This application describes strategies for the enantioselective total synthesis of (-)-cananodine, a naturally- occurring pyridine alkaloid that has activity against two types of liver cancer cells: Hep G2 (IC50 = 0.22 [unreadable]g/mL) and hepatitis B virus-transfected Hep 2,2,15 (IC50 = 3.8 [unreadable]g/mL). Liver cancer (hepatocellular carcinoma, or HCC) is a major public health problem in much of the world, and the frequency of HCC is increasing dramatically in the United States. Surgical resection of the liver or a liver transplant offers hope of a curative outcome, but only about 10% of HCC cases are operable. While effective treatments are available for a number of other cancers, HCC is generally drug-resistant; most chemotherapies tested have a low response rate and have not shown increased survival times. It is imperative that new compounds with activity against HCC be pursued and developed. Cananodine has a rare guaipyridine structure, and is available only in limited quantities from the fruits of the Cananga odorata (ylang-ylang) tree. Very few syntheses of the other guaipyridine alkaloids have been reported, and none of them allow for the preparation of cananodine in an efficient, regio- and enantioselective fashion. Specific aims of this project include: 1) optimization of palladium-catalyzed cross-coupling of alkenyl triflates, alkenyl boronates, or alkylzinc reagents with highly substituted pyridines having complementary functionality; 2) preparation of tetrahydro-5H-cyclohepta[b]pyridine derivatives via an intramolecular reaction of a stabilized carbanion and an epoxide; 3) preparation of tetrahydro-5H-cyclohepta[b]pyridine derivatives via a ring-closing metathesis strategy; 4) enantioselective synthesis of (-)-cananodine using the aforementioned methods; 5) application of the strategies developed in the cananodine synthesis to the preparation of other aryl- and heteroaryl-fused carbocycle targets of biological significance. Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, leading to an estimated 1 million deaths annually, and the incidence of HCC in the U.S. has increased dramatically over the last two decades. The primary treatment and only proven curative therapy is liver resection (or transplant), but only 10- 15% of HCC patients are surgical candidates due to decreased liver function or metastasis of the tumor. The vast majority of anticancer drugs tested as HCC treatments are ineffective. Therefore, new lead compounds that show activity against HCC should be pursued, especially if they may have a new mode of action. This project aims to synthesize cananodine, a recently isolated guaipyridine alkaloid with activity against two different types of HCC cells, in order to provide larger quantities of this compound for further study. [unreadable] [unreadable] [unreadable]