Chiral photocages based on phthalimide photochemistry

Article abstract of DOI:10.1021/ja066582n

A new class of photoremovable protecting groups, based on a photoinduced decarboxylation reaction coupled with the elimination of the caged molecule, is described for 2-phthalimido-3-hydroxy-propionate derivatives. When derived from enantiopure N-phthaloyl- serine or threonine, the chirality of the starting amino acid is transmitted to the protected (caged) molecule. These photocages possess good properties for their use in biological systems, and the introduction of chirality opens new possibilities for the study of diastereoselective photochemistry and stereodifferentiation processes involving the release of the caged molecule. Copyright

Full text of DOI:10.1021/ja066582n

Published on Web 12/09/2006
Chiral Photocages Based on Phthalimide Photochemistry
Alberto Soldevilla* and Axel G. Griesbeck
Institute of Organic Chemistry, UniVersity of Cologne, Greinstrasse 4, D-50939, Ko¨ln, Germany
Received September 12, 2006; E-mail: alberto.soldevilla@dq.unirioja.es
Scheme 1
The quest for new efficient caging groups is an active area of
research in bio-organic chemistry.1 More specifically, photoremov-
able protecting groups (PRPGs) constitute a powerful tool for the
masking of potentially bioactive molecules in biological media,
controlling the release of the molecule in space and time. Besides
the biological applications of these phototriggers (in neurobiology,
physiology, biochemistry),2 they have been applied in multistep
organic syntheses as conventional protecting groups,3 in combina-
torial chemistry, solid-phase syntheses, and for the preparation of
DNA microarrays using photolithographic techniques.4 Beyond the
widely used ortho-nitrobenzyl photocage, which suffers from several
disadvantages,5 a number of PRPGs have been developed,4,6 many
of them based in photoinduced electron transfer (PET) processes.5
Recently, a new kind of PRPG has been described based on the
PET-initiated photochemical decarboxylation of ketoprofen,7 which
allows a rapid and efficient photorelease of alcohols and carboxylic
acids. The interest on this kind of photodecarboxylation processes
as a basis for PRPG systems is increasing.8 Motivated by previous
studies on the PET decarboxylation photoreactions of the N-
phthaloylated derivatives of the natural amino acids serine and
threonine,9 we present a novel methodology, which introduces
chirality in the area of photocaged systems.
tion of (2S,3R)-1, the alkenylphthalimide trans-2 was detected as
the sole photoproduct.
The photocleavage of this PRPG was accomplished by irradiation
into the 300 nm absorption band. The high absorbance of the
phthalimide chromophore (ꢀ300 ≈ 2 × 103 mol-1 cm-1) is similar
to that of simple nitrobenzyl derivatives at the same wavelength.
Moreover, the phthalimide absorption properties can be tuned: for
example, 4,5-dimethoxy substituted phthalimides shift their absorp-
tion band ca. 50 nm to the red.13 Although the absorptivity of the
unsubstituted phthalimides at 350 nm is low (ꢀ350 ≈ 8 mol-1 cm-1),
the photocleavage is also possible (at lower rates) when irradiated
with 350 nm light (see Supporting Information, SI).
The 3-(2-phthalimido-propionate)-yl PRPG has several advan-
tages that make it especially appropriate for biological applica-
tions: The caged systems are soluble in aqueous solutions
(phosphate buffer at pH ≈ 7.0 was used for the irradiations) and
no organic cosolvent is needed. The major photoproduct, an
N-alkenylphthalimide, is expected to exhibit low toxicity/reactivity,
compared with the nitroso- compounds arising from ortho-nitroben-
zyl PRPGs.5 The photorelease process is rapid and quantum-
efficient. Finally, as a new feature, the introduction of chirality in
the photocaged system allows the study of stereodifferentiation
processes involving the release of the caged molecule. Enantiose-
lective photoreactions in biological chiral environments or in the
presence of biomolecules have been described.10 When involving
chiral triplet states, photophysical evidence for the stereodifferen-
tiation has been obtained as well.11 In the context of PRPGs, chiral
photocages could provide a method for the selective liberation of
the masked molecule when a specific (active) conformation of the
photocage is favored by the chiral environment.
Apart from the case of interaction with a chiral environment,
stereodifferentiation processes in the photochemistry of diastere-
omers are known.12 In this context, we tested the diastereoselective
photorelease from derivatives of 2-phthalimido-3-hydroxybutyric
acid, which include a second stereogenic center. The proof of
principle is given here for photocaged acetate, although synthetic
routes for new photocages are currently being explored (see below).
First, we synthesized compound (2S,3R)-1, derived from natural
threonine, possessing a threo-configuration. As depicted in Scheme
1, the photorelease of acetate involves the loss of a molecule of
CO2, initiated by a PET process from the carboxylate to the
electronically excited phthalimide chromophore. In the photoreac-
During the irradiation of (2S,3R)-1, the diminution of the UV
absorption in both bands of the phthalimide was observed in the
spectra recorded from 5 × 10-5 M solutions at different times. At
higher concentrations (10-2 M), used for general in vitro irradia-
tions, a precipitate is formed, composed by the coproduced poorly
soluble alkenylphthalimide. The insolubilization of the byproduct
also prevents it from competing for the absorption of light and from
being photoisomerized.
Regarding the nature of the active excited state, previous studies
on the intermolecular reaction between excited phthalimides and
carboxylates14 pointed out that the electron-transfer process involves
the triplet state of the phthalimide. In the case of the PRPG system,
which involves an intramolecular PET, we performed parallel
irradiations of (2S,3R)-1 in buffer solution purged with air and in
the presence of triplet sensitizers. Comparing with the reference
reaction (deoxygenated buffer solution), we did not observe an
appreciable decrease in the formation of trans-2 in the first case,
only a small increase in the yield (ca. 6%) when the reaction is
sensitized with acetone (300 nm) and an effective sensitization at
350 nm, using 2-carboxybenzophenone as sensitizer (see SI). These
observations are compatible with (i) a relatively high quantum yield
of intersystem crossing (ΦISC ) 0.8 has been determined for
N-methylphthalimide),14 therefore the acetone sensitization being
of little noticeable effect at 300 nm, and (ii) an intramolecular
electron-transfer faster than the intermolecular quenching of the
triplet state by oxygen. A PET process from the singlet state, as in
the case of the singlet-state decarboxylations of benzophenone (e.g.,
ketoprofen)7 or xanthone chromophores8 cannot be ruled out,
although phthalimide-mediated decarboxylation processes do not
9
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J. AM. CHEM. SOC. 2006, 128, 16472-16473
10.1021/ja066582n CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Quantum Yields of Acetate Release and Product
Distribution (%) of the Isolated Photoproducts after Irradiation of
(2S,3R)-1 and 3
Scheme 3
substrate
Φb
trans-2
cis-2
4
(threo-)(2S,3R)-1, 300 nm
(erythro-) 3, 300 nm
0.40 ( 0.05
0.22 ( 0.05
>95
20
>95
30
65
40
15
30
(threo-)(2S,3R)-1, 350 nmc
(erythro-) 3, 350 nmc
a 5 × 10-3 M, buffer solution pH ) 7, 120 min, using RPR-3000 Å and
3500 Å lamps in a rayonet housing. b Measured at 313 nm, monitoring the
formation of 2. c Irradiation times were longer, because of the low
absorbance (ca. 8 h).
A simple and general strategy for chiral caging is the use of the
serine-derived â-lactone 5 (Scheme 3) that can be ring-opened by
a variety of nucleophiles.16 The decaging activity depends on the
leaving group ability of the molecule thus inserted: For example,
caged pyrazole 6 did not lead to the liberation of pyrazole but to
the product of simple decarboxylation, as opposed to 7, which
cleanly liberates acetate.
In summary, a new PRPG has been developed, which can be
advantageously applied for the caging of carboxylates and similar
molecules. This PRPG includes a chiral moiety, derived from
natural amino acids. The scope of chiral photocaging has been
preliminarily explored by the analysis of a model system.
Figure 1. Newman projections of the threo and erythro configurations,
depicted in the conformations yielding the lower number of steric repulsions.
Scheme 2
Acknowledgment. A.S. thanks the Comunidad Auto´noma de
La Rioja (Spain) for a postdoctoral grant.
Supporting Information Available: Experimental procedures,
copies of NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
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