Regio- and stereoselective lithiation and C-substitution of (S)-2-(Dibenzylamino)-butane-1,4-diol via dicarbamates

摘要

The 1,4-O,O'-dicarbamate 5, derived from (S)-2-(dibenzylamino)butane-1,4-diol, 1,4-diol, is prepared from L-aspartic acid in three synthetic steps. Deprotonation with sec-butyllithium removes the 1-pro-S proton with essentially complete substrate-controlled diastereoselectivity. The resulting chiral lithium compound 7 is configurationally stable and reacts stereospecifically with retention of the configuration at C-1 with a large number of electrophiles. A good level of enantiofacial selectivity is observed in the addition reaction of 7 with achiral aldehydes. Medium kinetic resolution was observed with racemic 2-alkylcyclohexanones. Quite generally, the reagent 7 achieves the nucleophilic introduction of the (protected) stereohomogeneous 2-amino-1,4-dihydroxybutanide fragment. Decarbamoylation is best achieved by reduction with LiAlH4. Deuteration of the 1-pro-S position provides efficient protection against deprotonation in the 1-position owing to a large kinetic H/D-isotope effect. The (-)-sparteine-mediated deprotonation therein removes the 4-pro-S-H, which also was achieved for the 1-methylthio- and the 1-phenylthio derivative. The combined strategy makes possible the stereocontrolled chain-elongation of the 2-amino-1,4-dihydroxybutane unit at both termini by C-electrophiles. [References: 46]