A novel oxidative rearrangement of 6-methoxypyran-2-ones

Article abstract of DOI:10.1021/ol0513490

(Chemical Equation Presented) As part of our continuing studies of pyrone-containing natural products, a series 6-methoxypyran-2-ones were synthesized. These were found to react with molecular oxygen at 20°C, and this novel reaction yielded a series of hi

Full text of DOI:10.1021/ol0513490

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3705-3707
A Novel Oxidative Rearrangement of
6-Methoxypyran-2-ones
Serena J. Eade, Robert M. Adlington, Andrew R. Cowley, Magnus W. Walter,† and
Jack E. Baldwin*
Chemistry Research Laboratory, UniVersity of Oxford, Mansfield Road,
Oxford OX1 3TA, U.K., and Lilly Research Centre, Erl Wood Manor,
Windlesham, Surrey GU20 6PH, U.K.
jack.baldwin@chem.ox.ac.uk
Received June 9, 2005
ABSTRACT
As part of our continuing studies of pyrone-containing natural products, a series 6-methoxypyran-2-ones were synthesized. These were found
to react with molecular oxygen at 20 C, and this novel reaction yielded a series of highly functionalized -butenolides.
°
r,â
In our studies of pyrones and the synthesis of pyrone-
polyene natural products so far,1 we have achieved the
synthesis of cyercene A,2 9,10-deoxytridachione,3 aureothin,4
spectinabilin, and the SNF compounds.5 In the course of this
work, solid 4-hydroxy-6-methoxy-3,5-dimethyl-2H-pyran-
2-one 1 was synthesized by carboxylation of the dianion of
methyl 2-methyl-3-oxopentanoate6 and subsequent TFAA
activation and cyclization of the resulting tricarbonyl7 to the
pyrone 1 (Scheme 1).
Scheme 1. Pyrone Functionalization and Oxidation
Reaction of 1 with sodium hydride and 4-toluenesulfonyl
chloride yielded the R-pyrone 2a as the sole product (Scheme
1). However, this compound was found to be unstable in
CDCl3 solution in the presence of molecular oxygen at rt
† Lilly Research Centre.
(1) Moses, J. E.; Baldwin, J. E.; Bru¨ckner, S.; Eade, S. J.; Adlington, R.
M. Org. Biomol. Chem. 2003, 1, 3670.
(2) Moses, J. E.; Baldwin, J. E.; Adlington, R. M. Tetrahedron Lett. 2004,
45, 6447.
(3) Moses, J. E.; Adlington, R. M.; Rodriguez, R.; Eade, S. J.; Baldwin,
J. E. Chem. Commun. 2005, 1687.
(4) Jacobsen, M. F.; Moses, J. E.; Adlington, R. M.; Baldwin, J. E. Org.
Lett. 2005, 7, 641.
(5) Jacobsen, M. F.; Moses, J. E.; Adlington, R. M.; Baldwin, J. E. Org.
Lett. 2005, 7, 2473.
(6) Sung, K.; Wu, S. Synth. Commun. 2001, 31, 3069.
(7) Cha, J. K.; Harris, T. M.; Ray, J. A.; Venkataraman, H. Tetrahedron
Lett. 1989, 30, 3505. Venkataraman, H.; Cha, J. K. Tetrahedron Lett. 1989,
30, 3509.
and underwent conversion to a new product 3a which,
according to mass spectrometry, contained one more oxygen
atom than the starting material. The analogous 4-bromoben-
zenesulfonyl compound 2b was likewise synthesized and
recrystallized in the absence of oxygen to confirm its identity
(Figure 1, Scheme 1).8
10.1021/ol0513490 CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/19/2005

Figure 1. X-ray crystal structures of R-pyrone 2b and R,â-butenolides 3b and 3f.
Again, upon exposure to molecular oxygen in CDCl3
solution at rt, 2b gave oxidized R,â-butenolide 3b whose
structure was proven by X-ray crystallography (Figure 1,
Scheme 1).8 Further functionalizations of 1 were carried out
using 4-nitrobenzenesulfonyl chloride and benzoyl chloride
to afford 2c and 2d, respectively, which once again could
be simply oxidized to 3c and 3d (Scheme 1).
polyesters via R-lactones has been reported by Bartlett.10 We
therefore propose that the unusual oxidation mechanism
Scheme 2. Pyrone Scrambling Observed by Cha et al.7
Reaction of pyrone 1 with 2,4,6-triisopropylbenzene-
sulfonyl chloride gave two products: R-pyrone 2e, which
underwent oxidation to 3e, and γ-pyrone 4e, which was
stable in the presence of oxygen (Scheme 1). Methylation
of pyrone 1 with dimethyl sulfate similarly afforded R-pyrone
2f and γ-pyrone 4f. Compound 2f was oxidized to yield R,â-
butenolide 3f (Figure 1, Scheme 1).8 These results are
summarized in Table 1. Some similar 3-methoxy R,â-
butenolides were synthesized by Pelter et al. in their studies
of synthetic routes toward piperolides, fadyenolides, ep-
oxypiperolides, and related compounds.9
The solid 4-hydroxypyrone starting material 1 was also
observed to undergo slow oxidation in air (and in the
presence of molecular oxygen) in the absence of solvent over
2 months, yielding 3g. Reaction of 3g with NaH and
4-bromobenzenesulfonyl chloride yielded previously syn-
thesized 3b.
Cha et al.7 have previously reported scrambling of similar
6-methoxy-2H-pyran-2-ones pyrones via ring opening of
R-pyrones to form ketenes (Scheme 2). They also carried
out corresponding isotope labeling experiments to confirm
the intramolecular nature of the migration of the methoxy
group, as well as carrying out ketene-trapping experiments.7
In addition, the autoxidation of diphenylketene to form
proceeds first via a 6π thermal electrocyclic ring opening
of 2 to ketene 5, consistent with the observations of Cha et
al.7 (Scheme 3). This is followed by a radical reaction with
molecular oxygen in its triplet ground state and subsequent
reaction of 6 with a second molecule of the ketene to form
a dimeric species 7 which then collapses to R-lactone 8,
consistent with the results of Bartlett et al.10 However, unlike
in previous work, R-lactone 8 contains an intramolecular trap
Table 1. Reagents, Substituents, and Products of Functionalization and Oxidation
R
electrophile (Scheme 1)
R-pyrone 2
yield (%)
R,â-butenolide 3
yield (%)
γ-pyrone 4
yield (%)
4-MeC6H4SO2-
4-BrC6H4SO2-
4-NO2C6H4SO2-
C(O)Ph
2,4,6-(i-Pr)3C6H2SO2-
Me
4-MeC6H4SO2Cl
4-BrC6H4SO2Cl
4-NO2C6H4SO2Cl
Ph C(O)Cl
2,4,6-(i-Pr)3C6H2SO2Cl
Me2SO4
2a
2b
2c
2d
2e
2f
79
63
58
44
69
39
3a
3b
3c
3d
3e
3f
53
45
40
52
61
61
35
4e
4f
15
37
H
1
3g
3706
Org. Lett., Vol. 7, No. 17, 2005

Scheme 3. Proposed Mechanism for Conversion from R-Pyrone 2 to R,â-Butenolide 3
and thus R,â-butenolide 3 is formed in an analogous manner
In conclusion, we have found a novel oxidative reaction
of R-pyrones enabling facile synthesis of a variety of highly
functionalized 3-substituted R,â-butenolides.
to the conversion of a vinylcyclopropane to a cyclopentene,
via a [1,3] sigmatropic migration which could alternatively
be considered as an internal [π2 +σ2] cycloaddition. An
alternative mechanism in which conversion of the resonance
form of 7 to 3 directly without an intermediate R-lactone 8
is also possible. The stability of γ-pyrones 4e and 4f in the
presence of oxygen supports the mechanism since ring
opening of γ-pyrones to ketenes is not possible.
Acknowledgment. We thank Tim Claridge and Barbara
Odell for NMR assistance, the O’Hare group, Luke McNeill,
and Hermann Wegner. S.J.E. thanks the EPSRC for funding
and Eli Lilly Ltd. for CASE support.
To confirm the position of the oxygen atom in the oxidized
product originating from molecular oxygen, the oxidation
of 2f was carried out in the presence of 18O2. This afforded
18O-3f whose observed isotope shifts in the 13C NMR
spectrum (Figure 2) confirmed that the oxygen atom had been
incorporated into the ring.11
Supporting Information Available: Experimental pro-
cedure for the preparation of 1, general experimental
procedures for the preparation of 2-4, and associated
spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0513490
(8) CCDC 274197 contains the supplementary crystallographic data for
compound 2b, CCDC 274198 for 3b, and CCDC 274199 for 3f, respectively.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
(9) (a) Pelter, A.; Al-Bayati, R.; Lewis, W. Tetrahedron Lett. 1982, 23,
353. (b) Pelter, A.; Al-Bayati, R. Tetrahedron Lett. 1982, 23, 5229. (c)
Pelter, A.; Al-Bayati, R. I. H.; Ayoub, M. T.; Lewis, W.; Pardasani, P.;
Hansel, R. J. Chem. Soc., Perkin Trans. 1 1987, 717.
(10) Bartlett, P. D.; McCluney, R. E. J. Org. Chem. 1983, 48, 4165.
(11) For analogous 18O shifts of 13C signals and theory, see: (a) Hansen,
P. E. Ann. Rep. NMR Spectrosc. 1983, 15, 106. (b) Batiz-Hernandez, H.;
Bernheim, R. A. Prog. NMR. Spectrosc. 1967, 3, 63. (c) Jameson, C. J.
Bull. Magn. Reson. 1981, 3, 3.
Figure 2. Isotope shifts in the 13C NMR spectrum of 18O-3f.
Org. Lett., Vol. 7, No. 17, 2005
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