UC Santa Barbara

Chemical synthesis of structurally complex and biologically active natural products plays a critical role in bridging innovative synthetic methodologies with real world applications, particularly in medicinal fields. However, limited availability of many natural products impedes further studies of their biological activities and possible therapeutic utilization. Synthetic strategies for natural products have the potential to mitigate their scarcity and, at the same time, provide new insights into complex molecules and their practical uses. This dissertation features the synthetic developments of three natural products: thalassospiramide C, anatoxin-a, and xestospongins. The syntheses of these natural products are widely impactful: while thalassospiramide C and xestospongins are marine natural products with promising clinical significance for drug developments, isotopically labeled anatoxin-a is a key to developing a precise quantification analysis for toxins in fresh water. The first chapter of this dissertation focuses on the total synthesis of the N-desmethyl thalassospiramide C, a first in the family of thalassospiramides natural products. Moreover, its mode of binding was elucidated by the crystallography adduct of N-desmethyl thalassospiramide C with cathepsin K. The great inhibitory activity of thalassospiramides against cysteine proteases was clearly depicted through a covalent addition of cysteine residue to the α,β-unsaturated amide of the macrocycle. Our successful chemical synthesis allowed further evaluation of the bioactivities of this macrocyclic cysteine protease inhibitor and addressed the unique 12-membered depsipeptide macrocyclic core as a pharmacophore unit. The second chapter highlights the asymmetric total synthesis of (+)-[13C4]-anatoxin-a, the first isotopically labeled synthesis for this commonly found freshwater cyanotoxin. Two enantioselective synthetic approaches were introduced: a route centered around retaining the enantiopurity of materials established through a Sharpless asymmetric epoxidation of an early-stage allylic alcohol, and an approach employing a penultimate enantioselective intramolecular cyclization allowed for late-stage stereocontrol. The paramount aza-Morita–Baylis–Hillman cyclization strategically maneuvered a dynamic kinetic resolution of cyclic iminiums to construct the bicyclic core of anatoxin-a. Our novel and robust synthesis demonstrated high scalability, and the successful isotopically labeled synthesis allows for a more precise anatoxin-a quantification method to be established. The last chapter of this dissertation describes an ongoing study towards a 2nd generation large-scale synthesis of xestospongin-type natural products, a family of marine alkaloid with promising cancer therapeutics. Two key early-stage intermediates were identified as targets for synthesis optimizations—the α-alkoxy acid intermediate and the common azidoalcohol intermediate responsible for a non symmetrical synthetic design. Optimized routes for both intermediates showcased synthetic efficiencies, with the synthesis of the azidoalcohol featuring a titanium–salalen catalyzed asymmetric epoxidation with hydrogen peroxide of a typically challenging terminal and non-conjugated olefin intermediate. The accomplished shortened and greater yielding synthetic routes for the two intermediates ensures the overall scalability and synthetic ease for the ultimate synthetic access of various xestospongins.