Total synthesis of acetylcholinesterase inhibitor macakurzin C

Article abstract of DOI:10.1055/s-0034-1378904

A concise total synthesis of macakurzin C has been accomplished in nine steps (21% overall yield) from commercially available phloroglucinol, featuring a sequential aromatic Claisen rearrangement-cyclization.

Full text of DOI:10.1055/s-0034-1378904

2794▌
LETTER
letter
Total Synthesis of Acetylcholinesterase Inhibitor Macakurzin C
Total Synthesis of Macakurzin C
Dongjoo Lee,a Iljin Shin,a Eunjae Ko,a Kiyoun Lee,b Seung-Yong Seo,c Hyoungsu Kim*a
a
College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea
Fax +82(31)2193435; E-mail: hkimajou@ajou.ac.kr
b
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines, Road,
La Jolla, California 92037, USA
c
College of Pharmacy, Gachon University, Incheon 406-840, Republic of Korea
Received: 29.08.2014; Accepted after Revision: 02.10.2014
Interestingly, macakurzin C (3) showed potent AChE in-
hibitory activity (IC50 = 20 μM), while closely related ma-
cakurzin B (2) displayed no activity against AChE (no
inhibition at 50 μM against AChE). Based on the initial re-
sults, Mai and Pham demonstrated that the lack of a hy-
droxyl group in the pyran ring of 3 increased the activity
in comparison with 2. Due to the interesting biological
properties of 3, further studies on the structure–activity re-
lationship of 3 may be crucial for developing more potent
drug candidates. However, its natural source is too scarce
(0.006% isolated yield from crude EtOAc extracts).
Macakurzin C was previously synthesized in very poor
overall yield (<3%) by prenylation at C(6) in glalangin
and DDQ-mediated oxidative cyclization of the resultant
C(6)-prenylated galangin.3 Therefore, we sought to devel-
op an efficient and scalable synthetic route that would
provide a sufficient quantity of 3 and its analogues for ex-
tensive in vitro/in vivo biological studies to develop more
potent AChE inhibitors. Herein, we report a concise and
efficient synthetic route to 3 through a sequential aromatic
Claisen rearrangement and cyclization.4,5
Abstract: A concise total synthesis of macakurzin C has been ac-
complished in nine steps (21% overall yield) from commercially
available phloroglucinol, featuring a sequential aromatic Claisen re-
arrangement–cyclization.
Key words: total synthesis, natural products, aromatic Claisen re-
arrangement, acetylcholinesterase inhibitors, flavonoids
Natural products exhibiting acetylcholinesterase (AChE)
inhibition are considered as promising new entities for the
treatment of Alzheimer’s disease (AD), because most
promising drugs for symptomatic of AD are AChE inhib-
itors. Thus, flavonoids with AChE inhibitory activity are
of interest for the medicinal chemistry community.1
Recently, macakurzins A–C (1–3, Figure 1) were isolated
from the leaves of Macaranga kurzii (Euphorbiaceae) col-
lected from Yen-Bai, Vietnam by Mai and Pham in 2012.2
Their structures were determined by extensive NMR
spectroscopic analysis, and the absolute stereochemistry
of macakurzins A and B were both identified as racemic
mixture by their esterification with Mosher’s reagent.2
H
O
B
O
O
8
O
O
Ph
7
HO
O
7
D
A
C
O
O
1
2
3
OH
4
6
OBn
OH
5
5
O
OH
O
HO
OH
OH
O
macakurzin C (3)
H
OH
O
OH
4
macakurzin B (2)
macakurzin A (1)
HO
O
Ph
BzO
O
Ph
7
4
5
7
B
O
O
OBn
OBn
5
D
A
C
O
O
OH
O
OH
6
OH
O
5
macakurzin C (3)
Scheme 1 Retrosynthetic plan
Figure 1 Macakurzin A, B, and C
Our retrosynthetic plan for macakurzin C (3) is outlined in
Scheme 1. We envisioned that the synthesis of macakurz-
in C (3) could be accomplished from aryl propargyl ether
5 by a tandem aromatic Claisen rearrangement–cycliza-
tion for the D ring in the natural product. We expected that
the chemoselective cyclization of the C(7) phenolic
hydroxyl over the C(5) hydroxyl in allenyl bisphenol 4
SYNLETT 2014, 25, 2794–2796
Advanced online publication: 29.10.2014
DOI: 10.1055/s-0034-1378904; Art ID: ss-2014-u0726-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Total Synthesis of Macakurzin C
2795
should be dictated by the intrinsic reactivity of C(5) and gylation should be crucial. Thus, we investigated the C(7)
C(7) hydroxyl groups. Preparation of aryl propargyl ether hydroxyl protecting groups, which should be tolerant to
5 would be challenging because of the low reactivity of the reaction conditions of propargylation.
the C(5) hydroxyl group in flavonol 6.
O
K2CO3
pyridine
HO
OH
RO
OR
O
O
O
Ph
OBn
N,N-diethylaniline
Cl
8
270 °C, 1 h
89%
14/15 = 1:3
OBn r.t., 14 h
80%
AlCl3
OBn
Et2O–CH2Cl2
r.t., 16 h
63%
OH
phloroglucinol (7)
OR
O
OH
12
BzCl
pyridine
r.t., 14 h
92%
9 R = H
10 R = Bz
O
O
O
O
O
O
Ph
Cl
+
BzO
O
Ph
BzO
O
O
Ph
OBn
OBn
DBU, CuCl2
MeCN
7
OH
14
OH
15
OBn
OBn
5
0 °C ,14 h
O
O
OH
6
13 (~10%)
Scheme 3 Attempted aromatic Claisen rearrangement of 12
O
O
Ph
O
O
O
Ph
After an extensive investigation of the C(7) hydroxyl pro-
tecting groups,10 we were pleased to find that the THP
group is tolerant to the reaction conditions and can be eas-
ily removed under mild acidic conditions (Scheme 4).
Deprotection of the benzoyl group in 6 afforded bisphenol
165 in 92% yield, which was protected by the THP group
to provide 17 in 82% yield. Treatment of 17 with 3-
chloro-3-methylbut-1-yne and DBU in MeCN in the pres-
ence of a catalytic amount of CuCl2 gave rise to C(5) prop-
argyl ether 18 in a good yield (66%, 83% based on the
recovered starting material) along with the propargyl
ether 12 (5%). Deprotection of the THP group in propar-
gyl ether 18 provided the phenol 5 in 97% yield.
+
+
OBn
OBn
O
O
OH
12 (64%)
13 (10%)
Scheme 2 Attempted preparation of the substrate for the aromatic
Claisen rearrangement
Our synthesis of macakurzin C commenced with commer-
cially available phloroglucinol (7), which was trans-
formed to the known tribenzoate 106 by Friedel–Crafts
acylation7 followed by benzoylation of the resulting trihy-
droxyphenol 9 in 58% overall yield (Scheme 2). Exposure
of tribenzoate 10 to K2CO3 in hot pyridine (140–150 °C)
gave rise to flavonol monobenzoate 6 in 80% yield
through Baker–Venkataraman rearrangement and dehy-
dration followed by concomitant deprotection of the C(5)
benzoyl group.
BzO
O
Ph
HO
O
Ph
K2CO3, MeOH
r.t., 1 h, 92%
OBn
OBn
OH
O
OH
16
O
6
With monobenzoate 6 in hand, we attempted propargyla-
tion at the C(5) hydroxyl group. However, attempts to
propargylate the C(5) hydroxyl group were proven to be
problematic due to the low reactivity of the C(5) hydroxyl
group and instability of the C(7) benzoyl protection
group. Indeed, all our attempts using conventional condi-
tions [methyl- or trifluoro-(2-methylbut-3-yn-2-yl] car-
bonate, DBU, CuCl2, MeCN) failed to give 11. In
addition, exposure of monobenzoate 6 to more reactive
conditions (3-chloro-3-methylbut-1-yne, DBU, CuCl2,
MeCN) gave rise to the C(5) propargyl ether 11 in very
poor yield (<10%), but the C(7) propargyl ether 12 (64%)
as a major product along with C(5)/C(7) bispropargyl
ether 13 (<10%).8
Cl
THPO
O
Ph
DBU, CuCl2
CH3CN
DHP, PPTS
CH2Cl2
OBn
0 °C, 16 h
83% brsm
r.t., 10 h
82%
OH
17
O
THPO
O
Ph
HO
O
Ph
PTSA
EtOH–THF
OBn
OBn
r.t., 20 h
97%
O
O
O
O
18
5
The aromatic Claisen rearrangement of the C(7) propargyl
ether 12 provided 15 as a major product (14/15 = 1:3,
Scheme 3).9 To overcome this problem, the C(5) propar-
Scheme 4 Preparation of substrate for aromatic Claisen rearrange-
ment
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2794–2796

2796
D. Lee et al.
LETTER
ies to develop lead compounds for AChE inhibitors. The
biological evaluation of synthetic macakurzin C (3) and
its analogues are under way and will be reported in due
course.
HO
O
O
Ph
OBn
O
5
PhNEt2
250 °C, 4 h
93%
Acknowledgment
H
O
This work was supported by National Research Foundation of
Korea funded by the Ministry of Science, ICT & Future Planning
(NRF-2012R1A1A1009271).
HO
O
O
Ph
O
O
Ph
7
OBn
OBn
5
O
O
H
H
Supporting Information for this article is available online
A
at
http://www.thieme-connect.com/products/ejournals/journal/
B
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
O
X
HO
O
O
Ph
O
O
O
Ph
7
References and Notes
+
(1) Uriarte-Pueyo, I.; Calvo, M. I. Curr. Med. Chem. 2011, 18,
5289.
(2) Thanh, V. T. T.; Mai, H. D. T.; Pham, V. C.; Litaudon, M.;
Dumontet, V.; Guéritte, F.; Nguyen, V. H.; Chau, V. M.
J. Nat. Prod. 2012, 75, 2012.
(3) Jain, A. C.; Zutshi, M. K. Tetrahedron 1973, 29, 3347.
(4) For a recent review on Claisen rearrangement, see: (a) Ilardi,
E. A.; Stivala, C. E.; Zakarian, A. Chem. Soc. Rev. 2009, 38,
3133. (b) Castro, A. M. M. Chem. Rev. 2004, 104, 2939.
(5) For a recent aromatic Claisen rearrangement, see: (a) Kim,
U. B.; Furkert, D. P.; Brimble, M. A. Org. Lett. 2013, 15,
658. (b) Park, I.-K.; Park, J.; Cho, C.-G. Angew. Chem. Int.
Ed. 2012, 51, 2496. (c) Adachi, M.; Higuchi, K.; Thasana,
N.; Yamada, H.; Nishikawa, T. Org. Lett. 2012, 14, 114.
(d) Ramadhar, T. R.; Kawakami, J.-I.; Lough, A. J.; Batey,
R. A. Org. Lett. 2010, 12, 4446.
OBn
3
5
OBn
O
OH
14
19
O
O
Ph
BCl3
CH2Cl2
total 9 steps
in overall 21% yield
from
OH
0 °C to r.t.
2 h, 83%
commercially available
phloroglucinol
OH
O
macakurzin C (3)
Scheme 5 Total synthesis of macakurzin C (3)
Having successfully prepared C(5) propargyl ether 5, we
embarked on the final stage of the synthesis (Scheme 5).
As expected, the subjection of 5 to the conventional con-
ditions of the aromatic Claisen rearrangement smoothly
provided 14 in 93% as a single isomer.
(6) Kim, H.; Lim, D.; Shin, I.; Lee, D. Tetrahedron 2014, 70,
4738.
(7) Gerard, B.; Cencic, R.; Pelletier, J.; Porco, J. A. Jr. Angew.
Chem. Int. Ed. 2007, 46, 7831.
Finally, the deprotection of the benzyl group with BCl3 in
CH2Cl2 completed the synthesis of macakurzin C (3) in
83% yield. The spectral data for synthetic 3 were identical
with those reported for the natural product (1H NMR,
13C NMR, IR, and HRMS).2
(8) Under the reaction conditions, the benzoyl group in 6 was
easily cleaved to afford bisphenol 16, which was rapidly
propargylated to afford the C(7) propargyl ether 12.
(9) For similar results on this type of aromatic Claisen
rearrangement of flavone and isoflavone, see: (a) Zheng, S.
Y.; Li, X. P.; Tan, H. S.; Yu, C. H.; Zhang, J. H.; Shen, Z.
W. Eur. J. Org. Chem. 2013, 1356. (b) Zheng, S. Y.; Shen,
Z. W. Tetrahedron Lett. 2010, 51, 2883.
(10) We also prepared the corresponding MOM-, PMB-, and Bn-
protected analogues of 17, which were tolerant to the
reaction conditions. However, the C(5) propargyl ether
groups were very susceptible to the various reaction
conditions of deprotection, resulting in the decomposition of
the starting materials.
In summary, the concise synthesis of macakurzin C (3)
has been accomplished in nine steps (21% overall yield)
from commercially available phloroglucinol, featuring a
sequential aromatic Claisen rearrangement and cycliza-
tion. We strongly believe that our synthetic routes could
provide a sufficient amount of 3, which would enable us
to extensively investigate in vitro/in vivo biological stud-
Synlett 2014, 25, 2794–2796
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