Synthesis of the seed germination stimulant 3-methyl-2H-furo[2,3-c]pyran-2- one

Article abstract of DOI:10.1016/j.tetlet.2005.06.077

3-Methyl-2H-furo[2,3-c]pyran-2-one 1 was recently identified as the key agent in smoke, responsible for promoting the seed germination of a diverse range of fire-dependent and fire-independent plant species from around the world. The synthesis of this novel compound, obtained in three steps from pyromeconic acid, is described.

Full text of DOI:10.1016/j.tetlet.2005.06.077

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5719–5721
Synthesis of the seed germination stimulant
3-methyl-2H-furo[2,3-c]pyran-2-one
Gavin R. Flematti,a,* Emilio L. Ghisalberti,a
Kingsley W. Dixonb,c and Robert D. Trengoved
aSchool of Biomedical and Chemical Sciences, The University of Western Australia, Crawley, WA 6009, Australia
bKings Park and Botanic Garden, West Perth WA 6005, Australia
cSchool of Plant Biology, The University of Western Australia, Crawley WA 6009, Australia
dSchool of Engineering Science, Murdoch University, Rockingham WA 6168, Australia
Received 9 May 2005; revised 8 June 2005; accepted 15 June 2005
Available online 1 July 2005
Abstract—3-Methyl-2H-furo[2,3-c]pyran-2-one 1 was recently identified as the key agent in smoke, responsible for promoting the
seed germination of a diverse range of fire-dependent and fire-independent plant species from around the world. The synthesis of
this novel compound, obtained in three steps from pyromeconic acid, is described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, we have reported the isolation of a compound
from plant-derived smoke that is responsible for pro-
moting the seed germination of a wide range of plant
species from Australia, North America and South Afri-
ca.1 The compound was identified as 3-methyl-2H-
furo[2,3-c]pyran-2-one 1 on the basis of spectroscopic
analysis (MS, 1H NM R,13C NMR and 2D NMR).
We now report the synthesis of this new bioactive
compound.
Scheme 1. Retrosynthetic approach to 3-methyl-2H-furo[2,3-c]pyran-
2-one 1.
proved unsuccessful, so alternative methods for forming
the butenolide were investigated.
2. Results and discussion
Other methods attempted included treatment of the
propionyl ester 3 with acetic anhydride as described by
Belsky et al.3 Additionally, the analogous 2-chloropro-
pionyl ester of pyromeconic acid was treated with tri-
ethylphosphite in an attempt to form the phosphonate,
which could be treated under Horner–Emmons condi-
tions to form the butenolide.4,5 However, these methods
failed to yield the desired product.
Retrosynthetic analysis of 1 (Scheme 1) indicated that
pyromeconic acid 2 would provide a useful starting
compound.2 We envisaged that treatment of the propio-
nyl ester of pyromeconic acid 3 with a strong base, such
as lithium diisopropylamide (LDA), could lead to cycli-
sation and formation of the butenolide entity. This
A more promising approach was the method described
by Ohkata et al.6 for forming vinylogous 4H-pyrones
from 4H-pyran-4-thione and arenyl bromomethyl ke-
tones. Thus, the 2-chloropropionyl ester of pyromeconic
acid 4 was converted to the corresponding thione 5 by
Keywords: Butenolide; Germination stimulant; Seed germination;
Smoke.
*
Corresponding author. Tel.: +61 8 6488 4465; fax: +61 8 6488
1005; e-mail: gflematt@chem.uwa.edu.au
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.077

5720
G. R. Flematti et al. / Tetrahedron Letters 46 (2005) 5719–5721
Scheme 2. Synthesis of 3-methyl-2H-furo[2,3-c]pyran-2-one 1. Reagents and conditions: (a) 1.2 equiv Et3N, CH2Cl2, 10 min, rt; (b) 1.5 equiv P2S5,
6 equiv NaHCO3, THF, 3 h, rt; (c) 3 equiv NaOAc, 1.2 equiv Ph3P, Ac2O, 30 min, 140 ꢁC. On heating concentrated solutions of 5 in acetic anhydride
without Ph3P, some of the thia analogue 8 was formed.
treatment with phosphorus pentasulfide.7 Heating solu-
tions of 5 in a range of solvents (e.g., acetone, aceto-
nitrile, dioxane, anisole and dimethylformamide) under
reflux failed to yield the expected 4-mercaptopyrylium
salt. Heating 5 in acetic anhydride gave mainly the
transesterification product 6, together with a small
amount of the target compound 1 (Scheme 2). Optimisa-
tion of the reaction conditions improved the yield of 1,
but the yield of the acetyl ester 6 was still high at
approximately 50%. Isolation of the target compound
though was readily achieved by hydrolysis of the reac-
tion mixture, followed by extraction of 1 with dichloro-
methane. The synthetic sample of 1 was identical (UV,
identity of the potent germination stimulant found in
smoke.
3. Experimental
3.1. General procedure for the formation of 1
A mixture of anhydrous sodium acetate (280 mg,
3.4 mmol) and triphenylphosphine (330 mg, 1.3 mmol)
in acetic anhydride was heated at 140 ꢁC for 5 min. A
solution of 5 (250 mg, 1.1 mmol) diluted with acetic
anhydride (2 mL) was added dropwise to the heated mix-
ture over 5 min. The mixture was heated for a further
30 min and allowed to cool. The dark reaction mixture
was poured into ice/water (100 mL) and stirred until
one phase was formed. The aqueous solution was filtered
and extracted with dichloromethane (3 · 20 mL). The
1
MS, H NMR and 13C NMR) to that isolated from
smoke.1
A problem encountered in the formation of the thione
ester 5 by treatment of the corresponding pyrone 4 with
phosphorus pentasulfide was that almost 50% of the
ester was hydrolysed to the pyromeconic acid thione 7,
thus requiring re-esterification. Treatment of pyro-
meconic acid 2 directly with phosphorus pentasulfide
to form the corresponding thione 7, followed by esterifi-
cation with 2-chloropropionyl chloride to form 5, was
found to be more efficient (Scheme 2). It was also obs-
erved that heating concentrated solutions of 5 in acetic
anhydride led to the formation of the sulfur analogue,
3-methyl-2H-thiopyran[3,4-b]furan-2-one 8 (Scheme 2),
which was difficult to separate from 1 by chromatogra-
phy. The addition of a thiophile,8 such as triphenylphos-
phine, to the reaction mixture prevented this compound
from forming and improved the yield of 1.
organic extract was washed with 1 MNaHCO
3
(2 · 20 mL), dried (Na2SO4), filtered and evaporated un-
der reduced pressure. The residue was extracted with
0.2 Mpotassium carbonate solution (2 · 50 mL) by heat-
ing gently and the resulting yellow solution was filtered
and extracted with dichloromethane (3 · 15 mL). The
organic extract was washed with brine, dried (Na2SO4),
filtered and evaporated under reduced pressure to give
a yellow residue. The residue was purified by silica gel
chromatography (30% ethyl acetate/light petroleum) to
afford 1 as a light yellow crystalline solid (38 mg, 22%),
which re-crystallised from light petroleum as light yellow
needles (mp 118–119 ꢁC).
1
Compound 1: H NMR (500 MHz, acetone-d6): d 7.77
(1H, s, H-7), 7.62 (1H, d, J = 5.5 Hz, H-5), 6.79 (1H,
In conclusion, we have achieved the first synthesis of 3-
methyl-2H-furo[2,3-c]pyran-2-one 1 and confirmed the
d, J = 5.5 Hz, H-4), 1.86 (3H, s, CH3). 13C NM R

G. R. Flematti et al. / Tetrahedron Letters 46 (2005) 5719–5721
5721
(125.8 MHz, acetone-d6): d 171.1 (C@O), 149.8 (C-5),
References and notes
143.0 (C-7a), 140.6 (C-3a), 128.0 (C-7), 104.1 (C-4),
100.0 (C-3), 7.6 (CH3). HRMS calculated for C8H6O3:
150.0317. Found: 150.0320. UV (kmax in nanometers,
loge): 347 (3.99), 330 (4.27), 320 (4.27), 242 (3.49), 202
(4.00). IR (CH2Cl2): 1746 cmÀ1 (C@O).
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2. Pyromeconic acid (3) was prepared from kojic acid as
previously described: (a) Ellis, B. L.; Duhme, A. K.; Hider,
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989–995.
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2855–2862.
Acknowledgements
We wish to thank Dr. D. Wege and Dr. S. K. Brayshaw
for invaluable discussions on the synthetic approach.
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Supplementary data
7. Scheeren, J. W.; Ooms, P. H. J.; Nivard, R. J. F. Synthesis
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Supplementary data associated with this article can be
found, in the online version at doi:10.1016/j.tetlet.
2005.06.077.