(3-iodophenyl)methanol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A suspension of pyridinium chlorochromate (2.45 g, 11.4 mmol) and dry celite (˜2.00 g) in dry dichloromethane (20 ml) was stirred at room temperature for 15 min. 3-Iodobenzyl alcohol (11) (1.02 g, 4.35 mmol) in dry dichloromethane (5 ml) was added. The suspension was shielded from light and stirred at room temperature for 2 h after which it was diluted with ether, and filtered through celite. The cloudy brown filtrate was concentrated to a red-brown gummy paste which was re-dissolved in dichloromethane and passed through a short silica column, eluting with dichloromethane. This gave a clear, colourless solution which was concentrated to give 3-iodobenzaldehyde (12) as a white solid (0.953 g, 95%). dry celite (˜2.00 g) in dry dichloromethane (20 ml) stirred at room temperature for 2 h after which it filtered through celite The cloudy brown filtrate was concentrated to a red-brown gummy paste which was re-dissolved in dichloromethane eluting with dichloromethane This gave a clear, colourless solution which was concentrated

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

Procedure: Ethyl chloroformate (1.02 g, 11.1 mmol) in dry tetrahydrofuran (5 ml) was added slowly over 10 min to a stirred solution of 3-iodobenzoic acid (1.98 g, 7.98 mmol) and triethylamine (0.500 g, 11.6 mmol) in dry tetrahydrofuran at −8° (ice/salt/water bath). The yellow mixture soon became cloudy. It was shielded from light and stirred at −8° for 0.5 h, after which it was filtered to remove the triethylammonium chloride precipitate. The filtrate was added slowly to a suspension of sodium borohydride (0.795 g, 21.1 mmol) in water (30 ml) in a three necked flask, equipped with a thermometer, and connected to nitrogen, making sure that the temperature of the mixture is kept below 10° during the addition. Gas evolution (carbon dioxide) was observed. After the addition was completed, the mixture was stirred, shielded from light, at room temperature for 22 h under nitrogen. The resultant cloudy mixture was acidified with aqueous hydrochloric acid (10%) to pH˜1. The layers were separated, and the aqueous layer was extracted with ether (×3). The combined ether extract and tetrahydrofuran layer was washed with aqueous sodium hydroxide (×1, 10%) and then with water (×1). Drying with magnesium sulphate, and concentration gave 3-iodobenzyl alcohol (11) a pale yellow oil (1.02 g, 54%). after which it was filtered to remove the triethylammonium chloride precipitate equipped with a thermometer is kept below 10° during the addition After the addition the mixture was stirred shielded from light, at room temperature for 22 h under nitrogen The layers were separated the aqueous layer was extracted with ether (×3) The combined ether extract tetrahydrofuran layer was washed with aqueous sodium hydroxide (×1, 10%) Drying with magnesium sulphate, and concentration

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

Procedure: According to example 61, 10.0 g of 3-iodobenzyl alcohol (Aldrich) was treated with 30 mL of cyclopentene using 0.96 g of Pd(OAc)2, 2.60 g of tri-ortho-tolylphosphine, and 6.6 mL of Et3N. The resulting olefin mixture was hydrogenated for 2.5 h using 0.62 g of 5% Pt(C) in MeOH to afford 5.77 g (76%) of 3-cyclopentylbenzyl alcohol as a light yellow liquid.

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 3-iodo-benzyl alcohol (4.68 g, 20 mmol) in CH2Cl2 (40 mL) is added imidazole (1.49 g, 22 mmol) and t-butyldiphenylsilyl chloride (5.74 g, 22 mmol). The resulting mixture is stirred for 1 h diluted with ether washed with water and brine, dried over MgSO4 and concentrated to give the title compound as an oil (9.41 g). MS (EI) 472 (M)+. washed with water and brine dried over MgSO4 concentrated

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

Procedure: To a solution of 3-iodo-benzyl alcohol (4.68 g, 20 mmol) in CH2Cl2 (40 mL) is added imidazole (1.49 g, 22 mmol) and t-butyldiphenylsilyl chloride (5.74 g, 22 mmol). The resulting mixture is stirred for 1 h diluted with ether washed with water and brine, dried over MgSO4 and concentrated to give the title compound as an oil (9.41 g). MS (EI) 472 (M)+. washed with water and brine dried over MgSO4 concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %) and K3PO4 (430 mg, 2.03 mmol), evacuated and backfilled with argon. N,N′-Dimethylethylenediamine (11 μL, 0.10 mmol, 10 mol %), 3-iodobenzyl alcohol (128 μL, 1.01 mmol), 2-pyrrolidinone (94 μL, 1.24 mmol) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 80° C. for 3 h. The resulting white suspension was allowed to reach room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 5:1 ether-methanol (10 mL). The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; dichloromethane-methanol 25:1; 15 mL fractions). Fractions 14-19 provided 180 mg (93% yield) of the product as a white solid. Mp: 120-121° C. evacuated The Schlenk tube was sealed with a Teflon valve to reach room temperature filtered through a 0.5×1 cm pad of silica gel eluting with 5:1 ether-methanol (10 mL) The filtrate was concentrated the residue was purified by flash chromatography on silica gel (2×20 cm; dichloromethane-methanol 25:1; 15 mL fractions)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The procedure described in Reich, S. H. et. al. J. Med. Chem. 2000, 43, 1670 was followed. Pd(OAc)2 (8.2 mg, 0.037 mmol) and triethylamine (0.360 mL, 2.58 mmol) were added to a solution of 3-iodobenzyl alcohol 2-1 (0.27 mL, 2.13 mmol) and methyl acrylate 2-2 (0.220 mL, 2.44 mmol) in CH3CN (4.5 mL). The reaction vessel was sealed with a Teflon screw-cap and was heated at 100° C. for 5 h. At this time, the reaction was allowed to cool to room temperature and the tube was charged with 0.22 mL more of methyl acrylate, 11.7 mg Pd(OAc)2 and 0.360 mL triethylamine. The reaction was heated at 100° C. overnight and then 10 mL saturated ammonium chloride solution was added. The resulting mixture was extracted with dichloromethane (3×40 mL) and the combined dichloromethane solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (30% ethyl acetate/hexanes) gave 395 mg (97%) of 2-3. 3-(3-Hydroxymethyl-phenyl)-propionic acid methyl ester (2-4). (Ph3P)3RhCl (11.5 mg, 0.012 mmol) was added to a solution of 2-3 (25 mg, 0.13 mmol) in 0.400 mL ethanol. The reaction was stirred under 1 atm H2 balloon for 20 h and then was filtered through Celite. Evaporation to dryness and purification by flash chromatography on silica gel (30% ethyl acetate/hexanes) gave 2-4 (21 mg, 82%). 3-(3-Iodomethyl-phenyl)-propionic acid methyl ester (2-5). A mixture of Ph3P (36 mg, 0.14 mmol), I2 (41 mg, 0.16 mmol) and imidazole (10.5 mg, 0.15 mmol) in 0.40 mL 1,2-dichloroethane was stirred for 15 min. and then a solution of 2-4 (20.5 mg, 0.11 mmol) in 0.1 mL 1,2-dichloroethane was added by cannula. The resulting mixture was stirred for 1 h and then was filtered through basic alumina, washing with ethyl acetate. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel to give 2-5 (26 mg, 81%). 3-[3-((1R,2S,3R)-3-(tert-Butyl-dimethyl-silanyloxy)-2-{4-[1-(tert-butyl-dimethyl-silanyloxy)-hexyl]-phenyl}-5-oxo-cyclopentylmethyl)-phenyl]-propionic acid methyl ester (3-1). A −78° C. solution of aryl bromide 1-5 (759 mg, 2.0 mmol) in THF (3 mL) was treated with tert-butyllithium (2.6 mL, 4.4 mmol, 1.7 M/pentane). After 30 min., Me2Zn (1.1 mL, 2.2 mmol, 2 M/toluene) was added and the resulting solution was stirred for 15 min. at 0° C. and then was recooled to −78° C. A solution of enone 1-1 (319 mg, 1.5 mmol, Evotec OAI, 151 Milton Park, Abington, Oxon, OX 14 4SD, UK) in 1.7 mL THF was added by syringe pump over 1 h. The resulting mixture was stirred at −78° C. for 2 h, and then HMPA (2.2 mL, 12.6 mmol) was added followed by a solution of 2-5 (2.641 g, 8.7 mmol) in THF (1.6 mL). The reaction was stirred overnight at −40° C. and then was quenched by addition of 40 mL saturated ammonium chloride solution. A little water was added to dissolve the solids and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined ethyl acetate solution was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (10% ethyl acetate/hexanes) gave the title ketone contaminated with ca. 35% of benzyl iodide 2-5 (438 mg). screw-cap to cool to room temperature The reaction was heated at 100° C. overnight The resulting mixture was extracted with dichloromethane (3×40 mL) the combined dichloromethane solution was dried (Na2SO4) filtered evaporated Purification by flash chromatography on silica gel (30% ethyl acetate/hexanes)