Cyclic enaminones: synthons for piperidine containing natural products and natural product analogs.

Abstract

Cyclic Enaminones: Synthons for Piperidine Containing Natural Products and Natural Product Analogs.

Cyclic enaminones are important synthetic intermediates for the preparation of piperidine containing natural products and target molecules such as drugs, which require a piperidine moiety for bioactivity. They are valuable synthons because of their unique reactivity and chemical stability. In this thesis, I developed novel chemistry from which to derivatize enaminones, and additionally I utilized cyclic enaminones as synthons for the preparation of natural product derivatives. I discovered that α,β-unsaturated aldehydes add to the α-carbon of enaminones in the presence of organocatalysts and thereby, introduce aliphatic α-branched substituents; a reaction that was previously very difficult to accomplish. The chiral reaction products were obtained in good- to excellent yields and with high enantiopurity. The absolute stereochemistry of the reaction products was also determined. I prepared analogues of the cytotoxic phenanthropiperidines tylophorine and boehmeriasin A, and I synthesized dihydrolyfoline, a member of a group of natural biphenylquinolizidine lactone alkaloids that posses a wide variety of bioactivities. The natural occurring cytotoxic phenanthropiperidines suffer from poor physiochemical properties and adverse side effects. Thus, the target molecules were designed to mitigate the unwanted side effects by improving their physiochemical properties. I devised short, concise routes toward the synthesis of a library of simplified tylophorine analogs, as well as 15-hydroxyboehmeriasin A. The tylophorine analog library was screened for antiproliferative activity against several cancer cell lines and thus, insight was gained into the structure-activity relationships of this class of compounds including the indication that an intact indolizidine moiety is critical for high potency of tylophorine analogues. 15-Hydroxyboehmeriasin A was prepared and evaluated for cytotoxicity against the A549 human lung carcinoma cell line. An observed GI50 of 81 nM demonstrates that the addition of the 15-hydroxyl group was not detrimental to cytotoxicity and that this position should be explored for further modifications in efforts to improve the physicochemical properties. In addition I prepared (±)-dihydrolyfoline in a concise manner from a bicyclic enaminone precursor using a biomimetic oxidative biaryl coupling approach as the key reaction step.