Application of the excited state meta effect in photolabile protecting group design

Article abstract of DOI:10.1021/ol071085c

A novel photolabile protecting group for carbonyl compounds has been developed, based on the excited state meta effect.

Full text of DOI:10.1021/ol071085c

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2831-2833
Application of the Excited State Meta
Effect in Photolabile Protecting Group
Design
Pengfei Wang,* Huayou Hu, and Yun Wang
Department of Chemistry, UniVersity of Alabama at Birmingham,
Birmingham, Alabama 35294
wangp@uab.edu
Received May 9, 2007
ABSTRACT
A novel photolabile protecting group for carbonyl compounds has been developed, based on the excited state meta effect.
Controllable removal of a photolabile protecting group (PPG)
by photochemical means typically requires no chemical
reagents and can provide high spatial and temporal resolution.
These features are appealing to the researchers in the fields
of organic synthesis, solid-phase synthesis, combinatorial
chemistry, photolithography, and biochemical and biophysi-
cal research.1 Despite advances in developing PPGs for
various applications, practically useful PPGs for some
important functional groups (e.g., carbonyl group) are still
rare.2
we found that the application of the excited-state meta effect
could be further expanded.
In our design (Scheme 1), carbonyl compound 1 could be
protected by 3,5-dimethoxylsalicylic alcohol (2) in a cyclic
acetal/ketal form 3. The π-π* excitation of 3 would increase
the electron density at C-1 in S1 owing to the presence of
two m-methoxyl groups. This charge accumulation at C-1
should facilitate the benzylic C-O breakage, leading to the
release of 1, presumably via the zwitterionic intermediate 4.
Recently, we developed a robust PPG, 2-[hydroxy-
(diphenyl)methyl]-4-methoxyphenol, for the protection of
carbonyl groups.3 Herein we report our progress in the
development of another novel type of PPG based on the
excited state meta effect.4,5 The meta effect driven PPGs are
available for protecting carboxyl groups, amino groups (in
the carbamate form), or phosphate esters.1,4,6 To our delight,
(2) (a) Hebert, J.; Gravel, D. Can. J. Chem. 1974, 52, 187. (b) Gravel,
D.; Herbert, J.; Thoraval, D. Can. J. Chem. 1983, 61, 400. (c) Gravel, D.;
Murray, S.; Ladouceur, G. J. Chem. Soc., Chem. Commun. 1985, 24, 1828.
(d) Friedrich, E.; Lutz, W.; Eichenauer, H.; Enders, D. Synthesis 1977, 12,
893. (e) Hoshino, O.; Sawaki, S.; Umezawa, B. Chem. Pharm. Bull. 1979,
27, 538. (f) Aurell, M. J.; Boix, C.; Ceita, M. L.; Llopis, C.; Tortajada, A.;
Mestres, R. J. Chem. Res. Synop. 1995, 12, 452. (g) Ceita, L.; Maiti, A.
K.; Mestres, R.; Tortajada, A. J. Chem. Res. Synop. 2001, 10, 403. (h)
McHale, W. A.; Kutateladze, A. G. J. Org. Chem. 1998, 63, 9924. (i) Lin,
W.; Lawrence, D. S. J. Org. Chem. 2002, 67, 2723. (j) Lu, M.; Fedoryak,
O. D.; Moister, B. R.; Dore, T. M. Org. Lett. 2003, 5, 2119. (k) Blanc, A.;
Bochet, C. G. J. Org. Chem. 2003, 68, 1138. (l) Kantevari, S.; Narasimhaji,
C. V.; Mereyala, H. B. Tetrahedron 2005, 61, 5849.
(1) For reviews and monographs, see: (a) Pillai, V. N. R. Synthesis 1980,
1. (b) Binkley, R. W.; Flechtner, T. W. In Synthetic organic photochemistry;
Horspool, W. M., Ed.; Plenum: New York, 1984; p 375. (c) Pillai, V. N.
R. Org. Photochem. 1987, 9, 225. (d) Givens, R. S.; Kueper, L. W., III
Chem. ReV. 1993, 93, 55. (e) Pirrung, M. C. Chem. ReV. 1997, 97, 473. (f)
Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091. (g) Bochet,
C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125. (h) Pelliccioli, A. P.; Wirz,
J. Photochem. Photobiol. Sci. 2002, 1, 441. (i) Goeldner, M.; Givens, R.
S., Eds. Dynamic studies in biology; Wiley-VCH: Weinheim, Germany,
2005. (j) Mayer, G.; Heckel, A. Angew. Chem., Int. Ed. 2006, 45, 4900.
(3) Wang, P.; Hu, H.; Wang, Y. Org. Lett. 2007, 9, 1533.
(4) Chamberlin, J. W. J. Org. Chem. 1966, 31, 1658.
(5) (a) Zimmerman, H. E.; Sandel, V. R. J. Am. Chem. Soc. 1963, 85,
915. (b) Zimmerman, H. E.; Somasekhara, S. J. Am. Chem. Soc. 1963, 85,
922. (c) Zimmerman, H. E. J. Am. Chem. Soc. 1995, 117, 8988. (d)
Zimmerman, H. E. J. Phys. Chem. A 1998, 102, 5616.
(6) Birr, C.; Lochinger, W.; Stahnke, G.; Lang, P. Liebigs Ann. Chem.
1972, 763, 162.
10.1021/ol071085c CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/20/2007

Scheme 1. Protection of Carbonyls with 2
Scheme 2. Synthesis of the PPG (2)
Subsequent saponification, substitution of Br with OH
mediated by copper,9 and reduction with LiAlH4 produced
the desired protecting group 2.
Photochemical reactivity of 3a, 8, and 9 correlated well
with theoretical computations. Irradiation of 3a for 1 h led
to a 1a/3a ratio of 0.5/1 in CD3CN/D2O (9:1),10 while
irradiation of 8 under the same conditions led to a 1a/8 ratio
of only 0.08/1. For 9, no observable amount of 1a was
detected. These results suggest that the excited state meta
effect should have a significant role in the photochemical
deprotection process.
Excited state computations on the model acetals 5-7
revealed that the electron density at C-1 of 5 and 6 increased
in S1 (Figure 1).7 Model 5 has the largest negative charge
The PPG (2) seemed to be promising in protecting
carbonyl compounds and was then further examined with
other substrates (1a-f) for its application scope. Carbonyls
(1a-f) were protected with 2 in high yields (Table 1),
typically in the presence of a catalytic amount of pTsOH
and an excess of P2O5 in toluene at 0 °C. An alternative
protection protocol employed dimethyl ketal of the ketone
and the catalyst, B10H14 (Table 1, entry 3).11 The obtained
acetals/ketals are reasonably stable and insensitive to the
laboratory lighting.12
Photochemical releases of carbonyl compounds were best
achieved in MeCN with H2O as the cosolvent without
excluding air (Table 1). The obtained 3-phenylpropanal (1a)
and 2-adamantanone (1e) were derivatized and isolated as
the corresponding oximes to minimize loss of carbonyls
during purifications.13 Irradiations carried out under nitrogen
protection were relatively slower. For example, photoreaction
of 3a under N2 produced 51% of 1a with 36% of 3a
recovered after 3 h of irradiation.
Figure 1. Comparison of the PPG (2) with other models.
accumulation at C-1 in its S1, which suggests 5 should be
more prone to undertake the plausible pathway illustrated
in Scheme 1.
(8) Bringmann, G.; Hinrichs, J.; Henschel, P.; Kraus, J.; Peters, K.; Peters,
E. Eur. J. Org. Chem. 2002, 6, 1096.
(9) Comdom, P. F. P.; Palacios, M. L. D. Synth. Commn. 2002, 32, 2055.
(10) The runs in deuterium solvents were carried out in Pyrex NMR
tubes, and the ratios were determined by integrations.
(11) Lee, S. H.; Lee, J. H.; Yoon, C. M. Tetrahedron Lett. 2002, 43,
2699.
(12) Exploration of the stability of the ketals/acetals was exemplified
with 3a. 3a was stable under reflux in MeCN/H2O, and was also stable
toward the treatment of PhLi at -78 °C, KtOBu, NaBH4, or LiAlH4 at
room temperature. However, it slowly released 1a upon treatment with DDQ
(20 equiv) at room temperature in MeCN and completely released 1a after
heating with DDQ at 80 °C for 2 h. Treatment with CAN caused
decomposition of 3a with no detection of 1a. 3a was stable in the presence
of 20 equiv of AcOH (23-80 °C), but it was sensitive to stronger acids
such as HCl, TFA, and pTsOH. For details, see the Supporting Information.
(13) 3a and 3e were stable under the derivatizing conditions. The isolated
yields of the oximes are consistent with the yields estimated from 1H NMR
of the underivatized small-scale runs.10
To test the computation results, acetals 3a, 8, and 9 were
thus prepared by reacting 3-phenylpropanal (1a) with the
corresponding protecting groups under acidic conditions.
Salicylic alcohol (for protection in 9) is commercially
available. 5-Methoxylsalicylic alcohol (for protection in 8)
was prepared in one step by reduction of the commercially
available 5-methoxylsalicylic acid. 3,5-Dimethoxylsalicylic
alcohol 2 was readily synthesized from the commercially
available 3,5-dimethoxybenzoic acid (Scheme 2). Thus,
esterification of 10 followed by bromination provided 11.8
(7) (a) The computations made use of Gaussian 03, Revision C.02, with
CIS/3-21G for excited states (nstates ) 8) and the geometries were
optimized with HF/3-21G.
2832
Org. Lett., Vol. 9, No. 15, 2007

Table 1. Protection and Photorelease of the Carbonyls
Figure 2. Structural variation of the PPG (2).
protection deprotection recovered irradiation
photolyzed (Figure 2). Interestingly, contrary to what we
expected, irradiation of 12 for 20 min did not show any sign
of reaction, while 3a afforded a 1a/3a ratio of 0.16/1 under
the same conditions. However, this observation agreed with
the computations,7 which indicated that the electron density
at C-1 of the model molecule 13 increased from -0.066 in
S0 to only -0.118 in S1, which was less than that in S1 of
models 5-7 (Figure 1).
In summary, a novel PPG for carbonyl compounds was
developed. The PPG was readily installed upon carbonyls
in high yields and could be efficiently removed upon UV
irradiation. Our experimental results and theoretical com-
putations suggest the photochemical process and the meta
effect are correlated.
entry carbonyls yield (%)a
yield (%)c,d
s.m. (%)
time (h)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
92
81e
79
0
6
0
0
6
0
4.0
0.5
3.0
3.5
4.0
4.0
99
93 (99b)
91
96
93
86
93f
88e
86f
a 2 (0.15 mmol), pTsOH (0.002 mmol), carbonyl compound (0.10 mmol),
and P2O5 (0.2 mmol) in 1.0 mL of toluene, 0 °C, 2-4 h. b 2 (0.88 mmol),
B10H14 (0.028 mmol), and dimethyl ketal of 1c (0.72 mmol) in 1.5 mL of
MeCN, 23 °C, 2.5 h. c Irradiated with a 450 W medium-pressure mercury
lamp equipped with a Pyrex filter sleeve. d Irradiated in 200 mL of MeCN
with 50 mL of H2O. e Isolated as the oxime derivatives. f Irradiated in 240
mL of MeCN with 10 mL of H2O.
The PPG (2) was not stable under the irradiation conditions
and was not detected in any photoreaction mixture.14 Instead,
complex mixtures were obtained in addition to 1 (and 3) in
the photoreactions. We inferred that introduction of benzylic
alkyl groups would facilitate the deprotection. It is known
that photochemical cleavage of the benzylic C-O bond in
the R,R-dimethyl-3,5-dimethoxybenzyloxycarbonyl group is
more efficient than that in the original PPG without the two
benzylic methyl groups.6 Thus acetal 12 was prepared and
Acknowledgment. This work was financially supported
by the University of Alabama at Birmingham. We thank Dr.
M. Renfrow of the UAB Biomedical FT-ICR MS Laboratory
for assistance in mass spectroscopy.
Supporting Information Available: Experimental de-
tails, spectroscopic data, and NMR spectra for the compounds
2, 3a-f, 8, 9, and 12. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Photolysis of 2 in CD3CN/D2O (4:1) for 2 h caused substantial
decomposition of 2.
OL071085C
Org. Lett., Vol. 9, No. 15, 2007
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