Room Temperature Chemoselective Phosphine Oxide Reduction and Mechanism-Based Inhibitors of BioA

University of Minnesota Ph.D. dissertation. May 2017. Major: Medicinal Chemistry. Advisor: Courtney Aldrich. 1 computer file (PDF); xiv, 328 pages.The reduction of phosphine oxides with silanes occurs with high specificity and fidelity and represents one of the most useful methods for synthesis of phosphines. The chemoselectivity of this process also allows for in situ recycling of phosphine oxide by-products to afford catalytic versions of the Wittig, Staudinger, and Mitsunobu reactions, among others. However, silane-mediated reduction of phosphine oxides generally requires both elevated temperatures (80–120 °C) and additives, substantially limiting substrate scope. Abnormal patterns in the reduction rates of phosphetane oxides by phenylsilane were noted, causing initiation of a comprehensive investigation of silane-mediated phosphine oxide reduction which revealed widespread misunderstandings of the reduction process. This led to characterization of a required pre-activation step for all commercially available silane reductants as well as a key 6-membered transition state that explains reactivity trends. Such insight fueled rational reagent design, furnishing 1,3-diphenyldisiloxane (DPDS), a superior disiloxane reducing agent. DPDS allowed for development of room temperature phosphine recycling Wittig, Staudinger, and Appel methodologies and is broadly applicable in phosphine synthesis, reducing acyclic phosphine oxides either additive-free at 110 °C or in combination with an additive under ambient conditions. Mechanism-based inhibitors (MBIs) are widely employed in chemistry, biology, and medicine due to their exquisite specificity and sustained duration of inhibition. The global kinetic parameters kinact and KI have been used to characterize MBIs, but derivation reveals they provide far less information than is commonly assumed. A more rigorous approach is determination of the individual microscopic rate constants of inactivation, which is demonstrated in the optimization of MBI 1. 1 inactivates tubercular BioA through a four-step mechanism, and kinetic analysis revealed the rate-limiting step is the removal of the α-proton of 1. This knowledge was subsequently applied to rationally design dihydro-4-pyranone 42, dihydro-4-pyridone 43 and dihydro-4-thiopyranone 51. A unified synthetic strategy was employed for heterocycle construction featuring α-amino ynone generation followed by 6-endo-dig cyclization. However, competitive 5-exo-dig cyclization, β-elimination of the ynone, and dimerization of the resultant α-amino carbonyls had to be overcome through Teoc and Boc-MOM protection amino groups. Dihydro-4-pyridone 3 possessed an improved kinact value against BioA, validating the pKa–based design strategy