C‐3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

Nagy, Adrienn and Csordás, Barbara and Zsoldos-Mády, Virág and Pintér, István and Farkas, Viktor and Perczel, András (2017) C‐3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies. Amino Acids, 49 (2). pp. 223-240. ISSN 1438-2199

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Abstract

To obtain key sugar derivatives for making homooligomeric foldamers or α/β-chimera peptides, economic and multigram scale synthetic methods were to be developed. Though described in the literature, the costeffective making of both 3-amino-3-deoxy-ribofuranuronic acid (H–tX–OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H–cX–OH) from d-glucose is described here. The present synthetic route elaborated is (1) appropriate for large-scale synthesis; (2) reagent costs reduced (e.g. by a factor of 400); (3) yields optimized are ~80% or higher for all six consecutive steps concluding –tX– or –cX– and (4) reaction times shortened. Thus, a new synthetic route step-by-step optimized for yield, cost, time and purification is given both for d-xylo and d-ribo-amino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous-flow reactor). Our study encompasses necessary building blocks (e.g. –X–OMe, –X–OiPr, –X–NHMe, Fmoc–X–OH) and key coupling reactions making –Aaa–tX–Aaa– or –Aaa–tX–tX–Aaa– type “inserts”. Completed for both stereoisomers of X, including the newly synthesized Fmoc–cX–OH, producing longer oligomers for drug design and discovery is more of a reality than a wish.

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