SYNTHESIS OF (R)-(-)-2-HYDROXY-2-METHYLBUTANOIC ACID

All reaction solvents were anhydrous.

TigloyI chloride:

• [(E)-2-methylbut-2-enoyl chloride.]. Tiglic acid (20g) and phosphorus trichloride (15g) are heated together at 70-80 °C for 2 hours. 

• The upper, slightly yellow, layer is decanted from the lower syrupy layer and distilled at 64°C/35mmHg to give the acid chloride in 90 per cent yield.

(S)-(-)-N-TigIoylproIine:

• (S)-Proline ([𝝰]ᴅ²º -85.5° (c 4.00 in H₂O), 10.4g, 0.090 mol) is dissolved in 2M sodium hydroxide (53 ml, 0.106 mol) cooled in an ice bath, and the resulting alkaline solution is diluted with acetone (53 ml). 

• An acetone solution (53 ml) of tigloyl chloride (16.0g, 0.135 mol) and 2M sodium hydroxide solution (80 ml, 0.1 60 mol) are simultaneously added over 70 minutes to the aqueous solution of (S)-proline with stirring in an ice bath. 

• The pH of the mixture is kept at 10-11 during the addition of the acylating reagent. 

• After the addition, stirring is continued for 2 hours at room temperature and the mixture is submitted to evaporation in vacuo to remove the acetone. 

• The residual solution is washed with ether and acidified (pH 2) with concentrated hydrochloric acid. 

• The acidic mixture is extracted with ethyl acetate after being saturated with sodium chloride, and the combined ethyl acetate extracts are washed with saturated sodium chloride solution. 

• The organic layer is dried over anhydrous sodium sulphate and evaporated in vacuo to give the crude product as a colourless solid (19.5g, quantitative yield). 

• Recrystallisation from hexane-benzene, 2:3, gives pure (S)-N-tigloylproline as colourless pillars (15.3g, 86%), m.p. 112.5-113.5 °C, [𝝰]ᴅ²º -72.7° (c 1.00 in MeOH); i.r. (Nujol) 1740 (acid) 1582 cm⁻¹ (amide); p.m.r. (CDCl₃ ,TMS) 𝜹1.78 (s,3H, Me-CH=), 1.81 (s, 3H, =C(Me)CO), 1.50-2.50 (m, 4H, CH₂CH₂CH₂N), 3.35-3.75 (m, 2H, CH₂N), 4.53 (t, 1H, J = 7 Hz, NCHCO), 5.75 (br. s, 1H, CH=), 11.0 (s, 1H, CO₂H).

Bromolactonisation of (5)-N-TigIoyIproIine:

• A dimethylformamide solution (4 ml) of potassium t-butoxide (224 mg, 2.0 mmol) and a dimethylformamide solution (2 ml) of N-bromosuccinimide (712mg, 4.0 mmol) are successively added to a stirred solution of (S)-N-tigloylproline (395 mg, 2.0 mmol) in dimethylformamide (2 ml) at — 20 °C under nitrogen. 

• The mixture is stirred at — 20 °C for 2 hours, and then at room temperature for 48 hours. 

• Extractive isolation with ethyl acetate followed by evaporation in vacuo gives the crude bromolactone as a thick yellow oil (562 mg, 95%). 

• Thin-layer chromatography analysis (silica gel, solvent ether) of this oil shows three impurities (Rꜰ 0.47, 0.28, and 0.22) in addition to the desired bromolactone (Rꜰ 0.36). 

• The pure bromolactone is obtained by recrystallisation from hexane-ether and has m.p. 111.5-112.5 °C, [𝝰]ᴅ²º -83.2° (c 0.754 in MeOH); i.r. (Nujol) 1760 (lactone), 1670cm⁻¹ (amide); p.m.r (CDCl₃, TMS) 𝜹1.70 (s, 3H, MeCCON), 1.93 (d, 3H, J = 7.2 Hz, MeCHBr), 1.40-2.70 (m, 4H, CH₂CH₂CH₂N), 3.37- 3.92 (m, 2H, CH₂N), and 3.92-4.72 (m, 2H, NCHCO and MeCHBr).

Reductive debromination of bromolactone:

• A benzene solution (12 ml) of tributyltin hydride (2.33g, 8.00 mmol) is added dropwise over 1 minute to a stirred solution of pure bromolactone (1.70 g, 6. 16 mmol) in benzene (10 ml) at 70 °C under nitrogen. 

• The mixture is stirred at reflux for 15 hours and is evaporated in vacuo to afford a mixture of crystals and oil. 

• Addition of hexane to the mixture, followed by cooling to — 70 C, precipitates the crude reduction product as colourless needles (1.29 g, quantitative yield), m.p. 99-101 °C. 

• Recrystallisation from hexane-ether gives colourless needles (1.03 g, 85%), m.p. 105-106 °C, [𝝰]ᴅ²º - 112° (c 0.760 in MeOH); i.r. (Nujol) 1740 (lactone), 1683 cm⁻¹ (amide); p.m.r (CDCl₃, TMS) 𝜹1.00 (t, 3H, J = 7 Hz, MeCH₂), 1.57 (s, 3H, MeCCO), 1.92 (q, 2H, J = 7 Hz, MeCH₂), 1.80 (m, 4H, CH₂CH₂CH₂N), 3.40-3.90 (m, 2H, CH₂N), 4.10-4.50 (m, 1H, NHCO).

(R)-( — )-2-Hydroxy-2-methyIbutanoic acid:

• A mixture of the foregoing pure lactone (985 mg, 5.00 mmol) and 36 per cent hydrochloric acid (10.3 ml) is refluxed for 8 hours. 

• The acidic mixture is diluted with saturated sodium chloride solution (20 ml) and extracted with ethyl acetate. 

• The combined organic layers are extracted with saturated sodium hydrogen carbonate solution after being washed with saturated brine. 

• The sodium hydrogen carbonate extracts are combined, acidified (pH « 2) with concentrated hydrochloric acid and extracted with ethyl acetate. 

• The combined organic layers are washed with brine. 

• After drying over anhydrous sodium sulphate, filtering, and evaporation in vacuo, (R)-( — )-2-hydroxy-2-methylbutanoic acid is obtained as colourless needles (535 mg, 91%), m.p. 72-74°C, [𝜶]ᴅ²⁵-8.5° (c 3.01 in CHCl₃). 

• Recrystallisation from hexane gives the optically pure acid, m.p. 78-79 °C, [𝜶]ᴅ²⁵ - 8.9° (c 2.97 in CHCl₃), p.m.r. (CDCl₃, TMS) 0.94 (t, 3H, J = 6 Hz, MeCH₂), 1.45 (s, 3H, MeCCO), 1.42-2.02 (m, 2H, MeH₂ ), 6.12-7.12 (broad s, CO₂H and OH).