Photolabile protection of 1,2- and 1,3-diols with salicylaldehyde derivatives

Article abstract of DOI:10.1021/ol802141g

(Chemical Equation Presented) 1,2- and 1,3-diols, including carbohydrates, can be readily caged as acetals of 5-methoxy- or 5-hydroxysalicylaldehydes. Irradiation of these acetals with 300 nm light results in their efficient (Φ = 0.2-0.3) cleavage, regenerating an aldehyde and a glycol in excellent chemical yield. Photoreactive 5-hydroxysalicylaldehyde acetals can be produced by mild in situ reduction of photostable p-quinone precursors.

Full text of DOI:10.1021/ol802141g

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5277-5280
Photolabile Protection of 1,2- and
1,3-Diols with Salicylaldehyde
Derivatives
Alexey P. Kostikov and Vladimir V. Popik*
Department of Chemistry, UniVersity of Georgia, Athens, Georgia, 30602
Vpopik@chem.uga.edu
Received September 12, 2008
ABSTRACT
1,2- and 1,3-diols, including carbohydrates, can be readily caged as acetals of 5-methoxy- or 5-hydroxysalicylaldehydes. Irradiation of these
acetals with 300 nm light results in their efficient (Φ ) 0.2-0.3) cleavage, regenerating an aldehyde and a glycol in excellent chemical yield.
Photoreactive 5-hydroxysalicylaldehyde acetals can be produced by mild in situ reduction of photostable p-quinone precursors.
Photolabile protecting groups (PPGs), known as “cages” in
biochemistry, allow for the spatial and temporal control of
substrate release, as well as “reagentless” deprotection.1-3
PPGs have found numerous applications in biochemistry,3
organic synthesis,1,2 fabrication of high density probe arrays
(aka biochips),4 and time-resolved X-ray crystallography.5
While a large selection of photo cages is available for
carboxylic acids,6 phosphates,7 amines,8 and alcohols,9 the
choice of photolabile protecting groups for glycols is very
limited.10,11 Photolysis of o-nitrobenziledene acetal deriva-
tives of 1,2- and 1,3-diols results in the acetal ring opening
and the formation of two regioisomers of glycol mono-o-
nitrobenzoate.10 Acetals produced from 6-bromo-7-hydroxy-
coumarin-4-carbaldehyde and 1,2- and 1,4-diols liberate
(5) (a) Srajer, V.; Teng, T.-Y.; Ursby, T.; Pradervand, C.; Ren, Z.;
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10.1021/ol802141g CCC: $40.75
Published on Web 10/22/2008
2008 American Chemical Society

starting glycols under irradiation albeit with low quantum
efficiency (Φ ) 0.005-0.028).11a Corresponding derivatives
of 1,3-diols, on the other hand, are inert to photolysis.
Monoethers of glycerol were liberated under single and two-
photon photolyses from acetals of (8-bromo-7-hydroxyquino-
lin-2-yl)formaldehyde.11b Since glycol protection is a com-
mon procedure in natural product synthesis,1 especially in
carbohydrate chemistry,12 the search for general, reliable,
and efficient PPG for diols continues.
nm. The use of 254 nm irradiation for the deprotection is
impractical since aldehyde byproduct 4 is itself photoreactive
and has a stronger absorbance at this wavelength. UV spectra
of cyclic acetals produced from 5-methoxysalicylaldehyde,
however, have a strong band at 295 nm (log ε ) 3.6, Figure
1). The aldehyde itself (4, R′ ) 5-MeO), on the other hand,
is practically transparent at this wavelength.
Caged glycols 6a-d were prepared by the direct reaction
of 5-methoxysalicylaldehyde with diols 5a-d in the presence
of triethyl orthoformate and a catalytic amount of either
p-toluenesulfonic acid or tetra-n-butylammonium tribro-
mide14 (Scheme 2, Table 1).15
We have recently reported that alcohols caged with
o-hydroxybenzyl-based PPGs are efficiently liberated under
300 nm irradiation.13 This reaction proceeds via excited-
state intramolecular proton transfer (ESIPT) from the phe-
nolic hydroxyl to the ether oxygen, followed by the formation
of an o-quinone methide intermediate (2, Scheme 1). In the
presence of water, the latter undergoes rapid hydration to
diol 3 (Scheme 1). We reasoned that similar ESIPT in
salicylaldehyde acetals (1, X ) OR′) would generate an
unstable hemiacetal, which should undergo rapid dehydration
to liberate a second molecule of an alcohol. Cyclic acetals
in the same manner can serve as photolabile protecting
groups for glycols.
Scheme 2
.
Formation and Photodecomposition of the Acetals of
5-Methoxysalicylaldehyde
Scheme 1. Proposed Mechanism of the Photodecomposition
Irradiation of solutions of acetals 6a-d in 20% aqueous
methanol with 300 nm light results in rapid decomposition
of the starting material as evidenced by the bleaching of
absorbance at 295 nm. This decay is accompanied by the
formation of a characteristic 358 nm band of 5-methoxysali-
cylaldehyde (Figure 1). The yields of glycol release were
determined by HPLC (6b,c) or NMR spectroscopy (6a,d);
the quantum efficiencies of the uncaging reaction were
measured using chemical actinometry (Table 1).16
1,2-Glycols are liberated upon irradiation of dioxolanes
5a,b in excellent chemical (>90%) and high quantum yields
(Φ300 nm ∼ 0.3). Efficiency of the photorelease of 1,3-diols
from the corresponding dioxanes 6c,d is notably lower (Φ300
) 0.03-0.1). We believe that intermolecular nucleophilic
attack by the hydroxy group on the intermediate o-quinone
methide 2c,d, resulting in the ring closure and the regenera-
tion of starting material, efficiently competes with the
hydration of 2c,d to form hemiacetal 3c,d. At low conversion
of acetal 6c, 2-phenyl-1,3-propanediol (5c) is the only
photolysis product observed by HPLC. Further irradiation,
however, results in the formation of several secondary
photoproducts and the yield of 5c at complete consumption
of acetal 6c drops to ca. 60%.
We have explored the utility of several 2-hydroxybenzal-
dehydes for the photolabile protection of glycols. While both
the parent salicylaldehyde (4, R′ ) H) and o-vanillin (4, R′
) 3-MeO) readily produce cyclic acetals with 1,2- and 1,3-
diols, the latter have very weak absorbance at or above 300
(9) (a) Zehavi, U.; Amit, B.; Patchornik, A. J. Org. Chem. 1972, 37,
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U.; Smith, A. L. J. Am. Chem. Soc. 1993, 115, 7625. (d) Suzuki, A. S.;
Watanabe, T.; Kawamoto, M.; Nishiyama, K.; Yamashita, H.; Ishii, M.;
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M. K. Tetrahedron Lett. 1998, 39, 1653. (f) Furuta, T.; Hirayama, Y.;
Iwamura, M. Org. Lett. 2001, 3, 1809. (g) Pirrung, M. C.; Bradley, J.-C. J.
Org. Chem. 1995, 60, 1116.
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Zhu, Y.; Pavlos, C. M.; Toscano, J. P.; Dore, T. M. J. Am. Chem. Soc.
2006, 128, 4267.
Acetals 6a-d are not very stable neat or in chloroform or
dichloromethane solutions and slowly decompose in the dark.
We believe that an intramolecular hydrogen bond (1, Scheme
(12) (a) Fraser-Reid, B.; Jayaprakash, K. N.; Lopez, J. C.; Gomez, A. M.;
Uriel, C. ACS Symp. Ser. 2007, 960, 91. (b) Suzuki, K.; Mizuta, T.;
Yamaura, M. J. Carbohydr. Chem. 2003, 22, 143. (c) Calinaud, P.; Gelas,
J. In PreparatiVe Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker: New York, 1997; p 3. (d) Garegg, P. J. In PreparatiVe Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York, 1997; p 53. (e)
Inch, T. D. Tetrahedron 1984, 40, 3161.
(14) Gopinath, R.; Haque, S. J.; Patel, B. K. J. Org. Chem. 2002, 67,
5842.
(15) For details, see the Supporting Information.
(16) Murov, S. L.; Carmichael, I.; Hug, G. L. In Handbook of
Photochemistry; Marcel Dekker: New York, 1993; p 299.
(13) (a) Kostikov, A. P.; Popik, V. V. J. Org. Chem. 2007, 72, 9190.
(b) Kulkov, A.; Arumugam, S.; Popik, V. V. J. Org. Chem. 2008, 73, 7611.
5278
Org. Lett., Vol. 10, No. 22, 2008

Scheme 3
.
Preparation of 2,5-Dihydroxybenziledene-Caged
1,3-Glycols
Figure 1
.
UV spectra of 6b (solid line, ca. 1 × 10-4 M in 20%
aqueous methanol) and its 300 nm photolysis (dashed lines, every
4 min).
spectroscopy. Irradiation of 9d with 300 nm light resulted
in efficient decomposition (Φ300 ) 0.18) of the starting
acetal. The reduction of intensity of the acetal 9d
absorption band at 294 nm is concomitant with the
formation of a 357 nm band corresponding to 2,5-
dihydroxybenzaldehyde. NMR analysis of the photolysate
confirmed clean and quantitative uncaging of neopentylg-
lycol (5d) and the formation of 2,5-dihydroxybenzalde-
hyde as the only detectable byproduct.
Table 1. Yields of the Formation and the Hydrolytic Stability of
Acetals 6a-d; Quantum and Chemical Efficiencies of
Photochemical Release of Glycols 5a-d
yield of
6, %
yield of
uncaging, %
hydrolytic stability
Φ300nm
(τ, h)c
5a
5b
5c
5d
89
75
74
74
100a
96b
0.36
0.27
0.03
0.1
50
45
.500
500
59b
100a
a NMR. b HPLC. c 20% aqueous methanol at ambient temperature.
1) facilitates slow proton transfer, even in the ground state.
In fact, in hydrogen-bond-accepting solvents, such as metha-
nol or ethers, these compounds are stable for weeks at
ambient temperatures. In 20% aqueous methanol, which was
used for the uncaging experiments, 1,3-dioxanes 6c,d are
stable toward hydrolysis, whereas the stability of dioxolanes
6a,b is somewhat lower (Table 1). To increase the lifetime
of caged glycols we decided to explore the release of diols
from cyclic acetals of 5-hydroxysalicylaldehyde. This system
is an analogue of a recently developed “safety catch” caging
group for alcohols, which can be stored in a thermally and
photochemically stable p-quinone form and quantitatively
reduced in situ to the photoreactive hydroquinone.13a Acetals
of 2-formyl-1,4-benzoquinone (8d,e) were prepared by the
oxidative demethylation of 2,5-dimethoxybenzylidene acetals
7d,e using silver(II) oxide in nitric acid (Scheme 3).15 These
1,3-dioxanes are stable in the dark and under 300 nm
irradiation. Mild heterogeneous reduction of 8d,e in chlo-
roform with aqueous sodium dithionite yielded reactive
acetals 9d,e.
Figure 2
.
UV spectra of 9e (solid line, ca. 1 × 10-4 M in 20% aqueous
methanol) and its 300 nm photolysis (dashed lines, every 5 min).
The utility of the 2,5-dihydroxybenzylidene group as a
photoremovable benzylidene protecting group for carbohy-
drates was tested on the glucose derivative 5e (Scheme 3).
Phenyl 4,6-O-(2,5-dimethoxybenzylidene)-ꢀ-D-glucoside (7e)
was prepared by the treatment of 5e with R,R-2,5-tet-
ramethoxytoluene in the presence of a catalytic amount of
The release of neopentylglycol in the photolysis of
acetal 9d was monitored by both UV (Figure 2) and NMR
Org. Lett., Vol. 10, No. 22, 2008
5279

substrates upon 300 nm irradiation in a good to excellent
yield. Photodeprotection is accompanied by the bleaching
of the acetal band at ca. 295 nm and the rise of the
aldehyde absorption at ca. 360 nm. Efficient bleaching at
the irradiation wavelength allows for the use of a high
substrate concentration. The quinone precursor of the 2,5-
dihydroxybenzylidene cage is photochemically inert but
can be quantitatively converted in situ into a photoreactive
form using mild reducing agents.
Scheme 4. Photochemical Deprotection of a Glucose Derivative
p-toluenesulfonic acid. Conversion of 7e into 4,6-O-2,5-
dihydroxybenzylidene derivative 9e is discussed above
(Scheme 3).15 Irradiation of 9e with 300 nm light in 20%
aqueous methanol results in efficient (Φ300 ) 0.21) release
of the phenyl glucoside 5e in 97% chemical yield (Scheme
4).
In conclusion, two novel photolabile protecting
groups, 2-hydroxy-5-methoxybenzylidene and 2,5-dihy-
droxybenzylidene, were developed for the protection of
glycols. We have shown that 1,2- and 1,3-glycols can be
readily converted into acetals of 5-methoxysalicylaldehyde
and formylhydroquinone. These acetals efficiently release
Acknowledgment. We thank the Georgia Cancer Coalition
and donors of the ACS Petroleum Research Fund (48353-
AC4) for support of this project.
Supporting Information Available: Synthesis and char-
acterization of the compounds 6a-d, 7d,e, 8d,e, and 9d,e
and photolysis protocols. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL802141G
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Org. Lett., Vol. 10, No. 22, 2008