A. 2,6-Dimethylphenyl propanoate. To a 2-L, three-necked, round-bottomed flask is added 26.4 g (0.55 mol) of a 50% dispersion of sodium hydride in mineral oil (Note 1). The sodium hydride is washed several times by decantation with dry hexane and is then covered with 1 L of dry ether (Note 2). The flask is immersed in an ice bath and equipped with a dropping funnel, a mechanical stirrer, and a reflux condenser. A solution of 61.1 g (0.50 mol) of 2,6-dimethylphenol (Note 3) in 150 mL of dry ether is added dropwise over a 10-min period and the mixture is stirred for 5 min, during which time hydrogen evolution ceases. The cold solution is stirred continuously while a solution of 48 mL (50.9 g, 0.55 mol) of propanoyl chloride (Note 1) in 100 mL of dry ether is added dropwise over a 30-min period. After stirring for an additional hour the reaction mixture is poured into a 2-L separatory funnel containing 200 mL of water. The mixture is shaken vigorously and the ether layer is separated and washed successively with 200 mL of aqueous 10% sodium hydroxide, 200 mL of water, and 200 mL of 4% hydrochloric acid, then dried over magnesium sulfate. The ether is removed with a rotary evaporator and the residue distilled through a short, indented Claisen apparatus to obtain 85–86 g (96–97%) of 2,6-dimethylphenyl propanoate, bp 60–65°C (0.05 mm) (Note 4).

B. 2',6'-Dimethylphenyl (2SR,3SR)-2,4-dimethyl-3-hydroxypentanoate. The reaction is carried out in a 2-L, three-necked, round-bottomed flask equipped with an efficient mechanical stirrer, a thermometer, and a 500-mL, pressure-equalizing dropping funnel. The dropping funnel is marked to hold 325 mL and is topped with a rubber septum pierced with a syringe needle attached to a source of dry nitrogen. The flask is charged with 300 mL of dry tetrahydrofuran (Note 2) and 69 mL (0.49 mol) of diisopropylamine (Note 1). Butyllithium (325 mL, 0.49 mol, 1.5 M in hexane) (Note 5) is transferred into the addition funnel with a cannula. The reaction flask and its contents are cooled to below −5°C by immersion in a bath of dry ice and isopropyl alcohol, which is maintained at −10 to −15°C by periodic additions of dry ice. The butyllithium is added dropwise at such a rate as to maintain the temperature of the reaction mixture in the range 0 to −5°C. After the addition is complete the mixture is stirred for an additional 15 min and is then cooled to −70°C. While the reaction mixture is cooling, the septum is briefly removed and a solution of 85 g (0.48 mol) of 2,6-dimethylphenyl propanoate in 100 mL of dry tetrahydrofuran is added to the addition funnel, the septum is replaced, and nitrogen is passed through the apparatus in a slow stream for 5 min. The ester is then added to the lithium diisopropylamide solution at such a rate that the temperature of the reaction mixture does not exceed −65°C. The total addition time is 30–40 min. After the addition is complete the reaction mixture is kept at −70°C for an additional hour, during which time the dropping funnel is charged with a solution of 35.3 g (0.49 mol) of 2-methylpropanal (Note 1) in 100 mL of dry tetrahydrofuran. The aldehyde solution is added dropwise to the vigorously stirring enolate solution at such a rate as to maintain a reaction temperature of less than −65°C. After the addition is complete the reaction mixture is kept at −70°C for an additional 30 min. To the vigorously stirring solution is added 500 mL of saturated aqueous ammonium chloride. At this point stirring is discontinued, the cooling bath is removed, and the partially frozen mixture is allowed to warm to room temperature. The contents of the reaction flask are introduced into a large separatory funnel and diluted with 500 mL of ether. The layers are separated, and the organic phase is washed with 300 mL of water and 300 mL of saturated brine and then dried over magnesium sulfate. After removal of the drying agent the solvents are removed with a rotary evaporator to give 112–120 g of an oily semisolid, which is a 7 : 2 mixture of the β-hydroxy ester and 2,6-dimethylphenyl propanoate. This material may be crystallized from ether–hexane to provide 70 g (60%) of pure β-hydroxy ester, mp 75.5–76°C (Note 6). However, it is not necessary to purify the crude product before hydrolysis to the β-hydroxy acid (Note 7).

C. (2SR,3SR)-2,4-Dimethyl-3-hydroxypentanoic acid. The crude product from the foregoing preparation (112–120 g) is dissolved in 500 mL of methanol and placed in a 2-L Erlenmeyer flask. A solution of 112 g (2 mol) of potassium hydroxide in a mixture of 500 mL of water and 500 mL of methanol is added with stirring, whereupon the reaction mixture warms to about 40°C. After stirring for 15 min crushed dry ice is added in portions to the vigorously stirring mixture until the pH is 7–8. The resulting solution is concentrated to a volume of about 500 mL with a rotary evaporator and extracted with two 300-mL portions of methylene chloride, which are discarded. The aqueous phase is then acidified to pH 1–2 by addition of 75 mL of concentrated hydrochloric acid (vigorous evolution of CO₂) and extracted with two 500-mL portions of methylene chloride. The combined organic extracts are washed with 200 mL of saturated brine and dried over magnesium sulfate. After removal of the drying agent the solvent is removed with a rotary evaporator to obtain 36–53 g of (2SR,3SR)-2,4-dimethyl-3-hydroxypentanoic acid as a semisolid. Crystallization from hexane provides 30–43 g (41–60% overall yield) of pure hydroxy acid, mp 76–79°C (Note 8).