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time. A functionalised chiral dihydrazide 26 was synthesised by reacting (+)-diethyl L-tartrate 24
with ethyl 4-oxopiperidine-1-carboxylate 25 in the presence of the Lewis acid catalyst
BF 3 (OEt) 2 . [35] In situ condensation of the protected diesters with hydrazine monohydrate in
absolute ethanol afforded the corresponding dicarbohydrazide 26 (Fig. 4).
Figure 4. Synthetic route to chiral hydrazide 26.
For the modular assembly of chiral macrocycles, (2R,3R)-ethyl 2,3-di(hydrazinecarbonyl)1,4-
dioxa-8-azaspiro[4.5]decane-8-carboxylate 26, (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide 4, 4-
(4-formylphenoxy)benzaldehyde 2 and 4,4'-diformyltriphenylamine 3 were refluxed in a mixture
of DMF/MeOH in presence of catalytic AcOH (Fig. 5). After 24 h of reflux, 8 different
macrocycles were detected and assigned by ESI-TOF MS in the negative ion mode according to
their high resolution m/z values (Figs. 5 and 6). Peaks appearing at m/z 804.2512 and 729.2058
are fragments of macrocycles 30 and 33, respectively (Figs. 6 and 7). High resolution m/z values
for members of the dynamic library 27-34 are shown in table 3. Next, we turned our attention to
assess the molecular recognition ability of library members 27-34 to oligopeptides. For
molecular recognition, AcNH-D-Ala-D-Glu-L-Lys-D-Ala-D-Ala-Gly-COOH 37, AcNH-D-Glu-
L-Lys-D-Ala-D-Ala-Gly-COOH 38 and AcNH-L-Lys-D-Ala-D-Ala-Gly-COOH 39 were chosen
and synthesised using solid phase peptide synthesis using the Fmoc method. The purity and
identity of oligopeptides 37-39 were assessed by HPLC-tandem MS (Fig. 8). Tetra-carbohydrazide
cyclophanes 27, 33 and 34 are C 2 -symmetric, whereas 28-32 are non-symmetric.
Macrocycle 32 has a unique and fascinating structure since the four building blocks forming it
are all different. In comparison with other spectroscopic tools, mass spectrometry is the only
technique which can provide vital information about the chemical composition of the library
members based on high resolution m/z values.
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