Stereoselective Reactions for the Chemical Synthesis of Bioactive Compounds

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 DESCRIPTION (provided by applicant): The invention of new methods for the stereoselective chemical synthesis of chiral organic molecules is a critical objective in modern organic chemistry because it is essential for the efficient manufacture of pharmaceutical agents. Despite substantial progress in the field of enantioselective chemical synthesis, many significant challenges remain unsolved. In particular, there is a lack of generally effective methods for the enantioselective chemical synthesis of chiral cyclobutanes. In the absence of efficient strategies for the synthesis of these important molecules, their accessibility as biologically active syntheti targets and, more generally, their utility as synthons for chemical synthesis, have been hindered. The long-term goals of our research program are to introduce general and efficient strategies for the stereoselective synthesis of difficult- to-access cyclic and polycyclic molecula frameworks found in important bioactive molecules. Toward this end, the studies described in this application seek to invent efficient catalytic enantioselective [2+2] cycloadditions of alkene with electron deficient allenes that lead to chiral cyclobutanes. Our rationale for the development of these cycloadditions is that they combine readily available starting materials in a complexity building and atom economical transformation that leads to formation of strained four-membered rings with up to three new stereogenic centers. The rings generated by these transformations are either directly found in bioactive molecules or can be subject to a wide variety of chemical reactions to quickly establish complex structures. Therefore, successful implementation of these methods will greatly facilitate the synthesis of a wide range of complex molecules that are difficult or impossible to access with current technologies. Preliminary studies gathered in our lab are extremely encouraging for success in our proposed studies. Specifically, these investigations will lead to: 1) catalytic enantioselective [2+2] cycloadditions of prochiral alleni esters, 2) catalytic dynamic enantioselective [2+2] cycloaddition with racemic allenic esters, and 3) catalytic enantioselective synthesis of allenic ketones and chirality transfer [2+2] cycloadditions. These methods will be useful for the synthesis of several families of biologically active natural products and for the synthesis of scaffolds for drug discovery. The proposed research in this application is innovative because it outlines a new and significantly different approach to the enantioselective synthesis of chiral cyclobutanes, specifically catalytic enantioselective allene-alkene [2+2] cycloadditions. Furthermore, this exercise in reaction development will introduce new concepts and strategies in chemical synthesis by exploring methods to promote reactions with allenes.