The synthesis and evaluation of novel and potent anti-malarial compounds, and, The synthesis of 2-substituted pyrrolidines using tert-butanesulfinamide: The total synthesis of antofine

Malaria continues to be a major health threat, infecting over 300 million people resulting in 1--3 million deaths every year. The rapid spread of resistance to the currently used therapeutics presents an even more serious threat. Although there is an urgent need for new, effective, and inexpensive drugs, the pharmaceutical industry has not pursued the development of malaria drugs as the disease is prevalent in areas of the world that lack substantial economic resources. Additionally, a major issue in the drug discovery process is the development of an initial hit against a specific target into a viable preclinical candidate. Toxicity, metabolism, logD, specificity, and in vivo activity are all among the many parameters that must be optimized. For this reason, a project was undertaken in the Ellman group to attempt to address the need for new anti-malarial compounds. Chapters 1 and 2 of this dissertation detail our progress towards achieving this goal.; Chapter 1 presents our strategy and results elucidating the key pharmacaphores in a new class of compounds that provide anti-malarial activity against both drug sensitive and resistant strains of P. falciparum, the parasite that causes the majority of malaria deaths. Chapter 2 describes the further optimization of the activity of a novel class of antimalarials described in chapter 1. These compounds were also tested for cytotoxicity in human foreskin fibroblast assays, evaluated to determine their logD, and assayed for metabolism by human and murine hepatocytes. This work resulted in the development of two compounds that showed good potency, acceptable log D values, reasonable stability to metabolism, and promising initial results in murine malaria models.; tert-Butanesulfinamide chemistry has been extensively exploited in the Ellman group for the asymmetric synthesis of amines, including alpha-branched and alpha,alpha-dibranched amines, beta-amino acids, beta-amino alcohols, and 1, 2 amino alcohols. We sought to further extend the broad utility of tert-butane sulfinamide as a chiral auxiliary for the asymmetric synthesis of pyrrolidines. These are an important class of biologically active compounds as they are found in a wide variety of natural products and pharmaceuticals. As a result, the synthesis of pyrrolidines has been an active area of research.; Chapter 3 describes a new method for the asymmetric synthesis of 2-substituted pyrrolidines in three steps from commercially available starting materials. Addition of the Grignard reagent prepared from 2-(2-bromoethyl)-1,3-dioxane to N-tert-butanesulfinyl aldimines proceeds in high yields and with good diastereoselectivities. The sulfinamide products are then cleanly converted into pyrrolidines in one step. Chapter 4 describes the successful application of this new method to the total synthesis of (-)-antofine, a pentacyclic phenanthroindolizidine alkaloid.