Stereodivergent Synthesis of Highly Substituted Tetrahydropyrans

Intramolecular oxa-conjugate addition has been employed in a stereoselective synthesis of enantiopure polyalkyl-substituted tetrahydropyrans, which are frequently found as substructures in many natural products. The requisite cyclization precursors, 7-hydroxy-2-enimides 3 and 7-hydroxy-2-enoates 6 were easily accessible by silyloxy Cope rearrangements of the appropriate chiral syn-aldols. It was found that the stereoselectivity of the cyclization could be controlled by judicious choice of the carboxylic acid derivative, resulting in a kinetically controlled reaction for the imides and a thermodynamically controlled process for the esters. Mechanistic considerations that could account for the stereocontrol of the process are outlined.