Palladium(II)-catalyzed cyclization of unsaturated hydroperoxides for the synthesis of 1,2-dioxanes

Article abstract of DOI:10.1021/ol901046z

The cyclization of γ, δ-unsaturated tertiary hydroperoxides in the presence of a palladium(II) catalyst afforded 1,2-dioxanes resembling biologically active natural products. A variety of substrates were screened, and synthetic manipulations were accomplished to construct compounds with structural similarity to antimalarial targets.

Full text of DOI:10.1021/ol901046z

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3290-3293
Palladium(II)-Catalyzed Cyclization of
Unsaturated Hydroperoxides for the
Synthesis of 1,2-Dioxanes
Jason R. Harris, Shelli R. Waetzig, and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California, 92697-2025
kwoerpel@uci.edu
Received May 12, 2009
ABSTRACT
The cyclization of γ,δ-unsaturated tertiary hydroperoxides in the presence of a palladium(II) catalyst afforded 1,2-dioxanes resembling biologically
active natural products. A variety of substrates were screened, and synthetic manipulations were accomplished to construct compounds with
structural similarity to antimalarial targets.
The discovery of peroxide-containing natural products as
active agents against malaria1 and various cancers2 has led
to an increased effort to synthesize these compounds and
their derivatives.3 As a class, cyclic peroxides are the most
common peroxide-containing motifs isolated.4 The structures
in Figure 1 represent three important types of endoperoxides:
1,2-dioxolanes (as found in plakinic acid C);5 1,2,4-trioxanes
(as represented by artemisinin);3a and 1,2-dioxanes (as
exemplified by peroxyplakoric acid A1 methyl ester).6
In light of the pharmaceutical potential of peroxides, the
development of methods to prepare these compounds would
Figure 1. Cyclic peroxide natural products.
(1) (a) Wu, Y. Acc. Chem. Res. 2002, 35, 255–259. (b) Jefford, C. W.
Curr. Med. Chem. 2001, 8, 1803–1826. (c) Jefford, C. W. Curr. Opin. InVest.
Drugs 2004, 5, 866–872.
aid in the discovery of new peroxide-containing drugs.1c The
lability of the weak O-O bond makes installation and
functionalization of peroxides particularly challenging,
however.3d,7 The synthesis of 1,2-dioxanes has been ac-
complished in various ways. The intramolecular nucleophilic
displacement of leaving groups, such as halides8 or mesyl-
ates,9 has been employed. The use of peroxides as nucleo-
(2) (a) Woerdenbag, H. J.; Moskal, T. A.; Pras, N.; Malingre´, M. T.;
El-Feraly, F. S.; Kampinga, H. H.; Konings, A. W. T. J. Nat. Prod. 1993,
56, 849–856. (b) Efferth, T. Drug Res. Updates 2005, 8, 85–97. (c) Chen,
H.-H.; Zhou, H.-J.; Wang, W.-Q.; Wu, G.-D. Cancer Chemother. Phar-
macol. 2004, 53, 423–432.
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V. M.; Gloriozova, T. A.; Poroikov, V. V. Mini-ReV. Med. Chem. 2007, 7,
571–589. (c) Dembitsky, V. Eur. J. Med. Chem. 2008, 43, 223–251. (d)
McCullough, K. J.; Nojima, M. Curr. Org. Chem. 2001, 5, 601–636.
(4) (a) Casteel, D. A. Nat. Prod. Rep. 1999, 16, 55–73. (b) Faulkner,
D. J. Nat. Prod. Rep. 2002, 19, 1–48.
(7) Dussault, P. H. Synlett 1995, 997–1003
.
(5) Horton, P. A.; Longley, R. E.; Kelley-Borges, M.; McConnell, O. J.;
Ballas, L. M. J. Nat. Prod. 1994, 57, 1374–1381.
(8) (a) Porter, N. A.; Mitchell, J. C. Tetrahedron Lett. 1983, 24, 543–
546. (b) Porter, N. A.; Gilmore, D. W. J. Am. Chem. Soc. 1977, 99, 3503–
3504. (c) Dussault, P. H.; Zope, U. R. J. Org. Chem. 1995, 60, 8218–
8222.
(6) Kobayashi, M.; Kondo, K.; Kitagawa, I. Chem. Pharm. Bull. 1993,
41, 1324–1326.
10.1021/ol901046z CCC: $40.75
Published on Web 06/25/2009
 2009 American Chemical Society

philes for the intramolecular attack on epoxides is another
method for the synthesis of 1,2-dioxanes.10 While these
methods are useful, they require preformation of the desired
leaving group. A common strategy for the synthesis of
endoperoxides is the cyclization of pendant hydroperoxides
onto activated alkenes. For example, conjugate additions of
peroxide nucleophiles onto electron-deficient alkenes have
been used.11 These conditions also facilitate formation of
epoxide side products, arising from Weitz-Scheffer oxida-
tion,12 resulting in diminished yields of the desired endo-
peroxide. In addition, peroxyl radical cyclizations onto olefins
are well established in the literature.13 Methods involving
intramolecular attack of peroxide nucleophiles onto halo-
nium14 and mercuronium ions,15 generated in situ from
alkenes, have been used to yield 1,2-dioxanes. The potential
drawback to these reactions is that residual iodine and
mercury atoms may need to be removed by a subsequent
transformation.15c
In contrast, only one example of a transition metal-catalyzed
reaction resulting in peroxide-containing products has been
reported.19 Nonetheless, the formation of isomeric products
limits the reaction’s utility. In this Letter, we report the
palladium-catalyzed synthesis of cyclic peroxides that can
be functionalized to give compounds structurally related to
biologically active natural products.
Our first experiments were focused on the feasibility of
catalyzing the intramolecular addition of hydroperoxides onto
pendant olefins. The model substrate, unsaturated tertiary
hydroperoxide 1a, was synthesized from the corrresponding
alcohol.20 Next, hydroperoxide 1a was treated under Corey’s
conditions,19 but only decomposition products were observed
(Scheme 1). It was reasoned that a sacrificial oxidant could
Scheme 1. Initial Conditions for Peroxycyclization
Given the large number of cyclic peroxides containing the
1,2-dioxane moiety, we sought to develop a complementary
approach to synthesize this important structural motif. We
reasoned that a late transition metal could combine alkene
activation, intramolecular attack of the peroxide, and sub-
sequent removal of the activating species in a single
transformation. Related heteroatom nucleophiles, such as
alcohols16 and amines,17,18 have been widely demonstrated
to undergo cyclization onto olefins activated by electrophilic
transition metal catalysts, including palladium(II) complexes.
(9) Ghorai, P.; Dussault, P. H.; Hu, C. Org. Lett. 2008, 10, 2401–2404.
(10) Xu, X.-X.; Dong, H.-Q. J. Org. Chem. 1995, 60, 3039–3044.
(11) (a) O’Neill, P. M.; Searle, N. L.; Raynes, K. J.; Maggs, J. L.; Ward,
S. A.; Storr, R. C.; Park, B. K.; Posner, G. H. Tetrahedron Lett. 1998, 39,
6065–6068. (b) Murakami, N.; Kawanishi, M.; Itagaki, S.; Horii, T.;
Kobayashi, M. Tetrahedron Lett. 2001, 42, 7281–7285. (c) Murakami, N.;
Kawanishi, M.; Itagaki, S.; Horii, T.; Kobayashi, M. Bioorg. Med. Chem.
Lett. 2002, 12, 69–72.
oxidize an intermediate palladium(0) species to prevent
premature degradation of the free hydroperoxide. Addition
of 1 equiv of benzoquinone (BQ) gave a mixture of products
1
including the desired 1,2-dioxane, as identified by H and
13C NMR spectroscopy. Alcohol 4a, which was likely formed
by reduction of the peroxide, was observed, as was its
cyclized product, furan 3a.16
(12) Porter, M. J.; Skidmore, J. Chem. Commun. 2000, 1215–1225, and
references cited therein.
(13) (a) Porter, N. A.; Funk, M. O. J. Org. Chem. 1975, 40, 3614–
3615. (b) Porter, N. A.; Funk, M. O.; Gilmore, D.; Isaac, R.; Nixon, J.
J. Am. Chem. Soc. 1976, 98, 6000–6005.
Additional screening of reaction conditions with unsatur-
ated hydroperoxide 1b provided a set of standard conditions
for peroxycyclization. From these studies, it was clear that
employing catalytic Pd(OAc)2 afforded higher conversions
and yields than when using Pd(OCOCF3)2, [(NHC)Pd-
(allyl)Cl]2,21 Pd(PPh3)2Cl2, Pt(PPh3)2Cl2, or PdCl2. Exchang-
ing NaH2PO4 with pyridine suppressed furan formation,
simplifying isolation of the endoperoxide. In contrast to the
success with benzoquinone, some oxidants (N-chlorosuccin-
imide, 2,3-dichloro-5,6-dicyanobenzoquinone, K2S2O8, O2,
Re2O7, Ag2CO3/O2) gave mostly decomposition products,
while others (HOAc/MnO2, cumene hydroperoxide, Ag2O)
provided the desired 1,2-dioxane, albeit in lower yields.
When used as an oxidant in 1,4-dioxane, the combination
of catalytic benzoquinone and stoichiometric Ag2CO3 (or
AgOAc)22 gave comparable yields to the reaction using
stoichiometric benzoquinone (Scheme 2). Other viable
(14) (a) Dussault, P. H.; Davies, D. R. Tetrahedron Lett. 1996, 37, 463–
466. (b) Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCullough, K. J. J.
Org. Chem. 2000, 65, 1069–1075. (c) Kim, H.-S.; Begum, K.; Ogura, N.;
Wataya, Y.; Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCullough, K. J.
J. Med. Chem. 2002, 45, 4732–4736.
(15) (a) Porter, N. A.; Roe, A. N.; McPhail, A. T. J. Am. Chem. Soc.
1980, 102, 7574–7576. (b) Porter, N. A.; Zuraw, P. J.; Sullivan, J. A.
Tetrahedron Lett. 1984, 25, 807–810. (c) Porter, N. A.; Zuraw, P. J. J.
Org. Chem. 1984, 49, 1345–1348. (d) Bloodworth, A. J.; Curtis, R. J.;
Mistry, N. J. Chem. Soc., Chem. Commun. 1989, 954–955.
(16) For examples of intramolecular hydroalkoxylation, see: (a) Qian,
H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536–9537.
(b) Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106, 1496–
1498. (c) Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett. 2005, 7,
4553–4556. (d) Ohta, T.; Kataoka, Y.; Miyoshi, A.; Oe, Y.; Furukawa, I.;
Ito, Y. J. Organomet. Chem. 2007, 692, 671–677. (e) Wolfe, J. P.; Rossi,
M. A. J. Am. Chem. Soc. 2004, 126, 1620–1621. (f) Nakhla, J. S.; Kampf,
J. W.; Wolfe, J. P. J. Am. Chem. Soc. 2006, 128, 2893–2901.
(17) For examples of intramolecular hydroamination, see: (a) Bender,
C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070–1071. (b)
Fix, S. R.; Brice, J. L.; Stahl, S. S. Angew. Chem., Int. Ed. 2002, 41, 164–
166. (c) Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128, 4246–
4267. (d) Liu, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570–1571.
(e) Chianese, A. R.; Lee, S. J.; Gagne´, M. R. Angew. Chem., Int. Ed. 2007,
46, 4042–4059, and references cited therein. (f) Ney, J. E.; Wolfe, J. P.
Angew. Chem., Int. Ed. 2004, 43, 3605–3608. (g) Lira, R.; Wolfe, J. P.
(19) Yu, J.-Q.; Corey, E. J. Org. Lett. 2002, 4, 2727–2730.
(20) Complete synthetic details are provided as Supporting Information.
Peroxides can be explosive so appropriate safety measures should be taken
(avoid light and heat and run on small scale).
(21) NHC ) N-heterocyclic carbene ligand (1,3-bis(2,4,6-trimethyl-
phenyl)-1,3-dihydro-2H-imidazol-2-ylidene).
J. Am. Chem. Soc. 2004, 126, 13906–13907
.
(18) For cyclizations of hydroxylamines, see: Peng, J.; Lin, W.; Yuan,
S.; Chen, Y. J. Org. Chem. 2007, 72, 3145–3148
Org. Lett., Vol. 11, No. 15, 2009
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for these reaction are generally consistent among substrates.
The alkyl tertiary hydroperoxides afforded modest dia-
stereoselectivities, where the major diastereomer was as-
signed by comparing 13C NMR chemical shifts of the methyl
group on the endoperoxide ring.24 Cyclization of mixed
peroxyacetals (entries 2 and 6) gave higher diastereoselec-
tivities, which could result from placing the methoxy group
in the axial position due to the anomeric effect.25 Products
that resemble known biologically active natural products,
such as peroxyplakoric acid A1 methyl ester (Figure 1), were
obtained from R,ꢀ-unsaturated esters (entries 5 and 6). The
reaction appears to be specific for tertiary γ,δ-unsaturated
hydroperoxides, because substrates with different substitution
did not cyclize (entries 7 and 8).
Scheme 2. Optimized Reaction Conditions
A mechanism can be proposed by consideration of other
solvents include toluene and 1,2-dichloroethane.23 As ob-
served previously, reduction of peroxide 1b to alcohol 4b
was a major side product of the reaction when 1,2-
dichloroethane was used as the solvent. Using Ag2CO3
suppressed reduction, but promoted oxidation to other
unidentified products.
reactions of peroxides with alkenes (Scheme 3).19,26,27 Ligand
Scheme 3. Proposed Mechanism for Peroxypalladation
The application of this peroxypalladation to various
unsaturated hydroperoxides is displayed in Table 1. Yields
Table 1. Palladium-Catalyzed Cyclization of Unsaturated
Peroxides
exchange of peroxide 1 for the acetate and coordination of
the alkene would give peroxypalladium species 5.26 Syn-addition
across the double bond and subsequent ꢀ-hydride elimination
affords the 1,2-dioxane 2 and liberates a palladium(II) hydride,
which reductively eliminates acetic acid.26,27 Reoxidation of
the palladium(0) species with benzoquinone provides the
requisite palladium(II) catalyst.28
The stability of cyclic peroxides allowed further manipula-
tion of the products to provide structures that are analogous
(22) (a) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.;
Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510–3511. (b)
Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452–
6455.
(23) Calculation of the yield by NMR spectroscopy, based on an internal
standard, affords a 41% yield of the observed 1,2-dioxane products. See
the Supporting Information for details. Resubjecting products to chromato-
graphic conditions gave quantitative recovery of the product.
(24) (a) Boukouvalas, J.; Pouliot, R.; Frechette, Y. Tetrahedron Lett.
1995, 36, 4167–4170. (b) He, H. Y.; Faulkner, D. J.; Lu, H. S. M.; Clardy,
J. J. Org. Chem. 1991, 56, 2112–2115. (c) Capon, R. J.; Macleod, J. K.;
Willis, A. C. J. Org. Chem. 1987, 52, 339–342.
(25) (a) Pierrot, M.; Idrissi, M. E.; Santelli, M. Tetrahedron Lett. 1989,
30, 461–462. (b) Ichiba, T.; Scheuer, P. J.; Kelly-Borges, M. Tetrahedron
1995, 45, 12195–12202.
(26) (a) Mimoun, H.; Charpentier, R.; Mitschler, A.; Fischer, J.; Weiss,
R. J. Am. Chem. Soc. 1980, 102, 1047–1054. (b) Roussel, M.; Mimoun, H.
J. Org. Chem. 1980, 45, 5387–5390. (c) Mimoun, H. Angew. Chem., Int.
Ed. Engl. 1982, 21, 734–750.
a Conditions A: 0.50 mmol of substrate, 0.025 mmol of Pd(OAc)2, 0.10
mmol of pyridine, 0.50 mmol of BQ. b Conditions B: 0.50 mmol of substrate,
0.025 mmol of Pd(OAc)2, 0.10 mmol of pyridine, 0.050 mmol of BQ, 1.0
mmol of Ag2CO3. c dr of initial hydroperoxide ) 1:1. d NR ) no product
formed.
(27) (a) Nishimura, T.; Kakiuchi, N.; Onoue, T.; Ohe, K.; Uemura, S.
J. Chem. Soc., Perkin Trans. I 2000, 1915–1918. (b) Cornell, C. N.; Sigman,
M. S. J. Am. Chem. Soc. 2005, 127, 2796–2797.
(28) Palladium(0)-catalyzed coupling of endoperoxides has been dem-
onstrated: Xu, C.; Raible, J. M.; Dussault, P. H. Org. Lett. 2005, 7, 2509–
2511.
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to those found in biologically active compounds. In particu-
lar, the 1,2-dioxane core with an acetic acid side chain is a
common structural motif in naturally occurring peroxides,
such as peroxyplakoric acid A1 methyl ester (Figure 1) and
its derivatives. We were particularly interested in structures
2f and 2g because the ester functional group provided a
convenient synthetic handle (Scheme 4). Given that many
MeOH,31 and the chloroquine-derived amide 8f was then
formed with use of N-(3-dimethylaminopropyl)-N′-ethylcar-
bodiimide hydrochloride (EDC). Endoperoxide 8f resembles
the previously reported five-membered analogue 9, which
has demonstrated potent antimalarial activity against chlo-
roquine-resistant strains of Plasmodium falciparum, the most
virulent form of the malaria parasite.32,33
In conclusion, palladium-catalyzed cyclization of unsatu-
rated tertiary hydroperoxides gives rise to 1,2-dioxane
products. Following cyclization, further functionalization was
achieved without degradation of the peroxide. This method
is tolerant of functional groups that can be manipulated in
subsequent transformations to afford biologically significant
products.
Scheme 4. Synthetic Manipulation of Endoperoxide 2f
Acknowledgment. This research was supported by the
National Institute of General Medical Sciences of the
National Institutes of Health (GM-61066) and the National
Science Foundation (CHE-0315572). J.R.H. thanks Eli Lilly
for a graduate fellowship. S.R.W. thanks the National
Institute of General Medical Sciences for a postdoctoral
fellowship (GM-085910). K.A.W. thanks Amgen and Eli
Lilly for awards to support research. We would like to thank
Dr. John Greaves and Ms. Shirin Sorooshian (UCI) for
assistance with mass spectrometry, and Dr. Phil Dennison
(UCI) for help with NMR spectroscopy.
of the bioactive structures are saturated, hydrogenation of
the C-C double bond is an essential transformation. At-
tempts to hydrogenate in the presence of Pd/C failed to
produce the desired product, likely promoting cleavage of
the O-O bond. A procedure with diimide, which was
generated in situ, reduced the double bond smoothly to afford
the saturated endoperoxide 7f in good yield.29,30 Hydrolysis
to the carboxylic acid was achieved by using 1 M LiOH in
Supporting Information Available: Complete experi-
mental procedures and product characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL901046Z
(31) Herold, P.; Stutz, S.; Stojanovic, A.; Tschinke, V.; Marti, C.;
Quirmbach, M. PCT Int. Appl. WO 2005070877, 2005.
(32) Martyn, D. C.; Ramirez, A. P.; Beattie, M. J.; Cortese, J. F.; Patel,
V.; Rush, M. A.; Woerpel, K. A.; Clardy, J. Bioorg. Med. Chem. Lett. 2008,
(29) Adam, W.; Eggelte, H. J. J. Org. Chem. 1977, 42, 3987–3988
.
18, 6521–6524.
(30) The stereochemistry of the major diastereomer, as shown in Scheme
4, was assigned based on correlations of 1H and 13C chemical shifts to similar
compounds reported in the literature: Ibrahim, S. R. M.; Ebel, R.; Wray,
V.; Mu¨ller, W. E. G.; Edrada-Ebel, R.; Proksch, P. J. Nat. Prod. 2008, 71,
(33) The covalent attachment of the endoperoxide to a chloroquine
moiety has been shown to enhance antimalarial activity as compared to
either of these components individually: Walsh, J. J.; Coughlan, D.;
Heneghan, N.; Gaynor, C.; Bell, A. Bioorg. Med. Chem. Lett. 2007, 17,
1358–1364
.
3599–3602.
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