LEWIS ACID-CATALYZED VINYL ACETAL REARRANGEMENT OF 4,5-DIHYDRO-1,3-DIOXEPINES: STEREOSELECTIVE SYNTHESIS OF CIS- AND TRANS-2,3-DISUBSTITUTED TETRAHYDROFURANS AND STRUCTURE-BASED DESIGN AND SYNTHESIS OF NOVEL INHIBITORS OF HIV-1 PROTEASE AND SARS-3CLPRO PROTEASE

Lewis acid-catalyzed rearrangement reactions of 4,5-dihydro-1,3-dioxepines were carried out in a highly stereoselective manner. Rearrangement of these vinyl acetals under an assortment of conditions afforded cis- or trans-2,3-disubstituted tetrahydrofuran products depending on the reaction conditions. Rearrangement reactions at lower temperatures produced the cis-2,3-disubstituted tetrahydrofuran carbaldehydes as major products whereas at elevated temperatures, the analogous trans-2,3-disubstituted tetrahydrofuran carbaldehydes prevailed as the major products. This methodology was then employed in the synthesis of some novel HIV-1 and SARS-3CLpro protease inhibitors that displayed modest to potent activity.