Structurally Simple Benzyl-Type Photolabile Protecting Groups for Direct Release of Alcohols and Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.5b00699

Structurally simple benzyl-type photolabile protecting groups (PPGs) have been developed to release alcohols and carboxylic acids. Release of two substrates from one PPG chromophore has also been accomplished. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b00699

Letter
pubs.acs.org/OrgLett
Structurally Simple Benzyl-Type Photolabile Protecting Groups for
Direct Release of Alcohols and Carboxylic Acids
Pengfei Wang,* Wenya Lu, Dattatray A. Devalankar, and Zhenying Ding
Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States
S
* Supporting Information
ABSTRACT: Structurally simple benzyl-type photolabile protecting groups (PPGs) have
been developed to release alcohols and carboxylic acids. Release of two substrates from
one PPG chromophore has also been accomplished.
fficient photochemical cleavage of covalent bonds is in
high demand in many research areas, especially when
with both DMBn and the new 3-diethylaminobenzyl (DEABn)
PPG, only removed the DEABn group in high yield while the
DMBn PPG remained intact (eq 1). In a preparative scale
E
reactions that take place under neutral and reagent-free
conditions with precise spatial and temporal control are
desired. One application is for photolabile protecting group
(PPG) development.1−3 PPGs are an indispensable tool in a
broad range of basic research and applied sciences.4−9 Their
advantages stem from using light as a traceless reagent in the
deprotection process. Despite recent advances in PPG
development, ever increasing interest in utilizing a light-
controlled approach from a variety of research fields has
generated an increasing demand for more new PPGs to
complement the existing ones, and “efficient and fast systems
for poor leaving groups such as RO−, RHN− and RS− are
wanted in particular”.1
In 1962, Barltrop and Schofield first demonstrated that
glycine carbamate could be released from benzyl protection
upon irradiation at 254 nm.10 Subsequent efforts toward
improving photochemical efficiency of this reaction have been
directed to structural variations of the benzyl group by
adjusting its aromatic substitution, expansion of the aromatic
system, and/or modification at the benzylic carbon.3 For
example, introduction of two methoxy groups at the meta
positions of the benzyl group (i.e., 3,5-dimethoxybenzyl
(DMBn)) greatly increased the yields of the released amino
acids.11 The term for this substituent effect was coined by
Zimmerman as the excited state meta effect.12−15 However,
DMBn only releases a good leaving group such as carbamate or
carboxylate but not alkoxide. Recently, Toscano et al.
attempted to release diazeniumdiolates from 3-(dimethyl-
amino)benzyl protection;16 Falvey et al. demonstrated photo-
chemical heterolysis of 3,5-bis(dimethylamino)benzyl ester to
release carboxylic acids.17
reaction of 1 (5.0 mM in methanol), the product 2 was isolated
in 93% yield after 90 min irradiation (Pyrex, λ > 280 nm). We
further confirmed the photochemical inertness of DMBn by
irradiating DMBn-monoprotected 1,16-hexadecanediol with
higher energy UV (i.e., Vycor-filtered) irradiation under the
same conditions for 60 min, and only a trace amount of the
alcohol was released based on NMR analysis.19
Synthesis of the structurally simple PPG reagent 420 and its
installation are straightforward. From commercially available 3-
aminobenzyl alcohol 3, it takes two steps to synthesize the PPG
reagent 4 (Scheme 1).21 Its reaction with an alcohol (5)
deprotonated by sodium hydride resulted in the corresponding
ether 6 in high yields, for example, from primary alcohol 3-
Scheme 1. Preparation of DEABn Ether
Herein we report our recent discovery that by using only one
meta dialkylamino group, the benzylic C−O cleavage was
greatly facilitated and poor leaving groups such as alkoxide can
be released directly. For example, 15 min irradiation (Vycor, λ
> 220 nm) of 1 (5.0 mM in CD3CN/D2O 9:1),18 equipped
Received: March 9, 2015
Published: April 16, 2015
© 2015 American Chemical Society
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Letter
phenyl-1-propanol 5a to 6a in 91% yield and from secondary
alcohol 5b to 6b in 98% yield (Table 1, entries 1 and 2). The
ether of tertiary alcohol, i.e., 6c, was prepared in 91% yield by
treating 4 with potassium tert-butyloxide (Table 1, entry 3).
In a preparative run, irradiation of a 5.0 mM solution of 6b
(ε308 nm (MeCN) = 2900 M−1 cm−1, Φ = 0.26) in CH3CN/H2O
(4:1) released the rhamnoside 5b in 91% isolated yield (eq 2),
which confirmed the yield determined by H NMR analysis
(Table 1, entry 2).
1
Table 1. Preparation and Photolysis of DEABn Ether
The PPG part was isolated mainly as the benzyl alcohol 7
(51%) and the amide 8 (27%), formed by trapping the benzylic
cation intermediate with water and acetonitrile, respectively.
The amide 8 (5.0 mM solution in CD3OD or CH3OH) is
photochemically stable when irradiated (Pyrex filter) for 15 min
in control experiments. A minor byproduct 9 was also isolated
in 5% yield. Its identity was confirmed by a separate synthesis
of 9 from oxidation of 7. In a control experiment, similar
product distributions and reaction efficiencies were obtained in
the corresponding deaerated solutions except that the product
9 was not observed.
To further evaluate the DEABn PPG, we examined its
protection and deprotection efficiency with a number of
alcohols 5d−5j (Table 1, entries 4−10). High protection and
deprotection yields were obtained.
A side-by-side comparison of releasing 3-phenyl-1-propanol
from DEABn and DMATr (i.e., 3-(dimethylamino)trityl)22,23
protection showed similar yields under the same irradiation
conditions in both MeCN/water (4:1) and methanol.
Comparison of releasing the same alcohol (i.e., 3-phenyl-1-
propanol) from DEABn and 2-nitrobenzyl (2-NB)24,25
protection under the same irradiation conditions revealed
complete conversion upon 15 min irradiation in both cases;
however, for 2-NB, only 40% of the alcohol was observed after
15 min irradiation in CD3CN/D2O (4:1) and 30% in CD3OD,
while DEABn released the alcohol in nearly quantitative yield in
both solvent systems. The low efficiency of the 2-NB group
likely originates from the slow postirradiation thermal process
of substrate release.26−28 After standing in the dark at room
temperature after irradiation, the yield of the released alcohol
from 2-NB protection gradually increased to 64% at 4 h and
83% at 25 h in CD3CN/D2O, and 42% at 4 h and 77% at 25 h
in CD3OD.
a
b
c
THF, −10−50 °C. DMF, −10 °C−room temperature. 5.0 mM
solution (MeCN/water) irradiated with a 450 W medium pressure
mercury lamp without deaeration, and yield determined by H NMR
1
In contrast to the nitrobenzyl series of PPGs, deprotection of
DEABn does not destroy the working chromophore. Therefore,
we can design a more efficient and structurally simpler PPG
which can release two substrates from one chromophore. As
shown in Scheme 2, starting from the commercially available
dimethyl 5-aminoisophthalate 10, the PPG reagent diethyl-
aminoisophthalyl chloride (DEAIP-Cl, 11) was prepared in
three steps. Two 5b alcohol molecules were then protected by
analysis with isolated yield in parentheses.
Irradiation of DEABn ether 6 (5.0 mM in CD3CN/D2O 4:1)
with a Pyrex filter for 15 min resulted in release of the primary,
secondary, and tertiary alcohols 5a−c in 98%, 95%, and 90%
yield, respectively.18 The reaction was slightly slower in
methanol than in MeCN/H2O. Using deuterated solvent(s)
has no apparent effect on the efficiency and cleanness of the
reaction.
one PPG molecule to provide the diether 12 (ε313 nm (MeCN)
=
3000 M−1cm−1). Irradiation of 12 (Pyrex-filtered UV, 5.0 mM)
led to complete conversion in 30 min in both CD3CN/D2O
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than alkoxide. For example, under the same conditions, 15 min
irradiation of 6a−6c released the alcohols in 90%−98% yield
while only 50% of the acid was released from 13a.18 This
observation is not understood at this time, even though the
origin of the excited state meta effect has been inves-
tigated.12−15,17,29−32
Scheme 2. Preparation of DEAIP Ether and Photolysis
In summary, two new structurally simple benzyl-type PPGs
have been developed. The new PPGs are designed on the basis
of the excited state meta effect. However, in contrast to the
widely known DMBn (also based on the excited state meta
effect), the new PPGs release not only acid but also alcohol.
Due to the different absorption profiles of DEABn and DMBn,
they can be used together for sequential release of carboxylic
acids by control of the irradiation wavelength. Moreover,
release of two substrates from one chromophore has also been
achieved, which should be useful in developing practical
photocleavable linkers in various applications.
(4:1) and CD3OD.18 In a preparative run in CH3CN/H2O
(4:1), the released 5b was isolated in 88% yield.
DEABn can also protect carboxylic acids. Due to the
bathochromic shift of the DEABn’s effective absorption (∼310
nm) compared with that of DMBn (∼279 nm), DEABn and
DMBn can be used together for sequential release of carboxylic
acids. For example, the ester 13a (5.0 mM) releases octanoic
acid 14 in excellent yield (>97%) in methanol or in MeCN/
water (4:1) upon Pyrex-filtered UV irradiation in 1−2 h while
the ester 13b remained intact under the same irradiation
conditions.18 With Vycor-filtered UV irradiation, the con-
version of 13a was 65% in 15 min while the conversion of 13b
was only 23% under the same conditions.19
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, full characterization, and NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangp@uab.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE 1404063) and ACS PRF (51827-
ND7) for financial support.
We further demonstrated the different photochemical
behavior of DEABn and DMBn during irradiation of the
diester 15, equipped with both PPGs (Scheme 3). Thus,
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