Part I. A flexible strategy for the incorporation of ureas into peptide linkages. Part II. Two novel solid phase syntheses: Cyclo[(S)-norarginyl-(S)-phenylalanyl] and callipeltin B

Jennifer Ann Kowalski, Purdue University

Abstract

Novel methodology, involving the Hofmann rearrangement of L-amino amides, has been developed for incorporating urea linkages into the amide backbone of peptides forming “ureidopeptides”. The methodology is compatible with 17 of the 20 proteinogenic amino acids and common carbamate protecting groups for amino acids and peptides. The properties of ureidopeptides were tested by synthesizing two biologically-relevant ureidopeptides. The urea linkage, in the novel [Leu5]enkephalin analog H-YGGψ[NHCONH]FL-OH, was found to be stable to hydrolysis over a broad pH range and to proteolytic degradation. A second ureidopeptide, H-ALψ[NHCONH]PF-NH2, was synthesized as a probe to investigate the mechanism of cyclophilin A-catalyzed peptidyl-prolyl isomerization. A solid phase synthesis of the cyclic dipeptide cyclo[(S)-NorArg-( S)-Phe], a catalyst for the asymmetric Strecker amino acid synthesis, was developed to circumvent solubility problems and purification difficulties in the original solution synthesis. This synthesis involved Hofmann rearrangement of a resin-bound amide, on-resin guanylation using a novel reagent, and simultaneous acid-catalyzed resin cleavage/cyclization affording the final product in good yield and high purity. A modular, convergent, solid phase strategy was employed for the synthesis of callipeltin B, a cyclic depsipeptide marine natural product that exhibits potent anti-tumor activity. This approach involved the synthesis of several nonproteinogenic amino acid building blocks in solution and their assembly on a solid support. Side-chain attachment to the resin allowed the entire natural product to be assembled and cyclized on the solid support.

Degree

Ph.D.

Advisors

Lipton, Purdue University.

Subject Area

Organic chemistry

COinS