Synthesis of HC-Toxin via Matteson Homologation and C-H Functionalization.

A new synthetic route toward host-specific HC-toxin was developed. The HC-toxin belongs to a group of cyclic, tetrapeptide histone deacetylase inhibitors containing the unusual amino acid Aeo. Key steps in the synthesis of this building block include the Matteson homologation to generate the stereogenic centers in the side chain and a C-H functionalization to connect the side chain to a protected alanine.

Total synthesis and biological evaluation of histone deacetylase inhibitor WF-3161.

A novel synthesis of the naturally occurring HDAC inhibitor WF-3161 is described. Key steps include the Matteson homologation to generate the stereogenic centres in the side chain, and Pd-catalysed C-H functionalisation to connect the side chain to the peptide backbone. WF-3161 was found to be highly selective for HDAC1, whereas no activity was observed towards HDAC6. High activity was also found against the cancer cell line HL-60.

Total synthesis of Myxoprincomide, a secondary metabolite from Myxococcus xanthus.

Myxoprincomide, a secondary metabolite of the myxobacterium Myxococcus xanthus DK 1622, is synthesised for the first time. The central, unusual α-ketoamide is generated at the end of the synthesis to avoid side reactions during the synthesis of this rather reactive subunit. Nevertheless, the synthetic natural product is obtained as an isomeric mixture. Detailed analytical investigations show that the identical isomeric mixture is found in the isolated natural product.

C-H Functionalization of Peptides via Cyclic Aminal Intermediates.

Protected dipeptides can be converted into cyclic ketoaminals, which can be subjected to palladium-catalyzed regioselective C-H functionalization. The best results are obtained using the 2-(methylthio)aniline (MTA) directing group, which is superior to the commonly used 8-aminoquinoline (AQ) group. No epimerization of stereogenic centers is observed. Subsequent cleavage of the directing and protecting groups allows the incorporation of a modified dipeptide into larger peptide chains.