The clerodane ring system: Investigating the viability of a direct Diels-Alder approach

Article abstract of DOI:10.1039/c1ob05422h

A direct synthetic approach to the spiro-γ-lactone clerodane ring system has been investigated. This work builds on that of Jung and highlights the inherent difficulties associated with the otherwise obvious Diels-Alder approach. The Royal Society of Chem

Full text of DOI:10.1039/c1ob05422h

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The clerodane ring system: investigating the viability of a direct Diels–Alder
approach†
Andrew T. Merritt,a Rebecca H. Pouwer,b David J. Williams,c Craig M. Williams*b and Steven V. Ley*d
Received 17th March 2011, Accepted 27th April 2011
DOI: 10.1039/c1ob05422h
A direct synthetic approach to the spiro-c-lactone clerodane
ring system has been investigated. This work builds on that of
Jung and highlights the inherent difficulties associated with
the otherwise obvious Diels–Alder approach.
the authors have independently pursued total syntheses in this
area, with Ley achieving the total synthesis of ajugarin 56 and
Williams exploring an ambitious 6p-electrocyclisation as a general
route.7 During these pursuits both groups postulated that access
to the spiro-g-lactone sub-class might be more successful through
the direct application of a Diels–Alder (DA) reaction on densely
functionalised systems. Although Diels–Alder approaches to these
molecules have been utilised previously2–6,8 they were applied in
the early stages of the various synthetic strategies. We, however,
proposed a late stage DA reaction in which most of the required
functionality is delivered from a very advanced intermediate.
In fact we are not the first to propose such a strategy; Jung
reported9 that diene 8 and the phenyl allenic spiro-g-lactone 9
react to give 10 as a mixture of diastereomers. This method was not
further elaborated, presumably due to difficulties in accessing the
corresponding furano allenic spiro-g-lactone (Scheme 1). Based
on this premise we herein report studies in attempting to develop
an advanced intermediate based on the DA chemistry, poised to
access a number of clerodane natural products containing the
furanospiro-g-lactone moiety (i.e. montanin B 610 and teucrin A
711) (Fig. 1).
Clerodane natural products1 are a prolific family of biologically
active diterpenes numbering over a thousand. This series of natural
products has received comparatively little synthetic attention.2 For
example, only 4 total syntheses of clerodanes containing the spiro-
g-lactone moiety, a structural feature found in a large number of
all clerodane natural products isolated so far, have been reported
(i.e. teucvin 1,3 12-epi-teucvin 2,3 teuscorolide 3,4 montanin A 44)
(Fig. 1). Considering this apparent lack of synthetic attention and
the potential biological properties the clerodane systems offer5
aMedical Research Council Technology, 1–3 Burtonhole Lane, Mill Hill,
London, UK, NW7 1AD
bSchool of Chemistry and Molecular Biosciences, University of Queensland,
Brisbane, 4072, Queensland, Australia. E-mail: c.williams3@uq.edu.au
cChemical Crystallography Laboratory, Department of Chemistry, Imperial
College London, South Kensington, London, UK, SW7 2AZ
dDepartment of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK, CB2 1EW. E-mail: svl1000@cam.ac.uk
The approach to our desired target (12), although not grossly
dissimilar to that of Jung, has two significantly different chal-
lenges: 1) the questionable stability of the cis-furanospiro-g-
lactone 11 in terms of both access and reaction survival; and 2) the
† Electronic supplementary information (ESI) available. CCDC reference
numbers 814882. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob05422h
Fig. 1
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Scheme 1
Scheme 3
change in both electronic and steric demand of 11 compared to
allenic lactone 9 (Scheme 1). With this in mind the initial objective
was to test the viability of the Diels–Alder reaction with two model
dienophiles (i.e. 13 and 14), which would also give an indication
with respect to the availability and stability of 11.
Compound 13 was rapidly obtained in 90% yield via sonication
of methyl a-methylacrylate with 3-furaldehyde in the presence of
zinc,12 whereas compound 14 was accessed utilising the work of
Yamamoto13 via anti-elimination of aldol product 15 derived from
16 (Scheme 2).
Fig. 2 The molecular structure of 18.
separate variations starting from lactone 21,15 obtained from 3-
bromopropionic acid and 3-furaldehyde in 41% yield (Scheme
4). Pleasingly, following the Yamamoto route lactone 21 was
converted into 22 and subjected to elimination giving 11 in
42% yield over three steps. In an attempt to limit steps and
increase yield, lactone 21 was silylated (i.e. 23) and subjected to
a Peterson type olefination, which unfortunately did not lead to
an improvement in overall yield (Scheme 4). Again, like lactone
13, it was a pleasant surprise to observe that the cis-furanospiro-
g-lactone 11 was not as sensitive as first anticipated.
Scheme 2
Diels–Alder reactions with diene (8) and the corresponding
TMS derivative 17 involving both dienophiles 13 and 14 were
next investigated (Scheme 3). Surprisingly, attempts to drive the
reaction between 13 and 17 using Lewis acids completed failed,
even though stability studies involving the exposure of 13 to a
variety of Lewis acids at low and room temperature suggested
acceptable stability. It was not until heating at 130 ◦C in a
presilylated glass pressure vessel was adduct 18 obtained in 31%
yield (via treatment of 19 with hydrochloric acid). Fortuitously 18
was attained as the sole cis-decalin diastereomer as observed by
X-ray crystal structure analysis (Fig. 2). All attempts to enhance
the yield of the DA reaction using ultra high pressure and higher
temperature conditions were unsuccessful.
With the knowledge that 13 is sufficiently stable and undergoes
the DA reaction with excellent stereochemical control, together
with the observation that the trisubstituted system 14 also
undergoes reaction (albeit with limited stereocontrol), a synthesis
of cis-furanospiro-g-lactone 11 was sought. Unfortunately the
method used for 13 was not applicable to 11 as supported by
Loffler.14 Thus the method used for 14 was explored in two
Scheme 4
Having successfully obtained 11 in workable quantities the key
DA reaction with diene 8 could now be probed. Again, reaction
in the presence of Lewis acids returned starting material. Heating,
however, at 135 ◦C in a presilylated glass pressure vessel for
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90 h produced 24 in 46% yield as a mixture of 3 inseparable
diastereomers in a ratio of 6 : 3 : 1 (GC). Desilylation (protolysis)
did not improve the stereochemical outcome, however, treatment
of the mixture (i.e. 24) with phenylselenyl chloride afforded pure
25 as the major compound. Unfortunately, elimination using a
variety of oxidation–elimination protocols consistently gave a 1 : 3
ratio of enones 26 and 27, with the desired advanced intermediate
26 being obtained in only 13% yield (Scheme 5).
most of the functionality required for the spiro-g-lactone clerodane
ring system can be obtained via a direct Diels–Alder approach. The
likelihood of this approach being viable is, however, questionable
due to issues associated with stereocontrol most likely arising
from the methyl substituent contained with dienophile 11. Finally,
rapid access to the clerodane system remains elusive, requiring
new innovative strategies to facilitate syntheses in an acceptable
number of steps.
Acknowledgements
The authors thank the EPSRC (UK), Imperial College London,
the University of Cambridge and The University of Queensland
for financial support. Special thanks to Dr Andrew J. P. White
(Chemical Crystallography Laboratory, Department of Chem-
istry, Imperial College London, UK) for assistance with X-ray
crystal data.
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