SYNTHESIS OF (S)-( + )-2-METHYLHEXANOIC ACID

Trans-(4S,5S)-2-ethyI-4-hydroxymethyI-5-phenyl-2-oxazoIine

• A mixture of 126.5g (0.76mol) of (lS,2S)-( + )-2-amino-1-phenylpropane-1,3-diol (1) and 160g (0.91 mol) of triethyl orthopropanoate in 550 ml of 1,2-dichloroethane is heated under reflux for 7 hours. 

• The solvent is removed leaving an oil (159g) which crystallises on standing. 

• This is treated with 70 ml of ether and cooled in a dry-ipe-acetone bath and the partially purified product collected by filtration. 

• The crystalline material is dissolved in ether (c. 600 ml), treated with charcoal, filtered, concentrated to about 300 ml and cooled to — 78 °C. 

• The recrystallised material is filtered and washed with a small amount (15-20 ml) of precooled (-78 °C) ether. The yield of product is 106.9 g (69%), m.p. 68-69°C, [𝛼]²²₅₈₉-135.1° (c 10.4 in CHCl₃).

(4S,5S)-2-Ethyl-4-methoxymethyI-5-phenyI-2-oxazoline (2)

• The foregoing compound (18.0g, 88mmol) in 150 ml of dry tetrahydrofuran is added dropwise at room temperature to a stirred heterogeneous suspension (under nitrogen), of sodium hydride [105.3 mmol; oil removed by washing with 50 ml of dry benzene (CAUTION)] at a rate to maintain a mild evolution of hydrogen. 

• When addition is complete the mixture is heated at 50-60 °C for 1.5 hours and cooled to ambient temperature; a solution of methyl iodide (16.2g, 114 mmol, CAUTION) in tetrahydrofuran (10 ml) is added dropwise. 

• The reaction mixture is stirred for 2 hours and slowly poured into 300 ml of ice-water, and then extracted with two 200-ml portions of ether. 

• The combined ether extracts are dried over anhydrous sodium sulphate and concentrated to give an oil which is distilled in vacuo to furnish the product in 87 per cent yield, b.p. 91-93 °C/0.25mmHg.

(S)-( + )-2-MethyIhexanoic acid

• A solution of the foregoing compound (15.4g, 70 mmol) in tetrahydrofuran (160 ml) under nitrogen is cooled to — 78 °C in a dry-ice-acetone bath. 

• To this is added a solution of 70 mmol of lithium diisopropylamide (from 9.8 ml of diisopropylamine and 33 ml of 2.2 m butyllithium in 75 ml of tetrahydrofuran) over a 20-minute period. 

• The resulting solution is stirred for 40 minutes at — 78 °C, and then the cooling bath is changed to methanol-liquid nitrogen and the reaction mixture allowed to cool to -98 °C for 30 minutes (3). 

• A solution of butyl iodide (14.7 g, 80 mmol) in tetrahydrofuran (20 ml) is added over 1 5-20 minutes at — 98 °C and the resulting almost colourless solution is stirred at this temperature for 2 hours, then slowly allowed to reach room temperature. 

• The reaction mixture is poured into 300 ml of saturated brine and extracted with two 150 ml portions of ether, dried over magnesium sulphate and concentrated to give 17.7 g (92%) of 2-(l-methylpentyl)-4-methoxymethyl-5-phenyl-2-oxazoline. 

• A small portion is distilled (bulb to bulb) to give an analytically pure product [𝛼]²⁴₅₈₉-35.2° (c 10.1 in CHCl₃); i.r. (thin film) 1670cm⁻¹ ; p.m.r. (CDCl₃, TMS) 𝜹7.33 (s, 5H), 5.33 (d, J = 7Hz, 1H), 4.33-3.93 (q, 1H), 3.80-3.33 (m, 2H), 3.43 (s,3H), 2.87-2.33 (m, 1H), and 2.00-0.67 (m, 12H).

• The crude oxazoline (17.2 g) is dissolved in 250 ml of 2 m sulphuric acid and heated to reflux for 3.5 hours, at which time the solution becomes homogeneous. 

• When the heating of the solution is initiated a crystalline solid appears which slowly dissolves as the reflux progresses. 

• After the heating is discontinued, the solution is cooled to room temperature and extracted with two 75-ml portions of ether. 

• The combined ether extracts are washed with three 100-ml portions of 5 per cent aqueous potassium carbonate solution and the aqueous extracts neutralised to pH 1 with 12 m hydrochloric acid. 

• The resulting turbid mixture is extracted with three 75-ml portions of ether and the extract dried over magnesium sulphate. 

• Concentration of the ether solution leaves an oil which is distilled (bulb to bulb) to give 5.80 g (66%) of (S)-( + )-2-methylhexanoic acid. Gas-liquid chromatography analysis (10% UCW-98) indicates only a single compound; [𝛼]²⁴₅₈₉ +14.5° (neat) (ee 78%, (4)].

Notes to keep in mind:

1.  This amino alcohol may be recrystallised by dissolving 1 part in 1 part of methanol and adding 2 parts of ethyl acetate and cooling. The pure material has m.p. 112-113 °C,[𝛼]²⁴₅₈₉ 26.6° (c 10.0 in MeOH).

2.  The apparatus set-up for this, and the following reaction, should take into account the moisture sensitivity of the reagents and the reaction intermediates. The reagents should be added by syringe through a rubber septum, the reaction media should be held under an atmosphere of nitrogen via a suitable nitrogen bubbler device, and the solutions should be stirred magnetically.

3.  Continued use of the cooling bath held at —78 °C leads to only a small diminution of optical purity in the final product.

4.  The specific rotation of optically pure acid is [𝛼]ᴅ²⁵ —18.7° (neat).