Total Synthesis of Nakadomarin A

Nakadomarin A (1) was isolated in 1997 by Kobayashi and co-workers from the marine haplosclerid sponge Amphimedon sp. Natural Compound 1 belongs to the family of manzamines, complex, polycyclic marine-derived alkaloids featuring a unique hexacyclic ring system. Nakadomarin A (1) in particular shows a remarkable cytotoxicity against L 1210 murine lymphoma cells (IC 50 1.3 mg/ml) and inhibits the cyclin dependent kinase (CDK) 4 (IC 50 9.9 mg/ml). Moreover alkaloid 1 shows activity against fungi and gram-positive bacteria. There have been only few syntheses of nakadomarin A (1)I . Within this project we want to develop a strategy for a highly stereoselective and efficient total synthesis of Nakadomarin A (1), including a stereoselective ring closing metathesis (RCM) to close the 8-membered ring, an enantiselective Nazarov cyclisation as the key step, a Mannich reaction to form the piperidine ring and a reductive amination to build the pyrrolidine ring. Moreover the enantioselective Nazarov cyclisation with cumulenyl ethers will be investigated. II Improving and applying this methodology will make the synthesis even more straightforward and convergent. I J. Am. Chem. Soc. 2007, 129, 1465 -1469. J. Am. Chem. Soc. 2003, 125, 7484 -7485. II Org. Lett. 2003, 5, 1171-1174.