%0 Journal Article
%T Combinatorial Libraries on Rigid Scaffolds: Solid Phase Synthesis of Variably Substituted Pyrazoles and Isoxazoles
%A Andreas L. Marzinzik
%A Eduard R. Felder
%J Molecules
%D 1997
%I MDPI AG
%R 10.3390/jan97p5
%X The synthesis of combinatorial compound libraries has become a powerful lead finding tool in modern drug discovery. The ability to synthesize rapidly, in high yield, new chemical entities with low molecular weight on a solid support has a recognized strategic relevance (¡°small molecule libraries¡±). We designed and validated a novel solid phase synthesis scheme, suitable to generate diversity on small heterocycles of the pyrazole and isoxazole type. Appropriate conditions were worked out for each reaction, and a variety of more or less reactive agents (building blocks) was utilized for discrete conversions, in order to exploit the system¡¯s breadth of applicability. Four sequential reaction steps were validated, including the loading of the support with an acetyl bearing moiety, a Claisen condensation, an a-alkylation and a cyclization of a b-diketone with monosubstituted hydrazines. In a second stage, the reaction sequence was applied in a split and mix approach, in order to prepare a combinatorial library built-up from 4 acetyl carboxylic acids (R1), 35 carboxylic esters (R2) and 41 hydrazines (R4) (and 1 hydroxylamine) to yield a total of 11,760 compounds divided into 41 pyrazole sublibraries with 140 pairs of regioisomers and 1 isoxazole sublibrary of equal size.
%K Combinatorial chemistry
%K split synthesis
%K lead finding
%U http://www.mdpi.com/1420-3049/2/1/17