Development of hydrophilic photolabile hydroxyl protecting groups

Article abstract of DOI:10.1039/c1pp05281k

Hydrophilic photolabile protecting groups (PPGs) for hydroxyl protection have been developed. The new PPGs are derived from 3-(dimethylamino)trityl (DMATr) by replacing the two methyl groups with two hydrophilic butyryl groups. The new PPG reagents can be readily prepared and installed. They are stable in the dark but can be removed cleanly and efficiently in aqueous environments upon irradiation with a UV lamp or sunlight.

Full text of DOI:10.1039/c1pp05281k

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Cite this: Photochem. Photobiol. Sci., 2012, 11, 514
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PAPER
Development of hydrophilic photolabile hydroxyl protecting groups†‡
Haishen Yang, Lei Zhou and Pengfei Wang*
Received 2nd September 2011, Accepted 28th October 2011
DOI: 10.1039/c1pp05281k
Hydrophilic photolabile protecting groups (PPGs) for hydroxyl protection have been developed. The new
PPGs are derived from 3-(dimethylamino)trityl (DMATr) by replacing the two methyl groups with two
hydrophilic butyryl groups. The new PPG reagents can be readily prepared and installed. They are stable
in the dark but can be removed cleanly and efficiently in aqueous environments upon irradiation with a
UV lamp or sunlight.
Photolabile protecting groups (PPGs) are protecting groups that
can be removed with photo irradiation. They are indispensable
tools in a broad spectrum of basic and applied research areas.1–5
Their advantages stem from using light as a traceless reagent in
the removal process. Photochemical removal of protecting
groups often occurs under mild conditions and does not require
chemical reagents. In addition, light also provides precise tem-
poral and spatial control over the course of a reaction. Numerous
efforts have been devoted to developing new PPGs.1,4 However,
Scheme 1 Photolabile hydroxyl protecting group DMATr.
ever increasing interests in utilizing a light-controlled approach
in a broad range of research fields have spurred increasing
molecules and a low concentration of the caged compound is
demands for the further development of current and new PPGs.
sufficient, the caged substrate can have meaningful solubility in
We are interested in developing structurally simple and
water even if the photocage itself is hydrophobic. However,
mechanistically novel PPGs with different chemical/photochemi-
when a relatively high concentration of caged compounds is
cal properties for various applications. We have recently reported
needed, especially when the substrate to be caged is not polar
a series of new PPGs, featuring a salicyl alcohol skeleton, which
enough,8 increasing the water-solubility of the caged substrate
can be used for carbonyl protection.6 We hypothesize that the
will rely on improving the hydrophilicity of the PPG segment.
effective and efficient photolysis of the carbonyl PPGs starts
The hydrophobic nature of DMATr obstructs its wide appli-
from the heterolytic cleavage of the benzylic C–O bond. Based
cations in aqueous environments. Herein we report our effort in
on this assumption, we inferred that the structurally related tri-
modifying DMATr to improve its water solubility.
arylmethyl groups could be robust PPGs for hydroxyl groups.
We found that the new trityl PPG in the ether 4 proved to be a
Research along this direction produced useful results. For
robust hydroxyl PPG for releasing alcohols in aqueous solutions
example, heating an alcohol (1) with the PPG reagent 2 at
under neutral or basic conditions (Scheme 2).
120 °C smoothly installed the dimethylamino trityl PPG (i.e.
DMATr) to produce the ether 3 in high yield (Scheme 1). Upon
irradiation, the alcohol was released in high efficiency.7
One important aspect of PPG applications is in bio-related
research as so-called “photocages”, where the photochemical
removal of the photocages often takes place in aqueous environ-
ments. Since the substrates to be caged are often polar biological
Department of Chemistry, University of Alabama at Birmingham, 901
14th Street South, Birmingham, Alabama, United States. E-mail: wangp@
uab.edu; Fax: +1 205 934 2543; Tel: +1 205 996 5625
†This paper is part of a themed issue on photoremovable protecting
groups: development and applications.
‡Electronic supplementary information (ESI) available: experimental
details, spectroscopic data, UV spectra of 4a, and 1H and 13C NMR
spectra of 4a, 7a–7e, 8, 9, 11, 12, and 17–22, and HPLC profiles of the
reaction of 4a. See DOI: 10.1039/c1pp05281k
Scheme 2 New hydroxyl PPG.
514 | Photochem. Photobiol. Sci., 2012, 11, 514–517
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Table 1 Hydrophilic photolabile hydroxyl protecting group
Entry
1
R′OH (10)
Yield of 7a (%)
4
Yield of 5/6c,d (%)
Irradiation time (min)e
79
96/93f
96/92
12f
12
2
83
97/93
10
3
4
42b
97
99/96
95/96
10
10
5
81
100/95
10
a Protection reactions were completed by heating 1.5 equiv. of the PPG reagent (3 equiv. for 10a) and 1 equiv. of R′OH at 120 °C. b The reaction was
carried out with 1 equiv. of the PPG reagent and 6 equiv. of the alcohol. c Reactions were carried out in 3 mM aqueous solutions of 4 under basic
1
conditions without deaeration. d Yields were determined by H NMR with an internal reference. e Irradiation with a 450 W medium pressure mercury
lamp equipped with a Pyrex filter sleeve. f Reaction was carried out in 3 mM aqueous solutions of purified 4 under neutral conditions without
deaeration.
For example, a quantum yield of 0.23 was obtained in releas-
analysis of the crude reaction mixture 4a (pH ∼ 12) did not
show significant byproducts (see ESI‡). Irradiation of 4a for
12 min and 20 min did not cause a perceptible change in the
reaction outcomes based on NMR and HPLC analysis (for
HPLC profiles, see ESI‡). Encouraged by these results, we
examined the photo release of some representative compounds,
where consistent results were obtained (Table 1, entries 2–5).
Photoreactions proved to be clean with irradiation by both a
mercury lamp and sunlight. For example, the reaction of 4d
(3 mM aqueous solution) under sunlight resulted in clean depro-
tection after 80 min. It is interesting to note that with continuous
irradiation under sunlight for 7 h, slow decomposition of the
PPG reagent became detectable.
It has been demonstrated that DMATr is relatively stable
towards acid treatment, and constitutes orthogonal protecting
groups with the conventional acid-labile trityl type protect-
ing groups.7 As expected, the new PPG in 4 also showed remark-
able stability under acidic conditions. For example, treatment of
4a and its corresponding Tr counterpart with HCOOH/Et2O/
dichloromethane (2 : 3 : 1) for ca. 1 h resulted in the complete
removal of the Tr group in methyl 6-O-trityl-α-D-glucoside;
however, there was no detectable decomposition of 4a by NMR
and TLC.
ing methyl α-D-glucoside (5a) from the purified ether 4a
(εH O, 315 nm = 1.7 × 103 M−1 cm−1) in water without deaeration.9
2
The chemical yields of 5a and 6 after irradiation of a 3 mM
aqueous solution (pH ∼ 7) with a 450 W medium pressure
mercury lamp filtered through a Pyrex sleeve for 12 min were
1
96% and 93%, respectively, based on H NMR analysis. Alter-
natively, the ether 7 was hydrolyzed, and without purification,
the residue obtained after the removal of methanol was re-dis-
solved in water. The resulting basic solution (pH ∼ 12) was irra-
diated under the same conditions and provided similar results,
i.e., the chemical yields of 5a and 6 by NMR were 96% and
92%, respectively (Table 1, entry 1). The yields were further
confirmed in a preparative run. To simplify column purification,
the dicarboxylate 6 was treated with diazomethane and isolated
as its corresponding dimethyl ester 8 in 92% yield. A trace
amount of a byproduct 9 (<2%) was also isolated. The structures
of 8 and 9 differed in the substitution of the meta amino group:
where compound 9 has only one 4-butyryl chain connected to
the nitrogen. The structure of 9 was confirmed by its indepen-
dent synthesis.
Removal of the PPG DMATr in methanol or water often led to
multiple products derived from the PPG chromophore;7 however,
the new PPG provided much cleaner reactions with excellent
recovery yields of the PPG reagent. For example, LC-MS
We further synthesized two other protected alcohols, i.e. 11
and 12 equipped with similar PPGs (Scheme 3). Under the same
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(Table 1, entry 5). Subsequent saponification of 7, 11, and 12
provided the water-soluble caged compounds.
Conclusions
In conclusion, we converted the robust DMATr PPG to its water-
soluble counterparts. The new PPGs led to efficient and clean
photo-deprotection reactions in aqueous environments. The new
PPG reagents can be readily prepared, and the PPG installation
can be conveniently achieved by using the neutral protection pro-
tocol. We anticipate the new PPGs can be useful in a wide range
of research.
Scheme 3 Similar PPGs.
conditions of saponification and irradiation in water, 11 and 12
showed results similar to that of 7d, except that the reaction of
11 produced a minor byproduct derived from the PPG moiety
upon inspection of the crude reaction mixture by NMR spec-
troscopy. Interestingly, the reactions of 11 appeared to be slower
than the others when the photoreactions of 7d, 11 and 12 were
carried out in MeCN/water (9 : 1) or methanol after saponifica-
tion. In addition, the reactions in these solvents became less
clean than in wholly aqueous solution.
We are thankful to NSF for its support (CHE-0848489).
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From the commercially available 3-amino benzoic acid 16, the
trityl alcohol 17 was obtained after a sequence of esterification,
acetylation of the amino group, addition of phenyl groups to the
methyl ester moiety, and removal of the acetyl group under
alkali conditions. Alkylation of the amino group of 17 with
bromo esters led to 18 and 8. Conjugate addition of 17 to methyl
acrylate led to 19. Subsequent acetylation with acetic anhydride
catalyzed by MoCl2O2 converted the trityl alcohols 18, 19, and
8 to the corresponding PPG reagents 20, 21, and 22, respect-
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reagents. Thus, without using any other chemical reagents,
heating the trityl acetates and an alcohol R′OH at 120 °C resulted
in 7, 11, and 12, respectively. In the reaction to form 7a, a rela-
tively high 22/10a ratio (i.e. 3 : 1) was needed due to the un-
desired acetyl migration confirmed when heating 10a (Table 1,
entry 1). In the reaction of 10c with 22, glycerol was used in
excess (Table 1, entry 3). The low combined yields of 7c (42%)
and the di-protected byproduct (22%) were due to the presence
of water in glycerol, and the corresponding trityl alcohol 8 was
obtained as another byproduct. In the reaction of 10e, the di-pro-
tected thymidine was isolated as a byproduct in 18% yield
Scheme 4 Preparation and installation of the new PPGs.
516 | Photochem. Photobiol. Sci., 2012, 11, 514–517
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