Discovery and Development of Novel, Selective Metabotropic Glutamate Receptor 7 Negative and Positive Allosteric Modulators; A General, Enantioselective Synthesis of 2-Substituted Thiomorpholines and Thiomorpholine 1,1-Dioxides; and Total Synthesis of Natural (-)- and Unnatural (+)-Melearoride A

Abstract

The metabotropic glutamate (mGlu) receptors belong to the Class C family of G protein-coupled receptors (GPCRs) and are involved with the modulation of neuronal excitability and synaptic transmission within the central nervous system. Through the development of selective tool compounds, several mGlu receptors have recently been implicated in diseases such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia. Of the eight mGlu receptors, perhaps the least is known about mGlu7 due to the lack of fully selective tool compounds. Therefore, in order to understand the pharmacological and therapeutic relevance of this receptor, we propose that the use of an allosteric probe development strategy will engender the levels of selectivity needed in order to further interrogate the physiological importance of mGlu7 via the development of both negative and positive allosteric modulators. Thiomorpholines and their oxidized congeners (thiomorpholine 1,1-dioxides) are privileged medicinal chemistry scaffolds. However, synthetic routes to access 2-substituted thiomorpholines and 2-substituted thiomorpholine 1,1-dioxides rely on the use of chiral chromatography to obtain enantiomerically enriched substrates. Due to the lack of enantioselective synthetic routes, we present a robust, enantioselective synthetic strategy for obtaining either enantiomer of 2-substituted thiomorpholines and 2-substituted thiomorpholine 1,1-dioxides utilizing organocatalysis. The rise of antimycotic resistance has become a serious problem for patients suffering from azole-resistant fungal infections. Recently, efforts have focused on the identification of natural products that could serve as viable alternatives to azole-based therapeutics. Melearoride A, a natural product isolated from the marine fungus Penicillium meleagrinum var. viridiflavum, was recently isolated in 2016 by Koyama and coworkers and was shown to display synergistic activity with fluconazole against azole-resistant strains of Candida albicans. Therefore, we present a robust, modular synthetic strategy for accessing both enantiomers of Melearoride A that is amenable to future antifungal SAR studies.