Triacetic acid lactone methyl ether as a natural products synthon

Article abstract of DOI:10.1071/ch99119

Deprotonation at the 6-methyl group of 4-methoxy-6-methyl-3-trimethylsilyl-2H-pyran-2-one (ld) resulted in the formation of an extended enolate (le) which was spectroscopically identified. The utility of this enolate towards the synthesis of some natural products of polyketide origin has been described, e.g. the synthesis of 4-methoxy-6-(2-oxopropyl)-2H-pyran-2-one (4) and 4-methoxy-6-phenacyl-2H-pyran-2-one (5), the former having been isolated from Penicillium stipitatum culture, and the synthesis of 5,6-dehydrokawain (6), a natural product extracted from the wood of Aniba firmula and from the seeds of Alpina blepharocalyx. CSIRO 2000.

Full text of DOI:10.1071/ch99119

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Aust. J. Chem., 2000, 53, 589–591
Short Communications
Triacetic Acid Lactone Methyl Ether as
a Natural Products Synthon
Younis M. Younis and Shar S. Al-Shihry
Department of Chemistry, College of Education, King Faisal University,
P.O. Box 1759, Hofuf 31982, Eastern Province, Saudi Arabia.
Deprotonation at the 6-methyl group of 4-methoxy-6-methyl-3-trimethylsilyl-2H-pyran-2-one (1d) resulted in the
formation of an extended enolate (1e) which was spectroscopically identified. The utility of this enolate towards the
synthesis of some natural products of polyketide origin has been described, e.g. the synthesis of 4-methoxy-6-(2-
oxopropyl)-2H-pyran-2-one (4) and 4-methoxy-6-phenacyl-2H-pyran-2-one (5), the former having been isolated
from Penicillium stipitatum culture, and the synthesis of 5,6-dehydrokawain (6), a natural product extracted from
the wood of Aniba firmula and from the seeds of Alpina blepharocalyx.
Keywords. Enolate; natural product synthesis; pyrone.
to us since it is a system in which ring deprotonation is
blocked. It was, therefore, thought that deprotonation at
other sites of the molecule, particularly at the 6-methyl
group, would be easy. The trimethylsilyl group used for the
protection is very easy to remove after it has accomplished
its task.
A number of pyrones have been used as protected ␤-
polyketo acids in the biomimetic synthesis of natural prod-
ucts of polyketide origin,1–7 one of which is triacetic acid
lactone methyl ether* (1a) (Scheme 1), which is used in the
present investigation. It has been used as a versatile synthon
in polyketide-type biomimetic synthesis. In these earlier
investigations pyrone (1a) was used as an electrophile1–3 and
it can also behave as a nucleophile.4–7 The last reaction is pre-
sumably initiated by deprotonation.
There is no record in the literature in which the anion at
C 7 of compound (1a) is generated by treatment with strong
base in spite of the apparent stabilization available to the
system by delocalization of the charge onto the carbonyl
oxygen. This possibility was overlooked by Wachter and
Harris6 on the generation of the dianion and in exploratory
works on the preparation of the ylide (1b) (Scheme 1), which
was unable to be acylated with normal acylating agents.
A possible explanation for the difficulty in initiating reac-
tivity at C 7 of compound (1a) emerged as a result of an
observation that reaction of (1a) with lithium diisopropy-
lamide in tetrahydrofuran at –78°C followed by quenching
with deuterium oxide yielded the monodeuterated derivative
(1c). It was found that the anion at C 3 of the pyrone (1a)
could also be generated by treatment with either lithium
diisopropylamide or butyllithium and could be made to react
with chlorotrimethylsilane at –78°C to give the trimethyl-
silylpyrone (1d) in 45% yield.8
The silylpyrone (1d) was shown to be deprotonated at the
6-methyl group, by treating with lithium diisopropylamide in
tetrahydrofuran at –120°C to give the anion (1e). The 13C
n.m.r. spectrum of the parent silylpyrone and the anion
derived from it provided experimental evidence for the for-
mation of this enolate. The experiment consisted of cooling
a solution of the silylpyrone (1d) in tetrahydrofuran to
–120°C and adding 1 equiv. of lithium diisopropylamide.
The solution was then brought to –70°C and the 13C n.m.r.
spectrum was recorded. No resonance due to the starting
material could be observed. Furthermore, the lithium diiso-
propylamide was now present as diisopropylamine, indicat-
ing that deprotonation has occurred. It is interesting to note
that deprotonation was observed to occur in less than 10 min.
The assignment of the 13C n.m.r. spectrum of the anionic
species was made on the basis of the chemical shift and the
multiplicities in the proton-coupled spectrum. Thus it can be
seen that the trimethylsilyl group in the anion spectrum is
virtually unmoved (Table 1). C 7 is considerably deshielded
and occurs as a triplet in the proton-coupled spectrum, while
C 2 is shielded. Unfortunately, the very slowly relaxing qua-
ternary C 3 does not appear under the rapid pulsing condi-
tions employed, possibly due to saturation or accidental
superposition with solvent resonance. Hence, it can be con-
cluded that the anion is an extended enolate of the form (1e).
The synthetic utility of (1e) was tested by quenching with
acetyl chloride and with benzoyl chloride, affording after
alkaline workup compounds (2) and (3) in 63 and 81% yields
However, in the present investigation, when the pyrone
(1a) was treated with methyllithium in tetrahydrofuran at
–120°C, the anion at C 3 was generated in high yield. The
anion was made to react with chlorotrimethylsilane affording
the silylpyrone (1d) in higher than 92% yield. It was found
that the yields were high even when the reaction was carried
out on a large scale. This silylpyrone is of particular interest
* 4-Methoxy-6-methyl-2H-pyran-2-one.
Manuscript received 20 September 1999
© CSIRO 2000
10.1071/CH99119
0004-9425/00/070589

590
Short Communications
respectively (Scheme 1). On acidification, the silyl group is
other with a coupling constant of 3 Hz. Hence the structure
was assigned as 5,6-dehydrokawain (6). Further evidence
came from the infrared spectral frequencies of 1400, 1585,
1605, 1645 and 1710 cm–1. Compound (6) was first isolated
from the wood of Aniba firmula.12 It was, recently, isolated
from the seeds of Alpina blepharocalyx and reported to
strongly inhibit platelet aggregation induced by collagen
arachidonic acid.13,14
1
lost to give (4) and (5). Their H n.m.r. spectra showed the
presence of a methylene group and two vinylic protons
(pyrone protons). The latter are coupled to each other with a
coupling constant of 3 Hz. Compound (4) is the methyl ether
of the natural product tetraacetic acid lactone. It has been
isolated during studies on Penicillium stipitatum cultures.9
The importance of compounds (4) and (5) in the biomimetic
synthesis of polyketide-type aromatic compounds has also
been mentioned in the literature.9–11
Table 1. 13C n.m.r. spectral data, recorded at –70°C, of compound
(1d) and the extended enolate (1e)
After the extended enolate (1e) was quenched with ben-
zaldehyde at –120°C and the reaction worked up in acid
medium, a crystalline compound (6) was obtained in 52%
Cpd
C 2
C 4
C 6
C 3
C 5
C 8
C 7
C 9
1
yield. The H n.m.r. spectrum of this compound showed,
(1d) 175.2 164.5 164.4 96.4 93.6
54.8 19.0 –1.1
(1e) 169.2 168.0 161.2 75.2
—
52.8 68.9 0.2
beside the aromatic protons, vinylic hydrogens at ␦ 6.95, 1H,
d, and 7.40, 1H, d, the coupling constant being 15 Hz, indi-
cating that the two hydrogens are trans oriented. The n.m.r.
spectrum also showed pyrone protons at typical chemical
shifts, i.e., ␦ 5.55, 1H, d, and 6.15, 1H, d, coupled to each
In conclusion, this investigation has solved the following
chemical problems. Firstly an understanding of the relative
activities of the various sites of triacetic acid lactone methyl
ether (1a) towards strong bases is now established, particu-
larly at C 3 and C 7. Secondly, the reaction conditions
employed for the preparation of the silylpyrone (1d) in high
yields have been improved. Thirdly, and more importantly,
this work has established a new and easy method for the gen-
eration and synthetic use of the extended enolate (1e).
Experimental
Melting points were recorded on a Kofler hot-stage apparatus and
are uncorrected. Infrared spectra (KBr) were measured on
a
Perkin–Elmer 297 instrument. 1H and 13C n.m.r. spectra were recorded
on a Varian EM-360, CFT20, or XL-100 spectrometer. Chemical shifts
are expressed in ␦ values (ppm) relative to tetramethylsilane as the
internal reference standard; coupling constants (J) are given in Hz.
Mass spectra were recorded on AEI MS 50 and MS 30 spectrometers.
Ultraviolet spectra were recorded on a Pye Unicam SP-8-100 spec-
trophotometer. Tetrahydrofuran was refluxed over and distilled from
lithium aluminium hydride and stored over sodium wire, under an
atmosphere of argon. Chlorotrimethylsilane was distilled twice and
then treated with triethylamine and centrifuged. It was stored over
lithium hydride under an atmosphere of nitrogen. Acetyl chloride was
refluxed with phosphorus pentachloride for several hours and distilled.
It was then distilled from 1/10 its volume of dimethylamine. Benzoyl
chloride in benzene solution was washed several times with cold
aqueous potassium carbonate solution. The solution was then dried
over calcium chloride and distilled. Benzaldehyde was washed several
times with 10% aqueous sodium carbonate, then with saturated sodium
sulfite solution and then with water. It was dried over magnesium
sulfate and distilled under reduced pressure under an atmosphere of
nitrogen. Sodium hydride and potassium hydride were obtained as 50%
suspensions in oil, and were washed with n-hexane and tetrahydrofuran
to remove the oil prior to use. Preparative thin-layer chromatography
(p.l.c.) was carried out on 1 mm silica plates (Merck 60 PF254). The
following mixtures were used for cooling: 0°C, ice and water; –4°C,
salted ice/water; from –10 to –15°C, ice/methanol; –78°C, dry
ice/acetone; –120°C, liquid nitrogen/diethyl ether.
4-Methoxy-6-methyl-3-trimethylsilyl-2H-pyran-2-one (1d)
Method A. Triacetic acid lactone methyl ether (1a) (140 mg, 1
mmol) in tetrahydrofuran (10 ml) in a flask fitted with a serum cap,
flushed with nitrogen and cooled to –120°C, was transferred by means
of a double-ended needle to a flask containing lithium diisopropyl-
amide (1 mmol) in tetrahydrofuran (10 ml) cooled to –120°C. After a
few minutes, chlorotrimethylsilane (0.20 ml, excess) was added and the
reaction mixture left to warm to room temperature. Saturated potassium

Short Communications
591
hydrogen carbonate (10 ml) was then added and the reaction mixture
extracted with ether. The ethereal solution was dried over sodium
sulfate and evaporated to dryness in vacuum. P.l.c. (ether/light
petroleum 1: 1) afforded, beside unreacted (1a), a colourless crystalline
solid (1d) (84 mg, 40%), m.p. 77°C (lit.8 76–78°C). 1H n.m.r. (CDCl3)
␦ 0.02, s, 9H; 2.25, s, 3H; 3.90, s, 3H; 5.80, s, 1H. I.r. (cm–1) 1695, 1645,
1565.
5,6-Dehydrokawain (6)
Lithium diisopropylamide (1 mmol) in tetrahydrofuran was cooled
to –78°C and transferred by means of a double-ended needle to a solu-
tion of the silylpyrone (1d) (212 mg, 1 mmol) in tetrahydrofuran (10 ml)
in a flask fitted with a serum cap and cooled to –120°C under a nitrogen
atmosphere. After a few minutes dry benzaldehyde (0.1 ml, excess) was
injected. The reaction mixture was left to warm slowly to room tem-
perature over 3 h. Dilute sulfuric acid (5%, 20 ml) was added and the
reaction mixture was extracted with ethyl acetate (3×20 ml). The com-
bined organic extracts were dried over anhydrous magnesium sulfate
and the solvent was evaporated in vacuum. The product was purified by
p.l.c. (ether/light petroleum 1: 1), affording colourless needles of (6)
(118 mg, 51%), m.p. 139°C (lit.12 140°C). 1H n.m.r. ␦ 3.75, 3H, s; 5.55,
1H, d, J 3 Hz; 6.15, 1H, d, J 3 Hz; 6.95, 1H, d, J 15 Hz; 7.40, 1H, d, J
15 Hz; 7.37–7.66, 5H, m. I.r. (cm–1) 1710, 1645, 1605, 1585, 1455,
1400. U.v. ␭max 343, 255, 230 nm.
Method B. Triacetic acid lactone methyl ether (1) (140 mg, 1
mmol) was dissolved in tetrahydrofuran (100 ml) in a flask flushed with
nitrogen and cooled to –120°C. Methyllithium (0.60 ml, 1 mmol) was
added and the reaction mixture instantly turned a faint yellow colour.
After 1–2 min chlorotrimethylsilane (0.20 ml, excess) was injected. The
reaction mixture was then maintained at –78°C. A saturated solution of
potassium bicarbonate was added and the reaction mixture left to warm
to room temperature. It was then extracted into ether (3×15 ml) and the
ethereal solution dried over sodium sulfate and decolorized by charcoal.
The solvent was then evaporated in vacuum and purified by p.l.c. (same
solvent mixture as before) to give colourless needles of (1d) (184 mg,
92%), m.p. 77°C (lit.8 76–78°C). Spectral data were the same as those
recorded for this compound in the previous experiment.
Acknowledgments
The authors would like to acknowledge the British
Council, the University of Asmara and the International
Science Program (ISP, Sweden) for research grants. Thanks
are due to Professor Stefan Sjoberg, Uppsala University, for
his suggestions. The authors state their appreciation to
Professor Jim Staunton, Cambridge University (U.K.), for
his guidance.
4-Methoxy-6-(2-oxopropyl)-2H-pyran-2-one (4)
A solution of lithium diisopropylamide (0.50 mmol) was cooled to
–78°C and transferred by means of a double-ended needle to a flask
containing a solution of the silylpyrone (1d) (106 mg, 0.50 mmol) in
tetrahydrofuran (5 ml) at –120°C and kept under a nitrogen atmosphere.
After a few minutes dry acetyl chloride (0.1 ml, excess) was injected.
The reaction mixture was left to stir for 10 min at –120°C and then
warmed to –78°C. Dilute sulfuric acid solution (2%, 10 ml) was then
added. The reaction mixture was then extracted with ethyl acetate (3×15
ml); the solution was dried over anhydrous magnesium sulfate and
evaporated in vacuum. Recrystallization from methanol gave colourless
crystals (58 mg, 64%), m.p. 80–83°C (lit.9 83°C). 1H n.m.r., ␦ 2.20, 3H,
s; 3.45, 2H, s; 3.70, 3H, s; 5.40, 1H, d, J 3 Hz; 5.58, 1H, d, J 3 Hz. I.r.
(cm–1) 1720, 1710, 1415. U.v. ␭max 282 nm.
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A solution of lithium diisopropylamide (0.50 mmol) was cooled to
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