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

The stereodivergent synthesis of cis-and trans-2,6-disubstituted tetrahydropyrans (THPs) via sodium hexamethyldi-silazide-promoted oxa-Michael cyclization of (E)-zeta-hydroxy alpha,beta- unsaturated esters is presented. The cyclization affords the kinetically favored trans-THPs with high stereoselectivity (dr up to 93:7) at a low temperature (-78 degrees C), while the room-temperature reaction does not produce the thermodynamically preferred cis-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 cis-selectivity (dr up to 99:1). The remarkable effect of TMEDA indicates that the sodium cation plays an important role in controlling the stereoselectivity of the thermodynamically driven process, that is, complexation of the cation with the cyclization products results in diminished selectivity. DFT calculations support this conclusion, indicating a greater difference in Gibbs energies of sodium-free cis-and trans-enolates compared to the respective sodium chelate complexes. The synthetic utility of the method has been demonstrated by the formal syntheses of (+)-Neopeltolide and (-)-Diospongin B and the total synthesis of (-)-Diospongin A.

Automated summary

The stereodivergent synthesis of cis- and trans-2,6-disubstituted tetrahydropyrans (THPs) has been achieved through the oxa-Michael cyclization of (E)-zeta-hydroxy alpha,beta- unsaturated esters promoted by sodium hexamethyldisilazide. The reaction at low temperature (-78 degrees C) yields the thermodynamically favored trans-THPs with high stereoselectivity, while the reaction at room temperature does not produce the desired cis-THPs as major products and has poor stereocontrol. The addition of tetramethylethylenediamine significantly improves the stereochemical outcome of the room-temperature cyclization and allows for high cis-selectivity.