Wavelength-selective cleavage of photolabile protecting groups

Article abstract of DOI:10.1016/S0040-4039(00)01050-9

The selective photocleavage of protecting groups using monochromatic light is described. Some groups were found to react faster than others at 254 nm, whereas this trend was reversed at 419 nm. This behavior was preserved in solution mixtures of both grou

Full text of DOI:10.1016/S0040-4039(00)01050-9

Tetrahedron Letters 41 (2000) 6341±6346
Wavelength-selective cleavage of photolabile protecting
groups
Christian G. Bochet*
Department of organic chemistry, University of Geneva, 30 quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
Received 14 April 2000; accepted 20 June 2000
Abstract
The selective photocleavage of protecting groups using monochromatic light is described. Some groups
were found to react faster than others at 254 nm, whereas this trend was reversed at 419 nm. This behavior
was preserved in solution mixtures of both groups. The selective control of which group is activated is thus
achieved by using an in¯uence external to the reaction mixture. # 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: carbamates; deblocking, nitro compounds, photochemistry, protecting groups.
Photochemical reactions are very appealing processes from both economical and
environmental aspects. Indeed, light is a very cheap reagent, and it does not generate chemical
waste.1 These features have, however, been hampered for decades by a lack of selectivity and
sometimes quite unpredictable results. One area in organic photochemistry showing an ever-
increasing activity is the photodeprotection of functional groups.2 The absence of chemical
reagents indeed makes this process very tolerant towards otherwise sensitive functionalities. Very
ingenious applications have been developed, such as biologically active `caged' molecules3 (which
are liberated at their relevant site by irradiation with UV-light) or spatially addressable
combinatorial libraries.4 Despite the useful technologies that have been developed so far, it would
be highly desirable to have the same kind of selectivity that is found for conventional chemical
reactions. One of the only handles available to tune the properties of the light is its wavelength.
We recently initiated a program aimed at developing selective photochemical reactions promoted
by monochromatic light of speci®c wavelength, and we disclose here our preliminary results in the
area of photodeprotection of functional groups.
* Corresponding author. Fax: +41 22 328 7396; e-mail: christian.bochet@chiorg.unige.ch
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01050-9

6342
The most widely used photolabile protecting groups are based on Patchornik and Woodward's
2-nitroveratrole-derived carbamates5 (NVOC), such as 2a (Scheme 1). Their photolysis liberates
the free amine, carbon dioxide and an o-nitrosobenzaldehyde derivative. As it is well established,
the substitution pattern around the aromatic ring dramatically alters the absorbance in the UV±vis
spectra.6 Since the rate of reaction of the photodeprotection process is proportional to its ability
to capture a photon at a speci®c wavelength,7 we hypothesized that a series of analogues of 2a
with variable substitutions would have di€erent photolysis rates according to the irradiation
wavelength.
Scheme 1.
To this end, the carbamates 2a±f were prepared by the coupling of 1-dodecylamine and the
corresponding benzylic alcohols 1a±f with 1,10-carbonyldiimidazole,8 in yields consistently higher
than 85%. The alcohol 1c was prepared by benzylic bromination of the 4-bromo-2-nitrotoluene,
followed by displacement with potassium acetate and saponi®cation,9 whereas the other alcohols
were commercially available. The carbamate 2g was prepared by simple aromatic nucleophilic
substitution of the chloride 2e with piperidine (98%), and 2h by a ¯uoride-mediated Suzuki
coupling with the bromide 2c10,11(76%). The carbamates 2a±h were photolyzed in acetonitrile and
1
the deprotection rate and half-lives were determined by H NMR at di€erent wavelengths.12
These results are summarized in Table 1.
Table 1
Rate of photolysis of the carbamates 2a±h in MeCN at 30ꢀC
It is immediately apparent from Table 1 that some candidates have to be discarded as potential
photolabile groups. For example, an electron-donating group para to the strongly electron-
withdrawing nitro group (entry 7) greatly enhanced the absorbance at longer wavelengths
("=17880, l=396 nm), but drastically reduced the reaction rates. On the other hand, the bromo

6343
derivative 2c and the NVOC-derivative 2a showed complementary behavior: 2c reacted faster
than 2a at 254 nm by a factor of 3.4, whereas at 419 nm, this trend was reversed by a factor of
1.8. Our original hypothesis was thus validated, but the quite modest rate di€erences prompted us
to consider other families of photolabile groups.
The 3,5-dimethoxybenzyl alcohol derivatives are also known to be cleaved by light,13 and the
absence of a nitro group was expected to reduce the absorbance at longer wavelength. Indeed, the
deprotection rate of 3b was close to zero at 350 nm, but was exceedingly fast at 254 nm for both
carbamates and esters (Scheme 2).
Scheme 2.
This behavior was complementary with the carbamate 2a, with a rate constant ratio higher
than 30:1 at 254 nm, and lower than 1:100 at 350 nm, opening the prospect for a selective
liberation of either an acid or a base by only the choice of the wavelength.
Encouraged by these results, we then attempted the simultaneous and selective deprotection of a
mixture of ester 3b and carbamate 2a, ®rst under a 254 nm irradiation (Scheme 3).
Scheme 3.

6344
To our disappointment, the trend found for individual compounds was not followed as
mixtures. The highly reactive (at 254 nm) compound 3b seemed to act as a sensitizer for the other,
less reactive, species 2a14 (Fig. 1). This phenomenon was however not general. A similar
experiment with an equimolar mixture of 2a and 2c showed no variation of the photolysis rate
from the pure solutions (Fig. 2). Clearly, intermolecular energy transfer did not operate in this
system. In other words, it was possible to individually address each of the two photolabile groups in
the presence of the other by the choice of the irradiation wavelength.
Figure 1. Photolysis of a 3b/2a mixture at 254 nm
Figure 2. Photolysis of a 2a/2c mixture at 254 nm
Fig. 3 shows the 1H NMR portion of the benzylic hydrogens of a near equimolar 2a/2c mixture
in CDCl3, after increasing irradiation time. We can see that it is indeed possible to selectively
deprotect the high-energy labile group from 2c at 254 nm in the presence of the low-energy labile
group 2a, and, to a smaller extent, vice versa at a low energy 419 nm light.15 However, fast
cleavage at a short-wavelength UV-light (254 nm) is essential, in order to avoid undesired
reactions of conventional protecting groups (such as benzyloxycarbonyl) or peptide degradation.
Non-interference of these groups has been shown by Chamberlin using Vycor glass (essentially
transparent at 254 nm) ®ltered light.13

6345
Figure 3. 1H NMR of the benzylic protons of an equimolar mixture of 2a/2c after increasing irradiation time. The
vertical scale is adjusted to re¯ect the relative concentrations
In conclusion, we were able to show that di€erential reactivity of photolabile protecting groups
with monochromatic light16 can be tuned by changing the substitution pattern around the
aromatic ring. Although the selectivity factors are still modest, this new concept should open new
perspectives in orthogonal protection of functionalities, in automated organic synthesis, and
particularly in spatially addressable combinatorial libraries. In the latter application, immobilization
of the reacting species on a solid support will play a key role in the intermolecular energy transfer
process.17 This issue is currently being addressed in our laboratory and the results will be reported
in due course.
Acknowledgements
This work was supported by the Swiss National Science Foundation grant 2100-57044.99, and
by the Fonds Frederic Firmenich et Philippe Chuit. The generous support of Professor A. Alexakis
is gratefully acknowledged.
References
1. For a general reference, see: Suppan, P. Chemistry and Light, The Royal Society of Chemistry, 1994; Wayne, R. P.
Principles and application of photochemistry. Oxford University Press, 1988.
2. Pillai, V. N. R. Synthesis 1980, 1±26; Pillai, V. N. R. Org. Photochem. 1987, 9, 225±323.
3. Adams, S. R.; Kao, J. P. Y.; Grynkiewicz, G.; Minta, A.; Tsien, R. Y. J. Am. Chem. Soc. 1988, 110, 3212±3220;
Adams, S. R.; Kao, J. P. Y.; Tsien, R. Y. J. Am. Chem. Soc. 1989, 111, 7957±7968; Wilcox, M.; Viola, R. W.;

6346
Johnson, K. W.; Billington, A. P.; Carpenter, B. K.; McCray, J. A.; Guzikowski, A. P.; Hess, G. P. J. Org. Chem.
1990, 55, 1585±1589.
4. Fodor, S. P. A.; Read, J. L.; Pirrung, M. C.; Stryer, L.; Lu, A. T.; Solas, D. Science 1991, 251, 767±773.
5. Patchornik, A.; Amit, B.; Woodward, R. B. J. Am. Chem. Soc. 1970, 92, 6333±6335.
6. For an example, see: Bochet, C. G.; Piguet, C.; Williams, A. F. Helv. Chim. Acta 1993, 76, 372±384.
7. Hasan, A.; Stengele, K. P.; Giegrich, H.; Cornwell, P.; Isham, K. R.; Sachleben, R. A.; P¯eiderer, W.; Foote, R. S.
Tetrahedron 1997, 53, 4247±4264.
8. Bertolini, G.; Pavich, G.; Vergani, B. J. Org. Chem. 1998, 63, 6031±6034.
9. Makosza, M.; Baran, J.; Dziewonska-Baran, D.; Golinski, J. Liebig Ann. Chem. 1989, 825±832.
10. Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem. 1994, 59, 6095±6097.
11. All new compounds showed satisfactory spectroscopic data.
12. Typical experimental procedure: 25 mg of the carbamate were dissolved in 15 ml of UV-grade acetonitrile in a
quartz vessel. The solution was deaerated by a stream of argon for 15 min, and the mixture was irradiated at the
desired wavelength in a Rayonnet apparatus equipped with 16 ¯uorescent tubes: RPR2539 (254 nm), RPR3000
(300 nm), RPR 3500 (350 nm) or RPR 4190 (419 nm). Aliquots were taken after a given time, the solvent was
evaporated and the residue was analyzed by 1H NMR in CDCl3.
13. Chamberlin, J. W. J. Org. Chem. 1966, 31, 1658±1660. For a related system, see: Cameron, J. F.; Frechet, J. M. J.
J. Org. Chem. 1990, 55, 5919±5922.
14. Cameron, J. F.; Frechet, J. M. J. J. Am. Chem. Soc. 1991, 113, 4303±4313.
15. As this work aims at studying the reactivity versus the wavelength, no attempt was made to optimize the
formation of amine. It is a known fact that the amine can react with the aldehyde formed, and various solutions
have been proposed (see Ref. 5 and 14). After 120 min irradiation, 3a and 3c produced, respectively, 19 and 30%
of n-dodecylamine (characterized as the N-tosyl derivative).
16. By monochromatic light, we designate a light with a wavelength distribution centered around the nominal
wavelength. The half-height width is estimated by the manufacturer as 35 nm.
17. Scott, L. T.; Rebek, J.; Ovsyanko, L.; Sims, C. L. J. Am. Chem. Soc. 1977, 99, 625±626; Rebek, J.; Gavina, F.
J. Am. Chem. Soc. 1974, 96, 7112±7114; Wolf, S.; Foote, C. S.; Rebek Jr, J. J. Am. Chem. Soc. 1978, 100, 7770±
7771.