Synthesis of bis(tetronic acid)s via double Dieckmann condensation

Article abstract of DOI:10.1055/s-0029-1218738

A practical, straightforward synthesis of several bis(tetronic acid)s from a common precursor, dimethyl l-tartrate, is described. It involves a double Dieckmann condensation using tetrabutylammonium fluoride. The radical scavenging capacities of these compounds are measured. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218738

PAPER
1697
Synthesis of Bis(tetronic acid)s via Double Dieckmann Condensation
Synthesis of
B
o
is(tetronic ac
p
id)s hie A.-L. Thetiot-Laurent, Brice Nadal, Thierry Le Gall*
CEA Saclay, iBiTecS, Service de Chimie Bioorganique et de Marquage, Bât. 547, 91191, Gif-sur-Yvette, France
Fax +33(1)69087105; E-mail: thierry.legall@cea.fr
Received 12 February 2010
droxy esters with tetrabutylammonium fluoride
(TBAF).12 We thus tested this base for the construction of
tetronic rings in compounds 3.
Abstract: A practical, straightforward synthesis of several
bis(tetronic acid)s from a common precursor, dimethyl L-tartrate, is
described. It involves a double Dieckmann condensation using tet-
rabutylammonium fluoride. The radical scavenging capacities of
these compounds are measured.
O
R
CO2H
DCC, DMAP
CH2Cl2
1
R
OH
Key words: condensation, cyclization, esters
O
MeO2C
MeO2C
CO2Me
CO2Me
OH
O
Tartaric acid derivatives have found many uses as synthet-
ic building blocks and as asymmetric catalysts.1 Examples
of applications include the asymmetric epoxidation of al-
lylic alcohols,2 the asymmetric allyl boration using dialkyl
tartrate-modified allyl boronates3 and enantioselective
transformations catalyzed by titanium TADDOLates.4 Di-
acyltartaric acids have also been employed for the enan-
tioselective protonation of enolates.5 We recently made
use of dimethyl L-tartrate as precursor for tetronic acids,
including pulvinic acid derivatives, which are potentially
active as antioxidant compounds.6,7 In connection with
these studies, we now wish to report the convenient syn-
thesis of bis(tetronic acid)s derived from dimethyl L-tar-
trate, as well as first results on their antioxidant properties.
R
2
O
OH
R
O
O
O
TBAF
THF, r.t.
O
R
HO
3
Scheme 1 Synthesis of compounds 2 and 3
O
O
O
O
O
OH
O
MeO2C
MeO2C
CO2Me
2g
4
CO2Me
p-xylene
reflux, 78%
O
Compounds 3 were prepared from dimethyl L-tartrate as
described in Scheme 1. In the first step, esterification of
both alcohols with acids 1a–f in the presence of a mixture
of the coupling agents dicyclohexylcarbodiimide (DCC)
and 4-(dimethylamino)pyridine (DMAP) afforded the
corresponding esters 2a–f in 70–94% yields (Table 1).
The acetoacetyl derivative 2g was obtained by esterifica-
tion of dimethyl-L-tartrate with 2,2,6-trimethyl-1,3-diox-
in-4-one (4) in p-xylene at reflux in 78% yield8
(Scheme 2).
OH
O
O
Scheme 2 Synthesis of the acetoacetyl derivative 2g of dimethyl
L-tartrate
Table 1 Synthesis of Esters 2a–g
Entry
R
Acid
1a
Ester
2a
Yield (%)
1
2
3
4
5
6
4-FC6H4
4-MeOC6H4
4-BnOC6H4
3-thienyl
4-NO2C6H4
BnOC(O)
75
89
90
70
94
80
1b
1c
2b
2c
The Lacey version of the Dieckmann condensation is a
classical tetronic acid preparation method.9,10 Brandänge
et al. reported the Dieckmann condensation of the
monoacetate of diethyl tartrate using lithium hexamethyl-
disilazide (LiHMDS) as base.11 However, it was then
shown that, when treated with LiHMDS, the diacetate of
dimethyl L-tartrate underwent a b-elimination of one of
the acetoxy groups instead of leading to a bis(tetronic
acid) adduct. Hence a softer base had to be employed in
order to convert diesters 2 to the expected products 3. Ley
et al. have reported the preparation of 3-acyltetronic acids
by treatment of the corresponding acetoacetates of hy-
1d
1e
2d
2e
1f
2f
Compounds 3a–g were obtained uneventfully in 58–90%
yield by treatment of esters 2a–g with three equivalents of
TBAF in THF overnight at room temperature (Table 2).
To the best of our knowledge, no example of TBAF-
induced Lacey–Dieckmann condensation starting from an
aryl acetate derivative had previously been reported.
SYNTHESIS 2010, No. 10, pp 1697–1701
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x.
x
x
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Advanced online publication: 15.04.2010
DOI: 10.1055/s-0029-1218738; Art ID: P02010SS
© Georg Thieme Verlag Stuttgart · New York

1698
S. A.-L. Thetiot-Laurent et al.
PAPER
Table 2 Synthesis of Tetronic Acids 3a–g
Table 3 Compounds’ Capacity to Scavenge DPPH Radical
Entry
R
Ester
2a
Tetronic acid Yield (%)
Entry
Compound
EC50 (mM)
0.096 0.005
0.229 0.009
1.12 0.15
0.798 0.015
inactive
1
2
3
4
5
6
7
4-FC6H4
4-MeOC6H4
4-BnOC6H4
3-thienyl
4-O2NC6H4
BnOC(O)
Ac
3a
3b
3c
3d
3e
3f
85
75
72
90
81
70
58
1
2
5
2b
2c
6
3
3a
3b
3c
3d
3e
3f
3g
3h
2d
2e
4
5
2f
6
0.741 0.007
5.34 0.06
inactive
2g
3g
7
8
A quantitative cleavage of the benzyl protecting group of
compound 3c, using 10% Pd/C in a mixture of DMF and
methanol under a hydrogen atmosphere overnight, yield-
ed compound 3h bearing a 4-hydroxyphenyl R group. The
bis(tetronic acid)s were notably characterized by the pres-
ence, in the 1H NMR spectra, of a singlet at d = 5.21–5.13
for compounds 3a–d and 3h, and at d = 4.59, 5.01, and
4.87 for compounds 3e, 3f and 3g respectively, which cor-
responded to the proton on the tetronic ring. It is notewor-
thy that no epimerization occurred during the cyclization.
9
inactive
10
0.237 0.007
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
400 spectrophotometer and chemical shifts are reported in ppm
downfield from TMS for 1H NMR spectra. IR spectra were recorded
on a Perkin-Elmer System 2000 FT-IR using KBr pellets. MS were
recorded on a Mariner ESI TOF (Perseptive Biosystems) mass spec-
trophotometer. Mps were determined on a Büchi B-540 apparatus.
HRMS were performed at Service de Spectrométrie de Masse, IC-
SN, CNRS, Gif-sur-Yvette. Column chromatography was carried
out on silica gel (Merck, 40–63 mm). TLC analyses were done on
silica gel 60F254 plates with detection by UV light. THF and CH2Cl2
were freshly distilled on sodium-benzophenone and P2O5 respec-
tively. All reactants were purchased from Sigma-Aldrich, unless
otherwise stated.
The capacity of compounds 3a–h to scavenge the 2,2-
diphenyl-1-picrylhydrazyl radical (DPPH) was then mea-
sured. The radical has a violet color due to the unpaired ni-
trogen electron and after reaction with a radical scavenger
the yellow reduced DPPH is formed. The color change
can be followed spectrophotometrically at 515 nm.13 Gal-
lic acid (5) and ascorbic acid (6) were used as reference
antioxidant compounds (Figure 1). Results are summa-
rized in Table 3.
2-[4-(Benzyloxy)phenyl]acetic Acid (1c)
4-Hydroxyphenylacetic acid (5 g, 32.9 mmol, 1 equiv), benzyl bro-
mide (4.1 mL, 34.5 mmol, 1.05 equiv), KOH (4.6 g, 82.3 mmol, 2.5
equiv), and NaI (99 mg, 658 mmol, 0.02 equiv) were dissolved in ab-
solute EtOH (150 mL) and refluxed for 20 h. The solution was al-
lowed to stand at r.t. and then treated with 3 N aq HCl (150 mL).
The precipitate was filtered, washed with H2O (100 mL), and dried
under vacuum, affording compound 1c as a white powder; yield: 8
g (quant); Rf = 0.50 (cyclohexane–EtOAc, 50:50); mp 124–125 °C
(Lit.14 mp 124–125 °C, Lit.15 mp 120–122 °C).
CO2H
HO
OH
OH
O
O
HO
OH
OH
OH
5
6
Figure 1 Structures of gallic acid (5) and ascorbic acid (6)
IR (KBr): 3025, 2906, 2866, 2666, 1688, 1613, 1512, 1454, 1406,
1378, 1296, 1247, 1174, 1155, 1014, 917, 809, 799, 748, 720, 696,
626, 521, 512 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.35–7.32 (m, 5 H), 7.21 (d,
Compounds 3f and 3g bearing a carbonyl group linked to
the tetronic ring and benzyl ether 3c were found to be in-
active. On the contrary, methyl ether 3b showed a certain J = 8.5 Hz, 2 H), 6.96 (d, J = 8.5 Hz, 2 H), 5.07 (s, 2 H), 3.60 (s, 2
H).
capacity to scavenge DPPH, comparable to that of 3-thie-
13C NMR (100 MHz, CDCl3): d = 178.4, 158.2, 137.1, 130.6 (2 C),
128.7 (2 C), 128.1, 127.6 (2 C), 125.7, 115.1 (2 C), 70.2, 40.3.
ESI: m/z (%) = 240.1 (100, [M – H]–).
nyl derivative 3d. The nitro derivative 3e (entry 7) was the
least efficient compound. Finally, the capacity of the fully
deprotected phenol 3h to scavenge DPPH is similar to that
of ascorbic acid (6).
HRMS: m/z calcd for C15H14O3 + Na: 265.0841; found: 265.0837.
In conclusion, we have reported a practical, two-step syn-
thesis of enantiopure bis(tetronic acid)s obtained in 45–
76% overall yield from dimethyl-L-tartrate, under smooth
conditions. Utilization of these compounds in asymmetric
transformations is under progress. Several synthesized
products displayed promising antioxidant properties,
which will be further investigated.
3-(Benzyloxy)-3-oxopropanoic Acid (1f)
Malonic acid (13.1 g, 126 mmol, 1.5 equiv) was dissolved in anhyd
MeCN (200 mL) under argon. To this solution was added Et3N
(11.2 mL, 84 mmol, 1 equiv) dropwise, followed by benzyl bromide
(10 mL, 84 mmol, 1 equiv). The mixture was refluxed for 3 h,
cooled at 0 °C, and then treated with 5% aq HCl (100 mL). The
aqueous layer was extracted with EtOAc (3 × 70 mL). The organic
Synthesis 2010, No. 10, 1697–1701 © Thieme Stuttgart · New York

PAPER
Synthesis of Bis(tetronic acid)s
1699
layers were combined and extracted with sat. aq NaHCO3 (2 × 75
mL). The aqueous layers were combined, acidified with concd HCl
until pH 3, and extracted with toluene (3 × 70 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated af-
fording compound 1f as white crystals; yield: 18.3 g (quant);
Rf = 0.47 (CH2Cl2–MeOH, 90:10); mp 50.5 °C.
IR (KBr): 1733, 1434, 1382, 1334, 1166, 980, 902, 756, 700 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.81 (br s, 1 H), 7.38 (m, 5 H),
5.22 (s, 2 H), 3.50 (s, 2 H).
IR (KBr): 3327, 3034, 2933, 2854, 1752, 1708, 1612, 1512, 1454,
1437, 1360, 1279, 1225, 1178, 1129, 1065, 1023, 976, 820, 796,
737, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.41–7.37 (m, 10 H), 7.20 (d,
J = 8.8 Hz, 4 H), 6.94 (d, J = 8.8 Hz, 4 H), 5.66 (s, 2 H), 5.05 (s, 4
H), 3.67 (s, 4 H), 3.52 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 170.4 (2 C), 165.9 (2 C), 157.9 (2
C), 136.8 (2 C), 130.3 (4 C), 128.5 (4 C), 127.9 (2 C), 127.3 (4 C),
125.3 (2 C), 114.9 (4 C), 70.8 (2 C), 69.9 (2 C), 52.7 (2 C), 39.7 (2
C).
13C NMR (100 MHz, CDCl3): d = 170.9, 167.2, 135.2, 129.0 (2 C),
129.0 (2 C), 128.8, 68.1, 40.9.
ESI: m/z (%) = 649.3 (100, [M + Na]+).
ESI: m/z (%) = 195.0 (100, [M + H]+), 389.1 (16, [2 M + H]+).
HRMS: m/z calcd for C36H34O10 + Na: 649.2050; found: 649.2057.
HRMS: m/z calcd for C10H10O4 + Na: 217.0477; found: 217.0479.
(2R,3R)-Dimethyl 2,3-Bis[2-(thiophen-3-yl)acetoxy]succinate
(2d)
(2R,3R)-Dimethyl 2,3-Bis[2-(4-fluorophenyl)acetoxy]succinate
(2a); Typical Procedure
Yield: 70%; yellow pale oil; Rf = 0.55 (cyclohexane–EtOAc,
50:50); [a]D20 +9.6 (c 2.7, MeOH).
(+)-Dimethyl L-tartrate (1.25 g, 7.00 mmol, 1 equiv) and 4-fluo-
rophenylacetic acid (2.17 g, 14.0 mmol, 2 equiv) were dissolved in
freshly distilled CH2Cl2 (50 mL) under argon. To this solution were
then simultaneously added DCC (2.90 g, 14.0 mmol, 2 equiv) and
DMAP (683 mg, 5.6 mmol, 0.8 equiv), and the mixture was stirred
overnight. After the addition of Et2O (50 mL), the precipitate
formed was filtered and washed with Et2O (2 × 40 mL). The com-
bined Et2O layers were washed with 2 N aq HCl (20 mL), dried
(MgSO4), filtered, and concentrated. The residue was purified by
chromatography (SiO2, CH2Cl2–MeOH, gradient from 100:0 to
94:6), affording compound 2a as a colorless oil; yield: 2.4 g (75%);
Rf = 0.50 (cyclohexane–EtOAc, 50:50); [a]D20 +3.1 (c 0.19,
MeOH).
IR (KBr): 3500, 3294, 3107, 2931, 2852, 1755, 1695, 1651, 1538,
1437, 1411, 1350, 1281, 1251, 1222, 1127, 1065, 978, 859, 837,
772, 735, 610 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.29 (q, J = 5.2 Hz, 2 H), 7.19 (dt,
J = 3.2, 0.4 Hz, 2 H), 7.03 (dd, J = 4.8, 1.2 Hz, 2 H), 5.71 (s, 2 H),
3.80 (d, J = 13.6 Hz, 2 H), 3.76 (d, J = 13.6 Hz, 2 H), 3.67 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 169.6 (2 C), 165.9 (2 C), 132.4
(2C), 128.4 (2 C), 125.7 (2 C), 123.2 (2 C), 70.9 (2 C), 52.9 (2 C),
35.2 (2 C).
ESI: m/z (%) = 449.1 (100, [M + Na]+).
HRMS: m/z calcd for C18H18O8S2 + Na: 449.0341; found: 449.0347.
IR (KBr): 3045, 3010, 2957, 2853, 1898, 1755, 1667, 1605, 1511,
1438, 1359, 1281, 1224, 1131, 1064, 976, 859, 827, 798, 727, 689,
639 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.25 (m, 4 H), 7.02 (t, J = 6.8 Hz,
4 H), 5.67 (s, 2 H), 3.71 (s, 4 H), 3.59 (s, 6 H).
(2R,3R)-Dimethyl 2,3-Bis[2-(4-nitrophenyl)acetoxy]succinate
(2e)
Yield: 94%; orange powder; mp 116–116.5 °C; Rf = 0.78 (CH2Cl2–
MeOH, 94:6); [a]D20 –1.9 (c 1, CH2Cl2).
13C NMR (100 MHz, CDCl3): d = 169.9 (2 C), 165.8 (2 C), 162.0
(d, J = 244 Hz, 2 C), 130.9 (d, J = 8.1 Hz, 4 C), 128.7 (2 C), 115.4
(d, J = 21.4 Hz, 4 C), 70.9 (2 C), 52.8 (2 C), 39.4 (2 C).
IR (KBr): 3119, 3086, 2996, 2959, 2852, 1770, 1746, 1608, 1530,
1515, 1352, 1226, 1125, 1056, 971, 858, 732, 658 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.21 (d, J = 8.8 Hz, 4 H), 7.48 (d,
J = 8.8 Hz, 4 H), 5.72 (s, 2 H), 3.87 (d, J = 16.0 Hz, 2 H), 3.85 (d,
J = 16.0 Hz, 2 H), 3.67 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 168.8 (2 C), 165.6 (2 C), 147.3 (2
C), 140.1 (2 C), 130.3 (4 C), 123.7 (4 C), 71.0 (2 C), 53.1 (2 C), 40.1
(2 C).
ESI: m/z (%) = 473.1 (100, [M + Na]+).
HRMS: m/z calcd for C22H20F2O8 + Na: 473.1024; found: 473.1001.
(2R,3R)-Dimethyl 2,3-Bis[2-(4-methoxyphenyl)acetoxy]succi-
nate (2b)
ESI: m/z (%) = 505.0 (100, [M + H]+).
Yield: 89%; white powder; mp 85.1–85.3 °C; Rf = 0.60 (cyclohex-
ane–EtOAc, 50:50); [a]D20 +9.9 (c 0.38, MeOH).
HRMS: m/z calcd for C22H20N2O12 + Na: 527.0914; found:
IR (KBr): 3007, 2966, 2940, 2917, 2843, 2041, 1748, 1614, 1585,
1517, 1452, 1441, 1359, 1305, 1288, 1250, 1231, 1181, 1133, 1061,
1024, 966, 920, 895, 857, 820, 800, 777, 733, 709, 686, 578, 562,
521 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.20 (d, J = 8.8 Hz, 4 H), 6.86 (d,
J = 8.8 Hz, 4 H), 5.67 (s, 2 H), 3.79 (s, 6 H), 3.68 (s, 4 H), 3.57 (s,
6 H).
527.0939.
(2R,3R)-Dimethyl 2,3-Bis(benzyloxycarbonyloxy)succinate (2f)
Yield: 80%; colorless oil; Rf = 0.76 (CH2Cl2–MeOH, 94:6); [a]D
–26.0 (c 0.24, MeOH).
20
IR (KBr): 3034, 2957, 1764, 1741, 1328, 1280, 1217, 1138, 1065,
994, 751, 699 cm–1.
13C NMR (100 MHz, CDCl3): d = 170.5 (2 C), 165.9 (2 C), 158.8 (2
C), 130.3 (4 C), 125.1 (2 C), 114.0 (4 C), 70.8 (2 C), 55.2 (2 C), 52.7
(2 C), 39.7 (2 C).
1H NMR (400 MHz, CDCl3): d = 7.35–7.26 (m, 10 H), 5.78 (s, 2 H),
5.17 (d, J = 12.4 Hz, 2 H), 5.15 (d, J = 12.4 Hz, 2 H), 3.74 (s, 6 H),
3.57 (d, J = 16.0 Hz, 2 H), 3.51 (d, J = 16.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 165.9 (2 C), 165.8 (2 C), 165.4 (2
C), 135.4 (2 C), 129.0 (4 C), 128.9 (2 C), 128.7 (4 C), 71.6 (2 C),
67.8 (2 C), 53.6 (2 C), 41.2 (2 C).
ESI: m/z (%) = 497.2 (100, [M + Na]+).
HRMS: m/z calcd for C24H26O10 + Na: 497.1424, found: 497.1427.
ESI: m/z (%) = 531.09 (100, [M + H]+), 553.05 (20, [M + Na]+).
(2R,3R)-Dimethyl 2,3-Bis{2-[(4-benzyloxy)phenyl]acetoxy}suc-
cinate (2c)
HRMS: m/z calcd for C26H26O12 + Na: 553.1322; found: 553.1305.
Yield: 90%; colorless oil; Rf = 0.63 (cyclohexane–EtOAc, 50:50);
[a]D20 +8.1 (c 0.67, MeOH).
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1700
S. A.-L. Thetiot-Laurent et al.
PAPER
(2R,3R)-Dimethyl 2,3-Bis(3-oxobutanoyloxy)succinate (2g)
(+)-Dimethyl L-tartrate (200 mg, 1.12 mmol, 1 equiv) was dissolved
under argon in p-xylene (1 mL). To this solution was added 2,2,6-
trimethyl-1,3-dioxin-4-one (4; 292 mL, 2.24 mmol, 2 equiv). The
mixture was refluxed for 1.5 h, cooled to r.t. and concentrated. The
residue was purified by chromatography (SiO2, CH2Cl2–MeOH,
gradient from 100:0 to 96:4), affording compound 2g as an orange
pale oil; yield: 303 mg (78%); Rf = 0.80 (CH2Cl2–MeOH, 94:6);
[a]D20 –15.2 (c 5.3, MeOH).
1H NMR (400 MHz, DMSO-d6): d = 7.87 (d, J = 7.2 Hz, 4 H), 7.45
(d, J = 6.8 Hz, 4 H), 7.37 (d, J = 6.8 Hz, 4 H), 7.31 (t, J = 6.8 Hz,
2 H), 7.02 (d, J = 7.2 Hz, 4 H), 5.21 (s, 2 H), 5.01 (s, 4 H).
13C NMR (100 MHz, DMSO-d6): d = 174.1 (2 C), 172.6 (2 C),
158.0 (2 C), 137.9 (2 C), 128.8 (4 C), 128.2 (2 C), 128.1 (4 C), 127.9
(4 C), 123.8 (2 C), 115.2 (4 C), 97.5 (2 C), 74.5 (2 C), 69.5 (2 C).
ESI: m/z (%) = 585.2 (100, [M + Na]+).
HRMS: m/z calcd for C34H26O8 + Na: 585.1550; found: 585.1525.
IR (KBr): 3501, 3005, 2954, 2853, 1768, 1718, 1631, 1438, 1418,
1398, 1364, 1345, 1242, 1140, 1065, 998, 979, 860, 774, 754, 697,
634, 542 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.77 (s, 2 H), 3.82 (s, 6 H), 3.59
(d, J = 16.0 Hz, 2 H), 3.53 (d, J = 16.0 Hz, 2 H), 2.26 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 199.5 (2 C), 166.0 (2 C), 165.9 (2
C), 71.5 (2 C), 53.6 (2 C), 49.8 (2 C), 30.4 (2 C).
(2R,2¢R)-3,3¢-Dihydroxy-4,4¢-bis(4-thiophen-3-yl)-2,2¢-bifuran-
5,5¢(2H,2¢H)-dione (3d)
Yield: 90%; white powder; mp 231.9–232.3 °C; Rf = 0.42 (CH2Cl2–
MeOH, 90:10); [a]D20 +193.0 (c 0.03, DMSO).
IR (KBr): 3115, 2636, 1726, 1643, 1517, 1405, 1367, 1341, 1218,
1141, 1106, 1030, 997, 863, 798, 688 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.82 (m, 2 H), 7.70 (d, J = 8.5
Hz, 2 H), 7.52 (m, 2 H), 5.19 (s, 2 H).
ESI: m/z (%) = 369.0 (100, [M + Na]+).
HRMS: m/z calcd for C14H18O10 + Na: 369.0798; found: 369.0803.
13C NMR (100 MHz, DMSO-d6): d = 175.04 (2 C), 172.6 (2 C),
131.2 (2 C), 126.1 (2 C), 125.6 (2 C), 120.2 (2 C), 95.5 (2 C), 75.1
(2 C).
(2R,2¢R)-4,4¢-Bis(4-fluorophenyl)-3,3¢-dihydroxy-2,2¢-bifuran-
5,5¢(2H,2¢H)-dione (3a); Typical Procedure
ESI: m/z (%) = 385.28 (100, [M + Na]+).
Compound 2a (600 mg, 1.30 mmol, 1 equiv) was dissolved under
argon in freshly distilled THF (4 mL). To this solution was added a
molar solution of TBAF in THF (3.9 mL, 3.9 mmol, 3 equiv) and
the mixture stirred at r.t. overnight. Aq 6 N HCl (20 mL) and Et2O
(20 mL) were then added to the mixture. The mixture was concen-
trated and precipitated with CH2Cl2 at 0 °C, affording compound 3a
as a white powder; yield: 437 mg (85%); Rf = 0.38 (CH2Cl2–MeOH,
90:10); mp 249.5–249.8 °C; [a]D20 +105.0 (c 0.05, DMSO).
HRMS: m/z calcd for C16H10O6S2 + Na: 384.9817; found: 384.9813.
(2R,2¢R)-3,3¢-Dihydroxy-4,4¢-bis(4-nitrophenyl)-2,2¢-bifuran-
5,5¢(2H,2¢H)-dione (3e)
Yield: 81%; orange powder; mp >300 °C; Rf = 0.20 (CH2Cl2–
MeOH, 90:10); [a]D20 +334.9 (c 0.08, DMSO).
IR (KBr): 3452, 1708, 1596, 1571, 1505, 1434, 1331, 1188, 1112,
1023, 945, 857, 700, 679 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.49 (d, J = 9.0 Hz, 4 H), 8.07
(d, J = 9.0 Hz, 4 H), 4.59 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 189.4 (2 C), 174.8 (2 C),
144.2 (2 C), 140.9 (2 C), 123.5 (4 C), 122.1 (4 C), 89.3 (2 C), 76.9
(2 C).
IR (KBr): 2949, 1714, 1635, 1601, 1514, 1402, 1305, 1275, 1248,
1150, 1079, 1059, 1040, 966, 837, 799, 778, 714, 664, 575, 528
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.00 (m, 4 H), 7.19 (t, J = 6.8
Hz, 4 H), 5.20 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 177.0 (2 C), 172.7 (2 C),
160.6 (d, J = 240 Hz, 2 C), 128.2 (d, J = 7.0 Hz, 4 C), 127.9 (2 C),
115.2 (d, J = 20 Hz, 4 C), 96.8 (2 C), 74.9 (2 C).
ESI: m/z (%) = 439 (100, [M – H]–).
HRMS: m/z calcd for C20H11N2O10 (M – H): 439.0414; found:
439.0415.
ESI: m/z (%) = 384.8 (100, [M – H]–).
HRMS: m/z calcd for C20H12F2O6 + Na: 409.0500; found: 409.0518.
(2R,2¢R)-Dibenzyl 3,3¢-Dihydroxy-5,5¢-dioxo-2,2¢,5,5¢-tetrahy-
dro-2,2¢-bifuran-4,4¢-dicarboxylate (3f)
(2R,2¢R)-3,3¢-Dihydroxy-4,4¢-bis(4-methoxyphenyl)-2,2¢-bifu-
ran-5,5¢(2H,2¢H)-dione (3b)
Yield: 70%; white powder; mp 180.3–180.8 °C; Rf = 0.43 (CH2Cl2–
MeOH, 90:10); [a]D20 +262.0 (c 0.26, DMSO).
Yield: 75%; orange pale powder; mp 259.8–261.3 °C; Rf = 0.45
(CH2Cl2–MeOH, 90:10); [a]D20 +234.1 (c 0.14, DMSO).
IR (KBr): 3206, 3092, 3062, 3028, 2926, 1762, 1677, 1642, 1586,
1498, 1463, 1438, 1385, 1361, 1340, 1249, 1185, 1130, 1046, 901,
794, 726, 695, 578 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.47–7.32 (m, 10 H), 5.21 (s,
4 H), 5.01 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 188.2 (2 C), 170.7 (2 C),
162.5 (2 C), 137.9 (2 C), 129.3 (4 C), 128.6 (2 C), 128.4 (4 C), 90.8
(2 C), 75.8 (2 C), 65.0 (2 C).
IR (KBr): 3017, 2954, 2837, 1714, 1633, 1574, 1513, 1470, 1408,
1302, 1278, 1254, 1200, 1181, 1154, 1080, 1059, 1043, 1031, 965,
835, 797, 776, 582, 538, 506 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.88 (d, J = 8.8 Hz, 4 H), 6.93
(d, J = 8.8 Hz, 4 H), 5.13 (s, 2 H), 3.74 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): d = 175.4 (2 C), 173.0 (2 C),
157.8 (2 C), 127.8 (4 C), 123.5 (2 C), 113.8 (4 C), 97.5 (2 C), 74.8
(2 C), 55.4 (2 C).
ESI: m/z (%) = 465.0 (100, [M + H]+), 487.0 (25, [M + Na]+).
ESI: m/z (%) = 408.8 (100, [M – H]–).
HRMS: m/z calcd for C24H16NaO10: 487.0641; found: 487.0650.
HRMS: m/z calcd for C22H18O8 + Na: 433.0899; found: 433.0884.
(2R,2¢R)-4,4¢-Diacetyl-3,3¢-dihydroxy-2,2¢-bifuran-
5,5¢(2H,2¢H)-dione (3g)
(2R,2¢R)-4,4¢-Bis[4-(benzyloxy)phenyl]-3,3¢-dihydroxy-2,2¢-bi-
furan-5,5¢(2H,2¢H)-dione (3c)
Yield: 58%; white powder; mp 147.3–147.7 °C; Rf = 0.50 (CH2Cl2–
MeOH, 90:10); [a]D20 +264.5 (c 0.26, DMSO).
Yield: 72%; white powder; mp 245.1–245.4 °C; Rf = 0.25 (CH2Cl2–
MeOH, 90:10); [a]D20 +240.0 (c 0.12, DMSO–MeOH, 1:1).
IR (KBr): 3064, 2949, 1758, 1673, 1600, 1446, 1385, 1328, 1303,
1174, 1034, 878, 781, 749, 723, 687, 650, 575 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 4.87 (s, 2 H), 2.41 (s, 6 H).
IR (KBr): 2963, 1753, 1716, 1634, 1605, 1573, 1512, 1384, 1280,
1250, 1155, 1081, 1059, 1042, 835, 742, 696, 592, 569, 536 cm–1.
Synthesis 2010, No. 10, 1697–1701 © Thieme Stuttgart · New York

PAPER
Synthesis of Bis(tetronic acid)s
1701
13C NMR (100 MHz, DMSO-d6): d = 191.4 (2 C), 189.8 (2 C),
170.9 (2 C), 98.5 (2 C), 77.4 (2 C), 26.9 (2 C).
References
(1) Gawroński, J.; Gawrońska, K. Tartaric and Malic Acids in
Synthesis; Wiley-Interscience: New York, 1999.
(2) Reviews: (a) Johnson, R. A.; Sharpless, K. B. In
Comprehensive Organic Synthesis, Vol. 7; Trost, B. M.;
Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 389.
(b) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1.
(3) Review: Roush, W. R. In Comprehensive Organic
Synthesis, Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991, 1.
(4) Review: Seebach, D.; Beck, A. K.; Heckel, A. Angew.
Chem. Int. Ed. 2001, 40, 92.
(5) Reviews: (a) Fehr, C. Angew. Chem., Int. Ed. Engl. 1997, 35,
2566. (b) Duhamel, L.; Duhamel, P.; Launay, J.-C.;
Plaquevent, J.-C. Bull. Soc. Chim. Fr. 1984, II–421.
(6) Nadal, B.; Thuéry, P.; Le Gall, T. Tetrahedron Lett. 2009,
50, 2430.
(7) (a) Meunier, S.; Desage-El Murr, M.; Nowaczyk, S.;
Le Gall, T.; Pin, S.; Renault, J.-P.; Boquet, D.; Créminon,
C.; Saint-Aman, E.; Valleix, A.; Taran, F.; Mioskowski, C.
ChemBioChem 2004, 5, 832. (b) Meunier, S.; Hanédanian,
M.; Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.; Pin, S.;
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ESI: m/z (%) = 280.8 (100, [M – H]–).
HRMS: m/z calcd for C12H9O8 (M – H): 281.0297; found: 281.0300.
(2R,2¢R)-3,3¢-Dihydroxy-4,4¢-bis(4-hydrophenyl)-2,2¢-bifuran-
5,5¢ (2H,2¢H)-dione (3h)
Compound 3c (400 mg, 712 mmol, 1 equiv) and 10% Pd/C were dis-
solved in a mixture of DMF (2.4 mL) and MeOH (7.0 mL). The so-
lution was vigorously stirred under H2 atmosphere for 20 h. The
mixture was filtered over a Celite pad. The filtrate was washed with
aq 6 N HCl (2 × 15 mL), dried (MgSO4), and concentrated affording
compound 3h as a white powder; yield: 272 mg (quant); Rf = 0.1
(CH2Cl2–MeOH, 90:10); [a]D20 +171.0 (c 0.03, DMSO).
IR (KBr): 3336, 2681, 1729, 1660, 1611, 1518, 1398, 1343, 1266,
1220, 1158, 1111, 1046, 1024, 990, 961, 841, 768, 689, 587 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.74 (d, J = 8.8 Hz, 4 H), 6.75
(d, J = 8.8 Hz, 4 H), 5.13 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 172.5 (2 C), 172.0 (2 C),
156.4 (2 C), 128.4 (4 C), 121.3 (2 C), 115.3 (4 C), 99.2 (2 C), 74.1
(2 C).
ESI: m/z (%) = 380.8 (100, [M – H]–).
HRMS: m/z calcd for C20H13O8 (M – H): 381.0610; found:
381.0625.
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DPPH Scavenging Assay
Measurements were made in a 96-well microtiter plate using a
SpectraMax Plus384 (Molecular Devices) spectrophotometer. For
each compound, 100 mL of solutions in absolute EtOH, at concen-
trations ranging from 1 × 10–3 M to 1.95 × 10–6 M, were directly pre-
pared on the plate. Pure absolute EtOH and DPPH (100 mM)
samples were deposited in columns 1 and 12 of the plate, respective-
ly. Finally, 100 mL of an ethanolic 200 mM DPPH solution were
added in each well, except in columns 1 and 12. All measurements
were made in duplicate. The absorbance was followed spectropho-
tometrically at 515 nm immediately and then every 5 min over 1 h.
(13) Brand-Williams, B.; Cuvelier, M. E.; Berset, C. Lebensm.-
Wiss. Technol. 1995, 28, 25.
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Synthesis 2010, No. 10, 1697–1701 © Thieme Stuttgart · New York