180 mg, wet weight), photocatalyst (1 mol%) and reducing agent as specied in each
case, in 1.0 mL phosphate buffer solution (pH 8.0) at ambient temperature with 405 or 450 nm LED (3 W) irradiation on a shaking agitator (at
b
200 rpm, only used for reactions with biocatalyst) for 30 h under air. Yields were determined by 1H NMR analysis, enantiomeric excess was
determined by chiral phase GC or HPLC. c 10 h. d 3 h. e 20 h.
alkyl radical intermediates would proceed sufficiently rapidly intermediates by HAT is non-trivial. Depending on the substrate
(full experimental and mechanistic details are given in the ESI on type, the combination of ascorbic acid with aliphatic or
pages S15–S17†).17 Gratifyingly, this strategy provides an excellent aromatic thiol additives to enable polarity-matched catalysis for
yield (>95%) when using a combination of AscH2, MPAA-PEG, HAT is required. The cooperation between photoredox and
MPA-PEG as reductants and HAT donors, respectively, and enzymatic catalysis for light-driven asymmetric catalysis was
[Ru(bpy)3]Cl2 as a photocatalyst (Table 2, entry 7),22 and 35% rst demonstrated for aliphatic and aromatic cyclic imine to
enantiomeric excess of amine (R)-2e was obtained (entry 8). The enantioenriched amine synthesis. We anticipate that the
moderate enantioselectivity suggests that oxidation of (S)-2e by concepts and methods summarized herein will be widely
MAO-N-9 is still slow, presumably due to the relatively low oxygen applicable to a range of other chemical transformations,
concentration caused by both the photocatalyst and the direct including different photoredox reactions and biocatalysts.
aerobic oxidation of thiols.
Conflicts of interest
Conclusions
There are no conicts to declare.
In summary, this study provides a proof-of-concept of asym-
metric catalysis that results from combining photoredox and
biocatalysis in a cyclic reaction network. Thanks to their
exquisite catalytic properties, enzymes offer an attractive means
Acknowledgements
to complement previously explored strategies for performing Funding from the Swiss National Science Foundation through
asymmetric synthesis under photoredox conditions. The light- the NCCR Molecular Systems Engineering is gratefully
driven reduction of aliphatic and aromatic imines to (racemic) acknowledged. Y. O. acknowledges a JSPS Overseas research
amines in aqueous solution is an important result in itself, fellowship. Prof. Nick Turner is thanked for providing us with
because the rapid interception of carbon-centered radical the MAO-N-9 plasmid.
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22 The ground state reduction potential of [Ru(bpy)3]Cl2 (Ered
¼
ꢀ1.33 V vs. SCE) is sufficient to reduce the aromatic imine
substrate 1e (Ep ¼ ꢀ1.27 V vs. SCE, see ESI† page S30).
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