The evolution of a novel synthetic strategy towards polycyclic, stereochemically-complex, heterocycle-containing small molecules is described. The strategy first joins together two achiral building blocks (an enyne and an aldehyde or a ketone) along with a nucleophillic halide using an alkynyl halo-Prins protocol. Subsequently, in the same reaction vessel, acidic conditions initiate further ionization which results in a stereospecific halo-Nazarov electrocyclization, interrupted intramolecularly by a (hetero)arene nucleophile. The entire sequence three carbon–carbon bonds and an sp2 carbon–halogen bond, rapidly generating halocyclopentene adducts from simple precursors. The process occurs with excellent diastereocontrol at each stereogenic step, providing highly functionalized polycycles containing three tertiary or quaternary stereogenic centers in a linear array. It is even possible to install three contiguous all-carbon quaternary centers using this method.

Cyclization strategies for the synthesis of complex halocyclopentenes

2019 Fall National Meeting

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