A Heck-Based Approach to the Synthesis of Anacardic Acids and an Exploration of its Derivatives as Small-Molecule Inhibitors of the SUMO E1 Enzyme and Aminoalkylation of Adamantanes Using Dual Photoredox-HAT Catalysis

Anacardic acids are a family of naturally occurring phenolic lipids with well-established antibacterial and anticancer bioactivities. As such, the synthesis of these compounds has been the subject of some interest. However, previous attempts at their synthesis have often relied on inefficient protection and deprotection steps, demonstrated poor regiocontrol, and offer only narrow access to specific members of the anacardic acid family. Herein, a new Heck-based approach to the synthesis of anacardic acids that circumvents these issues is presented. The use of this strategy in conjunction with stereoselective olefination enables access to virtually any member of the anacardic acid family including unnatural isoforms. This method has been used to construct a small library of anacardic acids and were then used in an MMP-2 activity assay which revealed that inhibition is not strongly related to structural morphology. Anacardic acid is known to possess anticancer activity through inhibition of the SUMO E1 enzyme by exploiting a so called “non-oncogene addiction.” Based on these findings, a wide range of anacardic acid derivatives have been synthesized by first using computational molecular docking studies to identify promising synthetic candidates. These derivatives were then tested using in-situ sumoylation assays through interdisciplinary collaborations with other research groups at UCR.In a separate line of work, a method for aminoalkylation of adamantane using imine substrates has been developed as an extension of previous work in our lab with a dual catalyst system. This catalyst system employs the use an iridium photocatalyst with a quinuclidine-based hydrogen-atom transfer (HAT) co-catalyst. The reaction is remarkably selective for adamantyl C–H bonds, even in the presence of other, weaker alkyl C–H bonds. The aminoalkylative C–C bond formation between adamantane and a variety of imines is possible using this method and affords valuable amino acid building blocks. The use of a different photocatalyst with chiral amines allows for the enatioselective synthesis of rimantadine derivatives and the saxagliptin core