Total Synthesis of (+)-Discodermolide CHEM635 Kelsey Roberts Group B February 19, 2013 Patterson, I*; Florence, G. J.; Gerlach, K.; Scott, J. P. Agnew. Chem. Int. Ed. 2000, 39,

Ian Paterson Born in 1954 in Dundee, Scottland B.S. in Chemistry from U of Saint Andrews, 1976 PhD from Cambridge under Ian Flemming, 1979 NATO post-doctoral fellow with Gilbert Stork at Columbia Lectureship at University College London 1983-present Cambridge University Professor of Organic Chemistry and Fellow of Jesus College 237 Publications to date. Research focuses on synthetic methods, synthesis and structure determination of biologically active materials 1

History of (+) Discodermolide First isolated in 1990 by Gunasekera in Florida from the Caribbean sponge Discodermia dissoluta. 13 Stereogenic centers, tetrasubstituted δ-lactone, on di and one tri- substituted Z-alkene, a carbamate, and a terminal Z-diene Acts as a antimitotic agent by stabilizing microtubules and promotes polymerization of tubulin Inhibits growth of breast cancer cells in vitro, resistant ovarian and colon cancer cells. Before Ian Paterson, 2 total synthesis of (+)-Discodermolide (Schreiber et al) and 3 of (-)-Discodermolide (Kobayashi, Myles, Johns) Schreiber et al determined absolute stereochemistry 2

Retrosynthesis 3

Synthesis of 2 4

Synthesis of 3 5

Synthesis of 3 Continued 6

Synthesis of 4 7

Synthesis of 5 8

Synthesis of 5 Continued 9

Final Steps to (+)-Discodermolide 10

Conclusion (+) Discodermolide synthesized in overall 7.7% yield 27 steps for longest linear sequence 11