Kinetic Resolution of Racemic 4-Substituted Chroman-2-ones Through Asymmetric Lactone Hydrogenation

Esters are abundant in natural and synthetic products and their conversion into primary alcohols holds great importance in fine chemical synthesis. However, achieving asymmetric hydrogenation (AH) of racemic esters with remote stereocenters via kinetic resolution (KR) remains a formidable challenge due to the difficulties associated with discerning spatially distant stereocenters. To address this issue, we have designed a hydroxy-assisted strategy that introduces a hydroxy group into racemic beta-aryl esters to facilitate hydrogenation and enhance chiral discrimination through a lactone form. By employing chiral Ir-SpiroPAP catalysts, we achieved exceptional AH of racemic 4 -substituted chroman-2-ones, lactone form of ortho-hydroxylated beta-aryl esters, via KR, resulting in impressive selectivity factor (s) values of up to 600. This approach exhibited significant efficacy for racemic chroman-2-ones containing beta-aryl, alkenyl, alkynyl, and alkyl groups, enabling the synthesis of chiral gamma-aryl primary alcohols and the recovery of chiral beta-aryl esters or chroman-2-ones, typically difficult to access using existing methods. The scalability and broad synthetic applications of this method were exemplified by successfully synthesizing chiral drugs (R)-fesoterodine and enrasentan, alongside various chiral intermediates essential for producing chiral drugs and natural products. These promising results highlight the potential of this approach as a powerful tool for synthesizing valuable chiral compounds.