The Development of Novel Electron Transfer Initiated Cyclization (ETIC) Reactions: Discovery of the Diastereoselective ETIC Reaction and Its Application toward the Total Synthesis of Leucascandrolide A
The electron transfer initiated cyclization (ETIC) reaction has been shown to provide the efficient formation of cyclic acetals through the selective activation of carbon-carbon [sigma]-bonds. A simple arithmetical equation has been used to design new substrates with enhanced chemoselectivity and reactivity. The ability to design new cyclization substrates has expanded the scope of the ETIC reaction by providing access to more diverse products. Lowering the oxidation potential of the ETIC substrates led to the development of a ground state chemical-mediated protocol. This also allowed for the incorportation of electron rich olefins as carbon-centered nucleophiles. Substrates which undergo endo-cyclizations have shown excellent levels of stereocontrol in the synthesis of syn-2,6-dialkyl tetrahydropyranones, which are useful building blocks in natural product synthesis.
A highly stereoselective sequence has been developed for the synthesis of leucascandrolide A with the key transformation utilizing the diastereoselective endo-ETIC reaction. The homopropargylic ether required for installation of the enol acetate was obtained through the stereoselective opening of a cyclic acetal with allenyltributyltin in the presence of a Lewis acid. A metal mediated addition of acetic acid to the alkyne provided the homobenzylic ether with a suitably tethered enol acetate. The enol acetate was then subjected to the chemical mediated ETIC conditions to afford the desired syn-2,6-tetrahydropyranone as a single diastereomer.
Advisor:Joseph Grabowski; Dennis P. Curran; Eric Beckman; Paul E. Floreancig
School:University of Pittsburgh
School Location:USA - Pennsylvania
Source Type:Master's Thesis
Date of Publication:10/10/2005