Endoperoxide synthesis by photocatalytic aerobic [2 + 2 + 2] cycloadditions

Article abstract of DOI:10.1021/ol300428q

Structurally novel endoperoxides can be sythesized by the photocatalytic cyclotrimerization of bis(styrene) substrates with molecular oxygen. The optimal catalyst for this process is Ru(bpz)₃²⁺, which is a markedly more efficient catalyst for these photooxygention reactions than conventional organic photosensitizers. The 1,2-dioxolane products are amenable to synthetic manipulation and can be easily processed to 1,4-diols and γ-hydroxyketones. An initial screen of the biological activity of these compounds reveals promising inhibition of cancer cell growth.

Full text of DOI:10.1021/ol300428q

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1640–1643
Endoperoxide Synthesis by
Photocatalytic Aerobic [2 þ 2 þ 2]
Cycloadditions
†
†
†
‡
‡
€
Jonathan D. Parrish, Michael A. Ischay, Zhan Lu, Song Guo, Noel R. Peters, and
Tehshik P. Yoon*,†
Department of Chemistry, University of WisconsinꢀMadison, 1101 University Avenue,
Madison, Wisconsin 53706, United States, and University of Wisconsin Small Molecule
Screening Facility, Paul P. Carbone Cancer Center, Wisconsin Institutes for Medical
Research, 1111 Highland Avenue, Madison, Wisconsin 53792, United States
tyoon@chem.wisc.edu
Received February 21, 2012
ABSTRACT
Structurally novel endoperoxides can be sythesized by the photocatalytic cyclotrimerization of bis(styrene) substrates with molecular oxygen.
The optimal catalyst for this process is Ru(bpz)32þ, which is a markedly more efficient catalyst for these photooxygention reactions than
conventional organic photosensitizers. The 1,2-dioxolane products are amenable to synthetic manipulation and can be easily processed to 1,4-
diols and γ-hydroxyketones. An initial screen of the biological activity of these compounds reveals promising inhibition of cancer cell growth.
A number of endoperoxides from both natural and
synthetic sources have been identified as promising anti-
malarial, anticancer, and antiviral agents.1 Manystudies of
the mechanism of action of these remarkable compounds
suggest that the endoperoxide moiety is the key pharma-
cophore; homolytic cleavage of the oxygenꢀoxygen bond
by endogenous reductants produces free radicals that are
believed to be responsible for the biological activity of this
class of compounds.2 In addition, fragmentation reactions
of 1,2-dioxanes provide access to 1,4-diols, γ-ketoalcohols,
and similar substitution patterns that are difficult to
assemble using standard enolate chemistry.3 As a result
of both the biological activity and synthetic utility of this
class of compounds, there has been considerable interest in
the development of methods for the synthesis of structur-
ally novel 1,2-dioxanes.4
We recently reported that polypyridyl ruthenium(II)
photocatalysts can generate radical cations from olefins
upon irradiation with visible light, and we showed that
† Department of Chemistry, University of WisconsinꢀMadison.
‡ University of Wisconsin Small Molecule Screening Facility, Wisconsin
Institutes for Medical Research.
(1) For recent reviews of the biological activity of endoperoxides, see:
(a) Casteel, D. A. Nat. Prod. Rep. 1992, 9, 289–312. (b) Casteel, D. A. Nat.
Prod. Rep. 1999, 16, 55–73. (c) McCullough, K. J.; Nojima, M. Curr. Org.
Chem. 2001, 5, 601–636. (d) Tang, Y.; Dong, Y.; Vennerstrom,
J. L. Med. Res. Rev. 2004, 24, 425–448. (e) Posner, G. H.; D’Angelo, J.;
O’Neill, P. M.; Mercer, A. Expert Opin. Ther. Pat. 2006, 16, 1665–1672. (f)
Dembitsky, V. M. Eur. J. Med. Chem. 2008, 43, 223–251. (g) Hencken,
C. P.;Kalinda, A. S.;Solomon, A.; D’Angelo, J. G. Annu. Rep. Med. Chem.
2009, 44, 359–378.
(2) For recent reviews of the mechanism of action of biologically
active endoperoxides, see: (a) Wu, Y.-K. Acc. Chem. Res. 2002, 35, 255–
259. (b) Robert, A.; Dechy-Cabaret, O.; Cazelles, J.; Meunier, B. Acc.
Chem. Res. 2002, 35, 167–174. (c) O’Neill, P. M.; Posner, G. H. J. Med.
Chem. 2004, 47, 2945–2964. (d) Posner, G. H.; O’Neill, P. M. Acc. Chem.
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(3) For a review of synthetic applications of endoperoxide chemistry,
see: (a) Balci, M. Chem. Rev. 1981, 81, 91–108. (b) Clennan, E. L.
Tetrahedron 1991, 47, 1343–1382.
(4) Selected examples: (a) Porter, N. A.; Funk, M. O.; Gilmore, D.;
Isaac, R.; Nixon, J. J. Am. Chem. Soc. 1976, 98, 6000–6005. (b) Porter,
N. A.; Gilmore, D. W. J. Am. Chem. Soc. 1977, 99, 3503–3504. (c) Porter,
N. A.; Roe, A. N.; McPhail, A. T. J. Am. Chem. Soc. 1980, 102, 7574–
7576. (d) Xu, X.-X.; Dong, H.-Q. J. Org. Chem. 1995, 60, 3039–3044. (e)
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. (f) Ghorai, P.; Dussault, P. H.; Hu, C. Org. Lett. 2008, 10, 2401–
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r
10.1021/ol300428q
Published on Web 02/28/2012
2012 American Chemical Society

these intermediates could undergo intramolecular [2 þ 2]
cycloadditions to afford cyclobutane products.5ꢀ7 In the
course of exploring this reaction, we observed that irradia-
tion of bis(styrene) 1 in the presence of a tris(bipyrazyl)
ruthenium(II) complex (Ru(bpz)3(PF)2, 2•(PF6)2)8,9 under
an atmosphere of oxygen produced the expected [2 þ 2]
cycloadduct 3 as well as a byproduct that we identified as
endoperoxide 4 (Scheme 1). Intrigued by this result, we
initiated an investigation to optimize the reaction condi-
tions for production of 4.
Scheme 1
We reasoned that we should be able to partition the
reaction toward the [2 þ 2 þ 2] product by increasing the
concentration of oxygen. Indeed, by increasing the pres-
sure of oxygen to 4 atm, we were able to improve the ratio
of 4 to 3 to 2.8:1 (Table 1, entries 2 and 3). Next, we found
that lowering the reaction concentration led to improved
yields of the desired endoperoxide to 77% (entry 5). We
also investigated the effect of temperature on the reaction
and discovered that lowering the reaction temperature to
5 °C completely suppressed formation of the [2 þ 2]
cycloadduct without noticeably affecting the rate of en-
doperoxide formation (entry 6). At this concentration and
temperature, we further found that the catalyst loading
could be lowered to 0.5 mol % without adverse effect
(entry 7). We also attempted the same reaction using the
Table 1. Optimization and Control Studiesa
O2 concn temp
(atm) (M) (°C)
yield
entry
catalyst (mol %)
(3/4)b
1c Ru(bpz)3(PF6)2 (5)
2c Ru(bpz)3(PF6)2 (5)
3c Ru(bpz)3(PF6)2 (5)
4c Ru(bpz)3(PF6)2 (5)
1
3
4
4
4
4
4
4
4
4
4
0.1
23 29%/30%
23 22%/35%
23 16%/44%
23 16%/49%
23 11%/77%
0.1
2þ
tris(bipyridyl) complex Ru(bpy)32þ instead of Ru(bpz)3
0.1
0.05
0.02
0.02
0.02
0.02
0.02
0.02
0.02
and observednoreaction, indicating thatthe identityofthe
bipyrazyl ligands is critical to the success of the reaction
(entry 8).
5
6
7
8
9
Ru(bpz)3(PF6)2 (5)
Ru(bpz)3(PF6)2 (5)
5
5
5
5
5
5
<5%/79%
<5%/75%d
<5%/<5%
<5%/<5%
<5%/<5%
<5%/20%
Ru(bpz)3(PF6)2 (0.5)
Ru(bpy)3(PF6)2 (0.5)
tetraphenylporphyrin (5)
The scope of the photocatalytic endoperoxide synthesis
using 2•(PF6)2 is summarized in Table 2. An examination
of substituent effects (entries 1ꢀ6) revealed that the pre-
sence of an electron-donating substituent at the ortho or
para position of one of the styrenes is required for success-
ful reaction. As in the case of the [2 þ 2] cycloadditions we
previously reported, we suspect that one-electron oxida-
tion of the styrene is the initial step of this process; the
failure of lesselectron-richsubstratessuchasunsubstituted
or m-methoxy-substituted styrenes to initiate cycloaddi-
tion is consistent with this hypothesis (entries 2 and 4).
10 9,10-dicyanoanthracene (5)
11 triphenylpyrylium•BF4 (5)
a Reactions were conducted in a 135 mL glass pressure vessel and
irradiated for 30 min with a 200 W incandescent light bulb unless
otherwise noted. b Yields determined by 1H NMR spectroscopy using
an internal standard, unless noted. c Irradiated for 2 h. d Isolated yield.
Significant variation of the substitution pattern, however,
is possible; electron-withdrawing halogen substituents are
tolerated at the meta position, and other electron-donating
moieties such as silyloxy and carbamate can be used to
activate the styrene (entries 7ꢀ9). The reacting partner
cannot be an aliphatic olefin (entry 10), but olefins toler-
ated in this role include styrenes bearing both electron-
donating and -withdrawing substituents as well as enynes
(entries 11ꢀ14). Substitution on the R-position of the
olefin is also tolerated (entry 15), although β-substitution
results in lower yield and poorer diastereoselectivity.
Finally, while we were unable use these conditions to con-
duct efficient photooxidation of untethered styrenes, a
(5) Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132,
8572–8574.
(6) For recent reviews of transition metal photoredox catalysis, see:
(a) Zeitler, K. Angew. Chem., Int. Ed. 2009, 48, 9785–9789. (b) Yoon,
T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527–532. (c) Narayanam,
J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102–113. (d)
Teply, F. Collect. Czech. Chem. Commun. 2011, 76, 859–917.
(7) For leading references on transition metal photocatalysis from
other groups, see: (a) Nicewicz, D. A.; MacMillan, D. W. C. Science
2008, 322, 77–80. (b) Pham, P. V.; Nagib, D. A.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2011, 50, 6119–6122. (c) Narayanam, J. M. R.;
Tucker, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2009, 131, 8756–
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Chem., Int. Ed. 2011, 50, 9655–9659. (e) Andrews, R. S.; Becker, J. J.;
ꢀ
Gagne, M. R. Angew. Chem., Int. Ed. 2010, 49, 7274–7276. (f) Chen, Y.;
Kamlet, A. S.; Steinman, J. B.; Liu, D. R. Nat. Chem. 2011, 3, 146–153.
(g) Larraufie, M.-H.; Pellet, R.; Fensterbank, L.; Goddard, J.-P.;
(10) (a) Gollnick, K.; Schnatterer, A. Tetrahedron Lett. 1984, 25,
185–188. (b) Gollnick, K.; Schnatterer, A. Tetrahedron Lett. 1984, 25,
2735–2738. (c) Mattes, S. L.; Farid, S. J. Am. Chem. Soc. 1986, 108,
7356–7361. (d) Tamai, T.; Mizuno, K.; Hashida, I.; Otsuji, Y. Tetra-
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Utschick, G. J. Org. Chem. 1993, 58, 6049–6056. (f) Tamai, T.; Mizuno,
K.; Hashida, I.; Otsuji, Y.; Ishida, A.; Takamuku, S. Chem. Lett. 1994,
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^
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7128–7129.
(9) We recently reported radical cation DielsꢀAlder cycloadditions
catalyzed by Ru(bpz)32þ. See: Lin, S.; Ischay, M. A.; Fry, C. G.; Yoon,
T. P. J. Am. Chem. Soc. 2011, 133, 19350–19353.
Org. Lett., Vol. 14, No. 6, 2012
1641

variety of tethering groups can be used in this process
(entries 16ꢀ18).
because (1) superoxide reacts with alkene radical cations to
produce oxidative cleavage products,10b,12 which are the
main products when less electron-rich olefins are utilized,
and (2) competitive quenching of the photosensitizer by
oxygen reduces the efficiency of the desired cyclooxygena-
tion by decreasing the rate of formation of the key alkene
radical cation.
Table 2. Scope of the Endoperoxide Synthesisa
Scheme 2. Proposed Mechanism for Endoperoxide Formation
Compared to standard organic photosensitizers, Ru-
2þ
(bpz)3 is a superior photocatalyst for the formation of
endoperoxides and significantly extends the scope of this
reaction. Table 1, entries 9ꢀ11 show that the photooxy-
genation of 1 using tetraphenylporphyrin or DCA is not
successful and that the yield of photooxidation is drama-
tically reduced using triphenylpyrylium tetrafluoroborate
(TPT) even when the catalyst loading is increased to
5 mol %. We attribute these observations to several
a Unless otherwise noted, reactions were conducted using 0.5 mol %
Ru(bpz)3(PF6)2 in a glass pressure vessel and irradiated with a 200 W
incandescent light bulb. b Yields and diastereomer ratios represent the
averaged results of two reproducible experiments. c Conducted using
2 mol % Ru(bpz)3(PF6)2.
The photochemical synthesis of 1,2-endoperoxides by
[2 þ 2 þ 2] aerobic cycloaddition of olefins is most
commonly achieved by irradiation of 1,1-diarylalkenes in
the presence of oxygen and 9,10-dicyanoanthracene (DCA)
as a photosensitizer.10 The mechanism is believed to involve
photoinduced one-electron oxidation of the alkene to the
corresponding radical cation (e.g., 1 to 1•þ, Scheme 2). This
reactive intermediate undergoes [2 þ 2 þ 2] cyclooxygena-
tion with triplet oxygen to afford an endoperoxide radical
cation (5•þ) that gives the 1,2-dioxolane product (5) upon
reduction by either the reduced sensitizer or another equiva-
lent of substrate.10g The scope of the [2 þ 2 þ 2] cycloaddi-
tion, however, is quite limited when DCA is used as
a photosensitizer, and only extremely electron-rich 1,
1-disubstituted styrenes (e.g., 1,1-bis(p-methoxyphenyl)
ethylene) have been shown to give good yields of 1,
2-dioxolane. This has been attributed to the ability of
DCA to sensitize the formation of superoxide radical.11
The formation of this reactive oxygen species is problematic
2þ
factors. (1) The homoleptic bipyrazyl complex Ru(bpz)3
is significantly more electron-deficient than Ru(bpy)3
2þ
.
Thus, its photoexcited state, Ru*(bpz)32þ (þ1.4 V vsSCE),
can oxidize 1 (þ1.1 V) readily to generate the key radical
2þ
cation intermediate, while Ru*(bpy)3 (þ0.8 V) cannot.
(2) The observation that tetraphenylporphyrin fails to
generate any of the desired endoperoxide suggests that
singlet oxygen is not involved in the formation of endoper-
2þ
oxide 5. (3) Like photoexcited TPT*, Ru*(bpz)3 does
not generate superoxide that might lead to oxidative
cleavage of the olefin.11 (4) Ruthenium polypyridyl com-
plexes possess a longer excited state lifetime than common
organic PET sensitizers. For example, the excited state
lifetime of *TPT is only 3 ns,13 while the lifetime of Ru*-
(bpz)32þ has been reported to be 740 ns in MeCN.14
(12) Eriksen, J.; Foote, C. S. J. Am. Chem. Soc. 1980, 102, 6083–6088.
´
(13) Miranda, M. A.; Garcıa, H. Chem. Rev. 1994, 94, 1063–1089.
(14) Haga, M.-A.; Dodsworth, E. S.; Eryavec, G.; Seymour, P.;
Lever, A. B. P. Inorg. Chem. 1985, 24, 1901–1906.
(15) Kornblum, N.; DeLaMare, J. E. J. Am. Chem. Soc. 1951, 73,
880–881.
(16) See the Supporting Information for details about these screening
studies.
(11) In accord with this hypothesis, Mattay has reported that triphe-
nylpyrylium tetrafluoroborate (TPT), which cannot form superoxide, is
a more effective photosensitizer for photooxidation of 1,1-diphenylethy-
lene than DCA, although the reported yield was still modest. See:
Mattay, J.; Vondenhof, M.; Denig, R. Chem. Ber. 1989, 122, 951–958.
1642
Org. Lett., Vol. 14, No. 6, 2012

Finally, the endoperoxides synthesized in this study have
not previously been accessible using other synthetic meth-
ods, and we speculated that they might have biological
activity consistent with that of other endoperoxides. As an
initial exploration of their potential activity, a selection of
the compounds reported in Table 2 were assayed for
cytotoxicity in human prostate cancer cell lines (Du145).
Indeed, these novel endoperoxides exhibited a range of
IC50 values, varying from >100 μM for the least potent
members (Table 2, entries 1, 5, and 11) to 4.6 μM for the
most potent (entry 14).16 We believe, therefore, that this
method provides an attractive approach to the production
of endoperoxide structures whose biological activity pro-
files have yet to be fully explored.
2þ
In summary, Ru(bpz)3 is an excellent photocatalyst
for the synthesis of endoperoxides by [2 þ 2 þ 2] aerobic
photooxygenation of R,ω-dienes and is considerably more
effective than organic photosensitizers that have com-
monly been utilized for photooxygenation. This reaction
can rapidly generate structurally complex endoperoxides
that cannot be synthesized by other means from relati-
vely simple bis(styrene) starting materials. We expect
this method will be useful in the discovery of potential
antimalarial and anticancer compounds, and we are now
initiating a program aimed at studying this possibility in
greater detail.
Figure 1. Origin of regioselectivity in KornblumꢀDeLaMare
rearrangement of 5.
In addition to their biological activity, endoperoxide
structures are valuable as versatile synthetic intermedi-
ates. When endoperoxide 5 is treated with zinc metal in
acetic acid, the OꢀO bond undergoes reductive cleavage
in high yields to afford 1,4-diol 6, which retains all four
contiguous stereocenters set in the photooxygenation
reaction (Figure 1, eq 1). When 5 is treated with triethy-
lamine, the endoperoxide undergoes a highly regiose-
lective KornblumꢀDeLaMare rearrangement15 to
afford γ-hydroxyketone 7 (eq 2). We attribute the high
selectivity to better stereoelectronic overlap between the
equatorial CꢀH bond and the OꢀO σ* antibonding
orbital (Figure 1). Thus, the products of this new photo-
catalytic process enable the construction of stereoche-
mically well-defined 1,4-diols as well as γ-hydroxyke-
tones that are difficult to assemble using alternate
methods.
Acknowledgment. Financial support from the NIH
(GM095666), Beckman Foundation, Research Corpora-
tion, and Sloan Foundation is gratefully acknowledged.
The NMR facilities at UW;Madison are funded by the
NSF (CHE-9208463, CHE-9629688) and NIH (RR08389-
01).
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds (PDF
format) are provided. This information is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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