Synthesis and LCMS Characterization of a 1275-Member Library of 24-Atom Triazine Macrocycles Derived from Quantitative Dimerization Occurring with >99.9% Fidelity

Efficient routes to libraries of nonpeptidic macrocycles
facilitate
drug discovery. Monomers presenting hydrazine and acetal groups separated
by a triazine ring and glycine linker dimerize efficiently to yield
homodimers (when one monomer is employed) or a mixture of two homodimers
and a heterodimer (when two monomers are used). Descriptively, dimerization
proceeds quantitatively. The solvent and byproducts are volatile,
eliminating the need for additional purification. To evaluate the
functional group tolerances of this chemistry, a library of 1275 compounds
was created from 50 monomers. Liquid chromatography–mass spectrometry
validates the integrity of the library. All reactions yield macrocycles,
but under the reaction conditions employed, partial hydrolysis is
observed with three ester-containing monomers. Cleavage of a naphthylethyl
group is observed for another. Monomers containing a BOC-protected
amine, a tert-butyl ester or tert-butyl ether undergo quantitative deprotection as desired. Reaction
of three monomers (wherein one is subject to partial hydrolysis) gives
rise to the expected 10 macrocycles.