Synthesis of Complex Terpenes From Simple Precursors: Renewal

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PROJECT SUMMARY From Taxol® to artesunate to retapamulin, complex terpenes have had a profound impact on both the treatment and understanding of human disease. Despite their enormous medicinal relevance, however, most complex terpene architectures are not optimal starting points for exhaustive medicinal and chemical biological studies, and unlike many small molecule drug discovery programs, it is difficult to easily mix- and-match structural fragments. The proposed research program seeks to discover and develop simple, modular synthetic pathways to access complex, medicinally relevant terpenoid natural products and determine their protein targets. At the core of this proposal is the desire to greatly simplify terpene synthesis by using simple isoprene-derived units and chiral pool materials in concert with novel methodologies and synthetic strategies. The targets chosen for this program represent both state-of-the-art challenges for complex molecule synthesis as well as potential next- generation therapeutics ideal for in-depth chemical biological studies. Owing to their potent cytotoxic properties, complex quassinoid triterpenes have remained attractive targets for decades, yet synthetic routes to these molecules are lengthy and many members have yet to succumb to syntheses at all. Using novel cross-coupling methodology we have developed a blueprint for facile access to this family. Cyclized, marine cembranoids represent a structurally fascinating class of terpene targets with intriguing, yet poorly understood, cytotoxic activities. Despite much work from numerous laboratories, many flagship members have eluded practitioners of chemical synthesis for decades. Using a chiral pool building block-based approach and various radical cyclization strategies, we believe many such targets can be accesses efficiently allowing for their protein targets to be interrogated using cutting-edge proteomics techniques. Overall this program seeks to use advances in synthetic chemistry to construct rare, biologically active terpenes with high efficiency allowing interrogation of their anti-cancer properties and protein targets. In the process of this work, students will be provided with rigorous and intellectually stimulating training in synthetic chemistry.