be more sensitive to control the completeness of the reaction
step involving the coupling of acid 3 with the sterically
hindered amine obtained after Fmoc deprotection.
ethers present in the scaffold 3. The DMPM group proved
to be superior over an earlier investigated 4-methoxyphen-
ylmethyl benzyl ether protective group as a result of its
known higher sensitivity toward oxidative conditions. TB-
DPS deprotection: The procedure for deprotection of silyl
ethers using tetrabutylammonium fluoride (TBAF) led to
hydrolysis of the ester function present in 3. However, the
addition of 1 equiv of acetic acid led to a successful selective
deprotection.14
Although the on-resin deprotection of the protective groups
could be followed by 13C gel-phase NMR,11 we wished to
control the efficiency and the reproducibility of the above
procedures in a quantitative way. Therefore, in each case
after deprotection the free hydroxyl function was capped as
the acetate, and the resulting intermediate was subjected to
photocleavage. After chromatographic purification, the re-
leased acetates 10, 11, and 12 were obtained in 55%, 62%,
and 56% overall yield, respectively. These isolated yields
involving a six-step sequence were calculated taking into
account the original loading of the commercial resin. The
latter was determined by Fmoc UV-vis spectroscopy15 and
by the picric acid test.16
In summary, a new flexible scaffold 3 containing four
functionalities was developed. The carboxylic acid function
is used for the coupling on the solid support TentaGel via a
photocleavable linker 8, and the three protected hydroxyl
functions can be deprotected in an orthogonal way, allowing
for the introduction of molecular diversity. The use of this
tripodal scaffold in the development of chemical libraries is
currently under investigation.
At this point the photolytic release of the scaffold was
investigated. Exposure of resin 1 (50 mg) in 1,4-dioxane (1.5
mL) containing 1% DMSO to UV light (365 nm) for 20 h
gave primary amide 9 (86% yield). In this known procedure,
the presence of DMSO was shown to have a beneficial
influence on the rate of the cleavage.8d
The development of appropriate reaction conditions for
the selective deprotection of the three protective groups
required extensive optimization. In a first stage, the efficiency
of each deprotection step was assessed in a qualitative way
by 13C gel-phase NMR (see Supporting Information).11 THP
deprotection: The use of p-toluenesulfonic acid12a led to
deprotection of both THP and DMPM ethers, whereas
pyridinium p-toluenesulfonic acid was not strong enough to
effect complete deprotection.12b Treatment of the resin with
a solution of AcOH/CH2Cl2/H2O in a ratio of 80:15:5 at 60
°C led on the other hand to complete and selective depro-
tection of the THP ether.12c DMPM deprotection: Complete
and selective deprotection was achieved using dichloro-
dicyanoquinone (DDQ) at 0 °C for 1 h.13 Longer reaction
times or higher temperatures led to cleavage of the benzyl
Acknowledgment. A.M. is indebted to the FWO-Vlaan-
deren for a position as postdoctoral researcher. Financial
assistance of GOA (GOA96009), TMR (ERBFMRX-
CT960011), and TMR (HPRN-CT-2000-00014) is gratefully
acknowledged.
(7) Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091.
(8) (a) Holmes, C. P.; Jones, D. G. J. Org. Chem. 1995, 60, 2318. (b)
Ruhland, B.; Bhandari, A.; Gordon, E. M.; Gallop, M. A. J. Am. Chem.
Soc. 1996, 118, 253. (c) Teague, S. J. Tetrahedron Lett. 1996, 37, 5751.
(d) Rodebaugh, R.; Fraser-Reid, B.; Geysen, H. M. Tetrahedron Lett. 1997,
38, 7653. (d) Holmes, C. P. J. Org. Chem. 1997, 62, 2370. (e) Gennari, C.;
Longari, C.; Ressel, S.; Salom, B.; Piarulli, U.; Ceccarelli, S.; Mielgo, A.
Eur. J. Org. Chem. 1998, 11, 2437. (f) Halkes, K. M.; St. Hilaire, P. M.;
Jansson, A. M.; Gotfredsen, C. H.; Meldal, M. J. Chem. Soc., Perkin Trans.
1 2000, 2127.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
OL016980P
(9) Hancock, W. S.; Battersby, J. E. Anal. Biochem. 1976, 71, 260.
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(14) Pavia, M. R.; Cohen, M. P.; Dilley, G. J.; Dubuc, G. R.; Durgin, T.
L.; Forman, M. W.; Hediger, M. E.; Milot, G.; Powers, T. S.; Sucholeiki,
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