Modular synthesis for cooperative small molecule ligands and chemical education

Green, Nolan Michael

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https://hdl.handle.net/2142/132721 Copy

Description

Title

Modular synthesis for cooperative small molecule ligands and chemical education

Author(s)

Green, Nolan Michael

Issue Date

2025-07-28

Director of Research (if dissertation) or Advisor (if thesis)

Burke, Martin D

Doctoral Committee Chair(s)

Burke, Martin D

Committee Member(s)

• Moore, Jeffrey S
• van der Donk, Wilfred A
• Hergenrother, Paul J

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Modular synthesis, cooperative binding, chemical education

Abstract

Modular synthesis can be leveraged as both a synthetic strategy for accessing cooperatively binding small molecule ligands as well as a pedagogic framework for chemical education. Mimicking hemoglobin’s cooperative binding to oxygen stands as an unclimbed mountain in the field of protein mimicry despite countless efforts in developing cooperatively binding ligands and the reference to hemoglobin in those reports. 9,9’-bianthracene was determined to have the potential to serve as a cooperative scaffold given its rigidity and pseudosymmetry which allows the adoption of a global conformation to a higher energy state that prepays the enthalpic cost upon binding of a first equivalent of a guest. The coupling of function-infused building blocks enables the synthesis of a collection of model tetra-pyridyl bianthracene systems that do exhibit positive cooperativity. This result supports the notion that the 9,9’-bianthracene could serve as a scaffold for positive cooperativity if the pyridine rings are to be exchanged with metal-schiff bases complexes that are capable of reversibly forming µ-oxo bridges with molecular oxygen. As a framework for chemical education, modular synthesis serves the role of reducing the barrier to entry in organic chemistry and enabling students to discover structure-function relationships with the assistance of data science tools. Across four courses, we’ve developed a sequence of activities that introduce students to fundamental techniques such as K-nearest neighbors, K-medoids clustering, modularization of target molecules to identify repeating bond-types, and optimization of molecular function by identifying high-performing building blocks. Students also get hands-on experience in the power of modular synthesis to perform a classic diazo synthesis, a modern Suzuki-Miyaura cross-coupling that leverages a general purification procedure that enabled the development of an automated small molecule synthesis platform, an aerobic Suzuki-Miyaura coupling that generates an organic photovoltaic candidate for them to characterize and compare to a ML model. At the end of the sequence as well as the end of this dissertation, Organic Chemistry II students were challenged to shatter the traditional research-education barrier by synthesizing a collection of kinase inhibitor candidates. One student was able to successfully synthesize a molecule that is not reported in the literature and that molecule is currently undergoing screening against over 80 cell lines in collaboration with the CELLerator platform at UIUC.

Graduation Semester

2025-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/132721

Copyright and License Information

Copyright 2025 Nolan Green

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