| Isolated more than fifty years ago from the fermentation broths of Streptomyces azureus ATCC 14921, S. hawaiiensis ATCC 12236, and S. laurentii ATCC 31255, thiostrepton ( 1.1) has remained as an elusive target from total synthesis. Active against gram-positive bacteria, thiostrepton (1.1) possesses a novel mechanism of action, involving cooperative binding to the 23S region of ribosomal RNA and ribosomal protein L11, thereby blocking the GTPase-dependent activities of the 50S ribosomal subunit, ultimately leading to the termination of protein synthesis. In addition to antimicrobial activity, thiostrepton (1.1) exhibits impressive anti-malarial activity (by the same mode of action) against Plasmodium falciparum.; Chapter 1 describes the synthesis of two complex fragments of thiostrepton (1.1), namely the quinaldic acid moiety and the complex dehydropiperidine core.; An efficient construction of the quinaldic acid macrocycle model system is based on state-of-the-art asymmetric synthesis, which included a CBS reduction and Katsuki manganese mediated epoxidation. The 27-membered macrocycle includes the quinaldic acid moiety, a thiazole ring and a dehydroalanine unit. The key steps in the convergent assembly of the quinaldic acid moiety included a regioselective epoxide opening, Yamaguchi esterification and macrolactamization. A first generation strategy is outlined and optimized providing a new and improved second generation strategy.; The key step in the construction of thiostrepton's dehydropiperidine core is a biomimetic hetero Diels-Alder dimerization cascade reaction. Inspired by nature, the product of this reaction, constitutes the core of thiostrepton, bearing two contiguous stereocenters and one quaternary center.; Chapter 2, outlines the discovery of a new tool in solid phase organic synthesis (SPOS). A new photolabile linker enabling nucleophilic cleavage of a carboxyl functionality upon irradiation with UV light (>290 nm) was developed. When the photocleavage is carried out in the presence of primary or secondary amines, amides are obtained in high yields and purities, while the intramolecular versions of this reaction leads to heterocycles via a cyclorelease strategy. |
