Total synthesis of (±)-megistophylline I

Article abstract of DOI:10.1016/j.tetlet.2009.03.157

(±)-Megistophylline I (1), carrying a dienone residue in the acridone framework, was synthesized using the Claisen rearrangement to introduce a prenyl group as a key step.

Full text of DOI:10.1016/j.tetlet.2009.03.157

Tetrahedron Letters 50 (2009) 2801–2804
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of ( )-megistophylline I
*
Yuko Nishihama, Yuichi Ishikawa, Shigeru Nishiyama
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
( )-Megistophylline I (1), carrying a dienone residue in the acridone framework, was synthesized using
the Claisen rearrangement to introduce a prenyl group as a key step.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 21 February 2009
Revised 21 March 2009
Accepted 24 March 2009
Available online 27 March 2009
Keywords:
Sarcomelicope megistophylla Hartley
(Rutaceae)
Acridone
Claisen rearrangement
Ullmann reaction
Megistophylline I (1), isolated from the bark of Sarcomelicope
megistophylla Hartley (Rutaceae) by Papageorgiou et al.,1 possesses
the acridone framework with a prenylated dienone residue, which
may be produced by biogenetic oxidation of the corresponding
phenol precursor (Fig. 1).
studies on mangostins, the dienone derivative 2, which is very
similar to 1, was synthesized under anodic oxidation conditions.3
As 2 showed several biological activities, the structural similarity
of 1 to 2 suggested that 1 may also show similar antibacterial
activity. As information of new biological activity may contribute
to the development of efficient chemotherapeutic agents, we
planned to synthesize 1 using a similar phenolic oxidation ap-
Megistoquinones
were also isolated from the same plant species. In our previous
I
and II exhibiting antibacterial activity2
O
OMe
N
O
OMe
OMe
Me
N
O
OMe
4
3
2
O
MeO
MeO
MeO
N
H
O
1
O
OH
O
O
megistoquinone I
megistoquinone II
megistophylline I (1)
O
OH
OMe O
OH
O
HO
ref 3
HO
O
OH
HO
O
2
OH
γ-mangostin
Figure 1.
* Corresponding author. Tel./fax: +81 45 566 1717.
E-mail address: nisiyama@chem.keio.ac.jp (S. Nishiyama).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.157

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Y. Nishihama et al. / Tetrahedron Letters 50 (2009) 2801–2804
Me
N
H
N
HO
BnO
MeO
1
MeO
CO2H
OH
O
3
OBn
4
HO
HO
CO2Me
BnO
MeO
CO2Me
BnO
MeO
NH2
a, b
c, d, e
OH
5
OBn
6
OBn
7
Me
N
Me
N
I
BnO
MeO
BnO
MeO
g, h, i
f
j
7
+
4
HO2C
O
O
OH
O
9
8
10
Me
N
BnO
MeO
k
3
OH
O
11
Scheme 1. Reagents and conditions: (a) Li2CO3, MeI, DMF, 57%; (b) K2CO3, BnBr, acetone, 95%; (c) 20% NaOH, THF, 91%; (d) DPPA, Et3N, BnOH, PhMe, quant.; (e) 40% KOH,
MeOH, 90%; (f) KOAc, Cu(OAc)2ÁH2O, DMF, 80%; (g) TFAA, CH2Cl2, 91%; (h) NaH, MeI, DMF, 82%; (i) MgBr2ÁEt2O, PhH, Et2O, 97%; (j) prenyl bromide, NaH, THF, then silica gel,
40%; (k) Pd Black, 1,4-cyclohexadiene, MeOH, 71%.
proach to 2, as depicted in the retrosynthetic analysis (Scheme
1).
the expected diarylamine 4 in 80% yield (Scheme 1). Cyclization
of 4 with trifluoroacetic anhydride (TFAA) proceeded smoothly to
give an acridone, which was subjected to successive N-methylation
and selective removal of a benzyl group at the C-1 position to give
9.8 Prenylation by the standard procedure produced not only 10,
but also the automatically rearranged product 11 in 40% yield, after
chromatographic separation. Removal of a benzyl group in 11 un-
der hydrogen transfer conditions provided 3,8 without undesired
over-reduction, which will give a saturated alkyl chain.
Phenolic oxidation approach: According to the analysis men-
tioned above, the synthesis was commenced by selective protec-
tion of methyl gallate 5 by methyl4 and benzyl groups to give
fully protected 6. Compound 6 was subsequently subjected to alka-
line hydrolysis, Curtius rearrangement, and removal of a benzyl-
oxycarbonyl group generated to give the amine 7. Condensation
of 7 with 2-iodobenzoic acid by the Ullmann protocol provided
Among the oxidation conditions examined, clear reaction to the
target molecule was unsuccessful as shown in Table 1. When
Pb(OAc)4 in PhH was used as an oxidant, acetylated megistophyl-
line I (1’), was obtained in 72% yield. However removal of the acet-
yl group was unsuccessful under acidic or basic deprotection
conditions, involving 0.05 M KOH aq or 6 M HCl aq.
Table 1
Oxidation conditions of 3
Claisen rearrangement approach: After elaboration of synthetic
approaches to 1, we turned our attention to the Claisen rearrange-
ment of a prenyl group (12?1), as shown in Scheme 2.
OR
Me
N
Me
N
O
HO
Thus, selective methylation was followed by bromination using
1,3-dibromo-5,5-dimethylhydantoin (DBDMH),4 protection as a
benzyl ether, and then Ullmann reaction of the bromine leading
to a methoxy group to give 13. Alkaline hydrolysis of the ester
function in 13, Curtius rearrangement, and removal of the gener-
ated benzyloxycarbonyl group yielded 14, which on condensation
with 8 and subsequent cyclization, followed by N-methylation,
gave the acridone 16.
MeO
MeO
OH
O
3
OH
O
1'
Entry
R
Conditions
Result
1
2
3
4
5
6
Me
Me
Me
Me
Me
Ac
C.C.E. (0.7 mA/cm2, 2 F/mol), MeOH
PIFA, MeOH
Unknown
Unknown
Unknown
n.r.
n.r.
1’ (72%)
PhI(OCH2CF3)2,5 MeOH
FeCl3, MeOH
Removal of a benzyl group afforded the phenol 17, which on
reaction with 3-chloro-3-methylbut-1-yne and selective reduction
gave the desired product 12, through 18.6,8 At the final stage, 12
PbO2, MeOH
Ac Pb(OAc)4, PhH

Y. Nishihama et al. / Tetrahedron Letters 50 (2009) 2801–2804
2803
OMe
Me
O
N
1
MeO
OH
O
12
OMe
OMe
OMe
OBn
H
N
BnO
MeO
CO2Me
BnO
MeO
NH2
BnO
MeO
a, b, c, d
e, f, g
h
5
CO2H
OBn
13
OBn
14
15
OMe
OH
OMe
OMe
M
Me
N
e
Me
N
BnO
MeO
HO
N
O
i, j, k
m
l
MeO
MeO
O
OH
O
OH
O
16
17
18
OMe
Me
O
N
n
o
12
MeO
OH
O
+
( )-megistophylline
Scheme 2. Reagents and conditions: (a) Li2CO3, MeI, DMF, 57%; (b) DBDMH, CHCl3; (c) K2CO3, BnBr, DMF; (d) NaOMe, CuI, DMF, 38% in three steps; (e) 20% NaOH, THF, 88%;
(f) DPPA, Et3N, BnOH, PhMe, 81%; (g) 40% KOH, MeOH, 89%; (h) 8, KOAc, Cu(OAc)2ÁH2O, DMF; (i) TFAA, CH2Cl2, 73% in two steps; (j) 35% HCHO, NaCNBH3, AcOH, MeCN; (k)
K2CO3, MeI, acetone, 70% in two steps; (l) Pd black, 1,4-cyclohexadiene, MeOH, 93%; (m) K2CO3, KI, CuI, 3-chloro-3-methylbut-1-yne, acetone, 75%; (n) H2, Lindlar cat.,
quinoline, PhH–hexane (1:5), 12: 41%, 17: 28%; (o) neat, 200 °C, 65%.
was heated at 200 °C (neat) under an argon atmosphere7 to give
caused decomposition of the substrate. (2) Compound 19 was converted to the
regio-isomer 20 under BF3ÁEt2O in CH2Cl2 (À40 °C). (3) Compound 19 was
( )-megistophylline I (1), spectroscopic data of which were identi-
heated at 200 °C (neat) to give the desired product 21
cal to those reported previously.1 Assessments of biological activity
of synthetic samples will be performed in due course.
OMe Me
N
OMe Me
N
Acknowledgments
O
HO
This work was supported by Scientific Research C (20510203)
from MEXT, High-Tech Research Center Project for Private Univer-
sities matching fund subsidy from MEXT, 2006–2011, and Keio
Leading-edge Laboratory of Science and Technology (Y.N.).
MeO
MeO
O
O
OH
O
19
20
References and notes
OMe
Me
N
1. Papageorgiou, M.; Fokialakis, N.; Mitaku, S.; Skaltsounis, A.-L.; Tillequin, F.;
Sévenet, T. J. Nat. Prod. 2000, 63, 385–386.
2. Fokialakis, N.; Magiatis, P.; Chinou, I.; Mitaku, S.; Tillequin, F. Chem. Pharm. Bull.
2002, 50, 413–414.
O
3. Nishihama, Y.; Amano, Y.; Ogamino, T.; Nishiyama, S. Electrochemistry 2006, 74,
609–611.
4. Alam, A.; Takaguchi, Y.; Ito, H.; Yoshida, T.; Tsuboi, S. Tetrahedron 2005, 61,
1909–1918.
5. Amano, Y.; Nishiyama, S. Tetrahedron Lett. 2006, 47, 6505–6507.
6. In this reduction, 17 was also produced by undesired deprenylation with Pd
catalysts. Although this process has not been optimized, deprenylation
proceeded preferentially without hexane as a co-solvent.
7. Reaction conditions of the Claisen rearrangement were elaborated using 19,
which was synthesized by direct allylation of 17. (1) Heating at 140 °C in xylene
MeO
OH
O
21
.
8. Selected spectroscopic data 3: dH (CDCl3) 1.75 (3H, s), 1.76 (3H, s), 3.48 (2H, d,
J = 4.9 Hz), 3.83 (3H, s), 4.03 (3H, s), 5.36 (1H, t, J = 4.9 Hz), 6.75 (1H, s), 7.25 (1H,
t, J = 8.8 Hz), 7.39 (1H, d, J = 8.8 Hz), 7.68 (1H, t, J = 7.8 Hz), 8.34 (1H, d,
J = 7.8 Hz); dC (CDCl3) 18.2, 25.7, 27.2, 43.6, 60.8, 104.5, 107.1, 116.2, 121.0,
121.4, 123.5, 125.9, 128.3, 132.5, 133.7, 143.0, 145.5, 152.8, 155.3, 182.0.

2804
Y. Nishihama et al. / Tetrahedron Letters 50 (2009) 2801–2804
Compound 9: dH (CDCl3) 3.62 (3H, s), 3.91 (3H, s), 5.21 (2H, s), 6.17 (1H, s), 7.12-
128.1, 128.4, 134.2, 144.9, 150.7, 152.2, 180.2. Compound 12: dH (CDCl3) 1.59
(6H, s), 3.70 (3H, s), 3.91 (3H, s), 4.01 (3H, s), 5.15 (1H, dd, J = 10.8, 1 Hz), 5.22
(1H, dd, J = 17.4, 1 Hz), 6.30 (1H, dd, J = 10.8, 17.4 Hz) 7.28 (1H, t, J = 8.8 Hz), 7.48
(1H, d, J = 8.8 Hz), 7.73 (1H, td, J = 8.8, 1.6 Hz), 8.39 (1H, dd, J = 8.8, 1.6 Hz), 14.33
(1H, s); dC (CDCl3) 9.2, 25.7, 26.7, 35.5, 40.9, 60.36, 60.4, 61.1, 113.0, 115.6, 121.4,
126.4, 134.2, 134.8, 137.0, 143.3, 145.1, 151.3, 152.5, 182.2.
7.64 (8H, m), 8.25 (1H, d, J = 7.6 Hz), 14.72 (1H, s); dC (CDCl3) 29.8, 34.0. 60.8,
70.7, 88.6, 105.6, 114.4, 120.3, 121.2, 126.2, 127.1, 128.1, 128.6, 133.7, 136.1,
139.9, 141.6, 156.0, 158.1, 180.4. Compound 18: dH (CDCl3) 1.82 (6H, s), 2.46
(1H, s), 3.74 (3H, s), 3.96 (3H, s), 4.05 (3H, s), 7.27 (1H, t, J = 8.0 Hz), 7.49 (1H, d,
J = 8.0 Hz), 7.73 (1H, s, J = 8.0 Hz), 8.39 (1H, s, J = 8.0 Hz), 14.37 (1H, s); dC (CDCl3)
30.3, 40.8, 60.6, 61.3, 73.2, 76.7, 77.9, 85.5, 108.9, 115.5, 120.9, 121.3, 126.3,