Brandon Ashfeld

Brandon Ashfeld

Professor of Chemistry & Biochemistry; Director, Chemical Synthesis and Drug Discovery Facility, Warren Center for Drug Discovery and Development, Department of Chemistry and Biochemistry

University of Notre Dame

bashfeld@nd.edu

Complications relating to the strategic assembly of N-heterocyclic scaffolds, and the significance of this molecular framework to the development of therapeutics, diagnostics, and materials is difficult to overstate. Likewise, the stereoselective construction of quaternary stereogenic carbons remains a long-standing challenge in synthetic chemistry. By addressing these obstacles directly, our goal is to broadly impact organic chemistry, materials science, and medicinal chemistry through the development of new synthetic strategies that exploit underutilized functionality while leveraging the biphilic behavior of carbene-like intermediates to concurrently construct key C–C and C–N bonds. The main components of our program include:

  • Development of transition metal-catalyzed multicomponent couplings focused on (m+1)- and (m+3)-cycloaddition constructs for the convergent assembly of highly substituted carbon centers as a lynchpin to access biologically relevant alkaloid scaffolds in the development of cancer. chemotherapeutics
  • Synthetic modification of the squaraine core in the construction of designed sensing agents, and their use as a template in the development of new chiral ligands for asymmetric catalysis.
  • Design of thermoresponsive ionic liquids in liquid-liquid separations to explore temperature and medium-dependent biological processes while broadly impacting separation science.

The primary driving force behind each initiative is the need for new strategies to synthesize architecturally complex molecular architectures that are otherwise laborious or difficult to achieve using conventional strategies. Our long-term goals are to use these new chemical constructs in the development of improved chemotherapeutics and the design of new materials that improve chemical separations. To achieve these objectives, we have established a series of interdisciplinary collaborations wherein internationally recognized expertise is leveraged to address global challenges related to climate change and public health.

Selected Publications:

Zhu, Y.; Zhao, Y.; Wen, J.; Liu, S.; Huang, T.; Hatial, I.; Peng, X.; Al Janabi, H.; Huang, G.; Mittlesteadt, J.; Cheng, M.; Bhardwaj, A.; Ashfeld, B. L.; Kao, K.; Maeda, D.; Dai, X.; Wiest, O.; Blagg, B. S. J.; Lu, X.; Cheng, L.; Wan, J.; Lu, X. “Targeting Chromatin Effector Pygo2 Promotes Cytotoxic T cell Responses and Overcomes Immunotherapy Resistance in Prostate Cancer.” Sci. Immunol. 2023, 8, eade4656.
 
Hammers, D. E.; Donahue, D. L.; Tucker, Z. D.; Ashfeld, B. L.; Ploplis, V. A.; Castellino, F. J.; Lee, S. W. “Streptolysin S targets the sodium-bicarbonate cotransporter NBCn1 to induce inflammation and cytotoxicity in human keratinocytes during Group A Streptococcal infection.” Front. Cell. Infect. Microbiol. 2022, DOI: 10.3389/fcimb.2022.1002230.
Gulotty, E. M.; Sanadhya, S.; Tucker, Z. D.; Moghaddam, S.; Ashfeld, B. L. “Controlling Phase Separation Behavior of Thermo-responsive Ionic Liquids Through the Directed Distribution of Anionic Charge.” J. Mol. Liq. 2022, 360, 119401 (1-10), DOI: https://doi.org/10.1016/j.molliq.2022.119401.
 
Huizar, F. J.; Hill, H. M.; Bacher, E. P.; Eckert, K. E.; Gulotty, E. M.; Rodriguez, K. X.; Tucker, Z. D.; Wiest, O.; Zartman, J.; Ashfeld, B. L. “Rational design and identification of harmine-inspired, N-heterocyclic DYRK1A inhibitors employing a functional genomic in vivo Drosophila model system.” ChemMedChem, 2022, e202100512, DOI: https://doi.org/10.1002/cmdc.202100512.
 
Guo, J.; Tucker, Z. D.; Wang, Y.; Ashfeld, B. L.; Luo, T. “Ionic liquid enables highly efficient low-temperature desalination by directional solvent extraction.” Nat. Commun. 2021, 12 (437), DOI: 10.1038/s41467-020-20706-y.
 
Rodriguez, K. X.; Howe, E. N.; Bacher, E. P.; Burnett, M.; Meloche, J. L.; Meisel, J.; Schnepp, P.; Tan, X.; Chang, M.; Zartman, J.; Zhang, S.; Ashfeld, B. L. “Combined Scaffold Evaluation and Systems-level Transcriptome-Based Analysis for Accelerated Lead Optimization Reveals Ribosomal Targeting Spirooxindole Cyclopropanes.” ChemMedChem, 2019, 14 (18), 1653-1661.
 
Bacher, E. P.; Lepore, A. J.; Pena-Romero, D.; Smith, B. D.; Ashfeld, B. L. “Nucleophilic Addition of Phosphorus(III) Derivatives to Squaraines: Colorimetric Detection of Transition Metal-Mediated or Thermal Reversion.” Chem. Commun. 2019, 55, 3286-3289.
 
Eckert, K. E.; Ashfeld, B. L. “Aroyl Isocyanates as 1,4-Dipoles in a Formal [4+1]-Cycloaddition Approach Toward Oxazolone Construction.” Org. Lett. 2018, 20 (8), 2315-2319.
 
Rodriguez, K. X.; Pilato, T. C.; Ashfeld, B. L. “An Unusual Stereoretentive 1,3-Quaternary Carbon Shift Resulting in an Enantioselective RhII-Catalyzed Formal [4+1]-Cycloaddition Between Diazo Compounds and Vinyl Ketenes.” Chem. Sci. 2018, 9, 3221-3226.

White, E. E.; Rodriguez, K. X.; Ashfeld, B. L. “Stereochemical Implications in the Synthesis of 3,3´-Spirocyclopropyl Oxindoles from β-Aryl/Alkyl-Substituted Alkylidene Oxindoles.” Tetrahedron, 2015, Accepted manuscript, in press, DOI: 10.1016/j.tet.2015.06.004.

  • Invited article for the Symposium-in-Print in honor of Professor Barry M. Trost for receipt of the Tetrahedron Award for Creativity in Organic Synthesis.

Haugen, K. C.; Rodriguez, K. X.; Chavannavar, A. P.; Oliver, A. P.; Ashfeld, B. L. “Phosphine-Mediated Addition of 1,2-Dicarbonyls to Diazenes: An Umpolung Approach toward N-Acyl Hydrazone Synthesis.” Tetrahedron Lett.2015, 56 (23), 3527-3530.

  • Invited article for the Symposium-in-Print in honor of Professor Harry Wasserman.

Gianino, J. B.; Campos, C. A.; Lepore, A. J.; Pinkerton, D. M.; Ashfeld, B. L. “Redox and Lewis Acid Relay Catalysis: A Titanocene/Zinc Catalytic Platform in the Development of Multicomponent Coupling Reactions.” J. Org. Chem. 2014, 79 (24), 12083-12095.

  • Invited manuscript for the special issue titled Mechanisms in Metal-Based Organic Chemistry.
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