One-pot synthesis of optically active tetramic acids from amino acids mediated by 1-hydroxybenzotriazole

Article abstract of DOI:10.1055/s-2001-17452

A novel synthesis of chiral 3-ethoxycarbonyl-5-substituted tetramic acids in moderate yields (45-75%) is reported. HPLC analysis of these tetramic acids shows very good enantiomeric excesses (82-98%).

Full text of DOI:10.1055/s-2001-17452

LETTER
1653
One-pot Synthesis of Optically Active Tetramic Acids from Amino Acids
Mediated by 1-Hydroxybenzotriazole
One-pot
S
ynthesis
i
of Opt
o
A
ctive
r
T
etrami
g
c
Acids os Athanasellis, Efstathios Gavrielatos, Olga Igglessi-Markopoulou*
Laboratory of Organic Chemistry, Department of Chemical Engineering, National Technical University of Athens, Zografou Campus,
15773 Athens, Greece
Fax +30(1)7723072; E-mail: ojmark@orfeas.chemeng.ntua.gr
Received 11 June 2001
stereochemical integrity remains more or less conserved
Abstract: A novel synthesis of chiral 3-ethoxycarbonyl-5-substi-
in the structure of the products. Significant studies on the
tuted tetramic acids in moderate yields (45–75%) is reported. HPLC
synthesis of such optically active compounds have been
analysis of these tetramic acids shows very good enantiomeric ex-
made by Ley et al.2 who used a series of -ketoamides as
cesses (82–98%).
intermediates for the preparation of enantiomerically pure
Key words: tetramic acids, 1-hydroxybenzotriazole, natural prod-
ucts, amino acids
3-acyl tetramic acids. On the other hand, Moloney et al.10
provided a N-acyloxazolidine derived from L-serine as a
suitable precursor for the construction of chiral substitut-
ed tetramic acids with high enantiomeric excess. Other
The pyrrolidine-2,4-dione ring system containing a 3-acyl
methodologies based on the enantioselective Lacey-
substituent is a common skeleton of naturally occurring
Dieckmann cyclization, requiring strongly basic
tetramic acids.1,2 (Figure)
conditions11,12 have also been reported.
During the last decade, our research group has been inves-
O
HO
Y
Y
tigating the synthesis of nitrogen heterocycles containing
the pyrrolidine-2,4-dione nucleus. We have developed a
facile and convenient approach to highly functionalized
N-acyl and N-alkoxycarbonyl tetramic acids.13–15 This
methodology has also been proposed for the synthesis of
chiral tetramic acids in enantiopure form.16
O
O
N
N
Figure
The spectrum of biological activity displayed by these
natural products is remarkable in its diversity and it in-
cludes potent antibiotic, antiviral and antifungal proper-
ties, cytotoxicity and mycotoxicity as well as the
inhibition of tumors.3–6 It has also been reported that tet-
ramic acids have been designed as glycine site N-methyl-
D-aspartate (NMDA) antagonists, which may be of use in
the treatment of neurological diseases.7 Recently, the total
syntheses of reutericyclin,8 and physarorubinic acid9 have
also been reported.
Studies on the structure-activity relationships of these nat-
ural products have revealed that only one of their two
enantiomers has been isolated. This shows that the pure
enantiomers of tetramic acid display different activity and
toxicity profiles and their pronounced pharmacological
activity derives from only one single enantiomer.1 So, it is
obvious that the synthesis of optically active tetramic ac-
ids is a research field of major importance as it has rele-
vance to virtually all areas of pharmaceutical industries.
During the last 25 years numerous approaches to the syn-
thesis of chiral tetramic acids have been reported. They
mainly make use of amino acids derived precursors whose
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1653,1655,ftx,en;G11301st.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Scheme

1654
G. Athanasellis et al.
LETTER
As a continuation of these efforts, we managed recently to In conclusion, we have investigated a novel one-pot syn-
synthesize a series of 3-ethoxycarbonyl-5-substituted tet- thetic route to chiral 3-ethoxycarbonyl tetramic acids 4–9
ramic acids 4–9 using a simple and stereoselective method from N-acetyl- -amino acid hydroxybenzotriazole inter-
(Scheme). The one-pot synthesis comprises a C-acylation mediates. The results of this work are very promising and
reaction between the 1-hydroxybenzotriazole ester of the it is clear that the proposed methodology could be applied
appropriate optically active amino acid 1 and diethyl ma- for the synthesis of highly functionalized tetramic acids as
lonate 3. When the product was not the corresponding tet- well as other optically active heterocyclic compounds.
ramic acid 4–6 but the C-acylation compound A, a
cyclization reaction under basic conditions was per-
Acknowledgement
formed to afford the corresponding tetramic acid 7–9.17
We thank Ms V. Skouridou (National Technical University of
Table Optical Rotations, Enantiomeric Ratios and Enantiomeric
Excesses of Compounds 4–9
Athens, Biotechnology Laboratory) for recording the IR spectra.
We also thank the National Technical University of Athens for fi-
nancial support (project “Archimides”).
Compound Yield (%)
e.r.b
97:3
91:9
91:9
98:2
93:6
92:8
e.e.
94
82
82
96
87
84
[a]D (c1, MeOH)a
+2.4
4
5
6
7
8
9
43
75
44
45
74
59
References and Notes
+37.6
(1) Royles, B. J. L. Chem. Rev. 1995, 95, 1981.
(2) Ley, S. V.; Smith, S. C.; Woodward, P. R. Tetrahedron
1992, 48, 1145.
(3) (a) DeBoer, C.; Dietz, A.; Silver, W. S.; Savage, G. M.In
Antibiotics Annual; Welch, H.; Marti-Ibanez, J., Eds.;
Medical Encyclopedia, Inc.: New York, 1956, 886.
(b) Meyer, C. E. J. Antibiot. 1971, 24, 558.
+45.1
–38.4
–21.3
–4.2
(4) Terret, N. DDT 1998, 3, 1998.
(5) Hashidoko, Y.; Nakayama, T.; Homma, Y.; Tahara, S.
Tetrahedron Lett. 1999, 40, 2957.
(6) Sata, N. U.; Matsunaga, S.; Fusetani, N.; Van Soest, R. W.
M. J. Nat. Prod. 1999, 62, 969.
(7) Mawer, I. M.; Kulagowski, J. J.; Leeson, P. D.; Grimwood,
S.; Marshall, G. R. Bioorg. Med. Chem. Lett. 1995, 5, 2643.
(8) Marquardt, U.; Schmid, D.; Jung, G. Synlett 2000, 1131.
(9) Dixon, D. J.; Ley, S. V.; Longbottom, D. A. J. Chem. Soc.,
Perkin Trans 1 1999, 2231.
(10) Andrews, M. A.; Brewster, A. G.; Krapnell, K. M.; Ibbett, A.
J.; Jones, T.; Moloney, M. G.; Prout, K.; Watkin, D. J. Chem.
Soc., Perkin Trans 1 1998, 223.
(11) Paquette, L. A.; MacDonald, D.; Anderson, L. G.; Wright, J.
J. Am. Chem. Soc. 1989, 111, 8037.
(12) Jones, R. C. F.; Tankard, M. J. Chem. Soc., Perkin Trans 1
1991, 240.
(13) Detsi, A.; Markopoulos, J.; Igglessi-Markopoulou, O. Chem.
Commun. 1996, 1323.
(14) Detsi, A.; Micha-Screttas, M.; Igglessi-Markopoulou, O. J.
Chem. Soc., Perkin Trans 1 1998, 2443.
a Optical rotations were recorded on a Perkin-Elmer 241 polarimeter.
b Enantiomeric ratios were determined by HPLC analysis with a
CHIRALPAK AS column (4.6 250 mm), [254 nm, 0.6 mL/min, eth-
anol–hexane (1:1)]
The crucial parameter in the synthesis of the N-acylated 3-
ethoxycarbonyl tetramic acids 4–6 or N-H-3-ethoxycar-
bonyl tetramic acids 7–9 is the molar ratio between the N-
acylated amino acid 1 and diethyl malonate 3. We ob-
served that when diethyl malonate 3 was used in molar ex-
cess (2 equiv) the oily product containing the C-acylation
compound A and diethyl malonate 3 was obtained. This
mixture was stirred under basic conditions to afford the N-
H-3-ethoxycarbonyl tetramic acids 7–9. On the other
hand, when diethyl malonate 3 was used in stoichiometric
ratio (1 equiv), the N-acetyl-3-ethoxycarbonyl tetramic
acids 4–6 were obtained as white solids. In both circum-
stances, HPLC analysis showed that the enantiomeric ra-
tio between the two enantiomers of products was
satisfactory. (Table)
(15) Petroliagi, M.; Igglessi-Markopoulou, O. J. Chem. Soc.,
Perkin Trans 1 1997, 23, 3543.
(16) Petroliagi, M.; Igglessi-Markopoulou, O. Tetrahedron:
Asymmetry 1999, 10, 1873.
(17) General procedure for the synthesis of compounds 4–9:
In a typical reaction, 10 mmol of the optically active N-
acylated amino acid 1 was treated with 10 mmol of 1-
hydroxybenzotriazole 2 and 10 mmol DCC in anhyd THF at
0 °C for 1 h. The resulting mixture was refrigerated at 3–
5 °C overnight. The precipitated solid (DCCU) was filtered
off and discarded, the THF filtrate was added to a solution of
20 mmol of NaH and 10 or 20 mmol of diethyl malonate 3 in
anhyd THF. The resulting mixture was stirred at r.t. for 2.5
h. and then concentrated in vacuo. The obtained gummy
solid was diluted with water and washed with diethyl ether.
The aq extract was acidified with 10% HCl in an ice water
bath to give a white solid (1-hydroxybenzotriazole 2)
which was filtered off. The aq filtrate was extracted with 3
portions of CH2Cl2 and the combined organic extracts were
dried (Na2SO4) and concentrated in vacuo to afford either
These results indicate the success of the proposed method-
ology to maintain the stereochemical integrity of the cor-
responding -amino acids. Another advantage of the
proposed methodology is that there is no need for isolat-
ing the intermediates 1-hydroxybenzotriazole esters of the
chiral -amino acids, in contrast to previously described
methodologies.15,16 This fact reduces the time for the syn-
thesis of the desired products and is beneficial for the
overall yield of the reaction (45–75%). Additionally, the
reaction is simple, inexpensive, easily scaled up and pro-
ceeds with low racemization. The structures of the tetram-
ic acids 4–9 have been elucidated by elemental analyses,
NMR and FT-IR Spectroscopy.18
Synlett 2001, No. 10, 1653–1655 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
N-acetyl-3-ethoxycarbonyl tetramic acid 4–6 as a solid, or an
One-pot Synthesis of Optically Active Tetramic Acids
1655
CH); 13C NMR (75 MHz, CDCl3) (ppm)14.0 (C-8), 16.5
(CH3), 25.3 (C-10), 54.2 (C-5), 61.9 (C-7), 100.0 (C-3),
164.3 (C-9), 167.3 (C-2), 170.2 (C-6), 190.0 (C-4); Anal.
calcd for C10H13NO5: C, 52.86; H, 5.73; N, 6.17. Found: C,
52.67; H, 5.61; N, 6.01.
3-Ethoxycarbonyl-5-(S)-benzyl pyrrolidine-2,4-dione
(7): 45% yield, mp 110–112 °C; IR (KBr) 3205 (NH), 1721,
1657, 1639 (C=O) cm–1; 1H NMR (300 MHz, CDCl3)
(ppm) 1.39 (t, J = 6.9 Hz, 3 H, COOCH2CH3), 2.70 (dd,
J1 = 9.6 Hz, J2 = 13.5 Hz, 1 H, PhCH2), 3.31 (dd, J1 = 9.6
Hz, J2 = 13.5 Hz, 1 H, PhCH2), 4.31 (m, 1 H, CH), 4.40 (q,
J = 6.9 Hz, 2 H, COOCH2CH3), 5.60 (br s, 1 H, NH), 7.20–
7.35 (m, 5 H, phenyl protons); 13C NMR (75 MHz, CDCl3)
(ppm) 14.1 (C-8), 38.0, 38.3 (PhCH2), 58.4 (C-5), 61.6 (C-
7), 98.0 (C-3), 127.5, 127.6, 129.0, 129.2, 129.2, 129.4,
135.3, 135.8 (phenyl carbons), 167.8 (C-2), 170.7 (C-6),
187.8 (C-4); Anal. calcd for C14H15NO4: C, 64.37; H, 5.75;
N, 5.36. Found: C, 63.99; H, 6.01; N, 5.54.
3-Ethoxycarbonyl-5-(S)-isobutyl pyrrolidine-2,4-dione
(8): 74% yield, mp 156–158 °C; IR (KBr) 3192 (NH), 1720,
1677, 1644 (C=O) cm–1; 1H NMR (300 MHz, CDCl3)
(ppm) 0.97 (d, J = 6.1 Hz, 6 H, 2 CH3), 1.38 (t, J = 6.9 Hz,
3 H, COOCH2CH3), 1.43–1.50 [m, 1 H, (CH3)2CHCH2],
1.69–1.84 [m, 2 H, (CH3)2CHCH2], 4.16 (br d, J = 6.0 Hz, 1
H, CH), 4.39 (q, J = 6.9 Hz, 2 H, COOCH2CH3), 6.00 (br s,
1 H, NH); 13C NMR (75 MHz, CDCl3) (ppm) 14.3 (C-8),
21.9, 23.3, 25.4 [(CH3)2CHCH2], 41.0 ((CH3)2CHCH2), 54.7
(C-5), 61.6 (C-7), 98.6 (C-3), 168.0 (C-2), 168.7 (C-6),
189.7 (C- 4); Anal. calcd for C11H17NO4: C, 58.15; H, 7.49;
N, 6.17. Found: C, 58.41; H, 7.65; N, 6.18.
oily product. This oily product, a mixture of the C-acylation
compound A and of diethyl malonate 3, was stirred in a
solution of sodium ethoxide in absolute EtOH (prepared by
addition of 12 mmol of sodium in absolute EtOH) at r.t. for
24 h. The resulting solution was concentrated in vacuo and
the resulting gummy solid was diluted with water and
washed with diethyl ether. The aq extract was acidified with
10% HCl to afford N-H-3-ethoxycarbonyl tetramic acid 7–9
as a white solid.
(18) Compound spectroscopic and analytical data:
N-Acetyl-3-ethoxycarbonyl-5-(S)-benzyl pyrrolidine-
2,4-dione (4): 43% yield, mp 101–103 °C; IR (KBr) 1737,
1688, 1665, 1614 (C=O) cm–1; 1H NMR (300 MHz, CDCl3)
(ppm) 1.33 (t, J = 7.1 Hz, 3 H, COOCH2CH3), 2.52 (s, 3
H, COCH3), 3.26 (dd, J1 = 2.5 Hz, J2 = 14.0 Hz, 1 H,
PhCH2), 3.60 (dd, J1 = 6.2 Hz, J2 = 14.0 Hz, 1 H, PhCH2),
4.32 (m, 2 H, COOCH2CH3), 4.97 (dd, J1 = 2.5 Hz, J2 = 6.2
Hz, 1 H, CH), 6.97–7.01 (m, 2 H, phenyl protons), 7.20–7.26
(m, 3 H, phenyl protons); 13C NMR (75 MHz, CDCl3)
(ppm) 14.0 (C-8), 25.5 (C-10), 34.4 (PhCH2), 58.6 (C-5),
62.0 (C-7), 99.3 (C-3), 127.7, 128.7, 129.7, 133.6 (phenyl
carbons), 164.4 (C-9), 167.2 (C-2), 170.7 (C-6), 188.0 (C-4);
Anal. calcd for C16H17NO5: C, 63.37; H, 5.61; N, 4.62.
Found: C, 63.04; H, 5.61; N, 4.83.
N-Acetyl-3-ethoxycarbonyl-5-(S)-isobutyl pyrrolidine-
2,4-dione (5): 75% yield, mp 67–68 °C; IR (KBr) 1746,
1713, 1687, 1599 cm–1; 1H NMR (300 MHz, CDCl3) (ppm)
0.90, 0.96 (2d, J = 6.2 Hz, 6 H, 2 CH3), 1.41 (t, J = 7.0 Hz,
3 H, COOCH2CH3), 1.82–1.93 [m, 3 H, (CH3)2CHCH2],
2.54 (s, 3 H, COCH3), 4.41 (q, J = 7.2 Hz, 2 H,
3-Ethoxycarbonyl-5-(S)-isopropyl pyrrolidine-2,4-dione
(9): 59% yield, mp 132–133 °C; IR (KBr) 3175 (NH), 1707,
1660, 1618 (C=O) cm–1; 1H NMR (300 MHZ, CDCl3)
(ppm) 0.88 (d, J = 6.9 Hz, 3 H, CH3), 1.04 (d, J = 6.9 Hz, 3
H, CH3), 1.39 (t, J = 7.1 Hz, 3 H, COOCH2CH3), 2.18–2.24
[m, 1 H, (CH3)2CH], 4.08 (d, J = 2.4 Hz, 1 H, CH), 4.40 (q,
COOCH2CH3), 4.73–4.76 (m, 1 H, CH); 13C NMR (75 MHz,
CDCl3) (ppm)14.1 (C-8), 22.4, 23.5, 24.3 [(CH3)2CHCH2],
25.5 (C-10), 39.0 [(CH3)2CHCH2], 57.2 (C-5), 62.1 (C-7),
98.2 (C-3), 164.4 (C-9)167.6 (C-2), 170.3 (C-6), 190.5 (C-
4); Anal. calcd for C13H19NO5: C, 57.99; H, 7.06; N, 5.20.
Found: C, 57.78; H, 6.92; N, 5.34.
J = 7.1 Hz, 2 H, COOCH2CH3), 6.00 (br s, 1 H, NH); 13
C
N-Acetyl-3-ethoxycarbonyl-5-(S)-methyl pyrrolidine-
2,4-dione (6): 44% yield, mp 89–90 °C; IR (KBr) 1717,
1678, 1630, 1606 (C=O) cm–1; 1H NMR (300 MHz, CDCl3)
(ppm) 1.41 (t, J = 7.2 Hz, 3 H, COOCH2CH3), 1.57 (d,
J = 6.6 Hz, 3 H, CH3), 2.54 (s, 3 H, COCH3), 4.42 (q,
J = 7.2 Hz, 2 H, COOCH2CH3), 4.69 (q, J = 6.6 Hz, 1 H,
NMR (75 MHz, CDCl3) (ppm) 14.1 (C-8), 15.7, 18.8
[(CH3)2CH], 29.7 [(CH3)2CH], 41.4 (C-5), 61.2 (C-7), 99.4
(C-3), 167.8 (C-2), 169.1 (C-6), 188.5 (C-4); Anal. calcd for
C10H15NO4: C, 56.34; H, 7.04; N, 6.57. Found: C, 56.58;
H, 7.00; N, 6.49.
Synlett 2001, No. 10, 1653–1655 ISSN 0936-5214 © Thieme Stuttgart · New York