STEREOCONTROLLED SYNTHESIS OF CYCLIC ETHERS BY INTRAMOLECULAR HETERO-MICHAEL ADDITION .5. SYNTHESIS OF ALL DIASTEREOISOMERS OF 2,3,5,6-TETRASUBSTITUTED TETRAHYDROPYRANS

A systematic approach to the enantiomeric synthesis of all possible di astereoisomers of 2,6-dialkyl-3,5-dioxytetrahydropyrans is described. The key step in the described methodology is the intramolecular cycliz ation of enantiomerically enriched (greater than or equal to 95% ee) 7 -hydroxy-4-(benzoyloxy)-2,3-unsaturated esters. Infused systems, six o f the eight diastereoisomers for one enantiomeric series were synthesi zed using this procedure as a key step. Using those with the suitable stereochemistry, the two left were synthesized by simple chemical tran sformations: in one case by the basic isomerization of the carbon with the (methoxycarbonyl)methyl substituent or by a Mitsunobu inversion o f a secondary alcohol available from the benzoyloxy group,in the remai ning one by a consecutive sequence of oxidation and reduction reaction s again over the free secondary alcohol. The stereochemistry of the in tramolecular hetero-Michael addition leading to 2,3-disubstituted tetr ahydropyrans is highly predictable when kinetic conditions (low temper ature and sodium or potassium bases) are used and can be rationalized by invoking a model of a chair-like transition state in which the benz oyloxy group is located in the equatorial mode and the stereochemical course of the approach of the alpha,beta-unsaturated ester is controll ed by the geometry of the double bond. As a rule of thumb, the cycliza tion using E double bonds yielded cis-2,3-disubstituted tetrahydropyra ns, while (Z)-unsaturated esters yielded the trans compounds. This emp irical rule is followed in highly substituted systems, leading to fuse d 2,3,5,6-tetrasubstituted tetrahydropyrans, with the same absolute co nfiguration in the carbon where the nucleophilic oxygen is located and the one where the benzoyloxy group is located. Those systems having o pposite configurations yield the same trans-2,3-disubstituted compound . The isomerization under thermodynamic conditions (room or higher tem perature with excess of base) of the diastereoisomers with the (methox ycarbonyl)methyl substituent in the axial mode led quantitatively to t hose in which such a group was located equatorially. The scope and lim itations of the method are described in both the synthesis of the unsa turated precursor and the stereochemistry reached in the cyclization s tep.