Dynamic Kinetic Resolution of 2,3‐Dihydrobenzo[b]furans: Chemoenzymatic Synthesis of Analgesic Agent BRL 37959

Abstract

An efficient asymmetric synthesis of (S)-2,3-dihydrobenzo[b]furan-3-carboxylic acid (8 a) and (S)-5-chloro-2,3-dihydrobenzo[b]furan-3-carboxylic acid (8 b) was established. Key to the success was the highly stereoselective enzymatic kinetic resolution of the corresponding methyl or ethyl esters that was further developed into a dynamic process. As a reliable and fast tool for analysing the enantiomeric excess, HPLC coupled with a CD detector was utilized. The route was completed by a Friedel-Crafts acylation of ethyl (S)-5-chloro-2,3-dihydrobenzo[b]furan-3-carboxylate (7 c) followed by saponification leading to (S)-5-chloro-2,3-dihydrobenzo[b]furan-3-carboxylic acid (2), an analgesic agent.

Development of an enolate alkynylation approach towards the synthesis of the taiwanschirin natural products

“…The reduction of benzofuran 16 using magnesium turnings in MeOH then afforded the model dihydrobenzofuran 17 in 70% yield. 19 Transesterication of the ester from ethyl to methyl was also observed in this reaction.…”

An artificial metalloenzyme with the kinetics of native enzymes

“…Such reactivity is relevant to contemporary synthetic challenges. For example, compound (S)-5 is an intermediate in the synthesis of BRL 37959-a potent analgesic-and was prepared previously by means of kinetic resolution (18). This product was formed by variant 69Y-152W-213G in 94% ee.…”

Organocatalysis and Biocatalysis Hand in Hand: Combining Catalysts in One‐Pot Procedures

“…The chemoenzymatic synthesis of ( S )‐2,3‐dihydrobenzo[ b ]furan‐3‐carboxylic acid ( 39 ) and ( S )‐5‐chloro‐2,3‐dihydrobenzo[ b ]furan‐3‐carboxylic acid ( 40 ), valuable precursors in the synthesis of biologically active compounds, features as key step the sequential one‐pot biocatalysed hydrolysis of the racemic methyl or ethyl esters ( 38 ) combined with the substrate racemisation in the presence of an organic base . Initial screening on the enzymes for the kinetic resolution was performed by an HPLC‐CD selectivity assay, leading to CAL‐B and Bacillus subtilis esterase (BS3) as the best biocatalysts for this process.…”