Photocaging of carboxylic acids: A modular approach

Article abstract of DOI:10.1002/anie.201402665

Photocaged compounds are important tools for studying and regulating multiple processes, including biological functions. Reported herein is the use of the Passerini multicomponent reaction for modular preparation of photocaged carboxylic acids. The reaction is compatible with several functionalities and proceeds smoothly both in water and dichloromethane. The choice of aldehyde determines the wavelength used for deprotection and enables formation of orthogonally protected products. The isocyanide component can be used for introduction of reactive tags and photosensitizers, as well as for immobilization on a solid support.

Full text of DOI:10.1002/anie.201402665

Angewandte
Chemie
DOI: 10.1002/anie.201402665
Photochemistry
Photocaging of Carboxylic Acids: A Modular Approach**
´
Wiktor Szymanski, Willem A. Velema, and Ben L. Feringa*
Dedicated to the MPI fꢀr Kohlenforschung on the occasion of its centenary
Abstract: Photocaged compounds are important tools for
studying and regulating multiple processes, including biolog-
ical functions. Reported herein is the use of the Passerini
multicomponent reaction for modular preparation of photo-
caged carboxylic acids. The reaction is compatible with several
functionalities and proceeds smoothly both in water and
dichloromethane. The choice of aldehyde determines the
wavelength used for deprotection and enables formation of
orthogonally protected products. The isocyanide component
can be used for introduction of reactive tags and photo-
sensitizers, as well as for immobilization on a solid support.
groups to carboxylic acid moieties under aqueous conditions.
While the formation of esters in water is thermodynamically
unfavorable, we envisioned that the use of the Passerini
multicomponent reaction[12] could result in the formation of
the desired products. In this reaction, which has been
performed successfully in water,[13] a carboxylic acid, an
aldehyde, and an isocyanide react to form an a-acyloxyamide.
The numerous applications[12b–c,14] of the Passerini reaction
include the preparation of dendrimer–drug conjugates,[13a]
polymers,[14b] and heterocycles.[14c] In combination with enzy-
matic protocols, it has been used for the preparation of amino
acids[14d] and peptides.[14e]
U
sing molecular approaches for establishing control over
The use of a multicomponent reaction for photocaging
bioactive molecules could offer an additional advantage in
that it would allow the modular assembly of different
functions into the final molecule (Figure 1). In particular,
biological processes by light is a rapidly advancing research
area with numerous potential applications.[1] In particular,
introducing photolabile protecting groups into bioactive
molecules (photocaging) allows triggering of their activity
with light, and is an important tool for controlling biological
processes at a molecular level.[1a–c,2] It takes advantage of the
unique properties of light, such as low cellular toxicity, the
possibility to tune both quantitative (intensity) and qualita-
tive (wavelength) properties, and the high spatiotemporal
control over its delivery.
Figure 1. Modular approach for the photocaging of carboxylic acids.
Carboxylic acids are usually caged as photocleavable
esters.[3–10] Alternatively, more stable amides of substituted 7-
nitroindolines can be used.[11] Photocaging of carboxylic acid
moieties has been employed, among other things, for the
photochemical control of such biological processes as cell
adhesion,[3] activity of the receptors for glycine[4] and
GABAA,[5] and glutamate transporters.[6] Photoprotected
retinoic acid was reported as a potential tool to study the
developmental defects in zebrafish embryos.[7] Further appli-
cations include the photoactivation of fluorophores,[8] photo-
controlled drug delivery,[9] and release of agrochemicals.[10]
Since water is a solvent that is compatible with bioactive
molecules, it would be advantageous to establish a general
methodology for the introduction of photolabile protecting
the structure of the aldehyde substrate determines the
structure and photochemical properties of the photoactive
part of the caged molecule. We envisioned that by appropri-
ately choosing the aldehyde for the reaction, the wavelength
of light to be used for deprotection of the carboxylic acid can
be tuned. The use of different aldehydes could then allow the
preparation of photocaged products,[2] which could be ortho-
gonally deprotected in a mixture. Independently, the isocya-
nide component introduces a tag, which can be used for
visualization (fluorescence), affinity purifications, immobili-
zation on a solid support, or sensitized photodeprotection by
intramolecular, photoinduced energy transfer. While there
are two examples[5a,15] of using the Passerini reaction for the
formation of photolabile esters in dichloromethane, the
potential for the modular construction of photoprotected
products in water, which stems directly from the multi-
component nature of the Passerini reaction, to the best of our
knowledge, has not been explored.
´
[*] Dr. W. Szymanski, W. A. Velema, Prof. Dr. B. L. Feringa
Center for Systems Chemistry, Stratingh Institute for Chemistry
University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
E-mail: b.l.feringa@rug.nl
Herein, we present the application of the Passerini
reaction, in aqueous and organic media, for the modular
preparation of photocaged carboxylic acids, and their appli-
cation in orthogonal and photosensitized release.
To demonstrate the versatility of this approach with
respect to the structure of the carboxylic acid, a model
reaction was used (Scheme 1) that employed benzyl isocya-
[**] We thank Claudia Poloni for insightful discussions. Financial
support from and the Ministry of Education, Culture and Science
(Gravity program no. 024.001.035), Royal Netherlands Academy of
Sciences (KNAW academy chair), and European Research Council
(ERC Advanced grant 227897) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402665.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
(Table 1, entry 8) and substitution with a methoxy group
(Table 1, entry 7) results in a lower yield as compared to the
unsubstituted benzoic acid (Table 1, entry 6).
The uncaging of o-nitrobenzyl derivatives results in
formation of reactive species,[16] which might react with
reaction products and lower their yield. Therefore we
followed the deprotection of 4d (ca. 15 mm), under l =
Scheme 1. Passerini reaction of benzyl isocyanide (1a), 6-nitroveratral-
dehyde (2a), and carboxylic acids (3a–h) to form the products 4.
1
365 nm irradiation, by H NMR spectroscopy with TMS as
an internal standard (see the Supporting Information). After
18 hours of irradiation, we observed a greater than 95%
conversion of the substrate, and the product was obtained in
91% analytical yield, which indicates that the uncaging is
a selective process.
nide (1a), 6-nitroveratraldehyde (2a), and a series of acids
(3a–h). The reactions were performed in both water and
dichloromethane (Table 1). In the reactions of a homologous
series of aliphatic carboxylic acids 3a–c in water (Table 1,
The prospects offered by wavelength-selective, orthogo-
nal uncaging of two or more photoprotected, bioactive
compounds have recently attracted considerable attention.[17]
Since the initial report in 2000,[17a] this concept has been used
for the independent release of glutamate/GABA on living
neurons[17b] and for chromatically selective uncaging of
nucleotides,[17c] and cAMP,[17d] among others. The major
advantages of using multiple orthogonally photoprotected
compounds stem from the possibility to selectively trigger
various responses from the studied biological system. This
ability is particularly useful in cases where two independent
mechanisms are involved in the on/off triggering of a biolog-
ical process.[17d]
Table 1: Yields of the isolated products 4 from the Passerini reaction
with a series of carboxylic acids in water and dichloromethane.
Entry
R
Product
Water [%][a]
CH2Cl2 [%][a]
1
2
3
4
5
6
7
8
CH3
4a
4b
4c
4d
4e
4 f
25
85
<10
89
56
73
86
50
48
77
<10
72
CH3(CH2)6
CH3(CH2)16
PhCH2
FmocNHCH2
Ph
4-MeOC6H4
4-FC6H4
4g
4h
40
85
52
84
Since in the presented approach the wavelength used for
the deprotection is defined by the structure of the aldehyde
(Figure 1), we studied the possibility of applying different
aldehydes to obtain orthogonally photoprotected products
(Scheme 2). Besides 6-nitroveratraldehyde (2a), 2-nitroben-
[a] reaction conditions: 1a (0.125m), 2a (0.125m), and 3 (0.100m),
solvent (water or CH2Cl2), 20 h, RT. Fmoc=9-fluorenylmethoxycarbonyl.
entries 1–3), octanoic acid (3b) gave the best yield. The lower
yield in the case of the more hydrophilic acetic acid (3a) has
been observed previously in aqueous Passerini reactions.[13d]
This effect has been explained[13d] by the fact that the reaction
proceeds “on water”, and the hydration of acetic acid renders
it less effective. We believe that the lower yield in case of the
amphiphilic stearic acid (3c) could be caused by the fact that
it forms micelles and, therefore, is less accessible to the other
reactants. Results obtained in CH2Cl2 are complementary to
those obtained in water, as products 4a and 4c could be
obtained in higher yields.
The photocaged phenylacetic acid 4d was obtained in high
yield in both reaction media (Table 1, entry 4). When the
Fmoc-protected glycine 3e was used as a substrate (Table 1,
entry 5), the product was formed only in the reaction run in
water. For the conversions of the substituted benzoic acids
3 f–h, similar trends were observed in water and CH2Cl2, that
is, the highest yield was obtained for the fluoro-substituted
substrate 4h, and the lowest for methoxy-substituted com-
pound 4g. Hydrophobic effects have been suggested to
contribute to the rate acceleration of Passerini reactions in
water[13b] and higher yields were observed when more hydro-
phobic reactants were used.[13d] This trend correlates well with
our observation that good yields can be obtained for the
conversions of carboxylic acids containing hydrophobic
residues (Table 1, entries 2, 4–6, and 8). This trend is also
reflected in the changes in the outcome of the reactions using
substituted benzoic acids (Table 1, entries 6–8), wherein the
substitution with hydrophobic fluorine gives the best yield
Scheme 2. Preparation of the protected acids 4h–j for chromatically
selective uncaging.
zaldehyde (2b) and the coumarin-derived aldehyde 2c were
employed as substrates. We were delighted to observe that for
all the aldehydes 2a–c the products 4h–j were isolated in
good yields (Scheme 2). As expected, the obtained products
differed considerably in their spectral properties, with com-
pound 4i showing the most blue-shifted spectrum (lmax
<
300 nm) and compound 4j showing an absorption that
extended into the visible range. UV-vis spectroscopy meas-
urements confirmed the uncaging of the compounds 4h–j by
irradiation with light of different wavelengths, both in chloro-
form and in aqueous phosphate buffer (See the Supporting
Information).
By taking advantage of the differences in photochemical
properties of the orthogonally photoprotected compounds
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
Table 2: Yields of isolated products from the Passerini reaction with
a series of isocyanides.
4h–j, we attempted a selective uncaging of 4j in the presence
of 4i. Irradiation with white light (Figure 2, first 3 h) resulted
in a clean and almost complete conversion of 4j into the
uncaged 4-fluorobenzoic acid (3h), while the concentration of
Entry
Substrate
Product
Water [%][a]
CH2Cl2 [%][a]
1
2
3
1a
1b
1c
4h
4k
4l
85
35
38
84
56
86
[a] reaction conditions: 1 (0.125m), 2a (0.125m), and 3h (0.100m),
solvent (water or CH2Cl2), 20 h, RT.
1b and 1c. In both cases, the Passerini reaction gave
a moderate yield in water and a better result in CH2Cl2
(Table 2, entries 2 and 3). Notably, the products 4k and 4l
contain groups with the potential for further functionaliza-
tion, namely a protected carboxylic acid and amine moieties
(respectively).
We further explored the possibility of using the isocyanide
component for photocleavable immobilization of carboxylic
acids on a solid support (Figure 3). The photorelease of resin-
Figure 2. Selective deprotection of orthogonally protected 4i (ꢀ7 mm)
and 4j (ꢀ7 mm) in CDCl3. Studied by 19F NMR spectroscopy. See the
Supporting Information for NMR spectra.
Figure 3. Preparation of the isocyanide-modified resin C and its
application in a model Passerini reaction to immobilize azidoacetic
acid on a resin with a photocleavable linker (D). For experimental
details and IR spectra, see the Supporting Information. DIC=diisopro-
pylcarbodiimide, TEA=triethylamine.
4i remained stable. Subsequent irradiation with UV light
allowed the deprotection of 4i. These results highlight the
potential of applying the aqueous Passerini reactions to the
preparation of orthogonally protected carboxylic acids.
The isocyanide component is used in our system as
a highly reactive reagent which enables the ester formation in
water. However, further opportunities emerge if this compo-
nent carries a tag which could be used purposes such as
purification, immobilization on solid support, photosensitiz-
ing, or further functionalization.
With this in mind, we studied the model reaction of
various isocyanides with 4-fluorobenzoic acid (3h) and 6-
nitroveratraldehyde (2a; Scheme 3 and Table 2). The best
results were obtained when benzyl isocyanide was used as
a starting material (Table 2, entry 1), and this we consider to
be the reactant of choice for reactions both in water and in
CH2Cl2, if no tag is required in the final photoprotected
molecule. We also explored the reactions with the isocyanides
bound carboxylic acids has been used in solid-phase peptide
synthesis.[2,18] We studied the Passerini reaction involving the
isocyanide-decorated polystyrene resin C (Figure 3), which
was prepared from an aminomethylated polystyrene resin (A)
using a published procedure.[19] Coupling of the amine groups
of A to formic acid with subsequent formamide dehydration
yielded the resin C, as indicated by the formation of IR
stretching bands at 1694 cmÀ1 (B, formamide C O) and
=
2146 cmÀ1 (C, isocyanide; For IR spectra, see the Supporting
Information).[19b]
A Passerini reaction with the resin C was performed in
CH2Cl2, since it is a solvent compatible with the type of resin
used in this experiment. Azidoacetic acid was used as the acid
component, since the azide can be conveniently used as an IR
marker as a result of its characteristic and strong absorbance.
Finally, 6-nitroveratraldehyde (2a) was used to install a photo-
responsive moiety. Conversion into the resin D (Figure 3) was
confirmed by the disappearance of the isocyanide stretch and
emergence of the azide band at 2110 cmÀ1 in the IR spectrum
(in neat azidoacetic acid: 2108 cmÀ1), and the carbonyl group
stretches at about 1690 cmÀ1. This protocol constitutes a gen-
eral method for the immobilization of carboxylic acids on
resins with photolabile linkers, whose spectral properties
could be controlled by the choice of the aldehyde component.
The introduction of auxiliary chromophores to the photo-
protected compound is an attractive strategy which helps to
Scheme 3. Reaction of 4-fluorobenzoic acid (3h) and 6-nitroveratralde-
hyde (2a) with the isocyanides 1a–c. Boc=tert-butoxycarbonyl.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
improve the efficiency of the deprotection by photoinduced
energy transfer and allows the use of light with a longer
wavelength.[2] The 9H-thioxanthen-9-one moiety has been
used successfully as a photosensitizer[20] and a detailed
mechanism for the energy transfer to the o-nitrobenzyl
group was proposed.[20b] However, the covalent introduction
of a photosensitizer, while offering a way to tune the
photochemical properties of the photoactive group, is limited
by the tedious synthesis.[20b] Therefore we envisioned that
a multicomponent procedure, which brings together the
target compound and both the primary and auxiliary chro-
mophores in one step, would offer an unparalleled access to
such compounds.
We tested the possibility of using the isocyanide 1d
(Scheme 4), derived from 9H-thioxanthen-9-one, in the
Passerini reaction. The isocyanide 1d can be prepared in
one step from the respective aniline (see the Supporting
Figure 4. Photosensitized release of 3h from a mixture of 4i (ꢀ8 mm)
and 4m (ꢀ8 mm) in CDCl3. Studied by 19F NMR spectroscopy. Upper
graph: irradiation at l=312 nm. Lower graph: irradiation with white
light. See the Supporting Information for NMR spectra.
Scheme 4. Reaction of 4-fluorobenzoic acid (3h) and 2-nitrobenzalde-
hyde (2a) with the 9H-thioxanthen-9-one-based isocyanide 1d.
environment. The multicomponent character of the presented
procedure allows the modular assembly of the products in one
step. In particular, the aldehyde component dictates the
photochemical nature of the final product and determines the
wavelength of light that can be used for deprotection. Finally,
the isocyanide component can be used to introduce a diversity
of tags to the protected product. We have explored, in detail,
the possibility of using it for the photoreversible immobiliza-
tion on the solid support and for the covalent introduction of
a photosensitizer, which allows tuning of the photochemical
properties of the final compounds and deprotection with
visible light.
Information). However, it was found that the use of 1d is
limited by its low solubility, and the formation of the product
4m was observed only when CH2Cl2 was used as the solvent,
after an overnight reaction at an elevated temperature.
A comparison of the UV-vis spectra (See the Supporting
Information) of 4m and its analogue 4i, a 2-nitrobenzyl ester
which has no photosensitizer in its structure, revealed that 4m
has a much higher absorption within the range of wavelengths
studied. In particular, it shows a strong absorption at wave-
lengths greater than l = 400 nm, whereas the absorption of 4i
is negligible. With this in mind, we studied the release of 3h in
a roughly equimolar mixture of 4m and 4i (Figure 4, upper
panel) upon irradiation with light of different wavelengths.
Irradiation at l = 312 nm (Figure 4, middle panel) resulted in
clean release of 3h from 4m, about three times faster when
compared to release from 4i. The use of white light (Figure 4,
lower panel), in contrast, clearly showed the influence of the
secondary chromophores as it allowed the selective cleavage
of 4m, while the concentration of 4i remained unchanged.
Despite the moderate yield of 4m in the Passerini reaction
(Scheme 4), we find this an attractive, one-step alternative to
the multistep approaches used in the preparation of caged
compounds with the possibility of photosensitized release. As
long as respective isocyanides can be conveniently prepared,
this methodology may be useful for the introduction of
various photosensitizers with different photochemical proper-
ties.
Received: February 21, 2014
Revised: April 5, 2014
Published online: && &&, &&&&
Keywords: multicomponent reactions · photocaging ·
.
protecting groups · synthetic methods · water chemistry
[1] a) G. Mayer, A. Heckel, Angew. Chem. 2006, 118, 5020 – 5042;
Angew. Chem. Int. Ed. 2006, 45, 4900 – 4921; b) D. D. Young, A.
Deiters, Org. Biomol. Chem. 2007, 5, 999 – 1005; c) A. Deiters,
ChemBioChem 2010, 11, 47 – 53; d) A. A. Beharry, G. A.
Woolley, Chem. Soc. Rev. 2011, 40, 4422 – 4437; e) C. Brieke, F.
Rohrbach, A. Gottschalk, G. Mayer, A. Heckel, Angew. Chem.
2012, 124, 8572 – 8604; Angew. Chem. Int. Ed. 2012, 51, 8446 –
8476; f) W. Szymanski, J. M. Beierle, H. A. V. Kistemaker, W. A.
Velema, B. L. Feringa, Chem. Rev. 2013, 113, 6114 – 6178; g) Q.
Liu, A. Deiters, Acc. Chem. Res. 2014, 47, 45 – 55.
[2] a) H.-M. Lee, D. R. Larson, D. S. Lawrence, ACS Chem. Biol.
2009, 4, 409 – 427; b) Q. Shao, B. Xing, Chem. Soc. Rev. 2010, 39,
In summary, we present here the application of the
Passerini reaction for the introduction of photocleavable
groups to carboxylate moieties. The reaction can be per-
formed both in organic (dichloromethane) and aqueous
ˇ
2835 – 2846; c) P. Klꢀn, T. Solomek, C. G. Bochet, A. Blanc, R.
Givens, M. Rubina, V. Popik, A. Kostikov, J. Wirz, Chem. Rev.
2013, 113, 119 – 191.
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
[3] C. A. Goubko, A. Basak, S. Majumdar, H. Jarrell, N. H. Khieu,
X. Cao, J. Biomed. Mater. Res. A 2013, 101A, 787 – 796.
[4] C. Grewer, J. Jꢁger, B. K. Carpenter, G. P. Hess, Biochemistry
2000, 39, 2063 – 2070.
[5] a) L. Fan, R. W. Lewis, G. P. Hess, B. Ganem, Bioorg. Med.
Chem. Lett. 2009, 19, 3932 – 3933; b) R. W. Lewis, G. P. Hess, B.
Ganem, Future Med. Chem. 2011, 3, 243 – 250.
Mayer, J. Am. Chem. Soc. 2011, 133, 1790 – 1792; c) Q. Xia, B.
Ganem, Org. Lett. 2002, 4, 1631 – 1634; d) W. Szymanski, R.
Ostaszewski, Tetrahedron: Asymmetry 2006, 17, 2667 – 2671;
e) W. Szymanski, M. Zwolinska, R. Ostaszewski, Tetrahedron
2007, 63, 7647 – 7653.
[15] L. Li, A. Lv, X.-X. Deng, F.-S. Du, Z.-C. Li, Chem. Commun.
2013, 49, 8549 – 8551.
[6] K. Takaoka, Y. Tatsu, N. Yumoto, T. Nakajima, K. Shimamoto,
Bioorg. Med. Chem. Lett. 2003, 13, 965 – 970.
[16] A. P. Pelliccioli, J. Wirz, Photochem. Photobiol. Sci. 2002, 1, 441 –
458.
[7] P. Neveu, I. Aujard, C. Benbrahim, T. Le Saux, J.-F. Allemand, S.
Vriz, D. Bensimon, L. Jullien, Angew. Chem. Int. Ed. 2008, 47,
3744 – 3746; Angew. Chem. 2008, 120, 3804 – 3806.
[8] R. H. Pawle, V. Eastman, S. W. Thomas, J. Mater. Chem. 2011, 21,
14041 – 14047.
[9] M. W. Grinstaff, P. Barthelemy, C. Prata, L. Moreau, US2006/
241071A1, 2006.
[10] D. A. Morgenstern, WO2013/55944A2, 2013.
[11] a) B. Amit, D. A. Ben-Efraim, A. Patchornik, J. Am. Chem. Soc.
1976, 98, 843 – 844; b) G. Papageorgiou, D. C. Ogden, A. Barth,
J. E. T. Corrie, J. Am. Chem. Soc. 1999, 121, 6503 – 6504; c) J.-L.
Dꢂbieux, C. G. Bochet, J. Phys. Org. Chem. 2010, 23, 272 – 282.
[12] a) M. Passerini, L. Simone, Gazz. Chim. Ital. 1921, 51, 126 – 129;
b) A. Dçmling, I. Ugi, Angew. Chem. Int. Ed. 2000, 39, 3168 –
3210; Angew. Chem. 2000, 112, 3300 – 3344; c) A. Dçmling,
Chem. Rev. 2006, 106, 17 – 89.
[13] a) A. E. J. de Nooy, G. Masci, V. Crescenzi, Macromolecules
1999, 32, 1318 – 1320; b) M. C. Pirrung, K. Das Sarma, J. Am.
Chem. Soc. 2004, 126, 444 – 445; c) M. A. Mironov, M. N.
Istvanova, M. I. Tokareva, V. S. Mokrushin, Tetrahedron Lett.
2005, 46, 3957 – 3960; d) T. Sela, A. Vigalok, Adv. Synth. Catal.
2012, 354, 2407 – 2411.
[17] a) C. G. Bochet, Tetrahedron Lett. 2000, 41, 6341 – 6346; b) S.
Kantevari, M. Matsuzaki, Y. Kanemoto, H. Kasai, G. C. R. Ellis-
Davies, Nat. Methods 2010, 7, 123 – 125; c) A. Rodrigues-
Correia, X. M. M. Weyel, A. Heckel, Org. Lett. 2013, 15,
5500 – 5503; d) J. P. Olson, M. R. Banghart, B. L. Sabatini,
G. C. R. Ellis-Davies, J. Am. Chem. Soc. 2013, 135, 15948 –
15954; e) V. San Miguel, C. G. Bochet, A. del Campo, J. Am.
Chem. Soc. 2011, 133, 5380 – 5388; f) J.-L. Dꢂbieux, C. G.
Bochet, Chem. Sci. 2012, 3, 405 – 406.
[18] a) F. Guillier, D. Orain, M. Bradley, Chem. Rev. 2000, 100, 2091 –
2158; b) A. Ajayaghosh, V. N. R. Pillai, J. Org. Chem. 1987, 52,
5714 – 5717; c) C. Marinzi, J. Offer, R. Longhi, P. E. Dawson,
Bioorg. Med. Chem. 2004, 12, 2749 – 2757.
[19] a) J. J. Chen, A. Golebiowski, J. McClenaghan, S. R. Klopfen-
stein, L. West, Tetrahedron Lett. 2001, 42, 2269 – 2271; b) N. R.
Aguiam, V. I. Castro, A. I. F. Ribeiro, R. D. V. Fernandes, C. M.
Carvalho, S. P. G. Costa, S. M. M. A. Pereira-Lima, Tetrahedron
2013, 69, 9161 – 9165.
[20] a) D. Wçll, S. Walbert, K. P. Stengele, T. J. Albert, T. Richmond,
J. Norton, M. Singer, R. D. Green, W. Pfleiderer, U. E. Steiner,
Helv. Chim. Acta 2004, 87, 28 – 45; b) D. Wçll, S. Laimgruber, M.
Galetskaya, J. Smirnova, W. Pfleiderer, B. Heinz, P. Gilch, U. E.
Steiner, J. Am. Chem. Soc. 2007, 129, 12148 – 12158.
[14] a) Z. Y. Du, Y. H. Lu, X. D. Dai, D. Zhang-Negrerie, Q. Z. Gao,
J. Chem. Res. 2013, 37, 181 – 185; b) O. Kreye, T. Tꢃth, M. A. R.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Photochemistry
´
W. Szymanski, W. A. Velema,
B. L. Feringa*
&&&& — &&&&
Photocaging of Carboxylic Acids: A
Modular Approach
Mix and match: The multicomponent
Passerini reaction is used for the prepa-
ration of photocaged carboxylic acids,
both in dichloromethane and water. Judi-
cious choice of the aldehyde allows
tuning of the deprotection wavelength
and the preparation of orthogonally pro-
tected products. The isocyanide compo-
nent may be used for immobilization on
a solid support or introduction of either
a reactive tag or a photosensitizer.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!