Studies towards the synthesis of diazonamide A. Synthesis of a tyrosine-derived benzofuranone

Article abstract of DOI:10.1016/S0040-4039(00)01118-7

The benzofuranone 2, a potential intermediate for the synthesis of the marine natural product diazonamide A 1, has been synthesised in eight steps from the N-protected tyrosine ester 3. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01118-7

Tetrahedron Letters 41 (2000) 6893±6896
Studies towards the synthesis of diazonamide A.
Synthesis of a tyrosine-derived benzofuranone
Franck Lach and Christopher J. Moody*
School of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
Received 24 May 2000; accepted 29 June 2000
Abstract
The benzofuranone 2, a potential intermediate for the synthesis of the marine natural product diazonamide
A 1, has been synthesised in eight steps from the N-protected tyrosine ester 3. # 2000 Elsevier Science Ltd.
All rights reserved.
Keywords: Stille reaction; Claisen rearrangement; lactones.
Diazonamide A 1, a structurally unique secondary metabolite isolated from the colonial ascidian
Diazona chinensis, is reported to have potent in vitro cytotoxic activity against human and murine
tumour cell lines.1 The structure of the natural product, which was assigned on the basis of an
X-ray crystal structure of a closely related derivative,1 comprises a complex arrangement of aromatic
and heteroaromatic rings linked either directly as biaryls or via an intermediate quaternary centre
or peptide bonds, in a macrocyclic array. These unusual structural features and the interesting
biological activity have combined to make diazonamide A an extremely attractive target for
synthesis, and several groups, including our own, have reported a range of approaches to various
structural subunits of the natural product.2 14 We now report the synthesis of the tyrosine-derived
benzofuranone 2 by a route which involves a Claisen rearrangement as a key step.
* Corresponding author. E-mail: c.j.moody@ex.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01118-7

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Benzofuranone 2 was selected as a potential precursor to diazonamide A 1 on the basis that it
not only contains the required tyrosine unit (in protected form), but also a bromine at C-7
(benzofuran numbering) which will allow transition-metal catalysed sp2±sp2 coupling to form the
biaryl bond to the 4-position of an appropriate indole at a later stage in the synthesis. Addition-
ally, the use of Black's C-acylation procedure,15 should allow the introduction of an additional
carbon substituent at the 3-position of the benzofuran, the eventual C-10 quaternary centre in
diazonamide A. This C-acylation procedure was used in a simple benzofuranone in our early
preliminary studies,2,4 and also very recently by Vedejs in his approach to a fragment of
diazonamide A.12
The starting material for the synthesis of the benzofuranone 2 was the known N-benzyloxy-
carbonyl tyrosine tert-butyl ester 3.16 ortho-Iodination of the phenol was achieved under neutral
conditions using chloramine-T/sodium iodide.17 The ortho-iodophenol was not puri®ed, but
immediately O-alkylated under conditions known to minimise racemisation18 to give the benzyl
ether 4 in 60% yield over the two steps (Scheme 1). After considerable experimentation, it was
Scheme 1.

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found that the palladium-catalysed coupling of the iodotyrosine derivative 4 with allyl alcohol,
under the conditions developed by Je€ery to prevent subsequent isomerisation of the double
bond,19 gave the required cinnamyl alcohol derivative 6 but in modest yield (30±35%). Therefore,
we resorted to a Stille coupling of the iodide 4 with the tri-n-butylstannyl allyl alcohol 5, prepared
from propargyl alcohol,20 22 and this gave the cinnamyl alcohol 6 in excellent yield (91%).
Conversion into the allylic bromide 7 without any isomerisation of the double bond, was
followed by reaction with 2-bromophenol using sodium hydroxide as base under phase transfer
conditions to give the cinnamyl aryl ether 8. This substrate underwent Claisen rearrangement on
heating under re¯ux in DMF to give the phenol 9 as a mixture of diastereomers. Reaction of
alkene 9 with catalytic osmium tetroxide with potassium periodate as co-oxidant resulted in
oxidative cleavage of the double bond, and cyclisation of the intermediate aldehyde to the lactol
10. Oxidation of the lactol 10 to the desired lactone 2 proved surprisingly dicult, and a number
of commonly used reagents (PCC, PDC, Fetizon's reagent, Swern conditions) failed to e€ect this
transformation. Eventually it was found that the iodinane oxide 11,23 a reagent reported by
Grieco et al. to be useful for similar oxidations,24 converted the lactol 10 into the required lactone
2 in 83% yield (Scheme 1).
Thus the benzofuranone 2, a potential intermediate in the synthesis of diazonamide A, has
been prepared in eight steps from the N-protected tyrosine ester 3. Although obtained as a
mixture of diastereomers, the introduction of the additional carbon substituent at C-3 (benzofuran
numbering) and hence generation of the C-10 quaternary centre in diazonamide will involve
C-acylation and an sp2-hybridised intermediate at this centre (cf. Ref. 2, 4 and 12); experiments
along these lines are in progress.
Acknowledgements
We thank the Association pour la Recherche contre le Cancer for a fellowship (to F.L.), and
the EPSRC Mass Spectrometry Centre at Swansea for mass spectra.
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