Angewandte
Chemie
DOI: 10.1002/anie.201409773
Resveratrol
Hot Paper
A Scalable Biomimetic Synthesis of Resveratrol Dimers and Systematic
Evaluation of their Antioxidant Activities**
Bryan S. Matsuura, Mitchell H. Keylor, Bo Li, YuXuan Lin, Shelby Allison, Derek A. Pratt,* and
Corey R. J. Stephenson*
Abstract: An efficient synthetic route to the resveratrol
oligomers quadrangularin A and pallidol is reported. It
features a scalable biomimetic oxidative dimerization that
proceeds in excellent yield and with complete regioselectivity.
A systematic evaluation of the natural products and their
synthetic precursors as radical-trapping antioxidants has
revealed that, contrary to popular belief, this mode of action
is unlikely to account for their observed biological activity.
ing innovative approaches from the Nicolaou/Chen,[6a] Sar-
pong,[6b] and Studer[5f] groups. Following this precedent, we
sought to rapidly access chemical diversity from common
intermediates in a controlled fashion, and to address lingering
questions regarding the role of resveratrol-derived natural
products as bioactive small molecules. The total synthesis of
pallidol (2)[8] and quadrangularin A (3),[9] and the systematic
evaluation of their RTA activities, are reported herein.
Owing to the electron-rich nature of resveratrol (E(ox)
<
T
he resveratrol (1) oligomers are a diverse set of polyphe-
0.7 V vs Ag/AgCl),[10] we reasoned that its oxidation by
a visible-light photoredox catalyst would be feasible,[11] thus
enabling catalytic generation of the requisite phenoxyl radical
for dimerization. In considering our reaction design, we drew
inspiration from the seminal report of Hou and Li,[5a] in which
they demonstrated that tert-butyl resveratrol derivative 4a
(Scheme 1) could be dimerized regioselectively. However, as
a result of apparent issues with oxidation and oligomerization
of product dimers in the reaction mixtures, we instead elected
to use the benzyl-protected resveratrol derivative 4b. Pre-
liminary efforts using photoredox catalysis resulted in mix-
tures of the dimeric isomers 5, 6, and 8 (Scheme 1) in yields
highly dependent on the solvent and the presence/absence of
base.[12] Extensive reaction optimization[13] revealed that the
phenoxide of 4b[14] undergoes a remarkably efficient and
selective dimerization to bis-quinone methide 5 (60–80%)
under aerobic conditions, but a significant decrease in
selectivity and reproducibility was observed on scale-up. To
overcome this limitation, we exchanged O2 for ferrocenium
hexafluorophosphate ([FeCp2]PF6)[15] as the oxidant, which
reliably provided 5 in more than 95% yield on decagram
scale. To the best of our knowledge, this represents the highest
yield and largest scale yet reported for oxidative dimerization
of a resveratrol derivative.[4]
nolic natural products, the stress-factor-induced biosynthesis
of which constitutes an important chemical defense mecha-
nism in many plants.[1] Numerous reports of their health-
promoting potential have generated widespread interest in
these compounds,[2] much of which has been focused on their
capacity as radical-trapping antioxidants (RTAs). However,
systematic studies of this activity are lacking, since inves-
tigators often assay only the position of their thermodynamic
equilibrium with oxidants in solution, and not whether the
relevant radical-trapping reactions are kinetically competitive
under physiological conditions.[3]
With their intriguing biological activities and fascinating
molecular architectures, the resveratrol oligomers have
inspired a number of synthetic endeavors.[4] Early work
aimed to replicate nature’s approach, which is believed to
involve single-electron oxidative coupling processes. While
construction of these molecules in such a fashion would
support their proposed biogenesis, efforts to date have
resulted in low yields and/or complex mixtures of products.
Recognizing this shortcoming, Snyder and co-workers devel-
oped powerful de novo strategies towards resveratrol
dimers[5b,c,6c,d] and higher-order oligomers.[7] These impressive
studies prompted a number of subsequent syntheses, includ-
The dimerization produces an inseparable mixture of
meso and dl diastereomers 5/5’, and the relative configuration
of the vicinal stereogenic centers has important (and likely
biogenically relevant) consequences for the synthesis of
pallidol (2) and quadrangularin A (3; Scheme 1). The dl
diastereomer of 5 has the correct relative configuration to
undergo two sequential cyclizations to provide the [3.3.0] ring
system present in pallidol (2). By contrast, after the initial
Friedel–Crafts reaction of meso-5, the anti/anti configuration
of product indane 6 precludes a second cyclization event
owing to the thermodynamically unfavorable formation of
a trans-fused bicyclo[3.3.0]octane.[16] Addition of BF3·OEt2 to
a dilute solution of 5/5’ at À788C gave the desired pallidol
derivative 7a in 43% yield of isolated product. The remaining
mass balance was 6 (45%) and a complex mixture of
oligomerized material. Hydrogenolysis of 7a followed by
[*] B. S. Matsuura,[+] M. H. Keylor,[+] Prof. Dr. C. R. J. Stephenson
Department of Chemistry, University of Michigan
Ann Arbor, MI 48109 (USA)
E-mail: crjsteph@umich.edu
B. Li, Y. Lin, S. Allison, Prof. Dr. D. A. Pratt
Department of Chemistry, University of Ottawa
Ottawa, ON K1N 6N5 (Canada)
E-mail: dpratt@uottawa.ca
[+] These authors contributed equally to this work.
[**] Financial support was provided by grants from the NIH-NIGMS
(GM096129), University of Michigan, Alfred P. Sloan Foundation,
the Camille and Henry Dreyfus Foundation, Eli Lilly and Novartis to
CRJS and NSERC, CFI and the University of Ottawa to DAP. DAP is
Canada Research Chair in Free Radical Chemistry.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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