A facile solid phase synthesis of tetramic acid

Article abstract of DOI:10.1016/S0960-894X(03)00502-X

The condensation of N-acylated amino acids with polymer-supported cyclic malonic acid ester was carried out in the presence of DCC/DMAP. The cyclisation of the intermediate resin, by heating in an organic solvent, gave the N-protected tetramic acid derivatives in good yields and high purity.

Full text of DOI:10.1016/S0960-894X(03)00502-X

Bioorganic & Medicinal Chemistry Letters 13 (2003) 2505–2507
A Facile Solid Phase Synthesis of Tetramic Acid
Zhanxiang Liu, Xiuxiu Ruan and Xian Huang*
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou, 310028, People’s Republic of China
Received 14 January 2003; accepted 7 May 2003
Abstract—The condensation of N-acylated amino acids with polymer-supported cyclic malonic acid ester was carried out in the
presence of DCC/DMAP. The cyclisation of the intermediate resin, by heating in an organic solvent, gave the N-protected tetramic
acid derivatives in good yields and high purity.
# 2003 Elsevier Ltd. All rights reserved.
Tetramic acid derivatives are a class of natural products
that have attracted significant attention over the years
as a result of their biological activities and synthetic
challenges presented by their complex structures.1 Tet-
ramic acid derivatives are widely found as a metabolic
product and some have various biological activities.
Representative examples of this structural class include
Streptolydigin,2 Tirandamycin,3 BU2313A, BU2313B,4
BlasticidinA5 and Vancoresmycin.6 5-Oxotetramic acids
are known as active glycolic acid oxidase inhibitors.7
subsequent cyclisation step to provide the targeted tetra-
mic acid. Meldrum’s acid is a remarkable reagent for
synthesis of the heterocyclic compounds.13 In our pre-
vious research, we have reported the first application of
this chemistry to solid phase synthesis.14 Herein we wish
to report a facile solid phase synthesis of tetramic acid
from resin-bound cyclic malonic acid ester.
Our solid phase synthesis route begins with Merrifield
resin loaded with cyclic malonic acid ester 1 (Scheme 1),
which is prepared according to the prelimary commu-
nication.14a The C-acylation of polymer supported
Meldrum’s acid 1 by N-protected amino acids 2 was
carried out using the N,N0-dicyclohexylcarbodiimide
(DCC) and 4-N,N-dimethylaminopyridine (DMAP) as
the condensing agent. This conversion was proceeded in
dry CH2Cl2 at room temperature. After formation of
the polymer supported acylated compounds 3, excess
reagents were removed by washing with the solvents
(DMF, EtOH, CH2Cl2). Cyclative cleavage was accom-
plished by resuspending the resin 3 in CHCl3 or EtOAc
under reflux. After cleavage, the resin was filtered and
washed completely with EtOAc and MeOH. The filtrates
were combined to afford the product by evaporation.
The product 4 was obtained in good yield and high
The construction of heterocycles on solid phase via
linkage directly to the ring has proven in general to be a
valuable strategy because it permits facile variation of
substituents.8 Recently, several reports have appeared
describing the solid phase synthesis of tetramic
acids.9ꢀ11 Kulkarni and Ganesan9 describe the prepara-
tion of tetramic acids with substitutents other than acyl
at the 3-position. Tetrabutyl ammonium hydroxide was
employed as the cyclization reagent. However, this
requires further treatment of the product with Amber-
lyst A-15 ion exchange resin as scavenged reagents.
Matthews and Rivero10 also reported preparation of
tetramic acid, heating at 85 ꢁC or 24 h with sodium
ethoxide was required to effect cyclization. Campbell11
reported the solid phase synthesis of tetramic acid by
cyclative cleavage of the penultimate intermediate via
Dieckmann cyclization in the presence of KOH/MeOH.
1
purity (determined by H NMR without further puri-
fication)(Table 1).
For each resin-bound intermediate, the structure was
verified by FT-IR spectra. When the resin 1 was trans-
formed to the resin 3, the carbonyl peak in IR spectra
shifted from 1794, 1760 cmꢀ1 to 1731, 1660 cmꢀ1 (3a,
X=C6H5CO, R=H). Also a new peak appeared at
3439 cmꢀ1 (OH group). After cleavage in CHCl3, the
ketone resin 5 was obtained which showed carbonyl
peak at 1716 cmꢀ1 in IR spectra. The ketone resin 5 can
There are numerous examples12 in the literature utilizing
standard solution phase chemistry in which N-protected
amino acid are reacted with Meldrum’s acid followed by
*Corresponding author. Fax: +86-571-88807077; e-mail: huangx@
mail.hz.zj.cn
0960-894X/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00502-X

2506
Z. Liu et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2505–2507
The resin was filtered and washed completely with
DMF, AcOH/MeOH (1:10), MeOH, CH2Cl2. T he
newly formed resin in CHCl3 or EtOAc (20 mL) was
refluxed for 2 h. The resin was filtered and washed with
EtOH and acetone completely. The filtrates were com-
bined to afford the product by evaporation.17
In summary, we have developed an efficient, facile
method of solid phase synthesis of tetramic acid from
polymer supported cyclic malonic acid ester. This is a
traceless cyclative cleavage under mild conditions. The
N-protected tetramic acid was prepared with good yield
and high purity. Further work is in progress on the solid
phase synthesis of heterocyclic compounds via the resin-
bound cyclic malonic ester.
Scheme 1.
Acknowledgements
Table 1. Solid phase synthesis of tetramic acid
We are grateful to the National Nature Science Founda-
tion of China (Project 20072032) for financial support.
Entry Product
X
R
Yield Purity
(%)a
(%)b
1
2
3
4
5
6
7
8
9c
10
11
12
13
4a
4b
4c
4d
4e
4f
4g
4h
4a
4i
C6H5CO
4-CH3OC6H4 CO
4-CH3C6H4 CO
4-ClC6H4CO
COOCH2CH3
COOCH3
COOCH2C6H5
COCH3
H
H
H
H
H
H
H
H
H
92
90
78
67
88
78
76
90
92
80
84
81
88
>93
>90
>92
>90
>94
>91
>90
>95
>93
>95
>92
>90
>90
References and Notes
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C6H5CO
C6H5CO
Boc
Boc
CH3
Bui
C6H5CH2
CH3
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4j
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be recovered and reused to prepare the cyclic malonic
acid ester resin 1.15 The good result was also obtained
when the regenerated resin was used (Table 1, entry 9).
The synthesis of optically active tetramic acid is a
research field of major importance as it has relevance to
virtually all areas of pharmaceutical industries. The
development of such enantiomerically pure compounds
has gained increasing interest in organic and medicinal
16
chemistry. So we use an N-protected l-amino acid to
run this reaction. It was found that the reaction worked
very well and give the optically active compounds (4i–
4l) with good yield and high purity. The optical purity
of the amino acids is retained in the tetramic acids dur-
ing the synthesis.
12. (a) Hamilakis, S.; Kontonassios, D.; Sandris, C. J. Het-
erocyclic. Chem. 1996, 33, 825. (b) Hamilakis, S.; Konto-
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15. The loading of the regenerated cyclic malonic acid ester is
1.20 mmol/g which is determined by reversed titration with
hydrochloride acid after saponification with excess NaOH in
EtOH.
Typical Procedure for the Solid Phase Synthesis of
Tetramic Acid
To the suspension of cyclic malonic acid ester resin 1
(500 mg, 1.20 mmol/g) in CH2Cl2 (5 mL), N-protected
amino acid (3 mmol), DMAP (4.5 mmol, 0.55 g) were
added. Then the solution of DCC (3.6 mmol, 0.72 g) in
CH2Cl2 (5 mL) was added dropwise under nitrogen.
The mixture was stirred at room temperature for 10 h.

Z. Liu et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2505–2507
2507
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Markopowlou, O. Tetrahedron: Asymmetry 1999, 10, 1873. (c)
Jouin, P.; Castro, B.; Nisato, D. J. Chem. Soc., Perkin Trans 1
1987, 1177.
one. white solid. mp. 179–180 ꢁC (lit12a 180 ꢁC). 1H NMR
(DMSO-d6): d 4.40 (s, 2H), 4.96 (s, 1H), 7.34–7.41 (m, 2H),
7.47–7.51 (m, 3H), 12.57 (s, 1H). IR (KBr): nmax (cmꢀ1).
2928, 1671, 1620, 1574, 1353, 1330, 1286. MS m/z (relative
intensity) (EI, 70 eV) 203 (M+, 8), 175 (12) 105 (100) 77
(64).
17. Sample analysis: 4a: 1-benzoyl-4-hydroxy-3-pyrrolin-2-