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 α,β-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 α,β-unsaturated ester in axial mode for the E isomer and equatorial for the Z geometry rationalizes the experimental results. The scope and limitations of the model applied to 2,3,5,6-functionalized cases are discussed.

A systematic approach to the enantiomeric synthesis of all possible diastereoisomers of 2,6-dialkyl-3,5-dioxytetrahydropyrans is described. The key step in the described methodology is the intramolecular cyclization of enantiomerically enriched (g95% ee) 7-hydroxy-4-(benzoyloxy)-2,3unsaturated esters. In fused systems, six of the eight diastereoisomers for one enantiomeric series were synthesized using this procedure as a key step. Using those with the suitable stereochemistry, the two left were synthesized by simple chemical transformations: in one case by the basic isomerization of the carbon with the (methoxycarbonyl)methyl substituent or by a Mitsunobu inversion of a secondary alcohol available from the benzoyloxy group, in the remaining one by a consecutive sequence of oxidation and reduction reactions again over the free secondary alcohol. The stereochemistry of the intramolecular hetero-Michael addition leading to 2,3-disubstituted tetrahydropyrans is highly predictable when kinetic conditions (low temperature and sodium or potassium bases) are used and can be rationalized by invoking a model of a chair-like transition state in which the benzoyloxy group is located in the equatorial mode and the stereochemical course of the approach of the R,β-unsaturated ester is controlled by the geometry of the double bond. As a rule of thumb, the cyclization using E double bonds yielded cis-2,3-disubstituted tetrahydropyrans, while (Z)-unsaturated esters yielded the trans compounds. This empirical rule is followed in highly substituted systems, leading to fused 2,3,5,6-tetrasubstituted tetrahydropyrans, with the same absolute configuration in the carbon where the nucleophilic oxygen is located and the one where the benzoyloxy group is located. Those systems having opposite configurations yield the same trans-2,3-disubstituted compound. The isomerization under thermodynamic conditions (room or higher temperature with excess of base) of the diastereoisomers with the (methoxycarbonyl)methyl substituent in the axial mode led quantitatively to those in which such a group was located equatorially. The scope and limitations of the method are described in both the synthesis of the unsaturated precursor and the stereochemistry reached in the cyclization step.

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