Enantiomeric Separation of New Chiral Azole Compounds.

Marziyeh E Kenari,Huy Phan,Daniel W Armstrong,Brandon B Fulton,Ravi P Singh,Alain Berthod,Key Tse,Reem K Haimour,Joshua I Putman,Carl J Lovely

doi:10.3390/molecules26010213

Abstract

Twelve new azole compounds were synthesized through an ene reaction involving methylidene heterocycles and phenylmaleimide, producing four oxazoles, five thiazoles, and one pyridine derivative, and ethyl glyoxylate for an oxazole and a thiazole compound. The twelve azoles have a stereogenic center in their structure. Hence, a method to separate the enantiomeric pairs, must be provided if any further study of chemical and pharmacological importance of these compounds is to be accomplished. Six chiral stationary phases were assayed: four were based on macrocyclic glycopeptide selectors and two on linear carbohydrates, i.e., derivatized maltodextrin and amylose. The enantiomers of the entire set of new chiral azole compounds were separated using three different mobile phase elution modes: normal phase, polar organic, and reversed phase. The most effective chiral stationary phase was the MaltoShell column, which was able to separate ten of the twelve compounds in one elution mode or another. Structural similarities in the newly synthesized oxazoles provided some insights into possible chiral recognition mechanisms.

Highlights

Heterocyclic fragments or moieties are present in the majority of marketed active pharmaceutical ingredients (APIs) [1]
A degassed solution of toluene containing N-phenylmaleimide or ethyl glyoxylate reacted with the corresponding oxazoline [5] and thiazoline [6] methylidenes was heated at reflux overnight and resulted in an ene reaction providing twelve new chiral azole compounds
Ten compounds, coded I-IV and VII-XII, were N phenylmaleimide adducts having a stereogenic center on carbon 3 of the succinimide ring (Figure 1)

Summary

Introduction

Heterocyclic fragments or moieties are present in the majority of marketed active pharmaceutical ingredients (APIs) [1]. Heterocyclic moieties present in many APIs provide strong and specific points for a variety of intermolecular interactions. They afford a degree of rigidity that can enhance chiral recognition in stereoselective processes. Another aspect of the heterocyclic moiety is to influence API polarity and hydrophobicity, which can affect its water solubility [1]. It is well established that nitrogen-containing heterocyclic compounds are key players in many biochemical reactions and are present in API structures [2]

Methods

Results

Conclusion