Development and application of cyclic hydrazides as organocatalysts

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Research in our laboratory in the past 5 years has identified cyclic hydrazides as effective organocatalysts for the Cope rearrangement and these were extended to the Diels-Alder cycloaddition and Michael additions of alpha-substituted alpha,beta-unsaturated aldehydes. In this grant application, we will extend the use of these catalysts to new reactions and apply them to the synthesis of natural products. ******Polyene cyclizations. Based on the mechanism of our Cope rearrangement, we postulate that it should be possible to trap a cationic intermediate with alkenes and electron rich aromatics to mimic the reaction by which steroids and other terpenes are biosynthesized. We will develop enantioselective hydrazide catalysts which function through weak C-H-O hydrogen bonds and apply them to the synthesis of several terpene natural products.******Claisen rearrangement. The Claisen rearrangement is a highly useful reaction in organic synthesis that is closely related to the Cope rearrangement. We will extend our organocatalysis concept to the aromatic Claisen rearrangement, one of the more common variants of this reaction, and use the reaction to prepare chromane structures found in several biologically relevant molecule classes.******Oxy-Cope/Michael reaction. The oxy-Cope is another variant of the Cope rearrangement which has seen significant application in total synthesis. We will develop a cascade reaction which links the oxy-Cope with a Michael reaction to produce cyclopentanes and, if conducted on cyclic substrates, may be used to effect a simultaneous ring-expansion.******Application of oxy-Cope/Michael to the synthesis of fusicoccin A. Fusicoccin A is a glycosylated terpene that is of interest for its promotion of axonal growth, making it and its analogs of interest for treatment of nerve damage. We will develop a total synthesis of fusicoccin A which leverages two sequential oxy-Cope/Michael reactions in ring-expansion mode to prepare the 5-8-5 ring system at the core of this natural product.******Merging iminium catalysis with photoredox chemistry. We postulate that the formation of iminium ions should activate enals towards reduction by photoredox catalysts, for the first time merging iminium catalysis with photoredox chemistry. We will investigate this concept through a [2+2] cycloaddition