Stereoselective synthesis of constrained oxacyclic hydroxyethylene isosteres of aspartyl protease inhibitors. Nitroaldol methodology toward 2,3-substituted tetrahydrofurans

The Shibasaki heterobimetallic Binol lanthanide, and Trost dinuclear zinc catalysts were studied in a nitroaldol reaction of 3-methyl-1-nitrobutane with a chiral non-racemic tetrahydrofuran aldehyde. Other methods utilized KF, Amberlyst A-21, and t-BuOK as bases for the same nitroaldol reaction. The major isomer in the Binol lanthanide and dinuclear zinc catalyzed reactions was the syn/syn-nitroaldol product. Structures were confirmed by single-crystal X-ray crystallography. The major nitroaldol isomer was converted to a 2,3-substituted tetrahydrofuran 2-carboxylic acid containing a γ,δ-amino alcohol branch, corresponding to a constrained oxacyclic analogue of a hydroxyethylene isostere of aspartyl protease inhibitors.