Efficient construction of functionalized 5-carboxymethyl tetramic acids using N-Ac-l-aspartic anhydride as chiral building block

Article abstract of DOI:10.1016/j.tet.2010.03.083

A novel method for the synthesis of densely functionalized optically active 5-carboxymethyl tetramic acids is reported. The proposed strategy is focused on the synthesis of 3,3′-disubstituted pyrrolidine-2,4-diones as useful molecules for the synthesis of natural products. The proposed methodology has been established by X-ray diffraction structure analysis.

Full text of DOI:10.1016/j.tet.2010.03.083

Tetrahedron 66 (2010) 3944–3950
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Tetrahedron
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Efficient construction of functionalized 5-carboxymethyl tetramic acids using
N-Ac- -aspartic anhydride as chiral building block
L
,
Kyriakos C. Prousis a, John Markopoulos b, Vickie Mckee c, Olga Igglessi-Markopoulou a
*
a National Technical University of Athens, School of Chemical Engineering, Laboratory of Organic Chemistry, Zografou Campus, Heroon Polytechniou 9, Athens 15773, Greece
b University of Athens, Department of Chemistry, Laboratory of Inorganic Chemistry, Panepistimiopolis Zografou, Athens 15771, Greece
c University of Loughborough, Chemistry Department, Leicestershire LE113TU, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel method for the synthesis of densely functionalized optically active 5-carboxymethyl tetramic
acids is reported. The proposed strategy is focused on the synthesis of 3,30-disubstituted pyrrolidine-2,4-
diones as useful molecules for the synthesis of natural products. The proposed methodology has been
established by X-ray diffraction structure analysis.
Received 20 November 2009
Received in revised form
2 March 2010
Accepted 22 March 2010
Available online 27 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Tetramic acids
L-Aspartic anhydride
Lithium enolates
3,30-Disubstituted pyrrolidine-2,4-diones
C-acylation
1. Introduction
The development of new methodologies for the construction of
highly functionalized tetramic acids containing the pyrrolidine-2,4-
dione structural motif, is of continuing interest.1 The fascinating
biology of naturally occurring tetramic acids and their derivatives,
has resulted in several groups dedicating their efforts toward the
synthesis and biological evaluation of these important molecules,
and analogues thereof.
Representative examples of bioactive naturally occurring tetra-
mic acids are (Fig.1): reutericyclin(I) extracted from cell and culture
filtrates of Lactobacillus reuteri, which inhibits the growth of sal-
monella and helicobacter,2 ancorinosides(II) isolated from the
marine sponge Penares sollasi thiele as inhibitors of membrane type
1 matrix metalloproteinase,3 tenuazonic acid, produced by Alter-
naria spp., a biologically active compound with antitumor, antiviral
and antibiotic activities,4 and aurantoside B isolated from various
marine sponges exhibits antifungal and cytotoxic activity.5
Construction of densely functionalized tetramic acids attract
interest and the development of rapid and effective synthetic
methodologies have been the focus of many research groups.6
Figure 1. Natural occurring tetramic acids.
Recently an efficient stereocontrolled synthesis of various 3,30-
bisubstituted tetramic acids has been developed starting from 2,5-
diketopiperazines, giving access to 2-substituted statins, or the
synthesis of relevant lactam-constrained dipeptide mimetics.7
Furthermore, the genes responsible for several tetramic acids and
more modified relatives have been characterized.8 Janda and
co-workers demonstrated that N-(3-oxododecanoyl) homoserine
lacton (AHLS) generates the 3-substituted-5-(2-hydroxyethyl)
tetramic acid via an unusual Claisen-like condensation reaction.9
Additionally the 3-acetyl pyrrolidine-2,4-dione heterocycle
* Corresponding author. Tel.: þ30 210 772 3 079; fax: þ30 210 772 3 072; e-mail
address: ojmark@orfeas.chemeng.ntua.gr (O. Igglessi-Markopoulou).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.083

K.C. Prousis et al. / Tetrahedron 66 (2010) 3944–3950
3945
moiety has been shown to efficiently chelate a variety of metal
cations.10
It is well known that N-protected aspartic acid anhydrides
constitute useful intermediates in peptide synthesis. In these acti-
vated anhydrides the two carboxylic acid moieties can be opened
regioselectively, depending on the experimental conditions.14 The
C-2 carbonyl function of N-aspartates is susceptible toward a nu-
cleophilic attack and regioselective ring opening by alcohols,15
amines,16 and Grignard reagents.14 To our knowledge, there has
been no previous report concerning this nucleophilic attack by
active methylene compounds.
Furthermore, tetramic acids have been identified as a novel
starting point for the synthesis of peptide analogues. Methodolo-
gies for the incorporation of pyrrolidine-2,4-diones into peptide
chains, at the C- or N-terminus or in an intermediate position have
been explored by Hosseini and co-workers.11
Consequently construction of densely functionalized tetramic
acids containing a quaternary carbon center found within these
naturally occurring molecules has proven to be a significant syn-
thetic challenge.12
Despite the many diverse and creative approaches that have
been used to assemble the pyrrolidinone nucleus a general syn-
thesis for regioselective introduction of substituents at C-3 and C-5
is of great importance.
Herein a new class of functionalized optically active tetramic
acids were designed and synthesized using N-acetyl aspartic acid
anhydride as the chiral synthon. The electron-withdrawing group
activated the C-2 site, which was therefore preferentially attacked.
The requisite (S)-N-acetyl aspartic acid anhydride was easily pre-
pared from L
-aspartic acid following a literature procedure.17 The
acetyl N-protecting group was found to be stable under the re-
action conditions, as was the configuration at the C-2 stereogenic
center.
2. Results and discussion
The majority of natural products that contain the tetramic acid
moiety have an acyl group at the C-3 position of the heterocyclic
ring and their biological activity is essentially due to the presence of
the pyrrolidin-2,4-dione ring, the carbonyl group of the C-3 acyl
group, and the stereocenter at C-5. Owing to the importance of the
naturally occurring 3-acyl tetramic acids,6e our initial in-
During the course of our studies toward the development of
a new methodology on the synthesis of pyrrolidine-2,4-diones, we
have been interested in the possibility of developing a new ap-
proach to the synthesis and structure elucidation of tetramic acids
bearing a polar substituent at the C-5 position13 and a functional-
ized quaternary carbon at the C-3 position.
This paper described a new class of functionalized optically ac-
tive tetramic acids designed and synthesized using the (S)-N-pro-
tected aspartic acid anhydride as a novel chiral starting point, as
outlined in Scheme 1.
vestigations focused on the acylation of the appropriate
b-
ketoesters 2a–c by the anhydride 1 (Scheme 1).
Under the proposed reaction conditions, 2 equiv of NaH were
added to anhydrous THF followed by the addition of the -ketoester
b
Scheme 1. Reagents and conditions: (a) NaH, THF, 1 h at 0 ꢀC to rt; (b) EtONa/EtOH, rt, overnight.
The requisite (S)-N-acetyl aspartic acid anhydride 1 was utilized
as a convenient precursor for the introduction of the chiral C-5
carbon of the g-lactam ring. This anhydride was found to react in
a highly stereoselective manner at the hindered, more electron-
deficient carbonyl at the C-2 site, with carbon nucleophiles
2a–c (2 equiv). N-Acetyl aspartic acid anhydride 1, (1 equiv) was
then added and the mixture was stirred at room temperature for
1 h. After work-up (see Experimental section) a mixture was pro-
duced, which is based on the 1H NMR spectrum, contained the
C-acylation compound as the major product. Stirring the crude
mixture in EtONa/EtOH at room temperature for 20 h provided
3-acyl-5-carboxymethyl tetramic acids 3a–c in good yields (57–66%).
derived from the anions of suitable b-ketoesters (2a–c, 4a, 4b) or
appropriately substituted ethyl acetates (7a–d, 9a–f) (Schemes 2–4).
Scheme 2. Reagents and conditions: the molar ratio of 1:4: NaH is 1:2:2 for route A and 1:3:3 for route B.
The proposed protocol allows simultaneous construction of the
pyrrolidine-2,4-dione ring system with retention of the configura-
tion at the C-5 position and the installation of a quaternary carbon at
the C-3 position of the tetramic acid nucleus, which is a useful
complement to the synthetic approaches to natural products.
Acylation of the malonate anions 4 (2 equiv) (Scheme 2) under
the previous conditions, yielded the N-acetyl-3-alkoxycarbonyl-5-
carboxymethyl tetramic acids 6a and 6b. When the reaction of 1
and 4a with NaH (2 equiv) was quenched after 1 h, the intermediate
5a was isolated in 60% yield.

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K.C. Prousis et al. / Tetrahedron 66 (2010) 3944–3950
Scheme 3. Reagents and conditions: (i) LDA, THF, 1 h ꢁ78 ꢀC, 1 h rt; (ii) EtONa/EtOH/benzene (1:1) 3 h reflux, 20 h rt.
Scheme 4. Reagents and conditions: (a) LDA, THF, ꢁ78 ꢀC, 1.5 h, to rt, 1.5 h.
The scope of the reaction was further evaluated using lithium
reaction conditions, we obtained the deacetylated tetramic acids
directly, and no deacetylation step was required.
enolates derived from appropriately substituted ethyl acetates as
carbon nucleophiles; the corresponding 3-alkyl and 3-aryl
substituted tetramic acids have been prepared in good yields,
which can be regarded as useful key intermediates for the synthesis
of natural products18 (Scheme 3).
Initial acylation experiments were conducted at ꢁ78 ꢀC using
lithium base (LDA) in THF, followed by cyclization with EtONa/
EtOH, benzene, to form the corresponding 3-alkyl and 3-aryl tet-
ramic acids 8a–d, in 45–65% yield.
Careful analysis of the 1H NMR spectra indicated that tetramic
acids 10b–f exist as mixtures of two diastereomers, as can be de-
duced from the double signals appearing for each of the protons on
the nitrogen atom and at C-5 position of the ring. The di-
astereomeric ratio was determined to be approximately 70:30 from
the integration of either of these signals.
At this point it is important to notice that the nucleophilic at-
tack of active lithium enolates occurs in a highly regioselective
The enantiomeric excess (ee) of the compounds 8b–d has been
determined by HPLC analysis, using a chiral stationary phase.19 The
results (92–96%, ee) indicate that our methodology leads to opti-
cally active final compounds, in which the stereochemical integrity
of the 5-chiral center is retained to a great extent.
manner on the a-carbonyl of the N-aspartate, thus providing the
desired compounds in good yields. This regioselectivity is probably
the result of the following reasons: firstly, the electron with-
drawing effect of the N-acetyl group activates the
carbon and directs the attack of the nucleophile exclusively to the
-position. In addition, in the non-polar solvent (THF) used for
the acylation reaction, the intramolecular hydrogen bond between
the hydrogen of the amine group and the -carbonyl is favored,
-carbonyl carbon more susceptible for nucleophilic
a-carbonyl
Having established a high efficient route to N-protected and
NH– tetramic acids we turned our attention to the synthesis of 3,3-
disubstituted tetramic acids (Scheme 4), which constitute in-
teresting molecular scaffolds, though references concerning the
synthesis of this kind of compounds are rather limited.20 The 3,3-
dimethyl-2,4-pyrrolidinedione moiety would be the characteristic
heterocyclic core of the marine neurotoxin ‘janolusimide’, isolated
from nudibranch mollusc Janolus cristatus.21 Moreover, the syn-
thesis of 3,3-disubstituted tetramic acids would provide useful in-
formation concerning the diastereoselectivity of the reaction.
We were gratified to find out that our methodology gives rise to
the desired compounds in one step. As depicted in Scheme 4, the
C-acylation of the apropriate lithium enolates, derived from
disubstituted ethyl acetates 9a–f, using the N-acetyl-aspartic
anhydride 1 as acylating agent provided the 3,3-disubstituted
tetramic acids 10a–f, in good yields (60–70%). Under the proposed
a
a
rendering the
attack.16
a
The carboxymethyl functionality at position 5 of the heterocyclic
ring could be further modified to enable access to tetramic acids
analogues bearing a variety of substituents on this position.
The X-ray structure22 of compound 10d was carried out to
confirm the structure in the solid state. The molecular structure and
numbering scheme are shown in Figure 2.
There is some double bond character evident in the N (1)–C
(1) bond (1.3235 Å) compared to N (1)–C (8) bond (1.4566 Å), and
the O (1)–C (1) bond is distinctly longer than the conventional
carbonyl distance for
respectively.
O (2)–C (7) (1.2428 Å and 1.208 Å),

K.C. Prousis et al. / Tetrahedron 66 (2010) 3944–3950
3947
under nitrogen. (S)-N-Acetyl-
L-aspartic anhydride (1) (0.79 g,
5 mmol) in THF (5 mL) was added then by syringe, and the reaction
mixture was stirred at room temperature for 1 h, under nitrogen.
Water (10 mL) was added to the reaction and the THF evaporated
in vacuo. The aqueous layer was then washed with Et2O (20 mL),
acidified with HCl 10% to pH¼1–2 in an ice-water bath, and then
extracted with AcOEt (3ꢂ30 mL). The combined organic extracts
were dried over Na2SO4, and concentrated under reduced pressure,
dried in vacuo to give the C-acylation intermediate as an oily
product. After 1–2 h drying in vacuo the appropriate C-acylation
product was added to a solution of sodium ethoxide [prepared by
the addition of sodium (12.5 mmol) in absolute ethanol (44 mL)]
and the resulting solution was stirred at room temperature for
24 h. The solvent was removed under reduced pressure and the
residue was treated with water (10 mL), washed with Et2O (20 mL),
and acidified with HCl 10% to pH¼1–2 in an ice-water bath, to give
the corresponding (3) as solid products, which were dried in vacuo
over P2O5 for 2–3 h. Otherwise (2) was isolated by extraction of
aqueous layer with ethyl acetate (3ꢂ30 mL), the combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure, dried in vacuo to give a solid, after trituration with
methanol/diethylether.
Figure 2. Molecular structure of 10d. Thermal ellipsoids drawn at the 50% probability
level.
4.2.1.1. (S)-3-Acetyl-5-carboxymethyl tetramic acid (3a). Starting
from anhydride (1) and using ethyl acetoacetate (10.0 mmol, 1.3 g)
the title compound was obtained as a white solid (0.57 g, 57%). Mp:
3. Conclusions
157–159 ꢀC (lit., mp 168 ꢀC).24
[
a]
ꢁ14.7 (c 0.2, methanol). IR
20
D
(ATR): 3214, 3054, 1703, 1655, 1610 cmꢁ1
DMSO-d6):
2.35 (3H, s), 2.58 (1H, dd, J¼16.8, 6.6 Hz), 2.65 (1H, dd,
J¼16.8, 4.8 Hz), 4.07 (1H, pt), 8.79 (1H, br s), 10.37 (1H, br s), 12.40
(1H, br s). 13C NMR (75 MHz, DMSO-d6):
19.6, 35.7, 58.1, 101.5,
.
1H NMR (300 MHz,
N-Acetyl aspartic acid anhydride proved to be an excellent
acylating agent for C-nucleophiles. In all instances ring opening was
regioselective, occurring at position 2 of the anhydride ring. The
scope of our methodology has been investigated using various
nucleophiles and leads to the synthesis of tetramic acids bearing
a wide variety of substituents at position 3.
d
d
171.2, 174.6, 184.3, 194.8. Anal. Calcd for C8H9NO5: C, 48.25; H, 4.55;
N, 7.03. Found: C, 48.01; H, 4.28; N, 6.84.
4. Experimental section
4.1. General
4.2.1.2. (S)-3-Butanoyl-5-carboxymethyl tetramic acid (3b) Starting
from anhydride (1) and using ethyl butanoylacetate (10.0 mmol,
1.58 g) the title compound was obtained as a white solid (0.73 g,
20
64%). Mp: 161–163 ꢀC. [
a
]
D
ꢁ57.1 (c 0.2, methanol). IR (ATR): 3205,
3055, 1704, 1655, 1606 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d 0.89
Mps were determined on a Gallenkamp MFB-595 melting point
apparatus and are uncorrected. High resolution mass spectra were
obtained in the Department of Chemistry & Biochemistry of Uni-
versity of Notre Dame on a ESI instrument. IR spectra were recorded
by using the attenuated total reflection (ATR) method on a FTIR
Bruker Tensor 27 in the Institute of Organic and Pharmaceutical
Chemistry of National Hellenic Foundation. The NMR spectra were
recorded at 300 (1H) and 75 (13C) MHz on a Varian Gemini-2000
300 MHz spectrometer; chemical shifts are quoted in parts per
million (s¼singlet, d¼doublet, dd¼doublet of douplet, t¼triplet,
pt¼pseudotriplet, q¼quartet, m¼multiplet, br¼broad); J values are
given in hertz. Elemental analyses were obtained on a Euro EA3000
Series Euro Vector CHNS Elemental Analyzer. All commercially
available starting materials were used without further purification.
Commercially available THF was dried prior to use by refluxing over
Na. All other solvents (puriss quality) were used without further
purification. Compounds 7c, 7d, 9e, 9f were synthesized by fol-
lowing the well established literature procedures.23 N-Acetyl
aspartic acid anhydride (1) was synthesized according to the liter-
ature procedure.17 Column chromatography was performed with
silica gel 60 (230–400 mesh with eluents given in parentheses).
(3H, t, J¼7.2 Hz), 1.53–1.66 (2H, m), 2.56/2.66 (2H, 2dd, J¼16.8, 6.3,
17.1, 4.5 Hz), 2.72 (2H, t, J¼7.2 Hz), 4.06 (1H, pt), 8.86 (1H, br s),11.25
(1H, br s) 12.36 (1H, br s). 13C NMR (75 MHz, DMSO-d6):
d 13.5,
18.8, 34.2, 35.7, 58.2, 101.1, 171.2, 175.3, 187.6, 194.5. Anal. Calcd
for C10H13NO5: C, 52.86; H, 5.77; N, 6.16. Found: C, 52.52; H, 5.51;
N, 6.00.
4.2.1.3. (S)-3-Benzoyl-5-carboxymethyl tetramic acid (3c) Starting
from anhydride (1) and using ethyl benzoylacetate (10.0 mmol,
1.92 g) the title compound was obtained as a white solid (0.86 g,
20
66%). Mp: 202–204 ꢀC. [
a
]
D
ꢁ122.2 (c 0.5, methanol). IR (ATR):
3207, 3058, 1701, 1663, 1605, 1595 cmꢁ1. 1H NMR (300 MHz, DMSO-
d6):
2.62/2.72 (2H, 2dd, J¼16.8,6.0 Hz, J¼16.8,4.5 Hz), 4.14 (1H, pt),
7.53 (2H, t, J¼7.5 Hz), 7.64 (1H, t, J¼7.5 Hz), 8.11 (2H, d, J¼7.5 Hz),
9.22 (1H, br s), 11.72 (2H, br s). 13C NMR (75 MHz, DMSO-d6):
35.8,
d
d
57.7, 99.8, 128.1, 129.1, 132.5, 133.3, 171.3, 176.8, 180.3, 192.4. Anal.
Calcd for C13H11NO5: C, 59.77; H, 4.24; N, 5.36. Found: C, 59.52; H,
4.02; N, 5.14.
4.2.2. General procedure for the preparation of compounds (5a, 6a,
6b). The appropriate active methylene compound 4 (10 mmol) was
added dropwise to a suspension of NaH (60%, 0.9 g,15 mmol) in THF
(30 mL) and the mixture was stirred at 0 ꢀC for 30–40 min under
4.2. Synthesis
4.2.1. General procedure for the preparation of compounds (3a–
c). The appropriate active methylene compound (2) (10 mmol)
was added dropwise to a suspension of NaH (60%, 0.6 g, 10 mmol)
in THF (30 mL) and the mixture was stirred at 0 ꢀC for 30–40 min
nitrogen. (S)-N-Acetyl-L-aspartic anhydride (1) (0.79 g, 5 mmol) in
THF (5 mL) was added then by syringe, and the reaction mixture
was stirred at room temperature for 20 h. The same work up was
followed as for 3 to give the corresponding products 6a, 6b in an

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K.C. Prousis et al. / Tetrahedron 66 (2010) 3944–3950
oily form. After trituration with MeOH/Et2O/PE the precipitated
solids were collected by filtration and dried in vacuo over P2O5 for
2–3 h.
(8a–d) were isolated by extraction of the aqueous layer with AcOEt
(3ꢂ30 mL). The combined organic extracts were dried over Na2SO4
and concentrated to give after trituration with methanol/dieth-
ylether the final products (8a–d), which were dried in vacuo over
P2O5 for 2–3 h.
4.2.2.1. (S)-3-Acetamido-6-methoxy-5-(methoxycarbonyl)-4,6-
dioxohexanoic acid (5a). The title compound was afforded accord-
ing to the modified procedure for (6a, 6b), so after the addition of
anhydride (1) the reaction mixture was stirred for only 1 h and then
quenched [dimethyl malonate (10.0 mmol, 1.32 g) and sodium hy-
dride (10 mmol, 0.6 g, 60% in oil) was used]. The C-acylation in-
termediate 5a was solidified by treating of the oily crude reaction
mixture with Et2O and then refrigerated for several hours. The title
4.2.3.1. (S)-5-Carboxymethyl-3-methyl tetramic acid (8a) Starting
from anhydride (1) and using ethyl propionate (8.0 mmol, 0.82 g)
the title compound was obtained as a gummy solid (0.21 g, 45%).
20
Mp: 171–173 ꢀC. [
a]
þ25.9 (c 0.2, methanol). IR (ATR): 3408, 1715,
D
1687, 1640 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
(1H, dd, J¼16.2, 8.7 Hz), 2.70 (1H, dd, J¼16.2, 3.6 Hz), 4.07 (1H, pt),
7.28 (1H, br s). 13C NMR (75 MHz, DMSO-d6):
6.1, 37.7, 52.4, 100.3,
d 1.52 (3H, s), 2.16
compound was obtained as a white solid (0.87 g, 60%). Mp: 273–
d
20
275 ꢀC. [
a
]
ꢁ83.6 (c 0.35, methanol). IR (ATR): 3420, 3378, 1764,
167.9, 172.0, 174.6. Anal. Calcd for C7H9NO4: C, 49.12; H, 5.30; N,
8.18. Found: 48.95; H, 5.14; N, 8.01.
D
1737, 1701, 1641, 1512 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
. d 1.86
(3H, s), 2.56 (1H, dd, J¼16.8, 7.2 Hz), 2.73 (1H, dd, J¼16.8, 5.4 Hz),
3.68/3.69 (6H, 2s), 4.70 (1H, m), 4.98 (1H, s), 8.55 (1H, br d,
4.2.3.2. (S)-5-Carboxymethyl-3-Phenyltetramic acid (8b) Starting
from anhydride (1) and using ethyl phenylacetate (8.0 mmol, 1.31 g)
J¼8.1 Hz). 13C NMR (75 MHz, DMSO-d6):
d 22.1, 35.0, 52.96, 53.01,
54.6, 61.3, 164.6, 164.7, 170.1, 171.6, 198.4. Anal. Calcd for C11H15NO8:
45.68; H, 5.23; N, 4.84. Found: 45.46; H, 5.04; N, 4.62.
the title compound was obtained as a white solid (0.41 g, 65%). Mp:
20
222–224 ꢀC. [
a]
D
ꢁ52.1 (c 0.2, methanol), ee 92%. IR (ATR): 3402,
3061, 1720, 1643, 1596 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d 2.29
4.2.2.2. (S)-1-Acetyl-5-carboxymethyl-3-methoxycarbonyl tetra-
mic acid (6a). Starting from anhydride (1) and using dimethyl
malonate (10.0 mmol, 1.32 g) the title compound was obtained as
(1H, dd, J¼16.2,9.3 Hz), 2.95 (1H, dd, J¼16.2,3.0 Hz), 4.28 (1H, dd,
J¼9.3, 3.0 Hz), 7.16 (1H, t, J¼7.5 Hz), 7.31 (2H, t, J¼7.8 Hz), 7.59 (1H, br
s), 7.93 (2H, d, J¼7.5 Hz), 11.58/12.37 (2H, 2br s) 13C NMR (75 MHz,
20
a white solid (0.71 g, 55%). Mp: 168–170 ꢀC. [
a]
þ48.3 (c 0.2,
DMSO-d6): d 37.8, 52.1, 103.6, 125.8, 127.2, 127.7, 132.2, 170.0, 172.0,
D
methanol). Mp: 111–113 ꢀC. IR (ATR): 3177, 1722, 1688, 1614 cmꢁ1
1H NMR (300 MHz, DMSO-d6):
2.37 (3H, s), 2.80/2.88 (2H, 2dd,
J¼15.9, 3.6 Hz, J¼15.9, 5.7 Hz), 3.65 (3H, s), 4.65 (1H, dd, J¼5.7,
3.6 Hz), 10.29 (2H, br s). 13C NMR (75 MHz, DMSO-d6):
25.0, 34.2,
.
172.8. Anal. Calcd for C12H11NO4: C, 61.80; H, 4.75; N, 6.01. Found: C,
61.62; H, 4.52; N, 5.79.
d
d
4.2.3.3. (S)-5-Carboxymethyl-3-(4-methoxyphenyl)tetramic acid
50.6, 55.2, 96.3, 162.2, 166.5, 168.9, 170.5, 184.0. Anal. Calcd for
C10H11NO7: C, 46.70; H, 4.31; N, 5.45. Found: C, 46.48; H, 4.12; N,
5.22.
(8c). Starting from anhydride (1) and using ethyl 2-(4-methox-
yphenyl)acetate (8.0 mmol, 1.55 g) the title compound was
20
obtained as a light beige solid (0.36 g, 51%). Mp: 220–222 ꢀC. [
a]
D
ꢁ30.6 (c 0.2, methanol). IR (ATR): 3408, 1723, 1699, 1655,
1590 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
4.2.2.3. (S)-1-Acetyl-5-carboxymethyl-3-ethoxycarbonyl tetramic
acid (6b). Starting from anhydride (1) and using diethyl malonate
(10.0 mmol, 1.6 g) the title compound was obtained as a white solid
.
d
2.25 (1H, dd, J¼16.2,
9.3 Hz), 2.94 (1H, dd, J¼16.2, 3.0 Hz), 3.74 (3H, s), 4.25 (1H, dd,
J¼9.3, 3.0 Hz), 6.89 (2H, d, J¼9.0 Hz), 7.56 (1H, br s), 7.88 (2H, d,
J¼9.0 Hz), 11.30 (1H, br s), 12.45 (1H, br s). 13C NMR (75 MHz,
20
(0.68 g, 50%). Mp: 115–117 ꢀC. [
a
]
þ48.3 (c 0.2, methanol). IR
D
(ATR): 3215, 1735, 1691, 1663, 1608 cmꢁ1
DMSO-d6):
1.22 (3H, t, J¼6.9 Hz), 2.37 (3H, s), 2.80/2.89 (2H, 2dd,
J¼16.2, 3.6, 16.2, 6.0 Hz), 4.15 (2H, m), 4.66 (1H, dd, J¼5.7, 3.6 Hz),
8.37 (2H, br s). 13C NMR (75 MHz, DMSO-d6):
14.3, 25.0, 34.1, 55.1,
.
1H NMR (300 MHz,
DMSO-d6): d 37.8, 52.0, 55.0, 103.3, 113.0, 124.6, 128.2, 134.5, 157.2,
d
168.4, 172.0, 172.9. Anal. Calcd for C13H13NO5: C, 59.31; H, 4.98; N,
5.32. Found: C, 59.15; H, 4.81; N, 5.14.
d
59.2, 96.7,161.9, 166.3,168.9,170.5,183.7. Anal. Calcd for C11H13NO7:
C, 48.71; H, 4.83; N, 5.16. Found: C, 48.49; H, 4.61; N, 5.01.
4.2.3.4. (S)-5-Carboxymethyl-3-(3-methoxyphenyl)tetramic acid
(8d). Starting from anhydride (1) and using ethyl 2-(3-methoxy-
phenyl)acetate (8.0 mmol, 1.55 g) the title compound was obtained
20
4.2.3. General procedure for the preparation of compounds (8a–d). A
solution of the appropriate aryl or alkylacetates (7) (8 mmol) in THF
(4 mL) was added dropwise via a syringe over a period of 10 min to
a solution of lithium diisopropylamide (LDA) 2.0 M solution in THF/
hexane/ethylbenzene (8 mmol, 4 mL) in THF (20 mL) at ꢁ78 ꢀC
under nitrogen. The mixture was stirred for 45 min, then (S)-N-
as a light beige solid (0.29 g, 42%). Mp: 207–209 ꢀC. [
a
]
ꢁ70.8 (c
D
0.2, methanol). IR (ATR): 3307, 1720, 1647, 1609, 1575 cmꢁ1. 1H NMR
(300 MHz, DMSO-d6):
d
2.29 (1H, dd, J¼16.2, 9.3 Hz), 2.93 (1H, dd,
J¼16.2, 3.3 Hz), 3.73 (3H, s), 4.28 (1H, dd, J¼9.3, 3.3 Hz), 6.73–6.83
(1H, m), 7.21 (1H, t, J¼8.1 Hz), 7.54–7.59 (2H, m), 11.76/12.03
(2H, 2br s). 13C NMR (75 MHz, DMSO-d6):
d 37.8, 52.0, 54.8, 103.2,
acetyl-
L
-aspartic anhydride (1) (0.42 g, 2.67 mmol) in THF (4 mL)
111.2, 112.6, 119.6, 128.6, 133.5, 158.7, 170.5, 172.0, 172.7. Anal.
Calcd for C13H13NO5: C, 59.31; H, 4.98; N, 5.32. Found: C, 59.11; H,
4.79; N, 5.17.
was added by cannula over 10 min. The reaction mixture was stir-
red for 1 h at ꢁ78 ꢀC and 1 h at room temperature, quenched with
water (10 mL), and the THF evaporated in vacuo. The resulting
aqueous layer was then washed with Et2O (20 mL) and acidified
with HCl 10% to pH¼1–2 in an ice-water bath, and then extracted
with AcOEt (3ꢂ30 mL). The combined organic extracts were dried
over Na2SO4 and concentrated to give the C-acylation in-
termediates as oily products. After 1–2 h drying in vacuo the ap-
propriate C-acylation product was added to a solution of sodium
ethoxide [prepared by the addition of sodium (6.65 mmol) to a so-
lution of absolute EtOH/anhydrous benzene 1:1 (46 mL)] and the
resulting solution was refluxed for 3 h and then stirred for 20 h at
room temperature. The solvents were concentrated and the residue
was treated with water (10 mL), washed with Et2O (20 mL) and
acidified with HCl 10% to pH¼1–2 in an ice-water bath. Compounds
4.2.4. General procedure for the preparation of 3,3-disubstituted
carboxymethyltetramic acids (10a–h). A solution of the appropriate
disubstituted acetates (9) (8 mmol) in THF (4 mL) was added
dropwise via a syringe over a period of 10 min to a solution of
lithium diisopropylamide (LDA) 2.0 M solution in THF/hexane/
ethylbenzene (8 mmol, 4 mL) in THF (20 mL) at ꢁ78 ꢀC under ni-
trogen. The mixture was stirred for 45 min, then (S)-N-acetyl-L-
aspartic anhydride (1) (0.42 g, 2.67 mmol) in THF (4 mL) was added
by cannula over 10 min. The reaction mixture was stirred for
90 min at ꢁ78 ꢀC and 90 min at room temperature, quenched with
water (10 mL), and the THF evaporated in vacuo. The same work up
was followed as for (8) to give the corresponding products (10e–f),

K.C. Prousis et al. / Tetrahedron 66 (2010) 3944–3950
3949
in an oily form, which were purified by column chromatography on
silica gel with dichloromethane/MeOH/AcOH.
a¼6.7116(6),
b¼9.5530(8),
c¼8.4485(7) Å,
b
¼102.183(1)ꢀ,
V¼529.48(8) Å3, T¼150(2) K,
¼0.71073 Å, Z¼2, 5344 reflections
l
measured, 2578 unique (Rint¼0.0202), wR2¼0.0776 (all data),
4.2.4.1. (S)-5-Carboxymethyl-3,3-dimethyltetramic acid (10a)
Starting from anhydride (1) and using ethyl isobutyrate (8.0 mmol,
0.93 g) the title compound was obtained as a white solid (0.27 g,
55%) after purification by column chromatography [dichloro-
R1¼0.313 (I>2
s(I)). Crystallographic data have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 740987. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: þ44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
methane/methanol/acetic acid (94:4:2)] and trituration with
20
diethylether/petroleum ether. Mp: 286–288 ꢀC. [
a
]
D
þ37.0 (c 0.1,
methanol). IR (ATR): 3323, 1768, 1701, 1652 cmꢁ1
(300 MHz, DMSO-d6):
1.10 (6H, s), 2.64 (1H, dd, J¼17.7, 4.2 Hz),
2.81 (1H, dd, J¼17.4, 4.2 Hz), 4.23 (1H, pt), 8.23 (1H, br s), 12.41 (1H,
br s). 13C NMR (75 MHz, DMSO-d6):
18.8, 22.4, 35.6, 46.0, 56.5,
.
1H NMR
d
4.2.4.5. (S)-5-Carboxymethyl-3-ethyl-3-phenyltetramic
acid
(10e). Starting from anhydride (1) and using ethyl 2-methyl-
butanoate (8.0 mmol, 1.15 g) the title compound was obtained as
a colorless oil (0.37 g, 70%), after purification by column chroma-
tography [dichloromethane/methanol/acetic acid (94:4:2)] as
a mixture of two diastereomers (51:49). IR (ATR): 3247, 1769, 1697,
d
171.4, 176.9, 214.6. Anal. Calcd for C8H11O4N: C, 51.89; H, 5.99; N,
7.56. Found: C, 52.06; H, 6.11; N, 7.69. ESI-HRMS: m/z [MþNa]þ
calcd for C8H11NNaO4 208.0580, found 208.0569.
1658 cmꢁ1 1H NMR (300 MHz, CDCl3):
. d 0.87/0.91 (3H, 2 t,
4.2.4.2. (S)-5-Carboxymethyl-3-ethyl-3-methyltetramic
acid
J¼7.2 Hz), 2.03–2.27 (2H, m), 2.55 (0.49H, dd, J¼17.4, 10.2 Hz), 2.87
(0.51H, dd, J¼17.4, 3.0 Hz), 2.87 (0.51H, dd, J¼17.4, 3.0 Hz), 4.24–
4.32 (1H, m), 7.27–7.44 (5H, m), 8.48/8.54 (0.51/0.49H, 2br s), 11.26
(10b). Starting from anhydride (1) and using ethyl 2-methyl-
butanoate (8.0 mmol, 1.05 g) the title compound was obtained as
a colorless oil (0.37 g, 70%), after purification by column chroma-
tography [dichloromethane/methanol/acetic acid (94:4:2)] as
a mixture of two diastereomers (69:31). IR (ATR): 3315, 1758, 1701,
(1H, br s). 13C NMR (75 MHz, CDCl3):
d 9.6/10.0, 28.7/30.1, 35.4/37.3,
57.9/59.2, 60.2/60.9, 126.5/126.6, 128.1/128.3, 129.1/129.2, 135.2/
135.6, 174.2/174.4, 176.8/177.1, 208.5/209.3. ESI-HRMS: m/z [MþH]þ
calcd for C14H16NO4 262.1074, found 262.1056.
1639 cmꢁ1 1H NMR (300 MHz, CDCl3/DMSO-d6):
. d 0.70/0.76 (3H,
2 t, J¼7.2 Hz), 1.12/1.13 (3H, 2s), 1.58–1.66 (2H, m), 2.33/2.58 (0.31/
0.69H, 2dd, J¼17.1, 10.2/17.1, 7.2 Hz), 2.79 (1H, dd, J¼17.1,3.6 Hz),
4.01/4.23 (0.69/0.31H, 2dd, J¼3.6, 7.2/10.2, 3.6 Hz), 7.68/7.75 (1H,
4.2.4.6. (S)-5-Carboxymethyl-3-methyl-3-phenyltetramic
acid
(10f). Starting from anhydride (1) and using ethyl 2-phenyl-
propanoate (8.0 mmol, 1.43 g) the title compound was obtained as
a colorless oil (0.20 g, 30%), after purification by column chroma-
tography [dichloromethane/methanol/acetic acid (94:4:2)] as
a mixture of two diastereomers (81:19). IR (ATR): 3196, 1768, 1732,
2br s), 10.37 (1H, br s). 13C NMR (75 MHz, CDCl3/DMSO-d6):
d 8.8,
9.5, 18.5, 20.4, 27.5, 29.9, 35.9, 36.2, 51.5, 51.6, 57.7, 58.6, 172.4, 172.8,
177.8, 178.4, 212.9, 213.3. ESI-HRMS: m/z [MþH]þ calcd for
C9H14NO4 200.0917, found 200.0909.
1685,1654 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d 1.51/1.54 (3H, 2s),
4.2.4.3. (S)-5-Carboxymethyl-3-methyl-3-propyltetramic
acid
2.60 (0.19H, pt), 2.73/2.88 (1.82H, 2dd, J¼17.7, 3.6 Hz, J¼17.7, 3.6 Hz),
(10c). Starting from anhydride (1) and using ethyl 2-methyl-
pentanoate (8.0 mmol, 1.15 g) the title compound was obtained as
a colorless oil (0.37 g, 65%), after purification by column chroma-
tography [dichloromethane/methanol/acetic acid (94:4:2)] as
a mixture of two diastereomers (81:19). IR (ATR): 3318, 1758, 1702,
4.27/4.48 (0.81/0.19H, 2pt), 7.25–7.39 (5H, m), 8.62/8.73 (0.81/
0.19H, 2br s), 12.65 (1H, br s). 13C NMR (75 MHz, DMSO-d6):
d 19.3,
35.3, 54.7, 57.3, 126.1, 127.5, 128.9, 137.9, 171.2, 174.8, 211.5. ESI-
HRMS: m/z [MþH]þ calcd for C13H14NO4 248.0917, found 248.0893.
1643 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
1.09–1.27 (5H, m), 1.43–1.53 (2H, m), 2.57–2.68 (1.19H, m), 2.79
(0.81H, dd, J¼17.7, 4.2 Hz), 4.09/4.33 (0.81/0.19H, 2pt), 8.33/8.43
(0.81/0.19H, 2br s), 12.54 (1H, br s). 13C NMR (75 MHz, DMSO-d6):
d
0.81 (3H, t, J¼7.2 Hz),
Acknowledgements
K.C.P. is grateful to the Research Committee of the National
Technical University of Athens for financial support.
d
14.1/14.4, 17.2/17.6, 18.2/20.6, 35.7/35.9, 49.8/50.2, 57.0/57.8, 171.1,
175.9/176.3, 214.6/214.9. ESI-HRMS: m/z [MþH]þ calcd for
Supplementary data
C10H16NO4 214.1074, found 214.1066.
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2010.03.083.
4.2.4.4. (S)-3-allyl-5-Carboxymethyl-3-methyltetramic
acid
(10d). Starting from anhydride (1) and using ethyl 2-methylpent-
4-enoate (8.0 mmol, 1.14 g) the title compound was obtained as
a colorless oil (0.34 g, 60%), after purification by column chroma-
tography (dichloromethane/methanol/acetic acid (94:4:2)) as
a mixture of two diastereomers (79:21). Crystalization occures with
petroleum ether/drops MeOH in order to give colorless crystals. IR
(ATR): 3191,1771,1728, 1660, 1640 cmꢁ1. 1H NMR (300 MHz, DMSO-
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3950
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