Stereodivergent Assembly of 2,6-- and --Tetrahydropyrans via Base-Mediated Oxa-Michael Cyclization: The Key Role of the TMEDA Additive.

The stereodivergent synthesis of - and -2,6-disubstituted tetrahydropyrans (THPs) via sodium hexamethyldisilazide-promoted oxa-Michael cyclization of ()-ζ-hydroxy α,β-unsaturated esters is presented. The cyclization affords the kinetically favored -THPs with high stereoselectivity (dr up to 93:7) at a low temperature (-78 °C), while the room-temperature reaction does not produce the thermodynamically preferred -THPs as major products and occurs with poor stereocontrol. The addition of tetramethylethylenediamine (TMEDA) significantly improves the stereochemical outcome of the room-temperature cyclization and allows attaining high -selectivity (dr up to 99:1).