Total synthesis of (±)-quadrangularin A

Article abstract of DOI:10.1002/anie.200603097

The key to successful coupling in the synthesis of (±)- quadrangularin A (1) was the introduction of tert-butyl groups in the precursor to block two reactive positions. Thus, the oxidative coupling of 3,5-di-(tert-butyl) resveratrol was carried out regioselectively in an efficient total synthesis of the natural product. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200603097

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Chemie
Natural Products Synthesis
develop new strategies for the synthesis of these compounds.
As part of a program to study the biomimetic synthesis of
stilbene oligomers,[4] we report herein an approach to the
synthesis of compound 1 based on regioselective oxidative
coupling.
DOI: 10.1002/anie.200603097
Total Synthesis of (ꢀ )-Quadrangularin A**
To design a synthetic route to 1,it is essential to
understand the possible biosynthetic mechanism for the
dimerization of 7 in vivo. At least three important mesomers,
M5, M8,and M 10,have been identified as being derived from 7
under enzymatic catalysis in the organism.[5] Coupling reac-
tions between these radical mesomers could produce various
Wenling Li, Hao Li, Ying Li, and Zijie Hou*
Pais and co-workers isolated (ꢁ)-quadrangularin A (1) from
the stem of Cissus quadrangularis in 1999.[1] Several analogues
of 1,compounds 2–6,have been obtained from other plants
(Scheme 1).[1,2] These molecules are all dimers or substituted
dimers of resveratrol (7) with an indane skeleton. To date,no
synthetic effort towards this family of compounds has been
reported. Although cyclodimerizations of stilbene under
acidic conditions to form indanes and/or tetralins have been
studied extensively,[3] this strategy is not generally applicable
to the synthesis of natural oligostilbenes owning to poor
stereoselectivity and the limitation to stilbene substrates.
Therefore,it remained a significant challenge for chemists to
resveratrol dimers,such as the natural products 1, 8,and
9
(Scheme 2). The structural complexity of the oligomers
results from the diversity of the coupling modes,which also
increases the difficulty of their regiocontrolled biomimetic
synthesis in vitro.
Scheme 1. Quadrangularin A (1) and analogues 2–6.
Scheme 2. Possible biosynthetic pathways of resveratrol dimers.
[*] W. Li, H. Li, Prof. Y. Li, Prof. Z. Hou
State KeyLaboratoryof Applied Organic Chemistryand
Department of Chemistry
Resveratrol oligomers have novel structures and a wide
range of biological activity but low natural abundance;
therefore,many chemists have studied the oxidative coupling
of resveratrol under a variety of conditions since e-viniferin
(8) was first isolated in 1977 by Langcake and Pryce.[6]
However,the major product obtained was mostly the 5–8-
coupling product,that is,resveratrol trans-dehydrodimer (9),
regardless of whether enzymes (peroxidase[7] or laccase[8]) or
inorganic oxidants (FeCl3, K3(FeCN)6,or Ag 2O) were used.[9]
Thus,we deduced that the 5–8-coupling mode occurs
predominantly and that its product 9 is stable under the
oxidative conditions employed. We believed that the critical
step for the synthesis of the 8–8-coupling product 1 could be
Lanzhou University
222 Tianshui Street S., Lanzhou 730000 (P.R. China)
Fax: (+86)931-891-2582
E-mail: houzj@lzu.edu.cn
W. Li
Department of Chemical and Biological Engineering
Lanzhou RailwayUniversity
Lanzhou 730000 (P.R. China)
[**] We are grateful to Prof. H.-L. Zhang and Dr. J.-C. Liao for helpful
discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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made possible by impeding the formation of the 5–8-
coupling product 9.
Enlightened by the work of Sarkanen and Wallis,
who found that the presence of non-hydrogen
substituents (OMe or tert-butyl) adjacent to the
phenolic hydroxy group of some phenylpropanoids
hindered the undesired 5–8 and 8–O coupling and
greatly enhanced the chance of the 8–8 coupling
(Scheme 3),[10] we decided to introduce tert-butyl
protecting groups at C3 and C5 of resveratrol to
favor a regioselective coupling reaction. The advant-
age of this method is that tert-butyl substituents can
be conveniently incorporated into and efficiently
removed from aromatic substrates.[11] Thus,the
synthetic route to 1 was designed and carried as
shown in Scheme 4.
The coupling precursor 3,5-di-(tert-butyl)resver-
atrol (17) was prepared in seven steps from 3,5-
dihydroxybenzoic acid (10). First,the dibenzyl
alcohol 11 was made from 10 through a straightfor-
ward three-step sequence of esterification,benzyl
protection,and reduction. [12] Compound 11 was then
converted into the dibenzyl chloride 12,[13] and 12
was transformed into the phosphonium salt 13. To
form the second substrate for the planned olefina-
tion, 14 was oxidized with Br2 in tert-butanol to
produce the aldehyde 15.[14] A Wittig reaction
between 13 and 15 in toluene at reflux afforded the
E stilbene 16 in good yield; it was not necessary to
protect the phenolic hydroxy group of 15. Finally,the
benzyl protecting groups were removed[4] from 16 to
give the coupling precursor 17 in 53% overall yield.
Next,the treatment of 17 with horseradish
[15]
peroxidase (HRP) and H2O2 in aqueous acetone
at room temperature under an argon atmosphere for
48 h gave the 8–8-coupling product 18 in 35% yield.
This result validated our original hypothesis. It was
noted that the prolonged reaction time or the large
amount of H2O2 used resulted in the formation of
minor trimeric products.[16] The structure of 18 was
established on the basis of HRMS, 1H NMR,
13C NMR,and 2D correlation NMR spectral data.
The presence of a quinone methide moiety in 18 was
supported by the existence of three mutually coupled signals
corresponding to methine hydrogen atoms (8-H,8 ’-H,7 ’-H)
and a signal corresponding to an olefinic hydrogen atom (7-
H) in the 1H NMR spectrum,as well as a signal corresponding
Scheme 4. Total synthesis of (ꢀ)-1. Reagents and conditions: a) CH3OH, H2SO4,
reflux; b) PhCH2Br, K2CO3, DMF, RT; c) LiAlH4, Et2O, RT; d) SOCl2, Et3N, benzene,
08C!RT; e) PPh3, xylene, reflux; f) Br2, tert-butanol, RT; g) nBuLi, toluene, RT!
reflux; h) AlCl3, PhNMe2, CH2Cl2, 08C; i) HRP/H2O2, acetone/water (3:1), RT;
j) Al2O3, benzene, RT; k) AlCl3, CH3NO2, toluene, 608C. Bn=benzyl, DMF=N,N-
dimethylformamide.
to a carbonyl carbon atom (C4) in the 13C NMR spectrum.
The HMBC cross peaks of 7-H/C2,8 ’-H/C10’,C1’,C7, and 7’-
H/C9,C9’,C2’ further confirmed the positions of the aromatic
rings on the indane moiety. Furthermore,the relative trans
configuration of the three methine hydrogen atoms 8-H,8 ’-H,
and 7’-H was established by an NOE difference experiment,
which showed NOE correlations at 8-H/10’-H and 7’-H/10’-H.
Finally, 18 underwent a prototropic rearrangement in the
presence of Al2O3,[10] and the tert-butyl protecting groups
were removed from the resulting compound 19[11] to provide
the target racemic product 1. All spectral data of 1 were in
good agreement with the data reported in the literature for
the natural product.[1] The relative stereochemistry of 19 was
also assigned by an NOE difference experiment. The key
NOE correlation between 7-H and 14-H indicated an
E configuration of the double bond,and NOE interactions
Scheme 3. Proposed coupling mechanism of some phenylpropanoids.
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trimers 20 and 21 because of the prolonged reaction time or the
large amount of H2O2 used. The structures of 20 and 21 were
determined by 1D and 2D NMR spectroscopy.
at 8’-H/2’-H and 7’-H/10’-H suggested that rings D and E have
a trans relationship.
In summary,we have completed the first total synthesis of
(ꢀ )-quadrangularin A (1) in 11 steps and 15% overall yield
from 3,5-dihydroxybenzoic acid (10). The key coupling
reaction could be carried out regioselectively by introducing
tert-butyl groups to protect alternative reactive positions in
the coupling precursor. Most importantly,this strategy may be
used as an efficient general method for the synthesis of other
naturally occurring oligostilbenes. The application of this
synthetic route to analogues of 1 is currently in progress in our
laboratory.
Received: July 31,2006
Published online: October 19,2006
Keywords: biomimetic synthesis · natural products ·
.
oligostilbenes · oxidative coupling · total synthesis
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