Divergent Total Syntheses of Flavonoid Natural Products Isolated from Rosa rugosa and Citrus unshiu

Article abstract of DOI:10.1055/s-0035-1561851

The concise and step-economical total syntheses of three hydroxyaurones and one polymethoxyflavone from readily available starting materials is described. A divergent synthetic strategy is employed, which centres on a common chalcone scaffold from which both the aurone and flavone frameworks can be accessed through the use of different oxidative cyclisation methods. These are the first reported total syntheses of these biologically interesting compounds.

Full text of DOI:10.1055/s-0035-1561851

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–C
letter
A
T. J. Sum et al.
Letter
Synlett
Divergent Total Syntheses of Flavonoid Natural Products Isolated
from Rosa rugosa and Citrus unshiu
Tze Jing Sum
R2
Tze Han Sum
O
R1
R1
HO
O
Warren R. J. D. Galloway
David R. Spring*
O
HO
O
O
rugaurones A–C
+
R2
R1
Department of Chemistry, University of Cambridge, Lensfield
Road, Cambridge, CB2 1EW, U.K.
spring@ch.cam.ac.uk
MeO
R2
OMe
MeO
MeO
O
common chalcone
scaffold
OMe
OMe
readily available starting materials
O
3,6,7,8,2',5'-hexamethoxyflavone
Received 23.01.2016
Accepted after revision: 28.02.2016
Published online: 04.03.2016
R2
MeO
OMe
MeO
O
DOI: 10.1055/s-0035-1561851; Art ID: st-2016-d0044-l
OMe
MeO
O
MeO
OMe
O
Abstract The concise and step-economical total syntheses of three
hydroxyaurones and one polymethoxyflavone from readily available
starting materials is described. A divergent synthetic strategy is em-
ployed, which centres on a common chalcone scaffold from which both
the aurone and flavone frameworks can be accessed through the use of
different oxidative cyclisation methods. These are the first reported to-
tal syntheses of these biologically interesting compounds.
R1
O
rugaurone A (1); R1 = OMe, R2 = OH
rugaurone B (2); R1 = OH, R2 = OH
rugaurone C (3); R1 = OH, R2 = OMe
3,4,7,8,2',5'-
hexamethoxyflavone (4)
Figure 1 Naturally occurring hydroxyaurones 1–3 isolated from Rosa
rugosa and a 5-deoxyflavone (4) isolated from Citrus unshiu
Key words flavonoids, hydroxyaurones, chalcones, divergent, total
synthesis, natural products
thought that sufficient amounts of materials for biological
screening studies could only be secured by total synthesis.
Herein, we report the first total syntheses of compounds 1–
4, which were achieved in a step-efficient fashion by the
application of a divergent and concise synthetic strategy.
Based on our previous work on flavonoid synthesis,13
we envisaged a divergent strategy for the construction of
natural products 1–4 which used a chalcone scaffold (of the
general form 5) as the key branch point (Scheme 1). It was
anticipated that both the aurone and flavone frameworks
(general structures 6 and 7, respectively) could be accessed
from 5 by the application of different oxidation methods;4
mercury(II) acetate mediated oxidative cyclisation of chal-
cones 5 would yield aurones 6,1 whereas Algar–Flynn–Oya-
mada oxidation with H2O2 under alkaline conditions would
furnish the 5-deoxyflavone framework 7.4 Based on our
previous study,13 it was presumed that the chalcone precur-
sors 5 could be easily accessed via a Claisen–Schmidt aldol
condensation between benzaldehydes 8 and acetophenones
9.4
Aurones1 and flavones2 are two subclasses of the flavo-
noid family of natural products.3 Flavonoids have been
found to exhibit a diverse array of interesting biological
properties such as anticancer,4 antimalarial,5 anti-inflam-
matory,6 antioxidant,7 antibacterial8 and antifungal9 activi-
ties. Unsurprisingly therefore, natural flavonoids have at-
tracted considerable interest from both the synthetic and
medicinal chemistry communities.10
In 2012, Gao et al. reported the isolation and characteri-
sation of three new aurones, named rugaurones A–C (1–3)
from the flowers of Rosa rugosa (Figure 1).11 These com-
pounds were found to have promising cytotoxic and anti-
HIV properties. In the same year, Shin et al. reported the
isolation of three previously unreported flavonoids from
the peels of mature fruits of Citrus unshiu Marcow (Rutace-
ae), one of which was named 3,6,7,8,2′,5′-hexamethoxyfla-
vone (4).12 These peels have been used in traditional Chi-
nese medicine and some isolates from C. unshiu have been
reported to exhibit antiproliferative effects. Given the inter-
esting biological profiles of compounds 1–4 (and the di-
verse array of properties typically associated with flavo-
noids in general), we were interested in a more extensive
assessment of their biological activities. In view of the very
low isolation yields of 1–4 from natural sources, it was
The total syntheses of rugaurones A–C (1–3) was
achieved by the application of this divergent synthetic
strategy (Schemes 2 and 3). Benzaldehyde precursor 11 was
prepared from commercially available 4-hydroxybenzalde-
hyde (10) by MOM protection (Scheme 2). In parallel, the
acetophenone building block 13 was accessed from 3,4-di-
methoxyphenol (12). Claisen–Schmidt aldol condensation
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–C

B
T. J. Sum et al.
Letter
Synlett
ry(II) acetate in pyridine furnished the corresponding au-
rones 23 and 24 and MOM deprotection yielded the desired
natural products, rugaurones B (2) and C (3)
R1
R1
O
O
O
R2
R2
OH
MOMCl
hydroxyaurones (6)
5-deoxyflavone (7)
MeO
HO
OH
MeO
HO
OH
O
BF3⋅OEt2
K2CO3
acetone
MeCO2H
HO
O
16
17; 86%
O
R2
R1
chalcones (5)
MeO
OH
O
KOH, EtOH
R1
19; R1 = OMOM
20; R1 = OMe
MOMO
18; 49%
HO
O
CHO
R2
R1
+
MeO
OH
O
R1
O
21; R1 = OMOM; 33%
22; R1 = OMe; 23%
8
9
MOMO
Scheme 1 Retrosynthetic analysis of the hydroxyaurones 6 and 5-de-
oxyflavone 7
R1
Hg(OAc)2
pyridine
MeO
of 11 and 13 proceeded smoothly to afford the key chalcone
intermediate 14.4,14 Intramolecular mercury(II) acetate
mediated oxidative cyclisation1 produced the intermediate
aurone 15 in high yield and subsequent acid-mediated
MOM deprotection afforded the desired natural product,
rugaurone A (1).
O
23; R1 = OMOM; 78%
24; R1 = OMe; 70%
MOMO
R1
O
HCl
MeOH
MeO
HO
O
rugaurone B (2); R1 = OH; 93%
rugaurone C (3); R1 = OMe; 50%
HO
MeO
OH
O
O
Scheme 3 Synthesis of rugaurones B (2) and (3)
MeO
10
12
MOMCl
K2CO3, acetone
BF3⋅OEt2
MeCO2H
Attention was next turned toward the preparation of
the polymethoxyflavone 4 (Scheme 4).
MeO
MeO
OH
O
MOMO
O
H2O2
H2SO4
MeOH
OMe
OMe
11; 86%
13; 98%
BF3⋅OEt2
MeCO2H
MeO
MeO
OH
MeO
OMe
O
KOH
EtOH
OMe
25
26; 93%
KOH, EtOH
MeO
MeO
OH
O
OMOM
MeO
MeO
OH
O
Hg(OAc)2
pyridine
OMe
28
O
R
MeO
OMe
27; 79%
14; 17%
MeO
NaOH, H2O2
EtOH
MeO
MeO
OH
O
15; R = OMOM; 84%
HCl, MeOH
OMe
MeO
MeO
MeO
OMe
29; 59%
O
rugaurone A (1); R = OH; 49%
O
MeO
MeO
O
OMe
MeI
Scheme 2 Synthesis of rugaurone A (1)
K2CO3
acetone
OH
30; 55%
O
MeO
OMe
Rugaurones B (2) and C (3) were prepared in a similarly
efficient manner (Scheme 3). Starting from the commer-
cially available hydroquinone 16, acetophenone 17 was
synthesised in high yield. Regioselective MOM protection of
17 afforded 18, which was condensed with the correspond-
ing aldehydes 19 and 20 under basic ethanolic conditions to
give the required MOM-protected chalcones 21 and 22, re-
spectively. Subsequent oxidative cyclisation with mercu-
MeO
O
OMe
polymethoxyflavone (4); 94%
MeO
OMe
O
Scheme 4 Synthesis of polymethoxyflavone (4)
The synthesis commenced with the oxidation of benzal-
dehyde 25 to give phenol 26. Subsequent acylation fur-
nished acetophenone 27 in a good yield.15 A Claisen–
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–C

C
T. J. Sum et al.
Letter
Synlett
Schmidt aldol condensation between 27 and aldehyde 28
furnished chalcone 292 and Algar–Flynn–Oyamada oxida-
tion4 yielded the corresponding flavonol scaffold 30. Meth-
ylation of 30 with methyl iodide in acetone under reflux
then afforded the desired polymethoxyflavone 4 in an ex-
cellent yield.
European Union’s Seventh Framework Programme (FP7/2007–
2013)/ERC grant agreement no. [279337/DOS]. The authors also
thank AstraZeneca, the European Union (EU), the Engineering and
Physical Sciences Research Council (EPSRC), the Biotechnology and
Biological Sciences Research Council (BBSRC), the Medical Research
Council (MRC), and the Wellcome Trust for funding.
The divergent strategy employed in the synthesis of nat-
ural products 1–4 centres on the selective conversion of
chalcone intermediates into aurones or flavones through
the use of different oxidation procedures. Attempts to ra-
tionalise this selectivity are complicated by uncertainties
regarding the mechanisms of these oxidations. It has been
suggested that Algar–Flynn–Oyamada oxidation to form the
flavone scaffold may proceed by direct intramolecular at-
tack of the phenol oxygen on the alkene (presumably a con-
jugate addition process) or via an intermediate epoxide de-
rivative;16–18 it is possible that stereoelectronic factors play
a role in dictating the regioselectivity in both cases, though
these are difficult to delineate.18,19 The exact mechanistic
details of the mercury(II) acetate mediated oxidative cycli-
sation of chalcones to aurones are also unknown. Most evi-
dence points toward a mechanism which involves forma-
tion and cyclisation of an aryloxy–mercury(II) acetate spe-
cies,20–23 rather than an electrophilic addition pathway
(involving activation of the alkene bond by the mercury
species and hydroxy participation).20 It has been suggested
that five-membered ring formation from the aryloxy–mer-
cury(II) acetate species (which leads to the aurone scaffold)
is favoured over six-membered ring formation (which leads
to the flavone scaffold) due to steric effects.23
In conclusion, the first total syntheses of the natural
products rugaurones A–C (1–3) and polymethoxyflavone
(4) have been achieved. A divergent synthetic strategy was
employed,13 which allowed access to these biologically in-
teresting compounds in an expedient and step-efficient
fashion from readily available starting materials. Notably,
multi-milligram quantities of all four natural products were
generated, which should provide ample material for screen-
ing in biological assays. The divergent strategy is currently
being applied to the synthesis of unnatural analogues of
compounds 1–4 to allow the sampling of novel chemical
space around these biologically relevant structures. This
work, together with the results of biological screening in-
vestigations, will be reported in due course.
Supporting Information
Data accessibility: all data supporting this study are included in the
paper and provided as Supporting Information accompanying this pa-
per. It is available online at http://dx.doi.org/10.1055/s-0035-
1561851.
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We thank the Cambridge Commonwealth Trust for the awards of
scholarships to T.J.S. and T.H.S. The research leading to these results
has received funding from the European Research Council under the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–C