DOI: 10.1002/anie.201100271
Protecting Groups
Chelating Carboxylic Acid Amides as Robust Relay Protecting Groups
of Carboxylic Acids and their Cleavage under Mild Conditions**
Manuel C. Brꢀhmer, Stephan Mundinger, Stefan Brꢁse, and Willi Bannwarth*
In most cases, the preparation of complex organic molecules
entails the need to apply protecting groups.[1,2] Common
requirements when such groups are applied to multistep
synthesis are straightforward insertion, robustness to different
reaction conditions, and selective cleavage, preferably with
high yields and under mild conditions. In addition, a cleavage
step orthogonal to that used for common protecting groups
would also be desirable.
Recently, we published two new linker entities for solid-
phase synthesis.[3,4] These enable the attachment of carboxylic
acids to the solid phase through an amide bond and release
after an unusual complexation of the amide nitrogen atom
with Cu2+ ions followed by methanolysis. This sequence yields
the methyl ester of the originally bound carboxylic acid. The
release proceeded under very mild conditions at room
temperature and the linker entity proved to be stable not
Scheme 1. Coupling of the bpa group and deprotection to the methyl
ester (4) or the carboxylic acid (1).
only to base and acid but also under a wide range of different
reaction conditions. Numerous modifications of the originally
attached carboxylic acid were possible through the applica-
tion of various reaction conditions, and we have shown that
the attached acid can also serve as a starting point for
multistep reaction sequences.
Our results led us to surmise that the chelating units of
these linkers might be suitable as so-called relay protecting
groups[1] for carboxylic acids, as outlined in Scheme 1 for
bispicolylamine (bpa, 2). By definition, in a relay deprotec-
tion a robust protecting group is transformed into a labile
intermediate that participates in the cleavage process under
mild conditions. To the best of our knowledge, this envisaged
strategy would represent the first example of the protection of
carboxylic acids as amides. Straightforward cleavage of
amides is normally hampered by the large resonance energy.
According to Scheme 1 the protection process would be
performed as a standard coupling reaction between the
carboxylic acid 1 and bpa (2). After modifications by follow-
up reactions, treatment with Cu2+ in methanol would lead to
the methyl ester of the carboxylic acid (4). As in the linker
systems mentioned above, activation for methanolysis would
proceed by an unusual complexation involving the nitrogen
atom of the amide bond.[5] Alternatively, methanolysis
mediated by the complexation could be performed in the
presence of Ba(OH)2·8H2O,[6–8] which would then yield
carboxylic acid 1 directly after acidic workup. Activation by
complexation was hitherto only sparsely exploited in the
realm of protecting groups, despite the fact that it would add a
further degree of orthogonality to commonly used depro-
tection methods. Additional advantages would be the robust-
ness of the protecting group as well as the simplicity of the
approach and the very mild reaction conditions.
To evaluate these possibilities bpa was coupled to a
variety of carboxylic acids according to Scheme 1, with TBTU
used as the coupling reagent.[9] Treatment of the resulting
amides with Cu(OTf)2 in methanol at room temperature gave
the carboxylic acid methyl esters 4a–g. Alternatively, appli-
cation of Ba(OH)2·8H2O in combination with Cu(OTf)2 in
MeOH resulted in the carboxylates 1a–f (Table 1). These
carboxylates were obtained in higher yields when
Ba(OH)2·8H2O was added directly in a one-pot reaction
after cleavage of the methyl esters. All the reactions occurred
in good to very high yields, thus demonstrating the potential
of this relay protecting group principle. It is also noteworthy
that the formation of the carboxylic acids required only
20 equivalents of Ba(OH)2·8H2O instead of the 400 equiv-
alents reported in references [5–7]. The results revealed at the
same time that the system was compatible with aromatic
(Table 1, a–c), aliphatic (d, e), and amino acids (f, g).
[*] Dipl.-Chem. M. C. Brꢀhmer, Prof. Dr. S. Brꢁse
Institute of Organic Chemistry, KIT-Campus Sꢂd
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
S. Mundinger, Prof. Dr. W. Bannwarth
Institute of Organic Chemistry and Biochemistry
Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg (Germany)
Fax: (+49)761-203-8705
E-mail: willi.bannwarth@organik.chemie.uni-freiburg.de
[**] We thank Prof. Dr. C. C. Tzschucke for helpful discussions. M.C.B.
thanks the Landesgraduiertenfꢀrderung Baden-Wꢂrttemberg for a
PhD fellowship and Feasibility Studies of Young Scientists—KIT for
generous financial support.
To further investigate the versatility of the new protecting
group we carried out a number of reactions under different
reaction conditions (Scheme 2). These experiments indicated
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 6175 –6177
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