Total synthesis and biological evaluation of lipidic natural products and synthetic structural analogs

Marine organisms produce structurally unique natural products with promising biological activities such as antibacterial, antifungal, anti-inflammatory and antiproliferative properties. To circumvent the labor-intensive process of isolation from natural sources, total synthesis serves as a powerful tool to obtain sufficient quantities of these compounds for structural elucidation, stereochemical assignment, targeted modification and biological evaluation. Motivated by the significance of lipidic natural products and the continuous discovery of related molecules, this thesis focuses on the development of synthetic methodologies for the total synthesis of vicinal amino alcohols, sphingoid bases and N-acyl amino acids. The first part describes a highly stereoselective route to anti-1,2-amino alcohols using the directing effect of the underexplored 2,5-dimethylpyrrolo N-protecting group. The second part presents the total synthesis and structural revision of halisphingosine A through the synthesis of 33 regio- and stereoisomers via modular routes over 11–14 steps. The biological evaluation revealed moderate antimicrobial activity against Gram-positive and Gram-negative bacteria and C. albicans, along with low micromolar cytotoxicity against lung and liver carcinoma cell lines. The final part addresses the synthesis of 21 N-acyl amino acids and stieleriacine C congeners as future internal standards for targeted metabolomics. The total synthesis of epi-stieleriacine C confirmed its unusual D-amino acid configuration and led to the structural revision of the natural product.