2,3-Piperazinedione → Lysylthreonine

Beteiligte Stoffe

Reaktionsschritte

As shown in FIG. 4, synthesis of sansalvamide A peptide analog 1 was initiated from the N-terminus of phenylalanine silane linker 2. A low loading level (0.09 mmol/g) of 2 was selected to avoid problems of oligomer formation during the final cyclization step. Boc protecting groups were employed for peptide chain extensions to reduce the possibility of diketopiperazine formation, which is prevalent when Fmoc deprotection is used. Although oxazolone or oxazolonium ion formation occurs when acylating amine groups, and Boc-oxazolonium ions can decompose to N-carboxyanhydride derivatives much more readily than the corresponding Cbz- or Fmoc-protected derivatives, the undesired byproducts can be washed out after every coupling reaction. Deprotection of the Boc group of 2 followed by reaction of the resulting amine with Boc-Leu-OH and DIPEA, in the presence of a highly effective activating reagent HATU in NMP as a solvent, afforded polymer-bound dipeptide 7. Elongation of the peptide chain to the linear peptide 10 was accomplished by stepwise coupling of the appropriate Boc-protected amino acids under analogous conditions. Deprotection of the methyl ester and Boc protecting groups of 10 gave the resin-bound linear peptide. To avoid guanidine formation when employing an excess of the uronium salt HATU during the activation of the carboxylate acid group of the linear pentapeptide, the phosphonium salt PyBOP was substituted for HATU in the cyclization step. Sansalvamide A peptide 1 was released from the resin in an overall 66% yield (based on the loading level of 2) using neat TFA for 24 h. (See, FIG. 2) HPLC analysis proved the cyclic peptide to be 94% pure. The target molecule was characterized with 1H NMR, 13C NMR, and high-resolution mass spectrum. (See, examples 12-12k below.)

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