Orthogonal Photolysis of Protecting Groups

Full text of DOI:10.1002/1521-3773(20010601)40:11<2071::AID-ANIE2071>3.0.CO;2-9

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Int. Ed. Engl. 1997, 36, 486 ± 488; K. Himmel, M. Jansen, Chem.
Commun. 1998, 1205 ± 1206; K. Himmel, M. Jansen, Eur. J. Inorg.
Chem. 1998, 1183 ± 1186; b) K. Himmel, M. Jansen, Inorg. Chem. 1998,
37, 3437 ± 3439.
ever, orthogonality between such protecting groups has never
been observed. We recently published our preliminary results
on the possible use of monochromatic light to differentiate
photolabile groups,[4] and we wish to disclose here the first
orthogonal photochemical protection/deprotection of poly-
functional molecules.
Before considering applying a strategy such as that shown
in Scheme 1, several critical issues have to be addressed:
a) The intrinsic stability of each protecting group should be
very different at various wavelengths.
b) The energy transfer between an excited chromophore and
its ground-state neighbor should be suppressed.
c) The cleavage at high energy (for example, at 254 nm)
should be very fast, to avoid photodegradation of other-
wise sensitive groups.
[8] X-ray structural analysis of 1: black needles, crystal dimensions 0.4 Â
0.1  0.1 mm3, orthorhombic, space group Pna21 (no. 33), a ˆ
20.289(4), b ˆ 20.357(4), c ˆ 12.870(3) Š, Vˆ 5315(2) Š3, 1calcd
ˆ
3
1.563 gcm
,
Z ˆ 4, F(000) ˆ 2544, l ˆ 71.073 pm, Tˆ 143 K,
SMART-CCD (Bruker-AXS), 26738 measured reflections, 6954
symmetry independent reflections, empirical absorption correction
(SADABS[10]), Rint ˆ 0.2677. The Rint value given includes all data
measured up to an angle of 2q ˆ 45.48. This large value is caused by a
high proportion of reflections of very low intensity in the high-angle
range. If, for example, only the reflections up to an angle of 2q ˆ
308are taken into consideration, then Rint decreases to a value of
0.1606. The determination and refinement of the position of all the
atoms is, however, only possible when all the measured reflections are
taken into consideration. The determination of the positions of the
heavy atoms was carried out by direct methods,[11] the positions of the
light atoms were determined with difference Fourier transforma-
tion.[12] The best fit with anisotropic temperature factors was obtained
with the assumption of a noncrystallographic twofold rotation axis for
2
the C70 unit, as shown in Figure 4, in combination with the
correlating bond lengths. The anisotropic temperature factors were
positively defined, although in some cases they led to deflection
parameters which were not physically meaningful. No indication of
twinning was found during the refinement. The absolute configuration
found is validated with
a Flack parameter of 0.052. Refined
Scheme 1. General strategy for photochemical orthogonal deprotection of
functional groups. S ˆ substrate; P1, P2 ˆ groups which are photoactivatable
at n1 or n2; R ˆ reacting species (for example, H).
parameters ˆ 750, R1 ˆ 0.1188, wR2(all data) ˆ 0.2846, GOF ˆ 0.894.
Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-157752. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ (fax:
(‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
Among the known photolabile protecting groups, the 3',5'-
dimethoxybenzoin esters attracted our attention since they
were found to be equally reactive in nonabsorbent solvents
and in neat piperylene (1,3-pentadiene).[5] This suggested the
absence of quenching by the solvent and a very short-lived
excited state. This feature, combined with the very high
quantum yield (f ˆ 0.64) makes this ester an ideal candidate
for an orthogonal protecting group. On the other hand, the
nitrobenzyl derivatives are known to be less reactive, but with
sensitivity to much longer wavelengths (up to 420 nm).[3]
These differences in wavelength sensitivity are clearly illus-
trated by the UV spectra of 1 and 2 (Figure 1).
[9] J. Daniels, N. Korber, Z. Anorg. Allg. Chem. 1996, 622, 1833 ± 1838.
[10] G. M. Sheldrick, SADABS, Göttingen, 1998.
[11] G. M. Sheldrick, SHELXS97, Programs for Crystal Structure Deter-
mination and Refinement of Structures, Göttingen, 1997.
[12] G. M. Sheldrick, SHELXL97, Programs for Refinement of Crystal
Structures, Göttingen, 1997.
Orthogonal Photolysis of Protecting Groups**
Christian G. Bochet*
Dedicated to Professor Barry M. Trost
on the occasion of his 60th birthday
One of the major challenges in the chemistry of protecting
groups is orthogonality, that is, the possibility of selectively
removing one group in the presence of others in any
chronological sequence.[1] Photolabile protecting groups form
an attractive subclass of these groups, since they are essen-
tially cleaved without the need for any reagent, which thus
increases compatibility with other functionalities.[2, 3] How-
[*] Dr. C. G. Bochet
Department of Organic Chemistry, University of Geneva
30 quai Ernest Ansermet, 1211 Geneva 4 (Switzerland)
Fax : (‡41)22-328-7396
E-mail: Christian.Bochet@chiorg.unige.ch
[**] Financial support from the Swiss National Science Foundation (grant
Â
Â
no.: 21-57044.99) and the Fonds Frederic Firmenich et Philippe Chuit
is gratefully acknowledged.
Figure 1. UV spectra of benzoin ester 1 and benzyl ester 2.
Angew. Chem. Int. Ed. 2001, 40, No. 11
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We first exposed an acetonitrile solution of the lauryl ester
converted, by esterification with trimethylsilyldiazome-
thane,[9] into the methyl esters 6 and 7 in a 90:10 ratio (as
determined by GC analysis). A similar mixture, when
irradiated at 420 nm for 24 hours, gave a 15:85 mixture in
91% yield (Scheme 3).
1
[6] to UV light with a wavelength of 254 nm. The half-life was
determined as less than 5 minutes, which is significantly
shorter than that for the nitrobenzyl ester 2 (97 minutes). On
the other hand, 1 was totally unreactive at 420 nm, even for a
prolonged time (24 hours), whereas 2 was quantitatively
cleaved under these conditions.[7]
With these encouraging differential reactivities[8] establish-
ed, we then submitted a 1:1 mixture of 1 and 2 to UV light
with a wavelength of 254 nm. After irradiation for 5 minutes,
83% of 2 was ªintactº and 92% of the acid 3 was detected (by
1H NMR spectroscopy). The same experiment at 420 nm gave
93% of 3 and 92% of intact benzoin ester 1, after 14 hours
(Scheme 2). Figure 2 shows the 1H NMR spectra of the initial
1:1 mixture of 1 and 2 and of the mixture after irradiation at
different wavelengths. The signals around d ꢀ 2.5 arise from
the methylene group adjacent to the carboxyl groups and
clearly show the complementary behavior at the two wave-
lengths.
Scheme 3. Photochemical cleavage of orthogonal protecting groups from
different esters. TMS ˆ trimethylsilyl.
This experiment clearly shows the absence of the intermo-
lecular energy transfer that was observed with 3,5-dimethoxy-
benzyl alcohol derivatives.[4] The overall result is that is was
possible to activate individual components in a mixture by
using an external influence.
Intramolecular energy transfer was also found to be absent
in this system (Scheme 4). The mixed diester 8 bearing a
dimethoxybenzoin ester at one terminus and a nitrobenzyl
derivative at the other was photolyzed at 254 nm for 5 minutes
and the crude mixture was treated with trimethylsilyldiazo-
Scheme 2. Orthogonal stability of photolabile esters 1 and 2.
Figure 2. 1H NMR spectra before and after irradiation of a mixture of
esters 1 and 2.
We prepared a mixture of the two esters 4 and 5, which bear
saturated aliphatic chains of different length, to check further
the orthogonality. Photolysis at 254 nm for 5 minutes led to a
mixture of two carboxylic acids in 82% yield; these were
Scheme 4. Intramolecular photochemical cleavage of orthogonal protect-
ing groups.
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Angew. Chem. Int. Ed. 2001, 40, No. 11

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methane. The diester 9 was isolated in 70% yield after
chromatography (92% by 1H NMR spectroscopy). The same
experiment at 420 nm cleanly gave the diester 10 in 70% yield
(70% by 1H NMR spectroscopy). In other words, it was
possible to perform a photochemical orthogonal deprotection
of a bifunctional substrate.
Rate Enhancement and Enantioselectivity of
the Jacobsen ± Katsuki Epoxidation: The
Significance of the Sixth Coordination Site**
Jaouad El-Bahraoui, Olaf Wiest,* Derek Feichtinger,
and Dietmar A. Plattner*
In conclusion, we have shown that chromatic orthogonality
is indeed possible, in both inter- and intramolecular cases. This
new strategy could be successfully applied to orthogonal
deprotection of bifunctional molecules and to wavelength-
selective photorelease of compounds. We are currently
investigating the possibility of adding a third dimension to
the set, as well as testing applications in solution- and solid-
phase organic synthesis.
The oxygenation of olefins by high-valent transition metal
oxo complexes is one of the most useful and elegant
techniques for the functionalization of organic substrates. A
breakthrough was the introduction of chiral manganese ± sa-
len catalysts by Jacobsen and co-workers,[1] with a similar
system developed by Katsuki and co-workers.[2] The Jacob-
sen ± Katsuki reaction is universally recognized as one of the
most useful and widely applicable methods for the epoxida-
tion of unfunctionalized olefins.[3, 4]
Received: February 9, 2001 [Z16582]
Despite the synthetic utility of this catalytic transformation,
the origin of its high selectivity is not well understood. The key
problems that mechanistic studies of the catalytic reaction
cycle need to address are: 1) the nature of the oxygen-
transferring species; 2) the mechanism of oxygen transfer to
the olefinic substrate; and 3) the highly efficient stereo-
chemical communication between catalyst and substrate. By
electrospray tandem mass spectrometry, we were able to show
that the reaction proceeds via an oxomanganese(v) complex
as catalytically active species,[5] but the remaining questions
are still open despite numerous experimental[6] and computa-
tional studies.[7]
[1] a) T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis,
3rd ed., Wiley, New York, 1999; b) P. Kocienski, Protecting Groups,
Thieme, Stuttgart, 1994; c) M. Schelhaas, H. Waldmann, Angew. Chem.
1996, 108, 2192 ± 2219; Angew. Chem. Int. Ed. Engl. 1996, 35, 2056 ±
2083; d) R. B. Merrifield, G. Barany, W. L. Cosand, M. Engelhard, S.
Mojsov, Pept. Proc. Am. Pept. Symp. 5th 1977, 488 ± 502.
[2] a) V. N. R. Pillai, Org. Photochem. 1987, 9, 225 ± 323; b) V. N. R. Pillai,
Synthesis 1980, 1 ± 26.
[3] A. Patchornik, B. Amit, R. B. Woodward, J. Am. Chem. Soc. 1970, 92,
6333 ± 6335.
[4] C. G. Bochet, Tetrahedron Lett. 2000, 41, 6341 ± 6346.
[5] a) J. C. Sheehan, R. M. Wilson, J. Am. Chem. Soc. 1964, 86, 5227 ± 5281;
b) J. C. Sheehan, R. M. Wilson, A. W. Oxford, J. Am. Chem. Soc. 1971,
93, 7222 ± 7228; c) see also: M. C. Pirrung, S. W. Shuey, J. Org. Chem.
1994, 59, 3890 ± 3897; d) J. T. Corrie, D. R. Trentham, J. Chem. Soc.
Perkin 1 1992, 2409 ± 2417; e) J. F. Cameron, C. G. Wilson, J. M. J.
Herein, we report on the results of a high-level computa-
tional study[8] of oxomanganese(v) ± salen complexes of type 1
bearing different axial ligands. Ax-
ial ligation of the salen catalyst is
Â
Frechet, J. Chem. Soc. Perkin 1 1997, 2429 ± 2442.
O
N
O
N
[6] a) M. H. B. Stowell, R. S. Rock, D. C. Rees, S. I. Chan, Tetrahedron
Lett. 1996, 37, 307 ± 310; b) R. S. Rock, S. I. Chan, J. Org. Chem. 1996,
61, 1526 ± 1529.
[7] The typical concentrations were between 1 and 10 mm. The irradiations
were performed in a Rayonet apparatus.
known to have a favorable influ-
ence on the asymmetric induction.
This has been explained by a short-
ening of the Mn O bond length and
Mn
O
1
a decrease of the reactivity of the oxo species upon axial
coordination.[3d] We have recently shown experimentally that
axial coordination of an N-oxide ligand at the oxomanga-
nese(v) complex raises the oxygen transfer reactivity of the
catalyst dramatically.[5d] The question arises why it is possible
in this specific case of asymmetric catalysis to raise the
[8] By reactivity, we mean the net reaction rate under specific conditions; it
includes the quantum yield, the absorbance at the wavelength, and all
the experimental parameters.
[9] a) T. Shiori, T. Aoyama, S. Mori, Org. Synth. 1990, 68, 1 ± 7; b) N.
Hashimoto, T. Aoyama, T. Shiori, Chem. Pharm. Bull. 1981, 29, 1475 ±
1478.
[*] Prof. Dr. O. Wiest, Dr. J. El-Bahraoui
Department of Chemistry and Biochemistry
University of Notre Dame
Notre Dame, IN 46556-5670 (USA)
Fax : (‡1)219-631-6652
E-mail: owiest@nd.edu
Dr. D. A. Plattner, Dr. D. Feichtinger
Laboratorium für Organische Chemie der
Eidgenössischen Technischen Hochschule Zürich
ETH-Zentrum, Universitätstrasse 16, 8092 Zürich (Switzerland)
Fax : (‡41)1-632-1280
E-mail: plattner@org.chem.ethz.ch
[**] This work was made possible through generous allocation of computer
resources by the OIT at Notre Dame, the National Computational
Science Alliance and the Competence Center for Computational
Chemistry at ETH Zürich.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
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2073