A convergent total synthesis of ustiloxin D via an unprecedented copper-catalyzed ethynyl aziridine ring-opening by phenol derivatives

Article abstract of DOI:10.1021/ol052287g

(Chemical Equation Presented) The ustiloxins are a family of heterodetic cyclopeptides that have been isolated from the water extracts of false smut balls on the panicles of rice plants caused by the fungus Ustilaginoidea virens. A concise total synthesis of ustiloxin D has been achieved via an unprecedented ethynyl aziridine ring-opening of phenol derivatives. The longest linear sequence of the synthesis is 15 steps from commercially available compounds.

Full text of DOI:10.1021/ol052287g

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5325-5327
A Convergent Total Synthesis of
Ustiloxin D via an Unprecedented
Copper-Catalyzed Ethynyl Aziridine
Ring-Opening by Phenol Derivatives
Pixu Li, Cory D. Evans, and Madeleine M. Joullie´*
Department of Chemistry, UniVersity of PennsylVania, 231 S. 34th Street,
Philadelphia, PennsylVania 19104
mjoullie@sas.upenn.edu
Received September 21, 2005
ABSTRACT
The ustiloxins are a family of heterodetic cyclopeptides that have been isolated from the water extracts of false smut balls on the panicles
of rice plants caused by the fungus Ustilaginoidea virens. A concise total synthesis of ustiloxin D has been achieved via an unprecedented
ethynyl aziridine ring-opening of phenol derivatives. The longest linear sequence of the synthesis is 15 steps from commercially available
compounds.
Ustiloxins1 and phomopsins2 are naturally occurring hetero-
detic peptides that are potent antimitotic agents.3 Although
isolated from distinct sources, these natural products share
a similar 13-membered cyclic core structure with a unique
chiral tertiary alkyl-aryl ether linkage (Figure 1). The
stereocontrolled synthesis of tertiary alkyl-aryl ethers
remains a challenge, especially in the presence of a vicinal
stereogenic center. A goal of our program is to achieve the
(1) (a) Koiso, Y.; Natori, M.; Iwasaki, S.; Sato, S.; Sonoda, R.; Fujita,
Y.; Yaegashi, H.; Sato, Z. Tetrahedron Lett. 1992, 33, 4157. (b) Koiso, Y.;
Li, Y.; Iwasaki, S.; Hanaoka, K.; Kobayashi, T.; Sonoda, R.; Fujita, Y.;
Yaegashi, H.; Sato, Z. J. Antibiot. 1994, 47, 765. (c) Koiso, Y.; Morisaki,
N.; Yamashita, Y.; Mitsui, Y.; Shirai, R.; Hashimoto, Y.; Iwasaki, S. J.
Antibiot. 1998, 51, 418.
(2) (a) Culvenor, C. C. J.; Beck, A. B.; Clarke, M.; Cockrum, P. A.;
Edgar, J. A.; Frahn, J. L.; Jago, M. V.; Lanigan, G. W.; Payne, A. L.;
Peterson, J. E.; Petterson, D. S.; Smith, L. W.; White, R. R. Aust. J. Biol.
Sci. 1977, 30, 269. (b) Mackay, M. F.; Vandonkelaar, A.; Culvenor, C. C.
J. Chem. Commun. 1986, 1219.
Figure 1. Structures of ustiloxins and phomopsin A.
(3) Hamel, E. Biopolymers 2002, 66, 142.
(4) Cao, B.; Park, H.; Joullie´, M. M. J. Am. Chem. Soc. 2002, 124, 520.
(5) (a) Tanaka, H.; Sawayama, A. M.; Wandless, T. J. J. Am. Chem.
Soc. 2003, 125, 6864. (b) Sawayama, A. M.; Tanaka, H.; Wandless, T. J.
J. Org. Chem. 2004, 69, 8810.
(6) Evans, D. A.; Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew.
total synthesis of these intriguing molecules and to establish
the minimum structural requirements for their antimitotic
Chem., Int. Ed. 2001, 40, 1884.
activity.
10.1021/ol052287g CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/12/2005

Two total syntheses of ustiloxin D (4) have been reported
since its isolation in 1992.4,5 The first total synthesis in our
laboratory was accomplished in 31 steps utilizing a nucleo-
philic aromatic substitution (SNAr) reaction to construct the
chiral tertiary alkyl-aryl ether.4 A 20-step synthesis by the
Wandless group5 used an Evans Al-catalyzed asymmetric
aldol-type reaction,6 as well as a Trost Pd-catalyzed asym-
metric allylic O-alkylation (AAA) reaction7 to build the chiral
tertiary alkyl-aryl ether linkage.
A second-generation retrosynthetic analysis of ustiloxin
D (4) is shown in Figure 3. The disconnection of the valine
To synthesize other ustiloxin congeners and their ana-
logues for biological evaluation, a convergent and versatile
second-generation approach was required. Moreover, the
approach should be easily modifiable for the synthesis of
phomopsin A. Our initial studies showed that a late-stage
stereoselective tertiary alkyl-aryl ether formation was the
key to a convergent route. Three types of reactions have been
reported to form such a chiral tertiary ether motif, namely,
the SNAr reaction,8 Mitsunobu-type reaction,9,10 and AAA
reaction.7 However, our investigations indicated that the
SNAr and Mitsunobu reactions were highly substrate de-
pendent and not suitable for late-stage synthesis. The
asymmetric allylic O-alkylation reaction did not provide
satisfactory results, although our model studies provided
modest regio- and diastereoselectivity. Wandless also re-
ported that the AAA reaction yielded a 2:1 ratio of
inseparable diastereomers that were carried through all
subsequent manipulations to the end of the synthesis.5 As
very limited methods exist to construct chiral tertiary alkyl-
aryl ethers, a new method to build such a motif would not
only be useful for the total syntheses of ustiloxin and
phomopsin natural products but would also provide conve-
nient access to other chiral tertiary alkyl ethers.
Figure 3. Second-generation retrosynthetic analysis.
residue from the ustiloxin macrocycle provides 9. The advan-
tage of this strategy is that this residue could be replaced by
other amino acids to afford ustiloxin F (5) and other
analogues. Further disconnection of 9 at the alkyl-aryl ether
linkage provides two intermediates (10 and 11) of similar
structural complexity. Both 10 and 11 could be synthesized
rapidly from commercially available compounds. It should
be mentioned that our early results, which were almost
identical to those reported by Wandless,5 provided all four
diastereomers of 11 by an Evans aldol-type reaction.6 The
availability of these isomers makes the route modifiable for
the synthesis of phomopsin A.
The synthesis of ethynyl aziridine 10 started from methyl
ketone 12, an intermediate in our previous total synthesis of
ustiloxin D.4,12,13 It was obtained in 60% yield by a four-
step sequence from D-serine without chromatographic sepa-
ration. Grignard addition of ethynylmagnesium bromide to
12 afforded chiral tertiary alcohol 13 in 80% yield with an
11:1 diastereomeric ratio. The amino alcohol was liberated
by full deprotection with concentrated HCl, followed by
selective protection of the primary amino group as its
2-nitrobenzenesulfonamide (Ns) in one pot. A one-step
TEMPO-catalyzed oxidation protocol14 directly oxidized the
primary hydroxyl group of diol 14 to a carboxylic acid, which
was coupled with glycine tert-butyl ester to provide dipeptide
15 in 85% over two steps without affecting the tertiary
hydroxyl group. Mitsunobu reaction converted 15 to ethynyl
aziridine 10 in 84% yield. The sequence for the preparation
of aziridine 10 from D-serine was nine steps (Scheme 1).
To this end, an unprecedented copper-catalyzed ethynyl
aziridine ring-opening reaction by phenol derivatives was
developed and optimized (Figure 2).11 The new reaction
Figure 2. Copper-catalyzed ethynyl aziridine ring-opening by
phenol derivatives.
affords tertiary alkyl-aryl ethers in a highly stereo- and
regioselective fashion. Product 8 possesses the correct
absolute configuration at the two chiral centers for ustiloxins
and phomopsin A. More importantly, the ethynyl aziridine
ring-opening reaction tolerates many functional groups and
works with complex substrates.
The p-hydroxyl group of 3,4-dihydroxybenzaldehyde (16)
was selectively protected as its benzyl ether,15 followed by
acylation of the m-hydroxyl group. Al-catalyzed asymmetric
aldol-type reaction between aryl aldehyde 17 and 5-methoxy-
2-(4-methoxyphenyl)oxazole (18) provided cis-oxazoline 19
(7) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921.
(8) Woiwode, T. F.; Rose, C.; Wandless, T. J. J. Org. Chem. 1998, 63,
9594.
(9) Shi, Y.-J.; Hughes, D. L.; McNamara, J. M. Tetrahedron Lett. 2003,
44, 3609.
(10) Shintou, T.; Mukaiyama, T. J. Am. Chem. Soc. 2004, 126, 7359.
(11) Unpublished results.
(12) Ageno, G.; Banfi, L.; Cascio, G.; Guanti, G.; Manghisi, E.; Riva,
R.; Rocca, V. Tetrahedron 1995, 51, 8121.
(13) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis 1998,
1707.
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E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564.
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5326
Org. Lett., Vol. 7, No. 23, 2005

install all the required amino acid components for ustiloxin
D. Palladium black catalyzed hydrogenolysis of 22 simul-
taneously removed the benzyl carbamate, benzyl ester, and
benzyl ether and reduced the ethynyl group to the requisite
ethyl group to afford the linear precursor, which underwent
macrolactamization to provide the macrocycle in 18% yield
for two steps. Cleavage of the Boc carbamate and tert-butyl
ester by TFA in the presence of triethylsilane18 completed
the total synthesis of ustiloxin D (4) (Scheme 3).
Scheme 1. Synthesis of Ethynyl Aziridine 10
Scheme 3. Synthesis of Ustiloxin D (4)
in 85% yield as a single enantiomer after recrystallization.
DBU-mediated isomerization6 afforded the trans isomer 20.
Iminium ion formation of 20 with methyl triflate followed
by in situ NaBH4 reduction at -78 °C introduced the
N-methyl group required in ustiloxins.16 Since diastereomers
were formed upon reduction, the p-methoxybenzylidene was
cleaved by 10% aqueous HCl, and the resulting secondary
amine was protected as a Boc carbamate in one pot.
Hydrolysis of the acetate and methyl ester of compound 21,
followed by selective formation of the benzyl ester, afforded
the â-hydroxy tyrosine derivative 11 in a sequence of eight
steps (Scheme 2).
In conclusion, a concise total synthesis of ustiloxin D was
achieved in 15 steps by the application of an unprecedented
ethynyl aziridine ring-opening by a â-hydroxy tyrosine
derivative. This approach is significantly more convergent
than previous total syntheses, and it is also versatile for the
synthesis of other congeners of ustiloxin and phomopsin
natural products and their analogues.
Scheme 2. Synthesis of â-Hydroxy Tyrosine Derivative 11
Acknowledgment. We thank the NIH (CA-40081),
Wyeth Research, and the University of Pennsylvania (Re-
search Foundation) for financial support.
Note Added after ASAP Publication: There was an error
in Scheme 2 in the version published ASAP October 12,
2005; the corrected version was published ASAP October
13, 2005.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds and inter-
mediates in Scheme 3. This material is available free of
charge via the Internet at http://pubs.acs.org.
With compounds 10 and 11 in hand, the new ethynyl
aziridine ring-opening reaction was successfully catalyzed
by copper(I) acetate to provide the desired chiral tertiary
alkyl-aryl ether 9 in 90% yield. The o-nosyl group was
removed to afford the primary amine17 in 78% yield. The
amine was coupled with Z-valine using EDCI and HOBt to
OL052287G
(17) Nihei, K.; Kato, M. J.; Yamane, T.; Palma, M. S.; Konno, K. Synlett
2001, 1167.
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Lett. 1992, 33, 5441.
(16) Nordin, I. C. J. Heterocycl. Chem. 1966, 3, 531.
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