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

Abstract

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.

Thiamine Diphosphate Dependent KdcA‐Catalysed Formyl Elongation of Aldehydes

“…Indeed, nucleophilic formyl elongation of aromatic aldehydes provides access to chiral arylethanol compounds or substituted mandelic acid derivatives, which are core structures of a great variety of pharmacologically active substances (Scheme ). Prominent examples are the non‐catecholamine bronchodilators fenoterol, orciprenaline, salbutamol, biogenic amines such as halostachine, the catecholamines epinephrine and norepinephrine, and the mandelic acid esters cyclandelate and homatropine …”

“…Prominent examples are the non-catecholamine bronchodilators fenoterol, orciprenaline, salbutamol, [12] biogenic amines such as halostachine, [13] the catecholamines epinephrine and norepinephrine, and the mandelic acid esters cyclandelate and homatropine. [14] However, for aromatic 2-hydroxy aldehydes, instability due to tautomerisation, dimerisation, and polymerisation reactions is a major issue. [15] The identification of an initial product is made difficult by these undesired subsequent reactions.…”

Biocatalysis at Extreme Temperatures: Enantioselective Synthesis of both Enantiomers of Mandelic Acid by Transesterification Catalyzed by a Thermophilic Lipase in Ionic Liquids at 120 °C

“…Opting for EtOH was based on our previous studies on esterification of phthalic acids with BTL2 [92], and it has been very recently substantiated by Shehata et al [38]; indeed, these authors have published a molecular dynamics (MD) simulation of the effect of different polar and nonpolar solvents on the thermostability and lid-(R)-mandelic acid and analogs are key synthons in the preparation of several drugs or biologically active compounds, being in the core of semi-synthetic antibiotics (cephalosporins as cefamandole [81] or penicillins as MA-6-APA II [82]) or anticholinergic drugs (such as oxybutynin [83] and homatropine [84]). Moreover, derivatives of (R)-mandelic acid have been also used as chiral synthons in the preparation of some drugs with different therapeutic activities: platelet/antithrombotic agents (clopidogrel [85]), vasodilator (cyclandelate [86]), antitumor (complex of cis-[Pt{2-(α-hydroxy)benzylbenzimidazole))2Cl2] [87], antiobesity [88,89] or CNS-stimulant dopaminergic agents ((R)-pemoline [90]). Conversely, (S)-mandelic acid is used for the production of non-steroidal anti-inflammatory drugs such as deracoxib and celecoxib [91].…”

Palladium‐Catalyzed Decarboxylative 1,2‐Addition of Carboxylic Acids to Glyoxylic Acid Esters

“…[5] The stimulant pemoline and the antiplatelet agent clopidogrel can be prepared from the corresponding mandelic acid building blocks. [6,7] Therefore, the efficient synthesis of mandelic acids has received considerable attention. The addition of nucleophiles to glyoxylic acid esters offers an attractive and highly flexible approach for the construction of the mandelic acid scaffold (Scheme 1 1).…”