Synthesis and Reactivity of Spirocarbocycles as Scaffolds for Nucleoside Analogues.

Abstract

A novel class of substituted spiro[3.4]octanes can be accessed via a [2 + 2]-cycloaddition of dichloroketene on a readily prepared exo-methylene cyclopentane building block. This reaction sequence was found to be robust on a multigram scale and afforded a central spirocyclobutanone scaffold for carbocyclic nucleosides. The reactivity of this constrained building block was evaluated and compared to the corresponding 4'-spirocyclic furanose analogues. Density functional theory calculations were performed to support the observed selectivity in the carbonyl reduction of spirocyclobutanone building blocks. Starting from novel spirocyclic intermediates, we exemplified the preparation of an undescribed class of carbocyclic nucleoside analogues and provided a proof of concept for application as inhibitors for the protein methyltransferase target PRMT5.