The discovery and design of bivalent, small-molecule glucose-6-phosphate dehydrogenase activators and tetramethyleneethane equivalents for the convergent synthesis of the bicyclo[4.4.0]decane core
- Andrew Goodwin Raub.
- [Stanford, California] : [Stanford University], 2019.
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- This dissertation covers work carried out independently in both the Mochly-Rosen and Wender Labs. Chapters 1 and 2 focus on the relevant background and development of a novel class of enzyme activators to treat G6PD deficiency (Mochly-Rosen Lab). Chapter 3 (Wender Lab) focuses on the development of novel synthetic methods for the construction of the bicyclo[4.4.0]decane core. The application of this method in the construction of novel dyes is outlined. Chapter 1 provides a historical perspective on the discovery of mutated glucose-6- phosphate dehydrogenase (G6PD) as the underlying cause of favism and related diseases (e.g. primaquine sensitivity). A discussion follows which highlights certain pathologies associated with G6PD deficiency along with the consequences of reduced NADPH synthesis. The tertiary and quaternary structure of G6PD is discussed along with the functional consequences of altering the oligomeric state of the enzyme. Chapter 2 begins with background on small-molecule activators and protein-protein interaction (PPI) stabilizers. The high-throughput screening (HTS) campaign to find a small- molecule activator of G6PD is described, followed by a mechanistic investigation of the initial 'hit' molecule, AG1. This mechanistic understanding enabled the design of new analogs without the reactive liability of AG1 (disulfide) and led to the understanding of the general pharmacophore of these compounds. A discussion of the relevant synthetic methods and properties of these molecules is presented. Chapter 3 details the development of a novel class of reagents which enable two conjunctive cycloadditions for the synthesis of the bicyclo[4.4.0]decane core (naphthalene, higher acene and heterocyclic products). This class of reagents is a synthetic equivalent to the tetramethyleneethane (TME) diradical. These reagents use the vinylogous Peterson elimination for reactivity generation after the first cycloaddition between a dienophile and the novel diene. One reagent, DMTB, was found to enable the construction of bicyclic systems resulting from all thermal Diels-Alder (DA) cycloadditions or a mixture of DA cycloadditions followed by a transition-metal-catalyzed [4+2] reaction. Ultimately, DMTB was used in the synthesis of a new solvatochromic dye, 6-DMA in 69% overall yield. To enable back-to-back transition- metal-catalyzed [4+2] products, another reagent (THP-DMTB) had to be utilized due to decomposition of the original reagent under these conditions. In order to enable the formal synthesis of hetero-Diels-Alder products, AcDMTB was developed, which expands the methodology outside the constraints of Diels-Alder or metal-catalyzed cycloadditions.
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- Submitted to the Department of Chemistry.
- Thesis Ph.D. Stanford University 2019.