Angewandte
Communications
Chemie
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
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
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