Development of new tools for solid-phase organic library synthesis: Backbone amide linker (BAL) anchoring approaches and monitoring methods.

摘要

Solid-phase synthesis has emerged as a powerful tool in drug discovery because it provides simple work-up procedures, high yields, and the potential for automation. These advantages allow the rapid assembly and screening of combinatorial libraries, which makes the solid-phase method an appealing avenue for the discovery of biologically active compounds for pharmaceutical purposes. This rapid growth and practice of solid-phase chemistry has created a need for general linkers and reaction monitoring techniques to aid in the synthesis of diverse sets of important compounds.; Backbone amide linker (BAL) anchoring has provided solid-phase access to C-terminal modified and cyclic peptides, as well as a myriad of small organic and heterocyclic molecules of biological importance. New solid-phase BAL strategies have been developed for the synthesis of lidocaine and procainamide analogues. A manual parallel strategy was followed to provide sixty novel compounds, of which two dozen have not been described previously.; Working with the BAL system revealed the need for ways to monitor solid-phase aldehydes. Colorimetric and spectroscopic techniques offer simple and practical tools for qualitative or quantitative monitoring of solid-phase reactions, and also provide information on how to proceed with a solid-phase synthesis. Two simple and direct methods to achieve qualitative and quantitative colonmetric monitoring of solid-phase aldehydes were developed. These methods are based on reactions of aldehydes with either of two hydrazine-based reagents, the classical 2,4-dinitrophenylhydrazine (DNPH) to give a colorimetric assay, or the novel 4-(9-fluorenylmethyloxycarbonyl)-phenylhydrazine (FmPH) to give a quantitative result. Details are provided for preparation of the stable DNPH solution, and for the synthesis and application of FmPH. The qualitative (visual) and quantitative sensitivity of these two novel tests have been evaluated on several solid support systems, and their effectiveness in monitoring model aldehyde conversions is described.