An efficient synthesis of 4-oxoalkenoic acids from 2-alkylfurans

Article abstract of DOI:10.1055/s-2005-869833

An efficient synthesis of 4-oxo-2-alkenoic acids is achieved by the reaction of 2-alkylfurans with sodium chlorite in acidic aqueous solution. The method is applicable to the total synthesis of biologically active phospholipids containing this functional array. The oxidation procedure also converts 2,5-dialkyl furans to α,β-unsaturated-γ-diketones in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869833

1468
LETTER
An Efficient Synthesis of 4-Oxoalkenoic Acids from 2-Alkylfurans
Synthesis of
4
u
n
r
oic Acid
e
s
sh Palani Annangudi, Mingjiang Sun, Robert G. Salomon*
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA
Fax +1(216)3683006; E-mail: rgs@case.edu
Received 8 March 2005
singlet oxygenation.10 Generation of 4-oxo-2-alkenoic
acids from 2-alkyl furans has also been accomplished
previously through a variety of multi-step procedures in-
volving treatment with reagents such as bromine11 or
Abstract: An efficient synthesis of 4-oxo-2-alkenoic acids is
achieved by the reaction of 2-alkylfurans with sodium chlorite in
acidic aqueous solution. The method is applicable to the total syn-
thesis of biologically active phospholipids containing this function-
al array. The oxidation procedure also converts 2,5-dialkyl furans to NBS12 followed by oxidation with sodium chlorite; PCC
followed by Jones reagent;13 or nitration followed by
a,b-unsaturated-g-diketones in good yields.
acidic oxidation.14
Key words: furan oxidation, sodium chlorite, ring opening, oxi-
dized phospholipids, a,b-unsaturated acids
O
R
OR"
ref.6
4-Oxo-2-alkenoic acids, and the closely related a,b-unsat-
urated-g-diketones, are versatile intermediates for organic
synthesis.1,2 This functional array is present in many
pharmaceutically important natural products, e.g.,
pyrenophorin, patulolide, grahamimycin and others,3 that
have antifungal, antibacterial, and anti-inflammatory
properties.4 Recently, we found that free radical-induced
oxidative fragmentation of arachidonyl or linoleoyl
phosphatidylcholine (PC) in vivo generates bioactive
phospholipids, KOdiA-PC or KDdiA-PC (Scheme 1),5
that incorporate 4-oxo-2-alkenoic acid functionality.
O
OSiR''
R
ref.8
O
OR"
R
O
R
O
SiHR"
ref.9
O
ref.7
O
R
R"
Scheme 2
Alkyl furans are easily accessible,1 robust precursors that
are compatible with a wide variety of reagents and reac-
tion conditions making them highly desirable substrates.
We now report efficient stereocontrolled methodology,
that exploits sodium chlorite as an oxidizing agent, for the
conversion of 2-alkyl furans into 4-oxo-2-alkenoic acids
and for the conversion of 2,5-dialkylfurans into 1,4-ene-
diones. The oxidation cleanly generates cis-isomers
(butenolides) stereospecifically and in high yield. If
desired, these can be cleanly and quantitatively converted
to the corresponding trans-isomers by treatment with
pyridine.15
O
O
C4H9
O
P
C15H31
m
n
O
O
O
O
O
N(CH3)3
arachidonyl-PC, m = 4, n = 2
linoleoyl-PC, m = 2, n = 6
O2
O
O
O
HO
O
P
C15H31
n
O
O
O
O
O
O
N(CH3)3
KOdiA-PC, n = 3
KDdiA-PC, n = 7
Scheme 1
Oxidation of 2-alkyl furans 1 in the presence of sodium
chlorite in a slightly acidic aqueous solution (ca. pH 3.5)
at room temperature generates 2-alkyl-2-hydroxy-buteno-
lides 2,16 ring tautomers of 4-oxo-2(Z)-alkenoic acids
(Scheme 3).17 Owing to electron deficiency, 2-acetylfuran
did not react under these conditions.
An efficient synthesis of 4-oxo-2-alkenoic acids from
simple monosubstituted furan precursors is needed. An
important shortcoming of previous methods for preparing
4-oxo-2-alkenoic acids has been the requirement for more
elaborately functionalized furan intermediates such as 2-
alkoxy-5-alkyl,6 2-acyl-5-alkyl,7 2-siloxy-5-alkyl8 or 2-si-
lyl-5-alkyl9 as precursors (Scheme 2). A patent applica-
tion reported a one-pot synthesis of 4-oxo-5-phthalimido-
2-pentenoic acid from N-furfurylphthalimide through
OH
O
O
O
pH ~ 7
O
H
OH
H
pH ~ 5–6
Scheme 3
SYNLETT 2005, No. 9, pp 1468–1470
0
1.
0
6.
2
0
0
5
Advanced online publication: 10.05.2005
DOI: 10.1055/s-2005-869833; Art ID: S02905ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 4-Oxoalk-2-enoic Acids
1469
Table 1 Synthesis of 2-Alkyl-2-hydroxybutenolides from 2-Alkyl
Furans
Oxidation of 2,5-dialkyl furans gave the corresponding
1,4-diketones (Table 2).19 Substrates incorporating a vinyl
substituent present a special challenge. For example,
under the usual reaction conditions, 4j did not give any of
the corresponding enedione 5j. However, in the presence
of 2-methyl-2-butene, a chlorine scavenger, the sodium
chlorite oxidation protocol gave enedione 5j in good
yield.
O
HO
R
O
O
R
a
b
O
OH
R
O
1
2
3
Entry Alkyl furan 1
1 → 2
Yield 2 → 3
Yield
R
Time (h) 2 (%) Time (h) 3 (%)
Table 2 Synthesis of 2-Ene 1,4-Diones from 2,5-Dialkyl Furans
a
b
c
d
e
f
-(CH2)3-COO-PC c
-(CH2)7-COO-PC c
1
66d
64d
96e
95e
90e
78e
77e
75e
2
2
2
2
2
2
2
2
100
100
100
100
96
O
O
O
R
a
R'
1
R
R'
-CH3
0.5
1.5
4
4
5
-C5H11
Entry
R
R¢
-CH3
Product
Yield (%)
93b
-(CH2)4-OTs
-(CH2)4-OTHP
-(CH2)4-OTBDMS
1
2
3
-CH3
5i
2
90
-(CH2)7CHO
-CH3
-CH=CH(E)-C4H9 5jd
-CH=CH(E)-C4H9 5k
76c
g
h
2
95
78c
-(CH2)2-(CH-O-
TBDMS)-CH3
2
96
a NaClO2 (3 equiv), NaH2PO4 (1.5 equiv), t-BuOH–H2O (5:1).
b Reaction time 1 h.
a NaClO2 (3 equiv), NaH2PO4 (1.5 equiv), r.t.
c 2-Methyl-2-butene (0.1 mol equiv) added to the reaction, reaction
time ca. 20 min, yield based on unrecovered starting material.
d The aldehyde is completely oxidized to the acid.
b Pyridine (1 mol%), THF–acetone–H2O (5:4:2, 0.2 mL/mmol of 2),
2 h, r.t.
c PC = 2-lysophosphatidylcholine.
d Solvent: phosphate buffered saline (pH 3.5)–CHCl3–H2O, 2:1:1.
e Solvent: t-BuOH–H2O (5:1, 1 mL/mmol of 1).
In summary, this new methodology provides ready access
to either cis- or trans-isomers of 4-oxo-2-alkenoic acids
from simple precursors in high yields, using readily avail-
able reagents. Compared to our previous total synthesis,
the new procedure enables a major improvement in the
overall yield and ease of preparing biologically active
phospholipids that contain this functional array.
The butenolides can be isolated, virtually pure (by NMR)
by extraction into chloroform. This oxidative ring-open-
ing methodology is compatible with a variety of function-
al groups used routinely in organic synthesis (Table 1).
Stereoselective conversion of the alkyl butenolides 2 into
4-oxo-2(E)-alkenoic acids 3 is readily accomplished in
excellent yield by treatment with a catalytic amount of py-
ridine (Table 1).16
Acknowledgment
This work was supported by National Institute of Health grant
GM21249.
The uptake of oxidized low-density lipoprotein by mac-
rophage cells is an early event in the formation of athero-
sclerotic plaques. We recently identified the
phospholipids KOdiA-PC (3a) and KDdiA-PC (3b) as po-
tent ligands responsible for recognition and uptake of ox-
idized low-density lipoprotein.5 Our previous synthesis of
3a and 3b from 2-substituted furan phospholipid precur-
sors 1a and 1b, using oxidation with NBS followed by
further oxidation with sodium chlorite, gave 46% and
36% yields, respectively.18 Total syntheses involving
phospholipids present special challenges owing to their
unique solubility properties. We discovered that direct ox-
idation of 1a or 1b with sodium chlorite can be accom-
plished by employing a biphasic solvent system
containing pH 3.5 phosphate buffer, chloroform and water
in the ratio 2:1:1. For these phospholipids, the sodium
chlorite oxidation method using t-BuOH–water (5:1) as
solvent afforded poor yields, even after long reaction
times. The biphasic aqueous sodium chlorite protocol de-
creased the reaction time, from nine hours to one hour and
consistently gave 40–80% higher yields than the NBS–
NaClO2 procedure.
References
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Synlett 2005, No. 9, 1468–1470 © Thieme Stuttgart · New York

1470
S. P. Annangudi et al.
LETTER
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7.33 (d, J = 7.9 Hz, 2 H), 7.12 (d, J = 15.9 Hz, 1 H), 6.63 (d,
J = 16.1 Hz, 1 H), 4.03 (m, 2 H), 2.62 (m, 2 H), 2.43 (br s, 3
H), 1.60–1.80 (4 H). 13C NMR (50 MHz, CDCl3): d = 198.1,
168.1, 144.9, 144.8, 140.6, 132.9, 129.8, 127.8, 69.9, 40.5,
28.0, 21.6, 19.4. HRMS (FAB): m/z calcd for C15H19O6S+ [M
+ H+]: 327.0902; found: 327.0903.
(4) Ronsheim, M. D.; Zercher, C. K. J. Org. Chem. 2003, 68,
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5-Hydroxy-5-pentyl-5H-furan-2-one (2d).
(5) (a) Podrez, E. A.; Poliakov, E.; Shen, Z.; Zhang, R.; Deng,
Y.; Sun, M.; Finton, P. J.; Shan, L.; Febbraio, M.; Hajjar, D.
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Poliakov, E.; Shen, Z.; Zhang, R.; Deng, Y.; Sun, M.; Finton,
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(12) Kobayashi, Y.; Kishihara, K.; Watatani, K. Tetrahedron
Lett. 1996, 37, 4385.
(13) Ballini, R.; Bosica, G. J. Nat. Prod. 1998, 61, 673.
(14) Saldabol, N. O.; Popelis, J.; Slavinska, V. Chem. Heterocycl.
Compd. (Engl. Transl.) 2002, 38, 873.
(15) Williams, P. D.; LeGoff, E. Tetrahedron Lett. 1985, 26,
1367.
(16) Typical Procedure for Furan Oxidation.
To a magnetically stirred solution of alkyl furan 1 (0.1
mmol) in t-BuOH–H2O (5:1, v/v, 0.5 mL) was added
NaH2PO4 (0.15 mmol), NaClO2 (0.3 mmol). The resulting
mixture was stirred at r.t. for 2 h or until the yellow color
disappears. Then, the solvent was removed on a rotary
evaporator. The residue was extracted with CHCl3. The
extract was washed with brine, dried on MgSO4 and passed
through a short plug of Celite. The resulting butenolides are
at least 90% pure by NMR.
1H NMR (300 MHz, CDCl3): d = 7.17 (d, J = 5.7 Hz, 1 H),
6.11 (d, J = 5.7 Hz, 1 H), 1.98 (m, 2 H), 1.28–1.41 (7 H),
0.87 (t, J = 6.3 Hz, 3 H).
8-(tert-Butyldimethylsilanyloxy)-4-oxooct-2 (Z)-enoic
Acid (3g).
TLC: 20% EtOAc in hexanes, Rf = 0.37; yield 77%. 1H
NMR (200 MHz, CDCl3): d = 7.21 (d, J = 5.5 Hz, 1 H), 6.10
(d, J = 5.5 Hz, 1 H), 3.64 (t, J = 5.9 Hz, 2 H), 2.10–1.90 (2
H), 1.70–1.40 (4 H), 0.88 (s, 9 H), 0.05 (s, 6 H). 13C NMR
(75 MHz, CDCl3): d = 170.3, 154.2, 123.1, 108.0, 62.9, 36.9,
31.8, 25.9, 20.2, 18.3, –5.3. HRMS (FAB): m/z calcd for
C14H27O4Si+ [M + H+]: 287.1673; found: 287.1679.
5-[3-(tert-Butyldimethylsilanyloxy)butyl]-5-hydroxy-
5H-furan-2-one (2h).
TLC: 20% EtOAc in hexanes, Rf = 0.3. 1H NMR (300 MHz,
CDCl3, diastereomeric mixture): d = 7.19 (d, J = 6.0 Hz, 0.7
H), 7.15 (d, J = 6.0 Hz, 0.3 H), 6.05 (1 H), 4.01 (m, 0.7 H),
3.95 (m, 0.3 H), 1.60–2.20 (6 H), 1.10–1.20 (6 H), 0.80–0.90
(9 H), –0.01–0.16 (6 H).
1-Palmitoyl-2-[1-carboxy-4-(2-hydroxy-5-oxo-2,5-
dihydrofuran-2-yl)butanoyl]-sn-glycero-3-phospha-
tidylcholine (2a).
1H NMR (300 MHz, CD3OD): d = 7.41 (br s, 1 H), 6.15 (d,
J = 6.0 Hz, 1 H), 5.25 (m, 2 H), 4.39 (m, 1 H), 4.28 (m, 2 H),
4.21 (m, 1 H), 4.01 (m, 2 H), 3.66 (m, 2 H), 3.23 (s, 9 H),
2.30–2.40 (4 H), 1.50–2.10 (6 H), 1.20–1.30 (24 H), 0.88 (t,
J = 6.0 Hz, 3 H). HRMS (MALDI-TOF): m/z calcd for
C32H59NO11P+ [MH+]: 664.3826; found: 664.3820.
1-Palmitoyl-2-[1-carboxy-8-(2-hydroxy-5-oxo-2,5-
dihydrofuran-2-yl)octanoyl]-sn-glycero-3-phospha-
tidylcholine (2b).
1H NMR (300 MHz, CD3OD): d = 7.41 (br s, 1 H), 6.12 (d,
J = 6.0 Hz, 1 H), 5.25 (m, 2 H), 4.40 (m, 1 H), 4.27 (m, 2 H),
4.16 (dd, J1 = 12.6 Hz, J2 = 6.3 Hz, 1 H), 4.01 (t, J = 5.1 Hz,
2 H), 3.66 (m, 2 H), 3.23 (s, 9 H), 2.30–2.40 (4 H), 1.50–2.10
(5 H), 1.20–1.30 (30 H), 0.88 (t, J = 6.0 Hz, 3 H). HRMS
(MALDI-TOF): m/z calcd for C36H67NO11P+ [MH+]:
720.4457; found: 720.4424.
Typical Procedure for cis/trans Isomerization.
To a solution of 2 in 2 mL THF–acetone–H2O (5:4:1) was
added 10 mL of freshly distilled pyridine (1 mol%). The
mixture was stirred for 2 h at r.t. Solvents were removed on
a rotary evaporator and residual pyridine was removed in
vacuo using a dry ice cooled trap. The residue was purified
by flash chromatography on a silica gel column (30% EtOAc
in hexanes) to afford the pure product 3.
Toluene-4-sulfonic Acid 4-(Furan-2-yl)butyl Ester (1e).
1H NMR (300 MHz, CD3Cl): d = 7.77 (d, J = 8.4 Hz, 2 H),
7.32 (d, J = 8.4 Hz, 2 H), 7.25 (dd, J1 = 1.8 Hz, J2 = 0.9 Hz,
1 H), 6.24 (dd, J1 = 3.0 Hz, J2 = 1.8 Hz, 1 H), 5.92 (dd,
J1 = 3.0 Hz, J2 = 0.9 Hz, 1 H), 4.01 (t, J = 6.3 Hz, 2 H), 2.56
(t, J = 6.6 Hz, 2 H), 2.43 (s, 3 H), 1.63–1.64 (4 H). 13C NMR
(75 MHz, CD3Cl): d = 155.1, 144.6, 140.8, 132.9, 129.7,
127.8, 110.0, 105.0, 70.1, 28.1, 27.0, 23.8, 21.5. HRMS
(FAB): m/z calcd for C15H18O4S+ [M+]: 294.0926; found:
294.0924.
(17) Franzen, R.; Tanabe, K.; Morita, M. Chemosphere 1998, 38,
973.
(18) Sun, M.; Deng, Y.; Batyreva, E.; Sha, W.; Salomon, R. G. J.
Org. Chem. 2002, 67, 3575.
(19) 9,12-Dioxooctadeca-10(Z),13(E)-dienoic Acid (5j).
To a magnetically stirred solution of aldehyde 4j (39 mg,
0.14 mmol) in t-BuOH–H2O (5:1, v/v, 0.3 mL) and 2-
methyl-2-butene (1.44 mmol, 720 mL, 2 M in THF) were
added NaH2PO4 (30 mg, 0.22 mmol) and NaClO2 (40 mg,
0.4 mmol, 90%). The mixture was stirred at r.t. and
monitored by TLC. The solvent was removed. The residue
was purified by flash chromatography on a silica gel column
(first eluted with 25% EtOAc in hexanes then EtOAc)
affording yellowish crystals 5j. 1H NMR (200 MHz,
CDCl3): d = 6.83 (dt, J1 = 16.0 Hz, J2 = 6.8 Hz, 1 H), 6.48 (d,
J = 12.0 Hz, 1 H), 6.38 (d, J = 12.0 Hz, 1 H), 6.18 (dt,
J1 = 16.0 Hz, J2 = 1.5 Hz, 1 H), 2.52 (t, J = 7.2 Hz, 2 H),
2.10–2.40 (4 H), 1.10–1.80 (14 H), 0.91 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 202.9, 192.6, 179.6, 150.8,
136.9, 134.2, 130.2, 42.6, 34.0, 32.5, 30.1, 29.0, 28.9, 24.6,
23.4, 22.3, 13.9. HRMS (EI): m/z calcd for C18H28O4+ [M+]:
308.1988; found: 308.1978.
Toluene-4-sulfonic Acid 4-(2-Hydroxy-5-oxo-2,5-
dihydrofuran-2-yl)butyl Ester (2e).
1H NMR (300 MHz, CDCl3): d = 7.75 (d, J = 8.2 Hz, 2 H),
7.33 (d, J = 7.9 Hz, 2 H), 7.19 (d, J = 5.5 Hz, 1 H), 6.09 (d,
J = 5.5 Hz, 1 H), 4.03 (m, 2 H), 2.43 (br s, 3 H), 1.40–1.80
(6 H).
4-Oxo-8-(toluene-4-sulphonyloxy)oct-2-enoic Acid (3e).
1H NMR (200 MHz, CDCl3): d = 7.77 (d, J = 8.2 Hz, 2 H),
Synlett 2005, No. 9, 1468–1470 © Thieme Stuttgart · New York