(S)-tert-Butylphox could be produced through the following synthetic routes

A. 2-Bromo-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-benzamide. An oven-dried, 500-mL, 3-neck flask equipped with a 3.0 cm × 1.4 cm, egg-shaped, teflon-coated magnetic stirring bar, pressure-equalizing addition funnel, an internal thermometer, and a reflux condenser (central neck) equipped with a two-tap Schlenk adapter connected to a bubbler and an argon/vacuum manifold is assembled hot and cooled under a stream of argon. The flask is charged with (L)-tert-leucine (5.00 g, 38.1 mmol, 1.00 equiv, 99% ee) and tetrahydrofuran (100 mL, 0.38 M) under a positive pressure of argon. The resulting suspension is cooled to approximately 4 °C in an ice- bath and sodium borohydride (3.46 g, 91.5 mmol, 2.40 equiv) is added in one portion. The addition funnel is charged with a solution of iodine (9.67 g, 38.1 mmol, 1.00 equiv) in tetrahydrofuran (25 mL) via syringe and added dropwise to the suspension over 30 min. After complete addition, the bath is removed, the addition funnel and the thermometer are removed and replaced by glass stoppers and the reaction is warmed to reflux (80 °C oil bath temperature). After 18 h the reaction is allowed to cool to ambient temperature and methanol (50 mL) is added slowly resulting in an almost clear solution. After stirring for 30 min the solution is quantitatively transferred to a 500-mL, 1-necked flask with methanol (ca. 50 mL) and concentrated on a rotary evaporator under reduced pressure (40 °C, ca. 53 mmHg) to a white semi-solid. The resulting material is dissolved in 20% aqueous potassium hydroxide (75 mL) and stirred for 5 h at ambient temperature with a 3.0 cm × 1.4 cm, egg shaped, teflon-coated magnetic stirring bar. The aqueous phase is extracted with dichloromethane (6 × 60 mL) and the combined organic extracts are dried over sodium sulfate (ca. 7 g), filtered, and concentrated on a rotary evaporator under reduced pressure (40 °C, 38 mmHg) and dried under vacuum (0.13 mmHg) to yield 4.42-4.45 g (37.7-37.9 mmol, 99% yield) of crude (S)-tert-leucinol as a colorless oil. This material is used in the following step without purification.

A 500-mL flask containing a 3.0 cm × 1.4 cm, egg shaped, teflon-coated magnetic stirring bar is charged with crude (S)-tert-leucinol (4.42 g, 37.7 mmol, 1.00 equiv), dichloromethane (125 mL, 0.30 M) and then a solution of sodium carbonate (11.98 g, 113.1 mmol, 3.00 equiv) in distilled water (95 mL) is added at ambient temperature. The biphasic mixture is stirred vigorously to emulsify and neat 2-bromobenzoyl chloride (5.67 mL, 43.3 mmol, 1.15 equiv) is added dropwise via syringe over approximately 15 min. The reaction flask is capped with a two-tap Schlenk adapter connected to a bubbler and stirred for 10 h, after which time the layers are partitioned in a 500 mL separatory funnel and the aqueous phase is extracted with dichloromethane (4 × 50 mL). The combined organic extracts are stirred with 1 N potassium hydroxide solution in methanol (19 mL) in a 500 mL Erlenmeyer flask with a 3.0 cm × 1.4 cm, egg-shaped, teflon-coated magnetic stirring bar for 30 min at ambient temperature and then acidified to neutral pH with 1 N hydrochloric acid (ca. 16 mL). Water (25 mL) is added, the phases are partitioned in a 1-L separatory funnel, and the aqueous phase is extracted with dichloromethane (4 × 35 mL). The combined organic extracts are washed with saturated brine (75 mL), dried over sodium sulfate (3.00 g), filtered, and concentrated on a rotary evaporator under reduced pressure (40 °C, ca. 11 mmHg) to an off-white solid. The crude white solid is dissolved in a minimal amount of hot acetone (ca. 10 mL) and hexanes are added until a cloudy solution is obtained (ca. 45 mL). The crystals formed upon cooling and aging for 3 hours at 0 °C are collected, washed with hexanes, and dried under vacuum to afford 2-bromo-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-benzamide (9.23-9.61 g, 30.8-32.0 mmol) as white blocks. The filtrate is concentrated and recrystallized in a similar manner (with acetone (ca. 2 mL) and hexanes (10 mL)) to provide additional product (0.62-1.13 g, 2.1-3.76 mmol) as white blocks, for a combined yield of 9.85-10.74 g (32.8-35.77 mmol, 86-94 % yield over two steps).

B. 2-(2-Bromophenyl)-4-(1,1-dimethylethyl)-4,5-dihydro-(4S)-oxazole. An oven-dried, 500-mL, 3-necked flask equipped with a 3.0 cm × 1.4 cm, egg-shaped, teflon-coated magnetic stirring bar, an internal thermometer, a glass stopper and a reflux condenser (central neck) equipped with a two-tap Schlenk adapter connected to a bubbler and an argon/vacuum manifold is assembled hot and cooled under a stream of argon. The flask is charged with 2-bromo-N-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]-benzamide (9.85 g, 32.8 mmol, 1.00 equiv), dichloromethane (170 mL, 0.19 M), and triethylamine (11.0 mL, 78.6 mmol, 2.40 equiv) under a positive pressure of argon. The resulting colorless solution is cooled to approximately 4 °C in an ice-water bath and neat methanesulfonyl chloride (2.92 mL, 37.7 mmol, 1.15 equiv) is added dropwise via syringe over 3 min, at which point the solution turns slightly yellow. The reaction is warmed to reflux (50 °C oil bath temperature) while monitoring conversion by TLC. Upon completed cyclization, the reaction is allowed to cool to ambient temperature and 60 mL of saturated aqueous sodium bicarbonate is added with vigorous stirring for 5 min. The layers are partitioned in a 1-L separatory funnel, the aqueous phase is extracted with dichloromethane (2 × 35 mL), the combined organic phases are washed with saturated brine (75 mL), dried over anhydrous magnesium sulfate (1.50 g), filtered, and concentrated on a rotary evaporator under reduced pressure (40 °C, 23 mmHg) to afford a red-brown semi-solid. The residue is dissolved in a minimal amount of dichloromethane (ca. 35 mL), dry-loaded onto silica gel (8 g), and purified by silica gel chromatography to afford 8.85-8.86 g (31.4 mmol, 96% yield) of 2-(2-bromophenyl)-4-(1,1-dimethyl-ethyl)-4,5-dihydro-(4S)-oxazole as a pale yellow oil. This material solidifies when placed in a -20 °C freezer and is preferred in this state for the subsequent reaction.

C. 4-(1,1-dimethylethyl)-2-[2-(diphenylphosphino)phenyl]-4,5-dihydro-(4S)-oxazole ((S)-tert-ButylPHOX). A 150-mL Schlenk flask equipped with a glass valve, a glass stopper, and a 1.7 cm × 0.7 cm, egg-shaped, teflon-coated magnetic stirring bar is dried with a heat gun under vacuum and cooled under argon atmosphere. The glass stopper is removed under a positive pressure of argon and the flask is charged with copper(I) iodide (19.0 mg, 0.10 mmol, 0.005 equiv), diphenylphosphine (4.35 mL, 25.0 mmol, 1.25 equiv), N,N'-dimethylethylenediamine (53 μL, 0.50 mmol, 0.025 equiv) and toluene (20 mL). The flask is sealed with the glass stopper and the colorless contents are stirred at ambient temperature for 20 min. The glass stopper is then removed under a positive pressure of argon and the flask is charged with 2-(2-bromophenyl)-4-(1,1-dimethylethyl)-4,5-dihydro-(4S)-oxazole (5.64 g, 20.0 mmol, 1.00 equiv), cesium carbonate (9.78 g, 30.0 mmol, 1.50 equiv), and toluene (20 mL, 0.50 M total) to wash the neck and walls of the flask. The flask is equipped with a reflux condenser with a two-tap Schlenk adapter connected to a bubbler and an argon/vacuum manifold. The now yellow heterogeneous reaction is placed in a 110 °C oil bath and vigorously stirred under argon atmosphere. Following consumption of starting material, the reaction is allowed to cool to ambient temperature, filtered through a pad of celite, and the filter cake is washed with dichloromethane (2 × 40 mL). The filtrate is concentrated on a rotary evaporator under reduced pressure (40 °C, 15 mmHg) to a pale yellow semi-solid. The residue is dissolved in a minimal amount of dichloromethane (ca. 40 mL), dry-loaded onto silica gel (10 g), and purified by silica gel chromatography eluting with 24:1 hexanes/diethyl ether until excess Ph2PH elutes, then with a 9:1 dichloromethane/diethyl ether mixture until the desired product elutes. The combined fractions are concentrated on a rotary evaporator under reduced pressure (40 °C, 14 mmHg) to a viscous, pale yellow oil and layered with acetonitrile (ca. 5 mL) to facilitate crystallization. The flask is swirled while crystals form within seconds. After approximately 15 minutes, the flask is placed under high vacuum to remove volatiles to afford 6.81 g (17.6 mmol, 88% yield) of (S)-tert-ButylPHOX as white blocks.

Notice: This procedure should be carried out in an efficient fume hood due to the evolution of hydrogen gas during the reaction.