Development of a Vinylogous Horner-Wadsworth-Emmons Reagent: Syntheses of Siloxy Dienes, Aryl Amines and Medicinally Active Compounds

This thesis describes the progress on three different methodology projects and two multistep syntheses of a complex molecule. Specifically, we have synthesized a single isomer of a bis(siloxy)diene. To accomplish the synthesis of bis(siloxy)diene, we had to screen for conditions to produce a single isomer of its mono(silyl)enol ether. Additionally, a vinylogous Horner-Wadsworth-Emmons (HWE) reagent was developed, which can be used to provide 4-methyldienoates from an aldehyde starting material. With this HWE reagent, we have synthesized trichostatic acid through an improved method where the diene unit is installed in one step. Additionally we have used an analogous step-wise version of this synthesis to prepare trichostatin A. We have developed an efficient synthesis of 1-a-13, which allowed us to provide gram quantities of this pyrrolinone to our collaborators for biological evaluation as a Niemann-Pick type C disease (NP-C) therapeutic. We also discuss the synthesis of triazine 2-a-1, which was another NP-C drug candidate. We also report on the development of a new aryl amination protocol, which is able to transform aryl iodides, bromide, chloride, azides, and nitro compounds into the corresponding aryl amines. With this new method, we transformed 1-a-13 into the corresponding amine to establish an SAR for the pyrrolinones. This amine was converted into the corresponding azide 1-a-13-N3 for a photoaffinity labeling study.