This proposal details studies directed toward the total synthesis of amphidinolide C. The amphidinolides, a structurally diverse group of over 30 macrolides, exhibit potent and selective anti-tumor profiles. The unparalleled structural heterogeneity in this class is indicative either of a host of mechanistically unique inroads to the treatment of cancers or a single unidentified intracellular effector which exhibits tremendous promiscuity in ligand binding. The mechanisms of action of the amphidinolides have gone unstudied, primarily due to a lack of available natural products, analogs, and biochemical reagents (e.g., amphidinolide-based affinity probes and/or columns, etc.). The proposed synthesis involves the development of a tandem asymmetric Heck/enol-ether oxidation strategy for the preparation of chiral allylic 1,2-anti diols and describes its application toward the preparation of the highly oxygenated C3-C9 region of amphidinolide C. The route is highly convergent, will expand the scope of enantioselective and doubly-diastereoselective [3+2] annulation strategies for the efficient construction of tetrahydrofurans, and will represent the first total synthesis of amphidinolide C.
| Bates, Robert H; Shotwell, J Brad; Roush, William R (2008) Stereoselective syntheses of the C(1)-C(9) fragment of amphidinolide C. Org Lett 10:4343-6 |
| Heitzman, Cheryl L; Lambert, William T; Mertz, Eric et al. (2005) Efficient protiodesilylation of unactivated C(sp3)-SiMe2Ph bonds using tetrabutylammonium fluoride. Org Lett 7:2405-8 |
| Shotwell, J Brad; Roush, William R (2004) Synthesis of the C11-C29 fragment of amphidinolide F. Org Lett 6:3865-8 |
