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Employing C-H Activation Tools for the Construction of Biologically-Relevant Molecules from Heteroaryl Precursors

When: Tuesday, April 26, 2022, 11:30 AM - 1:00 PM
Where: Hybrid: Bancroft 1.02.6 and Ms Teams, Mile End

Speaker: Dr Savvas Georgiades

Modern C-H activation methodologies provide exciting and direct (single-step) chemical transformations for the late-stage modification and/or diversification of valuable organic precursors. As such, they are now finding applications in the production of fine chemicals and pharmaceuticals.

This presentation will discuss cases of Pd-catalyzed C-H bond functionalizations developed in our laboratory, which aimed at producing new C(sp2)-C(sp2) bonds at an intermediate or late-stage in a synthesis and afforded new molecules with desired structural properties for biological or medicinal chemistry use. The first project involved synthesis of oligomeric pyridyl-oxazoles, with alternating pyridine and oxazole rings, providing rotational flexibility around the new C-C bonds as well as tunable conformation for use as surface-adaptive ligands in DNA biomolecular recognition. In this study, the oxazole synthesis relied on Van Leusen conditions, while Cu-mediated C–H activation of the produced oxazoles in conjunction to Pd-catalyzed C–C cross-coupling to 2-bromopyridines led to the assembly of variable-length (5-mer, 6-mer, 7-mer), ‘head-to-tail’-connected, pyridyl-oxazole oligomers. The interactions of these ligands with various cancer-relevant G-quadruplex DNA topologies (human telomeric/22AG hybrid and antiparallel and c-myc oncogene promoter parallel G4s) were investigated using biophysical methods, which demonstrated a prominence of the asymmetric pyridyl-oxazole motif as recognition element for G-quadruplexes.

Fluorescence titrations revealed excellent binding affinities of the 7-mer and 6-mer for all examined DNAs and selectivity for the Na-induced antiparallel telomeric G-quadruplex. The ligands stabilized G-quadruplexes (selectively, against a competitive duplex DNA, ds26), based on a competitive FRET DNA-melting assay. Additionally, the 7-mer and 6-mer were able to promote a ‘switch’-like topological transition of the hybrid telomeric G-quadruplex to antiparallel. In a second project, we have demonstrated that a LED-activated, photoredox-mediated, Pd(II)-catalyzed C–H arylation reaction, employing a phenyldiazonium salt as phenyl donor and tris(2,2′-bipyridine)ruthenium(II) or (2,2′-bipyridine)bis[3,5-di-fluoro-2-[5-(trifluoromethyl)-2-pyridinyl -kN][phenyl-kC]iridium(III) as photoredox initiator, may successfully generate a series of unprecedented mono- and bis-phenyl derivatives of functionality-rich 2,6-diphenylpyrimidine substrates, under mild conditions. The selected substrates share the medicinally-relevant N-heterocyclic scaffold, 4-methyl-2,6-diphenylpyrimidine-5-carboxylate. The substrates were obtained via (3-component) Biginelli condensation, oxidative dehydrogenation of the obtained 3,4-dihydropyrimidin-2(1H)-one to 2-hydroxypyrimidine, O-sulfonylation, and Suzuki-Miyaura C–C cross-coupling. Submission of these substrates to our N-atom-directed C–H arylation conditions caused regioselective phenylation at the ortho site(s) of the pyrimidine-C2-connected phenyl ring, revealing substituent-dependent electronic and steric effects. A focused compound library of mono- and bis-phenyl derivatives was generated, exhibiting interesting 3D and peripheral substitution diversity among its members, which render them promising for evaluation in drug discovery efforts. 

 

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