Biseokeaniamides A, B and C are the first isolated linear lipopeptides possessing inhibitory activity against both sterol O-acyltransferase (SOAT) isozymes[1], important targets for the treatment of hypercholesterolemia and atherosclerosis. These heavily backbone N-methylated peptide natural products possess an intriguing C-terminal thiazole unit and a short N-terminal lipid chain – distinctive structural features which pose considerable challenges to their total synthesis through conventional strategies employing solid phase peptide synthesis (SPPS). Our aim is to develop efficient new strategies for the synthesis and late-stage modification of the biseokeaniamides to enable the development of new SOAT isozyme-specific inhibitors for biological testing.
This presentation will detail our progress toward the syntheses of biseokeaniamides A-C and the development of new methods for late-stage thiazole incorporation. In our first-generation synthesis, the linear structure of these natural products was assembled using Fmoc-SPPS, and subsequent coupling with a preformed N-methyl-(α-thiazole) methanamine building block afforded the first total synthesis of biseokeaniamide C. To expedite the preparation of the key thiazole building block, a non-Kolbe type electrochemical decarboxylation method was next investigated to enable the direct assembly of the terminal thiazole from a simple protected amino acid. Motivated by our initial successes and inspired by the early research of D. Seebach et al.[2] on the anodic oxidation of peptides, we envisaged that peptide carboxylic acids (readily accessible by conventional SPPS) would undergo late-stage electrochemical decarboxylation to generate N, O-acetals as viable intermediates for subsequent modification. Herein, we demonstrate that peptide-derived N, O-acetals are competent substrates for the Lewis acid-mediated addition of various (hetero)aromatic nucleophiles and showcase this method as a promising tool for the installation of diverse aromatic functionalities at the C-terminus of peptides. We envision that this strategy will enable the rapid generation of valuable structural analogues of the biseokeaniamides and related natural products.