Low energy light-triggered oxidative cleavage of olefins

Article abstract of DOI:10.1016/j.tetlet.2008.12.069

A series of substituted olefins were tested for their reactivity with singlet oxygen as a singlet oxygen-mediated cleavable linker. Low intensity light of 200 mW/cm² was irradiated to the solution of an olefin and 5,10,15-triphenyl-20-(4-hydroxyphenyl)-21H,23H-porphyrin under atmospheric condition. Among the tested olefins, 1,2-cis-diphenoxyethylene reacted fast with singlet oxygen, >80% within 15 min yielding a stoichiometric conversion to aldehyde product without any side reactions.

Full text of DOI:10.1016/j.tetlet.2008.12.069

Tetrahedron Letters 50 (2009) 1041–1044
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Low energy light-triggered oxidative cleavage of olefins
*
Rajesh S. Murthy, Moses Bio, Youngjae You
Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD 57007, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 June 2008
Revised 13 December 2008
Accepted 15 December 2008
Available online 24 December 2008
A series of substituted olefins were tested for their reactivity with singlet oxygen as a singlet oxygen-
mediated cleavable linker. Low intensity light of 200 mW/cm2 was irradiated to the solution of an olefin
and 5,10,15-triphenyl-20-(4-hydroxyphenyl)-21H,23H-porphyrin under atmospheric condition. Among
the tested olefins, 1,2-cis-diphenoxyethylene reacted fast with singlet oxygen, >80% within 15 min yield-
ing a stoichiometric conversion to aldehyde product without any side reactions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Olefin
Photocleavage
Dioxetane
Singlet oxygen
1. Introduction
Ideally, an olefinic linker should be cleaved within a short per-
iod of time without any side reactions. Although there are several
Singlet oxygen is a toxic species in photodynamic therapy
(PDT). PDT involves three main components: low energy (visible/
near IR) light, oxygen, and a photosensitizer.1 The energy of the
light is transferred to triplet oxygen through a photosensitizer that
generates singlet oxygen. PDT has been clinically practiced in the
treatment of various diseases, such as cancers, the wet form of
age-related macular degeneration, psoriasis, and acne.2 Although
PDT has been proved effective against such diseases, the mechanis-
tic details of the reactions of singlet oxygen with bio-molecules
have not been fully understood at the molecular level.
reports on the kinetic study of the reactions of singlet oxygen with
olefins, the irradiation conditions were not described in detail such
as intensity and/or wavelength of the light at target samples.10–16
Since intensity and wavelength of light are important for drug
delivery applications, we examined various olefins to find appro-
priate linkers for this drug delivery strategy and to examine effects
of substituents at the olefins on the rate of oxidation. In this Letter,
we report the comparative yields of photo-oxidation of a series of
substituted olefins after irradiation by visible light (400–800 nm)
at 200 mW/cm2.
Applications of the 1,2-cycloaddition reaction of singlet oxygen
have been proposed for the photo-triggerable drug delivery sys-
tems such as liposomes, cyclodextrin complexes, and prodrugs
(Fig. 1).3–7 Free drugs can be released upon the irradiation of low
energy light via the cleavage reaction of singlet oxygen following
the 1,2-cycloaddition reaction with olefins (Scheme 1). This strat-
egy provides two critical advantages over other drug delivery or
prodrug systems. First, the release of free drugs can be more ac-
tively controlled than in the strategies using enzymes or specific
pH conditions. Second, low energy light allows practical applica-
tions of this strategy at a tissue level. High energy UV has been
used for releasing drugs or biologically important molecules by
UV irradiation.8 Although the UV light cannot penetrate deeper
than 1 mm into tissues, the low energy light can reach much dee-
per tissue, ꢀ1 cm.9
2. Results and discussion
To evaluate oxidative cleavage of olefins, we irradiated olefins
1–15 in the presence of 5,10,15-triphenyl-20-(4-hydroxyphenyl)-
21H,23H-porphyrin (TPP-OH) as a photosensitizer (Fig. 2). To
maintain the significance of this research for biological applica-
tions, we used low intensity light (200 mW/cm2) with a wave-
length range of 400–800 nm. At the standard condition, the
reaction solution was irradiated for 1 h. Experimental conditions
are described in the Supplementary data. The olefins were first
irradiated without TPP-OH to observe their stability in the absence
of singlet oxygen generation (Table 1). All the substrates showed
negligible reactivity (<1%) with atmospheric oxygen and the irradi-
ation without TPP-OH, except for benzophenone oxime 13, which
was oxidized to benzophenone with 7% conversion. It was previ-
ously demonstrated that benzophenone oxime was slowly con-
verted to a mixture of benzophenone and nitric acid in the
presence of oxygen and moisture.
* Corresponding author. Tel.: +1 605 688 6905; fax: +1 605 688 6364.
E-mail address: youngjae.you@sdstate.edu (Y. You).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.069

1042
R. S. Murthy et al. / Tetrahedron Letters 50 (2009) 1041–1044
D
P
D
L
R
X
D
R
R
hv
3O2
D : drug
R : receptor (target of D)
L : linker
P : porphyrin
Biological Effects!
D
P
R
Figure 1. Singlet oxygen cleavable prodrug.
The photo-oxidation of 2,3-dimethyl-2-butene 1 resulted in the
formation of 3-hydroperoxy-2,3-dimethyl-1-butene 1a in 99% by
ene reaction.17,18 The higher reactivity of 1 with singlet oxygen,
as compared to other substrates, can be attributed to its elec-
tron-rich double bond.19 Substrate 2 was studied to observe 1,2-
cycloaddition reaction with singlet oxygen yielding the dicarbonyl
compounds as oxidative cleavage products. It also seemed interest-
ing to study the effect of aryl groups as substituents on the olefin.
As previously reported, singlet oxygen reaction with aryl-substi-
tuted olefins does not tend to be an accelerated process.20 Benzal-
dehyde 2a was formed as the only product in a low conversion.
Substrates 3 to 6 are vinyl ethers and diethers. Substrate 3 affor-
ded the ene reaction product 3a due to the presence of three
hydrogens at the allylic position. The hydroperoxide 3a was
formed in competition with carbonyl compounds as oxidative
cleavage products via the 1,2-cycloaddition reaction. For the car-
bonyl compounds, we detected only ethyl formate 3b in the reac-
tion mixture by 1H NMR. The other product, acetaldehyde, seemed
to evaporate due to its low boiling point, 21 °C. Dihydropyran 4
also exhibited a similar reactivity to the substrate 3. The 1,2-cyclo-
addition reaction product 4b was formed twice more than the ene
reaction product 4a which was consistent with previous reports.21
However, for substrate 3, the ene reaction product 3a was formed
slightly more than the 1,2-cycloaddition reaction product 3b. Both
substrates 5 and 6 on photo-oxidation gave high yields of the prod-
uct esters 5a and 6a, respectively. The strong electron-donating ef-
fects of disubstituted hetero atoms O and S enhanced the reactivity
with singlet oxygen.
fur-substituted olefins. Substrate 8 was synthesized by the previ-
ous method.22 Initially, 8 and 9 disappeared completely after the
1 h irradiation with TPP-OH. Hence, a time-dependent study was
conducted to determine the reaction kinetics of 8 and 9. They were
irradiated for every 5 min with TPP-OH and monitored by 1H NMR
each time. The formation of product 8a was directly proportional
to the decrease of substrate 8 (Fig. 3). However, the conversion
of substrate 9 did not show a corresponding increase of product
9a. Product 9a was formed in much lower yield although the start-
ing material was consumed to a much greater extent, 88% after
15 min. There might be other oxidation products as side products
which cannot be detected by 1H NMR. Substrate 8 seemed to be
a better linker for the singlet oxygen-cleavable drug delivery sys-
tems with respect to its reaction kinetics and side reactions. How-
ever, if the formyl group of the cleaved product (i.e., a formylated
drug) is stable, it might attenuate the activity of a drug. To address
this concern, the kinetics of regeneration of a phenol from the for-
mate (8a) by biological nucleophiles such as amines and thiols is
under investigation.
N-Methyl-N-vinyl acetamide 10 showed a reasonable reactivity
with singlet oxygen as compared to vinyl ethers (Table 1). This is
probably due to the keto-amine resonance which can decrease
the electron density of the
p bond, thereby retarding the 1,2-cyclo-
addition reaction. Substrate 11 showed a higher reactivity with
singlet oxygen possibly due to the availability of the lone pair elec-
trons of nitrogen for enriching the double bond. Substrate 12 on
irradiation showed complete disappearance of the starting mate-
rial without any formation of the aldehyde product. However,
some unrecognizable products in 1H NMR were obtained in the
reaction mixture.
Substrate 7 is sulfur-activated olefin and exhibited a compara-
tively lower reactivity than vinyl ethers 3 and 4. Substrates 8 and
9 were chosen to compare the reactivities of dioxygen versus disul-
Substrates 13–15 are examples of the reactivity of a
p bond be-
tween carbon and nitrogen other than olefins. Substrate 13 was
more reactive than 14. On the contrary, 13 showed lower reactivity
with singlet oxygen than 14 under a saturated oxygen condition
and in methanol.23 Oxidation of imine 15 gave benzaldehyde in a
16% conversion. Interestingly, 15 showed a similar reactivity to 13.
1PS
3PS
1O2
hv (visible/near IR)
3. Conclusion
PS
R2
3O2
* PS: photosensitizer
In summary, heteroatom-activated olefins, 5, 6, 8, and 9,
showed a promising reactivity with singlet oxygen, >75% conver-
sion within 1 h. Olefins 8 and 9 were cleaved more than 80% by
the irradiation of light of 400–800 nm at 200 mW/cm2 within
15 min without oxygen saturation. 1,2-Dioxy olefin 8 seems more
advantageous because the cleavage reaction does not generate any
O
O
R3
R4
O
1O2
R1
R2
O
R3
R3
+
R1
R4
R2
R1 R4
Scheme 1. Singlet oxygen generation and 1,2-cycloaddition reaction of olefin
followed by cleavage of dioxetane.

R. S. Murthy et al. / Tetrahedron Letters 50 (2009) 1041–1044
1043
X
X
S
O
Ph
Ph
Ph
Ph
E1
E2
1
2
3
4
: E1 = CH2, E2 = O, X = H
: E1 = E2 = O, X = H
7
5
6: E1 = O, E2 = S, X = C6H5
O
O
Ph
Ph
X
E
Ph
N
Ph
N
Ph
E
N
X
N
8
10
11
12
13
14
: E = O (cis
)
: X = CH3
:2-pyridinyl
: X = OH
: X = OCH3
15
9: E = S
O
H
H
Ph
O
O
HOO
HOO
HOO
O
H
O
H
H
1a
3a
3b
4a
2a, 7a & 15a
H
X
O
Ph
Ph
H
O
O
N
O
O
O
Ph
E
E1
N
O
E2
X
H
4b: E1 = CH2, E2 = O, X = H
5a: E1 = E2 = O, X = H
8a: E = O
9a: E = S
10a
11a
13a & 14a
6a
: E1 = O, E2 = S, X = Ph
Figure 2. (A) Olefins studies for photo-oxidation, (B) photo-oxidation products of olefins 1–15 with hydrogen used for the quantification by 1H NMR.
Table 1
Conversion of the photo-oxidation products
Olefin
Products
1
2
1a (99%)a
2a (11%)
3
4
5
3a (23%) and 3b (18%)
4a (34%) and 4b (65%)
5a (77%)
6
6a (99%)
7
7a (22%)
8b
9b
10
11
12c
13
14
15
8a (80%)
9a (14%)
10a (30%)
11a (64%)
—
13a (18%)
14a (1%)
15a (16%)
Figure 3. Comparison of reaction kinetics of 8 and 9.
a
Conversion determined by NMR integration from photo mixture, except sub-
strates 6, 13, and 14 determined by HPLC.
b
Substrates irradiated only for 15 min.
c
Olefin peaks completely consumed but no aldehyde peak was observed on 1H
Acknowledgment
NMR.
Financial support from the South Dakota Board of Regents is
gratefully acknowledged.
side products. Recently, Dr. Dolphin’s group showed the potential
of dioxy olefin as a linker for the site-specific prodrug release.7
The low energy light-induced C@C bond cleavage reaction is prac-
tical, fast, and clean providing a new tool for drug delivery
strategies.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.12.069.

1044
R. S. Murthy et al. / Tetrahedron Letters 50 (2009) 1041–1044
10. Faler, G. R., Ph.D. thesis, In I. A Study of the Kinetics of the 1,2-Cycloaddition of
References and notes
Singlet Oxygen to Vinyl Ethers. II. An Investigation of the Reaction of Singlet Oxygen
with Adamantylideneadamantane, Wayne State University, 1977.
11. Frimer, A. A.; Bartlett, P. D.; Boschung, A. F.; Jewett, J. G. J. Am. Chem. Soc. 1977,
99, 7977.
12. Jefford, C. W.; Kohmoto, S. Helv. Chim. Acta 1982, 65, 133.
13. Gollnick, K.; Knutzen-Mies, K. J. Org. Chem. 1991, 56, 4017.
14. Machado, A. E. d. H.; Andrade, M. L. d.; Severino, D. J. Photochem. Photobiol. A
1995, 91, 179.
15. Matsumoto, M.; Kobayashi, H.; Matsubara, J.; Watanabe, N.; Yamashita, S.;
Oguma, D.; Kitano, Y.; Ikawa, H. Tetrahedron Lett. 1996, 37, 397.
16. Suga, K.; Ohkubo, K.; Fukuzumi, S. J. Phys. Chem. A 2003, 107, 4339.
17. Gollnick, K. Adv. Photochem. 1968, 6, 1.
1. Dougherty, T. J.; Gomer, C. J.; Henderson, B. W.; Jori, G.; Kessel, D.; Korbelik, M.;
Moan, J.; Peng, Q. J. Natl. Cancer Inst. 1998, 90, 889.
2. Allison, R. R.; Mota, H. C.; Sibata, C. H. Photodiagn. Photodyn. Ther. 2004, 1,
263.
3. Shum, P.; Kim, J. M.; Thompson, D. H. Adv. Drug Delivery Rev. 2001, 53,
273.
4. Zhang, Z. Y.; Shum, P.; Yates, M.; Messersmith, P. B.; Thompson, D. H.
Bioconjugate Chem. 2002, 13, 640.
5. Ruebner, A.; Yang, Z.; Leung, D.; Breslow, R. Proc. Natl. Acad. Sci. U.S.A. 1999, 96,
14692.
6. Baugh, S. D.; Yang, Z.; Leung, D. K.; Wilson, D. M.; Breslow, R. J. Am. Chem. Soc.
2001, 123, 12488.
18. Kearns, D. R. Chem. Rev. 1971, 71, 395.
19. Kearns, D. R. J. Am. Chem. Soc. 1969, 91, 6554.
7. Jiang, M. Y.; Dolphin, D. J. Am. Chem. Soc. 2008, 130, 4236.
8. Goeldner, M.; Richard, G. In Dynamic Studies in Biology: Phototriggers,
Photoswitches and Caged Biomolecules; Wiley-VCH, 2005.
9. Wilson, B. C. In Photosensitizing Compounds: Their Chemistry, Biology, and Clinical
Use; Wiley: Chichester, 1989; p 60.
20. Rio, G.; Berthelot, J. Bull. Soc. Chim. Fr. 1969, 3609.
21. Bartlett, P. D.; Mendenhall, G. D.; Schaap, A. P. Ann. N.Y. Acad. Sci. 1970, 171, 79.
22. Sales, F.; Serratosa, F. Tetrahedron Lett. 1979, 20, 3329.
23. Wamser, C. C.; Herring, J. W. J. Org. Chem. 1976, 41, 1476.