Synthetic Studies in the Selective Functionalization of Unsaturated Compounds: From Initial Applications in Medicinal Chemistry to General Applications in Unactivated Systems

Medicinal chemistry and reaction development have influenced one another in the field of organic chemistry. The synthesis of therapeutic small molecules often requires the use of practical synthetic methodologies, while reaction development is frequently inspired by the demands of medicinal chemistry. First the development of small molecule inhibitors of hypoxia inducible factors, which are heterodimeric transcription factors that have been implicated in a number of cancer environments, will be discussed. Two scaffolds have been designed and evaluated for their ability to selectively bind within the binding domain of the hypoxia inducible factor-2α isoform and inhibit heterodimerization, with the most potent agonist exhibiting a half maximal inhibitory concentration value of 23 nanomolar. Inspired by the stereospecific mode of action exhibited by the diaryl-tetrazolo-tetrahydropyrimidine-based scaffold of hypoxia inducible factor-2 antagonists, a potential co-catalyst system for the asymmetric synthesis of these derivatives has been identified, utilizing a synergistic combination of a cinchona alkaloid-based primary amine and acid catalysts. While the enantioselectivity of this reaction as it currently stands remains modest, these products can be isolated in up to 96:4 enantiomeric ratio through recrystallization efforts. Secondly, the development of a series of general and efficient methods for the synthesis of functionalized olefin products from simple unsaturated systems will be described. Unfunctionalized olefins and dienes are ideal substrates for chemical synthesis due to their low cost and ease of availability. However they present a variety of challenges when attempting to selectively differentiate between sterically and electronically similar carbon-hydrogen bonds. The processes described herein exploit the ability of sulfurimide and sulfurdiimide reagents to undergo hetero-ene reactions with terminal and internal olefins as well as [4+2] couplings with dienes. These reactions result in reactive intermediates that are utilized in a host of chemical transformations, including [2,3]-rearrangements to generate allylic amines and alcohols, Grignard coupling to generate linear and branched alkylated products, and aminoarylation chemistry. Most notably, a regio- diastereo- and enantioselective synthesis of multifunctional allylic sulfinimides from internal olefins is discussed.