Studies in synthetic organic chemistry: Part I. The synthesis of novel antimalarial artmeisinin dimers. Part II. Electronically stabilized versions of antimalarial acetal trioxanes. Part III. Novel analogs of natural hormone 1-alpha, 25-dihdroxyvitamin D3: Design, synthesis and biological evaluation of CYP24 inhibitors. Part IV. New silicon mediated ring expansions of N-sized 2-cycloalkenones into homoallylic N+3 sized lactones.

摘要

Part I. The synthesis of novel antimalarial artmeisinin dimers. Antimalarial chemotherapy is faced with the dual challenge of widespread resistance of the infectious parasite, and the absence of resources to administer treatment in economically challenged nations was malaria is widespread. Artemisinin-based chemotherapy is in a class by itself due to the lack of hard evidence of parasite resistance to the molecule. With that said however, a salient down side to current artemisinin based therapies is their poor water and oil solubility that have hindered the efficacious artemisinin-based antimalarial treatments. Utilizing a variety of functionalized reagents we were able to prepare a number of artemisinin dimer esters, amides and sulfonamides.;Part II. Electronically stabilized versions of antimalarial acetal trioxanes. From C-9-substituted DHA, several new artemisinin-derived C-10 acetal ethers and esters were prepared with either a C-9-fluoro or a C-9-sulfonyl substituent. The very strong inductive electron-withdrawing C-9 substituent is shown to retard considerably acid-promoted etherification at C-10 via ionization of C-9-fluoro-DHA and C-9-sulfonyl-DHA thereby creating a longer last antimalarial.;Part III. Novel analogs of natural hormone 1-alpha,25dihydroxyvitamin D3: Design, synthesis and biological evaluation of cyp24 inhibitors. The natural hormone 1α,25-dihydroxyvitamin D3 (calcitriol) is known to be involved in several physiologic functions in animals and humans. It is the most important regulator of calcium and phosphorus homeostasis, affects the immune system and suppresses cell proliferation and differentiation. A short series of non-calcemic enantiomerically pure (-) A-ring attached to a known potentiating C,D-ring side chain were synthesized from commercially available (-) carvone and vitamin D2 respectively. Studies determining the CYP24 hydroxylase inhibition activities of these analogs are ongoing.;Part IV. New silicon mediated ring expansions of n-sized 2-cycloalkenones into homoallylic n+3 sized lactones. The ring expansion of small carbocycles into larger, more valuable cyclic products is an important goal for an organic chemist. Work established in the Posner group, focused on a new, silicon-mediated ring expansion of simple cycloalkenones into ring expanded, functionalized lactones. This two step sequence was initiated by a rapid Lewis acid catalyzed ketone enolate epoxide opening followed by an oxidative fragmentation with hypervalent iodine. With the exception of epoxides that possessed olefins in their side chains, most functional groups survived the enolate opening and oxidative fragmentation with good to moderate overall yields to provide Z-homoallylic medium sized lactones.