Natural products continue to inspire synthetic chemists to develop novel methodologies to provide efficient and expedient syntheses of the target molecules. Haterumalide NA aroused our interest and prompted development of four differing methodologies. Three of the strategies pursued involved use of B-lactone scaffolds as intermediates. Extensions of the nucleophile catalyzed, aldol-lactonization (NCAL) reaction were also pursued and targeted toward alternative natural product targets. The reactivity of the unexpectedly stable strained spirocycle, spiroepoxy-B- lactone, was explored. Spiroepoxy-B-lactones exhibited a wide range of reactivity, but largely rearranged to tetronic acids. The desired reaction manifold remained inaccessible and led to application of the NCAL process to tetrahydrofuran-fused B-lactones. Several tetrahydrofuran-fused B-lactones were prepared, which displayed low diastereoselectivity. The diastereoselectivity could be somewhat improved in a double diastereoselective NCAL process with varied solvent systems, yet the carbocyclic analogues gave much more promising results. The use of carbocycle-fused !-lactones ultimately culminated in a double diastereoselective NCAL process, and overall led to improvements in diastereoselectivities from 1:1-2 up to >19:1. Further expansion of the substrate scope for the NCAL process was studied for application to bridged tricyclic B- lactones, access to carbocycle-fused y-lactones, and towards development of a dynamic kinetic resolution NCAL process. With our interest aimed at haterumalide NA, a modified Negishi cross coupling between zincates and dichloroolefins was also revisited. The stringent anhydrous reaction conditions led to reexamination of initial leads, which provided user-friendly anhydrous conditions by utilizing commercially available anhydrous solvent. However, application was implemented solely to a simplified model system.

Natural products are essential tools for basic cellular studies leading to the identification of medically relevant protein targets and the discovery of potential therapeutic agents. We have developed a set of second generation diazo reagents with small steric footprints, namely an alpha-trifluoroethyl (HTFB) diazo reagent, for simultaneous arming and SAR studies of bioactive natural products. The Rh(II)-catalyzed O-H insertions of several alcohol-containing natural products, including the potent translation inhibitor lactimidomycin, are investigated and useful reactivity and both chemo- and site- (chemosite) selectivities are observed. The alpha-trifluoroethyl diazo reagents (HTFB) shows clear differences in the IL-2 reporter assay with FK506 derivatives and provides greater retention of biological activity in a hMetAP2 proliferation assay of fumagillol derivatives compared to the first generation pbromophenyl diazo reagent (HBPA). The synthetic utilities of the new alpha-trifluoroethyl diazo reagent (HTFB) provide a great new tool for basic cellular studies facilitating the discovery of new drug candidates for human disease. Furthermore, we are interested in methodologies for beta-lactone synthesis and transformations. In this study, we demonstrated synthetic versatilities of beta-lactones for the synthesis of beta-lactam congeners of orlistat as fatty acid synthase inhibitors via SnCl4- promoted tandem Mukaiyama aldol-lactonization (TMAL) reaction and a one-pot, mild conversion of beta-lactones to beta-lactams. The inhibitory activities of the derived beta-lactam derivatives are determined in a biochemical fluorogenic assay using recombinant FASTE, and the micro-molar range FAS-TE inhibitory activities were observed. Additionally, we pursued synthetic studies toward the total synthesis of spongiolactone, which is a unique beta-lactone-containing marine diterpenoid, isolated from the marine sponge Spongionella gracilis. This natural product bears a unique tricyclic beta-lactone core possessing four contiguous stereogenic centers and an additional stereogenic quaternary carbon on a cyclohexyl appendage. We completed the total synthesis of 6,15-bis-epi-spongiolactone by employing an intramolecular nucleophilecatalyzed aldol-lactonization (NCAL) process as the key step to construct the fused tricyclic beta-lactone core. Importantly, we developed a double diastereoselective and, for the first time, a kinetic resolution via the NCAL process that enables an enantioselective strategy to the tricyclic beta-lactone core of (+)-spongiolactone.