Part 1. Synthesis and Bioassay of SNF Analogues; Part 2. 1,2-Addition of Organometallic Reagents to Unprotected Juglones and Progress Toward the Synthesis of Ravidomycins; Part 3. Synthesis of Cis-Alkenes via a Novel Copper-Mediated Cross-Coupling of 1,1-Dibromoalkenes and Halides

Abstract

Part 1. Multidrug resistance (MDR), one of the major clinical problems in cancer chemotherapy, is a condition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety of structure and function targeted at eradicating the organism. One of the mechanisms is an overexpression of P-glycoprotein, the product of the mdr-1 gene in human cells. SNF (the code name of Snow Brand Milk Prod. Co.) compounds showed a potent immunosuppressive activity in vitro by suppressing B-cell proliferation (induced by lipopolysaccharide) and T-cell proliferation (induced by concanavalin A) in non-cytotoxic concentrations. They also showed a multidrug resistance (MDR) reversal activity in tumor cells by inhibition of P-glycoprotein. In order to obtain MDR reversal agents with better activities, 14 SNF analogs were designed and prepared. During the bioassay of the SNF analogs, some of the compounds exhibited very good multidrug resistance (MDR) reversal effects. In particular, SNF analog 11 was the most active in modulating sensitivity to Paclitaxel (99% reduction in IC50 at 1.0 æM in MCF7-R). SNF analog 12 also showed a good activity by reducing 99% of Paclitaxel IC50. Moreover, a new strategy for the synthesis of the tricyclic core of spatol, a potent inhibitor of cancer cell replication, was developed based on the SNF bicyclo[4,2,0] structure.Part 2. p-Quinols can undergo mild reductions to form p-phenols. Oxidations of p-phenols can reverse these reductions back to give corresponding p-quinols. Some biochemical compounds in nature contain p-quinol substructures, such as coenzyme Q. p-Quinols have a variety of uses principally associated with their actions as reduction or oxidation agents. We developed a new synthetic methodology for the preparation of quinol-containing nature products, in which organometallic reagents regioselectively added to the non-hydrogen bonding carbonyl groups. Ravidomycin is a potent antitumor and antibiotic, which has attracted the attention of chemists for many years. The new synthetic methodology for the synthesis of quinols was applied to the total synthesis of ravidomycin and a series of models were established. The total synthesis of ravidomycin is still in progress.Part 3. Organo-copper reagents are very frequently applied in organic syntheses because of this selective reactivity and lower nucleophilicity for carbon. However, organo-copper compounds are thermally unstable. Thus they can not undergo consecutive cross-coupling processes like some other transition organometals. A new highly stereoselective olefination methodology for preparation of cis-alkenes is developed based on a novel copper-mediated cross-coupling. This is the first example of consecutive cross-couplings of organocopper intermediates and aryl/vinyl halides in a one-pot reaction.