Many compounds from the annonaceous acetogenin class of natural products exhibit highly potent and selective cytotoxicities against several types of human tumor cells. Members of this class bearing central bistetrahydrofuran cores are of particular interest as anti-cancer drugs. One obstacle towards this goal is the lack of precise information regarding the mechanism of the natural products' biological activity. To facilitate understanding the role these compounds have in promoting tumor death, there is a need for efficient and stereochemically general synthetic routes towards the annonaceous acetogenins. The proposed research will develop total syntheses of three members of the annonaceous acetogenin family: 10-hydroxytrilobacin, bullatacin, and rollimembrin. These three bis-tetrahydrofuran containing compounds all have cytotoxic or anti-tumor properties, and the total syntheses of two are currently unknown. A key [3+2] annulation reaction of chiral allylsilanes will be employed to construct the bis-tetrahydrofuran fragment of each natural product in a stereocontrolled fashion. Completion of the proposed total syntheses will demonstrate the stereochemical and functional diversity that the [3+2] annulation approach provides in the construction of annonaceous acetogenins and their analogs. ? ? ?
| Mertz, Eric; Tinsley, Jennifer M; Roush, William R (2005) [3 + 2]-annulation reactions of chiral allylsilanes and chiral aldehydes. studies on the synthesis of bis-tetrahydrofuran substructures of annonaceous acetogenins. J Org Chem 70:8035-46 |
| Tinsley, Jennifer M; Mertz, Eric; Chong, Pek Y et al. (2005) Synthesis of (+)-bullatacin via the highly diastereoselective [3+2] annulation reaction of a racemic aldehyde and a nonracemic allylsilane. Org Lett 7:4245-8 |
| 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 |
