The goal of the proposed research is to understand how to exert control over stereochemically ambiguous but structurally simplifying cyclization reactions of linear chains for the synthesis of complex anticancer leads. The long-term goal is to learn how to control the polycyclization of linear motifs to access each possible isomer with high selectivity. The proposed research comprises exploration of three families of complex alkaloids with promising activity for the treatment of cancer. The first area of research concerns the development of a practical polyhydroamination transform that exhibits broad substrate scope and high stereoselectivity. Preliminary findings in our lab indicate that directed, cyclic hydroboration of unsaturated amines enables a broadly applicable, regio- and stereoselective intramolecular hydroamination transform for the rapid synthesis of the widespread izidine structural motif. The proposal seeks to investigate the scope of the transformation and explore its application to the synthesis of two anticancer leads. A second research area concerns the synthesis of the selectively cytotoxic asmarine alkaloids. Careful control of the conformational preferences of a linear unsaturated hydrocarbon chain should allow for a formal hydroamination addition to either diastereotopic face of the alkene to install a remote stereocenter. Stereocontrol via a combination of linear conformational control and ring topological control can lead to a stereochemically diverse library of alkaloids. The third area of research explores the synthesis of the anti-metastatic nuphar dimers. Preliminary results indicate that dimerization of a linear surrogate of the nuphar dimers can be used to rapidly assemble these complex alkaloids. Auxiliary and catalyst-control over stereoselective thiaspirane formation will be investigated to rapidly synthesize al four stereoisomers and all sixteen possible family members of this fascinating class.

Public Health Relevance

The complexity inherent to natural products has hindered their use in drug design, despite their demonstrated and disproportionate impact on pharmaceuticals. The ability to select for different regio- and stereochemical outcomes from the covalent folding of linear chains has the potential to dramatically simplify complex molecule synthesis and lead to diverse analogs. The objective for this proposal is to understand how to exert control over stereochemically ambiguous but structurally simplifying cyclization reactions for the synthesis of complex anticancer leads.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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Scripps Research Institute
La Jolla
United States
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Iwasaki, Kotaro; Wan, Kanny K; Oppedisano, Alberto et al. (2014) Simple, chemoselective hydrogenation with thermodynamic stereocontrol. J Am Chem Soc 136:1300-3
Jansen, Daniel J; Shenvi, Ryan A (2014) Synthesis of medicinally relevant terpenes: reducing the cost and time of drug discovery. Future Med Chem 6:1127-48