Application of Sugar Amino Acids: Flow Chemistry Used for alpha/beta-Chimera Synthesis

Two ring size beta-Sugar Amino Acids, beta SAAs, Fmoc-RibAFU(ip)-OH and Fmoc-GlcAPU(Me,Bn)-OH, as Lego-elements are introduced to make alpha/beta-chimera peptides by flow-based solid phase peptide synthesis (SPPS). Their synthesis alongside selected alpha-amino acids, alpha AA, is fine-tuned. The recently published 50 % TFA cleavage protocol of tBu protected shorter (Ser, Asp) and larger aromatic (Tyr, Trp), with bulky side chain protected Arg(Pbf) and Gln(Trt) residues was probed. We found that this milder condition is sufficient to successfully remove both the 1,2-O-isopropylidene from RibAFU(ip) and tBu, Pbf and Trt from the other alpha AA residues, but to preserve the 2,3-di-O-benzyl protection of GlcAPU(Me,Bn). Note that O-benzyl groups can be subsequently cleaved by HF or catalytic hydrogenation. Tuned protocols allow the efficient synthesis of 16-mer penetratin analogues via continuous flow conditions incorporating either RibAFU(ip) or GlcAPU(Me,Bn) beta SAAs. Both acid concentration (50 %/95 %) and type (TFA/HF) allow a versatile protecting group removal and thus, to fine-tune the hydrophilicity and aromaticity of the above building blocks in chimera constructs.