Potential Niemann-Pick Type C Disease Therapeutics: Synthesis of Pyrrolinones and Enolate-Derived Thiadiazoles, and the Development of a Palladium-Catalyzed Alpha Alkenylation Reaction as a Means to Prepare Trichostatin A

Niemann-Pick type C disease (NPC) is a rare, fatal, autosomal recessive lipid storage disorder. There is currently no cure for NPC and very few treatment options exist. Working in collaboration with the Maxfield laboratory at the Cornell Medical School, we completed several projects aimed at discovering and developing potential therapeutic agents for the treatment of NPC. The first involved the identification of N-aryl alkylidenepyrrolinones via high throughput screening as agents that lowered cholesterol within NPC cells. We developed a concise synthesis that allowed for a thorough investigation into these compounds. The second project with the Maxfield laboratory involved the synthesis of carbamoylated 1,2,5-thiadiazoles as novel inhibitors of lysosomal acid lipase (LAL). We again developed a concise synthesis for these compounds and, in the process, developed a useful protocol that permitted the direct displacement of chlorine from the thiadiazole core using enolates. Both esters and ketones can be utilized as substrates, furnishing a wide range of substituted thiadiazole products. This new protocol allowed for several new potential thiadiazoles to be synthesized and tested for activity against NPC. Additionally, we demonstrated that the reaction proceeds via a ring opening reaction and concomittant enolate attack on the ring opened intermediate leads to the desired product. The third major project involved the development of a mild Pd-catalyzed cross-coupling between zinc enolates and alkenyl halides. The alkenyl halides we employed included functionalized alkenyl bromides and iodides as well as conjugated dienyl bromides and iodides. The conditions we developed were mild and effective, and we never observed any isomerized or rearranged products. The purpose of the cross-coupling was to apply the methodology to the synthesis of trichostatin A, a potent histone deacetylase inhibitor (HDACi). As a result of these studies, we developed a concise, convergent synthesis of this highly coveted natural product. Also resulting from these studies was the development of a useful catalytic DDQ oxidation that utilized Mn(OAc)3 as the cooxidant. The oxidation was utilized not only in the preparation of material for the cross-coupling studies, but also implemented in the synthesis of TSA as well, displaying its useful and versatile capabilities.