Efficient two directional syntheses of a homophthalate ester and novel resorcylate oligomers

Article abstract of DOI:10.1016/j.tetlet.2011.01.100

Thermolysis of 6,6′-(2-oxopropane-1,3-diyl)bis(2,2-dimethyl-4H-1,3- dioxin-4-one) in the presence of methanol gave a triketo-ester which subsequently aromatized to provide a synthetically useful homophthalate ester. Enolate C-acylation in the presence of diethylzinc was used to synthesize other double diketo-dioxinones, which on cyclization, aromatization and dioxinone ring opening gave novel double resorcylate derivatives.

Full text of DOI:10.1016/j.tetlet.2011.01.100

Tetrahedron Letters 52 (2011) 2258–2261
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient two directional syntheses of a homophthalate ester and novel
resorcylate oligomers
Bhavesh H. Patel a, Scott F. A. Heath a, Andrew M. Mason b, Anthony G. M. Barrett a,
⇑
a Department of Chemistry, Imperial College, London SW7 2AZ, UK
b GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Thermolysis of 6,60-(2-oxopropane-1,3-diyl)bis(2,2-dimethyl-4H-1,3-dioxin-4-one) in the presence of
methanol gave a triketo-ester which subsequently aromatized to provide a synthetically useful homo-
phthalate ester. Enolate C-acylation in the presence of diethylzinc was used to synthesize other double
diketo-dioxinones, which on cyclization, aromatization and dioxinone ring opening gave novel double
resorcylate derivatives.
Article history:
Available online 1 February 2011
Keywords:
Resorcylate
Double dioxinone
Homophthalate ester
Aromatization
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Biomimetic syntheses of simple resorcylates were first reported
by Harris,6 and we have shown that functionalized diketo-dioxi-
Numerous biologically active natural products contain the b-
resorcylate unit 1,1 including the fungal metabolites W1278A–C
(2) in which the unit serves as the backbone (Fig. 1).2 These oli-
go-esters are antibiotics and possess activity against the influenza
A virus. We have recently reported the total syntheses of such nat-
nones 5 are ideal intermediates for this purpose. They can be aro-
matized either by thermolysis, ketene trapping and aldol reaction
and dehydration sequence to give resorcylates 6, or cyclized by
base mediated cycloaromatization to give isopropylidene pro-
tected resorcylates 7 (Scheme 1).7
Double dioxinones are intriguing building blocks for the two
directional syntheses of the target double resorcylates 4 and we
initially targeted the synthesis of homophthalate ester 8, an impor-
tant building block for the synthesis of DNA-binding ligands8 and
the total synthesis of other bioactive natural products.9 We consid-
ered that 8 should be available from double dioxinone 9 (Scheme
2), whereas the symmetrical double resorcylates 4 should be avail-
ural products,3 and marine antifungal agent 15G256
s
(3),4 which
were designed following consideration of their polyketide biosyn-
thesis.5 The symmetrical nature of these resorcylate structures
along with their interesting bioactivities lead us to undertake the
synthesis of novel resorcylate oligomers 4 with two resorcylic ester
entities linked by a generic bridge R.
Figure 1. b-Resorcylate unit 1, resorcylate antibiotic oligo-esters W1278A–C (2), resorcylate natural product 15G256s (3) and novel resorcylate oligomers 4.
⇑
Corresponding author. Tel.: +44 020 7594 5766; fax: +44 020 7594 5805.
E-mail address: agm.barrett@imperial.ac.uk (A.G.M. Barrett).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.100

B. H. Patel et al. / Tetrahedron Letters 52 (2011) 2258–2261
2259
Scheme 1. Two alternate transformations of diketo-dioxinones 5.
Scheme 3. Synthesis of double dioxinone 9 leading to homophthalate ester 8.
Our approach towards double diketo-dioxinones was based on
extending our previously reported use of Weinreb amides for
crossed Claisen condensation reactions.3 The symmetric diacids
14a–c were heated with 2-chloro-1,3-dimethyl-1H-imidazolium
chloride 15 to form the corresponding diacid chlorides12 which
were directly reacted with N,O-dimethylhydroxylammonium chlo-
ride 16 in the presence of base to give the desired double Weinreb
amides with 1,4-phenylene- 17a, trans-1,4-cyclo-hexylene- 17b
and 4,40-biphenylene- 17c linkers in 70–75% yield (Scheme 4).
Other commercially available diacid chlorides 18a,b were con-
verted in a similar fashion to the corresponding diamides with eth-
ylene- 17d and 2,6-pyridylene- 17e linkers in 77% and 84% yields,
respectively.
Keto-dioxinone 20 was synthesized on a 17 g scale by the Clais-
en condensation of the lithium enolate of 11 with acetyl chloride
Scheme 2. Retrosynthesis: resorcylates from double dioxinones.
able from double diketo-dioxinones 10. As such, we sought to find
a general, efficient and robust method for the synthesis of such
double dioxinones and their derived resorcylates. Herein we report
our initial studies in this area, which is notable for concise syn-
thetic sequences, two-directional synthesis and the absence of
any phenolic protection.
2. Results and discussion
A double Claisen condensation between the lithium enolate of
11 and bis(4-nitrophenyl) carbonate 12 in the presence of zinc
chloride10 provided double dioxinone 9 in 54% yield (Scheme 3).
Thermolytic retro-Diels–Alder reaction11 of 9 at 110 °C and ketene
trapping by methanol gave triketo-diester 13. Upon further heating
at 110 °C, 13 underwent cyclization and aromatization, giving res-
orcylate 8 in 95% yield.
This novel and convenient two-step synthesis provides the first
example of an acid and base free cyclization and aromatization
without the use of elevated pressure or drying agents. It also
underscores the value of dioxinones in controlling the regioselec-
tivity of biomimetic multi-keto-ester cyclization reactions to give
specific aromatic products.
Scheme 4. Synthesis of functionalized double Weinreb amides.

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B. H. Patel et al. / Tetrahedron Letters 52 (2011) 2258–2261
Scheme 5. Synthesis of novel resorcylate oligomers 4a–e.
19 (Scheme 5).13 Following on from our previous observations on
Claisen condensations of dioxinone derivatives, generation of the
dilithium enolate of 20, transmetallation with diethylzinc,14 and
reaction with diamides 14a–e gave the diketo-dioxinones 21a–
e.15 The incorporation of diethylzinc along with temperatures
above ꢀ10 °C was essential for complete consumption of the Wein-
reb amides. These successful extensions to dioxinone functionali-
zation presumably were the result of the reduction in basicity of
the enolate dianion from 20 through transmetallation with zinc(II).
It is also worth noting that of the diamides discussed, there are no
reported examples of double Claisen condensation reactions.
Compounds 21a–e proved to be slightly unstable and therefore
were directly subjected to double cyclization catalyzed by triethyl-
amine rather than thermolysis in methanol solution (Scheme 5).
The rates of these cyclization reactions were variable and the
course of reaction in each case was followed by 1H NMR spectros-
copy.16 The crude adducts 22a–e were directly methanolyzed in
the presence of cesium carbonate to provide the double resorcy-
lates 4a–e in 36–44% yield over the three steps.
This efficient and reproducible multi-step synthesis gave sev-
eral novel symmetrical resorcylate dimers (Fig. 2). Some of these
compounds portrayed significant and rather interesting physical
properties especially with regards to thermal stability and solubil-
ity. Double resorcylates 4a–c, all have melting points in the range
of 250–280 °C, and that of 4e is greater than 310 °C. Compound 4e
also did not readily dissolve in organic solvents except for DMSO.
In conclusion, we have shown that double dioxinones are useful
intermediates for the efficient two-step synthesis of 2,4-dihy-
droxy-homophthalates, and the four-step synthesis of double res-
orcylates. It should be possible to extend the methodology for
the synthesis of a wider range of resorcylates with additional struc-
tural complexity. Further applications of dioxinones in synthesis
will be reported in due course.
Figure 2. Structures of novel resorcylate oligomers synthesized and the associated
multi-step reaction yield.
grant support (to B.H.P.), and P. R. Haycock and R. N. Sheppard
(Imperial College) for high-resolution NMR spectroscopy.
Acknowledgements
Supplementary data
We thank GlaxoSmithKline for the generous endowment (to
A.G.M.B.), the Engineering and Physical Sciences Research Council
(EPSRC) Pharma Synthesis Programme and GlaxoSmithKline for
Supplementary (experimental procedures, characterization
data and copies of 1H and 13C NMR spectra for all new compounds)

B. H. Patel et al. / Tetrahedron Letters 52 (2011) 2258–2261
2261
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