Chemoenzymatic Preparation of Enantiomerically Enriched (R)‐(–)‐Mandelic Acid Derivatives: Application in the Synthesis of the Active Agent Pemoline

The enantioselective resolution of several racemic derivatives of mandelic acid methyl ester catalyzed by lipases from Pseudomonas fluorescens (Amano AK) or Burkholderia cepacia (Amano PS‐C II and Amano PS‐IM) has been achieved. A gram‐scale lipase‐mediated kinetic resolution approach has been developed that allows the facile synthesis of the corresponding methyl (R)‐(–)‐mandelates with excellent enantiomeric excesses (up to >99 % ee) and reaction enantioselectivity (E values up to >200). The dopaminergic agent pemoline, used in the treatment of attention‐deficit hyperactivity disorder (ADHD) and narcolepsy, was synthesized with 98 % ee in a straightforward route by condensing the prepared methyl (R)‐(–)‐mandelate with guanidine hydrochloride under basic conditions. The desired (R)‐(+)‐pemoline in optically pure form (>99 % ee) was obtained after two recrystallizations from ethanol. However, it was confirmed by chiral HPLC that optically active pemoline undergoes racemization in methanol solution. A chemoenzymatic synthesis of homochiral (R)‐pemoline has been developed. Methyl (R)‐(–)‐mandelate was prepared by an environmentally benign approach involving a cyanide‐free synthesis of racemic mandelic acid and acetylative kinetic resolution using lipases as biocatalysts. This enzymatic protocol can also be applied with excellent enantioselectivity to novel mandelic acid derivatives.