Studies in organic synthesis: Vitamin D analogs, trioxane dimers and enantioselective selenenylations and [2,3]-sigmatropic rearrangements.

摘要

Vitamin D plays an essential role in human health through the regulation and absorption of calcium and phosphate, and more importantly cell differentiation, Kra immunology and the regulation of gene transcription. As vitamin D has become more understood within the scientific community the value of this hormone has been recognized, and focus has been on the development of new analogs of 1alpha,25-dihydroxyvitamin D for treatment of diseases such as psoriasis, osteoporosis, and a large variety of cancers. However, due to the calcemic nature of the natural hormone, the challenge in synthesizing alternate analogs is to find the optimal balance between the desired antiproliferative properties of the analog and low calcemic activity. Within this thesis, a variety of different analogs have been synthesized, including novel 16-ene-20-epi analogs, novel 1-deoxy analogs designed as prodrugs to be activated in vivo, and a 24-oxa analog designed to inhibit catabolic degradation. Some of these analogs exhibited desireable antiproliferative properties.;In addition to biologically active vitamin D analogs, a several different series of antimalarial trioxane dimers have been prepared. Malaria is one of the most infectious diseases in the world, infecting 250-300 million people worldwide per year. Of those infected over 3 million people lose their life to this devastating disease, with the majority of those deaths being children under the age of five. These statistics make finding a treatment and cure for malaria of the utmost importance. The challenge for developing new antimalarial treatment lies in fighting the spread of resistance to current chemotherapies as well as gaining the resources for the administration of new treatments in economically underdeveloped countries, which are most affected by the disease.;Artemisinin based chemotherapies have become the first line treatment against malaria because until recently, no parasite resistance has been reported. While artemisinin is highly potent against malaria, the natural product has poor water and oil solubility, making it difficult to be absorbed into the system. It is this challenge that has led to the development of more efficacious artemisinin based analogs to treat malaria. Through the use of carbon based linkers, dimers of artemisinin have been prepared with various functionalities, including ketals, hydrazones, oximes, and beta-hydroxy or beta-fluoro sulfones with the intent of optimizing the bioavailabilty of the compounds, making them more efficacious aganst malaria. Several novel dimers of artemisinin were curative at oral doses of 3 x 30 mg/kg, and some increased the lives of infected mice upon oral dosage of 3 x 10 mg/kg.;Finally, an efficient and enantiocontrolled 3-step synthesis of alphaa-hydroxy-( E)-beta13,gamma7-unsaturated esters has been designed utilizing asymmetric, organocatalytic selenium chemistry. Enantioenriched alpha-selenyl aldehydes, prepared in one step by asymmetric, organocatalytic alpha-selenyation of aldehydes, were directly subjected to a Wittig reaction followed by allylic selenide to selenoxide oxidation and final spontaneous [2,3]-sigmatropic rearrangement to yield the target compounds in 43-65 % overall yield and in 94-97% ee.