| Complex natural products continue to inspire synthetic chemists to improve the state of the art of synthetic organic chemistry. As part of these efforts, the Boger lab has pioneered the understanding of the aza-diene Diels-Alder which converges its reacting partners regio- and stereospecifically. The Diels-Alder reaction of oxadiazoles not only does this, but also subsequently generates a reactive carbonyl ylide that can be used for further 1,3-dipolar cycloadditions. This [4+2]/[3+2] cycloaddition cascade was first developed for a synthesis of vindoline and is extended in Part I to the parent members of the aspidoalbine natural products, fendleridine and 1-acetylaspidoalbidine. The synthesis takes advantage of the C19 oxidation state of the N,O -ketal introduced from the 1,3-dipolar cycloaddition to form the sixth fused tetrahydrofuran ring of the natural products. The described synthesis not only complements previous total syntheses but also provides access to the rest of the aspidoalbine alkaloid family.;Whole genome sequencing has unveiled the vast percentage of the mammalian proteome that is poorly annotated with respect to physiological substrates and functions. Among the poorly characterized proteome are individual members of structurally and mechanistically related families, such as the serine hydrolases, a diverse and biologically relevant class of enzymes. The Cravatt lab has significantly furthered the annotation of serine hydrolases particularly through activity-based protein profiling (ABPP). This work combines a high-throughput ABPP screening platform with more traditional gel-based techniques to discover novel scaffolds for serine hydrolase inhibition. Selective probes for the poorly characterized enzymes protein phosphatase methylesterase-1 (PME-1), alpha,beta-hydrolase domain-containing 10 (ABHD10), and the serine hydrolase subunits of platelet-activating factor acetyl hydrolase (PAFAH1B2 and PAFAH1B3) are disclosed. These inhibitors expand the current pharmacological coverage of the serine hydrolase family and demonstrate the importance of combining integrated organic synthesis, high-throughput screening, and chemoproteomics to identify small molecule probes. |
