| Abstrakt: |
The use of peptides as therapeutics has often been associated with several drawbacks such as poor absorption, low stability to proteolytic digestion, and fast clearance. Peptidomimetics are developed by modifications of native peptides with the aim of obtaining molecules that are more suitable for clinical development and, for this reason, are widely used as tools in medicinal chemistry programs. The effort to disclose innovative peptidomimetic therapies is recurrent and constantly evolving as demonstrated by the new lead compounds in clinical trials. During the synthesis of our peptidomimetic analogs, ß-Amino-alcohols derived from natural amino acids have been used extensively as a powerful source of chirality. In fact, amino alcohols are present in a large variety of naturally occurring and pharmacologically active molecules, and the relative stereochemistry of the hydroxy and amino groups is highly important for the biological activity of these molecules. Thus, amino alcohols have also been used extensively in asymmetric synthesis, both as chiral ligands and auxiliaries. In addition, they have been widely employed in the fields of peptide and pharmaceutical chemistry. In our laboratories, ß-Amino alcohols and their derivatives have played seminal roles in peptidomimetic synthesis while serving as important precursors for a variety of uses. With this goal in mind, the formation of chiral amino alcohols was accomplished by the reduction of a-amino acids occurring in moderate to high yield using sodium borohydride and iodine in anhydrous tetrahydrofuran (THF). Typically, the lithium aluminum hydride procedure is one of the most widely used techniques but on large scale, suffers from the disadvantage of cost, flammability, and, in certain cases, laborious isolation procedures resulting in widely varying yields. Therefore, this cheaper, safer, and simpler process using the NaBH4-I2 system was the procedure employed and no racemization of the chiral center was detected. In turn, protection of the primary amine using benzyl bromide in acetonitrile produced the N,N-Dibenzylamino alcohols, respectively. Subsequently, the N,N-Dibenzylamino alcohols were smoothly converted to the desired bromide in high yield by reacting with thionyl bromide and DMF. The product was spectroscopically pure, and no further purification was necessary. It was found, participation by the ß-amino group (anchimeric participation of the neighboring nitrogen atom) in brominations not only enhanced reaction rates but also promoted stereo- and regioselectivities. With various structurally diverse N,N-dibenzylamino bromides as building blocks in hand, the synthesis of carbamate, carbazate, dithiocarbazate, polyamine and phophono-pseudopeptides is underway and biological activity of these artificial biomolecular targets will be disclosed in due course. [ABSTRACT FROM AUTHOR] |
