Synthesis of functionalised cyclopentenones via rearrangement of pyranones

Article abstract of DOI:10.1016/S0040-4039(00)01043-1

Substituted functionalised cyclopentenones could be obtained via base-mediated isomerisation of pyranones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01043-1

Tetrahedron Letters 41 (2000) 6879±6882
Synthesis of functionalised cyclopentenones via
rearrangement of pyranones
Stephen Caddick,a,* Steven Cheung,a Lisa M. Frost,a Safraz Khana
and Garry Pairaudeaub
aThe Chemistry Laboratory, University of Sussex, Falmer, Brighton BN1 9QJ, UK
bDepartment of Medicinal Chemistry, AstraZeneca R & D Charnwood, Bakewell Rd, Loughborough LE11 5RH, UK
Received 22 May 2000; accepted 20 June 2000
Abstract
Substituted functionalised cyclopentenones could be obtained via base-mediated isomerisation of
pyranones. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: pyranone; cyclopentenone; rearrangement; isomerisation.
During our investigation into the dienediyne anticancer antibiotics1 we required a practical
synthetic approach to functionalised cyclopentenone derivatives. We were particularly attracted
to a seminal report which showed the isomerisation reaction of a pyranone to a dihydroxylated
cyclopentenone derivative.2 We were able to devise a modi®ed procedure, which could be carried
out on preparative scale (ca. 30 g) without the requirement of metal catalysts using only an amine
base.3 In this report we make observations on this isomerisation reaction, and describe the
synthesis and isomerisation of C-2 substituted pyranones.
Pyranones 3 can be prepared from furan derivatives 1 using the sequence shown below,4 which
can be carried out on large scale (50±100 g scale, Scheme 1).
Scheme 1.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01043-1

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A study on the rearrangement of pyranones 3 is presented in Table 1. Our early work on the
parent pyranone 3a is noteworthy because it can deliver good quantities of substituted
cyclopentenones under basic conditions (entry 1). Intriguingly, the conditions used are
reminiscent of those used by a number of workers to generate oxidopyrilium species from related
acetoxy pyranone derivatives (i.e. 2).5 It is clear that the reactivity of a pyranone is sensitive to
substrate structure and/or reaction conditions. Consistent with this hypothesis is our ®nding that
the nature of the amine base can have a profound and detrimental impact on the reactivity of
pyranone 3a (entries 2, 3). Further to this observation is that solvent can a€ect the reaction and
we discovered that performing the reaction in methanol led to the isolation of product 5 (entry 4),
which we assume is derived from isomerisation of the initially formed cyclopentenone 4a. In
order to further support this assumption we stirred cyclopentenone 4a with Et3N and obtained 5
(entry 5). In order to extend this methodology we embarked upon a study on the isomerisation of
C-2 substituted pyranone derivatives 3b±d. We felt that this would be a considerable test of our
protocol, particularly in view of the lack of similar transformations in the literature. Indeed the
early report describing related work suggested that isomerisation of this type could not be
extended to C-2 substituted pyranones.2 In agreement with these early reports we found that the
isomerisation of precursors 3b±d were disappointing; despite numerous attempts we were unable
to promote ecient isomerisation using standard base, DMF reaction conditions (entries 6, 7 and
8). However, we were delighted to ®nd that simply changing from DMF to MeOH as the reaction
solvent gave the isomerisation products 4b±d in moderate to good yield (entries 9±11).
Table 1
Base-mediated isomerisation reaction of substituted pyranones

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One of the diculties associated with developing this methodology is the characterisation of
the isomerised products and the stereochemical outcome can only convincingly be corroborated
using X-ray crystallography. We have con®rmed the structure of 4b by X-ray crystallography and
by analogy we tentatively assign the other adducts as possessing the trans arrangement of the
two-hydroxyl groups (Fig. 1).
Figure 1. Cyclopentenone 4b
In mechanistic terms one could envisage at least three distinct pathways for this transformation:
. cyclisation of an intermediate 30 formed by electrocyclic ring opening of an enol derived
from 3;
. 1,2-Wittig rearrangement invoking biradical 300;6 and
. cyclisation to give epoxide 3000 followed by nucleophilic ring opening.7
Of these three possibilities the intermediate epoxide 3000 is least likely given the success of the
isomerisations in methanol. Further work will be required to further delineate the mechanistic
features of this rearrangement.
In conclusion, we have shown that the appropriate choice of reaction condition can lead to
base-mediated isomerisation of pyranones to cyclopentenones. We have shown that by careful
choice of the reaction conditions we can extend this protocol to prepare C-2 substituted
cyclopentenones which have not previously been synthesised and which have not previously been
accessible using this or any other related methodologies.8 The synthetic value of these highly
functionalised cyclopentane derivatives is yet to be rigorously established. However, given the
number of academic and industrially interesting cyclopentanoid compounds, we envisage this
methodology ®nding application in synthesis.9
Acknowledgements
We would like to thank AstraZeneca and the Association for International Cancer Research
(St Andrews, Scotland) for ®nancial support of this work. We also thank Drs Abdul Sada, Tony

6882
Avent and Peter Hitchcock for their assistance. Additionally, we acknowledge the EPSRC mass
spectrometry service at Swansea.
References
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1989, 30, 4489.
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4. Products were isolated as inseperable mixtures of diastereoisomers (d.e.s variable and estimated by H NMR at
1
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8. For other elegant strategies for the synthesis of related compounds see: Raeppel, S.; Toussaint, D.; Su€ert, J.
Synlett 1997, 1061; Toyama, K.; Iguchi, S.; Oishi, T.; Hirama, M. Synlett 1995, 1243; Johnson, C. R.; Nerurkar,
B. M.; Golebiowski, A.; Sundram, H.; Esker, J. L. J. Chem. Soc., Chem. Commun. 1995, 1139.
9. All compounds exhibited analytical and spectroscopic data consistent with their structures.