Synthesis and evaluation of potent yaku'amide A analogs.

Two full-length analogs of the anticancer peptide yaku'amide A (1a) and four partial structures have been synthesized. These analogs were identified by computational studies in which the three E- and Z-ΔIle residues of the natural product were replaced by the more accessible dehydroamino acids ΔVal and ΔEnv. Of the eight possible analogs, modeling showed that the targeted structures 2a and 2b most closely resembled the three-dimensional structure of 1a. Synthesis of 2a and 2b followed a convergent route that was streamlined by the absence of ΔIle in the targets. Screening of the compounds against various cancer cell lines revealed that 2a and 2b mimic the potent anticancer activity of 1a, thereby validating the computational studies.

Towards a streamlined synthesis of peptides containing α,ß-dehydroamino acids.

Investigation of a strategy to streamline the synthesis of peptides containing α,ß-dehydroamino acids (ΔAAs) is reported. The key step involves generating the alkene moiety via elimination of a suitable precursor after it has been inserted into a peptide chain. This process obviates the need to prepare ΔAA-containing azlactone dipeptides to facilitate coupling of these residues. Z-dehydroaminobutyric acid (Z-ΔAbu) could be constructed most efficiently via EDC/CuCl-mediated dehydration of Thr. Formation of Z-ΔPhe by this or other dehydration methods was unsuccessful. Production of the bulky ΔVal residue could be accomplished by DAST-promoted dehydrations of ß-OHVal or by DBU-triggered eliminations of sulfonium ions derived from penicillamine derivatives. However, competitive formation of an oxazoline byproduct remains problematic.

Convergent Total Synthesis of Yaku'amide†A.

Total synthesis of the anticancer peptide natural product yaku'amide A is reported. Its ß-tert-hydroxy amino acids were prepared by regioselective aminohydroxylation involving a chiral mesyloxycarbamate reagent. Stereospecific construction of the E- and Z-ΔIle residues was accomplished through a one-pot reaction featuring anti dehydration, azide reduction, and O→N acyl transfer. Alkene isomerization was negligible during this process. These methods enabled a highly convergent and efficient synthetic route to the natural product.