The goal of the research outlined in this proposal is to investigate the scope and utility of a tandem intramolecular asymmetric Heck cyclization / carbonylation / nucleophile trapping reaction as a general entry to the 2-oxaspiro[5.5]undecane core. Further chemistry, such as transmetallation, heteroatom and hydride addition to the acyl-palladium intermediate will be investigated to determine the scope of the nucleophile trapping. The 2-oxaspiro[5.5]undecane core is an underlying molecular architecture present in greater than 100 compounds belonging to the 6,7-seco-ent-kaurane diterpenoids, which are known to possess antibacterial, anti-tumor, anti-inflammatory, and anti-feeding activity. Initial efforts will focus on the successful development of the Heck cyclization / carbonylation reaction sequence, which could involve an elaborate screening of palladium precatalysts as well as chiral bidentate phosphine ligands. Following the realization of this goal, an efficient chemical synthesis will allow elaboration of the properly functionalized 2- oxaspiro[5.5]undecane core into the natural product maoecrystal Z, a compound exhibiting micromolar affinity against the human tumor cell lines K562 leukemia, MCF7 breast, and A2780 ovarian. This will establish the necessary synthetic groundwork needed for access to this biologically active family of diterpenoids. The challenging structure as well as the exciting biological profile makes this diterpene an intriguing compound for asymmetric total synthesis.
The battle against cancer is ongoing, and small molecules still play a very important role as therapeutics and treatment options. Many of the ent-kaurane diterpenes, including maoecrystal Z, are recognized for their anti-tumor activity and low toxicity, making them attractive anticancer drug candidates. A general approach to these compounds that allows access to analogues is a worthwhile endeavor.
| DeLorbe, John E; Horne, David; Jove, Richard et al. (2013) General approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors: enantioselective total syntheses of (+)- and (-)-gliocladine C, (+)-leptosin D, (+)-T988C, (+)-bionectin A, and (+)-gliocladin A. J Am Chem Soc 135:4117-28 |
| DeLorbe, John E; Jabri, Salman Y; Mennen, Steven M et al. (2011) Enantioselective total synthesis of (+)-gliocladine C: convergent construction of cyclotryptamine-fused polyoxopiperazines and a general approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors. J Am Chem Soc 133:6549-52 |
