Synthetic C6-Functionalized Aminoflavin Catalysts Enable Aerobic Bromination of Oxidation-Prone Substrates

Article abstract of DOI:10.1002/anie.202009657

Flavoenzymes catalyze oxidations via hydroperoxide intermediates that result from activation of molecular O₂. These reactions—such as hydroxylation and halogenation—depend on the additional catalytic activity of functional groups in the peptide

Full text of DOI:10.1002/anie.202009657

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Accepted Article
Title: Synthetic C-6 Aminoflavin Catalysts Enable Aerobic Bromination
of Oxidation-Prone Substrates
Authors: Alexandra Walter and Golo Storch
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202009657
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Synthetic C6-Functionalized Aminoflavin Catalysts Enable
Aerobic Bromination of Oxidation Prone Substrates
Alexandra Walter[a] and Golo Storch*[a]
[a]
M.Sc. A. Walter and Dr. G. Storch
Department Chemie
Technische Universität München
Lichtenbergstr. 4, 85747 Garching (Germany)
E-mail: golo.storch@tum.de
Supporting information for this article is given via a link at the end of the document.
Abstract: Flavoenzymes catalyze oxidations via hydroperoxide
intermediates that result from activation of molecular O2. These
reactions—such as hydroxylation and halogenation—depend on the
additional catalytic activity of functional groups in the peptide
environment of the flavin cofactor. We report synthetic flavin catalysts
that contain C-6 amino modifications at the isoalloxazine core and are
consequently capable of mediating halogenations outside the peptide
surrounding. The catalysts are competent in selective, biomimetic
bromination of oxidation-prone phenols, flavones, and flavanones
using a halide salt in combination with 2,6-lutidinium oxalate as flavin
reductant under visible light irradiation. Our studies show the
beneficial effect of stacked bisflavins, as well as the catalytic activity
of the flavin modifications. The designed flavin catalysts outperform
isolated, natural (–)-riboflavin and contribute to the continuing search
for tailored flavins in oxidation reactions.
One strategy was reported by the Gulder laboratory and centered
around the flavin mononucleotide (FMN) cofactor, which was
used for conversion of O2 from air to hydrogen peroxide in
combination with vanadium-dependent enzymes for halogenation
of aromatic substrates (Figure 1B, middle).[13] The first fully non-
enzymatic flavin-mediated halogenation reaction was reported by
König et al. using (–)-riboflavin for hydrogen peroxide generation
and subsequent oxidation of hydrochloric acid (Figure 1B,
bottom).[14] The authors used para-methoxybenzyl alcohol
(pMBA) as reductant for photoexcited (–)-riboflavin and identified
acetic acid as crucial catalytic shuttle for hydrogen peroxide via
intermediate peracetic acid formation under the acidic conditions.
In nature, flavoenzymes mediate a large variety of chemical
transformations relying on the identical cofactor flavin adenine
dinucleotide (FAD).[1] Upon conversion to FADH2 by reduced
nicotinamide adenine dinucleotide (NADH), they are able to
activate molecular oxygen from air, which occurs via one electron
reduction and HOO· radical recombination with the cofactor
(Figure 1A, left side).[2] The resulting C-4a hydroperoxide is a
highly activated reactive intermediate—with more than 103-fold
increased reactivity for oxygen transfer when compared to
hydrogen peroxide[3]—and mediates reactions including olefin
epoxidation,[4] hydroxylation,[5] heteroatom oxidation,[6] and
Baeyer-Villiger oxidation.[7] A unique subset of these oxidations is
the conversion of inorganic halide salts into hypohalites in
halogenase enzymes. Mechanistic studies suggest that
hypohalites are transferred to substrates via a lysine residue’s
primary amino group, which either serves as hydrogen bond
donor when protonated or is converted to an intermediate
haloamine (Figure 1A, right side).[8]
Flavoenzymatic halogenations have also been transferred to the
organic laboratory,[9] highlighted by the successful application of
the fungal halogenase RadH in mono-bromination of monocillin II
and other bioactive compounds (Figure 1B, top).[10] While in
general the potential of flavin-mediated transformations for
organic synthesis has been recognized,[11,12] reports on
biomimetic flavin-catalyzed halogenation are scarce—
presumably due to the absence of catalytically active residues,
when the cofactor is isolated from the enzymatic surrounding.
Figure 1. Aerobic halogenation reactions with flavins. A) Mechanistic proposal
for flavoenzymatic halogenation. B) Representative strategies for flavin-
mediated halogenations in organic synthesis. RFTA: (–)-Riboflavin tetraacetate.
1
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We were intrigued by the idea to synthetically modify non-
enzymatic flavin catalysts in order to achieve activation of
molecular oxygen as well as electrophilic halogenation without the
need of additional catalysts or mediators. Moreover, we aimed to
facilitate these reactions in organic solvents and also to apply
them successfully to oxidation-prone substances containing free
phenols, which would significantly increase the synthetic utility of
these reactions. Modification of the isoalloxazine core with an
amino group seemed promising, since the resulting flavins were
anticipated to be less oxidizing,[15] reducing substrate
decomposition, while also providing a synthetic handle for
installing hydrogen bond donors or nitrogen-based Lewis bases
in analogy to the lysine side chain activity. Two synthetic flavin
designs were studied (Figure 2A): First, in flavins based on amine
1, the C-6 position is functionalized in order to position the ‘side
arm’ close to the reactive quinoid center. Second, bisflavins 2,
based on trans-1,2-diaminocyclohexane,[16] contain two
isoalloxazines in a stacked arrangement, thereby locating the C-6
functionality proximal to the opposite side’s quinoid center as well.
reductants is known,[11] including Hantzsch ester, dithionite, zinc,
and hydrazine, however, none of the common reductants is (i)
soluble in organic solvents, (ii) unreactive towards other functional
groups, and additionally (iii) not quenched by oxidizing catalysis
intermediates such as hydroperoxides, hypohalous acids, or
hydrogen peroxide. Inspired by studies on oxalate oxidase
enzymes and the activity of photoexcited (–)-riboflavin in CO2
release from oxalic acid,[17] we became interested in using the
latter as convenient flavin reductant. Oxalic acid itself is insoluble
in organic solvent but 2,6-lutidinium oxalate (2:1 mixture, ‘LutOx’)
indeed acts as
a competent reductant for (–)-riboflavin
tetraacetate (RFTA) in dichloromethane upon irradiation with blue
LED light (Figure 3A and supporting information).
Figure 3. Reversible flavin reduction using 2,6-lutidinium oxalate (‘LutOx’).
A) Reduction of RFTA in dichloromethane. B) Divergent reactivity of thiourea
flavin 4 upon exposure to aerobic conditions and halide salt.
Figure 2. Synthesis of C-6 aminoflavin catalysts. A) Route to aminoflavin
platform compounds. i) CbzCl, MgO, 71%. Preparation of 1: ii) CyNH2, K2CO3,
93%; iii) SnCl2, quant.; iv) alloxan, B2O3, 92%; v) C12H25I, K2CO3, 65%; vi) HBr,
77%. Preparation of 2: ii) (R,R)-DACH, K2CO3, 78%; iii) SnCl2, 85%; iv) alloxan,
B2O3, 78%; v) C12H25I, K2CO3, 94%; vi) HBr, 86%. B) Functionalization of 2: vii)
3,5-bis(trifluoromethyl)phenyl
isocyanate,
48%,
viii)
3,5-
bis(trifluoromethyl)phenyl isothiocyanate, 65%. Functionalizations of 1 were
performed analogously. DACH: 1,2-diaminocyclohexane.
We then studied the reactivity of thiourea flavin 4 towards
hydrogen peroxide—as a mimic for flavin C-4a hydroperoxides—
in the presence of inorganic halide salt (Figure 3B). Within
minutes, we observed selective formation (91% isolated yield) of
disulfide-type compound 5 by a reaction that proceeds especially
Both synthetic procedures commence with 3-fluoro-2-nitroaniline
and consist of a sequence of Cbz protection, SNAr reaction, nitro
group reduction, condensation with alloxan, N-3 alkylation, and
Cbz deprotection (Figure 2A). Amines 1 and 2—bench stable,
deep black compounds—were obtained in multigram quantities
and N-3 dodecylation ensures their solubility in a wide range of
organic solvents. The C-6 amino groups were converted into urea
(3) and thiourea (4) functionalities, which serve as efficient
hydrogen bond donors (Figure 2B).
well in dilute solution (1.5 mM, see supporting information) and is
similar to the dimerization of simple alkyl thioureas.[18] In stark
contrast, when irradiated with ‘LutOx’ under otherwise similar
conditions, clean Jacobsen-Hugershoff-type[19] reaction occurred
and bis-2-aminobenzothiazole flavin
6 was formed. This
divergence is also observed when 4 is treated with excess I2
under argon, which leads to 5 in the dark while 6 is formed
predominantly under blue LED irradiation. We assume that a
photoredox mechanism is operative under irradiation and
outcompetes sulfur-sulfur bond formation. Consistent with this
With our synthetic route established, we then focused on the
reduction of the isoalloxazine core as the first crucial step in
aerobic flavin halogenation (see Figure 1A). A number of suitable
analysis, the thiourea derived from monoflavin
1 shows
2-aminobenzothiazole (7) formation within minutes also when
2
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using H2O2 and LiBr since no competing intramolecular reaction
partner is present.
times did not result in increased yield. We then moved to C-6
amino monoflavins (entries 2–3) and observed that urea catalyst
8 led to less decomposition of 9, but both reactions did not
improve the bromination yield. However, we noted that the
experiment with monoflavin 7 had decolored during the course of
the reaction, and after applying shorter reaction times, the yield of
bromination increased. We aimed for beneficial effects of slow
and controlled formation of oxidizing species using bisflavins 3, 5,
and 6 under oxidative halogenation conditions, and indeed
decreased decomposition was observed in these cases (entries
4—6). While 3 and 5 did not improve the product yield,
benzothiazole 6 resulted in 58% bromination with a good overall
mass balance of 70%. Control experiments confirmed that light,
flavin catalyst, and reductant are each required (see supporting
information, which also contains a solvent screening). The optimal
catalyst loading was 5 mol%, which highlights the flavin stability.
We then studied, whether benzothiazole flavins 6 and 7 are also
reduced by ‘LutOx’ via irradiation under inert conditions (Figure 4).
They appear as deep red compounds with absorption in the
visible range (ꢀꢁꢂꢃ= 420 (6) and 426 nm (7) in CH2Cl2) and show
fluorescence (ꢀꢄꢃ= 410 nm, see supporting information) at ꢀꢁꢂꢃ
=
593 (6), and 573 nm (7). This prompted us to apply blue LED light
for excitation and indeed, clean reduction of 7 occurred. When
exposed to air, the sample was re-oxidized concomitant to O2
reduction. This method was also suitable for bisflavin 6 albeit
significantly slower when compared to 7. Urea flavins 3 and 8
(urea derived from 1) were reduced even more slowly (see
supporting information). Decomposition was observed when
applying the conditions to disulfide 5.
Figure 4. ‘LutOx’ reduction of benzothiazole flavin catalysts. A) Under argon, a
sample of 7 and ’LutOx’ (5 equiv.) in CD2Cl2 was irradiated for 3 h with a blue
Kessil® LED (43% reduction). The tube was then opened to air.
B) Photochemical ‘LutOx’ reductions of 6 and 7 under O2 with (red) and without
(black) lithium bromide. Concentrations were monitored by HPLC.
Before employing the flavin catalysts in aerobic halogenation
reactions with inorganic halide sources, we probed the stability of
Figure 5. Application of C-6 aminoflavin catalysts in the aerobic, biomimetic
halogenation of model tyrosine 9. Sodium dihydrogen phosphate was added as
a mild proton source. Yields were determined by NMR spectroscopy versus
internal standard. [a]: Reaction time 4 h. [b]: Reaction time 45 min. [c]: No
catalysts 6 and 7 under these conditions. When irradiated (ꢀꢁꢂꢃ
=
457 nm, LED) under O2 (Figure 4B, black triangles) in the
presence of ‘LutOx’ reductant, 7 was observed to be almost fully
intact (>90%) after 2 h. However, when inorganic lithium bromide
salt was added, rapid decomposition occurred (red triangles). The
catalyst lifetime of 6 was much higher (red squares), presumably
as a result of the continuous slow generation of Br+ equivalents.
This encouraged us to apply flavin 6 in catalysis.
irradiation since Hantzsch ester (HEH) reduces
3,5-Bis(trifluoromethyl)phenyl. SM: Starting material.
6 in the dark. Ar =
Hantzsch ester[20] and para-methoxybenzyl alcohol[21]—both
competent flavin reductants—did not yield significant quantities of
10 under our conditions (entries 7–8). Interestingly, the
N-methylated catalyst 11 showed diminished activity, and
positional isomer 12 did not even yield 10 in any measurable
quantity (entries 9–10). This observation stimulated our interest in
probing the catalytic activity of the 2-aminobenzothiazole
functionality during halogenation catalysis. Therefore, we studied
the activity of flavin 7 in two different routes for bromination of
tyrosine derivative 9, which mimic the early and late stage
processes of the full biomimetic halogenation sequence. We first
As
a proof-of-principle reaction, we chose the biomimetic
halogenation of model tyrosine 9 with molecular O2 and inorganic
bromide salt in dichloromethane as solvent (Figure 5). These
conditions were expected to be compatible with the oxidation-
prone phenol as well as acid- (N-Boc) and base-sensitive (methyl
ester) protecting groups. Parent (–)-riboflavin tetraacetate (RFTA)
resulted in unselective substrate decomposition, and only 12%
bromination products were observed (Entry 1). Shorter reaction
3
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probed for activity when using tert-butylhydroperoxide—as flavin
C-4a hydroperoxide mimic—in combination with lithium bromide
under otherwise identical catalytic conditions (see supporting
information). Indeed, flavin 7 showed significant catalytic activity.
In a second approach, we used N-bromosuccinimide as Br+-
source and again found rate enhancement when using flavin 7 as
catalyst (see supporting information). Both experiments point
towards active catalytic participation of the 2-aminobenzothiazole
group in bromination catalysis.
present study is, therefore, anticipated to serve as critical starting
point for site-selective flavin catalysis.
Acknowledgements
The Chemical Industry Funds (PhD Fellowship to A.W and Liebig
Fellowship to G.S) is gratefully acknowledged. Our group is
supported by the Technical University of Munich through the
Junior Fellow Programme. G.S. is very grateful to Prof. T. Bach
for his continuous support. We thank Dr. A. Bauer for assistance
with UV/Vis spectroscopy and O. Ackermann for HPLC analyses.
Having observed bromination over unselective substrate
decomposition, we expanded our catalysis studies to different
kinds of oxidation-prone, phenolic substrates (Figure 6). Other
N-terminal tyrosine protecting groups such as Cbz (13) and Fmoc
(14) are tolerated, which highlights the compatibility with
oxidation-prone benzylic positions. Dipeptides like Boc-Tyr-Val-
OMe 15 are suitable substrates as well. Additionally, a variety of
flavones, umbelliferon, and flavanones resulted in efficient,
regioselective mono-bromination (16–19). Throughout all
examples, (–)-riboflavin tetraacetate led to decomposition
independent of the chosen reaction time (see supporting
information).
Keywords: Flavin catalysis • Biomimetic halogenation •
Reversible Redox interconversion • Non-covalent interactions •
Photoredox catalysis
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Entry for the Table of Contents
From decomposition to oxalate-fueled halogenation: Upon photoexcitation with visible light, synthetic C-6 aminoflavin catalysts
are reversibly reduced by 2,6-lutidinium oxalate and allow activation of molecular oxygen. In the presence of halide salt, the strategy
is successful in biomimetic halogenation of oxidation-prone tyrosine, flavone, as well as flavanone substrates, while natural
(–)-riboflavin leads to decomposition.
6
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