Total synthesis of peroxyacarnoates A and D: Metal-mediated couplings as a convergent approach to polyunsaturated peroxides

Article abstract of DOI:10.1021/ol050291m

(Chemical Equation Presented) The first syntheses of peroxyacarnoates A and D, members of a family of enyne-containing alkoxydioxanes, have been achieved on the basis of chemoselective ozonolysis within a polyunsaturated framework and Pd-mediated cross-couplings of a functionalized 1,2-dioxane.

Full text of DOI:10.1021/ol050291m

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2509-2511
Total Synthesis of Peroxyacarnoates A
and D: Metal-Mediated Couplings as a
Convergent Approach to
Polyunsaturated Peroxides
Chunping Xu, Joseph M. Raible, and Patrick H. Dussault*
Department of Chemistry, UniVersity of Nebraska-Lincoln,
Lincoln, Nebraska 68588-0304
pdussault1@unl.edu
Received February 11, 2005
ABSTRACT
The first syntheses of peroxyacarnoates A and D, members of a family of enyne-containing alkoxydioxanes, have been achieved on the basis
of chemoselective ozonolysis within a polyunsaturated framework and Pd-mediated cross-couplings of a functionalized 1,2-dioxane.
The peroxyacarnoates are a family of sponge-derived natural
products containing polyunsaturated side chains affixed to
an alkoxydioxine acetic acid core and displaying activity
against fungal and/or cancer cell lines (Table 1).1,2 No
total synthesis of peroxyacarnoates A (1) and D (2) by a
route applicable to any member of the family.
Several 3-alkoxy-1,2-dioxine acetic acid natural products
have been prepared in racemic form through a route
involving photooxidation of an enone and photomediated
cyclization of the resulting γ-hydroperoxy R,â-unsaturated
ketone.4 More recently, asymmetric syntheses of alkoxy-
dioxine natural products have been reported on the basis of
photomediated cyclization of enantiomerically enriched hy-
droperoxyenones.5 However, the application of these ap-
proaches to synthesis of the peroxyacarnoates or peroxypla-
korates is constrained by the challenge of removing the
endocyclic alkene in the presence of side chain unsaturation.
Similarly, while simplified 3-alkoxy-1,2-dioxane acetates
have been prepared through intramolecular conjugate addition
of hydroperoxy-2,3-enoates,6 any approach to the peroxy-
acarnoates proper must simultaneously accommodate instal-
Table 1. Peroxyacarnoates
R
this work
peroxyacarnoate
8-nonenyl
nonanyl
8-nonynyl
8-oxononanyl
(1)
(2)
A (ref 1)
D (ref 2)
B (ref 1)
C (ref 2)
syntheses of either the peroxyacarnoates or the related
peroxyplakorates3 have been reported. We now report the
(3) Kobayashi, M.; Kondo, K.; Kitagawa, I. Chem. Pharm. Bull. 1993,
41, 1324.
(4) Snider, B. B.; Shi, Z. J. Am. Chem. Soc. 1992, 114, 1790.
(5) Dussault, P. H.; Eary, C. T.; Woller, K. R. J. Org. Chem. 1999, 64,
1789.
(6) (a) Murakami, N.; Kawanishi, M.; Itagaki, S.; Horii, T.; Kobayashi,
M. Bioorg. Med. Chem. Lett. 2001, 12, 69. (b) Murakami, N.; Kawanishi,
M.; Itagaki, S.; Horii, T.; Kobayashi, M. Tetrahedron Lett. 2001, 42, 7281.
(1) Yosief, T.; Rudi, A.; Wolde-ab, Y.; Kashman, Y. J. Nat. Prod. 1998,
61, 491 (peroxyacarnoates A and B).
(2) Fontana, A.; d’Ippolito, G.; D’Souza, L.; Mollo, E.; Parameswaram,
P. S.; Cimino, G. J. Nat. Prod. 2001, 64, 131 (peroxyacarnoic acids A, C,
and D).
10.1021/ol050291m CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/19/2005

lation of both a reduction-sensitive 1,2-dioxane and an
oxidation-sensitive enyne. A possible solution arose from
our previous research into carbon-carbon bond constructions
compatible with protected hydroperoxides.7 The successful
application of Pd-mediated couplings to a functionalized
alkoxydioxane would allow us to employ an oxidation-stable
synthon in place of the enyne while also providing a
convergent entry approach for the synthesis of any desired
peroxyacarnoate. Our synthetic strategy, illustrated in Scheme
1, introduces the enyne side chain via a Pd-mediated sp/sp2
derived from 2-bromoethyl-1,3-dioxolane furnished a stable
ketoacetal. The keto aldehyde derived from acidic depro-
tection was subjected to Horner-Emmons homologation to
furnish a 6-keto-2-enoate. However, attempts to install the
hydroperoxyketal via a reported Sc(OTf)3-promoted hemiket-
alization produced only traces of the desired product.6
We therefore chose to introduce the hydroperoxyacetal
via methanolic trapping of a carbonyl oxide. Wittig meth-
ylenation of the ketone, followed by ozonolysis in meth-
anol/methylene chloride, furnished the desired 6-hydroper-
oxy-6-methoxy-2-enoate, accompanied by byproducts de-
rived from cleavage of the enoate. Base-promoted cycliza-
tion of the hydroperoxyenoate in trifluoroethanol6 pro-
vided the 1,2-dioxane acetate as a 82:18 mixture of stere-
oisomers favoring the trans-3,6-dialkyl isomer. For the
purposes of the model synthesis, the two isomers were car-
ried on as a mixture. Silver-promoted iodination of the
trimethylsilylalkyne, followed by Pd-mediated coupling of
the resulting iodide with 1-tributylstannyl-1,10-undecadiene,
produced enyne-containing product with 1H and 13C spectra
corresponding to peroxyacarnoate A.1 However, the yield
for this reaction was consistently less than 10%.
Scheme 1. Retrosynthetic Approach
coupling8 of an alkynyl-substituted alkoxydioxane, in turn
derived from base-promoted conjugate addition of a 6-hy-
droperoxyenoate. The precursor hydroperoxyacetal will arise
through selective ozonolysis of a dienyne.
The results of our model studies guided us to a comple-
mentary approach based upon coupling of an alkynyl
nucleophile with an sp2 electrophile (Scheme 3). Acylation
Enyne introduction could be conceivably accomplished
from an alkynyl nucleophile (stannane, silane, or free alkyne)
or electrophile (alkynyl iodide). Our model investigations,
shown in Scheme 2, were based upon coupling of an alkenyl
Scheme 3. Total Synthesis of Peroxyacarnoates A and D
Scheme 2. Model Approach to Alkoxydioxanes
of the same Grignard reagent with 5-hexynoyl chloride
furnished a ketoalkyne, which underwent methylenation to
alkene 4; a preparative route involving minimal purification
of ketone 3 provided 4 in 67% overall yield from 5-hexynoic
acid. Deprotection and Wittig homologation were achieved
under conditions similar to those used before. The selective
ozonolysis, which had proven problematic in the model
nucleophile with an iodoalkyne. The route began with the
conversion of 5-hexyn-1-ol to the Weinreb amide of 6-tri-
methylsilylhexynoic acid. Acylation of the Grignard reagent
(7) (a) Dussault, P. H.; Eary, C. T. J. Am. Chem. Soc. 1998, 120, 7133.
(b) Dussault, P. H.; Eary, C. T.; Lee, R. J.; Zope, U. R. J. Chem. Soc.,
Perkin Trans. 1 1999, 2189.
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Org. Lett., Vol. 7, No. 12, 2005

system with regard to undesired oxidation of the enoate, was
examined more closely. After some optimization, we found
that the best yields of hydroperoxyacetal 6 were obtained
by introduction of a dilute solution of O3/O2 (reduced
generator voltage) into a rapidly stirred and dilute (8 mM)
methanolic solution of dienynoate 5.9 Diethylamine-catalyzed
conjugate addition furnished a 6:1 ratio of trans- and cis-
6-alkoxy-1,2-dioxane-3-acetates, accompanied by a small but
variable amount (4-14%) of 6-oxo-2-en-10-undecynoate.
Formation of the ketone could be minimized by use of a
mixed solvent containing both methanol and trifluoroethanol,
by slow introduction of the diethylamine, and by careful
monitoring of the reaction to minimize reaction times. The
diastereomeric alkoxydioxanes and the ketone, although
separable by analytical HPLC, were carried as a mixture
through the subsequent coupling. Pd-catalyzed reaction of 7
with (E)-1-iodo-1,10-undecadiene, available in approximately
90% geometric purity from Takai homologation of 9-dece-
nal,10 selectively furnished the (E)-enyne. Selective con-
sumption of (E)-haloalkenes has been previously observed
in Pd-mediated processes.11 Semipreparative HPLC of the
reaction products afforded the trans-dioxane peroxyacarnoate
A (1) and, separately, a mixture of the cis isomer and the
ketone byproduct. Attempted acid-catalyzed epimerization
(TsOH‚H2O, MeOH) of the cis-alkoxydioxane resulted
mainly in decomposition.
approach to peroxyplakorates (eq 1)3 will be reported in due
course.
Acknowledgment. Spectra were acquired, in part, on
instruments purchased with support from NSF (MRI 0079750
and CHE 0091975). We thank the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, for support of portions of this research.
Supporting Information Available: Experimental pro-
cedures and spectral characterization for compounds 1-7
and comparison of NMR spectra for 2 with previously
reported values for 2 and other peroxyacarnoates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050291M
(8) Reviews: (a) Sonogashira, K. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3,
p 521. (b) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998;
p 203. (c) Brandsma, L.; Vasilevsky, S. F.; Verkruijsse, H. D. Application
of Transition Metal Catalysts in Organic Synthesis; Springer: Berlin, 1998;
p 179. (d) Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic Reactions;
John Wiley and Sons: New York, 1997; Vol. 50, p 1.
(9) Ozonolysis of the corresponding enal proceeded with greater selectiv-
ity for attack on the C6 methylene; however, attempts to prepare the 1,2-
dioxane from the resulting 6-hydroperoxy-6-methoxy-2,3-enal furnished only
the 2,3-epoxy-6-oxo-alkanal.
The broad utility of the approach is illustrated by the
corresponding reaction of alkyne 7 with 1-iodoundecene
(2.5:1 E/Z mixture) to selectively furnish a mixture of the
trans and cis diastereomers of 2. Semipreparative HPLC
afforded peroxyacarnoate D (2).12
(10) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408.
(11) (a) Uenishi, J.; Matsui, K. Tetrahedron Lett. 2001, 42, 4353. (b)
Uenishi, J.; Matsui, K.; Ohmaya, H. J. Organomet. Chem. 2002, 653, 141.
(12) Chemical shift values reported for aliphatic portions of the side chain
of 2 differ significantly from our observations and are also inconsistent
with values reported for similar structures (ref 1). See Supporting Informa-
tion for details.
In conclusion, we have demonstrated the use of Pd-
mediated couplings for the efficient and convergent introduc-
tion of sensitive polyunsaturated side chains onto a cyclic
peroxide core. Ongoing efforts in our group to extend this
Org. Lett., Vol. 7, No. 12, 2005
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