Synthesis of a C1-C9 fragment of rhizoxin

Article abstract of DOI:10.1016/S0040-4039(00)01337-X

A C1-C9 fragment of the antitumour macrolide rhizoxin has been synthesised. An Evans' asymmetric aldol reaction was used to set up the first two chiral centres, and an α,β-unsaturated δ-lactone was then formed on the acyclic system by an intramolecular Wadsworth-Emmons reaction. Stereoselective hydrogenation was used to set up the cis relative stereochemistry in the saturated δ-lactone ring. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01337-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7619–7622
Synthesis of a C1–C9 fragment of rhizoxin
Richard J. Davenport and Andrew C. Regan*
Department of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 2 August 2000; accepted 7 August 2000
Abstract
A C1–C9 fragment of the antitumour macrolide rhizoxin has been synthesised. An Evans’ asymmetric
aldol reaction was used to set up the first two chiral centres, and an a,b-unsaturated d-lactone was then
formed on the acyclic system by an intramolecular Wadsworth–Emmons reaction. Stereoselective hydro-
genation was used to set up the cis relative stereochemistry in the saturated d-lactone ring. © 2000
Published by Elsevier Science Ltd.
Rhizoxin 1, a macrolide isolated from Rhizopus chinensis in 1984,1 has a 16-membered
macrocyclic ring structure, which also unusually bears two epoxides, and a d-lactone at C5–C7.
Rhizoxin has antitumour activity, and acts as an antimitotic agent by binding to tubulin.2 It has
recently undergone clinical trials for a variety of cancers.3 The didesepoxy macrolide rhizoxin D
2 is a putative biosynthetic precursor of rhizoxin.4 Not surprisingly, in view of its biological
activity and structural complexity, rhizoxin has attracted considerable synthetic interest,5 and
both rhizoxin6 and rhizoxin D7 have recently been synthesised.
Scheme 1.
* Corresponding author. Fax: +44 161 275 4617; e-mail: andrew.regan@man.ac.uk
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01337-X

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The retrosynthetic analysis for our planned synthesis of rhizoxin is shown in Schemes 1 and
2. Disconnection of the macrolide ring in 2 at the CꢀO bond of the lactone and at the C9–C10
alkene gives the two fragments 3 and 4. A similar disconnection strategy has also been used by
other groups.5b,d,h,6,7c Our approach to the C1–C9 fragment 4 is based upon formation of the
5,7-cis stereochemistry about the d-lactone by stereoselective hydrogenation of a suitable
a,b-unsaturated lactone, which in turn will be created by an intramolecular Wadsworth–
Emmons ring closure. The two stereogenic centres in the acyclic precursor will be formed using
an Evans’ asymmetric aldol reaction on the protected aldehyde 9 (Scheme 3).
Scheme 2.
Scheme 3.
Dimethyl acetonedicarboxylate 5 was chosen as the starting material for the preparation of
aldehyde 9, since it already contains a five-carbon chain with the required 1,3,5-oxygenation
pattern. The ethylene ketal 6 was prepared in conventional manner (Scheme 3), and the two
ester groups were then reduced to primary alcohols using lithium aluminium hydride. Monopro-
tection of the resulting diol 7 afforded the monobenzyl ether 8 in a greater than statistically
expected yield of 76%. Finally the remaining hydroxyl group was oxidised using the Dess–
Martin periodinane8 to give the aldehyde 9.
An Evans’ asymmetric aldol reaction9 between the N-propionyloxazolidinone 10 and aldehyde
9 was then used to set up the first two chiral centres at C7 and C8 in 11 (Scheme 4). The aldol
product 11 was formed as a single diastereoisomer, as judged by 500 MHz 1H NMR
spectroscopy, and the 7,8-syn relationship was confirmed by the small vicinal coupling constant
of 5 Hz. The chiral auxiliary was removed by reduction with LiBH4 to give the diol 12, which
was then selectively protected on the primary alcohol group as the tert-butyldiphenylsilyl ether.
The remaining secondary alcohol group in 13 was then converted into the diethyl phosphono-
acetate ester 14 using a carbodiimide coupling, and the ethylene ketal protecting group was
selectively removed with FeCl3 on silica gel,10 to give the ketone 15. Intramolecular Wadsworth–
Emmons reaction11 of 15 using sodium hydride as the base then gave the unsaturated lactone 16

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in 67% yield (91% based on unrecovered starting material), whereas the combination of lithium
halide salts and amine bases resulted in substantial amounts of b-elimination.
Scheme 4.
Stereoselective hydrogenation of the unsaturated lactone 16 gave exclusively the cis-disubsti-
tuted lactone 17, and the stereochemistry was confirmed by observation of the expected large
trans-diaxial coupling constants.12 The benzyl protecting group on the side chain had been
chosen from the outset in order that it would also be removed during this hydrogenation step.
The primary alcohol group thus revealed in 17 was oxidised to the aldehyde 18 using the
Dess–Martin periodinane, and the side chain was then extended in a Wadsworth–Emmons
reaction, to give the E-a,b-unsaturated ester 19. Finally, deprotection of the silyl group afforded
the target C1–C9 fragment 4 of rhizoxin.
In summary an efficient route to a C1–C9 fragment of rhizoxin has been developed (13 steps,
24% overall yield to the protected fragment 19), which compares well with other approaches to
related C1–C9 intermediates.

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Acknowledgements
We thank the EPSRC for a studentship (to R.J.D.).
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