Synthesis of Phostones via Phosphono Substituted Metal Allyl Intermediates

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AbstractIn this project, funded by the Chemical Synthesis Program of the Chemistry Division, Professor Christopher D. Spilling of the University of Missouri St. Louis is developing new carbon-carbon bond forming reactions with applications in the synthesis of medicinally relevant phosphate-substituted sugars. The phosphate group is a fundamental component of all living systems, and is important for molecular replication, cell biochemistry, cell signalling pathways, and activation in metabolic processes. The research builds on prior phosphorous-based research developing new nickel-based processes to access important carbon scaffolds. The broader impact of this program lies in developing new tools for organic synthesis and the training of undergraduate and graduate students. A particular emphasis is placed on undergraduate participation in research to provide a solid training in the techniques of synthetic organic chemistry. The training will help provide skilled workers to support pharmaceutical research and related chemical industry in the US.The intellectual merit is focused on developing synthetic methods based on new organophosphorous chemistry. Metal allyl intermediates derived from precursors such as epoxy-vinyl phosphonates, 1- and 2- substituted phosphono-1,3-dienes and phosphono allylic carbonates provide unique methods of stereoselective C-C and C-heteroatom bond forming reactions. These reactions allow complimentary approaches to the synthesis of phostones and phosphonosugars that have novel biological properties and may serve as lead compounds for medicinal chemistry. This de novo approach provides phostones with unique substitution patterns and stereochemistry which deviate from the readily available (common) carbohydrates that is ideally suited to the synthesis of potential antagonists of lipid A.