Studies in organic synthesis: Methodology, vitamin D analogs, and trioxane analogs

Organic Chemistry is a subject of chemical architecture. One starts with small building blocks, while guided by physical laws and builds beautiful chemical structures. There are two main applications to organic chemistry that I have studied in the past five years and those include: medicinal chemistry and methodology. In medicinal chemistry I have studied the design and synthesis of novel hybrid analogs of the natural hormone vitamin D as antiproliferative agents, and Artemisinin based trioxane dimers as anti-malarial drugs. Meanwhile the methodology studies were focused on silicon-mediated ketone enolate ring opening of epoxides.; Calcitriol, the natural hormone of vitamin D3, plays an important role in calcium and phosphorous homeostasis, in promoting cell differentiation, and in inhibiting cell proliferation of various tumor cells. The hormone is used therapeutically for the treatment of osteoporosis, osteoarthritis, and abnormalities of the parathyroid hormones. However the therapeutic use of the steroid in treatment of cancer is handicapped by its high calcemic index. A challenge facing chemists involves designing analogs similar to calcitriol that sustain, if not surpass, its efficacy while diminishing its undesired side-effect of hypercalcemia. Convenient synthetic routes to the synthesis of novel sulfoximine and hydroxamate analogs of calcitriol have been developed. The synthesis of these analogs is efficient with good yields. Some of the analogs exhibit antiproliferative activity 2 to 3-fold higher than that of the natural hormone calcitriol, while still maintaining at least a 40-fold lower calcemic index than calcitriol.; Artemisia annua has been used by the Chinese for more than a thousand years in the treatment of many illnesses, and in 1972 Tu Youyou isolated artemisinin (qinghousu) in the leaves of Artemisia. Artemisinin and its derivatives are now standard components in treating malaria. Artemisinin has the attractive property of treating malaria and showing no resistance to the parasite, however, it suffers from poor bioavailability. In addressing the issue of bioavailability a new generation of Artemisinin based analogs were synthesized, the C-10 acetates, currently being used in treatment for malaria. These compound show great antimalarial activity, bioavailability and lack of resistance but the C-10 acetates are easily hydrolized and the new generation suffers a short plasma half life. Recent contributions by the Posner lab include artemisinin based trioxane dimers designed in an effort to improve the antimalarial activity and stability of artemisinin by introducing another trioxane moeity linked by a short nonhydrolyzable linker. The second generation of the trioxane-dimers is extremely promising with a number of the analogs being able to cure malaria infected mice after a single subcutaneous dose or three oral doses.; Commercially available (cyclopentenyloxy)trimethylsilane reacts with various epoxides to afford a hemiketal intermediate, which subsequently is exposed to oxidative fragmentation conditions, and it is converted into a pair of diastereomeric 8-membered ring iodolactones. These iodolactones are separately treated with sodium azide to afford the corresponding azide in great yields. The final conversion is reduction of the azide to the amine, where the system undergoes a lactone ring contraction to form 6-membered lactams.