Concise synthesis of prenylated and geranylated chalcone natural products by regiospecific iodination and Suzuki coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2013.12.044

Four natural chalcones bearing prenyl or geranyl groups, i.e., isobavachalcone (1), bavachalcone (2), xanthoangelol (3), and 2′,4′,4-trihydroxy-5′-geranylchalcone (isoxanthoangelol, 4) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. Among them, the first total synthesis of 2′,4′,4-trihydroxy-5′-geranylchalcone was achieved in 36% overall yield. Comparing with the reported methods based on C-alkylation or O-alkylation followed by Claisen rearrangement to introduce the side chain, this new strategy capitalizes on a precious regiochemical control during iodination. The overall yields for the synthesis of the first three chalcones were improved from 17% to 53%, 12% to 35%, and 28% to 50%, respectively.

Full text of DOI:10.1016/j.tetlet.2013.12.044

Tetrahedron Letters 55 (2014) 897–899
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise synthesis of prenylated and geranylated chalcone natural
products by regiospecific iodination and Suzuki coupling reactions
a,
Haomeng Wang a, Zhihong Yan a, Yanan Lei a, Kai Sheng b, Qingwei Yao c, Kui Lu a, , Peng Yu
⇑
⇑
a Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, College of Biotechnology, Tianjin University of Science
& Technology, Tianjin 300457, China
b Tianjin Tianfayuan Agency Center for Environmental Protection Affairs Co. Ltd, Tianjin 300384, China
c Chemo Dynamics, Inc., 3 Crossman Road South, Sayreville, NJ 08872, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Four natural chalcones bearing prenyl or geranyl groups, i.e., isobavachalcone (1), bavachalcone (2), xan-
thoangelol (3), and 20,40,4-trihydroxy-50-geranylchalcone (isoxanthoangelol, 4) were synthesized by using
a regio-selective iodination and the Suzuki coupling reaction as key steps. Among them, the first total
synthesis of 20,40,4-trihydroxy-50-geranylchalcone was achieved in 36% overall yield. Comparing with
the reported methods based on C-alkylation or O-alkylation followed by Claisen rearrangement to intro-
duce the side chain, this new strategy capitalizes on a precious regiochemical control during iodination.
The overall yields for the synthesis of the first three chalcones were improved from 17% to 53%, 12% to
35%, and 28% to 50%, respectively.
Received 11 October 2013
Revised 1 December 2013
Accepted 10 December 2013
Available online 19 December 2013
Keywords:
Chalcones
Regiospecific
Iodination
Ó 2013 Elsevier Ltd. All rights reserved.
Suzuki coupling reaction
Introduction
subsequently finished the total synthesis of 1, 2, and 3 with
17.2%, 12.4%, and 28.1% overall yield, respectively.11 Both of these
Chalcones containing prenyl or geranyl groups are an abundant
subclass of flavonoids widely found in nature and display a variety
of biological and pharmacological activities. Isobavachalcone (1),
first isolated from Psoralea corylifolia,1a showed antibacterial, anti-
fungal, anticancer, anti-reverse transcriptase, antitubercular, and
antioxidant activities;1–3 Bavachalcone (2), also isolated from
Psoralea corylifolia,1a,4a, was shown to display a significant inhibi-
tory effect on baculovirus-expressed BACE-1 in vitro4b as well as
inhibition on osteoclast differentiation.4c This natural chalcone also
syntheses used O-alkylation followed by Claisen rearrangement as
key steps to introduce the prenyl or geranyl groups and poor regio-
selectivity of the latter process was found to be the main reason for
the low overall yield. Recently McGlinchey applied iodination and
OH
OH
HO
OH
HO
exhibits extremely high a
-glucosidase inhibitory activity.5 Xantho-
angelol (3), isolated from fresh roots of A. keiskei,6 exhibits antibac-
terial activity against Gram-positive pathogenic bacteria7
antitumor-promoting activity and cytotoxicity against neuroblas-
toma cells;8 The newly discovered compound 4, 20,40,4-trihy-
droxy-50-geranylchalcone and coined here as isoxanthoangelol,
which was isolated from the leaves of Artocarpus communis, was
reported to possess anticancer activity in SW 872 human liposar-
coma cells (Fig. 1).9 Due to their structural uniqueness and potent
bioactivity, the synthesis of prenylated or geranylated chalcone
natural products has attracted much attention in recent years. In
2010, Jung reported the first total synthesis of 3 with a total yield
of 16.8% starting from 2,4-dihydroxyacetophenone.10 Sugamoto
O
OH
O
2
1
Bavachalcone
Isobavachalcone
OH
OH
HO
HO
OH
OH
O
4
O
3
2',4',4-trihydroxy-5'-geranylchalcone
(Isoxanthoangelol)
Xanthoangelol
⇑
Corresponding authors. Tel.: +86 22 60601268; fax: +86 22 60602298.
E-mail addresses: lukui@tust.edu.cn (K. Lu), yupeng@tust.edu.cn (P. Yu).
Figure 1. Selected chalcones containing prenyl or geranyl groups.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.044

898
H. Wang et al. / Tetrahedron Letters 55 (2014) 897–899
Stille coupling to the synthesis of isobavachalocone. However,
overall efficiency was observed due to poor regiochemical control
for the iodination as well as the low yield for the Stille coupling.12
As part of our ongoing program on the synthesis of flavonoid
and chalcone natural products, we recently reported a regioselec-
tive iodination of flavonoids by NIS under neutral conditions
(Scheme 1).13 In this Letter, we report regioselective iodinations
of chalcone derivatives using this protocol and the total synthesis
of the aforementioned chalcone natural products by Suzuki cou-
pling of the iodinated intermediates as the key step.14
In the event, iodide 8 was readily synthesized from the bis-
MOM derivative 10 by iodination with NIS in DMF.13 Base pro-
moted condensation of 8 with aldehyde 11 afforded the iodo pre-
cursor 6 (Scheme 3).
HO
Me
OH
MOMO
Me
OMOM
NaH
NIS (1.2 eq)
DMF, 50 ºC
MOMCl
CH2Cl2
87%
70%
O
O
9
10
CHO
(11)
MOMO
OMOM
Results and discussion
MOMO
O
OMOM
MOMO
Me
OMOM
Scheme 2 shows our retro-synthetic analysis for the synthesis
of the chalcones 1–4. The prenyl or geranyl groups will be installed
by Suzuki coupling of the two iodo chalcone derivatives 5 and 6
with the corresponding boronic acid esters. The required iodo
precursors can be derived from compounds 7 and 8. Based on
our findings on the regioselective monoiodination of flavonoids,
the latter two iodo derivatives can be readily prepared from a
common starting material, 4-acetylresorcinol (9), through regiose-
lective iodination of its MOM-protected forms.
I
I
60% KOH (aq), EtOH
92%
O
8
6
Scheme 3. Synthesis of key intermediate 6.
Table 1
Suzuki coupling reaction of compound 6 under different conditionsa
O
B
O
MOMO
MOMO
O
OMOM
(12)
1.2 eq
6
Y
Pd/ligand
base, DMF
R2O
O
O
13
X
OR1
NIS
NIS
(1.2 equiv)
Entry Temperature °C Pd/ligand (5 mol%) Base (1.4 equiv) Yieldb (%)
(1.2 equiv)
DMF, 70 oC
58%-86%
1
2
3
4
5
6
7
8
70
70
70
70
70
70
70
80
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
PdCl2(dppf)
PdCl2(PPh3)2
PdCl2(dppf)
CsF
35
30
30
25
58
84
53
55
DMF, r.t.
52%-80%
KOAc
I
Cs2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Y
Y
R2O
I
O
R2O
O
O
X
X
OH
O
OR1
R1 = H; R2 = Me, Et, Bn;
X = H, OMe, OEt, OBn, O-glycone
R1 = R2 = Me, Et, Bn;
X = H, OMe, OEt, OBn, O-glycone
a
Reaction conditions: 6 (1.0 mmol), 12 (1.2 mmol), catalyst (0.05 mmol), and
base (1.4 mmol) in DMF (3 mL) were heated to 70 °C or 80 °C by microwave for 2 h.
Scheme 1. Regioselective iodination of flavonoids by NIS.13
b
Isolated yield after purification by silicon gel chromatography.
R
HO
HO
O
OH
1N HCl
MeOH
75%
HO
HO
O
OH
HO
HO
O
OH
R
13
2
Isobavachalocone (1): R = prenyl;
Xanthoganelol (3): R = geranyl
Bavachalcone (2): R = prenyl
Isoxanthoangelol (4): R = geranyl
Bavachalocone
Scheme 4. Synthesis of bavachalone (2).
Suzuki at C-3'
I
Suzuki at C-5'
HO
HO
OMOM MOMO
MOMO
OMOM
O
I
MOMO
MOMO
OMOM
B
O
O
O
5
6
(14)
6
PdCl2(dppf), Cs2CO3
O
DMF, 70 o
82%
C
I
15
HO
Me
OMOM
MOMO
Me
OMOM
I
HO
HO
O
OH
O
O
2N HCl
MeOH,THF, 55 oC
72%
7
8
HO
Me
OH
mono-MOM
protection
bis-MOM
protection
4
9
O
Isoxanthoangelol
Scheme 2. Retro-synthetic analysis for the synthesis of chalcones 1–4.
Scheme 5. The first total synthesis of isoxanthoangelol (4).

H. Wang et al. / Tetrahedron Letters 55 (2014) 897–899
899
To guarantee an effective Suzuki coupling protocol for the
installation of the desired alkyl group, the reaction of 6 with 3,3-
dimethylallylboronic acid pinacol ester (12) was optimized by test-
ing a variety of palladium catalysts and bases. (entries 1–8, Table 1).
This led us to the identification of PdCl2(dppf) along with Cs2CO3 in
DMF at 70 °C as the optimal catalyst system for the formation of
intermediate 13, which was isolated in 84% yield after purification
by column chromatography. Removal of the MOM protecting
groups furnished the final target, bavachalcone (2) (Scheme 4).
By using the same protocol, the first total synthesis of 20,40,4-tri-
hydroxy-50-geranylchalcone, isoxanthoangelol (4) was achieved
through Suzuki coupling of geranylboronic acid pinacol ester
1415 with the same iodo precursor followed by MOM removal in
59% overall yield from 6 (Scheme 5).
protected substrate 16 led to the formation of 7 along with a
significant amount of its regioisomer 17 (Scheme 6). However,
utilization of an alternative iodination system (I2/KIO3)16 provided
a much cleaner access to the analogous iodide 19 directly from 9
(Scheme 7).
With compound 19 in hand, the total synthesis of both xanthog-
anelol (1) and isobavachalocone (3) uneventfully achieved under
similar conditions with an overall yield of 53% and 50%, respec-
tively, from the commercial material 9 (Scheme 8).
Conclusion
In summary, 20,40,4-trihydroxy-50-geranylchalcone or isoxan-
thoangelol (4) was first synthesized in 36% overall yield from 4-
acetylresorcinol along with another three C-alkylated chalcone
natural products, isobavachalcone (1), bavachalcone (2) and xan-
thoangelol (3) in significant improved overall yields over the meth-
ods previously reported by employing regio-selective iodination
and the Suzuki coupling reaction as the key steps. Extension of
the new approach developed in this work to the synthesis of other
C-alkyl substituted flavonoids, biflavonoids, and their derivatives is
underway in our lab.
Synthesis of isobavachalocone (1) and xanthoganelol (2) neces-
sitates a 2-iodo-4-acetylresorcinol derivative such as 7 (Scheme 2).
Unfortunately, the protocol for the regieoselective iodination
developed for the flavonoid substrates did not work as anticipated
for the desired iodination product 7. Iodination of the mono-MOM
I
HO
Me
OMOM
HO
Me
OMOM
HO
Me
OMOM
NIS
(1.2 eq)
+
I
DMF, r.t.
Acknowledgments
O
O
O
I
16
7
40%
17
32%
The authors sincerely thank the financial support from National
Science Foundation of China (Grants 21202118, 81241104), and
China International Science and technology cooperation projects
(2013DFA31160).
Scheme 6. Iodination of compound 16.
I
Supplementary data
HO
Me
OH
HO
Me
OH
I2, KIO3
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
12.044.
EtOH, H2O
98%
O
O
9
19
Scheme 7. Iodination of compound 9.
References and notes
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I
NaH
MOMO
Me
OMOM
MOMO
CHO
(11)
MOMCl
CH2Cl2
90%
19
60% KOH (aq), EtOH
95%
O
20
O
I
12: R = prenyl
R
B
14: R = geranyl
MOMO
MOMO
OMOM
O
PdCl2(dppf), Cs2CO3
DMF, 70 o
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O
21
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MOMO
MOMO
OMOM
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O
22: R = prenyl, 84%
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R
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HO
HO
OH
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O
1: R = prenyl,75%
3: R = geranyl, 73%
Scheme 8. Synthesis of xanthoganelol (1) and isobavachalocone (3).