Targeting the “undruggable” proteome remains one of the big challenges in drug discovery. Recent innovations in the field of targeted protein degradation and manipulation of the ubiquitin-proteasome system open up new therapeutic approaches for disorders that cannot be targeted with conventional inhibitor paradigms. Proteolysis targeting chimeras (PROTACs) are bivalent ligands in which a compound that binds to the protein target of interest is connected to a second molecule that binds an E3 ligase via a linker. The E3 protein is usually either Cereblon or Von Hippel-Lindau. Several examples of selective PROTAC molecules with potent effect in cells and in vivo models have been reported. The degradation of specific proteins via these bivalent molecules is already allowing for the study of biochemical pathways and cell biology with more specificity than was possible with inhibitor compounds. In this review, we provide a comprehensive overview of recent developments in the field of small molecule mediated protein degradation, including transcription factors, kinases and nuclear receptors. We discuss the potential benefits of protein degradation over inhibition as well as the challenges that need to be overcome.

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The intramolecular 1,3-diyl trapping reaction served as the key step in a total synthesis of (±)-coriolin (1) and the first total synthesis of (±)-hypnophilin (3). In the process, four of the required eight (coriolin) or six (hypnophilin) stereocenters were established. The reaction was studied as a function of temperature. The highest yield and greatest stereo-/ regioselectivity was obtained when the reaction was initiated photochemically at -6(3 °C in methyl alcohol. From the temperature dependence, it was established that enthalpic rather than entropic factors were responsible for governing the selectivity of the process. The required cis, anti ring-fused product 10 was favored over the minor products by * = -2.19 kcal mol""1 2. Two noteworthy steps in the conversion of tricyclopentanoid 10 to the natural products included the Lewis acid facilitated 1,4-addition of Li2Cu(CN)(CH3)2 to the hindered C2 carbon in 26 and the epoxidation of compounds 10, 24, and 29. Each olefin 10 and 24 led to the formation of products containing both cis-and trans-fused bicyclo[3.3.0]octane ring systems. Molecular mechanics calculations (MM2) were used to calculate differences in strain energies between the two types of products. In the case of olefin 39, only the trans-fused AB-ring junction stereochemistry was observed. Single-crystal X-ray analysis verified the stereochemical assignments and served to provide a rationale for the unanticipated formation of these trans-fused products. ' UCSB.

Both base-assisted non-concerted metallation-deprotonation (nCMD) and concerted metallation-deprotonation (CMD) have been identified as two potent operating mechanisms in palladium-catalysed direct C-H coupling of oxazole and thiazole-4-carboxylate esters with halides through base- and solvent-effect experiments. Novel C2- and C5-selective CMD direct arylation procedures in oxazole- and thiazole-4-carboxylate series were then designed by controlling the balance between electronic and steric factors. Notably, charge interactions between the palladium catalyst and substrate were identified as a parameter for controlling selectivity and reducing the impact of steric factors in the CMD reaction.

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