Use of organocatalysis for the synthesis of phenyl-hydroxylated-butyric acids

Abstract

The 4-(p-nitro)-phenyl-hydroxylated-butyric acids 1 (2,3-anti-3,4-syn) and 2 (2,3-syn-3,4-syn) were synthesized from TBS-dihydroxyacetone (TBS-DHA) and p-nitrobenzaldehyde using an organocatalyzed aldol reaction as the key step. The stereoselectivity of the syn-aldol coupling was suggested as resulting from a transition state (TS) including a low energy anti-Z enamine, derived from the condensation of TBS-DHA and O-tBu-L-threonine. The Houk-List TS, which shows a hydrogen-aldehyde stabilizing interaction, furnished a syn-adduct as the major product in high yield and diastereo- and enantioselectivity. Selective anti- and syn-carbonyl reduction of the carbonyl adducts led to 2,3-anti-3,4-syn and 2,3-syn-3,4-syn hydroxy compounds, respectively, which underwent the same sequence of transformations (ketal synthesis, primary TBS-deprotection, oxidation and deprotection) to afford 4-(p-nitro)-phenyl-hydroxylated-butyric acids 1 and 2 in seven steps and 22% and 24% overall yield, respectively.