Studies in organic synthesis: Design, synthesis and biological evaluation of novel 1-alpha, 25-dihydroxyvitamin D3 analogs and asymmetric, organocatalytic, 3-step synthesis of gamma-hydroxy-(E)-alpha, beta-unsaturated sulfones and esters

The active form of vitamin D3, 1alpha,25-dihydroxyvitamin D3 is essential maintaining our good health. However, medicinal use of supraphysiological amounts of this hormone in humans often causes toxic hypercalcemia by inducing excessive increases in intestinal calcium absorption and bone resorption. Many calcitriol analogs have been designed and synthesized with the goal of maximizing therapeutic potential while minimizing undesirable calcemic activity. Some of these synthetic analogs are currently used as safe and efficacious drugs for chemotherapy of patients having osteoporosis, psoriasis, or renal dysfunction. Described in this thesis are two series of vitamin D analogs designed to have high therapeutic potential and low calcium side effects. The first series involves the replacement of the 1alpha-OH group in the natural hormone with a 1alpha-CHF2 group. The new difluoromethyl group was predicted to act as a weak hydrogen-bonding surrogate for the natural hydroxyl group. When such a change was accompanied by the incorporation of a potentiating side chain new hybrid analogs with a desirable therapeutic profile were produced. The second series of analogs involves the replacement of C-23 with and oxygen atom. The new 23-oxa ether analogs are easily synthesized and involve either a ketone, oxime, allylic, propargylic, benzylic, or heteroaromatic moiety. Two of these analogs in particular have a promising biological profile and are in the process of undergoing further biological testing.;While studying the metabolites of certain vitamin D analogs, we became interested in the synthesis of gamma-hydroxy-alpha,beta-unsaturated sulfones and esters. This interest led to the development of an efficient and enantiocontrolled method for the synthesis of such systems. The methodology involves the reaction of enantioenriched alpha-selenyl aldehydes with EWG-stabilized carbanions and then a one-pot selenide oxidation, in situ epoxide formation, and final in situ epoxide opening.