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

Abstract

The stereodivergent synthesis of cis- and trans-2,6-disubstituted tetrahydropyrans (THPs) via sodium hexamethyldisilazide-promoted oxa-Michael cyclization of (E)-ζ-hydroxy α,β-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 °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.

Brønsted acid-mediated selective α-alkenylation of 3,4-dihydro-2H-pyrans

“…)-catalyzed hemiacetals or hemiketals can achieve the α-allylation of oxygen-containing heterocyclic compounds 7 (Scheme 1B, strategy 2). Alternatively, cyclization can also proceed under basic or acidic conditions 8 to provide substituted THPs by utilizing prefabricated substrates (Scheme 1B, strategy 3). Besides, in 2019, Manolikakes and coworkers developed a novel domino reaction for the highly stereoselective synthesis of pentasubstituted THPs 9 by a two-fold addition of enamides to aldehydes (Scheme 1B, strategy 4).…”