A. 5-Hydroxy-2,4,6-trimethyl-2-(trimethylsiloxy)heptan-3-one. A dry, 1-L, four-necked (including a thermometer well), round-bottomed flask equipped with an efficient mechanical stirrer, thermometer, graduated 250-mL pressure-equalizing addition funnel sealed with a rubber septum, and a nitrogen inlet is charged with 125 mL of dry tetrahydrofuran (Note 1) and 31 mL (0.22 mol) of diisopropylamine (Note 2). The stirrer is started and 137 mL (0.20 mol) of 1.5 M butyllithium in hexane is transferred to the addition funnel by means of a 16-gauge cannula and argon pressure (Note 3). The reaction flask and its contents are cooled to below −5°C by immersion in a dry ice–acetone bath that is maintained at −10 to −15°C by the occasional addition of dry ice. The butyllithium is added dropwise over a period of 20 min. After the addition is complete 10 mL of dry tetrahydrofuran is added to the addition funnel with a syringe to rinse the walls of the funnel, and the rinse is then added to the pale-yellow solution. After the addition is complete, the solution is stirred for an additional 15 min and is then cooled to below −70°C (dry ice–acetone bath). While the reaction solution is cooling, a solution of 37.7 g (0.20 mol) of 2-methyl-2-(trimethylsiloxy)pentan-3-one (Note 4) in 10 mL of dry tetrahydrofuran is introduced through the septum into the addition funnel. When the lithium diisopropylamide (LDA) solution has cooled to below −70°C, the ketone is slowly added to the solution over a period of 20–25 min to ensure that the reaction temperature is maintained below −70°C. After the addition is complete 10 mL of dry tetrahydrofuran is added to rinse the walls of the addition funnel, the rinse is added, and the stirred reaction solution is maintained below −70°C for an additional 30–40 min. During this time the addition funnel is charged through the septum with a solution of 14.4 g (0.20 mol) of 2-methylpropanal (Note 5) in 10 mL of dry tetrahydrofuran. The aldehyde solution is added dropwise to the vigorously stirring yellow enolate solution at −70°C over a 15-min period, and then the addition funnel is again rinsed with 10 mL of dry tetrahydrofuran and the rinse added to the reaction mixture. After 10–15 min 200 mL of a saturated aqueous ammonium chloride solution is added to the vigorously stirring, −70°C reaction mixture. 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 2-L separatory funnel, 200 mL of ether is added to the flask, and the ether rinse is then transferred to the separatory funnel. The layers are shaken and then separated, and the aqueous phase is extracted again with 200 mL of ether. The combined organic phase is washed with 200 mL of water and 200 mL of saturated brine and then dried over magnesium sulfate. After removal of the drying agent by filtration the solvents are removed with a rotary evaporator at aspirator pressure to give 52.1–52.4 g of a pale-yellow oil that is a 63 : 37 mixture of the expected product and the starting material. Most of the starting material is then selectively removed by stirring (magnetic stirring bar) at 25°C at reduced pressure (vacuum pump, 0.1–0.08 mm) for 19 hr to yield 35.2 g of a 90 : 10 mixture (31.7 g, 61%), which is used without further purification for Step B (Note 6) and (Note 7).

B. (2SR,3RS)-2,4-Dimethyl-3-hydroxypentanoic acid. A dry, 500-mL, three-necked, round-bottomed flask equipped with a mechanical stirrer, thermometer, and a nitrogen inlet is flushed with nitrogen, charged with 12.5 g (55 mmol) of periodic acid (Note 8) and 150 mL of dry tetrahydrofuran (Note 1), and then sealed with a stoppered, 25-mL, pressure-equalizing addition funnel. The solution is stirred vigorously and cooled to 0–5°C with an ice–salt bath. During this time the addition funnel is charged with a solution of 12.0 g of 5-hydroxy-2,4,6-trimethyl-2-(trimethylsiloxy)heptan-3-one (10.8 g, 41 mmol of ketone from a 90 : 10 mixture from Part A) in 10 mL of dry tetrahydrofuran, which is then rapidly introduced (1 min) to the cold, stirring solution. After the addition is complete 5 mL of dry tetrahydrofuran is added to the addition funnel to rinse the walls of the funnel, and the rinse is then added to the reaction solution. The cooling bath is removed after 15 min and stirring is continued for 1.5 hr, during which time a white precipitate forms. In the meantime, 52 g (0.5 mol) of sodium bisulfite is mixed with 100 mL of distilled water in a 500-mL filtering flask with a side hose connection and cooled to 0–5°C with an ice–salt bath. The reaction mixture is filtered directly through filter paper with suction into the cold slurry of sodium bisulfite. The residue is rinsed with 50 mL of dry ether (Note 9), which is added to the filter funnel and drawn by suction into the yellow solution. After magnetic stirring of the cold mixture for 20 min the contents of the flask are introduced into a 500-mL separatory funnel and the layers are separated. The aqueous layer (pH 4.3) is extracted twice with 100 mL of ether and the combined yellow organic layer is washed with 125 mL of distilled water and separated (the pH of the wash is 2.6–3.5). The organic layer is dried over magnesium sulfate for 1 hr and filtered to remove the drying agent, and the solvents are removed with a rotary evaporator at aspirator pressure. Distillation of the dark-yellow oil affords 4.9–5.4 g (82–89%) of (2SR,3RS)-2,4-dimethyl-3-hydroxypentanoic acid, bp 85–89°C (0.01 mm), as a viscous, yellow–green liquid (Note 10). Crystallization from hexane using decolorizing carbon provides 4.6–5.0 g (77–83%) of pure hydroxy acid, mp 75–76°C, as white crystals (Note 11).