3,3-Dimethylbutanal → HCID 15633569, compound

Participants

Reaction Steps

Tert-butylacetic acid (b) is reduced with a hydride reducing agent, preferably lithium aluminum hydride, to provide 3,3-dimethyl-1-butanol (c). Oxidation of alcohol (c) with 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO), provides 3,3-dimethylbutyraldehyde (d), which is isolated by co-distillation with tetrachloroethane. Aldehyde (d) is treated sequentially with trimethylsilyl cyanide and a catalytic amount of zinc iodide, followed by methanol to afford (±)-4,4-dimethyl-2-hydroxypentanenitrile (e). This nitrile is hydrolyzed first with hydrochloric acid, followed by 50% NaOH to provide racemic pentanoic acid (f). Sequential treatment of racemate (f) with neat acetyl chloride, followed by either oxalyl chloride or thionyl chloride and N,N-dimethylformamide, provides 4,4-dimethyl-2-acetoxypentanoyl chloride (g), which is then coupled with (R)-(−)-4-phenyl-2-oxazolidinone in the presence of 4-dimethylaminopyridine and N,N-diisopropylethylamine in dichloromethane to give a mixture of the acetoxy diastereomers. This diastereomeric mixture of acetates is separated by column chromatography to provide the single diastereomeric acetate (h). The acetate (h) is treated with sodium hydroxide in a solution of tetrahydrofuran/methanol/water to give the desired (2S)-(−)-4,4-dimethyl-2-hydroxypentanoic acid IV. The crude pentanoic acid IV is converted to an ester, preferably the allyl ester, and is then purified by chromatography to provide allyl (2S)-(−)-4,4-dimethyl-2-hydroxypentanoate (i).

Provenance & Evidence