Chiral auxiliary-mediated enantioenrichment of (±)-ibuprofen, under steglich conditions, with secondary alcohols derived from (R)-carvone

Marcela Amongero,Teodoro S Kaufman,Damian Visnovezky

doi:10.1590/s0103-50532010000600011

Abstract

The synthesis of a series of chiral secondary alcohols derived from (R)-carvone, and the stereochemical outcome of their reaction with (±)-ibuprofen, is reported. The racemic drug was transformed into the corresponding diastereomeric esters mediated by DCC/DMAP, affording up to 5.7:1 diastereomeric ratios of the esters derived from either (S)- or (R)-ibuprofen, depending on the type of chiral auxiliary employed.

Highlights

During the past two decades, the preparation of optically active drugs has received considerable attention both, from academics and industry. The reasons behind this interest are threefold, including the medical benefit from using a single chemical entity, the changing pharmaceutical regulations, which require the development of optically active drugs as single stereoisomers, and advances in strategies for the synthesis of optically pure compounds, which facilitated the task.[1]
In the first one, (R)-carvone was submitted to a conjugate addition reaction with thiophenol under thermodynamic conditions,[20] furnishing thioethers (7a-c, Scheme 1) in 4, 34 and 16% yield, respectively
Reaction with PhSH and 2-naphthalenethiol under kinetic[21] conditions afforded sulfides (7a and 8, Scheme 1) in 60 and 92% yield, respectively. The stereochemistry of these products was deduced by comparison with literature data,[22] analysis of the enhancement of signals in nuclear Overhauser effect experiments and examination of their 1H NMR spectra, which revealed that H-3 was considerably more deshielded in 7a (d 3.89 ppm) than in 7b (d 2.91 ppm) and 7c (d 3.29 ppm), pointing out to a pseudo-axial orientation of the heteroatomic substituent

Summary

Introduction

During the past two decades, the preparation of optically active drugs has received considerable attention both, from academics and industry. When chiral alcohols 20a and 20b were subjected to esterification with (±)-ibuprofen under Steglich conditions (Table 3), it was observed that the best results were obtained when chloroform was employed as solvent (entries 1, 2 and 13) and that the product was enantioenriched in the ester derived from (R)-ibuprofen.

Results

Conclusion