Biogenic small molecules (BSMs), simply referred to as “metabolites”, are highly diverse, naturally occurring compounds that often serve essential roles in biological systems. Identification of BSMs contributes to the understanding of an organisms’ primary metabolism, reveals intra- and inter-organismal signaling pathways, and provides new leads in drug discovery. While decades of research have led to impressive and unprecedented discoveries in the small molecule world, the majority of BSMs in the metabolomes of even the most well-studied organisms remain uncharacterized. In this work, the author identifies and/or synthesizes a diverse collection of BSMs primarily from nematodes and one family of plant-derived compounds. Chapters 1-3 focus on the metabolome of Caenorhabditis elegans, a versatile nematode species used widely as a model organism for biomedical research. C. elegans produces a vast diversity of BSMs from several metabolic pathways, which includes nucleoside metabolism. Despite their involvement in many aspects of cellular signaling and function as well as biomedical relevance, nucleosides are an understudied class of BSMs, and very few derivatives beyond canonical ribonucleosides have been described in animals. Here, the author shows that C. elegans produces a diverse collection of non-canonical nucleosides that strikingly are based on glucose and its corresponding 3-phosphate. These gluconucleosides are specifically derived from a pool of modified nucleobases, which include uric acid, methylpurines, and a conserved hypermodified base found in tRNA. In addition, we identified a series of acylated gluconucleoside derivatives, integrating diverse moieties from amino acid and fatty acid metabolism. Production of gluconucleosides was found to be species-specific and often life stage and sex dependent. Identification of the gluconucleoside class was facilitated by combining innovative mass spectrometric strategies with novel synthetic approaches. The amorfrutins, of which are benzoic acid derivatives that contain various isoprene moieties, are a medicinally important class of BSMs characterized from several plant species. Amorfrutins function as peroxisome proliferator-activated receptor gamma (PPARγ) modulators and exhibit antiproliferative and antidiabetes properties. Previously reported synthetic approaches involve lengthy sequences and inconvenient reagents. In Chapter 4, the author reports two convergent approaches based on [4+2] assembly logic that efficiently access amorfrutins and related derivatives, such as cannabigerolic acid (CBG). The first approach involves a novel anionic cascade reaction whereas the other utilizes a tandem Diels-Alder/retro-Diels-Alder sequence instead. The disclosed routes are shorter than many of the previously described syntheses and are also modular, providing the ability to generate diverse analogs or chemical probes.