Regioselective ring opening of thiomalic acid anhydrides by carbon nucleophiles. Synthesis and X-ray structure elucidation of novel thiophenone derivatives

Article abstract of DOI:10.1016/j.tet.2009.02.081

Novel and promising thiophenone derivatives were synthesised by regioselective ring opening of activated thiomalic acid anhydrides, with a variety of active methylene nucleophiles via a C-acylation/cyclisation process involving an S-C bond formation. This

Full text of DOI:10.1016/j.tet.2009.02.081

Tetrahedron 65 (2009) 3711–3716
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective ring opening of thiomalic acid anhydrides by carbon
nucleophiles. Synthesis and X-ray structure elucidation
of novel thiophenone derivatives
,
Stefanos Kikionis a, Vickie McKee b, John Markopoulos c, Olga Igglessi-Markopoulou a
*
a National Technical University of Athens, School of Chemical Engineering, Laboratory of Organic Chemistry, Zografou Campus, Athens 15773, Greece
b University of Loughborough, Chemistry Department, Leicestershire LE113TU, UK
c University of Athens, Department of Chemistry, Laboratory of Inorganic Chemistry, Panepistimiopolis, Zografou, Athens 15771, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel and promising thiophenone derivatives were synthesised by regioselective ring opening of acti-
vated thiomalic acid anhydrides, with a variety of active methylene nucleophiles via a C-acylation/cyc-
lisation process involving an S–C bond formation. This regioselective approach could be moreover
established by X-ray diffraction structure analysis. The thiolactone ring can act as valuable synthetic
scaffold for the preparation of natural and synthetic compounds with important biological and phar-
macological activities.
Received 23 October 2008
Received in revised form 2 February 2009
Accepted 23 February 2009
Available online 6 March 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Thiomalic anhydride
Mercaptosuccinic anhydride
Thiotetronic
Thiophenone
Thiolactone
Thiolactomycin
1. Introduction
Thiophenone derivatives found in a substantial number of bio-
active compounds possessing the common thiotetronic acid ring
system (Fig. 1) are structurally related to the natural antibiotics
thiolactomycin and thiotetramycin (Fig. 2).
Figure 1. Thiotetronic acid ring system.
Thiolactomycin is one of the most important biologically active
thiophenone-based natural products. It has been isolated from the
actinomycete Nocardia sp.1,2 and exhibits antibiotic activity against
many species of pathogens including gram-positive and gram-
negative bacteria,3 mycobacterium tuberculosis4 and malaria
parasite Plasmodium falciparum.5 Thiolactomycin also exhibits
inhibitory activity against fatty acid synthase FAS I and FAS II
systems.6–9
thiolactic acid chlorides were used as acylating agents. A similar
method has been applied for the synthesis of various thiotetronic
acids.11,12
The first synthetic method for the racemic TLM analogues was
developed by Salvino and Wang2 starting from
a-propionylpro-
pionate as precursor by a three-step procedure. Significant studies
have been made by Thomas and Chambers13 who described an
asymmetric synthesis of (5S)-thiolactomycin. Townsend et al.14
synthesised (5R)-thiolactomycin from (2R)-alanine. Moreover,
To generate the thiolactone core required for the synthesis of the
thiotetronic acid nucleus a number of methods involving formation
of a C(3)–C(4) bond or S–C(2) bond were employed.
The first synthetic approach for the construction of 3-
substituted thioteronic acids was reported by Benary10 in which
* 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).
Figure 2. Thiolactomycin (i) and thiotetramycin (ii).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.081

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S. Kikionis et al. / Tetrahedron 65 (2009) 3711–3716
The proposed protocol involves (a) deprotonation of an active
methylene compound, (b) nucleophilic attack at the 2-carbonyl of
thiomalic anhydride (c) in situ intramolecular cyclisation of the
intermediate precursor, affording substituted thiophenones with
flexible substituted patterns, for example, a polar group (CH2COOH)
at C-5 and acyl, alcoxycarbonyl or phenyl group at C-3 position.
The ‘key control element’ for the preparation of 4-hydroxy thio-
phenone ring system,5 containing the 5-carboxymethyl group, 9–
13, was the polyfunctional synthon derived from thiomalic acid
(mercaptosuccinic acid) (1), the S-protected mercaptosuccinic an-
hydride 2, possessing carbonyl groups activated towards nucleo-
philic attack (Scheme 1).
The S-acetylthiomalic acid anhydride (2) is found to react
regioselectively at the more reactive electro-deficient carbonyl at
the C-2 site with carbon nucleophiles for a subsequent coupling
reaction. The observed high regioselectivity of the nucleophilic
attack to the more hindered carbonyl could be attributed to the
electron withdrawing effect of the S-acetyl group. In this way, the
use of this anhydride serves as a potential precursor for the pro-
tection, activation and deprotection of carboxylates.
Figure 3. S-Acetylthiomalic acid anhydride (S-acetylmercaptosuccinic anhydride).
Gilbert et al.15 have synthesised a number of TLM analogues and
undertook a complete structure–activity relationships (SAR) study.
Recently, Ohata and Terashima,16 synthesised (5R)-thiolactomycin
from D
-alanine and Bru¨ckner and Dormann17 proposed a short
asymmetric synthesis of the natural products, (þ)-thiolactomycin,
thiotetramycin and 834-B1. Also, synthesis and spectroscopic
studies of 2- and 4- alkoxythiotetronic acids have been
described.18
During the course of our research program on the synthesis of
nitrogen,19 oxygen20,21 and sulfur heterocycles22,23 containing the
b,b
0-dicarbonyl system, we required the construction and structure
elucidation of thiophenone nucleus containing ‘polar functional-
ities’ from simple building blocks.
We now wish to report a useful methodology, which allows an
approach to the synthesis of novel heterocycles, containing the
thiolactone nucleus starting from a new scaffold, the S-acetylth-
iomalic acid anhydride (S-acetylmercaptosuccinic anhydride)
(Fig. 3).
We discovered that the regioselectivity of this reaction is ap-
plicable for a series of active methylene compounds 3–7 with good
yields (52–81%). Now we herein report a highly regioselective ring
opening of S-acetylthiomalic acid anhydride with the enolate of an
Scheme 1. Reagents and conditions: (i) CH3COCl, reflux; (ii) NaH, THF; (iii) LDA, THF ꢀ78 ꢁC; (iv) MeOH, 2 M NaOH.

S. Kikionis et al. / Tetrahedron 65 (2009) 3711–3716
3713
Table 1
Bond lengths [Å] and angles [ꢁ] for 11
S(1)–C(1)
S(1)–C(6)
C(1)–O(1)
C(1)–C(2)
C(2)–C(5)
C(2)–C(3)
C(3)–O(2)
1.791(4)
1.821(3)
1.210(4)
1.459(5)
1.379(5)
1.442(5)
1.260(4)
C(3)–C(4)
C(5)–O(3)
C(5)–C(6)
C(6)–C(7)
C(7)–C(8)
C(8)–O(5)
C(8)–O(4)
1.489(5)
1.309(4)
1.489(5)
1.516(4)
1.496(5)
1.227(4)
1.302(4)
C(1)–S(1)–C(6)
O(1)–C(1)–C(2)
O(1)–C(1)–S(1)
C(2)–C(1)–S(1)
C(5)–C(2)–C(3)
C(5)–C(2)–C(1)
C(3)–C(2)–C(1)
O(2)–C(3)–C(2)
O(2)–C(3)–C(4)
C(2)–C(3)–C(4)
93.95(16)
128.6(3)
121.5(3)
109.9(2)
120.6(3)
113.0(3)
126.4(3)
118.5(3)
120.7(3)
120.8(3)
O(3)–C(5)–C(2)
O(3)–C(5)–C(6)
C(2)–C(5)–C(6)
C(5)–C(6)–C(7)
C(5)–C(6)–S(1)
C(7)–C(6)–S(1)
C(8)–C(7)–C(6)
O(5)–C(8)–O(4)
O(5)–C(8)–C(7)
O(4)–C(8)–C(7)
126.3(3)
116.0(3)
117.7(3)
112.2(3)
105.4(2)
112.6(2)
114.1(3)
124.5(3)
122.9(3)
112.5(3)
Figure 4. Molecular structure of 11, the dashed line represents a hydrogen bond.
Thermal ellipsoids drawn at the 50% probability level.
active methylene compound and subsequent intramolecular cycli-
sation of the ‘C-acylation intermediates’ 8 to a stable five-mem-
bered thiolactone ring system.
2. Results and discussion
Thiomalic acid (mercaptosuccinic acid) (1) on treatment with
acetyl chloride furnished the corresponding S-acetylthiomalic acid
anhydride (S-acetylmercaptosuccinic anhydride) (2) isolated in 91%
yield (Scheme 1) as a white solid, which was used in the C-acylation
reaction without further purification. Subsequently, the efficiency
of compound 2 as acylating agent of active methylene compounds
Figure 5. Intermolecular interactions in 11: hydrogen-bonded chain with dashed lines
representing hydrogen bonds (top) and
p-stacking interactions (bottom). Symmetry
transformations used to generate equivalent atoms: #1 ꢀxꢀ1,ꢀy, ꢀzþ1; #2 ꢀxþ1,
Scheme 2. Enol–enol equilibrium of the 3-acetyl-5-carboxymethylthiotetronic acid
(11).
ꢀyꢀ1, ꢀz; #3 ꢀx, ꢀy, ꢀzþ1.

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S. Kikionis et al. / Tetrahedron 65 (2009) 3711–3716
Table 2
position of the thiolactone ring. These compounds bear structural
Hydrogen bonds in 11 [Å and ꢁ
]
similarities to thiolactomycin antibiotics and the proposed strategy
paves the way for the synthesis of a variety of thiophenone de-
rivatives with a potential of structural diversity. Detailed bio-
evaluation of these compounds for different activities will be
reported in due course.
D–H/A
d(D–H)
d(H/A)
d(D/A)
<(DHA)
O(3)–H(3O)/O(2)
O(3)–H(3O)/O(2)#1
O(4)–H(4O)/O(5)#2
0.97
0.97
0.97
1.71
2.40
1.73
2.574(3)
3.076(4)
2.674(3)
146.8
126.2
164.7
Symmetry transformations used to generate equivalent atoms: #1 ꢀxꢀ1, ꢀy, ꢀzþ1;
#2 ꢀxþ1, ꢀyꢀ1, ꢀz.
4. Experimental section
4.1. General
was examined. The reaction protocol involved the addition of
1 equiv of 2 to a dispersion of 2 equiv of the anion of active
methylene compounds 3–6 generated by the action of sodium
hydride in anhydrous tetrahydrofuran. The reaction mixture was
stirred at 0 ꢁC for 30 min and the C-acylation intermediate 8
extracted with water and isolated after acidification of the aqueous
extracts with 10% aqueous hydrochloric acid. We noted that the C-
acylation intermediate products were obtained in a mixture with
the corresponding cyclised compounds as determined on the basis
of NMR spectroscopic data. Ring closure of the intermediates 8a–8d
was achieved under basic conditions, by treating them with 2 M
NaOH in MeOH at room temperature for 2–3 h.
The cyclisation of 8 by intramolecular nucleophilic attack of the
sulfurlonepairontheestercarbonyl groupwouldproducestructures
such as 10–12 whereas the intermediate 8 possessing the CN group
produces the structure of amino thiophenone ring (compound 9, 3-
alkoxycarbonyl-2-amino-5-carboxymethylthiophenone) by an
intramolecular interaction of the electron-deficient carbon atom
with the nucleophilic sulfur in the cyclisation process.22
Having established the feasibility of this approach to the syn-
thesis of 3-alkoxycarbonyl and 3-acylthiotetronic acids, we ex-
tended our methodology to the synthesis of the thiotetronic acid
bearing phenyl group at C-3 position. The nucleophilic ring opening
of S-acetylmercaptosuccinic anhydride (2) by the anion of ethyl
phenylacetate, generated with LDA in THF at ꢀ78 ꢁC resulted the C-
acylation synthon 8e as an oily product, which could be easily
transformed to 5-carboxymethyl-3-phenylthiotetronic acid (13),
using basic conditions by treating with 2 M NaOH in MeOH at room
temperature for 2 h.
Mps were determined on a Gallenkanp MFB-595 melting point
apparatus and are uncorrected. FTIR spectra were recorded on a FTIR
Jasco 4200 instrument. Mass spectra were obtained on a TSQ 7000
Finnigan MAT (ESI) instrument. The NMR spectra were recorded at 300
(1H) and 75 (13C) MHz on a Varian Gemini-2000 300 MHz spectro-
meter; chemical shifts are quoted in parts per million (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad); J values are
given in hertz. Elemental analyses were obtained on a Euro EA3000
Series Euro Vector CHNS Elemental Analyzer. Petroleum ether refers to
the fraction with bp 40–60 ꢁC. 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.
4.2. Synthesis
4.2.1. Synthesis of S-acetylmercaptosuccinic anhydride (2)
A mixture of mercaptosuccinic acid (1) (50 mmol, 7.5 g) and
acetyl chloride (170 mmol, 12 mL) was heated under reflux for 3 h.
The clear solution that formed was concentrated under reduced
pressure at 60 ꢁC and dried in vacuo to afford a crude solid, which
was washed with diethyl ether and filtered off to afford the S-
acetylmercaptosuccinic anhydride (2) as white solid.
4.2.1.1. S-Acetylmercaptosuccinic anhydride (2). The title compound
was obtained as white solid. Yield: 7.9 g, 91%; mp 84–86 ꢁC (lit.24
83–86 ꢁC). IR (ATR): 1867, 1793, 1733, 1718, 1678, 1558, 1540, 1508,
1468, 1418 cmꢀ1. 1H NMR (300 MHz, DMSO-d6):
d
¼2.39 (s, 3H, CH3),
The structures of the above mentioned functionalised thiophen-
4-ones were proved by the combination of 1H and 13C NMR, FTIR
and mass spectroscopy (ESI-MS) (see Experimental).
2.97 (dd, J¼18.6, 6.6, 1H, CH2), 3.43 (dd, J¼18.6, 10.2, 1H, CH2), 4.76
(dd, J¼10.2, 6.6, 1H CH). 13C NMR (75 MHz, DMSO-d6):
¼29.6
d
(COCH3), 36.0 (C-4), 40.1 (C-3), 170.0 (COCH3), 171.7 (C-5), 195.5 (C-
2). Anal. Calcd for C6H6O4S: C, 41.37; H, 3.47; S, 18.41. Found: C,
41.51; H, 3.29; S, 18.26.
An X-ray structure determination of 3-acetyl-5-carboxy-
methylthiotetronic acid (11) was carried out to confirm the struc-
ture in the solid state (Table 1). The molecular structure and
numbering scheme are shown in Figure 4. The structure resembles
that of tautomer a (Scheme 2) with a double bond character in the
C(2)–C(5) bond (1.379 Å) and the O(3)–C(5) bond is distinctly lon-
ger that the conventional carbonyl distance for O(1)–C(1) (1.379
and 1.210 Å, respectively). There is a short intramolecular hydrogen
bond between the enol and the carbonyl oxygen atoms (O(2)–O(3),
2.574 Å). Figure 5 shows the intermolecular interactions. Hydrogen
bonds link the molecules into chains (Fig. 5) via a conventional
carboxylic acid H-bond interaction, and also an unsymmetric bi-
furcated H-bond involving the OH group (Table 2). The molecules
4.2.2. General procedure for the preparation of 3-substituted-5-
carboxymethylthiotetronic acids
To a suspension of sodium hydride (10 mmol, 0.4 g) in anhy-
drous THF (30 mL), chilled at 0 ꢁC, was added dropwise the ap-
propriate active methylene compound (methyl cyanoacetate,
malononitrile, dimethyl malonate, ethyl acetoacetate and ethyl
benzoylacetate) (10 mmol) and after stirring at 0 ꢁC for 30 min,
a clear solution resulted. A solution of 2 (5 mmol, 0.87 g) in anhy-
drous THF (5 mL) was added at once. The reaction mixture was
stirred at 0 ꢁC for 30 min, and after the addition of water (10 mL),
the mixture was concentrated under reduced pressure. The aque-
ous residue was washed with diethyl ether (5 mL) and then
acidified with aqueous hydrochloric acid (10%) under cooling in an
ice–H2O bath. The acidified mixture was extracted with dichloro-
methane (3ꢂ15 mL), and the combined extracts were dried over
anhydrous Na2SO4, concentrated under reduced pressure and dried
in vacuo to afford the crude (non isolated) C-acylation intermediate
8 in an oily form. A solution of crude 8 (w4 mmol) in methanol
(2 mL) was chilled at 0 ꢁC, and a 2 M NaOH solution (6 mL) was
added dropwise. The solution was stirred at room temperature for
2–3 h and then acidified with aqueous hydrochloric acid (10%)
show
p-stacking principally involving the partially conjugated
carbonyl and C]C portion of the molecule.
3. Conclusions
In summary, a new and promising synthetic methodology has
been established for the synthesis of the thiotetronic acid family of
thiolactomycin antibiotics. The key step involved the regioselective
ring opening of S-acetylthiomalic acid anhydride with active
methylene nucleophiles under basic conditions. The new synthetic
protocol allow us to introduce the CH2COOH functionality at C-5

S. Kikionis et al. / Tetrahedron 65 (2009) 3711–3716
3715
under cooling in an ice–H2O bath. The products 9–12 were either
filtered off or extracted with ethyl acetate.
vacuo to afford the crude (non-isolated) C-acylation intermediate 8e
in anoilyform. A solution ofcrude 8e(w4 mmol) in methanol(2 mL)
was chilled at 0 ꢁC, and a 2 M NaOH solution (6 mL) was added
dropwise. The solution was stirred at room temperature for 2 h and
then acidified with aqueous hydrochloric acid (10%) undercooling in
an ice–H2O bath. The product 13 was extracted with ethyl acetate.
4.2.2.1. 2-Amino-5-carboxymethyl-3-methoxycarbonylthiophenone
(9). Using methyl cyanoacetate as the active methylene compound,
the title compound was obtained as a pale yellow solid. Yield:
0.68 g, 59%; mp 246–248 ꢁC. MS (ESI) m/z¼230.0 ([MꢀH]þ). IR
(ATR): 2388, 2348, 1748, 1716, 1669, 1607, 1558, 1487 cmꢀ1. 1H NMR
4.2.3.1. 5-Carboxymethyl-3-phenylthiotetronic acid (13). Using ethyl
phenylacetate as the active methylene compound, the title com-
pound was obtained as a white solid. Yield: 0.57 g, 76%; mp 171–
173 ꢁC. MS (ESI) m/z¼249.1 ([MꢀH]þ). IR (ATR): 1704, 1579, 1557,
(300 MHz, DMSO-d6):
d
¼2.53 (dd, J¼17.7, 11.1, 1H, CH2), 3.04 (dd,
J¼17.7, 3.9, 1H, CH2), 3.63 (s, 3H, CH3), 3.96 (dd, J¼11.1, 3.9, 1H, CH),
8.92 (s, 1H, NH2), 9.41 (s, 1H, NH2). 13C NMR (75 MHz, DMSO-d6):
d
¼37.4 (COOCH3), 48.1 (CH2), 50.3 (C-5), 95.0 (C-3), 164.9 (C-2),
1540, 1508, 1403 cmꢀ1
.
1H NMR (300 MHz, DMSO-d6):
d
¼2.62 (dd,
172.6 (COOH), 182.5 (COOCH3), 191.4 (C-4). Anal. Calcd for
C8H9O5NS: C, 41.55; H, 3.92; N, 6.06; S, 13.87. Found: C, 41.68; H,
3.80; N, 5.92; S, 13.71.
J¼17.4, 11.4, 1H, CH2), 3.39 (dd, J¼17.4, 3.3, 1H, CH2), 4.53 (dd, J¼11.4,
3.3, 1H, CH), 7.23–7.52 (m, 5H, aromatic H). 13C NMR (75 MHz,
DMSO-d6):
d
¼38.7 (C-6), 43.4 (C-5), 113.4 (C-3), 126.8, 127.8, 128.7,
131.1, 134.0 (C6H5), 172.1 (C-7), 179.1 (C-2), 193.1 (C-4). Anal. Calcd for
C12H10O4S: C, 57.59; H, 4.03; S,12.81. Found: C, 57.71; H, 4.18; S,12.93.
4.2.2.2. 5-Carboxymethyl-3-methoxycarbonylthiotetronic acid (10).
Using dimethyl malonate as the active methylene compound, the
title compound was obtained as a white solid. Yield: 0.81 g, 70%;
mp 159–161 ꢁC. MS (ESI) m/z¼231.0 ([MꢀH]þ). IR (ATR): 1710,1653,
4.2.4. Crystal structure determination of 11
Compound 11: C8H8O5S, triclinic, P1, a¼5.057(2), b¼8.028(4),
1591, 1460 cmꢀ1. 1H NMR (300 MHz, DMSO-d6):
d
¼2.62 (dd, J¼17.1,
c¼11.167(5) Å,
a
¼81.017(6),
b
¼87.832(6),
g
¼80.515(6)ꢁ, V¼441.6(3) Å3,
10.2, 1H, CH2), 3.21 (dd, J¼17.1, 3.3, 1H, CH2), 4.45 (dd, J¼10.2, 3.3,
T¼150(2) K, ¼0.71073 Å, Z¼2, 3306 reflections measured,1539 unique
l
1H, CH), 9.31 (br s, 1H, OH). 13C NMR (75 MHz, DMSO-d6):
d¼38.1
(Rint¼0.037), wR2¼0.1413 (all data), R1¼0.0513 (I>2
s(I)). Data were
(COOCH3), 44.6 (CH2), 51.1 (C-5), 104.1 (C-3), 163.4 (COOCH3), 171.9
(COOH), 189.5 (C-2), 190.3 (C-4). Anal. Calcd for C8H8O6S: C, 41.38;
H, 3.47; S, 13.81. Found: C, 41.51; H, 3.32; S, 13.68.
collected on a Bruker ApexII CCD diffractometer. Structure was solved
by direct methods and refined on F2 using all the reflections.25 All the
non-hydrogen atoms were refined using anisotropic ADPs and hydro-
gen atoms bonded to carbon were inserted at calculated positions.
Hydrogen atoms involved in H-bonding were located from difference
maps and not refined. Crystallographic data (excluding structure fac-
tors) for the structure in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC 716355. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44
(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
4.2.2.3. 3-Acetyl-5-carboxymethylthiotetronic acid (11). Using ethyl
acetoacetate as the active methylene compound, the title com-
pound was obtained as a pale yellow soliþd. Yield: 0.85 g, 81%; mp
136–138 ꢁC. MS (ESI) m/z¼215.0 ([MꢀH] ). IR (ATR): 1715, 1558,
1508,1418 cmꢀ1. 1H NMR (300 MHz, DMSO-d6):
d
¼2.47 (s, 3H, CH3),
2.82 (dd, J¼17.1, 9.3, 1H, CH2), 3.12 (dd, J¼17.1, 3.6, 1H, CH2), 4.6 (dd,
J¼9.3, 3.6, 1H, CH). 13C NMR (75 MHz, DMSO-d6):
¼23.4 (COCH3),
d
36.8 (CH2), 46.8 (C-5), 109.5 (C-3), 171.6 (COOH), 192.5 (COCH3),
192.6 (C-2),199.0 (C-4). Anal. Calcd for C8H8O5S: C, 44.44; H, 3.73; S,
14.83. Found: C, 44.59; H, 3.85; S, 14.93.
Acknowledgements
The author S.K. would like to thank the National Technical
University of Athens, Chemical Engineering Department for finan-
cial support. The author J.M. would like to thank the National and
Kapodistrian University of Athens for financial support (special
account for research grant no. 70/4/3337).
4.2.2.4. 3-Benzoyl-5-carboxymethylthiotetronic acid (12). Using
ethyl benzoylacetate as the active methylene compound, the title
compound was obtained as a pale yellow solid. Yield: 0.73 g, 52%;
mp 158–160 ꢁC. MS (ESI) m/z¼277.1 ([MꢀH]þ). IR (ATR): 1703, 1581,
1540, 1508, 1488, 1434 cmꢀ1. 1H NMR (300 MHz, DMSO-d6):
d¼2.84
(dd, J¼17.1, 9.9, 1H, CH2), 3.25 (dd, J¼17.1, 3.3, 1H, CH2), 4.62 (dd,
References and notes
J¼9.9, 3.6, 1H, CH), 7.45–7.79 (m. 5H, aromatic H). 13C NMR
(75 MHz, DMSO-d6):
d
¼37.7 (CH2), 45.5 (C-5), 113.0 (C-3), 128.4,
1. Oishi, H.; Noto, T.; Sasaki, H.; Suzuki, K.; Hayashi, T.; Okazaki, H.; Ando, K.;
Sawada, M. J. Antibiot. 1982, 35, 391.
129.3,133.2,136.7 (C6H5),172.0 (COOH),187.5 (COC6H5),189.7 (C-2),
191.3 (C-3). Anal. Calcd for C13H10O5S: C, 56.11; H, 3.62; S, 11.52.
Found: C, 56.23; H, 3.74; S, 11.41.
2. Wang, C.-L. J.; Salvino, J. M. Tetrahedron Lett. 1984, 25, 5243.
3. Noto, T.; Miyakawa, S.; Oishi, H.; Endo, H.; Okazaki, H. J. Antibiot. 1982, 35, 401.
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4.2.3. Synthesis of 5-carboxymethyl-3-phenylthiotetronic acid (13)
A solution of the ethyl phenylacetate (6 mmol, 0.98 g) in anhy-
drous THF (8 mL) was added dropwise, under argon, to a solution of
LDA (2.0 M solution in THF/hexane/ethylbenzene, 6 mmol) in an-
hydrous THF (20 mL) at ꢀ78 ꢁC. The addition was completed in
15 min and the mixture was stirred at ꢀ78 ꢁC for 45 min. A solution
of S-acetylmercaptosuccinic anhydride (3 mmol, 0.52 g) in anhy-
drous THF (5 mL) was added dropwise over 15 min and the mixture
was allowed to stir at ꢀ78 ꢁC for 1 h. After stirring for an additional
hour to room temperature, the reaction quenched with 10 mL of
water and the mixture was concentrated under reduced pressure.
The aqueous residue was washed with diethyl ether (20 mL) and
then acidified with aqueous hydrochloric acid (10%) under cooling in
an ice–H2O bath. The acidified mixture was extracted with ethyl
acetate (3ꢂ15 mL), and the combined extracts were dried over an-
hydrous Na2SO4, concentrated under reduced pressure and dried in
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