UC San Diego

Polyketide natural products are valuable components of the modern pharmacopea. These secondary metabolites have a diverse range of structures and activities. Studies of their biosynthesis and activity will help to provide access to better medicinal compounds. To this end, directly probing these mechanisms with derivatives of natural products is an important goal. Synthetic organic chemistry allows production of a greater variety of compounds than can be accessed by manipulation of isolated natural products. In some cases, these bioactive molecules are only obtainable in small quantities or at great expense. Herein, a modular synthesis of the Coenzyme A (10) precursors pantethine (35) and phosphopantetheine (14) is described. CoA is a cofactor that interacts with an estimated 4% of all enzymes known in nature, and it is central to the biosynthesis of polyketide antibiotics. Using d-pantolactone (50) to provide the key units, 53 and 63, pantetheine, phosphopantetheine, and derivatives were assembled through peptide couplings. Next, synthetic methods were applied toward the total synthesis of two related macrolide antibiotics, pladienolide B (70b) and FD -895 (71), in an attempt to elucidate their stereochemistries and to get a supply of each molecule for studies into the their stereochemistries and to get a supply of each molecule for studies into the molecule relies on a Stille coupling to connect the sidechain (133) to the 12-membered macrocyclic core (111), and an esterification / ring-closing metathesis sequence to furnish the ring from compounds 115 and 114. The sidechain of pladienolide B was completed and involved in model studies to demonstrate the overall retrosynthetic background. The core structure was proposed to arise from the chiral pool, but the strategy to combine the two units with the necessary stereochemistry met with failure under many different conditions. Due to complications in obtaining an authentic sample of pladienolide B (70b), and subsequent outside publication of a total synthesis incorporating many aspects of the work contained herein, FD-895 (71) was chosen as an alternative target. The same retrosynthetic breakdown was applied to FD-895