HELAN-DISSERTATION-2017.pdf (10.01 MB)
Novel Synthetic Methods for the Preparation of Heterocycles and Alkynes via Carbenoids
thesisposted on 2018-02-08, 00:00 authored by Victoria Helan
The first three chapters of this thesis concern the development of distinct synthetic methodologies, which exploit the reactivity of metal carbenoids and unencumbered alkylidenecarbenes for the preparation of N-fused heterocycles (imidazo[1,2-a]pyridines, indolizines) and alkynes, respectively. In the concluding chapter, the design and synthesis of a family of small molecules that inhibit the fusion of influenza A virus with mammalian cells is described. The Lewis acid-mediated dehydrative fragmentation of 5-hydroxyalkyl-1H-tetrazole as a means to generate alkylidenecarbenes has been investigated. Previous studies showed that treatment of these substrates with a range of carbodiimindes or high temperatures leads to the extrusion of two molar equivalents of dinitrogen and the concomitant formation of a reactive alkylidenecarbene. We screened various Lewis acids in order to find mild, catalytic conditions for the formation of alkylidenecarbenes from tetrazoles. These carbenes are also known to spontaneously undergo various transformations including 1,2-shifts to form alkynes. Optimization of the reaction conditions revealed that CuCl/Cu(OTf)2 efficiently catalyzed the fragmentation of the tetrazole substrates and the corresponding alkyne was formed almost quantitatively. Three-component coupling (3-CC) reactions represent an attractive opportunity to develop atom-economical transformations, which generate molecules with a high degree of complexity. A Lewis acid-catalyzed 3-CC reaction employing 2-aminoazines, aromatic aldehydes, and diazo-compounds was developed; β-amino-α-diazocarbonyl compounds were produced in moderate to good yields even though the imine generated by addition of the 2-aminoazine to the aldehyde did not bear an electron-withdrawing group. Moreover, the pyridine group on the imine acted as a proton shuttle leading to the conservation of the diazo group in the final products. These diazo-compounds were found to be valuable building blocks for the preparation of β-amino acid derivatives, imidazo[1,2-a]pyridines, and pyrido[1,2-a]pyrimidine-4-ones. Optimization studies on the transannulation reaction of pyridotriazoles and terminal alkynes to generate indolizines were also conducted in order to replace the rhodium catalyst commonly employed in the reaction of 1,2,3-triazoles with a more abundant and less expensive catalyst. Through screening of the reaction conditions, it was found that Cu(MeCN)4PF6 efficiently catalyzed the transannulation reaction. Aerobic conditions were now tolerated and a broader reaction scope of pyridotriazoles and terminal alkynes was developed. In a collaborative effort with the laboratories of Caffrey and Lavie at UIC, a novel family of small molecule inhibitors of H5 HA influenza A viruses have been developed. While MBX2546 was previously characterized as fusion inhibitor of H5 HA, additional crystallographic data were needed to confirm the binding to the viral protein. We therefore designed analogs of MBX2546 to improve the solubility of the H5 HA complex with the inhibitor in the X-ray crystallography experiments. Two batches of analogs were produced in good yields following a 4-step synthetic route. Preliminary results showed that the analog bearing the chlorine substituents could bind the same binding site as MBX2546 but with lower affinity.
AdvisorWardrop, Duncan J
ChairWardrop, Duncan J
Degree GrantorUniversity of Illinois at Chicago