4-Hydroxybenzaldehyde → 9,10-Phenanthrenedione

Participants

Reaction Steps

The synthetic route toward the intercalating nucleic acid monomers (6a,b) is shown in FIG. 1. The key intermediates 3a,b were synthesized from (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (1) by reaction with 4-hydroxybenzaldehyde (2a) or 4-hydroxy-1-naphthaldehyde (2b) under Mitsunobu conditions32 (DEAD, THF, and Ph3P) in high yields 81% and 92%, respectively (FIG. 1). Subsequent treatment of 3a,b with phenanthrene-9,10-dione (4) and ammonium acetate in hot glacial acetic acid afforded the monomers 6a,b. When starting from 3a the product mixture was separated by silica gel column chromatography to afford the deprotected (S)-4-(4-(1H-phenanthro[9,10-d]imidazol-2-yl)phenoxy)butane-1,2-diol (6a) in 72% yield and a minor amount of the corresponding diol (5) still protected with an isopropylidene group. Due to exchange of the imidazole protons, a line broadening was observed in the 1H NMR spectrum of (5). This resulted in a broad singlet for the neighboring protons in the phenanthrene ring at C-4 and C-11. The corresponding compound (S)-4-(4-(1H-phenanthro[9,10-d]imidazol-2-yl)naphthalen-1-yloxy)butane-1,2-diol (6b) was isolated fully deprotected by precipitation in 80% yield without chromatographic purification. The primary hydroxy group of compounds (6a,b) was protected by reaction with 4,4′-dimethoxytrityl chloride (DMT-Cl) in anhydrous pyridine at room temperature under a N2 atmosphere. Silica gel purification afforded the DMT-protected compounds 7a,b in 79% and 56% yield, respectively. The secondary hydroxy group of these compounds was phosphitylated overnight with 2-cyanoethyl N,N,N′,N′-tetraisopropyl phosphorodiamidite in the presence of diisopropyl ammonium tetrazolide as activator in anhydrous CH2Cl2 to afford 8a,b in 86% and 81% yield, respectively (FIG. 1).

Provenance & Evidence