A Study of Exocyclic Radical Reductions of Polysubstituted Tetrahydropyrans

Exocyclic
radical reductions were thoroughly investigated in the
context of the synthesis of polysubstituted tetrahydropyrans, which
are found in numerous macrolides. The radical precursors studied herein
were generated by tandem cycloetherification and iodoetherification
reactions or, alternatively, by semicyclic acetals substitutions.
DFT calculations (BHandHLYP/TZVP) performed at the transition-state
level for the hydrogen radical delivery are in good accordance with
the experimental data and enabled the identification of important
conformational factors that govern the selectivities obtained. This
study demonstrates that both the preferred reactive conformation of
the radical and steric interactions with the incoming hydride have
to be considered in order to fully rationalize the levels of diastereoselection
generated in acyclic free-radical processes.