The first one-pot asymmetric synthesis of esters of highly biologically active (+)- and (-)- 3-[2-(6-methoxynaphthyl)]-2,2-dimethylpentanoic acid (Vallestril®)

Abstract

Our recent studies on the biological activity of (+)-and (−)-3-[2-(6-hydroxynaphthyl)]-2,2-dimethylpentanoic acid led to several intriguing discoveries that warrant further investigation. As a result it became advisable to provide a straightforward, efficient asymmetric synthesis of these enantiomeric acids. Thus, for the first time, a one-pot asymmetric synthesis of esters of the two acids was designed and carried out, involving Michael addition followed by methylation. With (−)-menthyl as the chiral auxiliary group, 77% of the desired diastereomeric products was obtained, but without stereoselectivity. When the chiral auxiliary group was (−)-8-phenylmenthyl, the yield, based on consumed starting material, was 77%, with a de value of 26% determined by 1 H NMR.Further work to optimize the reaction conditions to improve the yield and de value is underway.