Synthesis of the pyridone analogues of territrem B

Article abstract of DOI:10.1016/j.mencom.2008.07.004

Two series of territrem B analogues were synthesised in nine linear steps from commercially available starting materials.

Full text of DOI:10.1016/j.mencom.2008.07.004

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 186–187
Synthesis of the pyridone analogues of territrem B
Yinghua Yang,*a Lianli Sun,a Shengyi Dong,a Xiaoyu Wang,a
Leixiang Yang,a Xiumei Wu,a Hua Baib and Yu Zhao*a
a Department of Traditional Chinese Medicine and Natural Drug Research, College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou 310058, China. Fax: +86 571 8820 8449; e-mail: yinghuayang1997@yahoo.com.cn
;
dryuzhao@zju.edu.cn
b Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou 318000, China
DOI: 10.1016/j.mencom.2008.07.004
Two series of territrem B analogues were synthesised in nine linear steps from commercially available starting materials.
Territrem B 1 (Figure 1), as an acetylcholinesterase (AChE)
OMe
E
inhibitor isolated from the rice cultures of Aspergillus terreus
23-1,1 is 20 times more potent than neostigmine.2 A prelimi-
nary study showed that both the enone and the pyrone moieties
play important roles in inhibitory activity on electric eel AChE.3
To further disclose essential pharmacophores of territrem B
(rare from natural sources), we have prepared A/B ring analogues
of territrem B starting from triterpenoid jujubogenin. However,
only a few synthetic analogues were found to exhibit satisfactory
inhibitory activity against AChE.4 In our continued investiga-
tions, the A/B/C ring system with multiple stereocenters was
simplified and a number of pyranone derivatives of territrem B
were synthesised.5 The experimental results and molecular
modeling studies indicated that an additional piperazine ring
(see compounds 2) (Figure 1) might favour a planar conforma-
tion and could enhance the inhibitory effects on AChE. From
the viewpoint of medicinal chemistry, the bromine of aromatic
moiety in 2 was abandoned because the bromoarenes are more
prone than others to yield unwanted toxic metabolites.6 To
testify this proposition, territrem B analogues, 6-arylpyridin-
2(1H)-ones 3 and their derivatives 10, were designed and
synthesised.
OMe
OMe
O
O
D
OMe
Br
O
A
OMe
C
O
B
R
O
O
OH
N
N
OH
1
2
Territrem B
R = EtOC(O), cyclohexyl, pyrimidin-2-yl
Figure 1 Structures of compounds 1 and 2.
acetophenone with dimethyl sulfate and 4b from commercially
available anisole with acetic anhydride and ZnCl2 as a catalyst.
Treatment of acetophenone 4 with ethyl formate employing the
standard Claisen–Schmidt reaction gave intermediate sodium
formylacetophenones,7 which were cyclised (without purifica-
tion) with cyanoacetamide to afford pyridones 5. The pyridones
were then refluxed with N,N-dimethylformamide dimethyl acetal
(DMF DMA) in DMF to afford methyl-protected pyridones 6.
Compounds 6 were then hydrolysed with a 30% KOH aqueous
The syntheses of 3 and their derivatives are outlined in
Scheme 1. Acetophenone 4a was prepared from m-hydroxy-
CN
CN
COOH
OMe
O
v
iii
iv
i, ii
N
O
N
OMe
N
R1
R1
R1
R1
R1
R1
H
6a,b
7a,b
4a,b
5a,b
CH2OH
CH2Cl
OMe
4–9 a R1 = 3''-MeO
b R1 = 4''-MeO
vi
vii
3, 10 a R1 = 4''-MeO, R2 = benzhydryl
b R1 = 4''-MeO, R2 = 11'-fluorobenzyl
c R1 = 4''-MeO, R2 = 11'-fluorophenyl
d R1 = 4''-MeO, R2 = ethoxycarbonyl
N
OMe
N
R1
8a,b
9a,b
e R1 = 4''-MeO, R2 = 10',11'-dichlorophenyl
f R1 = 4''-MeO, R2 = benzyl
1'
2'
1'
4
4
1
3'
6'
3'
6'
2'
4'
4'
g R1 = 4''-MeO, R2 = ethyl
N
7'
N
3
3
N5'
N5'
2''
2''
7'
1''
1''
h R1 = 4''-MeO, R2 = 9'-methoxyphenyl
i R1 = 4''-MeO, R2 = cyclohexyl
10 j R1 = 3''-MeO, R2 = 10',11'-dichlorobenzyl
3''
3''
2
2
R2
R2
viii
N
OMe
N
O
R1
1
H
6''
6''
5''
5''
k R1 = 3''-MeO, R2 = 11'-fluorophenyl
10a–k
3a–i
Scheme 1 Reagents and conditions: i, HCOOEt, Na, MeOH, Et2O, 0 °C ® room temperature; ii, CNCH2CONH2, H2O, reflux, 8 h; iii, DMF DMA, DMF,
reflux, 12 h; iv, 30% KOH, EtOH–H2O (1:1), reflux, 12 h, then 6 M HCl; v, LiAlH4, THF, 0 °C ® room temperature; vi, Et3N, MsCl, CH2Cl2, 0 °C ® room
temperature, 12 h; vii, K2CO3, substituted piperazine, MeCN, 60–80 °C, 1–6 h; viii, 40% HBr, AcOH, 50–80 °C.
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© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 186–187
ethanol solution to yield corresponding acids 7, which were
owing to the electron-deficient pyridine ring. This signal is
absent from the spectra of compounds 3; therefore, it was
concluded that the methoxy group linked to the pyridine ring of
compounds 10a–i was selectively demethylated.9
In summary, two series of territrem B analogues were designed
and synthesised based on previous molecular modeling studies.
This work was supported in part by Zhejiang Hisun Phar-
maceutical Co., and Zhejiang University. We are grateful to
Professor J. Stöckigt for his useful discussions.
reduced with LiAlH4 to give desired alcohols 8. In the presence
of Et3N, alcohols 8 reacted with mesyl chloride (MsCl) in
CH2Cl2 to give chlorides 9.8 The latter reacted with substituted
piperazines to afford compounds 10a–k. Compounds 10a–i were
selectively demethylated to provide pyridinones 3a–i (Scheme 1).
The structures of 10a–k and 3a–i, as well as all of the inter-
mediates involved (Scheme 1), were confirmed by 1H NMR
and ESI-MS data.† The proton signal of the methoxy group
linked at C-2 in compounds 10 appeared at d 3.99–4.07 (s, 3H)
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2008.07.004.
†
3h: yield 89%, pale yellow solid, mp 151–152 °C (MeCN). Rf 0.46
(CH2Cl2–MeOH, 20:1). 1H NMR (400 MHz, CDCl3) d: 2.81 (br. s, 4H,
H-3', H-7'), 3.15 (br. s, 4H, H-4', H-6'), 3.66 (s, 2H, H-1'), 3.86 (s, 6H,
4''-MeO, 9'-MeO), 6.58 (d, 1H, H-5, J 6.8 Hz), 6.85–7.01 (m, 6H, H-10',
H-11', H-12', H-13', H-3'', H-5''), 7.57 (d, 1H, H-4, J 6.8 Hz), 7.67 (d,
2H, H-2'', H-6'', J 8.4 Hz). ESI-MS (m/z): 406 ([M + 1]+). Calc. for
C24H27N3O3, M = 405.21.
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3i: yield 86%, pale yellow solid, mp 125–127 °C (MeCN). Rf 0.30
1
(CH2Cl2–MeOH, 20:1). H NMR (400 MHz, CDCl3) d: 1.08–1.90 (m,
10H, H-9', H-10', H-11', H-12', H-13'), 2.24 (br. s, 1H, H-8'), 2.64 (br. s,
8H, H-3', H-4', H-6', H-7'), 3.56 (s, 2H, H-1'), 3.86 (s, 3H, 4''-MeO),
6.59 (d, 1H, H-5, J 7.2 Hz), 6.99 (d, 2H, H-3'', H-5'', J 8.8 Hz), 7.48 (d,
1H, H-4, J 7.2 Hz), 7.67 (d, 2H, H-2'', H-6'', J 8.8 Hz). ESI-MS (m/z):
382 ([M + 1]+). Calc. for C23H31N3O2, M = 381.24.
10h: yield 73%, white solid, mp 73–74 °C (EtOH), Rf 0.35 (light
petroleum–EtOAc, 3:1). 1H NMR (400 MHz, CDCl3) d: 2.74 (br. s, 4H,
H-3', H-7'), 3.12 (br. s, 4H, H-4', H-6'), 3.64 (s, 2H, H-1'), 3.87 (s, 6H,
4''-MeO, 9'-MeO), 4.05 (s, 3H, 2-MeO), 6.85–7.02 (m, 6H, H-10', H-11',
H-12', H-13', H-3'', H-5''), 7.29 (d, 1H, H-5, J 7.2 Hz), 7.69 (d, 1H, H-4,
J 7.2 Hz), 8.01 (d, 2H, H-2'', H-6'', J 7.6 Hz). ESI-MS (m/z): 420
([M + 1]+). Calc. for C25H29N3O3, M = 419.22.
10j: yield 65%, colourless oil, Rf 0.36 (light petroleum–EtOAc, 3:1).
1H NMR (400 MHz, CDCl3) d: 2.50 (br. d, 8H, H-3', H-4', H-6', H-7'),
3.46 (s, 2H, H-8'), 3.57 (s, 2H, H-1'), 3.89 (s, 3H, 3''-MeO), 4.04 (s, 3H,
2-MeO), 6.93 (dd, 1H, H-14', J 2.4 and 8.0 Hz), 7.16 (d, 1H, H-5, J 8.4 Hz),
7.32–7.38 (m, 3H, H-10', H-13', H-4''), 7.43 (s, 1H, H-2''), 7.60 (d, 1H,
H-4, J 8.4 Hz), 7.66 (m, 2H, H-5'', H-6''). ESI-MS (m/z): 472 ([M + 1]+).
Calc. for C25H27Cl2N3O2, M = 471.15.
For 1H NMR and ESI-MS spectral data for compounds 3a–g, 9a,b and
10a–g,i,k see Online Supplementary Materials.
Received: 16th January 2008; Com. 08/3069
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