Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers

Article abstract of DOI:10.1002/anie.201810870

A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of p-unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radical-trapping antioxidants; more so than the phenols from which they are derived—or transformed to—despite the fact that they do not possess a labile H-atom for transfer to the peroxyl radicals that propagate autoxidation.

Full text of DOI:10.1002/anie.201810870

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201810870
German Edition: DOI: 10.1002/ange.201810870
Electrochemical Synthesis
Electrochemical Dimerization of Phenylpropenoids and the Surprising
Antioxidant Activity of the Resultant Quinone Methide Dimers
Kevin J. Romero, Matthew S. Galliher, Mark A. R. Raycroft, Jean-Philippe R. Chauvin,
Irene Bosque, Derek A. Pratt,* and Corey R. J. Stephenson*
Abstract: A simple method for the dimerization of phenyl-
propenoid derivatives is reported. It leverages electrochemical
oxidation of p-unsaturated phenols to access the dimeric
materials in a biomimetic fashion. The mild nature of the
transformation provides excellent functional group tolerance,
resulting in a unified approach for the synthesis of a range of
natural products and related analogues with excellent regio-
control. The operational simplicity of the method allows for
greater efficiency in the synthesis of complex natural products.
Interestingly, the quinone methide dimer intermediates are
potent radical-trapping antioxidants; more so than the phenols
from which they are derived—or transformed to—despite the
fact that they do not possess a labile H-atom for transfer to the
peroxyl radicals that propagate autoxidation.
P
olyphenolic natural products arising from stilbene- or
styrene-derived monomers have drawn substantial interest
due to a wide range of observed biological activities, including
their widely-touted antioxidant properties.[1–3] Their biosyn-
thesis is hypothesized to proceed via the regio- and stereo-
selective coupling of phenoxyl radicals of form 2a–2c to
À
generate products such as hierochin D (3) via C3 C8’
À
coupling and quadrangularin A (4) via C8 C8’ coupling
(Figure 1A).[3,4] Several of the synthetic efforts to recapitulate
this strategy, including our own, have used enzymatic catalysis
or single-electron oxidants, while others have targeted these
molecules through de novo routes.[5–7] Our previous
approaches employed ferrocenium hexafluorophosphate as
a mild stoichiometric oxidant to promote dimerization of
protected resveratrol derivatives, which ultimately enabled
the total synthesis of several dimeric and tetrameric resver-
atrol natural products.[5c–d] While these conditions were high-
yielding and afforded excellent regioselectivity, we sought to
develop a catalytic method that would translate more readily
Figure 1. A) Phenylpropenoid oligomerization occurs via phenoxyl rad-
ical coupling. B) Our electrochemical approach to the oligomerization
of phenylpropenoid scaffolds.
to other systems, especially those that may be prone to
overoxidation. We previously investigated the use of photo-
catalysis to achieve this goal.[5c] Unfortunately, competing
energy transfer pathways resulted in stilbene isomerization,
while stoichiometric terminal oxidants led to decomposition
of the products and/or starting materials. Therefore, an
alternative method for catalytic phenol oxidation was desired.
Several reports have demonstrated the utility of anodic
oxidation in total synthesis,[8–14] but efforts to apply this
approach in the context of phenylpropenoid natural product
total synthesis have been limited by low yields and lack of
regiocontrol.[15–18] Here, we present an electrochemical
method for the regioselective dimerization of various
hydroxystilbene derivatives (Figure 1B). The anodic oxida-
tion reactions proceed at low potential and deliver the
corresponding quinone methide dimers (QMDs) in good to
excellent yields, providing rapid access to multiple natural
product scaffolds in a selective fashion.
[*] K. J. Romero, M. S. Galliher, Dr. I. Bosque,
Prof. Dr. C. R. J. Stephenson
Department of Chemistry, University of Michigan
Ann Arbor, MI 48109 (USA)
E-mail: crjsteph@umich.edu
Homepage: https://www.thestephensongroup.org/
Dr. M. A. R. Raycroft, J.-P. R. Chauvin, Prof. Dr. D. A. Pratt
Department of Chemistry and Biomolecular Sciences
University of Ottawa
Ottawa, Ontario, K1N 6N5 (Canada)
E-mail: dpratt@uottawa.ca
Homepage: https://www.theprattgroup.org/
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.201810870.
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Figure 2. Substrate scope for the electrochemical dimerization of 4-hydroxystilbenes.
To determine whether the desired dimerization would be
feasible under anodic oxidation conditions, we interrogated
the oxidation potential of various 4-hydroxystilbene sub-
strates using cyclic voltammetry (see page S38 of the Sup-
porting Information). In all cases, direct oxidation of the
substrate occured above + 0.8 V, however in the presence of
2,6-lutidine oxidation occurred below + 0.6 V in all cases.
With this information in hand (see page S43 of the Supporting
Information for complete details), we developed conditions
where anodic oxidation in the presence of 2,6-lutidine enables
phenoxyl radical dimerization (Figure 2). The scope of this
reaction was investigated by first varying the substituents of
the resorcinol ring. A range of 3,5-di-tert-butyl-4-hydroxy-
stilbene substrates were prepared from commercially avail-
able starting materials in 2–3 steps (see Supporting Informa-
tion). Various protecting groups were tolerated on the
resorcinol ring without diminishing the yield (5–7). When
the tert-butyl substituents at C3 were exchanged with
trialkylsilyl groups (8, 9), the yield diminished due to the
decreased stability of the QMDs, which we have reported on
previously.[5d] It was apparent that both electron-withdrawing
and electron-donating groups were tolerated at each position
of this aromatic ring as reactions proceeded with a wide
variety of electronically distinct substrates in excellent yields
(10–20). The scope of this chemistry was extended to include
dimerization of the e-viniferin analogue (21/22), whose QMD
product is the key intermediate in our recently reported
syntheses of the natural products nepalensinol B and vater-
iaphenol C.[5d] As observed in the preparation of 5 and 8, the
electrochemical yields of 23 and 24 were comparable to those
obtained using a stoichiometric chemical oxidant, demon-
strating the generality of this method for selective biomimetic
À
synthesis of C8 C8’ resveratrol oligomers (Figure 3A).
Regarding the observed diastereoselectivities in the synthesis
of these QMD products, we presume that these dimers are in
dynamic equilibrium with the corresponding phenoxyl radical
À
monomers via C8 C8’ homolysis as we have previously
characterized for QMDs 5, 8, 23, and 24.[5d] Therefore, the
minimal diastereoselectivity observed for 5–20 is in agree-
ment with prior methods for preparing these materials, as is
the excellent diastereoselectivity observed for 23 and 24. The
influence of additional stereocenters present in 23/24 pre-
sumably has a greater impact on the orientation in which the
persistent radicals recombine, resulting in an increase in
diastereoselectivity when moving from the dimer to the
tetramer system.[19] Importantly, the preparation of tert-
butylated dimers (5–7, 10–20, 23) did not require chromato-
graphic purification, which is highly advantageous for multi-
step syntheses and provides an attractive alternative to
stoichiometric dimerization methods.
The removal of one of the C3 blocking groups resulted in
À
C3 C8’ dimerization, enabling access to the cores of the
natural products d-viniferin (27) and shegansu B (28) exclu-
sively as the trans-diastereomers (Figure 3B), consistent with
prior biomimetic dimerization studies of these types of
hydroxystilbenes.[3] As a result, the regioselectivity for this
transformation is controlled exclusively by the presence or
absence of a C3-blocking group.
2
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Figure 3. A) Electrochemical dimerization delivers the key intermediate for the synthesis of resveratrol tetramers. 2,6-lut.=20 mol%, Electro-
lyte=KPF6 (50 mm), Reference Electrode=Ag/AgCl. B) The removal of the C3-substituent results in a direct C3-C8’ dimerization, affording
dihydrobenzofuran products. 2,6-lut.=20 mol%, Electrolyte=KPF6 (50 mm), Reference Electrode=Ag/AgCl. C) Electrochemical synthesis of (Æ)-
hierochin D. 2,6-lut.=50 mol%, Electrolyte=KPF6 (50 mm), Reference Electrode=Ag/AgCl. D) Preparation of natural product analogue cores
from QMDs.
As described in Figure 1B, the analogous biosyntheses of
the lignan class of natural products prompted us to investigate
an extension of this electrochemical dimerization strategy.
Subjection of coniferyl alcohol (29) to anodic oxidation under
our optimized conditions afforded moderate conversion of
the starting material; gratifyingly, a simple increase in the
concentration of 2,6-lutidine from 20 mol% to 50 mol%
afforded the neolignan natural product (Æ)-hierochin D in
53% yield (3, Figure 3C).
To explore the utility of the electrochemically-synthesized
quinone methide dimers for the preparation of natural
product-like indane and diquinane scaffolds, the QMDs
described in Figure 2 were exposed to Lewis acids that
promote intramolecular Friedel–Crafts cyclizations. While
direct, double cyclization of 5 was successful in our previous
synthesis of the resveratrol dimer pallidol,[5c] QMDs lacking
the resorcinol moiety present in 5 did not react in this fashion.
Instead, substrates with electron-donating groups at C12 (and
their corresponding phenoxyl radicals) were susceptible to
redox disproportionation conditions, returning half of the
material as the stilbene precursor (reduction product) with
loss of the remaining mass to oxidative decomposition (see
Figure S1 on page S85 of the Supporting Information). The
QMDs depicted in Figure 2 were, however, found to be
suitable intermediates for the preparation of analogues of
quadrangularin A (4). Base-mediated isomerization of one
quinone methide followed by Lewis acid activation and
Friedel–Crafts cyclization onto the remaining quinone
methide forged a series of tert-butylated quadrangularin A
analogues (30–33, Figure 3D).
PBD-BODIPY and 1-hexadecene in chlorobenzene at 378C
(Figure 4).[21] PBD-BODIPY enables quantitative determina-
tion of the reaction progress of the autoxidation by UV-vis
spectrophotometry; its consumption by reaction with chain-
carrying peroxyl radicals is associated with a loss of absorb-
ance at 588 nm (Figure 4A). Kinetic analysis of the reaction
progress data according to Equations (1) and (2) enables
determination of the rate constant for the reaction of the RTA
with peroxyl radicals (kinh) as well as the reaction stoichiom-
etry (n) (Figure 4B). Representative data are shown in
Figure 4C and kinetic parameters are tabulated in Figure 4D.
The quadrangularin A analogues 30–33 are all good
RTAs. Their inhibition rate constants are roughly one order
of magnitude greater than BHT (kinh = 2 ꢀ 104 mÀ1 sÀ1), the
quintessential hindered phenolic RTA.[5c] Substitution of the
resorcinol ring has little impact on the reactivity of the
quadrangularin A analogues; most kinh values are within
experimental error of each other, and the maximum differ-
ence is less than a factor of 2. These results are consistent with
our expectation that quadrangularin A and its tert-butylated
derivative inhibit autoxidation via H-atom transfer from the
(hindered) phenolic moiety. The number (n) of peroxyl
radicals trapped per molecule is ca. 4 for all four compounds.
Since compounds 30—33 contain two hindered phenols per
molecule, the maximum expected stoichiometry is 4, corre-
sponding to double that of BHT and other hindered phenols
(e.g. the parent phenols, see Table S2).[22]
To our great surprise, the QMDs from which the quad-
rangularin A analogues were synthesized are very good
RTAs.[23] In fact, despite being devoid of phenolic moieties,
the QMDs are > 10-fold more reactive than the quadrangu-
larin A derivatives (up to 36-fold more reactive for the 4-SMe
derivative 32). Interestingly, monomeric quinone methides
have been reported to be—at best—poor RTAs,[24] suggesting
that the QMD scaffold is special, perhaps due to the
persistence of the quinone methide functionalities relative
to those that have been previously studied.[25]
With these derivatives in hand, we sought to extend our
previous investigations of the radical-trapping antioxidant
(RTA)[20] activities of resveratrol derivatives, which had
revealed that the quadrangularin A scaffold was more
potent than either the pallidol scaffold or the parent
resveratrol scaffold.[5c] Thus, the quadragularin A analogues
were evaluated for their ability to inhibit co-autoxidations of
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Figure 4. A) PBD-BODIPY serves as the signal carrier in 1-hexadecene autoxidations. B) Determination of inhibition rate constants (kinh) and
stoichiometries (n) for reactions of inhibitors with chain-carrying peroxyl radicals. C) Co-autoxidations of 1-hexadecene (2.9m) and PBD-BODIPY
(10 mm) initiated by AIBN (6 mm) in chlorobenzene at 378C (dashed black trace) and inhibited by 5 mm substituted quadrangularin A analogues
(dashed traces) and quinone methide dimers (solid traces). D) Inhibition rate constants and stoichiometries. E) Plausible mechanistic possibilities
for the radical-trapping antioxidant activity of the quinone methide dimers; the DFT-optimized TS structure represents a model for the addition of
(methyl)peroxyl radicals to the meso diastereomer of a model quinone methide dimer.
Mechanistic possibilities for the impressive reactivity of
the QMDs are presented in Figure 4E. At first glance,
mechanism 1 can be excluded solely on the basis of the
magnitude of kinh determined from the inhibited autoxida-
tions (kinh = 2–3 ꢀ 106 mÀ1 sÀ1). H-atom transfer from carbon is
well known to be a relatively slow reaction, even when highly
thermodynamically favorable.[26] Indeed, the CBS-QB3-pre-
dicted[27] rate constants for HAT from a truncated form of the
unsubstituted dimer to a model (methyl)peroxyl radical is
a mere 6mÀ1 sÀ1 (see Supporting Information for the opti-
mized structures, their energies, and the rate constants
estimated therefrom). Mechanism 2 requires tautomerization
of the QMD; however, upon exposing NMR samples of QMD
to deuterated methanol (CD3OD), no deuterium incorpora-
tion was observed. Furthermore, if tautomerization were to
occur, the phenolic tautomer would be expected to exhibit
similar reactivity to the monomeric resveratrol derivative
from which the QMD is derived (kinh ꢀ 105 mÀ1 sÀ1). Mecha-
nism 3 can be excluded solely on the basis of the magnitude of
Keq for the QMD dissociation/recombination equilibrium
(1.8 ꢀ 10À10 m),[5d] as it would necessitate the phenoxyl-peroxyl
combination to proceed with a rate constant well in excess of
the diffusion limit.
substrates (e.g. styrene), not in its inhibition! Of course, the
primary difference in the current context is that the resultant
radical (a hindered phenoxyl) is unreactive to O2 and does not
propagate the autoxidation. Moreover, not only does peroxyl
radical addition produce a more stabilized phenoxyl radical,
but the thermodynamics are greatly enhanced by aromatiza-
tion of the quinone methide. Indeed, CBS-QB3 predicts
DH = À31.5 kcalmolÀ1 for the addition of a model (methyl)-
peroxyl radical to a truncated form of the unsubstituted dimer
along with a rate constant of 4 ꢀ 106 mÀ1 sÀ1, in excellent
agreement with experiment. Further exploration of the RTA
activity of QMDs and how/why they differ from simple
quinone methides are ongoing and will be reported in due
course.
In summary, a general, regioselective method for the
dimerization of 4-hydroxystilbenes and related cinnamyl
alcohol derivatives has been realized utilizing electrochemical
oxidation, providing an operationally simple strategy for the
synthesis of complex phenylpropenoid scaffolds. The adop-
tion of this method will result in a more streamlined approach
for the synthesis of a wide range of naturally-occurring (and
synthetic) phenylpropenoid oligomers, which will greatly
enable studies of their potential biological activities. An
example of such a (preliminary) study is included here,
wherein we have found that the quinone methide dimers
produced upon 4-hydroxystilbene oxidation are surprisingly
potent RTAs.
To the best of our knowledge, mechanism 4 has little
precedent.[23] Although the addition of peroxyl radicals to
carbon-carbon double bonds is well-known, it generally
features in the propagation of autoxidation of unsaturated
4
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We acknowledge the financial support for this research from
the NIH NIGMS (R01-GM121656), the Camille Dreyfus
Teacher–Scholar Award Program, and the University of
Michigan. This material is based upon work supported by
the National Science Foundation Graduate Research Fellow-
ship under Grant No. DGE 1256260 (for K.J.R.). The Ramꢁn
Areces Foundation (Becas para Estudios Postdoctorales) is
acknowledged for a postdoctoral fellowship (for I.B.). This
work was supported by grants from the Natural Sciences and
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The authors declare no conflict of interest.
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Keywords: antioxidants · electrochemistry · phenylpropenoids ·
quinone methides · resveratrol
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Manuscript received: September 20, 2018
Version of record online: && &&, &&&&
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Communications
Electrochemical Synthesis
Quinone methide dimers are prepared via
mild anodic oxidation mediated by
K. J. Romero, M. S. Galliher,
M. A. R. Raycroft, J.-P. R. Chauvin,
I. Bosque, D. A. Pratt,*
a cheap and readily available amine base
with excellent yield and regiocontrol. This
strategy provides rapid access to inter-
mediates for the synthesis of phenylpro-
penoid oligomers in a catalytic fashion,
providing a new tool for the total syn-
thesis of these complex molecules.
C. R. J. Stephenson*
&&&& — &&&&
Electrochemical Dimerization of
Phenylpropenoids and the Surprising
Antioxidant Activity of the Resultant
Quinone Methide Dimers
6
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