Self-sensitized photooxygenation of 3,4-dialkoxyfurans to vitamin C or its derivatives

Article abstract of DOI:10.1021/jo010531l

Self-sensitized photooxygenation of 3,4-dialkoxyfurans 3a-d with molecular oxygen and UV- or sunlight at room temperature gave vitamin C derivatives 2a-d in good to excellent yields. Furan 3c, having photodegradable protecting groups, was also photooxygenated to give L-ascorbic acid (1) in a "one-pot" reaction. Furthermore, a novel photolytic transformation was developed for deuteration of furan 3b at the C-2 position with D₂O to give furan 3d in 95% yield. Toxicity of furans 3a-c and butenolides 2a-c against human embryonic cell, murine embryo fibroblasts, normal fibroblasts, HeLa, and Vero cell lines in the presence of oxygen and indirect solar light was found to be much less than those of the antipsoriasis drugs anthralin and 8-methoxypsoralen.

Full text of DOI:10.1021/jo010531l

J . Org. Chem. 2001, 66, 7067-7071
7067
Self-Sen sitized P h otooxygen a tion of 3,4-Dia lk oxyfu r a n s to Vita m in
C or Its Der iva tives
Gholam H. Hakimelahi,*,† Moti L. J ain,† Tai Wei Ly,† I-Chia Chen,† Krishna S. Ethiraj,†
J ih Ru Hwu,† and Ali A. Moshfegh‡
Institute of Chemistry, Academia Sinica, Taipei, Taiwan 115, Republic of China, and
Department of Pharmacology, Shiraz University, Shiraz, Iran
hosein@chem.sinica.edu.tw
Received May 24, 2001
Self-sensitized photooxygenation of 3,4-dialkoxyfurans 3a -d with molecular oxygen and UV- or
sunlight at room temperature gave vitamin C derivatives 2a -d in good to excellent yields. Furan
3c, having photodegradable protecting groups, was also photooxygenated to give L-ascorbic acid
(1) in a “one-pot” reaction. Furthermore, a novel photolytic transformation was developed for
deuteration of furan 3b at the C-2 position with D2O to give furan 3d in 95% yield. Toxicity of
furans 3a -c and butenolides 2a -c against human embryonic cell, murine embryo fibroblasts,
normal fibroblasts, HeLa, and Vero cell lines in the presence of oxygen and indirect solar light was
found to be much less than those of the antipsoriasis drugs anthralin and 8-methoxypsoralen.
Sch em e 1. P r ep a r a tion of 3,4-Dia lk oxyfu r a n s
In tr od u ction
3a -c fr om L-Ascor bic Acid (1)
3,4-Dialkoxyfurans are known to be much more reac-
tive than furan itself.1 Quantum mechanical calculations
by PPP- and CNDO-methods showed that, in comparison
to furan, 3,4-dialkoxyfurans possess enhanced partial
negative charge at the C-2 and C-5 positions, higher
acidity at the R-positions, a stronger and, at the same
time, inverted dipole moment, and high reactivity even
toward electrophiles.1 As such, it occurred to us that 3,4-
dialkoxyfurans may also readily react with oxygen to
serve as efficient antioxidants. Thus, suitable analogues
may be useful as therapeutic agents.
Psoriasis is a highly proliferative skin disease;2a its
topical treatment often involves anthralin2b or psoralens2c
(i.e., 8-methoxypsoralen, 8-MOP). Psoriatic cells have
been shown to consume more molecular oxygen than
normal epidermal cells,3 and so drugs such as anthralin
act as oxygen scavengers within the cell and thus lower
the proliferative rate.4 However, the generation of super-
oxide anion, a highly toxic species,5 by anthralin inside
the cell is a source of serious side effects.6 On the other
hand, 8-MOP, administered orally or topically, is acti-
vated by UV light which the patient is subjected to after
administration. Photosensitization, and consequently
antiproliferative effects, occur when psoralen reaches the
skin, either by local absorption following topical applica-
tion or through the circulation after ingestion and
absorption through the gastrointestinal tract.2c However,
mutagenic and photocarcinogenic properties related to
these drugs are undesired side effects.2c The immune
system, the Langerhans cells, and circulating T-lympho-
cytes may also be affected.2d Herein we report our
findings that 3,4-dialkoxyfurans 3a -d can function as
efficient oxygen scavengers, yet do not produce super-
oxide. Newly synthesized furans 3a -c and their photo-
oxygenated products 2a -c exhibited much less cellular
toxicity than either anthralin or 8-MOP.
* To whom correspondence should be addressed. Phone: (886)-2-
2789-8682. Fax: (886)-2-2783-1237.
† Academia Sinica.
‡ Shiraz University.
(1) Iten, P. X.; Hofmann, A. A.; Eugster, C. H. Helv. Chim. Acta
1978, 61, 430.
(2) (a) Ramsay, D. L.; Hurley H. J . In Dermatology; Moschella, S.
L., Hurley H. J ., Eds.; W. B. Saunders: Philadelphia, 1985; Vol. 1, pp
499-556. (b) Ashton, R. E.; Andre, P.; Lowe, N. J .; Whitefield, M. J .
Am. Acad. Dermatol. 1983, 9, 173. (c) Acqua, F. D.; J ori, G. Photo-
chemistry. In Principles of Medicinal Chemistry; Foye, W. O., Lemke,
T. L., Williams, D. A., Eds.; Williams & Wilkins: London, 1995; pp
893-907 and references cited therein. (d) Roelandts, R. Arch. Dermatol.
1984, 129, 662.
(3) Hammer, H.; Hellerstorm, C. Acta Derm. Venereol. (Stockholm)
1968, 48, 563.
(4) Bruce, J . M.; Kerr, C. W.; Dodd, N. J . F. J . Chem. Soc., Faraday
Trans. 1 1987, 83, 85.
(5) Singh, A. CRC Handbook of Free Radicals and Antioxidants in
Biomedicine; Miquel, J ., Quintanilha, A., Weber, A. Eds.; CRC: Boca
Raton, Florida, 1989; Vol 1, pp 17-36.
(6) Muller, K.; Gurster, D.; Piwek, S.; Wiegrebe, W. J . Med. Chem.
1993, 36, 4099.
Resu lts a n d Discu ssion
3,4-Dialkoxyfurans 3a -c were prepared from L-ascor-
bic acid (vitamin C, 1) in three steps as shown in Scheme
1. After sequential protection of the hydroxy groups in
10.1021/jo010531l CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/27/2001

7068 J . Org. Chem., Vol. 66, No. 21, 2001
Hakimelahi et al.
Sch em e 2. Mech a n ism for th e Con ver sion of
Dia lk oxyfu r a n s 3 to Bu ten olid es 2
alcohol and the corresponding tert-butyldimethylsilyl
ether derivative under the same reaction conditions.
Furthermore, the oxidation of furans 3a and 3b to the
respective butenolides 2a and 2b did not take place in
the dark even when the reaction temperature was raised
to 77 °C.
The strong absorption of 3,4-dialkoxyfurans 3a and 3b
in the 270-300 nm range suggested that the oxidation
might be promoted by sunlight.9a-c This was ascertained
by exposing an air-saturated solution of 3a or 3b in CCl4
to sunlight for 8 h. In this way, butenolides 2a or 2b were
isolated in 82-87% yield. Replacement of air with oxygen
gas allowed for a more efficient reaction; quantitative
yields were obtained after 6 h. The efficiency of the
oxidation process was found to be solvent dependent. The
half-life of 3a was 3.5, 12.0, and ∼75 h for its oxidation
to 2a in CCl4, CDCl3, and MeOH, respectively, in which
1
the corresponding lifetimes of O2 are 700, 300, and 5.0
µs, respectively.9d Thus, we conclude that the rate of
conversions of 3a f 2a and 3b f 2b depends on the
1
lifetime of O2 in reaction media.
We also measured consumption of molecular oxygen
by furan 3b under sunlight. A slow and yet steady uptake
of oxygen10 by 3b (0.886 g, 3.63 mmol) in CCl4 (15 mL)
proceeded in a catalytic hydrogenator under atmospheric
1
pressure for 6 h. Results from H NMR studies indicate
paralleled rate of oxygen uptake and the conversion of
3b f 2b. The reaction was complete after a 99% mol
equiv of 3b uptake of oxygen gas (22.8 mL) was reached.
The above photochemical transformation was then con-
ducted in the presence of nitro blue tetrazolium11 to check
for the presence of superoxides. Gratifyingly, the UV
absorption at 560 nm associated with nitro blue difor-
mazan, the reaction product between nitro blue tetrazo-
lium and superoxide, was not observed. As well, the
conversion of furan 3b to butenolide 2b was also found
to occur in the presence of superoxide dismutase in 80%
yield. Given these two results, we are confident that the
superoxide anion is not involved in these reactions. The
conversion of 3 f 2 (85% yield) was also found to be
achieved in the presence of a stoichiometric amount of a
radical scavenger, 2,6-di-tert-butyl-4-methylphenol, which
indicates that radical intermediates are not involved in
the above conversions. In addition, the toxicity of furans
3a -c and butenolides 2a -c against various cell lines in
the presence of sunlight and oxygen was found to be
much less than anthralin and 8-MOP.
1, the resultant butenolides7 2a -c were treated with
diisobutylaluminum hydride in toluene at -78 °C to give
the desired furans 3a -c (∼82% yield).
Upon irradiation with UV light (λ > 250 nm) under
an oxygen atmosphere at room temperature, 3a and 3b
in CDCl3, MeOH, or 65:35 (mL/mL) MeOH/H2O were
respectively converted to butenolides 2a and 2b in 70-
76% yields within 3 h (Scheme 2). The optical rotations
of 2a ([R]21 39.869°, c ) 1.17 g/100 mL, CHCl3) and 2b
D
([R]23D 9.758°, c ) 1.00 g/100 mL, CHCl3) obtained in this
way were in good agreement with those synthesized
directly from L-ascorbic acid (1) (Scheme 1). Photochemi-
cal conversion of triplet molecular oxygen (3O2) to singlet
oxygen (1O2) often requires a sensitizer, such as rose
bengal.8 Although the conversion of 3a ,b to 2a ,b occurred
in the presence of rose bengal, it was discovered that the
photosensitizer was not necessary. This result is interest-
ing since furans acting as sensitizers is not hitherto
described. The ability of furans 3a and 3b to act as
sensitizers may be due to the presence of electron-
donating groups at C-3 and C-4 positions, which facilitate
the intersystem crossing of an excited singlet to the
triplet and therefore generation of 1O2. To prove this, we
irradiated, individually, 3a and 3b in the presence of
oxygen and a singlet oxygen quencher such as 1,4-
diazabicyclo[2.2.2]octane (DABCO). The reactions failed
to produce the corresponding butenolides 2a and 2b, and
only starting materials were recovered. Moreover, we
found that the alkoxy groups in furans were essential
for their conversions to butenolides, as evidenced in the
unsuccessful photooxygenation of 2,5-dimethylfuran and
dimethyl 3,4-furandicarboxylate, along with furfuryl
A proposed mechanism for the photooxidation of 3,4-
dialkoxyfurans 3 to 2 is depicted in Scheme 2. Under
3
1
photolytic conditions, furans 3 could convert O2 to O2,
which would be consumed through [4 + 2] cycloaddition12a
with furan to form endoperoxides 4.12b,13 Structural
(9) (a) Urbach, F. Man and Ultraviolet Radiation. In Human
Exposure to Ultraviolet Radiation: Risk and Regulations; Passchier,
W. F., Bosnjakovic, B. F. M., Eds.; Elsevier: Amsterdam, 1987; pp
3-17. (b) Moan, J .; Dahlbach, A. Ultraviolet Radiation and Skin
Cancer: Epidermiological Data from Scandinavia. In Environmental
UV Photobiology; Young, A. R., Bjorn, L. O., Moan, J ., Nultsch, W.,
Eds.; Plenum: New York, 1993; pp 255-293. (c) Gies, H. P.; Roy, C.
R.; Toomey, S.; MacLennan, R.; Watson, M. Photochem. Photobiol.
1995, 62, 1015. (d) Bellus, D. In Advances in Photochemistry; Pitts, J .
N., J r.; Hammond, G. S., Gollnick, K., Grosjean, D., Eds.; J ohn Wiley
& Sons: New York, 1979; Vol. 11, p 105.
(7) (a) J ung, M. E.; Shaw, T. J . J . Am. Chem. Soc. 1980, 102, 6304.
(b) Mei, N.-M. Ph.D. Thesis, National Tsing Hua University, Hsinchu,
Taiwan, 2001.
(10) Hakimelahi, G. H.; J ust, G. Helv. Chim. Acta 1982, 65, 1359.
(11) Muller, K. Arch. Pharm. (Weinheim) 1988, 321, 385.
(8) (a) Horspool, W.; Armesto, D. Organic Photochemistry:
A
(12) (a) Adam, W.; Peters, E. M.; Peters, K.; Prein, M.; von
Schnering, H. G. J . Am. Chem. Soc. 1995, 117, 6686. (b)Feringa, B. L.
Recl. Trav. Chim. Pays-Bas 1987, 106, 469 and references therein.
(13) Gollnick, K.; Griesbeck, A. Tetrahedron 1985, 41, 2057.
Comprehensive Treatment; Ellis Horwood: New York, 1992; pp 10-
12. (b) Turro, N. J . In Molecular Photochemistry; W. A. Benjamin: New
York, 1965; pp 132-133.

Self-Sensitized Photooxygenation
J . Org. Chem., Vol. 66, No. 21, 2001 7069
Ta ble 1. Toxicity of F u r a n s 3a -c, Bu ten olid es 2a -c, Rose Ben ga l, An th r a lin , a n d 8-Meth oxyp sor a len (8-MOP ) in th e
P r esen ce of Sola r Ligh t a n d Oxygen on th e Gr ow th of Cell Lin es
a
CC50 (µM)
compound
2a
2b
2c
3a
HEL
MEF
Hef522
HeLa
Vero
>120
>120
>120
>120
>120
>120
>120
>120
>120
>120
>120
>120
>120
>120
>120
83.25 ( 3.14
93.04 ( 2.87
87.69 ( 1.90
<0.05
14.96 ( 0.45
4.25 ( 0.16
70.11 ( 2.61
77.35 ( 3.04
80.46 ( 2.51
<0.05
9.67 ( 0.58
3.21 ( 0.07
90.05 ( 2.79
95.76 ( 1.94
98.14 ( 3.02
0.13 ( 0.04
16.05 ( 1.32
7.08 ( 0.55
63.92 ( 1.35
52.63 ( 0.86
39.78 ( 1.15
<0.05
6.99 ( 0.21
0.87 ( 0.06
78.51 ( 1.97
84.12 ( 2.13
95.69 ( 1.88
0.08 ( 0.01
13.49 ( 0.76
5.28 ( 0.30
3b
3c
rose bengal
anthralin
8-MOP
a
Cytotoxic concentration required to reduce cell growth by 50%.
features of furan endoperoxides govern formation of
different products.12 We believe that the C-3 alkoxy group
in 4 would induce a C-O bond cleavage to generate
oxonium ion 5,14 which undergoes a 1,2-hydride shift15
to afford â,γ-butenolides 6. The oxygen atom that was
lost during the conversion of 5 to 6 was transferred to a
suitable acceptor such as dimethyl sulfide to produce
dimethyl sulfoxide.13,14,16 Finally, the C-C double bond
in 6 shifts to the thermodynamically more stable R,â-
position through tautomerizations to give vitamin C
derivatives 2, a class of nontoxic compounds (see Table
1).17 To observe the endoperoxide intermediate, photo-
oxygenation of 3b at -75 °C in CDCl3/CFCl3 was carried
Sch em e 3. A p la u sible Mech a n ism for P h otolytic
Deu ter a tion of 3,4-Dia lk oxyfu r a n 3b
1
out. After 4 h, the H NMR spectrum, recorded at -70
°C, showed the presence of only the endoperoxide 4b.
When the solution was allowed to warm-up to room
temperature, the spectrum of endoperoxide 4b collapsed
to that of butenolide 2b. It should be noted that the
reaction of dimethoxyfuran 3b with other standard
oxidants such as bromine or 3-chloroperbenzoic acid
produced a mixture of unidentifiable compounds. As such,
bimolecular oxygen transfer is a critical element of the
mechanism.
obtain evidence in support of this mechanism, we irradi-
Furan 3c, possessing photodegradable groups,18 was
then synthesized as a precursor to vitamin C (1) in a
“one-pot” reaction. Thus, irradiation of 3c in a mixture
of CCl4 and MeOH (1:1) under an oxygen atmosphere
produced ascorbic acid (1) in 74% yield after 7 h. Analysis
of the above reaction after 2.0 h showed that butenolide
2c is an intermediate for the formation of 1, as expected.
After 3.0 h, we isolated 2,3-bis(4-methoxybenzyl)-5,6-iso-
propylidene-L-ascorbic acid (2c, 40% yield) and 2,3-
bis(4-methoxybenzyl)-L-ascorbic acid (30% yield). This
indicates that photodegradation of isopropylidene group
is faster than that of the 4-methoxybenzyl functionality.
On the other hand, the same reaction under direct
exposure to sunlight produced butenolide 2c in 78% yield
after 16 h. Indirect exposure of furans 3a -c to sunlight
in a mixture of DMSO-d6 and D2O (1:1) under oxygen
atmosphere also generated butenolides 2a -c in about
80% yield after 42 h.
ated furan 3d bearing a deuterium at the C-2 position
in the presence of O2 in CDCl3 with UV light (λ > 250
3
nm). Butenolide 2d bearing a deuterium at the C-4
position was obtained in 90% yield along with butenolide
2b in 10% yield. In less anhydrous conditions, the yield
of the deuterated butenolide 2d decreased to 60%,
whereas the yield of 2b increased to 40%. These results
lend support to the proposed mechanism involving a
tautomerization of 6 to 2 (Scheme 2), rather than a
photochemically allowed suprafacial 1,3-hydrogen shift.
Furthermore, we developed an efficient and intriguing
method for the preparation of deuterated furan 3d .
Irradiation of 3b in a mixture of CDCl3 and D2O with
UV light (λ > 250 nm) in the absence of oxygen gave 3d
in 95% yield. The proposed mechanism shown in Scheme
3 can account for the transformation. Cyclopropene
intermediate 819a,19b is generated via diradical 7 by
photolysis of 3b. Deuterium exchange of 8 with D2O to
generate 10 via oxonium ion 9 could result from the
electron-donating capability of the vinylic methoxy group.
Finally, photoisomerization of 10 will give deuterated
furan 3d .
According to the pathway shown in Scheme 2, the C-2
hydrogen in 3 is transferred to the C-4 position of 2. To
(14) For furan endoperoxides as oxygen atom donors, see: Adam,
W.; Rodriguez, A. J . Am. Chem. Soc. 1980, 102, 404 and references
therein.
(15) Sorensen, T. S.; Whitworth, S. M. J . Am. Chem. Soc. 1990, 112,
6647.
(16) Wasserman, H. H.; Saito, I.; Vinick, F. J . cited In Matsuura,
T.; Saito, I. Photochemistry of Heterocyclic Compounds; Buchardt, O.,
Ed.; Wiley: NewYork, 1976; p 456.
(17) Sato, T.; Niino, Y.; Kakegawa, T.; Matsumoto, H. J apan Patent
01 228 989, 1989; Chem. Abst. 1990, 112, 158838.
(18) Hakimelahi, G. H. Unpublished results.
An ticellu la r Activity. Inhibition of the proliferation
of human embryonic cell (HEL), murine embryo fibro-
blasts (MEF), normal fibroblasts (Hef522), HeLa, and
(19) (a) Dean F. M. In Advances in Heterocyclic Chemistry; Katritzky
A. R., Ed; Academic Press: New York, 1982; Vol. 31, pp 238-239 and
references therein. (b) Rendall, W. A.; Torres, M.; Strausz, O. P. J .
Org. Chem. 1985, 50, 3034.

7070 J . Org. Chem., Vol. 66, No. 21, 2001
Hakimelahi et al.
Sta n d a r d P r oced u r e for P r ep a r a tion of 5-Su bstitu ted -
3,4-d ia lk oxyfu r a n s 3a -c. To a solution of butenolides 2a -c
(1.0 mmol) in toluene (17.0 mL) was added diisobutylalumi-
num hydride at -78 °C under argon. After stirring for 1.0 h
at the same temperature, phosphate buffer (1.0 M, pH 7.2, 20
mL) solution was added. The organic layer was washed with
water (20 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue was purified by use of column
chromatography (CH2Cl2 as eluant) to give the corresponding
furans 3a -c in about 82% yield. For 3a : 1H NMR (CDCl3) δ
3.73 (dd, J ) 8.00, 6.02 Hz, 1H, HC(7)), 3.84 (dd, J ) 8.00,
6.02 Hz, 1H, HC(7)), 4.79 (dd, J ) 6.02, 6.02 Hz, 1H, H-C(6)),
4.88 (s, 2H, OCH2O), 4.95 (d, J ) 15.60 Hz, 2H, H2COC(4)),
5.04 (s, 2H, H2COC(3)), 6.92 (s, 1H, H-C(2)), 7.30-7.37 (m,
10H, 2C6H5); 13C NMR (CDCl3) δ 66.38, 68.33, 72.98, 75.09,
95.39, 124.10, 127.36, 128.15, 128.25, 128.34, 128.54, 136.30,
136.70, 137.80, 142.99; UV (EtOH): λmax 269 (ꢀ 19030), 275 (ꢀ
18500), 298 (ꢀ 17300); CIMS m/z: 353 (M+ + 1), 352 (M+). Anal.
Calcd for C21H20O5: C, 71.58; H, 5.72. Found: C, 71.55; H,
5.74. For 3b: 1H NMR (CDCl3) δ 1.40 (s, 3H, CCH3), 1.46 (s,
3H, CCH3), 3.69 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.04 (dd,
J ) 7.00, 5.50 Hz, 1H, HC(7)), 4.11 (dd, J ) 7.00, 5.50 Hz, 1H,
HC(7)), 5.07 (dd, J ) 5.50, 5.50 Hz, 1H, H-C(6)), 6.91 (s, 1H,
H-C(2)); 13C NMR (CDCl3) δ 25.90, 26.13, 58.11, 61.21, 66.13,
68.94, 109.43, 122.74, 136.31, 138.24, 144.28; UV (EtOH): λmax
267 (ꢀ 18330), 274 (ꢀ 17410), 296 (ꢀ 18400); CIMS m/z: 229
(M+ + 1), 228 (M+). Anal. Calcd for C11H16O5: C, 57.89; H,
7.07. Found: C, 57.91; H, 7.12. For 3c: 1H NMR (CDCl3) δ
1.28 (s, 3H, CCH3), 1.35 (s, 3H, CCH3), 3.68 (s, 3H, OCH3),
3.70 (s, 3H, OCH3), 3.72 (dd, J ) 7.00, 5.45 Hz, 1H, HC(7)),
3.83 (dd, J ) 7.00, 5.45 Hz, 1H, HC(7)), 4.78 (dd, J ) 5.45,
5.45 Hz, 1H, H-C(6)), 4.73 (s, 2H, OCH2), 4.89 (s, 2H, OCH2),
6.86 (s, 1H, H-C(2)), 6.96 (AB, 4H, C6H4), 7.02 (AB, 4H, C6H4);
13C NMR (CDCl3) δ 25.83, 26.10, 55.12, 66.08, 68.72, 72.70,
74.70, 109.23, 113.64, 113.85, 124.09, 128.47, 128.95, 129.96,
130.22, 136.59, 137.39, 142.96, 159.55; UV (EtOH): λmax 270
Vero cells by furans 3a -c, butenolides 2a -c, rose bengal,
anthralin, and 8-MOP were carried out20 in the presence
of oxygen and solar light. The control cell lines received
the same amount of oxygen. Toxicity of the tested
compounds is expressed as the cytotoxic concentration
required to reduce normal cell growth by 50% (CC50).
Results are summarized in Table 1.
Anthralin generates superoxide anion, a highly toxic
species;5,6 yet furans 3a -c did not form superoxide in the
photooxidation process. Thus, furans 3a -c were found
to be much less toxic than anthralin. As such, the second
oxygen atom lost after ring opening of the endoperoxide
(cf. step 5 f 6) did not outweigh the benefit of not forming
superoxide. On the other hand, oxygen-dependent photo-
degradation of 8-MOP will produce furocoumarin deriva-
tives, which can react with membrane components,
causing irreversible damage to the cell.2c As a result,
8-MOP exhibited higher toxicity than furans 3a -c. Rose
bengal as a sensitizer converted 3O2 to 1O2, which
damaged the cells (Table 1). Under solar light, furans
3
3a -c also converted O2 to 1O2; yet consumption of which
by the furans produced nontoxic butenolides 2a -c.
Con clu sion s
3,4-Dialkoxy-5-alkylfurans 3a -d were developed as
novel oxygen scavengers, yet they did not produce
noxious superoxide. In the presence of UV- or sunlight
and air, photooxygenation of 3a -d proceeded through an
unprecedented pathway at room temperature to give
ascorbic acid 1 or its derivatives 2a -d in good to excellent
yields. Newly synthesized furans 3a -c were found to
be much less toxic than anthralin toward various cell
lines. These properties may prove to be of great potential
to the development of furans 3a -c as antipsoriasis
therapeutics.
(ꢀ 21000), 278 (ꢀ 19490), 297 (ꢀ 18550); CIMS m/z: 441 (M+
+
1), 440 (M+). Anal. Calcd for C25H28O7: C, 68.17; H, 6.41.
Found: C, 68.20; H, 6.51.
2-Deu ter io-3,4-d im eth oxy-6,7-isop r op ylid en -5-ylfu r a n
(3d ). A solution of 3b (114 mg, 0.491 mmol) in a mixture of
CDCl3 (1.6 mL) and D2O (1.6 mL) was irradiated with UV light
by use of a medium-pressure mercury lamp (450 W, λ > 250
nm) equipped with a Pyrex glass filter at room temperature
under argon for 5 h. The solution contained >95% of 3d as
Exp er im en ta l Section
Gen er a l. For anhydrous reactions, glassware was dried
overnight in an oven at 120 °C and cooled in a desiccator over
anhydrous CaSO4 or silica gel. Reagents were purchased from
Fluka Chemical Co. and used as is. Solvents, including dry
ether and tetrahydrofuran (THF), were obtained by distillation
from the sodium ketyl of benzophenone under nitrogen. Other
solvents, including chloroform, dichloromethane, ethyl acetate,
and hexanes were distilled over CaH2 under nitrogen. Absolute
methanol and ethanol were purchased from Merck and used
as received.
Melting points were obtained with a Bu¨chi 510 melting point
apparatus. Infrared (IR) spectra were recorded on a Perkin-
Elmer Paragon 1000 Fourier Transform spectrophotometer.
Carbon-13 NMR and proton NMR spectra were obtained on a
Varian XL-300 (300 MHz) spectrometer. Mass spectra were
carried out on a VG 70-250 S mass spectrometer. Photolytic
experiments were carried out by use of a 450-watt medium-
pressure mercury Canrad-Hanovia lamp with a Pyrex filter.
A sunlight lamp was obtained from Surprise. Com., Inc.
Purification on silica gel refers to gravity column chroma-
tography on Merck Silica Gel 60 (particle size 230-400 mesh).
Analytical TLC was performed on precoated plates purchased
from Merck (Silica Gel 60 F254). Compounds were visualized
by use of UV light, I2 vapor, or 2.5% phosphomolybdic acid in
ethanol with heating.
1
evidenced by NMR analyses. H NMR (CDCl3) δ 1.44 (s, 3H,
CCH3), 1.49 (s, 3H, CCH3), 3.72 (s, 3H, OCH3), 3.87 (s, 3H,
OCH3), 4.10 (dd, J ) 6.96, 6.57 Hz, 1H, HC(7)), 4.17 (dd, J )
6.96, 6.57 Hz, 1H, HC(7)), 5.14 (dd, J ) 6.57, 6.57 Hz, 1H,
H-C(6)); 13C NMR (CDCl3) δ 25.73, 25.92, 58.14, 61.22, 66.16,
68.99, 109.45, 122.54 (t, J ) 125.00 Hz, D-C(2)), 136.29, 138.29,
144.19; UV (EtOH): λmax 266 (ꢀ 18,000), 275 (ꢀ 16,500), 295 (ꢀ
17,600); CIMS m/z: 230 (M+ + 1), 229 (M+).
Sta n d a r d P r oced u r e for P r ep a r a tion of 2,3-Dia lk oxy-
5,6-a lk ylid en e-L-a scor bic Acid s 2a -d . A solution of 3a -d
(0.50 mmol) in CDCl3 (2.70 mL) was irradiated by a 450-W
medium-pressure Hanovia mercury lamp (λ > 250 nm) placed
inside a water cooled (15-25 °C) Pyrex immersion well.
Oxygen flow was maintained during photolysis, and the
reaction temperature was kept near 20 °C by regulating the
temperature of the water. After 3.0 h, the solvent was
concentrated under reduced pressure, and the residue was
purified by use of column chromatography (20% EtOAc in
hexanes as eluant) to give the corresponding vitamin C
derivatives 2a -d in about 75% yield. For 2a : mp 62-63 °C;
IR (KBr) 1764 (CdO), 1681 (CdC) cm-1; H NMR (CDCl3) δ
3.82 (dd, J ) 8.60, 6.60 Hz, 1H, HC(6)), 3.91 (dd, J ) 8.60,
6.60, 1H, HC(6)), 4.09-4.14 (ddd, J ) 6.60, 6.60, 2.80 Hz, 1H,
H-C(5)), 4.46 (d, J ) 2.80 Hz, 1H, H-C(4)), 4.81 (s, 2H, OCH2O),
5.02 (s, 2H, H2COC(2)), 5.09 (d, J ) 8.60 Hz, 2H, H2COC(3)),
7.09-7.28 (m, 10H, 2C6H5); 13C NMR (CDCl3) δ 65.56, 72.98,
73.45, 73.59, 74.64, 96.06, 121.04, 127.62, 128.45, 128.90,
135.13, 135.75, 156.39, 168.66; MS m/z: 368 (M+); CIMS m/z:
369 (M+ + 1), 368 (M+). Anal. Calcd for C21H20O6: C, 68.47;
H, 5.47. Found: C, 68.58; H, 5.59. For 2b: mp 91-92 °C; IR
(20) (a) Rai’c-Mali’c, S.; Hergold-Brundi’c, A.; Nagl, A.; Grdisa, M.;
Paveli’c, K.; DeClercq, E.; Mintas, M. J . Med. Chem. 1999, 42, 2673-
2678. (b) Rai’c-Mali’c, S.; Svedruzi’c, D.; Gazivoda, T.; Marunovi’c, A.;
Hergold-Brundi’c, A.; Nagl, A.; Balzarini, J .; DeClercq, E.; Mintas, M.
J . Med. Chem. 2000, 43, 4806-4811.

Self-Sensitized Photooxygenation
J . Org. Chem., Vol. 66, No. 21, 2001 7071
(KBr) 1760 (CdO), 1677 (CdC) cm-1; 1H NMR (CDCl3) δ 1.33
(s, 3H, CCH3), 1.36 (s, 3H, CCH3), 3.82 (s, 3H, H3COC(2)), 3.94
(dd, J ) 8.40, 6.40 Hz, 1H, HC(6)), 4.02 ((dd, J ) 8.40, 6.40
Hz, 1H, HC(6)), 4.12 (s, 3H, H3COC(3)), 4.21-4.29 (ddd, J )
6.40, 6.40, 3.00 Hz, 1H, H-C(5)), 4.48 (d, J ) 3.00 Hz, 1H,
H-C(4)); 13C NMR (CDCl3) δ 25.52, 25.78, 59.43, 60.30, 65.20,
73.83, 74.43, 110.34, 123.20, 156.66, 168.88. MS m/z: 244 (M+),
229 (M+ - CH3), 187 (M+ - CH3 - C(CH3)2); CIMS m/z: 245
Con ver sion s of Fu r an s 3a-c to Respective Bu ten olides
2a -c in t h e P r esen ce of Su n ligh t . To a solution of 3a ,
3b, or 3c (0.10 mmol) in CCl4 containing CH3SCH3 (0.065
1
mmol) was bubbled air for 1.0 min. The H NMR spectrum at
25 °C was taken immediately; then the solution was exposed
to sunlight. After 8 h, the spectrum of 3a -c changed to
that of 2a -c, respectively, and CH3SCH3 was converted to
CH3S(O)CH3. In the large scale reactions (2.0 mmol of 3a -c),
2a (82% yield), 2b (87% yield), and 2c (85% yield) were
isolated.
(M+ + 1), 244 (M+), 229 (M+ - CH3), 187 (M+ - CH3
-
C(CH3)2). Anal. Calcd for C11H16O6: C, 54.09; H, 6.60. Found:
C, 54.18; H, 6.71. For 2c: Foam; IR (CHCl3) 1763 (CdO), 1679
P h otolysis of F u r a n 3c to Ascor bic Acid (1). A solution
of 3c (440 mg, 0.998 mmol) in a mixture of CCl4 (4.0 mL) and
MeOH (4.0 mL) was irradiated with UV light by use of a
medium-pressure mercury lamp (450 W, λ > 250 nm) equipped
with a Pyrex glass filter at room temperature under oxygen
for 7 h. Then, the solution was concentrated, and diethyl ether
was added to afford a solid. Filtration and crystallization of
the solid with EtOH gave ascorbic acid (1) in 74% yield. It was
identical with an authentic sample. Filtrate was evaporated,
and the resultant 4-methoxybenzaldehyde was also character-
ized.
1
(CdC) cm-1; H NMR (CDCl3) δ 1.33 (s, 3H, CCH3), 1.37 (s,
3H, CCH3), 3.77 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.94 (dd,
J ) 8.42, 6.41 Hz, 1H, HC(6)), 4.01 (dd, J ) 8.42, 6.41 Hz, 1H,
HC(6)), 4.14-4.20 (ddd, J ) 6.41, 6.41, 2.90 Hz, 1H, H-C(5)),
4.46 (d, J ) 2.90 Hz, 1H, H-C(4)), 4.98-5.10 (m, 4H, 2OCH2),
7.08 (AB, 4H, C6H4), 7.22 (AB, 4H, C6H4); 13C NMR (CDCl3) δ
25.51, 25.75, 54.92, 55.07, 65.09, 73.23, 73.84, 74.54, 109.98,
113.55, 113.78, 120.76, 127.35, 128.05, 129.64, 130.62, 130.74,
131.04, 156.72, 179.78, 169.08; CIMS m/z: 457 (M+ + 1), 456
(M+). Anal. Calcd for C25H28O8: C, 65.78; H, 6.18. Found: C,
65.81; H, 6.22. For 2d : mp 98-102 °C; IR (KBr) 1770 (CdO),
Toxicity Test P r oced u r e in Vitr o. Human embryonic cell
(HEL), murine embryo fibroblasts (MEF), normal fibroblasts
(Hef522), HeLa, and Vero cell lines were cultured in DMEM
supplemented with 10% FBS, 2.0 mM glutamine, 100 U/mL
1675 (CdC) cm-1 1H NMR (CDCl3) δ 1.36 (s, 3H, CCH3),
;
1.39 (s, 3H, CCH3), 3.84 (s, 3H, H3COC(2)), 4.03 (dd, J ) 9.6,
6.40, 1H, HC(6)), 4.12 (dd, J ) 9.6, 6.40, 1H, HC(6)), 4.09
(s, 3H, H3COC(3)), 4.29 (dd, J ) 6.40, 6.40 Hz, 1H, H-C(5));
CIMS m/z: 246 (M+ + 1), 245 (M+), 230 (M+ - CH3), 188
(M+ - CH3 - C(CH3)2).
penicillin, and 100 µg/mL streptomycin in
a humidified
atmosphere with 5% CO2 and 20% O2 at 37 °C. After 24 h,
furans 3a -c, butenolides 2a -c, rose bengal, anthralin, and
8-MOP, at various concentrations, were added, and the
cultures were exposed indirectly to solar light during the day
and to the sunlight lamp at night. The cell numbers of the
control cultures as well as those cultures supplemented with
the test compounds were determined after 12, 24, 48, 72, and
96 h of growth. The CC50 values were estimated from dose-
response curves compiled from two independent experiments
and represent cytotoxic concentration (µM) required to reduce
normal cell growth by 50% after 96 h incubation (Table 1).
Obser va tion of En d op er oxid e 4b th r ou gh P h otooxy-
gen a tion of F u r a n 3b a t Low Tem p er a tu r e. A solution of
3b (0.20 mmol) in CDCl3/CFCl3 (1.2 mL, 3:1) was irradiated
with a 450-W medium-pressure Hanovia mercury lamp (λ >
250 nm). During the irradiation, oxygen was bubbled through
the solution which was kept at -75 °C. After 4.0 h the reaction
1
was complete, and the H NMR spectrum recorded at -70 °C
showed only the endoperoxide 4b. 1H NMR (CDCl3/CFCl3, -70
°C) δ 1.50 (br s, 6H, 2 CCH3), 3.59 (br s, 6H, 2 OCH3), 4.21
(dd, J ) 9.51, 6.70 Hz, 1H, HC(7)), 4.35 (dd, J ) 9.51, 6.70
Hz, 1H, HC(7)), 5.26 (dd, J ) 6.70, 6.70 Hz, 1H, H-C(6)), 6.24
Ack n ow led gm en t. For financial support, we thank
Academia Sinica, Shiraz University, and the National
Science Council of Republic of China.
1
(s, 1H, H-C(2)). At -27 °C, the H NMR spectrum showed the
presence of both endoperoxide intermediate 4b and butenolide
2b (∼1:2). At ambient temperature, product 2b was present
exclusively.
J O010531L