Combined Photoredox/Enzymatic C?H Benzylic Hydroxylations

Article abstract of DOI:10.1002/anie.201909426

Chemical transformations that install heteroatoms into C?H bonds are of significant interest because they streamline the construction of value-added small molecules. Direct C?H oxyfunctionalization, or the one step conversion of a C?H bond to a C?O bond, could be a highly enabling transformation due to the prevalence of the resulting enantioenriched alcohols in pharmaceuticals and natural products,. Here we report a single-flask photoredox/enzymatic process for direct C?H hydroxylation that proceeds with broad reactivity, chemoselectivity and enantioselectivity. This unified strategy advances general photoredox and enzymatic catalysis synergy and enables chemoenzymatic processes for powerful and selective oxidative transformations.

Full text of DOI:10.1002/anie.201909426

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201909426
German Edition: DOI: 10.1002/ange.201909426
À
C H Functionalization
À
Combined Photoredox/Enzymatic C H Benzylic Hydroxylations
Rick C. Betori, Catherine M. May, and Karl A. Scheidt*
Abstract: Chemical transformations that install heteroatoms
synthesis, leading to chemical processes that are less wasteful,
into C H bonds are of significant interest because they
ultimately more sustainable.[2] Direct C H oxyfunctionaliza-
À
À
streamline the construction of value-added small molecules.
tion is of vital importance, in particular due to the prevalence
of the resulting enantioenriched alcohols and ketones in
pharmaceuticals, natural products, and fine chemicals.[3]
À
Direct C H oxyfunctionalization, or the one step conversion
À
À
of a C H bond to a C O bond, could be a highly enabling
transformation due to the prevalence of the resulting enan-
tioenriched alcohols in pharmaceuticals and natural products,.
Here we report a single-flask photoredox/enzymatic process
À
While traditional methods to effect C H oxidations of
activated bonds require harsh conditions,[4] contemporary
À
approaches can provide C H oxidations employing catalytic
for direct C H hydroxylation that proceeds with broad
metal complexes and mild oxidants.[5] With the emergence of
À
reactivity, chemoselectivity and enantioselectivity. This unified
strategy advances general photoredox and enzymatic catalysis
synergy and enables chemoenzymatic processes for powerful
and selective oxidative transformations.
photoredox[6] and electrochemical catalysis,[7] additional ave-
À
nues to afford C H functionalization products have emerged
as valuable synthetic possibilities.[8] Moreover, molecular
oxygen (O2) has emerged as a powerful and “green” oxidant
under simple and mild conditions, in both thermal and
photoredox contexts.[9] However, despite the well-established
À
T
he selective activation of C H bonds has attracted the
attention of chemists as a powerful strategy to directly install
À
À
chemical methods for C H oxidation, enantioselective C H
oxidation processes pose additional challenges because not
only must a reagent or catalyst be chiral and capable of
new functionality into the hydrocarbon framework of com-
pounds (Figure 1A).[1] As a result, C H functionalization has
À
À
emerged as a powerful strategy to streamline multi-step
oxygenating C H bonds, but also its reactivity must be
properly tuned to minimize over-oxidations.
Notably, enzymatic oxygenases and halogenases, such as
cytochrome P450s, have emerged as alternative means for
À
enantioselective C H functionalization processes (Fig-
ure 1B).[10] Despite the utility of P450s and related enzymes
À
in enantioselective C H oxidations, these enzymes are
À
dependent on substrate-enzyme interactions for both C H
activation and engendering stereocontrol, resulting in the
observed reactivity being difficult to predict.[11] This approach
results in catalysts that are selective towards focused substrate
classes, albeit functioning with superb reactivity and stereo-
selectivity.[12] While these advances have revolutionized C H
À
À
functionalization logic, the integration of C H bond activa-
tion by substrate-guided chemical catalysis with the selectivity
control by enzymatic catalysts promiscuous across substrate
classes has the potential to provide a complementary new
À
avenue for enantioselective C H oxidation chemistries.
This union of chemical and enzymatic catalysis (termed
“chemoenzymatic”) has emerged because of its capability in
powerful bond transformations.[13] In particular, the merger of
photocatalysis with biocatalysis has gained increased atten-
tion recently.[14] In general, these two reaction manifolds are
suitable candidates for combination because photocatalytic
reactions typically occur at or neat ambient temperature and
proceed through reactive intermediates that are stable
towards water and function groups in proteins. Of particular
note, the Hartwig laboratory disclosed a tandem cooperative
photocatalytic/ene-reductase reaction to afford enantio-
enriched chiral building blocks.[14c] The Hyster laboratory
disclosed utilizing photocatalysis in combination with nicoti-
namide adenine dinucleotide phosphate (NAD(P)H) depen-
dent ketoreductases (KREDs)[14a] and ene-reductases[14b,15] to
facilitate non-native enzymatic reactivity. The Hçhne and
À
Figure 1. Approaches to benzylic C H hydroxylation.
[*] R. C. Betori, C. M. May, Prof. Dr. K. A. Scheidt
Department of Chemistry, Center for Molecular Innovation and Drug
Discovery, Northwestern University
2145 Sheridan Road, Evanston, IL 60208 (USA)
E-mail: scheidt@northwestern.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.201909426.
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Schmidt laboratories demonstrated the combination of pho-
À
tocatalytic C H functionalization with benzaldehyde lyases,
ene-reductases, ketoreductases and aminotransferases; how-
ever, this chemistry was limited to low conversion and
restricted substrate classes.[16]
Additionally, both photoredox and enzymatic catalysis
have attracted great attention in the pharmaceutical industry
for the synthesis of active pharmaceutical ingredients.[17]
Notwithstanding the potential of photocatalytic/enzymatic
chemoenzymatic catalysis, this merger provides new oppor-
tunities to develop selective and valuable chemical trans-
formations. Despite the established capabilities of photo-
À
chemical methods for C H oxidations and enzymatic car-
bonyl reductions, the union of these two distinct chemistries
has not yet been realized to its fullest potential. Of particular
value is that this sequential catalytic reactivity affords not
only a powerful bond transformation, but also is attractive
because of the decreased operation costs and waste gener-
ation associated with a two-step procedure, as well as
minimizing the need for purification/isolation of intermedi-
ates. Herein we report the realization of this approach using
combined, single-flask photoredox/enzymatic catalysis for
Figure 2. Optimization of reaction conditions.
À
enantioselective hydroxylation of benzylic C H bonds (Fig-
ure 1C).
With optimal catalysts for both reactions, we turned to the
optimization of a process that would allow for both of these
operations to occur in a single flask. After considerable
experimentation, we found that IPA was deleterious to the
photoredox oxidation, and irradiation resulted in the enan-
tioenriched alcohol being reverted to the aromatic ketone
(Figure 2A). We circumvented this issue by delayed addition
of IPA after complete conversion of 1a with cessation of
irradiation, allowing for isolation of 3a in 85% yield with
> 99:1 er (Figure 2C). Control experiments demonstrated
that no conversion was observed when Acr+-Mes ClO4À, O2,
or light were omitted, and only aromatic ketone was observed
in the absence of either the KRED or NADPH (Figure 2B).
We envisioned 9-mesityl-10-methylacridinium ion (Acr+-
Mes ClO4 )[18] as an ideal catalyst for the photocatalytic
À
À
oxygenation of a C H bond due to its strong oxidizing ability
(E1/2 = 2.06 V vs. SCE). Mechanistically, we hypothesize that
the photocatalyst Acr+-Mes ClO4À is excited by blue LEDs to
generate [Acr+-MesClO4 ]* which undergoes single electron
À
À
transfer (SET) with the electronically benzylic C H bond to
generate the [Acr+-MesClO4 ] radical anion and the benzylic
À
radical cation.[19] The [Acr+-MesClO4 ]CÀ is subsequently
À
oxidized by O2 to regenerate Acr+-Mes ClO4 and form
À
O2CÀ, while the benzylic radical cation loses one proton to
form the benzylic radical. The benzylic radical may then react
with either an additional equivalent of O2 or O2CÀ to form the
hydroperoxidate intermediate, which upon dehydration ren-
ders the desired ketone product. Alternatively, the hydro-
peroxidate intermediate may also disproportionate to the
benzyl alcohol, which is subsequently oxidized by Acr+-Mes
ClO4À. The ketone is then reduced by a KRED using
NAD(P)H as the hydride source to provide the alcohol
product and NAD(P), which is regenerated to NAD(P)H
using isopropyl alcohol (IPA). Before attempting a single
flask photoredox/enzymatic procedure, we sought to identify
suitable conditions for the photoredox and enzymatic reac-
tion steps independently (Figure 2). The independent photo-
À
With this single flask C H hydroxylation process firmly
developed, we investigated the scope of this process (Table 1).
We surveyed a variety of substituted ethylbenzenes, and the
desired products were obtained in excellent yields and
enantioselectivities. Substrates bearing either electron-rich
or electron-neutral substituents were well tolerated across
substitution patterns on the aromatic ring (3a–3j). Unsur-
prisingly, unstabilized or electron-poor ethylbenzenes showed
no conversion under our optimized conditions, presumably
because the Acr+-Mes ClO4À is unable to oxidize the benzylic
methylene (E1/2 = 2.21 V vs. SCE for ethylbenzene). How-
ever, substituting for the more strongly oxidizing 4-mesityl-
redox reaction with Acr+-Mes ClO4 and O2 in 1:9
2,6-diphenylpyrylium tetrafluoroborate photocatalyst (E1/2 =
À
CH3CN:H2O provided 2a in 89% isolated yield after 4
hours. With these optimized photoredox oxidation conditions,
we evaluated the enzymatic reduction with 2a by surveying
a panel of isolated enzymes from Codexis Inc. (see the
Supporting Information for experimental details). We were
pleased to find that KRED-P1-A04 delivered 3a in 94%
isolated yield with > 99:1 er from 2a. Notably, no loss of
KRED activity was observed in the presence of 10% v/v
CH3CN, indicating the compatibility of the two reaction
processes.
2.62 V vs. SCE) provided facile oxidation of these substrates,
allowing for synthesis of the alcohols in good yields and
enantioselectivities (3k–3m).[20] A variety of diarylmethane
substrates were investigated, allowing access to diarylmetha-
nols.[21] Diarylmethanols are precursors for compounds with
physiologically interesting properties.[22] Electron-rich and
electron-poor substituents were well tolerated on either
aromatic ring (5a–5i). In addition, two substrates, 1a and
4a, were demonstrated on gram scale.g (7a–7d), d-lactones
(9a–9d) and a-hydroxy esters (11a–11d) were accessible in
2
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[a]
À
Table 1: Scope of photoredox/enzymatic C H hydroxylation.
Figure 3. Site-selectivity studies.
Radical scavenger experiments with either (2,2,6,6-tetra-
methylpiperidin-1-yl)oxyl (TEMPO) or butylated hydroxyto-
luene (BHT) resulted in neither 5a nor 20 being observed,
indicating this transformation involves radical intermediates
(Figure 4A). Likewise, radical clock experiments validated
Figure 4. Mechanistic studies.
this, where 21 provided 22 in 61% yield (Figure 4B). To
evaluate if the racemic benzyl alcohol is a potential inter-
mediate in the photoredox catalysed synthesis of the aromatic
ketone, we exposed racemic 5a to our optimized reactions
conditions, and were pleased to find that we obtained
enantiopure 5a in excellent yield. Notably, this one-pot
oxidation/reduction process serves as a deracemization of
benzyl alcohols (Figure 4C). “Light/dark” experiments (see
SI) and quantum yield measurements (f = 0.85) demon-
strated that this photoredox process proceeds through
a closed catalytic photoredox cycle.[24] Lastly, deuterium-
labelling studies demonstrated a primary kinetic isotope
[a] Reported yields are determined after isolation by column chroma-
tography. See the Supporting Information for experimental details.
[b] Reactions ran using 2 mol% 4-mesityl-2,6-diphenylpyrylium tetra-
fluoroborate photocatalyst.
good yields and enantioselectivities. A series of b-amino
alcohols were also prepared in good yields and enantioselec-
tivities (13a–13i). Attempts to access heteroaromatic or
allylic alcohols resulted in decomposition, and substrates
À
À
with non-activated C H bonds were inert.
effect, making it likely that the C H bond cleavage is rate
determining (see SI).
To evaluate the factors that govern the site-selectivity in
À
À
this reaction, substrates with multiple benzylic C H bonds
An efficient photoredox/enzymatic protocol to access C
were evaluated. The subjection of ortho-ethyl/benzyl-substi-
tuted phenyl acetates (14a–14b) demonstrated superb site
selectivity, providing isochroman-3-ones (15a–15b) in excel-
lent yield and enantioselectivity. 16 and 18 results in selective
hydroxylation at the more electron rich site as the sole
product observed (17 and 19). These results represent a highly
streamlined method for the preparation of enantioenriched
benzylic alcohols.[23]
H hydroxylation products with high yield and enantioselec-
tivities has been developed. Notably, this reaction broadens
the opportunities of combining light-based activation and
enzymatic processes. We anticipate that the concepts herein
integrating substrate-guided oxidation with enzymatically-
enforced enantioselectivity will be applicable to a range of
À
transformations involving photoredox/biocatalysis and C H
functionalization.
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Acknowledgements
We thank the National Institute of General Medical Sciences
(GM073072, GM131431) for financial support. R.C.B. was
supported in part by the Chicago Cancer Baseball Charities at
the Lurie Cancer Center of Northwestern University and
T32GM105538.
À
Tehshik, Site-Selective Alkoxylation of Benzylic C H Bonds via
Photoredox
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Conflict of interest
The authors declare no conflict of interest.
À
Keywords: C H oxidation · chemoenzymatic catalysis ·
chiral alcohols · ketoreductase · photoredox catalysis
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Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
À
C H Functionalization
R. C. Betori, C. M. May,
K. A. Scheidt*
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À
Combined Photoredox/Enzymatic C H
Benzylic Hydroxylations
Light and enzymes: A strategy for
chemoenzymatic catalysis combining
photoredox catalysed oxidation and
enzymatic reduction has been developed.
This single-flask process affords value-
added enantiomerically enriched benzylic
alcohols across a wide variety of sub-
strate classes.
6
www.angewandte.org
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
These are not the final page numbers!