| Natural products have been instrumental in unraveling some key biological processes, either as biological probes or as engines for drug discovery and therapeutics intervention. Developments in synthetic methods and total synthesis have enabled the synthesis of exceedingly complex natural products with acceptable efficiency. Unfortunately, the syntheses of these complex, biologically active natural products are lengthy and low yielding, rendering total synthesis an inefficient source of small molecules to interrogate biology. Diversity-oriented synthesis aims to generate collections of small molecules of complexity reminiscent of natural products efficiently and, in conjunction with small molecule screening, to use those small molecules to investigate biological processes. Herein, we describe two separate strategies toward the generation of skeletally diverse small molecules. In the second chapter we describe the development of a synthetic strategy that generates skeletally diverse small molecules by using fragmentation reactions. Synthetic pathways that generate different skeletons in sequential reactions are highly valuable in the development of a DOS pathway. We were able to employ this strategy to the solid-phase, split pool synthesis of a library of 4000 small molecules representing three distinct skeletons. In the third chapter we describe the development of a novel DOS pathway emanating from a simple propargyl alcohol, leading to multiple skeletons. We report the use of the Smiles rearrangement to generate several distinct skeletons from one common precursor by carefully manipulating reaction conditions. Within the same pathway, we were able to use reactions such as the Nicholas reaction, the Pauson-Khand reaction, the Diels-Alder reaction, and enyne metathesis to generate skeletally and stereochemically distinct small molecules. A representative set of small molecules was submitted to the Broad Institute screening effort and preliminary screening data has revealed interesting structure-activity relationships and selective biological activity in two assays. |
