Enantioselective total synthesis of ustiloxin D

Article abstract of DOI:10.1021/ja035429f

Ustiloxin D and phomopsin A are potent antimitotic agents that bind to tubulin and interfere with cellular microtubule function. A synthetic strategy has been developed to allow access to both of the natural products as well as a variety of variants of th

Full text of DOI:10.1021/ja035429f

Published on Web 05/14/2003
Enantioselective Total Synthesis of Ustiloxin D
Hiroko Tanaka, Andrew M. Sawayama, and Thomas J. Wandless*
Department of Chemistry, Stanford UniVersity, Stanford, California 94305
Received April 2, 2003; E-mail: wandless@stanford.edu
Ustiloxin D1 and phomopsin A2 (Chart 1) are potent antimitotic
Chart 1. Ustiloxin D and Phomopsin A
agents that bind to tubulin and interfere with cellular microtubule
function.3 To understand the molecular mechanisms by which
mammalian cells monitor the integrity of their microtubules, we
have been pursuing the synthesis of both natural products as well
as synthetic variants designed to illuminate details of the mammalian
spindle assembly checkpoint.4
Ustiloxin D and phomopsin A are representative members of a
family of 13-membered macrolactams that possess a unique chiral
tertiary alkyl-aryl ether linkage. The compounds differ in several
respects, including the stereochemistry of the C10-benzylic hydroxyl
group, the substituents on the aromatic ring, and the structure of
the side chain attached to the macrocycle. Several groups have
reported the syntheses of simplified ustiloxin analogues,5,6 and the
aryl sulfoxide substituent of ustiloxin A has been synthesized.7 The
Joullie´ group recently published the first total synthesis of ustiloxin
D starting from D-serine, using a longest linear sequence of 31
steps.8 Key steps in their synthesis include the use of a nucleophilic
aromatic substitution reaction to construct the chiral tertiary alkyl-
aryl ether,4b as well as Sharpless’s asymmetric aminohydroxylation
reaction to install the C10-benzylic hydroxyl group and the adjacent
nitrogen functionality.9,10 Herein we report the enantioselective
synthesis of ustiloxin D with a longest linear sequence of 20 steps
and using two new catalytic asymmetric reactions in the context
of a total synthesis.
Scheme 1
A requirement for our synthesis was to develop a strategy that
allows us to access the natural products as well as unnatural variants
of both the ustiloxin and phomopsin family members in order to
provide sufficient quantities for our biological studies. During our
previous studies, we discovered that the phomopsins could not be
constructed by directly coupling the side chain to the macrolactam.11
As a result, our present strategy incorporates the side chain before
cyclization. Additionally, the use of Evans’s new Al-catalyzed
asymmetric aldol reaction between a benzaldehyde derivative and
glycine enolate equivalent allows us to access both syn and anti
products corresponding to the different stereochemistries at the
benzylic hydroxyl group found in ustiloxins and phomopsins.12
Finally, due to its high functional group tolerance, we used Trost’s
reaction between a phenol and a chiral π-allyl palladium complex
to construct the chiral tertiary alkyl-aryl ether.13 Taken together,
these synthetic strategies allow us to use densely functionalized
intermediates to realize an efficient synthesis of ustiloxin D.
The meta hydroxyl group of 3,4-dihydroxybenzaldehyde was
selectively acetylated using acetic anhydride in excess sodium
hydroxide, followed by benzylation at the para position to give
protected benzaldehyde 3 (Scheme 1). The asymmetric aldol
reaction was performed using oxazole 4, 10% (S)-chiral aluminum
catalyst 5, and benzaldehyde 3 to provide cis-oxazoline 6 in 99%
yield and 98% ee.12 Treatment of 6 with K2CO3 in THF and
methanol coincidently epimerized the methyl ester and hydrolyzed
the aryl acetate to give the trans-oxazoline 7 in 95% yield. Reaction
of phenol 7 with the π-allyl palladium precursor 8 in the presence
of (S,S)-ligand 9 and Pd2(dba)3‚CHCl3 proceeded smoothly to give
the key ether linkage in 70% yield as a 2:1 ratio of inseparable
diastereomers. This mixture was carried through all subsequent steps
to the end of the synthesis. We are currently exploring the use of
9
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J. AM. CHEM. SOC. 2003, 125, 6864-6865
10.1021/ja035429f CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
Al-mediated aldol reaction is a highly flexible and enantioselective
method to prepare the substituted phenylserine residues that possess
the correct C10 stereochemistries for both ustiloxin and phomopsin
family members. Furthermore, this reaction furnished the oxazoline
product as a protecting group for the C9-C10 amino alcohol, and
following 10 intervening transformations, our alkylative strategy
for oxazoline deprotection delivered the desired N-methylated amine
that is found in the natural product. Finally, the incorporation of
the peptide side chain prior to macrocyclization will allow us to
extend this strategy to the synthesis of more complex phomopsin
family members.
Acknowledgment. We thank Dr. Yukiko Koiso for providing
a sample of natural ustiloxin D. We also thank Professors Evans
and Trost and members of their laboratories for helpful advice. This
work was supported by a Dreyfus Foundation Teacher-Scholar
Award to T.J.W.
Supporting Information Available: Full characterization of natural
and synthetic samples of ustiloxin D (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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The enantioselective total synthesis of ustiloxin D has been
achieved starting with 2,3-dihydroxybenzaldehyde. Three catalytic
asymmetric reactions were employed to set the four stereocenters
at C2, C3, C9, and C10. In particular, the use of Evans’s
JA035429F
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J. AM. CHEM. SOC. VOL. 125, NO. 23, 2003 6865