An efficient synthesis of (±)-piliformic acid

Article abstract of DOI:10.1039/b004115g

The synthesis of (±)-piliformic acid was studied. It was done through Wittig reaction of methyl(triphenylphosphoranylidene)succinimide with hexanal followed by acid-induced hydrolysis of the formed succinimide derivatives. The structural assignment of pil

Full text of DOI:10.1039/b004115g

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An efficient synthesis of (± ±)-iliformic acid†
Siva-rakasam Mangaleswaran and Narshinha P. Argade*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008,
India
1
Received (in Cambridge, UK) 23rd May 2000, Accepted 27th July 2000
First published as an Advance Article on the web 7th September 2000
An easy, four-step access to naturally occurring (± ±-(E±-2-hexylidene-3-methylsuccinic acid (piliformic acid, 1± with
9% overall yield has been described via Wittig reaction of methyl(triphenylphosphoranylidene±succinimide 7 with
hexanal followed by acid-induced hydrolysis of the formed succinimide derivatives (E±-8 plus (Z±-9.
4
Introduction
anhydride–sodium acetate gave the citraconimide 6 in 90%
yield. A mixture of equimolar amounts of imide 6 and tri-
phenylphosphine (TPP± on refluxing with 1.5 equivalents of
hexanal in glacial acetic acid for 10 h yielded a combination of
geometric isomers 8 and 9 as a thick oil in 83% yield, via an
Piliformic acid (2-hexylidene-3-methylsuccinic acid, 1± was
1
identified in 1985 as a metabolite of several closely related
fungi of the Xylariaceous genera. It was isolated in small quan-
tities from Hypoxylon deustum, while it was obtained in sub-
stantial quantities as the major metabolite of the dung fungus
Poronia piliformis and also from four members of the morpho-
logically related Xylaria genus, X. polymorpha, X. longipes,
X. mali and X. hypoxylon, which grow on dead and decaying
wood. In nature, piliformic acid 1 exists in laevo, dextro and
racemic forms, although the absolute stereochemistry has not
been determined. The structural assignment of piliformic acid 1
has been done on the basis of IR, H NMR, C NMR and
mass spectral data. On the basis of H NMR data the carbon–
carbon double bond in 1 has been assigned (E±-geometry and
this has been further confirmed by comparison with a synthetic
sample. Until now only one, four-step synthesis of this natural
1
adduct 7. The integral values for vinylic protons in the H NMR
spectrum of this mixture of geometric isomers (E±-8 and (Z±-9
revealed that they are formed in an 85:15 ratio. Several reaction
conditions were tried for hydrolysis of 8 plus 9 to obtain (E±-
plus (Z±-piliformic acids, and without the concomitant isomeri-
sation of trisubstituted exocyclic to tetrasubstituted endocyclic
double bond in the 8 plus 9 mixture, and the best results were
obtained with a combination of acetic acid and conc. hydro-
chloric acid. The mixture of isomers 8 plus 9 on refluxing with
conc. hydrochloric acid and glacial acetic acid (1:1± for 60 h
furnished only the required mixture of (E±- and (Z±-piliformic
acids in 98% yield with the same ratio and without migration of
the carbon–carbon double bond. Recrystallisation of this mix-
ture from excess of hot water gave the desired pure (E±-isomer
in more than 70% yield. The analytical and spectral data
1
13
1
1
product 1 is known, from Anderson and Edwards, starting
from Meldrum’s acid via condensation of ethyl 3-oxo-
octanoate with ethyl 2-bromopropionate to obtain diethyl
1,2
obtained for 1 were in agreement with the reported data.
2
-hexanoyl-3-methylsuccinate, followed by its sodium boro-
In summary, we have demonstrated an efficient 4-step syn-
thesis of naturally occurring (± ±-piliformic acid 1 with a 49%
overall yield.
hydride reduction to give the ethyl ester of paraconic acid,
which on treatment with sodium ethoxide followed by alkaline
hydrolysis furnishes 1 in 1.75% overall yield. They examined a
number of possible routes for the synthesis of diacid 1 and
reported that attempts to condense hexanal with diethyl meth-
ylsuccinate using potassium tert-butoxide or sodium hydride as
base and the attempted reaction of 1,2-bis(ethoxycarbonyl±-
propylidene(triphenyl±phosphorane with hexanal in refluxing
benzene met with failure. Recently the biosynthesis of pili-
formic acid 1 has been studied and the provision of a simple
synthetic approach to this natural product is a challenging task
of current interest. In our studies towards the synthesis of the
bioactive natural product chaetomellic acid A, we have
developed conditions for the condensation of the methyl-
Ex-erimental
Mps were taken on a Buchi melting point B-540 apparatus and
1
are uncorrected. H NMR spectra were recorded in CDCl with
3
TMS as an internal standard on a Bruker AC 200 NMR spec-
13
2
trometer (200 MHz±. The C NMR spectrum was recorded on
a Bruker MSL 300 NMR spectrometer (75 MHz±. Mass spectra
were recorded on a Finnigan Mat 1020 mass spectrometer at
70 eV. The FT-IR spectra were recorded on a FT-IR-8300
Shimadzu spectrometer, and microanalyses were carried out
on a Carlo-Erba instrument. Column chromotographic separ-
ations were done on ACME silica gel (60–120 mesh±. TPP and
hexanal were obtained from Aldrich Chemical Co. Petroleum
spirit refers to the fraction with distillation range 60–80 ЊC.
3–5
4
6
(
triphenylphosphoranylidene±succinimide
7
with aliphatic
aldehydes and now we herein report yet another application of
this condensation reaction to complete an efficient synthesis of
(
± ±-piliformic acid 1 (Scheme 1±.
N)(p)Tolyl±)ꢀ) and )ꢁ)methylmaleanilic acids 4 ؉ 5
Results and discussion
The reaction of p-toluidine 2 with citraconic anhydride 3 in
diethyl ether at room temperature furnished a mixture of
methylmaleanilic acids (α-methyl:β-methyl = 9:1± in 95% yield.
To a constantly stirred solution of citraconic anhydride 3 (3.92
g, 3.5 mmol± in diethyl ether (25 mL± at rt was added a solution
of p-toluidine 2 (3.75 g, 3.5 mmol± in diethyl ether (25 mL±,
dropwise over a period of 10 min. The reaction mixture was
stirred at rt for 50 min and the precipitated product was filtered
off, washed with diethyl ether (10 mL × 2±, and dried in vacuo
to obtain a mixture of the α- and β-isomers in the ratio 9:1
7
8
This mixture of regioisomers 4 plus 5 on treatment with acetic
†
NCL Communication No. 6593.
3
290
J. Chem. Soc., Perkin Trans. 1, 2000, 3290–3291
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b004115g

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Scheme 1 Reagents, conditions and yields: (i) Et O, rt, 1 h (95%); (ii) Ac O–NaOAc, water-bath, 60–65 ЊC, 1 h (90%); (iii) TPP, AcOH, hexanal,
2
2
reflux, 10 h (83%); (iv) (a) AcOH, conc. HCl, reflux, 60 h (98%); (b) recrystallisation from excess of hot water, (E)-isomer (70%).
(
7.29 g, 95%); mp 195–199 ЊC. The above mixture of acids on
HCl (25 mL) was added to the reaction mixture, which was
recrystallisation from methanol gave exclusively the α-isomer 4,
mp 201 ЊC; IR (Nujol) νmax 3400, 1715, 1660, 1620 cm .
further refluxed for 12 h, concentrated in vacuo and the
obtained residue was dissolved in 5% aq. sodium bicarbonate
Ϫ1
(
25 mL). The aqeous layer was washed with ethyl acetate
N-(p-Tolyl)citraconimide 6
(2 × 15 mL) and acidified with dil. HCl. The acidified aqueous
layer was extracted with ethyl acetate (3 × 30 mL), and the
organic layer was washed successively with water (15 mL) and
brine (15 mL), and dried over Na SO . Concentration of the
A mixture of the methylmaleanilic acids 4 plus 5 (2.2 g, 10
mmol) in Ac O (15 mL) and fused NaOAc (0.1 g) was heated
2
2
4
in a water-bath at 60–65 ЊC for 1 h. The reaction mixture was
allowed to reach rt and was poured into ice-cold water (200
mL). The formed precipitate was filtered off, washed with
excess of water, and vacuum dried to give 6 (1.82 g, 90%), mp
organic layer in vacuo gave mixture of (E)- plus (Z)-piliformic
acids (0.81 g, 98%). The mixture of acids was recrystallised
from excess of hot water (120 mL) to obtain pure (E)-piliformic
acid 1 (0.57 g, 70%), mp 155 ЊC (from H O); IR (Nujol) ν
max
Ϫ1
1
2
1
15–116 ЊC (from EtOH); IR (Nujol) νmax 1710, 1685 cm ; H
NMR δH 2.18 (d, J 2 Hz, 3 H), 2.38 (s, 3 H), 6.47 (q, J 2 Hz,
H), 7.20 (d, J 10 Hz, 2 H), 7.27 (d, J 10 Hz, 2 H); MS m/z 201
Ϫ1
1
1
717, 1678, 1637 cm ; H NMR δ 0.90 (t, J 6.0 Hz, 3 H),
H
1
.15–1.47 (m, 7 H), 1.47–1.65 (m, 2 H), 2.05–2.40 (m, 2 H), 3.58
1
(
q, J 8.0 Hz, 1 H), 7.03 (t, J 8.0 Hz, 1 H), 11.00–12.50 (br s, 2 H)
in the (E ϩ Z)-isomer mixture, the signals for the vinylic pro-
ton and allylic methylene protons from the Z-isomer appeared
ϩ
(
(
M , 100%), 186 (7), 172 (13), 157 (30), 144 (27), 132 (32), 117
40), 104 (28), 91 (22), 86 (13), 77 (26), 68 (31), 57 (3).
[
13
at δ 6.23 and δ 2.63, respectively]; C NMR (CDCl ) δ 13.9,
3
C
(
±)-(E/Z)-2-Hexylidene-3-methyl-N-(p-tolyl)succinimides 8 ؉ 9
1
5.3, 22.4, 28.1, 28.7, 31.4, 37.6, 131.4, 147.1, 172.4, 180.7; MS
ϩ
A mixture of the citraconimide 6 (1.51 g, 7.5 mmol), TPP (1.97
g, 7.5 mmol) and hexanal (1.13 g, 11.25 mmol) in glacial acetic
acid (20 mL) was refluxed with stirring for 10 h. Acetic acid was
distilled off in vacuo at 50 ЊC and the residue was dissolved in
ethyl acetate (50 mL). The organic layer was washed succes-
sively with water (15 mL) and brine (15 mL), and dried over
Na SO . Concentration of the organic layer in vacuo followed
m/z 214 (M , 2%), 196 (22), 168 (38), 139 (27), 125 (100), 112
(100), 99 (60), 95 (100), 91 (24), 81 (91), 67 (84), 55 (58) (Calc.
for C H O : C, 61.66; H, 8.47. Found: C, 61.74; H, 8.72%).
11
18
4
Acknowledgements
2
4
S. M. thanks C.S.I.R., New Delhi, for the award of a fellowship.
N. P. A. thanks D.S.T., New Delhi, for financial support under
the Young-Scientist Scheme. We thank Dr K. N. Ganesh,
Head, Division of Organic Chemistry (Synthesis), for constant
encouragement.
by silica gel column chromatographic purification of the resi-
due using a mixture of petroleum spirit and ethyl acetate (9:1)
gave 8 plus 9 (8:9 = 85:15, by H NMR) as a thick oil (1.78 g,
1
Ϫ1
1
8
3%); IR (neat) νmax 1771, 1710, 1672 cm ; H NMR δ 0.92 (t,
H
J 6.0 Hz, 3 H), 1.25–1.45 (m, 4 H), 1.45–1.70 (m, 2 H), 1.48 (d,
J 6.0 Hz, 0.45 H, Z-isomer), 1.53 (d, J 6.0 Hz, 2.55 H), 2.20–
References
2
3
.38 (m, 1.70 H), 2.39 (s, 3 H), 2.75–2.95 (m, 0.3 H, Z-isomer),
.30–3.55 (m, 1 H), 6.23 (dt, J 8.0 and 3.0 Hz, 0.15 H,
1
J. R. Anderson and R. L. Edwards, J. Chem. Soc., Perkin Trans. 1,
1985, 1481.
Z-isomer), 6.92 (dt, J 8.0 and 3.0 Hz, 0.85 H), 7.21 (d, J 8.0 Hz,
ϩ
2
H), 7.29 (d, J 8.0 Hz, 2 H); MS m/z 286 (MH , 100%), 230
2 N. C. J. E. Chesters and D. O’Hagan, J. Chem. Soc., Perkin Trans. 1,
997, 827.
A. M. Deshpande, A. A. Natu and N. P. Argade, J. Org. Chem., 1998,
3, 9557.
1
(
(
10), 147 (24), 106 (9), 91 (15), 81 (19), 77 (10), 73 (47), 55 (10)
Calc. for C H NO : C, 75.76; H, 8.12; N, 4.91. Found: C,
3
18
23
2
6
7
5.83; H, 8.07; N, 5.02%).
4
5
S. B. Desai and N. P. Argade, J. Org. Chem., 1997, 62, 4862.
N. P. Argade and R. H. Naik, Bioorg. Med. Chem., 1996, 4, 881.
(
±)-(E)-Piliformic acid 1
6 E. Hedaya and S. Theodoropulos, Tetrahedron, 1968, 24, 2241.
7
R. L. Shriner, S. G. Ford and L. J. Roll, Org. Synth., 1943, Coll. Vol. II,
40, 368.
A mixture of 8 plus 9 (1.10 g, 3.86 mmol) was dissolved in
glacial acetic acid plus concentrated hydrochloric acid (1:1; 100
mL) and the solution was refluxed for 48 h. Additional conc.
1
8
N. B. Mehta, A. P. Phillips, F. L. Florence and R. E. Brooks,
J. Org. Chem., 1960, 25, 1012.
J. Chem. Soc., Perkin Trans. 1, 2000, 3290–3291
3291