Abstracts E1 - E4
Category E. Chemical Biology and Drug Design
E1. Complementary Pairing: An Aziridine Opening/SNAr Approach to Novel Benzofused Sultams
Joanna K. Loh, Naeem Asad, Thiwanka B. Samarakoon and Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, 2010 Malott Hall, Lawrence, KS 66045.
The University of Kansas Center for Chemical Methodologies and Library Development (KU-CMLD), 2034 Becker Drive, Shankel Structural Biology Center, West Campus, Lawrence, KS 66047.
The generation of common and stereochemically-rich medium-sized benzofused sultams via the complementary pairing (CP) of o-fluorophenyl-sulfonyl aziridines in a modular one-pot, sequential protocol using an aziridine ring-opening and intramolecular nucleophilic aromatic substitution (SNAr) is reported. The strategy employs a variety of amines/amino alcohols and proceeds with 6+1 and 6+4/6+5 cycloetherification pathways to obtain skeletally and structurally diverse, polycyclics, 7- and 10- to 11-membered benzofused sultams for broad scale screening.
E2. Phosphorus-based Methods for Natural Product Synthesis
Paul R. Hanson*, Soma Maitra, Susanthi Jayasinghe, Jana L. Markley, Salim Javed, Cornelius N. Ndi, Mahipal Bodugam, Arghya Ganguly
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Dr., 2010 Malott Hall, Lawrence, KS 66045-7582
Phosphate triester tether methods developed in our laboratory for the synthesis of complex biologically relevant natural products are reported. These methods are serving as the cornerstone in the asymmetric synthesis of IKD-8344 (which possesses strong cytotoxicity against L5178Y mouse leukemia cells with IC50 = 0.54 ng mL-1) and leustroducsin B. The method to the synthesis of antifungal δ-lactone strictifolione and a related family natural product, (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one will also be reported. In addition, expanded efforts toward spirastrellolide B (spirastrellolide A is a potent PP2A inhibitor; IC50 = 1 nM), as well as the development of phosphate-tether mediated one-pot processes that lead to differentiated polyol fragments, will be discussed. Finally, progress toward the identification and full understanding of alternative tripodal tether systems (specifically, phosphite-borane tethers), which could possess orthogonal reactivity patterns to the previously implemented bicyclic phosphate, will be introduced.
E3. Synthesis of Small Molecules Utilizing ROMP-Derived Oligomeric Reagents Under Purification-free Processes
Pradip K. Maity a, Patrick C. Kearney a, Saqib Faisal a, Oliver Reiser b, and Paul R. Hanson *a
aDepartment of Chemistry, 1251 Wescoe Hall Dr., University of Kansas, Lawrence, KS 66045. NIH Center for Chemical Methodologies and Library Development at the University of Kansas (KU-CMLD), 2034 Becker Drive, Del Shankel Structural Biology Center, Lawrence, KS 66047.
bInstitute for Organic Chemistry, University of Regensburg, Universitatsstr. 31, D-93053 Regensburg, Germany.
The development and application of ROMP-derived oligomeric soluble reagents and scavengers for the synthesis of small molecules are reported. Utilizing oligomeric reagents for benzylation and triazolation reactions with a variety of nucleophiles in purification-free processes is reported. In addition, generation of an array of high-load, ROMP-derived oligomeric reagents, and scavengers immobilized on Co/C magnetic nanoparticles utilizing surface-initiated ROM polymerization has been developed. We have discussed the utilization of these hybrid magnetic Co/C reagents in synthetic transformation for the facilitated synthesis of small molecules and high throughput methods for application in parallel synthesis and sequestration protocols.
E4. Utilization of Pd-catalyzed intramolecular C-vinylation of triazoles for the generation of Novel Sultams
Andie Jo Cassity, Jung Ho Jun, Nicole Marie Windmon, Naeem Asad, Anna J Diepenbrock and Paul R. Hanson*
Department of Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS, 66045
Synthesis of novel triazole-fused vinyl sultams via utilization of intramolecular C-arylation of triazoles is reported. The use of intramolecular C-vinylation on triazoles is relatively under explored. In this regard, we are investigating a versatile “Click-Click Cyclize” method for rapidly assembly of an array of diverse triazole-fused vinyl sultams. Several Pd-catalysts have been screened to optimize the intramolecular C-arylation reaction. Taken collectively, this facile method has been developed for generating novel electrophilic probes for screening.