Preparation Of A Library Of Dipeptide Aldehydes By Parallel Solution Phase Synthesis

Peptide aldehydes exhibit important activities against biologicaltargets, such as inhibition of proteinase. Some of them are important leadsin medicinal chemistry. In this thesis, for the first time, we attempted atpreparing a library of 20×20 dipeptide aldehydes based on 20 naturalamino acids by parallel solution phase method. In addition, librarysynthesis of 3,6-disubstituted-5,6-unsaturated-2-ketopiperazine wasinvestigated.One way to prepare dipeptide aldehydes was by coupling reaction ofsemicarbazone of amino aldehydes with amino acids. The starting naturalamino acids were converted to their aldehydes through Winreb amideformation and reduction, followed by protection as semicarbazones. Thesemicarbazones were coupled with amino acids in solution phase andsubsequently deprotected to give the desired dipeptide aldehydes. Allproducts were purified by LC-MS. This strategy was applied to thesynthesis of 304 dipeptide aldehydes and 274 were obtained. Among thefinal compounds 244 were with purity up to 80%.The rest of desired dipeptide aldehydes were prepared by oxidationof their dipeptide alcohols. This precursor alcohols were prepared bycoupling of amino alcohols with amino acids, and purified by LC-MS.Subsequently, they were oxidized into aldehydes by a Parikh-Doeringprocedure, and purified by LC/MS. This two-step procedure provided 55out of 76 dipeptide aldehydes, and 26 were with purity up to 80%.3,6-Disubstituted-5,6-unsaturated-2-ketopiperazine could be formedby intramolecular dehydrate cyclization of dipeptide aldehydes inpresence of TFA. Library of 57 2-ketopiperazines were prepared andpurified by LC-MS.