Preparation of N β-Fmoc-Protected Aza-β³-Amino Acids with Nonproteino­genic Hydrophobic Side Chains for Solid-Phase Syntheses of Pseudopeptides

Abstract

The preparation of twelve new N b -Fmoc-protected aza- b 3 -amino acids (aza-b 3 aa) with nonproteinogenic hydrophobic side Due to proteolytic degradation, peptides are not ideal can- didates for pharmaceutical development. For this reason, numerous research groups try to develop non-natural pep- tidic analogues in order to enhance metabolic stability, bioavailability, and biological absorption. 1-4 In this class of peptidomimetics, pseudopeptides either consisting ex- clusively or including aza-b 3 -amino acids have emerged as a promising new class of compounds that favor hydro- gen bond formation and can enhance biological activi- ties. 5-7 N b -Fmoc-protected aza-b 3 -amino acids with both nonfunctionalized and functionalized side chains that are analogues of natural proteinogenic amino acids have been already published, 8-10 and we have demonstrated that pseudopeptides including aza-b 3 -amino acids can be more active than the natural parent peptides. 6 In light of the in- stability of aza-b 3 -Tyr and aza-b 3 -Trp analogues in a strongly acidic medium, and in the context of our ongoing projects on the synthesis of antimicrobial pseudopeptides, we needed to develop N b -Fmoc-protected aza-b 3 -amino acid building blocks with non-proteinogenic side chains that are more hydrophobic than natural side chains and more stable. We already know that Trp residues can be re- placed by naphthylalanine, pyridylalanine, biphenylala- nine residues and many other compounds. 11-13 Furthermore, lipophilic long alkyl chains are very useful for enhancing or modifying antimicrobial activities and cytotoxicity. 14-17 Additionally, the incorporation of fluor- inated amino acids have generated great interest since such modifications can enhance the activity of antimicro- bial peptides. Such modifications can also allow structural NMR studies since fluorine labels are very suitable for an- alyzing molecular orientations. 18-20 Thus, we describe here a detailed preparation of twelve new aza-b 3 -amino acid derivatives (Table 1), with the side chains of 9-anthracenylalanine (9-Ath), 4,4¢-biphenylala-