Browsing by Subject "Diversity oriented synthesis"
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Item Design and synthesis of conformationally constrained ligands for Grb2 SH2 binding and thermodynamic evaluation and the development of a diversity oriented synthesis of 2-arylpiperidines(2016-12) Goodnough, Alex Michael; Martin, Stephen F.The ways in which torsional strain in the bound form of a ligand affects the energetics of protein binding are poorly understood. In order to study this feature of protein-ligand interactions, a conformationally constrained ligand for Grb2 SH2 containing a 1,1,2 trisubstituted cyclopropane was designed, and the synthesis of this ligand attempted. Additionally, a novel iminium ion formation/cyclization cascade was applied to the synthesis of a library of 2-arylpiperidines with varying aryl group substitution, and nitrogen atom functionalization. This strategy should allow further access to chemical space already identified as containing potential therapeutics and tool compounds for biological interrogation.Item The development of a four component reaction and its application to the synthesis of diverse heterocyclic scaffolds and the total synthesis of alkaloid natural products : the total synthesis of roelactamine and efforts towards the syntheses of rosicine and pseudotabersonine(2009-08) Sunderhaus, James Dennis; Martin, Stephen F.A four component reaction involving the coupling of functionalized aldehydes, amines, acid chlorides, and [pi]- and organometallic nucleophiles has been developed to prepare multifunctional substrates that may be employed in subsequent ring-forming reactions to generate diverse arrays of functionalized heterocyclic scaffolds. Allyl metals, Grignard reagents, silyl ketene acetals, silyl enol ethers, and silyloxy furans have been utilized as the nucleophile in the four component reaction (4CR). The 4CR has been sequenced with intramolecular Heck reactions, Diels-Alder and [3+2] cycloadditions, ring closing metathesis (RCM), and Dieckmann condensations to provide a number of diverse heterocyclic structures. The practical utility of this approach to diversity-oriented synthesis (DOS) was further exemplified by its application to the first total synthesis of the isopavine alkaloid roelactamine, which was completed in only four steps from commercially available materials. The application of this methodology towards the synthesis of the Aspidosperma alkaloids rosicine and pseudotabersonine is also presented. To this end, an imine pentadienylation/double RCM strategy has been adopted to rapidly access the pentacyclic core of the aspidospermine alkaloids. This sequence involved the use of a pentadienyl aluminum reagent, which was found to react with aryl imines to give branched products in good yields.