Photolabile protection of alcohols, phenols, and carboxylic acids with 3-hydroxy-2-naphthalenemethanol

Article abstract of DOI:10.1021/jo801302m

(Chemical Equation Presented) Irradiation of alcohols, phenols, and carboxylic acids "caged" with the (3-hydroxy-2-naphthalenyl)methyl group results in fast (k_release ≈ 10⁵ s^-1) release of the substrates with good quantum (Φ = 0.17-0.26) and chemical (>90%) yields. The initial byproduct of the photoreaction, 2-naphthoquinone-3-methide, reacts rapidly with water (k_H2O = 144 ± 11 s^-1) to produce parent 3-hydroxy-2-naphthalenemethanol. The o-quinone methide intermediate can be also trapped by other nucleophiles or converted into a photostable Diels-Alder adduct with ethyl vinyl ether.

Full text of DOI:10.1021/jo801302m

Photolabile Protection of Alcohols, Phenols, and Carboxylic Acids
with 3-Hydroxy-2-Naphthalenemethanol
Anton Kulikov, Selvanathan Arumugam, and Vladimir V. Popik*
Department of Chemistry, UniVersity of Georgia, Athens, Georgia 30602
Vpopik@uga.edu
ReceiVed June 19, 2008
Irradiation of alcohols, phenols, and carboxylic acids “caged” with the (3-hydroxy-2-naphthalenyl)methyl
group results in fast (krelease ≈ 105 s-1) release of the substrates with good quantum (Φ ) 0.17-0.26) and
chemical (>90%) yields. The initial byproduct of the photoreaction, 2-naphthoquinone-3-methide, reacts
rapidly with water (kH O ) 144 ( 11 s-1) to produce parent 3-hydroxy-2-naphthalenemethanol. The
2
o-quinone methide intermediate can be also trapped by other nucleophiles or converted into a photostable
Diels-Alder adduct with ethyl vinyl ether.
Introduction
ideal photolabile protecting group should be stable in the dark
and should release the caged substrate in high quantum and
chemical yields upon irradiation. In addition, a high rate of
substrate release is crucial for kinetic and time-resolved studies,
and substantial absorbance above 300 nm is beneficial for
biochemical applications. For many common PPGs, the ef-
ficiency of uncaging depends on the basicity of the substrate,
because the deprotection reaction proceeds via heterolysis of a
C-O bond. Therefore, poor leaving groups such as alcohols
represent an especially difficult target for photolabile protection.
Several examples of successful release of alcohols and carbo-
hydrates caged with o-nitrobenzyl-based PPGs have been
reported.2,7 However, substrate release can take minutes after
irradiation, since this reaction proceeds via several slow dark
steps.8 Other common PPGs, such as 3′,5′-dimethoxybenzoin,9
p-hydroxyphenacyl,10 and a family of cages utilizing photo-
chemical heterolysis of the C-O bond,11 allow for the rapid
release of a substrate but work well only with good leaving
Photolabile protecting groups (PPG), known as “cages” in
biochemistry, allow for the spatial and temporal control of
substrate release, as well as for “reagentless” deprotection.1-3
PPGs have found numerous applications in biochemistry,3
organic synthesis,1,2,4 fabrication of high density probe arrays
(aka biochips),5 and time-resolved X-ray crystallography.6 An
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe groups in Organic Synthesis;
Wiley: New York, 1991.
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(4) (a) Pillai, V. N. R. Photoremovable protecting groups in organic synthesis.
Synthesis 1980, 1, 1. (b) Pillai, V. N. R. In Organic Photochemistry; Padwa, A.,
Ed.; Marcel Dekker: New York, 1987; Vol. 9, pp 225-323.
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2003, 4, 129. (c) Gao, X.; LeProust, E.; Zhang, H.; Srivannavit, O.; Gulari, E.;
Yu, P.; Nishiguchi, C.; Xiang, Q.; Xiaochuan, Z. Nucleic Acids Res. 2001, 29,
4744. (d) Lipshutz, R. J.; Fodor, S. P. A.; Gingeras, T. R.; Lockhart, D. J. Nat.
Genet. 1999, 21, 20. (e) Pirrung, M. C.; Fallon, L.; McGall, G. J. J. Org. Chem.
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Masson, P.; Zaccai, G.; Sussman, J. L.; Goeldner, M.; Silman, I.; Bourgeois,
D.; Weik, M. Acta Crystallogr. D 2007, 63, 1115. (b) Bourgeois, D.; Royant,
A. Curr. Opin. Struct. Biol. 2005, 15, 538. (c) Srajer, V.; Teng, T.-Y.; Ursby,
T.; Pradervand, C.; Ren, Z.; Adachi, S.-I.; Schildkamp, W.; Bourgeois, D.; Wulff,
M.; Moffat, K. Science 1996, 274, 1726. (d) Schlichting, I.; Almo, S. C.; Rapp,
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Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 1 1993, 2161. (c) Watanabe, S.;
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10.1021/jo801302m CCC: $40.75
Published on Web 09/10/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7611–7615 7611

Kulikov et al.
SCHEME 1
groups, making them unsuitable for the direct caging of
alcohols.12 The quantum and chemical yield of alcohol photo-
release can be substantially improved by the introduction of a
carbonate linker between the substrate and the cage.13 In this
case, however, the relatively slow dark decarboxylation of a
mono carbonate becomes the rate-determining step of the alcohol
release.14 Photoremovable protecting groups based on photo-
induced electron transfer often allow for the efficient deprotec-
tion of alcohols but require the addition of a sensitizer and/or
an electron donor.15 In our search for PPGs suitable for the direct
caging of alcohols, we decided to explore the utility of
photochemical dehydration of o-hydroxybenzyl alcohols.16
Phenols and naphthols are known to be substantially more acidic
in the excited state than in the ground state.17 Their photoacidity
allows for protonation of weakly basic sites in the molecule, a
process that is known as excited-state intramolecular proton
transfer (ESIPT).18 ESIPT from phenols to oxygen,19 nitrogen,20
and even sp2-hybridized carbon21 is well documented. Zwitte-
rionic species produced as a result of ESIPT are short-lived and
rapidly undergo reverse proton transfer to regenerate starting
material. However, ESIPT to the hydroxyl group in o-hydroxy-
benzyl alcohol or its derivatives is accompanied by C-O bond
cleavage and the formation of an o-quinone methide.16,22
o-Quinone methides are very reactive species and readily add
nucleophiles or react with electron-rich alkenes to form
Diels-Alder adducts.16,23 The formation of an o-quinone
methide is usually complete within a nanosecond laser pulse.16
Since the o-hydroxybenzyl chromophore has little absorbance
above 250 nm, we have focused our attention on its naphthalene
analog (3).
(Scheme 1). 2-Naphthoquinone-3-methide (2) formed in this
reaction undergoes rapid hydration to the parent diol 3 or is
trapped as a Diels-Alder adduct with ethyl vinyl ether 4.
Results and Discussion
Synthesis of (3-Hydroxy-2-naphthalenyl)methyl-Caged
Compounds. Simple esters and ethers of type 1 can be prepared
by the direct reaction of an acid24 or alcohol24b with 3-hydroxy-
2-naphthalenemethanol (3). For caging of more complex
substrates, where the use of large excesses of reagents becomes
impractical, we have employed mono-TBDMS-protected diol
5 as a caging reagent (Scheme 2).
(3-Hydroxy-2-naphthalenyl)methyl carboxylates 6c,g were
prepared in a good yield by either the direct acylation of 5 with
an acid chloride in the presence of pyridine (6c) or by a DCC/
DMAP-promoted esterification of a free acid with 5 (6g). Aryl
ether 6e was synthesized by the coupling of estrone and 5 under
modified Mitsunobu conditions. For the caging of alcohols, 5
was converted into bromide 7, which was then reacted with
target alcohols in the presence of silver triflate and di-(tert-
butyl)pyridine to produce ethers 6b,d,f. The conventional TBAF/
THF treatment of 6b-f resulted in clean deprotection to give
caged compounds 1b-f (Scheme 2).
Photophysical and Photochemical Properties of (3-Hy-
droxy-2-naphthalenyl)methyl-Caged Compounds. The UV
spectra of derivatives 1a-f are similar to that of the parent
3-hydroxy-2-naphthalenemethanol (3, Figure 1). In aqueous
acetonitrile, two major absorption bands are observed above
250 nm: at λmax ) 276 nm (log ε ) 3.76) and at λmax ) 327
nm (log ε ) 3.38). It is interesting to note that this chromophore
also shows strong fluorescence (λem ) 360, 423 nm, ΦFl ) 0.230
( 0.002). This property can be used to monitor the distribution
of caged substrates in various media. The release of the substrate
from compounds 1a-f apparently proceeds via formation of
the intermediate 3-methylene-2(3H)-naphthalenone (o-quinone
methide 2, Scheme 1). To test this mechanism, we have
employed ethyl vinyl ether as a polar dienophile to trap 2 as a
Diels-Alder adduct. Irradiation of a 1 mM solution of parent
diol 3 in aqueous acetonitrile (1:1 v/v) in the presence of 10
mM ethyl vinyl ether results in the efficient formation of
2-ethoxy-3,4-dihydro-2H-naphtho[2,3-b]pyran 4 in 87% pre-
parative and 96% analytical yield (by HPLC, Scheme 1). It is
important to note that 4 is formed almost quantitatively despite
a large excess of nucleophilic solvent (28 vs 0.01 M). Adduct
Here we report that photolysis of (3-hydroxy-2-naphthale-
nyl)methyl-caged alcohols (1a,b,d,g), phenols (1e), and car-
boxylic acids (1c,f) results in efficient release of the substrates
(11) (a) Chamberlin, J. W. J. Org. Chem. 1966, 31, 1658. (b) Scho¨nleber,
R. O.; Bendig, J.; Hagen, V.; Giese, B. Bioorg. Med. Chem. 2002, 10, 97. (c)
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97, 1837.
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7612 J. Org. Chem. Vol. 73, No. 19, 2008

Photolabile Protection of Alcohols, Phenols, and Carboxylic Acids
SCHEME 2a
a Reagents and conditions: (a) CBr4/Ph3P or PBr3; (b) DTBP, AgOTf, R′CH2OH; (c) ADDP, Bu3P, ArOH; (d) DMAP/DCC, R′CO2H; (e) TBAF.
TABLE 1. Yields and Quantum Efficiencies of Photochemical
Release of Substrates from Caged Compounds 1a-g at Various
Conversions
Φ versus conversion
(in parentheses)
yield in %
yield in % with
(conversion) CH2dCHOEta (conversion)
1a 0.19 ( 0.03b c (5%)
95 ( 5b c f (5%)
95 ( 1b,c,f (11%)
96 ( 1b d g (91%)
,
,
,
, ,
0.173 ( 0.006b c (11%)
,
0.17 ( 0.01b c (17%)
91 ( 2b c f (17%)
,
, ,
0.17 ( 0.01d e (10-17%) 76 ( 1b c f (60%)
,
, ,
1b 0.24 ( 0.01d e (20-80%) 97 ( 4d e (100%)
,
,
1c 0.26 ( 0.01d e (10-80%) 96 ( 5d e (100%)
,
,
1d 0.24 ( 0.02b h (9%)
91 ( 4b h (29%)
91 ( 2b h (100%)
,
,
,
94 ( 1b h (57%)
,
86 ( 3b h (97%)
,
1e 0.18 ( 0.02b h (22%)
96 ( 3b h (22%)
92 ( 1b h (98%)
,
,
,
98 ( 2b h (46%)
,
89 ( 3b h (96%)
,
1f 0.24 ( 0.004b h (14%)
95 ( 1b h (33%)
95 ( 1b h (98%)
,
,
,
94 ( 2b h (62%)
,
FIGURE 1. UV spectra of ca. 10-4 M solutions of 3-hydroxy-2-
naphthalenemethanol (3, solid line) and adduct 5 (dashed line) in (1:1)
acetonitrile-water.
89 ( 3b h (95%)
,
96 ( 4e i (100)%
,
1g
b
a Approximately 0.03
M
ethyl vinyl ether. λirr
)
254 nm.
c Approximately 6 × 10-4 M in water. d In 40% CH3CNaq. λirr ) 300
nm. f Yield of 3. g Yield of 4. h In CH3CN/THF/water (4:3:3) mixture.
i 40% MeOHaq.
e
4 (spectrum is shown in Figure 1) is photochemically stable
and shows virtually no decomposition after prolonged exposure
to UV light.
The rate of substrate release from caged compound 1a has
been studied using nanosecond kinetic spectroscopy. Laser flash
photolysis of 1a in aqueous solution allowed us to detect the
rapid formation (kobs ) (8.03 ( 0.04) × 104 s-1) and then
somewhat slower decay (kobs) 135 ( 7 s-1) of an intermediate
by the growth and decay of absorbance at 310 nm. While the
first process is not affected by the presence of ethyl vinyl ether,
the rate of the transient decay was linearly proportional to the
concentration of the dienophile (kquench ) (4.07 ( 0.32) ×104
higher conversion (1a, Table 1). The quantum yield measure-
ments were conducted using substrate solutions with high optical
density (OD ) 1.5-2) at the irradiation wavelength. During
the course of the reaction, accumulation of the byproduct 3,
which has the same chromophore as the caged molecule, causes
the so-called filtering effect and somewhat reduces the efficiency
of photolysis. This effect becomes negligible at concentrations
at or below 0.001 M.
The chemical yield of the uncaging reaction is also slightly
reduced at higher conversions (1d-f, Table 1). This effect might
be caused by the photochemical reactivity of the accumulating
byproduct 3 via the regeneration of reactive o-quinone methide
2. We decided to avoid the formation of 3 by trapping the
initially formed 2 as the photostable Diels-Alder adduct 4 (vide
supra). High conversion (98-100%) photolyses of caged
compounds 1d-f in aqueous acetonitrile in the presence of a
10-fold excess of ethyl vinyl ether produced 3-6% higher yield
of the target substrates and quantitative amounts of adduct 4
(1d-f, Table 1).
M-1 -1
s ). This observation allowed us to identify this intermedi-
ate as o-quinone methide 2. Since the release of a caged substrate
happens before or simultaneously with the formation of 2, we
can set the lower limit for the rate of the uncaging reaction at
105 s-1
.
Substrate Release from 1a-f. (3-Hydroxy-2-naphthalenyl)-
methyl-caged compounds 1a-f are stable in the dark or under
ambient light in the pure form, as well as in THF, aqueous
acetonitrile, or methanol solutions. Compounds 1a-f were
irradiated at 254 and/or 300 nm using a Rayonet photoreactor
in water-containing solvent mixtures. The presence of water was
necessary to trap the o-quinone methide intermediate 2 formed
upon deprotection (Scheme 1). The release of the substrates was
followed by HPLC and quantum yields of uncaging were
measured using chemical actinometry25 (Table 1). Photolysis
of (3-hydroxy-2-naphthalenyl)methyl-caged substrates 1a-f
results in efficient (Φ ) 0.17-0.26) deprotection, releasing
substrates in good to excellent chemical yields (Table 1). The
quantum yield of the uncaging reaction decreases slightly at
Conclusions
A novel photolabile protecting group suitable for the direct
caging of alcohols, as well as carboxylic acids and phenols,
has been developed. (3-Hydroxy-2-naphthalenyl)methyl-caged
(25) Murov, S. L.; Carmichael, I.; Hug, G. L. In Handbook of Photochemistry;
Marcel Dekker: New York, 1993; p 299.
J. Org. Chem. Vol. 73, No. 19, 2008 7613

Kulikov et al.
afford 120 mg (90%) of 6c as a yellowish oil. 1H NMR (300 MHz)
8.13 (m, 2H), 7.91 (s, 1H), 7.79 (d, J ) 8.67 Hz, 1H), 7.71 (d, J
) 7.56 Hz, 1H), 7.57 (m, 1H), 7.50-7.40 (m, 3H), 7.35 (m, 1H),
7.21 (s, 1H), 5.57 (s, 2H), 1.07 (s, 9H), 0.36 (s, 6H); 13C NMR (75
MHz) 166.5, 152.0, 134.4, 132.9, 130.4, 126.7, 129.3, 128.8, 128.3,
128.2, 127.8, 126.4, 126.3, 124.0, 113.3, 63.0, 25.8, 18.3, -4.2;
MS m/z: 394 (M+ 2, 2), 392 (M+, 5), 337 (8), 336 (23), 335 (100),
255 (5), 230 (12), 229 (16), 216 (5), 215 (58), 200 (10), 199 (42),
185 (19), 179 (56), 155 (9), 153 (10), 142 (16), 139 (17), 128 (42).
FW calcd for C18H28O3Si 392.1808, EI-HRMS found 392.1808.
(3-Hydroxy-2-naphthalenyl)methyl Benzoate (1c). Tetrabuty-
lammonium fluoride (0.33 mL of 1 M THF solution) was added
dropwise to the solution of 6c (120 mg, 0.31 mmol) in dry THF (2
mL) at 0 °C, and the mixture was stirred for 5 min and then poured
into 50 mL of brine. The reaction mixture was extracted with ethyl
acetate; combined organic layers were washed with brine and dried
over sodium sulfate. Solvent was removed under reduced pressure,
and the residue was dissolved in dichloromethane and passed
through a short silica gel column to afford 75 mg (87%) of 1c as
compounds have a long shelf life in the solid state and in various
solvents but efficiently (Φ ≈ 0.2) release substrates upon 254
or 300 nm irradiation in good chemical yield. The half-lifetime
of substrate release is below 10 µs. The intermediate 2-naph-
thoquinone-3-methide (2) is rapidly deactivated by hydroxylic
solvents or is trapped as a photostable Diels-Alder adduct with
ethyl vinyl ether.
Experimental Section
3-Hydroxy-2-naphthalenemethanol (3) was prepared by the
LiAlH4 reduction of methyl 3-hydroxy-2-naphthoate.26
Ethyl (3-Hydroxy-2-naphthalenyl)methyl Ether (1a).24b Con-
centrated HCl (5 mL) was added to a solution of 3 (500 mg, 0.53
mmol) in 95% ethanol (20 mL), and the reaction mixture was stirred
for 10 h at room temperature and then heated for 3 h at 70-75 °C.
After cooling to room temperature, the reaction mixture was poured
into crushed ice, and the precipitate was separated by filtration,
washed with water until the washings were neutral, and dried under
vacuum. The crude product was purified by column chromatography
(25% dichloromethane in hexane) to give 1a as a white solid (348
mg, 65%). Mp 80-82 °C (lit.24b 80-82 °C); 1H NMR (400 MHz)
1.29 (t, J ) 6.8 Hz, 3H), 3.64 (q, J ) 6.8 Hz, 2H), 4.86 (s, 2H),
7.25 (s, 1H), 7.30 (m, 1H), 7.40 (m, 1H), 7.53 (s, 1H), 7.7 (m,
2H), 7.78 (s, OH); 13C NMR (100 MHz, DMSO-d6) 15.3, 66.5,
72.2, 111.2, 123.8, 125.4, 126.60, 126.64, 127.77, 127.80, 127.84,
128.6; GC-MS m/z (%) 202 (17), 157 (8), 156 (35), 129 (13), 128
(100), 127 (12), 115 (9), 102 (6), 77 (6), 64 (6), 51 (5).
1
a colorless oil. H NMR (300 MHz) 8.08 (m, 2H), 7.90 (s, 1H),
7.77 (d, J ) 8.1 Hz, 1H), 7.69 (d, J ) 8.1 Hz, 1H), 7.63 (s, 1H),
7.57 (m, 1H), 7.50-7.38 (m, 3H), 7.36-7.28 (m, 2H), 5.56 (s,
2H). 13C NMR (300 MHz) 168.4, 152.8, 135.4, 133.6, 132.0, 130.0,
129.4, 128.6, 128.5, 127.8, 127.0, 126.3, 124.1, 123.9, 112.2, 63.8;
MS m/z 265 (11), 264 (44), 171 (5), 168 (7), 158 (13), 157 (23),
156 (97), 139 (5), 129 (20), 128 (92), 127 (17), 115 (23), 105 (6),
102 (5), 92 (10), 91 (100). FW calcd for C18H14O3 278.0943, EI-
HRMS found 278.0939.
21-((3-Hydroxy-2-naphthalenyl)methyloxy)progesterone (1d).
2,6-Di-tert-butylpyridine (80 µL) and silver triflate (64 mg) were
added to a solution of 21-hydroxyprogesterone (40 mg, 0.12 mmol)
in 1 mL of dichloromethane. The resulting suspension was cooled
to 0 °C, and 7 (80 mg, 0.23 mmol) in 0.5 mL of dichloromethane
was added. The reaction mixture was stirred at room temperature
for 2 h and diluted with dichloromethane, and solids were removed
by filtration. The filtrate was filtered through a short silica gel
column, and solvent was removed under vacuum. TBAF (0.5 mL
1 M in THF) was added to the solution of crude 21-((3-tert-
butyldimethylsilyloxy-2-naphthalenyl)methyloxy)progesterone (6d)
in 1 mL of dry THF. The mixture was stirred for 15 min at 0 °C,
poured into 50 mL of brine solution, and extracted with ethyl
acetate, and the combined organic layers were dried over sodium
sulfate. The solvent was removed under reduced pressure, and the
residue was purified by chromatography (30% ethyl acetate in
Benzyl (3-Hydroxy-2-naphthalenyl)methyl Ether (1b). Di(tert-
butyl)pyridine (164 mg, 193 µL, 0.86 mmol) and silver triflate (162
mg, 0.63 mmol) were added to the solution of benzyl alcohol (52
mg, 50 µL, 0.48 mmol) in dichloromethane (0.65 mL). The reaction
mixture was cooled to 0 °C, and a solution of 7 (200 mg, 0.53
mmol) in dichloromethane (0.45 mL) was added dropwise under
vigorous stirring. The reaction mixture was stirred for 1 h, diluted
with dichloromethane (50 mL), washed consecutively with 10%
HCl, a saturated solution of sodium bicarbonate, and brine, and
dried over sodium sulfate. Solvent was removed under reduced
pressure and the residue was purified using short silica gel column
(3% ethyl acetate in hexane) to give 148 mg of crude benzyl (3-
tert-butyldimethylsilyloxy-2-naphthalenyl)methyl ether (6b).
Tetrabutylammonium fluoride (0.44 mL of a 1 M THF solution)
was added dropwise to the solution of 6b in THF (2 mL) at 0 °C,
and the mixture was stirred for 5 min and then poured into 50 mL
of brine. The reaction mixture was extracted with ethyl acetate;
combined organic layers were washed with brine and dried over
sodium sulfate. Solvent was removed under reduced pressure, and
the residue was purified by chromatography (dichloromethane) to
afford 51 mg (48%) of 1b as colorless crystals. Mp 102-104 °C.
1H NMR (300 MHz) 7.69 (m, 2H), 7.53 (m, 2H), 7.45-7.20 (m,
7H), 4.87 (s, 2H), 4.61 (2H); 13C NMR (75 MHz) 154.1, 136.7,
134.8, 128.7, 128.3, 128.2, 128.1, 127.8, 127.5, 126.44, 126.35,
124.7, 123.6, 111.1, 72.4, 71.4; EIMS m/z: 264 (M+, 19), 172 (5),
168 (5), 156 (45), 141 (6), 128 (20), 127 (8), 115 (15), 91 (100),
77 (12), 71 (7). FW calcd for C18H16O2 264.1150, EI-HRMS found
264.1150.
1
hexanes) to yield 20 mg (34%) of 1d as a colorless oil. H NMR
(400 MHz) 8.71 (s, 1H), 7.72 (m, 2H), 7.60 (m, 1H), 7.45 (m,
1H), 7.29 (m, 2H), 5.74 (s, 1H), 4.69 (m, 2H), 4.26 (m, 2H),
2.62-2.12 (m, 6H), 2.10-0.53 (m, 17H), 0.73 (s, 2H), 2.89 (m,
2H), 2.6-1.8 (m, 8H), 1.72-1.30 (m, 6H), 0.9 (s, 3H). 13C NMR
(100 MHz, DMSO- d6) 13.6, 17.3, 21.0, 23.0, 24.5, 31.9, 32.7,
33.9, 35.5, 35.7, 38.5, 38.6, 44.8, 53.5, 56.2, 59.0, 72.1, 70.6, 111.4,
123.4, 124.0, 124.5, 126.3, 126.5, 127.6, 128.0, 128.9, 135.4, 154.3,
170.6, 199.3, 210.2; MS (DIP) m/z 486 (17), 300 (6), 299 (19),
272 (5), 271 (15), 253 (19), 172 (9), 159 (5), 158 (19), 157 (100),
156 (38), 129 (15), 128 (37), 105 (10), 91 (17), 79 (12), 77 (10),
55 (24); FW calcd for C32H38O4 486.2770, EI-HRMS found
486.2774.
O-(3-Hydroxy-2-naphthalenyl)methyl)estrone (1e). 1,1′-
(Azodicarbonyl)dipiperidine (225 mg, 0.89 mmol) was added to a
solution of 0.23 mL of tributylphosphine in dry toluene (6 mL) at
0 °C and stirred for 1 h. A solution of estrone (165 mg, 0.61 mmol)
and 5 (390 mg, 1.35 mmol) in 1:1 toluene and THF was added
dropwise to the reaction mixture over 15 min at 0 °C, and the
mixture was stirred for 1 h, kept at -15 °C for 48 h, poured into
40 mL of pentane, and stirred for 1 h at 0 °C. Solids were removed
by filtration, and solvents were removed under reduced pressure.
Crude O-(3-tert-butyldimethylsiloxy-2-naphthalenyl)methyl)estrone
(6e) was redissolved in ethyl acetate and passed through a short
silica gel column, the solvent was removed by evaporation, and
(3-tert-Butyldimethylsilyloxy-2-naphthalenyl)methyl Benzoate
(6c). Benzoyl chloride (60 µL, 49 mg, 0.35 mmol) was added to
the solution of 5 (100 mg, 0.35 mmol) in dry pyridine (0.7 mL),
and the mixture was was stirred at room temperature for 2 h and
poured into 50 mL of a saturated solution of sodium bicarbonate.
The resulting suspension was extracted with ethyl acetate; combined
organic layers were washed with brine and dried over sodium
sulfate. Solvent was removed under vacuum, and the residue was
purified by chromatography (20% of ethyl acetate in hexanes) to
(26) Georghiou, P. E.; Ashram, M.; Clase, H. J.; Bridson, J. N. J. Org. Chem.
1998, 63, 1819.
7614 J. Org. Chem. Vol. 73, No. 19, 2008

Photolabile Protection of Alcohols, Phenols, and Carboxylic Acids
the residue was taken up in dry THF (2 mL). TBAF (0.5 mL of
THF 1 M) was added to the solution of 6e, stirred for 5 min, and
poured into 30 mL of brine. The reaction mixture was extracted
by ethyl acetate; the combined organic layers were washed with
brine and dried over sodium sulfate, and the solvent was removed
under reduced pressure. Crude 1e was purified by chromatography
(25% of ethyl acetate in hexanes) to yield 145 mg (50%) of 7 as a
pale yellow oil. 1H NMR (400 MHz) 7.74-7.77 (m, 3H), 7.70 (d,
8.4 Hz), 7.45 (m, 1H), 7.35 (m, 1H), 7.28 (s, 1H), 7.23 (d, 8.4
Hz), 6.86 (dd, 8.8 Hz, 2.8 Hz, 1H), 6.81 (d, 2.8 Hz, 1H), 6.6 (s,
1H), 5.38 (s, 2H), 2.89 (m, 2H), 2.6-1.8 (m, 8H), 1.72-1.30 (m,
6H), 0.9 (s, 3H); 13C NMR (100 MHz, DMSO-d6) 13.8, 21.5, 25.4,
26.4, 29.6, 31.5, 35.9, 38.2, 43.9, 48.0, 50.4, 68.6, 110.9, 112.6,
115.3, 124.7, 124.8, 126.5, 126.8, 126.8, 127.9, 128.4, 128.8, 133.3,
134.6, 138.0, 153.0, 155.9, 220.1; DIP-MS m/z 426 (M, 47), 283(8),
261 (4), 157 (100), 144 (7), 128 (29), 115 (4), 97 (4), 77 (4), 45
(4); HRMS: 426.2195; FW calcd for C29H30O3 426.2195, EI-HRMS
found 426.2195.
5′-O-(3-Hydroxy-2-naphthalenyl)methyl-3′-O-3-dimethylthy-
midine (1f). 2,6-Di-tert-butylpyridine (200 µL, 0.89 mmol) and
silver triflate (150 mg, 0.58 mmol) were added to the solution of
3′-O-3-dimethylthymidine (8, 110 mg, 0.41 mmol) in dichlo-
romethane (2 mL) and cooled to 0 °C, and 7 (230 mg, 0.66 mmol)
in dichloromethane (1 mL) was added dropwise. The reaction
mixture was stirred at room temperature for 2 h and diluted with
dichloromethane (20 mL), and the solids were removed by filtration.
The filtrate was passed through a short silica gel column, and the
solvent was removed under reduced pressure to produce 150 mg
of crude 5′-O-(3-tert-butyldimethylsiloxy-2-naphthalenyl)methyl-
3′-O-3-dimethylthymidine (6f). DIP-MS m/z: 540 (5), 501 (3), 483
(8), 353 (13), 311 (20), 296 (5), 281 (8), 271 (15), 255 (5), 229
(16), 215 (51), 199 (8), 185 (5), 176 (11), 156 (5), 141 (21), 131
(20), 111 (9), 81 (100), 57 (29), 55 (31), 45 (21).
TBAF (0.3 mL of 1 M THF, 0.3 mmol) was added to the solution
of crude 6f in THF (2 mL) at 0 °C. The reaction mixture was stirred
for 10 min, poured into 30 mL of brine, and extracted with ethyl
acetate. The combined organic layers were washed with brine and
dried over sodium sulfate, and the solvent was removed under
reduced pressure. The residue was purified by column chromatog-
raphy (50% of ethyl acetate in hexanes) to give 103 mg (60%) of
1f as a colorless oil. 1H NMR (400 MHz) 7.68-7.74 (m, 2H), 7.62
(s, 1H), 7.42-7.46 (m, 2H), 7.31-7.37 (m, 2H), 7.24 (s, 1H), 7.03
(s, 1H), 6.29-6.32 (m, 1H), 4.87-97 (m, 2H) 4.15-4.18 (m, 1H),
4.0-4.04 (m, 1H), 3.88-3.91 (m, 1H), 3.78-3.81 (m, 1H), 3.35
(s, 1H), 3.32 (s, 1H), 2.41-2.47 (m, 1H), 2.05-2.12 (m, 1H), 1.76
(s, 3H); 13C NMR (100 MHz, DMSO-d6) 13.3, 28.1, 37.4, 57.4,
70.8, 72.5, 80.8, 83.2, 86.1, 110.5, 111.2, 124.1, 124.8, 126.5, 127.0,
127.8, 128.4, 128.6, 133.7, 135.0, 151.3, 153.5, 163.9; DIP-MS
m/z: 426 (4), 296 (4), 254 (27), 236 (14), 172 (5), 157 (100), 128
(59), 81 (95), 71 (12), 57 (5), 45 (5); HRMS 426.1295; FW calcd
for C23H26 N2O6 426.1791, EI-HRMS found 426.1785.
524 mg (98%) 6g as a colorless oil. 1H NMR (300 MHz) 7.74 (m,
2H), 7.67 (d, J ) 7.7 Hz, 1H), 7.43 (m, 1H), 7.34 (m, 1H),
7.22-6.95 (m, 6H), 5.34 (s, 2H), 5.01 (d, J ) 8.3 Hz, 1H), 4. 66
(dt, J ) 8.3 Hz, 6.0 Hz, 5.8 Hz, 1H), 3.1 (m, 2H), 1.41 (s, 9H),
1.05 (s, 9H), 0.33 (s, 6H); 13C NMR (75 MHz) 171.7, 155.0, 151.8,
135.9, 134.5, 129.9, 129.3, 128.7, 128.4, 127.8, 127.3, 126.9, 126.6,
126.5, 124.0, 113.2, 69.1, 63.1, 54.5, 38.4, 28.3, 25.7, 18.3, -4.17,
-4.21; EI-MS m/z 422 (15), 404 (10), 378 (29), 350 (20), 333 (10),
332 (31), 271 (11), 246 (12), 232 (18), 231 (79), 229 (13), 220(20),
216 (20), 215 (100), 214 (17), 213 (21), 201 (13), 200 (10), 199
(39), 185 (16), 164 (13), 158 (25), 157 (38), 146 (15), 141 (38),
129 (14), 128 (53), 120 (80), 115 (10), 100 (20); FW calcd for
C31H41NO5Si 535.2754, EI-HRMS found 535.2762.
N-BOC-L-Phenylalanine (3-Hydroxy-2-naphthalenyl)methyl
Ester (1g). TBAF (1 mL of 1 M THF solution, 1 mmol) was added
dropwise to a solution of 6g (426 mg, 0.98 mmol) in dry THF (4
mL). The reaction mixture was stirred at room temperature for 10
min, poured into saturated NH4Cl solution, and extracted with ethyl
acetate. Combined extracts were washed with brine and dried over
sodium sulfate. The solvent was removed, and the residue was
purified using a short layer of silica gel (methylene chloride) to
give 404 mg (98%) of 1g as a yellowish oil. 1H NMR (300 MHz)
7.70 (m, 2H), 7.64 (d, J ) 8.1 Hz, 1H), 7.41 (m, 1H), 7.31 (m,
1H), 7.23 (s,1H), 7.19-6.89 (m, 5H), 5.34 (dd, J ) 33.7, 12.4 Hz,
2H), 5.07 (d, J ) 7.9 Hz, 1H), 4.66 (m, 1H), 3.05 (d, J ) 5.64 Hz,
2H), 1.42 (s, 9H); 13C NMR (75 MHz) 173.0, 155.3, 152.7, 135.4,
135.1, 131.2, 129.2, 128.4, 127.8, 127.0, 126.8, 123.73, 123.69,
111.2, 80.4, 63.8, 54.5, 38.1, 28.2, 24.6; EI-MS m/z 395 (5), 351
(6), 264 (5), 263 (19), 178 (10), 158 (18), 157 (100), 156 (10), 129
(10), 128 (18), 127 (5), 107 (22); FW calcd for C25H27NO5
421.1889, EI-HRMS found 421.1888.
2-Ethoxy-3,4-dihydro-2H-naphtho[2,3-b]pyran (4). A solution
of 3 (50 mg, 0.29 mmol) and ethyl vinyl ether (2.8 mL, 29 mmol)
in acetonitrile-water (1:1, 290 mL) was irradiated at 254 nm in
mini-Rayonet photoreactor for 1.5 h. The photolysate was extracted
with ethyl acetate and dried over sodium sulfate, and solvents were
removed under vacuum. The residue was purified by chromathog-
raphy (20% ethyl acetate in hexane) to give 57 mg (87%) of 4 as
1
a colorless oil. H NMR (400 MHz) 7.69 (m, 2H), 7.55 (s, 1H),
7.69 (d, 8.3 Hz, 1H), 7.36 (m, 1H), 7.29 (m, 1H), 7.23 (s, 1H),
5.38 (t, 2.8 Hz, 1H), 3.89 (m, 1H), 3.64 (m, 1H), 3.21 (m, 1H),
2.87 (m, 1H), 2.15 (m, 2H), 1.10 (t, 7.0 Hz, 3H); 13C NMR (100
MHz) 16.0, 20.5, 27.5, 64.0, 98.0, 112.1, 123.8, 124.9, 125.6, 126.6,
127.3, 127.79, 127.83, 129.2, 133.7, 152.0; EI-MS m/z 229(18),
228(100), 183 (20), 182 (39), 181 (33), 154 (11), 153 (11), 152
(11), 128 (36), 115 (12), 102 (5), 89 (4); FW calcd for C15H16O2
228.1150, EI-HRMS found 228.1147.
Acknowledgment. Authors thank the NSF (CHE-0449478)
and Georgia Cancer Coalition for the support of this project.
N-BOC-L-Phenylalanine (3-tert-Butyldimethylsilyloxy-2-naph-
thalenyl)methyl Ester (6g). DMAP (14 mg, 0.11 mmol) and DCC
(480 mg, 2.33 mmol) were added to a solution of N-BOC-L-
phenylalanine (265 mg, 1 mmol) and 5 (334 mg, 1.21 mmol) in
dichloromethane (7 mL), and the reaction mixture was stirred
overnight at room temperature Solids were removed by filtration,
the organic layer was washed with brine and dried over sodium
sulfate, and solvent was removed under vacuum. The residue was
purified by chromatography (10% ethyl acetate in hexanes) to afford
Supporting Information Available: General experimental
methods, detailed preparative procedures for caging reagents 5
1
and 7, as well as 3′-O-3-dimethylthymidine (8); copies of H
and 13C NMR spectra of newly synthesized compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO801302M
J. Org. Chem. Vol. 73, No. 19, 2008 7615