Selective Synthesis of exo-Spiro[2′,2′-difluorocyclopropane-3′,2′-tropanes]

Abstract

Conformationally restrained exo-isomers of N-Boc-protected spiro[2′,2′-difluorocyclopropane-3′,2′-tropanes] were synthesized in 62–83% yield via absolutely diastereoselective cycloaddition of CF₂, generated in situ from Me₃SiCF₃/NaI in refluxing THF, to double bonds of 3-alkylidenetropanes. Standard removal of Boc protecting groups afforded corresponding exo-spiro[2′,2′-difluorocyclopropane-3′,2′-tropane] hydrochlorides in 82–94% yields. DFT and CCSD(T) calculations revealed that the observed exo-selectivity of difluorocarbene addition is likely to be caused by a lower activation barrier of the exo-difluorocyclopropanation compared to the endo-reaction.

Key words

tropane - difluorocarbene - diastereoselective difluorocyclopropanation - DFT - CCSD(T)

• References

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