Stereocontrolled synthesis of cyclic ethers by intramolecular hetero-Michael addition .6. A computational study of the annelation to 2,3-disubstituted tetrahydropyrans

A computational study at the ab initio level of the cyclization of (E)- and (Z)-7-hydroxy-4-substituted-2,3-unsaturated esters leading to 2,3-disubstituted tetrahydropyrans has been performed. The study showed the requirement of coordination between the pre-tetrahydropyranyl oxygen and that of the carbonyl of the alpha,beta-unsaturated ester with the cation of the base used to obtain a suitable transition state model. The calculations using the 6-31G*//3-21G basis set show different relative stabilities for the final products and transition states leading to them. The 6-31+G* basis set was used as a calibration of the less energetic transition states. A model assuming a pre-chair conformation locating the chiral inductor equatorial and approaching the alpha,beta-unsaturated ester in axial mode for the E isomer and equatorial for the Z geometry rationalizes the experimental results. The scape and limitations of the model applied to 2,3,5,6-functionalized cases are discussed.