(S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (Aldrich, 5 g, 34.2 mmol) in THF was added sodium hydride 60% (1.504 g, 37.6 mmol, 1.1 eq) portionwise and the mixture stirred for 1 h (cloudy solution). The mixture was cooled to 0° C. and to it was added 4-methoxybenzyl chloride (5.89 g, 37.6 mmol, 1.1 equivalent (eq.)) in one portion and the mixture stirred at the temperature for 30 min and heated to 65-70° C. overnight. After cooling to rt and quenching with saturated NH4Cl/water, the mixture was extracted with ethyl acetate (2×) and the organic extracts were washed with water, brine and dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (15% ethyl acetate/hexanes) to give desired product as a colorless oil. 1H NMR (400 MHz, Acetone-d6): δ7.28 (2 H, d), 6.93-6.91 (2 H, m), 4.43 (2 H, s), 4.20-4.14 (1 H, m), 4.04-3.98 (1 H, m), 3.80 (3H, s), 3.56-3.50 (3H, m), 1.88-1.76 (2H, m), 1.31 (3H, s), 1.28 (3 H, s). the mixture stirred at the temperature for 30 min heated to 65-70° C. overnight After cooling to rt quenching with saturated NH4Cl/water the mixture was extracted with ethyl acetate (2×) the organic extracts were washed with water, brine dried over MgSO4 The mixture was filtered the filtrate was concentrated in vacuo The crude product was purified by silica gel chromatography (15% ethyl acetate/hexanes)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (Aldrich, 5 g, 34.2 mmol) in THF was added sodium hydride 60% (1.504 g, 37.6 mmol, 1.1 eq) portionwise and the mixture stirred for 1 h (cloudy solution). The mixture was cooled to 0° C. and to it was added 4-methoxybenzyl chloride (5.89 g, 37.6 mmol, 1.1 equivalent (eq.)) in one portion and the mixture stirred at the temperature for 30 min and heated to 65-70° C. overnight. After cooling to rt and quenching with saturated NH4Cl/water, the mixture was extracted with ethyl acetate (2×) and the organic extracts were washed with water, brine and dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (15% ethyl acetate/hexanes) to give desired product as a colorless oil. 1H NMR (400 MHz, Acetone-d6): δ7.28 (2 H, d), 6.93-6.91 (2 H, m), 4.43 (2 H, s), 4.20-4.14 (1 H, m), 4.04-3.98 (1 H, m), 3.80 (3H, s), 3.56-3.50 (3H, m), 1.88-1.76 (2H, m), 1.31 (3H, s), 1.28 (3 H, s). the mixture stirred at the temperature for 30 min heated to 65-70° C. overnight After cooling to rt quenching with saturated NH4Cl/water the mixture was extracted with ethyl acetate (2×) the organic extracts were washed with water, brine dried over MgSO4 The mixture was filtered the filtrate was concentrated in vacuo The crude product was purified by silica gel chromatography (15% ethyl acetate/hexanes)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (1.58 mL, 10.0 mmol) in CH2Cl2 (25 mL) was added DMAP (120 mg, 1.0 mmol) and triethylamine (2.08 mL, 15.0 mmol). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (12.0 mmol, 0.928 mL) was added slowly dropwise under N2 atmosphere. The reaction mixture was stirred for 2 h (monitored by TLC, 1:2 EtOAc-Hexanes). Saturated NH4Cl solution (20 mL) was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide a yellow oil, which was dissolved in dry acetone (25 ml), followed by addition of NaI (7.5 g, 50 mmol). The reaction mixture was refluxed for 2 h (monitored by TLC, 1:4 EtOAc-Hexanes), cooled to room temperature and water (50 mL) was added. Extraction with ethyl acetate, washing of the combined organic layers with brine, drying over anhydrous Na2SO4, filtration and concentration provided a yellow oil, which was purified by flash chromatography (25% EtOAC-Hexane) to afford the title compound, (S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (0.82 g, 32% over two steps) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 3H), 1.41 (s, 3H), 1.99-1.16 (m, 2H), 3.25 (dd, J=18.19, 8.84 Hz, 2H), 3.58 (t, J=7.20 Hz, 1H), 4.03-4.13 (m, 1H), 4.13-4.24 (m, 1H). MS (ES) [M+H] calculated for C7H14IO2, 257.00. found 257.08. the mixture was extracted with CH2Cl2 The combined organic layers were washed with brine dried over anhydrous Na2SO4 filtered concentrated to provide a yellow oil, which cooled to room temperature Extraction with ethyl acetate washing of the combined organic layers with brine drying over anhydrous Na2SO4, filtration and concentration provided a yellow oil, which was purified by flash chromatography (25% EtOAC-Hexane)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (1.58 mL, 10.0 mmol) in CH2Cl2 (25 mL) was added DMAP (120 mg, 1.0 mmol) and triethylamine (2.08 mL, 15.0 mmol). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (12.0 mmol, 0.928 mL) was added slowly dropwise under N2 atmosphere. The reaction mixture was stirred for 2 h (monitored by TLC, 1:2 EtOAc-Hexanes). Saturated NH4Cl solution (20 mL) was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide a yellow oil, which was dissolved in dry acetone (25 ml), followed by addition of NaI (7.5 g, 50 mmol). The reaction mixture was refluxed for 2 h (monitored by TLC, 1:4 EtOAc-Hexanes), cooled to room temperature and water (50 mL) was added. Extraction with ethyl acetate, washing of the combined organic layers with brine, drying over anhydrous Na2SO4, filtration and concentration provided a yellow oil, which was purified by flash chromatography (25% EtOAC-Hexane) to afford the title compound, (S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (0.82 g, 32% over two steps) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 3H), 1.41 (s, 3H), 1.99-1.16 (m, 2H), 3.25 (dd, J=18.19, 8.84 Hz, 2H), 3.58 (t, J=7.20 Hz, 1H), 4.03-4.13 (m, 1H), 4.13-4.24 (m, 1H). MS (ES) [M+H] calculated for C7H14IO2, 257.00. found 257.08. the mixture was extracted with CH2Cl2 The combined organic layers were washed with brine dried over anhydrous Na2SO4 filtered concentrated to provide a yellow oil, which cooled to room temperature Extraction with ethyl acetate washing of the combined organic layers with brine drying over anhydrous Na2SO4, filtration and concentration provided a yellow oil, which was purified by flash chromatography (25% EtOAC-Hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (S)-(−)-1,2,4-butanetriol (30 g, 283 mmol), acetone (200 ml) and p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) were added and the mixture was stirred at room temperature overnight. To the reaction mixture, triethylamine (4 ml) was added and the mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel 350 g, elution solvent: ethyl acetate/heptane=18/82→6/4) to obtain the title compound (30.2 g, yield: 73%) as a colorless oil. the mixture was concentrated The residue was purified by silica gel column chromatography (silica gel 350 g, elution solvent: ethyl acetate/heptane=18/82→6/4)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (S)-(−)-1,2,4-butanetriol (30 g, 283 mmol), acetone (200 ml) and p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) were added and the mixture was stirred at room temperature overnight. To the reaction mixture, triethylamine (4 ml) was added and the mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel 350 g, elution solvent: ethyl acetate/heptane=18/82→6/4) to obtain the title compound (30.2 g, yield: 73%) as a colorless oil. the mixture was concentrated The residue was purified by silica gel column chromatography (silica gel 350 g, elution solvent: ethyl acetate/heptane=18/82→6/4)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (Aldrich) (21.1 g, 0.14 mol) and triethylamine (40 mL, 0.28 mol) in dichloromethane (250 mL) at 0° C. was added methanesulfonyl chloride (13.4 mL, 0.17 mol) dropwise. The reaction mixture was stirred at 0° C. for 1.5 h, then water was added. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated to give methanesulfonic acid 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester as a yellow oil (31.7 g, 98%). The organic layer was separated washed with water, brine dried over MgSO4 concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol (1.58 mL, 10.0 mmol) in CH2Cl2 (25 mL) was added DMAP (120 mg, 1.0 mmol) and triethylamine (2.08 mL, 15.0 mmol). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (12.0 mmol, 0.928 mL) was added slowly dropwise under N2 atmosphere. The reaction mixture was stirred for 2 h (monitored by TLC, 1:2 EtOAc—Hexanes). Saturated NH4Cl solution (20 mL) was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide a yellow oil, which was dissolved in dry acetone (25 ml), followed by addition of NaI (7.5 g, 50 mmol). The reaction mixture was refluxed for 2 h (monitored by TLC, 1:4 EtOAc—Hexanes), cooled to room temperature and water (50 mL) was added. Extraction with ethyl acetate, washing of the combined organic layers with brine, drying over anhydrous Na2SO4, filtration and concentration provided a yellow oil, which was purified by flash chromatography (25% EtOAC-Hexane) to afford the title compound, (S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (0.82 g, 32% over two steps) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 3H), 1.41 (s, 3H), 1.99-1.16 (m, 2H), 3.25 (dd, J=18.19, 8.84 Hz, 2H), 3.58 (t, J=7.20 Hz, 1H), 4.03-4.13 (m, 1H), 4.13-4.24 (m, 1H). MS (ES) [M+H] calculated for C2H14IO2, 257.00; found 257.08. the mixture was extracted with CH2Cl2 The combined organic layers were washed with brine dried over anhydrous Na2SO4 filtered concentrated to provide a yellow oil, which cooled to room temperature Extraction with ethyl acetate washing of the combined organic layers with brine drying over anhydrous Na2SO4, filtration and concentration provided a yellow oil, which was purified by flash chromatography (25% EtOAC-Hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (S)-4-amino-butane-1,2-diol (prepared from (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H41C12N4O4 [(M+H)+] 627.25, observed 627.2497.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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). in high yields 81% and 92%, respectively (FIG. 1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triphenyl phosphine (31.0 g, 118.21 mmol) and imidazole (8.05 g, 118.21 mmol) were dissolved in a mixed solution (400 ml) of diethyl ether-acetonitrile (3:1), iodine (30.0 g, 118.21 mmol) was added thereto under cooling on ice and the mixture was stirred at room temperature for 3 hours. The solution was cooled on ice again, a mixed solution (100 ml) of (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (15 g, 98.51 mmol) in diethyl ether-acetonitrile (3:1) was added thereto and stirred at room temperature for 18 hours. A saturated sodium thiosulfate aqueous solution was added to the reaction solution under cooling on ice and stirred for a while. The solution was extracted with diethyl ether and the extract was washed with saturated sodium chloride solution. The solvent was removed under reduced pressure and the obtained residue was triturated by adding a mixed solvent of ether/hexane to remove the insoluble material by filtration. The filtrate was concentrated under reduce pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 23.1 g (92%) of the title compound in the form of a colorless clear oily product. was added under cooling on ice The solution was cooled on ice again stirred at room temperature for 18 hours under cooling on ice stirred for a while The solution was extracted with diethyl ether the extract was washed with saturated sodium chloride solution The solvent was removed under reduced pressure the obtained residue was triturated by adding a mixed solvent of ether/hexane to remove the insoluble material by filtration The filtrate was concentrated the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (Aldrich, 5 g, 34.2 mmol) in THF was added sodium hydride 60% (1.504 g, 37.6 mmol, 1.1 eq) portionwise and the mixture stirred for 1 h (cloudy solution). The mixture was cooled to 0° C. and to it was added 4-methoxybenzyl chloride (5.89 g, 37.6 mmol, 1.1 equivalent (eq.)) in one portion and the mixture stirred at the temperature for 30 min and heated to 65–70° C. overnight. After cooling to rt and quenching with saturated NH4Cl/water, the mixture was extracted with ethyl acetate (2×) and the organic extracts were washed with water, brine and dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (15% ethyl acetate/hexanes) to give desired product as a colorless oil. 1H NMR (400 MHz, Acetone-d6): δ7.28 (2 H, d), 6.93–6.91 (2 H, m), 4.43 (2 H, s), 4.20–4.14 (1 H, m), 4.04–3.98 (1 H, m), 3.80 (3H, s), 3.56–3.50 (3H, m), 1.88–1.76 (2H, m), 1.31 (3H, s), 1.28 (3 H, s). the mixture stirred at the temperature for 30 min heated to 65–70° C. overnight After cooling to rt quenching with saturated NH4Cl/water the mixture was extracted with ethyl acetate (2×) the organic extracts were washed with water, brine dried over MgSO4 The mixture was filtered the filtrate was concentrated in vacuo The crude product was purified by silica gel chromatography (15% ethyl acetate/hexanes)